I. SYNTHESIS OF SATURATED, DNA, AND RNA SPIROCYCLIC-4,4- NONANE NUCLEOSIDES. II. STUDIES TOWARD EPOXY CARBONATE FORMATION AND THE SYNTHESIS OF SUITABLE PRECURSORS. III. METHODOLOGICAL INVESTIGATIONS INVOLVING THE REACTIONS OF DIAZOMETHANE WITH DI-, TRI-, AND TETRAKETONES. IV. TOWARDS THE TOTAL SYNTHESIS OF SALICIFOLINE.
DISSERTATION
Presented in Partial Fulfillment of the Requirements for
the Degree of Doctor of Philosophy in the Graduate
School of The Ohio State University
By
Ryan Eugene Hartung, M.S.
●●●●●●●●●
The Ohio State University 2005
Dissertation Committee: Approved by Professor Leo A. Paquette, Advisor
Professor T. V. Rajanbabu ______Professor Christopher M. Hadad Advisor Graduate Program in Chemistry
ABSTRACT
Nucleoside analogues, which can be incorporated into oligonucleotide chains, are of considerable current interest in the fight against cancer. When viral reverse transcriptase enzymes encounter the foreign nucleosides they are forced to shut down, therefore halting reproduction of the virus. Normal cellular enzymes, as they are often more complex, have the ability to “repair” the unnatural nucleosides and replication can continue. In this area of study we have designed a novel set of restricted nucleosides by spirocyclic annulation at C4' and insertion of a methylene unit in place of the furanoside oxygen. These two additions should generate enhanced duplex stability, increase lipophilicity relative to natual nucleosides, and augment resistance to cellular nucleases.
These unnatural nucleosides also consist of an alcohol at position C5' of the added spirocycle, thus giving rise to two sets of diasteromers. The incorporation of all five free nucleoside bases into the spirocyclic framework at C1', which consisted of the DNA,
RNA, and saturated skeletons, resulted in the synthesis of 30 novel unnatural nucleoside analogues.
The second quarter of this thesis involves the synthesis of a relatively unknown functionality. This functionality consists of an epoxide and a carbonate, which share a central carbon. The epoxy carbonate was initially stumbled upon by accident en route to
ii taxol, where DMAP and phosgene were added to a α,α'-dihydroxyketone in the hopes a
carbonate would be generated. Since this new functionality had not yet been reported
upon in the literature, it was the goal of this research project to determine the types of
systems which could readily accommodate the strained moiety. These efforts included a
novel synthetic strategy to form cis and trans α,α'-dihydroxycycloheptanone and α,α'-
dihydroxycyclooctanone, which had also not been reported in the literature. The research
led to the conclusion that epoxy carbonate formation relies upon the rigidity of the α,α'- dihydroxyketone and that the two alcohols must be trans, otherwise a sterically unfavorable cis epoxide or carbonate must be formed.
The third project was happened upon as a side reaction during the synthesis of the
α,α'-dihydroxycyclooctanone. It was discovered that when a diketone was reacted with diazomethane, a ketoepoxide could be generated. Although this reaction was present in the literature, there was relatively little research on the subject and the reactions presented did not attempt to cover the scope or limitations of the process. This project dealt with the reaction of a wide variety of di-, tri-, and tetraketones with diazomethane. In almost
all the examples studied, a reaction occurred and interestingly, when the diketone was
part of a strained ring system, ring expansion was seen to immediately follow carbon
insertion.
The last project I have attempted is the synthesis of the natural product
salicifoline. Salicifoline was isolated from Euphorbia saliciforia in 2000. Herein is
detailed the partial synthesis of intermediates A and B, where A is realized from a
zirconium-mediated ring contraction of a synthetically modified sugar.
iii
Dedicated to my beautiful wife Elizabeth.
iv
ACKNOWLEDGMENTS
I would first and foremost like to thank Dr. Leo A. Paquette for always being
there when I needed any type of assistance. If asked if I would do things differently a
second time around I can honestly say that without a doubt I would join his group again.
Dr. Paquette has demonstrated to me what it means to be an advisor, a respected boss,
and how one should lead when people are depending on you. Thanks for everything Doc.
I would like to thank Dr. Rajanbabu and Dr. Hadad for serving on my dissertation
committee. I would also like to thank Donna Rothe and Rebecca Martin for everything
they have done for me during my tenure.
A very special thanks must go out to the Paquette group as a whole. Everyone in
the group that I have come into contact with has changed me in some way. In particular I
would like to send out a special thanks to Dr. Matt Kreilein, Dr. Chris Seekamp, and Dr.
Kallol Basu. You guys have been great friends to me and I know that I could rely on any
one of you any time for anything, chemistry or personal. Also Dr. Ray Bishop and Dr.
Alex Kahane deserve thanks for helping with problems I encountered in my chemistry
and Dave Hilmey, a special thanks to you for proofreading this thesis.
v I also must thank Dr. David B. Berkowitz at the University of Nebraska for the
chance to participate in undergraduate research and my high school chemistry teacher
Mr. Richmond who showed me that science could be fun.
Lastly I would like to thank my family for always being there for me. I want to
thank my parents for always giving me encouragement and wishing me well. I wish to
thank my in-laws, Patty and Phil, who always understood whenever I gave the “excuse”
that I was working and couldn’t see them. They were always supportive and made
genuine effort to take an interest in my research. Finally I must thank my wife
Elizabeth. This thesis is dedicated to her and all that she has done for me and put up with
during the past five years.
vi
VITA
April 3, 1978………………………………………..Born – Lincoln, Nebraska
May 6, 2000………………………………………...B.S. Chemistry, University of Nebraska – Lincoln.
2003…………………………………………………M.S. Chemistry, The Ohio State University
2000-2004, 2005……………………………………Graduate Teaching Assistant, The Ohio State University.
2004-2005…………………………………………..Lubrizol Industrial Fellow
PUBLICATIONS
Research Publications
1. Hartung, R. E.; Paquette, L. A. “Direct Comparison of Sn2 Mesylate Displacement Versus the Mitsunobu Protocol for 2',3'- Dideoxyspirocarbanucleoside Construction” Heterocycles 2005, 67 485.
2. Hartung, R. E.; Paquette, L. A. “Development of a Generic Stereocontrolled Pathway to Fully Hydroxylated Spirocarbocyclic Nucleosides as a Prelude to RNA Targeting” Synthesis, 2005, 1248.
3. Hartung, R. E., Paquette, L. A. “Practical Synthesis of Enantiopure Spiro[4,4]nonane C-(2')-Deoxyribonucleosides” J. Org. Chem. 2005, 70, 1597.
4. Hartung, R. E.; Paquette, L. A. “Homologation of Vicinal Polyketone Networks to Epoxy Ketones with Diazomethane” Heterocycles 2004, 64, 23-26.
vii 5. Hartung, R. E.; Hilmey, D. G.; Paquette, L. A. “Fluoride Ion-Promoted α-Ketol Rearrangement during Unmasking of Silyl-Protected Medium-Ring Dihydroxy Ketones” Adv. Synth. Catal. Chem. 2004, 346, 713-716.
6. Hartung, R. E.; Paquette, L. A. “Recent Synthetic Applications of the Tandem Staudinger-Aza Wittig Reaction” Chemtracts 2004, 17, 72-82.
7. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.; Yang, J. “Synthesis of Stereoisomeric Medium-Ring α,α'-Dihydroxy Cycloalkanones” J. Org. Chem. 2004, 69, 2454-2460.
8. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Gallucci, J. C. “Reactions of α,α'-Dihydroxy Ketones with Phosgene. Structural Requirements for Spiro Epoxy Carbonate Formation” Org. Lett. 2004, 6, 969-971.
9. Paquette, L. A.; Hartung, R. E. “Chemical Consequenses of the Ground-State Conformations of Cyclooctyl Rings. Examples of Reactivity Differences in α- Hydroxy and α,α'-Dihydroxy Eight-Membered Cyclic Ketones” J. Indian Chem. Soc. 2003, 80, 1201-1208.
10. Paquette, L. A.; Hartung, R. E.; France, D. “Conversion of the Enantiomers of Spiro[4,4]nonane-1,6-Diol into Both Epimeric Carbaspironucleosides Having Natural C1' Absolute Configuration” J. Org. Lett. 2003, 5, 869-871.
11. Hartung, R. E.; Paquette, L. A. “New Synthetic Tactics Designed to Access Diynes and Polyynes” Chemtracts 2002, 15, 106-116.
12. Berkowitz, D. B.; Hartung, R. E.; Choi, S. “Hydrolytic and Enzymatic Transformation of Advanced Synthetic Intermediates: On the Choice of the Organic Cosolvent” Tetrahedron: Asymmetry 1999, 10, 4513-4520.
FIELDS OF STUDY
Major Field: Chemistry
viii
TABLE OF CONTENTS
Page Abstract...... ii
Dedication...... iv
Acknowledgements...... v
Vita...... vi
List of Schemes...... xiii
List of Figures...... xix
List of Tables ...... xxi
List of Abbreviations ...... xxii
Chapters:
1. A Highly Stereocontrolled Synthesis of Saturated Spiro[4,4]nonae Nucleoside
Analogues Utilizing the Mitsunobu Reaction and SN2 Chemistry ...... 1
1.1 Background...... 1
1.2 Purpose of Research...... 9
1.3 Previous Synthetic Work ...... 14
1.4 Purpose of Thesis Work...... 15
1.5 Retrosynthetic Strategy and Synthetic Background in the Saturated (R)-
Series...... 16
ix 1.6 Conclusion of the Saturated (R)-Series of Nucleoside Analogues ...... 18
1.7 Synthetic Background in the Saturated (S)-Series of Nucleoside
Analogues ...... 22
1.8 Conclusion of the Saturated (S)-Series of Nucleoside Analogues...... 24
1.9 Attempts at an (R)- and (S)-Unsaturated Series of Nucleoside
Analogues ...... 26
2. A Highly Stereocontrolled Synthesis of DNA and RNA Spiro[4,4]nonane
Nucleosides...... 30
2.1 Synthesis of the (R)-Series of DNA Nucleoside Analogues...... 30
2.2 Synthesis of the (S)-Series of DNA Nucleoside Analogues ...... 33
2.3 Synthesis of the (R)-Series of RNA Nucleoside Analogues...... 35
2.4 Synthesis of the (S)-Series of RNA Nucleoside Analogues ...... 43
2.5 Conclusion...... 48
3. Studies Toward Epoxy Carbonate Formation and the Synthesis of Suitable
Precursors...... 49
3.1 Background...... 49
3.2 Synthesis of cis-α,α'-Dihydroxy Cycloheptanone...... 51
3.3 Synthesis of trans-α,α'-Dihydroxy Cycloheptanone...... 55
3.4 Synthesis of cis-α,α'-Dihydroxy Cyclooctanone...... 57
3.5 Synthesis of trans-α,α'-Dihydroxy Cyclooctanone...... 59
3.6 Synthesis of Epoxy Carbonates ...... 72
3.7 Conclusion...... 74
3.8 Equilibrium of α,α' and α,β-Dihydroxy Ketones in the Presence of t-
x BuOK and TBAF ...... 75
3.9 Conclusion of the Fluoride Ion Promoted α-Ketol Rearrangement
Project ...... 83
4. I. Epoxy Ketone Formation with Diazomethane and Polyketones, II. O- Versus C-
Alkylation in Medium Ring α,β-Unsaturated Hydroxy Ketones...... 84
4.1 Background...... 84
4.2 Epoxy Ketone Formation with Diazomethane and Polyketones ...... 86
4.3 Conclusion of the Diazomethane Reaction with Polycarbonyls...... 94
4.4 Background for O- Versus C-Alkylation Project...... 94
4.5 O- Versus C-Alkylation in Medium Rind α,β-Unsaturated Hydroxy
Ketones, Hydroxy Ketone 4.42...... 99
4.6 O- Versus C-Alkylation in Medium Rind α,β-Unsaturated Hydroxy
Ketones, Hydroxy Ketone 4.43...... 105
4.7 O- Versus C-Alkylation in Medium Rind α,β-Unsaturated Hydroxy
Ketones, Hydroxy Ketone 4.63 and Hydroxy Ketone 4.64 ...... 107
4.8 Conclusion of the O- Versus C-Alkylation Project ...... 110
5. Towards the Total Synthesis of Salicifoline ...... 111
5.1 Background and Retrosynthesis...... 111
5.2 Efforts Towards the Synthesis of Vinyl Iodide 5.5...... 114
5.3 Synthesis of Aldehyde 5.6 Through Acyclic Chemistry ...... 127
5.4 Synthesis of Aldehyde 5.6 Through Sugar Chemistry...... 137
5.5 Conclusion of the Salicifoline Project ...... 142
6. Experimental Section...... 144
xi References...... 294
Appendix: 1H NMR Spectra ...... 300
xii
LIST OF SCHEMES
Scheme Page
1.1 Keto Ester to [4,4]-Spirononane-1,6-diol ...... 14
1.2 New Route ...... 14
1.3 Retrosynthetic Approach ...... 16
1.4 Previous Synthesis of Allylic Alcohol 1.9...... 17
1.5 Previous Synthesis of Saturated (R)-Thymidine and Cytidine ...... 18
1.6 Direct Comparison SN2 Mesylate Displacement Versus the Mitsunobu
Protocol...... 19
1.7 SN2 Reaction of Protected Uracil Versus Unprotected Uracil...... 20
1.8 SN2 Versus Mitsunobu Reaction of Mesylate 1.16 and 2-Amino-
6-chloropurine...... 21
1.9 Generation of Alcohol 1.25...... 23
1.10 Synthesis of Cytidine and Thymidine Nucleoside Analogues...... 23
1.11 Mitsunobu Versus SN2 Displacement in the (S)-saturated Series...... 24
1.12 Synthesis of (S)-Saturated Uracil and Guanine Unnatural Nucleosides...... 25
1.13 A Mixture of Diastereomers due to an Allyl Cation...... 27
1.14 Failed Attempts at Base Installation via the Mitsunobu Reaction...... 27
1.15 Problems with Mesylation Chemistry...... 28
1.16 Failed Attempts at Palladium Chemistry ...... 28
xiii 2.1 Synthesis of Mesylate 2.6 ...... 30
2.2 NOE Proof of Compound 2.5 ...... 31
2.3 Completion of the (R)-DNA Series of Nucleoside Analogues ...... 32
2.4 Synthesis of α,β-Unsaturated Ketone 2.32...... 33
2.5 Synthesis of Mesylate 2.37 ...... 34
2.6 Completion of the (S)-DNA Series of Nucleoside Analogues...... 35
2.7 Dihydroxylation of α,β-Unsaturated Ketone 2.1 ...... 36
2.8 Allylation Elimination ...... 37
2.9 Problems with the Reduction of Diacetate 2.52...... 37
2.10 Sythesis of TiPDS Protected Mesylate 2.55 ...... 38
2.11 Failed Attempts at Further Silyl Protection ...... 39
2.12 Synthesis of Mesylate Acetonide 2.58...... 40
2.13 Different Reducing Agents Demonstrate Different Selectivities...... 40
2.14 Failure of both the Mitsunobu and SN2 Reactions...... 41
2.15 Synthesis of Mesylate Benzylidene Acetal 2.65...... 42
2.16 Protecting Group Failures...... 43
2.17 Synthesis of Triflate 2.66...... 43
2.18 Synthesis of the (R)-RNA Nucleoside Analogues...... 44
2.19 Dihydroxylation of α,β-Unsaturated Ketone 2.32 ...... 45
2.20 The too Bulky TIPDS Protected Diol is Synthesized Again ...... 46
2.21 Synthesis of Triflate 2.90...... 47
2.22 Synthesis of the (S)-RNA Nucleoside Analogues ...... 47
3.1 Conformationally Unlocked α,α'-Dihydroxyketones...... 50
xiv 3.2 Complete Synthesis of Dihydroxyketone 3.9 ...... 52
3.3 Proof 3.17 is not desilylated 3.16...... 53
3.4 Proof of the Trans Stereochemistry ...... 54
3.5 Failed Attempts Towards the cis-Dihydroxycyclohetpanone...... 55
3.6 Complete Synthesis of cis-Dihydroxyketone 3.10...... 56
3.7 First Synthesis of Dihydroxy Ketone 3.11...... 57
3.8 An Alternant Route to Dihydroxy Ketone 3.11...... 58
3.9 Rearrangement of a Diketone Under Reduction Conditions ...... 59
3.10 Proof of the 1,2-Hydride Shift ...... 60
3.11 Attempts at the Reduction of Diketone 3.40...... 61
3.12 Reaction of Ketone 3.35 with the Nysted Reagent...... 62
3.13 Evidence Alkene 3.46 was a Product of a 1,2-Hydride Shift ...... 63
3.14 Problems with Rearrangements ...... 63
3.15 The Final Complete Synthesis of cis-Dihydroxy Ketone 3.12 ...... 64
3.16 Proof of the cis-Hydroxy Ketone...... 65
3.17 Synthesis of Two Novel Epoxy Carbonates ...... 66
3.18 Reaction of Ketone 3.35 with the Nysted Reagent...... 66
3.19 Evidence Alkene 3.57 was a Product of a 1,2-Hydride Shift ...... 67
3.20 Unsatisfactory Attempts at the Mitsunobu Reaction ...... 68
3.21 Problems with Rearrangements ...... 69
3.22 The Final Complete Synthesis of cis-Dihydroxy Ketone 3.12 ...... 71
3.23 Proof of the cis-Hydroxy Ketone Structure ...... 71
3.24 Synthesis of Two Epoxy Carbonates ...... 72
xv 3.25 Rearrangement of trans-α,α'-Dihydroxy Cycloheptanones ...... 76
3.26 Rearrangement of cis-α,α'-Dihydroxy Cycloheptanone ...... 76
3.27 No Rearrangement of α,β-Dihydroxy Cycloheptanones...... 77
3.28 Rearrangement of cis- and trans-α,α'-Dihydroxy Cyclooctanone ...... 79
3.29 No Rearrangement of α,β-Dihydroxy Cyclooctanones...... 79
3.30 Synthesis of Silylated 3.72 and Diol 3.73...... 80
3.31 Reaction of Free Hydroxyls with TBAF...... 81
3.32 Reaction of Free Hydroxyls with t-BuOK...... 82
4.1 The Reaction of Diazomethane with Diketones versus Diosphenols ...... 85
4.2 Synthesis of trans-Diol 4.44 ...... 99
4.3 Oxidation to a Mixture of Isomers...... 100
4.4 Reduction Gives a 1:1 Isomeric Mixture...... 100
4.5 Use of the TBS Protecting Group ...... 101
4.6 Synthesis of α,β-Unsaturated Hydroxy Cyclooctanone 4.42...... 102
4.7 Oxidation with Molecular Oxygen and Sodium Hydride...... 103
4.8 Acetate Migration During Reduction...... 105
4.9 The TBS Route ...... 106
4.10 Rearrangement of Pivalate 4.60...... 107
4.11 Conversion of Diene 4.62 into Diol 4.65...... 108
4.12 Attempts at Dithiane Chemistry and Grubbs Ring Closing Metathesis ...... 109
5.1 First Attempt at Cyano Compound 5.12...... 115
5.2 Second Route to Cyanide 5.12...... 116
5.3 Synthesis of Alcohol 5.20...... 117
xvi 5.4 Decomposition During Vinyl Halide Synthesis...... 117
5.5 A Published Route for Vinyl Bromide 5.26...... 118
5.6 Coupling of Aldehyde 5.17 and Vinyl Bromide 5.26...... 119
5.7 Unsuccessful Attempts at Crystallization ...... 120
5.8 An Interesting Payne Rearrangement ...... 121
5.9 Protecting Groups and Problems ...... 122
5.10 Two Failed Protecting Groups...... 123
5.11 BOM and TBS Protecting Groups and Oxidation ...... 124
5.12 Attempts at Dihydroxylation...... 125
5.13 Payne Rearrangement over Epoxide Opening ...... 126
5.14 Ozonolysis, but Failed Protections ...... 127
5.15 Synthesis of Diene 5.45 ...... 128
5.16 Synthesis of Hydroxy Aldehyde 5.51 ...... 129
5.17 Various Oxidation Conditions ...... 130
5.18 Silyl Rearrangement During Oxidation ...... 131
5.19 Changing of Protecting Groups ...... 131
5.20 Oxidation to Aldehyde 5.55...... 132
5.21 Problems with the Protecting Groups ...... 132
5.22 New Route to 5.54 ...... 133
5.23 Benzylation of an Acetate...... 134
5.24 Attempt at a Higher Yield Leads to 1,4-Reduction ...... 135
5.25 Failed Attempt at Better Selectivity Through a Larger Protecting Group...... 136
5.26 The End of the Road for this Route Towards Compound A...... 136
xvii 5.27 The New Sugar Route...... 138
5.28 First Synthesis of PMP Acetal 5.79 ...... 139
5.29 Second Synthesis of PMP Acetal 5.79...... 140
5.30 Synthesis of Zirconium-Mediated Ring Contraction Precursor 5.7...... 141
5.31 Zirconium Mediated Ring Contraction...... 142
5.32 Current Synthetic Route...... 143
xviii
LIST OF FIGURES
Figure Page
1.1 Transcription and Translation...... 2
1.2 Virus Life Cycle...... 3
1.3 Glaxo Wellcome Drugs...... 4
1.4 Aristeromycin, Neplanocin A, and Entecavir...... 6
1.5 Antisense Mechanism...... 7
1.6 RNase H-dependent Mechanism...... 8
1.7 Nucleoside Analogues...... 9
1.8 Numbering the [4,4]-Spirononanol Nucleoside...... 10
1.9 Minimum Energy Conformations of Thymidine and Spirocyclic Analogues...... 11
1.10 Computer Model of DNA Containing Spirocyclic Nucleoside
(DNA D, Spirocycle E)...... 12
3.1 Fate of a Conformationally Restricted System ...... 49
3.2 Target α,α'-Dihydroxyketones ...... 51
3.3 Global Minimum Energy Conformations of the 2,8- and 2,3-Dihydroxy
Cyclooctanones...... 70
3.4 Hydride Migration ...... 75
3.5 Global Minimum Energy Conformations of the α,α'- and α,β-Dihydroxy
Cycloheptanones...... 78
4.1 Ring Expansion Mechanism ...... 91
xix 4.2 The Three Lowest Energy Conformations of 2-Hydroxy Cyclooctanone...... 95
4.3 The Three Lowest Energy Conformations of 2-Hydroxy Cyclooct-5-enone ...... 96
5.1 Natural Product Salicifoline...... 111
5.2 Retrosynthesis of Salicifoline ...... 113
5.3 Coupling of 5.8 and 5.9 to Synthesize Vinyl Iodide 5.5...... 114
xx
LIST OF TABLES
3.1 IR and 13C NMR Data of Three Epoxy Carboantes...... 73
4.1 Acyclic Systems...... 87
4.2 Unstrained Cyclic Systems ...... 89
4.3 Rigid Cyclic Systems...... 90
4.4 Aryl-fused Diketones...... 92
4.5 Cyclobutene-1,2-dione as Reactants...... 93
4.6 Alkylation Products from 4.39...... 97
4.7 Alkylation Products from 4.40...... 98
4.8 O- versus C-Alkylation with Hydroxy Ketone 4.42 ...... 104
xxi
LIST OF ABBREVIATIONS
α alpha
[α] specific rotation
Ac acetyl
Β beta n-Bu normal-butyl
t-Bu tertiary-butyl
Bn benzyl
Bz benzoyl
c concentration
oC degrees Celsius
calcd calculated
δ chemical shift in parts per million downfield from tetramethylsilane
d doublet (spectra); day(s)
dd doublet of doublets
DCM dichloromethane
DIAD diisopropyl azodicarboxylate
DIBAL-H diisobutylaluminum hydride
DMAP 4-(N,N-dimethylamino)pyridine
DMF N,N-dimethylformamide
xxii DMP dimethylpyrazole
EI electron impact (mass spectroscopy) eq. equivalent
ES electrospray (mass spectroscopy) g gram(s) h hour(s)
HRMS high resolution mass spectroscopy
IR infrared
J coupling constant in Hz (NMR) k kilo
KHMDS potassium hexamethyldisilazide
L liter(s) m milli; multiplet (NMR)
μ micro
M moles per liter mCPBA meta-chloroperbenzoic acid
Me methyl
MHz megahertz min minute(s) mol mole(s)
Ms methanesulfonyl
MS mass spectrometry m/z mass to charge ratio (MS)
xxiii NaHMDS sodium hexamethyldisilazide
NBS N-bromosuccinimide
NMR nuclear magnetic resonance obsd observed p para
Ph phenyl
PMB p-methoxybenzyl
ppm parts per million
py pyridine
q quartet
rt room temperature
RMS root mean square
s singlet (NMR)
t tertiary (tert)
t triplet (NMR)
TBAF tetrabutylammonium fluoride
TBDPSCl tert-butyldiphenylsilyl chloride
TBSCl tert-butyldimethylsilyl chloride
Tf trifluromethanesulfonyl
THF tetrahydrofuran
TLC thin layer chomatrography
TMS trimethylsilyl
TMSCl trimethylsilyl chloride
xxiv p-TsOH para-toluenesulfonic acid
xxv
CHAPTER 1
A HIGHLY STEREOCONTROLLED SYNTHESIS OF SATURATED
SPIRO[4,4]NONANE NUCLEOSIDES UTILIZING THE MITSUNOBU
REACTION AND SN2 CHEMISTRY
1.1 BACKGROUND
The genetic makeup of living systems is stored in the deoxyribonucleic acid
(DNA) double helix. The DNA strand is a duplex of two complementary strands, both
of which contain the four DNA bases; cytosine, adenine, thymine, and guanine. This
double helix is held together by Watson-Crick base pairing via hydrogen bonding between adenine and thymine (A:T) and guanine and cytosine (G:C).1 The
information needed for the synthesis of proteins is encoded within the DNA strand
and almost all cells contain one or more complete copies. When this information is
needed for protein synthesis transcription ensues (Figure 1.1).2 During transcription,
the DNA helix is opened, read, and its genetic message is transcribed into a less
1
Figure 1.1: Transcription and Translation
stable form, as messenger ribonucleic acid (mRNA). The mRNA, also known as the
sense strand, then travels to the cytoplasm, where several ribosomes attach
themselves to the mRNA and protein synthesis begins (translation). Every three
nucleoside bases in the mRNA code for a specific amino acid and each time that the
mRNA undergoes translation, a new protein is synthesized.2
Viruses have developed ways in which to use the aforementioned cellular
processes to their advantage. The mode of action of the virus is to gain entry into the cell and take over the cell’s metabolic machinery. Instead of the cell’s normal proteins being synthesized through transcription and translation, copies of the virus
are produced, which ultimately results in lysis and death of the host cell (Figure
1.2).3 Also shown in Figure 1.2, a virus typically consists of two entities; a protein coat, which is shed at will by the retro virus to realease its contents into the cell and
2
Figure 1.2 Virus Life Cycle
the genetic material within. There are two types of viruses. However; the one which concerns us is a retrovirus, which has its genetic code stored as RNA, whereas a normal virus uses DNA. Upon entering the cell, the retro virus sheds its protein coat and releases a viral enzyme known as reverse transcriptase. The viral enzyme helps to overtake the metabolic systems by converting the viral RNA into viral DNA. The viral DNA is then spliced into normal cellular DNA and then undergoes transcription and translation along with the normal cellular DNA. Therefore, each time transcription and translation is carried out more of the retrovirus is synthesized. This
3 occurs in the cell until it is saturated with complete retro viruses and the cell bursts to
give rise to many more viral entities, which are free to infect other cells. This is the
mode of action of the human immunodeficiency virus (HIV) retrovirus.2
DNA strands in most mammalian species are far longer and more complex
than that of viruses. Therefore, the enzymes that forward DNA replication are highly advanced and have evolved to hold finely tuned proofreading mechanisms to detect
and repair damaged DNA. Because the viral reverse transcriptase enzyme is less
highly developed but equally evolved for its purpose than its DNA counterpart, this
weakness has become a significant area exploited in research and drug design
research. There are currently two major areas of research that focus on this
shortcoming of the reverse transcriptase enzyme. The first is synthetically modified
nucleosides called reverse transcriptase inhibitors (NRTIs). Two of the NTRIs are
4 shown in Figure 1.3. These drugs appear very similar to the natural nucleosides
O NH
N NH N
HO N O HO N N NH2 O
N3 Retrovir® Ziagen®
Figure 1.3 GlaxoWellcome Drugs
found in the body. They are taken in the forms shown in Figure 1.3, but once in the
body they are converted to the triphosphates, which is their active form. Two
4 examples are retrovir® and ziagen®, which were developed by GlaxoSmithKline.
Retrovir was the first drug approved by the FDA for use against HIV. The reverse
transcriptase enzyme becomes confused between retrovir and the naturally occurring
thymine nucleoside. This confusion slows down the synthesis of the essential viral
DNA; however, the true potency of the drug is when it is actually used in place of the
normal thymine nucleoside. If this occurs, there is not an alcohol present at C3' to
continue the chain, and since the reverse transcriptase enzyme is not designed to fix the problem the viral DNA synthesis is terminated. Normal cellular enzymes, such as
DNA polymerase, are much more complex and can fix any such mistakes with only moderate side effects. When retrovir was initially used versus a placebo, after a certain amount of time, only one death occurred among patients taking the drug versus nineteen taking the placebo. However, after an elongated period the death rates evened out as the HIV retrovirus mutated into resistant strains. Even when retrovir is used with epivir (called combivir), the virus will still eventually change in order to protect itself. When these two drugs are used together in combination with another HIV drug, ziagen (called trizivir), a “drug cocktail” is generated and a person with HIV can have a much longer life. Eventually, however, the virus will mutate and become uncontrollable. This is the constant battle replaying itself in the hunt for new and advanced drugs. There are also a few other examples of carbocyclic nucleosides, some of which are being tested as potent inhibitors of various viral infections (Figure 1.4). Aristeromycin5 and neplanocin A6 were early discoveries in this field and entecavir®7 is in the advanced stages of clinical trials for the treatment
5 NH2 NH2 O
N N N N N NH
N N N HO N HO N HO N NH2
OH OH OH OH OH Aristeromycin® Neplanocin A® Entecavir®
Figure 1.4 Aristeromycin, Neplanocin A, and Entecavir
of chronic hepatitis B viral infections. With the numerous examples of carbocyclic drugs finding their way into modern medicine, the design and synthesis of different analogues is definitely warranted.
The other area of research for which the subject of nucleoside analogues may be well suited is as antisense agents. The human body has found ways in which it can suppress gene expression. As stated earlier, the mRNA strand’s purpose is for the synthesis of new proteins. When the body feels a need to suppress this activity, complementary strands (antisense strands) of RNA or DNA are synthesized and bind to the mRNA to stop gene expression. This can occur for two reasons. The first is that this creates a double strand and the ribosomes can only read single strands of
mRNA. The second reason is if the antisense strand is in the form of DNA an
enzyme called RNase H, which selectively looks for double helices between DNA
and RNA, will degrade any mRNA that is bound to DNA. Therefore since HIV is in the form of viral RNA this technology can be used to our advantage. The first drug
used in this manner was vitravene® (formivirsen) by Novartis, which is used to fight cytomegalovirus (CMV) retinitis. CMV retinitis is a sight threatening disease
6 associated with late-stage AIDS, developed by about one-fourth of all AIDS patients.
Vitravene is a 21-mer that is complementary to a region of CMV mRNA.8 Vitravene
will bind site-selectively to the viral RNA, where RNase H will degrade the RNA and
the virus will be halted. Figure 1.59 depicts the antisense mechanism. The antisense
Figure 1.5 Antisense Mechanism8
oligonucleotide (AO) will bind to a specific region and halt gene expression or the
synthesis of viral DNA depending on the site being targeted. However, if the AO
only binds to a specific site but does not invoke RNase H degradation, a one to one
ratio of drug to virus is needed. As the cost of a large amount of any drug is
extremely expensive and usually quite toxic to the system, most AOs are designed to work by the mechanism shown in Figure 1.6.9 In this mechanism, the AO must be in
7
Figure 1.6 RNase H-dependent Mechanism8
the form of deoxyribonucleic acid since RNase H only degrades RNA:DNA double helixes. Once RNase H degradation is complete, the AO is again free to bind to another piece of viral RNA. This makes the needed dosage of the drug much less than the simple antisense mechanism.
1.2 PURPOSE OF RESEARCH
In the development of this project, certain considerations were taken into perspective that would lead to active drugs in the two areas of research previously presented. Such considerations were the stability of the nonnatural nucleoside,
8 binding ability to viral RNA stands, synthesis, and other such issues. The overall
purpose of this research project is three-fold: (1) to synthesize different nucleoside analogues shown in Figure 1.7 using all five natural nucleic acids (a total of 30
R1 R2 R1 R2 R1 R2 Base Base Base
OH OH OH
a, R1 = H, R2 = OH; b, R1 = OH, R2 = H
Figure 1.7 Nucleoside Analogues
analogues), (2) to check for anti-viral biological activity against a wide range of
diseases by acting as NRTIs, and (3) to quantify the amount of Watson-Crick base
pairing of nonnatural nucleoside analogues with natural nucleosides when incorporated into DNA oligomers as AOs. The incorporation of the nonnatural nucleoside analogues into DNA oligomers will not be discussed as it is out of the scope of my research and will be performed by other individuals.
The target structure chosen for the nucleoside analogues serves a wide range
of purposes. The first is that by the removal of the sugar oxygen, the ring is less
reactive towards cleavage of the glycosidic linkage. The enhanced stability should
also help the nucleoside analogue withstand degradation by cellular nucleases.
Secondly, three methylene units have been added in a spirocyclic array around the 4'
and 5' position shown in Figure 1.8, which gives rise to the thirty different analogues
9
R1 R2 Base
5' 4' 1' 3' 2'
Figure 1.8 Numbering the [4,4]-Spirononanol Nucleoside
(15 of each diastereomer based on the hydroxyl configuration at C5'). Crystal
structure data from DNA and RNA fragments show that there exists open space
below C4' of each nucleoside. This open space should be more than adequate to
accommodate the three extra methylene groups. The spirocyclic nature of C4' should
also lead towards extra stability of the newly generated compounds. Certain agents
are known to abstract hydrogens from both the C4' and C5' positions of
deoxyribose.10-13 In the target spirocycle, both of these positions are now vastly
different in that C4' no longer has a hydrogen to abstract and C5' is now much more
sterically hindered with the substitution of one of its hydrogens for a methylene unit.
Due to these factors, the susceptibility of the aforementioned carbons to cellular degradation should be much less pronounced. Certain variations at C4' have been widespread in the literature14-23 owing to the ability of some derivatives to block
DNA polymerase20,21 and reverse transcriptase enzymes such as HIV-1 RT.24,25
The added methylene units around the pseudo sugar backbone also add to the
lipophilicity of the compound. In terms of drug travel and transfer efficiency, the
lessened polarity should help dissolve the drug in non-polar cellular membranes,
10 which will allow it to reach the nucleus or cytoplasm, although its bioavailability should also not be a problem based on the base’s polar nature.
As one purpose of this project is to incorporate the nonnatural nucleosides into
DNA oligomers, supporting evidence must be present to warrant such an attempt.
AMBER calculations were performed to find the minimum energy conformation of
thymine relative to the spirocyclic sugar glycosidic linkage (Figure 1.9). Although
Figure 1.9 Minimum Energy Conformations of Thymidine and Spirocyclic Analogues
the AMBER calculations were performed on a spirocyclic sugar system, the
replacement of the ethereal oxygen with a methylene unit should be of limited
difference. In Figure 1.9, structure A is the naturally occurring thymidine nucleoside and structures B and C are the (R) and (S) spirocyclic diastereomers at C5' respectively. The overlay of B and C on A, when all three structures have been fully minimized in AMBER for the gas phase, is quite astonishing with a (RMS = 0.007) for B and (RMS = 0.058) for C. These values show that the actual deviation from the conformation of the true nucleoside is minimal. The AMBER calculations predict the
11 minimum energy conformation about the glycosidic linkage to be the C2' endo conformer and that the free alcohol will acquire a pseudoequatorial position, both the same as in natural DNA.
The model studies also indicated that the hydroxyl group linked to C5' is constrained with regards to the nucleoside location but there is, however, neither too much nor too little movement allowed. The movement allowed is important based on work recently reported in the literature.26-32 When some of the modified sugars have been incorporated into oligonucleotides, a rise in duplex stability has been observed.
As seen in Figure 1.10, the rigidity of the spirocyclic framework appears to be
D E
Figure 1.10 Computer Model of DNA Containing Spirocyclic Nucleoside (DNA D, Spirocycle E)
12 compatible with the DNA strand and a high duplex stability is expected. AMBER calculations predict the added spirocycle should not hinder the base pairing of the double helix, as the nucleoside analogue and the natural nucleoside are almost equivalent in their conformations. As would be expected from crystal data of DNA, the three extra methylene units fit into the major groove of the DNA double helix.
The third purpose outlined in this area of research is anti-viral biological testing. A selection of the nucleoside analogues have been tested against various virus strains. With the synthesis of the DNA fragments complete with nucleoside analogues, biological testing will occur based on the premise of the reverse transcriptase’s inability to undergo transcription in the presence of the nonnatural nucleosides.
1.3 PREVIOUS SYNTHETIC WORK
As the main goal of this project is to synthesize optically pure nucleoside analogues, a suitable starting compound was needed. In a previous publication by
Nieman and Keay,33 a scheme was outlined where keto ester 1.1a was transformed
into racemic diol (±1.5) and was resolved by the use of (R)-(+)-camphor to give 1.6a
and 1.6b (Scheme 1.1). With a few transformations, a cheap starting material can be
13 O O O O O
1. KH, toluene aq. HCl, Δ OH O OEt 2. Ethyl-4-bromobutyrate, OEt
toluene O OEt 1.1a 1.2 1.3
O O OH OH
TsOH, toluene Li-t-Bu-DIBAL-H, 1. (R)-(+)-camphor, TsOH, DCM Δ THF, -78 oC 2. TsOH, H2O, DCM
1.4 (+/-) 1.5
H OH HO H OH
OH +
1.6a 1.6b
Scheme 1.1 Keto Ester to [4,4]-Spirononane-1,6-diol
converted to spiro[4,4]nonane-1,6-diols (1.6a, 1.6b). However, large quantities were needed and the conversion of 1.1a to 1.2 did not proceed smoothly above a one gram scale. Another article showed the conversion of diethyl adipate (1.1b) to 1.2, which proceeded in good yield up through multigram quantities (Scheme 1.2).34,35 A 1:1
O O O
OEt 1. Na, toluene O EtO 2. Ethyl-4-bromobutyrate, OEt toluene O OEt 1.1b 1.2
Scheme 1.2 New Route
14 mixture of 1.5 is achieved by forming the “ate” complex between t-BuLi and DIBAL-
H where the reducing agent formed is sufficiently bulky enough that the reduction must occur on the outer face. The racemic diol forms an acetal with (R)-(+)-camphor and the diastereomers can be separated by column chromatography. Each acetal is hydrolyzed to yield optically pure diols 1.6a and 1.6b.
1.4 PURPOSE OF THESIS WORK
Starting with the aforementioned enantiomerically pure diol 1.6, the aim of this thesis was to devise a concise route towards the formation of different spiro[4,4]nonane nucleosides. As there are two enantiomeric diols, the synthetic route must be two-fold.
The broad scope of this project hinges on the creation of three unique nucleoside analogue series: DNA, RNA, and 2,3-dideoxy nucleosides. The synthetic pathway should then rest on a common intermediate from which each of the three
different analogue series could be synthesized. Chapter 1 will be focused on the
synthesis of the saturated series and the subject matter of Chapter 2 will involve the
formation of the DNA and RNA series.
1.5 RETROSYNTHETIC STRATEGY AND SYNTHETIC BACKGROUND IN
THE (R)-SATURATED SERIES
15 The retrosynthetic strategy for this project begins with the previously
mentioned, enantiomerically pure, levorotatory diol 1.6a (Scheme 1.3). This diol,
OH OTBS OTBS Base
OH
OH OH
1.6a
Scheme 1.3 Retrosynthetic Approach
when protected at either alcohol, yields only one enantiomerically pure product. The free alcohol can then be dehydrated followed by an allylic oxidation. The α,β- unsaturated ketone can be reduced, the alkene hydrogenated, where the free alcohol can either undergo a Mitsunobu36 reaction with a base or it can be converted into a
mesylate and undergo a SN2 displacement with an anionic base.
Previously, a synthetic route to the alcohol utilizing the Mitsunobu reaction
had been accomplished.37 As seen in Scheme 1.4, the synthesis begins with the
16 OH OTBS OH 1. TBSCl, imid, CH2Cl2, DMAP, 98% 1. CrO3, 3,5-DMP, 53% 2. POCl3, py, 56% 2. NaBH4, CeCl3, 99%
1.6a 1.7
OTBS OTBS OTBS OH 10% Pd-C, H2, MeOH, 72% OH OH 1.8 1.9 1.10 1. Ph3P, DIAD, PhCO2H, 90% 2. NaOH, aq MeOH, 90%
Scheme 1.4 Previous Synthesis of Allylic Alcohol 1.9
protection of diol 1.6a followed by dehydration with phosphorous oxychloride to give
alkene 1.7. Alkene 1.7 can then undergo allylic oxidation followed by a Luche38 reduction with NaBH4 to give a mixture of allylic alcohols. Due to the inversion of
stereochemistry brought on by the Mitsunobu reaction, alcohol 1.8 must be converted
to 1.9. This was accomplished by a Mitsunobu reaction followed by cleavage of the benzoyl group. After very few successes were witnessed using 1.9 in the Mitsunobu
reaction to generate the unsaturated series of nucleoside analogues, the alkene was
hydrogenated to give 1.10.
Alcohol 1.10 was then reacted under Mitsunobu conditions with either N4- benzoylcytosine or N3-benzoylthymine,39,40 which under both cases was followed
with removal of the benzoate by ammonia and methanol and subsequent deprotection of the TBS ether with TBAF to generate 1.11 and 1.12 (Scheme 1.5).
17 NH2 O NHBz O 1. Bz N NH N N OH OH OTBS or N O N O N O N O H H + OH DIAD, Ph3P, THF or dioxane, 30%, 30% 2. NH3, MeOH, 84%, 74% 1.10 3. TBAF, THF, 74%, 75% 1.11 1.12
Scheme 1.5 Previous Synthesis of Saturated (R)-Thymidine and Cytidine
1.6 CONCLUSION OF THE SATURATED (R)-SERIES OF NUCLEOSIDE
ANALOGUES
Although the general outline of Scheme 1.5 proved successful, only pyrimidine nucleosides had been prepared. We then took it upon ourselves to test the generality of the Mitsunobu protocol towards purine bases. As shown in Scheme 1.6 fully deprotected adenosine 1.14 was synthesized using two different routes.41 By use
of the Mitsunobu reaction, alcohol 1.10 was again converted to base adduct 1.13.
Adenine itself cannot be used in the Mitsunobu reaction due to the presence of a
primary amino group, which would be reactive under the said reaction conditions.
Solubility would also be an issue. Therefore, 6-chloropurine was used instead. The
18 Cl
Cl N N H N N OTBS NH2 N N N N NH3, MeOH, N o N DIAD, PPh3, 80 C, 91% OTBS THF, DMF, 31% OR 1.13 N N
OH OTBS 1.10 THF, R = TBS, 1.14 TBAF, R = H, 1.15 MsCl, Et3N, adenine, NaH, DMF, 90% DCM, 98% 80 oC, (58% conv; 64% OMs yield) 1.16
Scheme 1.6 Direct Comparison SN2 Mesylate Displacement Versus the Mitsunobu Protocol
chloride in 1.13 was subsequently displaced by heating at 80 oC in a sealed tube with ammonia and methanol. The product was then desilylated with TBAF in THF to yield 1.15 in 90% yield. After this reaction it was apparent that the use of the
Mitsunobu reaction, was probably not the most efficient pathway. Due to the mechanism of the Mitsunobu reaction all five of the free nucleoside bases had to be protected beforehand owing to the reactivity inherent in multiple nitrogen atoms. By protecting the free nucleoside bases, selective attack by only one of the nitrogens could occur. Protection of the free nucleosides also greatly increases the solubility of the bases. Though the free bases are soluble in DMF, the Mitsunobu reaction did not perform well in that medium. Of the previously reported Mitsunobu reactions, the yields were around the thirty percent range, and no starting material could be recovered. Due to these problems, attention was turned to an SN2 displacement of
readily available mesylate 1.16. Mesylate 1.16 could be easily prepared from alcohol
1.10 with mesyl chloride and sodium hydride in dichloromethane 98% yield. In order 19 to synthesize nucleoside analogue 1.15, the natural form of adenine was added to
DMF and deprotonated with sodium hydride followed by the addition of mesylate
1.16. The reaction mixture was refluxed at 80 oC for two days, whereupon workup of the reaction mixture produced the adduct in 64% yield based on a 58% recovery of starting material. This was a tremendous success as it now allowed for the recovery of starting material, the bases did not need to be protected beforehand, solubility in
DMF is not an issue, and deprotection of the bases could be omitted.
Since both the thymine and cytosine pyrimidines had been attached to the spirocycle skeleton via the Mitsunobu reaction, we decided to incorporate uracil, the last in this group of bases, by an SN2 reaction. The first reaction attempted used some of the left-over N3-benzoyluracil with mesylate 1.16 in DMF (Scheme 1.7).
O Bz N OTBS
N O H OBz NaH, DMF, 80 OTBS oC, 81% O O 1.17
NH NH OMs OTBS OH 1.16 N O N O uracil, NaH, DMF, 80 TBAF, oC, (78% conv; 72% THF, 90% yield) 1.18 1.19
Scheme 1.7 SN2 Reaction of Protected Uracil Versus Unprotected Uracil
Surprisingly under these conditions, the only product observed was a diastereomeric mixture of 1.17 where the mesylate had been replaced with a benzoyl group. As it
20 appeared that these conditions might have been too harsh for the protected base, the
same reaction was run in CH3CN; however, no reaction was evident after stirring at
80 oC for 2 days. The reaction was then attempted with the free nucleoside base
under the predescribed conditions to yield 1.18 in 72% yield after the recovery of starting material. Compound 1.18 was further deprotected in the usual manner to give 1.19.
The last of the five nucleoside bases to be attached to the spirocycle skeleton was guanine. The naturally occurring form of guanine is an extremely polar molecule, too polar to be reacted as its free base in DMF. Therefore, the base is usually handled as its protected counterpart 2-amino-6-chloropurine. Initial attempts at installation of the base with the Mitsunobu reaction proved unsuccessful in a 1:1 mixture of tetrahydrofuran to N,N-dimethylformamide. In this case, N,N-
dimethylformamide had to be used as the cosolvent due to solubility problems and
could have been partially responsible for the failure of the reaction(Scheme 1.8). The
O Cl N H NH N N OR N N N NH N NH2 2 no reaction DIAD, PPh3, OTBS THF, DMF R = TBS, 1.21 TBAF, Cl THF, R = H, 1.22 Cl 96% N H N OMs N N OTBS 1.16 N N NH SH N N NH 2 2 HO NaH, DMF, 80 oC, NaOMe, MeOH o (85% conv, 41% yield) 40 C, 81% 1.20
Scheme 1.8 SN2 versus Mitsunobu Reaction of Mesylate 1.16 and 2-Amino-6-chloropurine 21
reaction was therefore run under SN2 conditions to give adduct 1.20 in 41% overall yield. The chlorine substituent was displaced in hot methanol via a thioacetal intermediate, which was hydrolyzed with water to yield the fully deprotected guanine base 1.21.42 After removal of the TBS protecting group with TBAF, compound 1.22 was isolated. This brought an end to the saturated (R)-series of nucleoside analogues, where use of an SN2 displacement of mesylate 1.16 proved a much more efficient route for base installation.
1.7 SYNTHETIC BACKGROUND IN THE SATURATED (S)-SERIES OF
NUCLEOSIDE ANALOGUES
The chemistry involved in the (S)-saturated series closely parallels that of the
(R)-saturated series. There is however one difference, the initial stereochemistry of diol 1.6b, after monoprotection with tert-butyldimethylsilyl chloride, positions the free alcohol on the opposite side of the carbocycle than did the previous series. The reaction conditions were however easily modified to take into account this difference.
Instead of an allylic oxidation following the dehydration of protected 1.6b, a
22 OH OTBS OH
1. TBSCl, imid, CH2Cl2, disiamylborane DMAP, 98% H2O2, NaOH, 70% 2. POCl3, py, 56%
1.6b 1.23
OTBS OTBS OH
OH 1.24 1.25 1. Ph3P, DIAD, PhCO2H, 86% 2. NaOH, aq MeOH,71%
Scheme 1.9 Generation of Alcohol 1.25
hydroboration was performed, which gave a easily separable mixture of isomeric alcohols 1.24 and 1.25. As before unwanted alcohol 1.24 could be converted to 1.25 through use of the Mitsunobu reaction.
Similarly, as shown in Scheme 1.5, alcohol 1.25 was converted to the cytidine and thymidine nucleoside analogues (Scheme 1.10). As before the reaction was
1. DIAD, Ph3P, THF or dioxane, 52%, 43% NH2 O NHBz O NH NH N NBz OTBS or OH OH N O N O N O N O H H + 2. NH3, MeOH, 80%,79% OH 3. TBAF, THF, 90%, 95% 1.25 1.26 1.27
Scheme 1.10 Synthesis of Cytidine and Thymidine Nucleoside Analogues
23 plagued with an extra deprotection step, no recovery of starting material, and low yields. Recourse was then made to use the predescribed chemistry involving a direct
SN2 displacement of a mesylate by the anion of the five unprotected nucleoside bases.
1.8 CONCLUSION OF THE SATURATED (S)-SERIES OF NUCLEOSIDE
ANALOGUES
As before, a direct comparison was first made between the Mitsunobu reaction and the SN2 displacement involving adenine and its protected counterpart 6- chloropurine (Scheme 1.11). In this set of reactions, under the same conditions, the
Cl NH2
N N Cl N N H OTBS OR N N N N N N N N NH3, MeOH, 80 oC, 78% DIAD, PPh3, THF, DMF, 42% 1.28 TBAF, R = TBS, 1.29 OTBS THF, 93% R = H, 1.30 adenine, NaH, DMF, 80 oC, 80% O
F OH NH 1.25 OTBS OR N O
MsCl, Et3N, 5- fluorouracil, NaH DCM, 98% DMF, 80 oC,45% OMs 1.31 TBAF, R = TBS, 1.32 THF, 45% R = H, 1.33
Scheme 1.11 Mitsunobu versus SN2 Displacement in the (S)-Saturated Series
24 SN2 displacement again showed a marked improvement over the existing Mitsunobu reaction yields. In this case product 1.30 was produced in 70% yield over three steps starting from alcohol 1.25. The 5-fluorouracil derivative was also attached in this fashion to show that unnatural nucleoside bases can also be included in this manner.
Lastly, mesylate 1.31 was reacted with N3-benzoyluracil in an attempt to demonstrate that not only could derivatized nucleoside bases be incorporated by this method, but protected nucleoside bases would work also. As shown in Scheme 1.12,
O O
NBz NH
OTBS OTBS OR N O N O 3 N -benzoyluracil, NaH, MeOH, NH3, DMF, 80 oC, (34% conv, 95% OMs 86% yield) 1.31 1.34 TBAF, R = TBS, 1.35 THF, 70% R = H, 1.36
Cl NH2
N N NH NH OTBS OTBS OR N N N O N O 2-amino-6-chloropurine, MeOH, NaOMe, o NaH, DMF, 80 C, (45% HOCH2CH2SH, 40 o OMs conv, 26% yield) C, 81% 1.31 1.37 TBAF, R = TBS, 1.38 THF, 96% R = H, 1.39
Scheme 1.12 Synthesis of (S)-Saturated Uracil and Guanine Unnatural Nucleosides
the actual yield was only 10%, but was close to 90% when recovered starting material was taken into account. Finally, guanine adduct 1.37 was synthesized in the previously described manner with the conventional deprotection strategy.
In conclusion, with regards to the (R)- and (S)-saturated series, a total of eleven different nucleoside analogues were synthesized, where the eleventh 25 nucleoside is the 5-fluorouracil adduct. Although the Mitsunobu reaction initially led
to some of these compounds, recourse towards a better installation method proved
most useful. By incorporating the free nucleoside bases through a direct SN2 displacement starting material could be recovered, an extra set of protection- deprotection steps could be omitted, and solubility was no longer a factor.
1.9 ATTEMPTS AT AN (R)- AND (S)-UNSATURATED SERIES OF
NUCLEOSIDE ANALOGUES
While working on the saturated series of nucleoside analogues, efforts were made to expand our synthetic targets to include an unsaturated series of analogues. With respect to the (R)-saturated series, allylic alcohol 1.9 was already in hand. All that needed to be accomplished was insertion of the nucleoside base followed by deprotection. However, this proved to be much more difficult than expected. When unwanted allylic alcohol 1.8 was reacted under Mitsunobu conditions, the reaction was always complete by TLC and percent yield of the isolated product was quantitative. However, after methanolysis of the benzoate, which should yield only alcohol 1.9, some of alcohol 1.8 was always present. This led us to believe that an allyl cation may be formed, where the deprotonated benzoic acid could be adding in from either side causing racemization of that center to a small degree. When the conversion of alcohol 1.8 to alcohol 1.9 was attempted with the stronger acid p- nitrobenzoic acid, a 1:1 ratio of isomers was recovered (Scheme 1.13).
26
OTBS OTBS OTBS OH O2CPhNO2 DIAD, p-NO PhCO H, 2 2 + PPh3, THF, 90% O2CPhNO2 1.8 1.40 1.41
Scheme 1.13 A Mixture of Diastereomers Resulting from an Allyl Cation
Even with this unwanted equilibration occurring in the reaction mixture, it was assumed that utilization of the Mitsunobu reaction to install the protected nucleoside bases, even if a 1:1 mixture was produced, would still provide some compounds for testing. In Scheme 1.14, three different Mitsunobu reactions were
DIAD, PPh3, THF, no reaction N3-benzoylthymine OTBS
DIAD, PPh3, THF, no reaction N3-benzoyluracil OH 1.9 DIAD, PPh3, THF, no reaction 6-chloropurine
Scheme 1.14 Failed Attempts at Base Installation via the Mitsunobu Reaction
attempted, all of which resulted in no apparent reaction.
With the failed attempts at base installation through the Mitsunobu reaction, recourse was made to the involvement of the mesylated derivative of allylic alcohol
1.42 (Scheme 1.15). However, when mesylation conditions were used with allylic
27 OTBS OTBS
CH2Cl2, Et3N, MsCl decomposition + 0 oC to rt OH 1.42 1.43
Scheme 1.15 Problems with Mesylation Chemistry
alcohol 1.42, only decomposition products and presumably diene 1.43 were observed.
Diene 1.43 was realized by four distinct alkenyl protons in the 1H NMR spectrum.
Due to the inability of formation of the proposed mesylate and the failed attempts at Mitsunobu chemistry, one last avenue was explored. Since the product has an alkene present within the carbocycle, attempts were made to use palladium chemistry. Alcohol 1.8 was converted to allylic acetate 1.44 with acetic anhydride and pyridine (Scheme 1.16). Acetate 1.44 was then subjected to palladium
OTBS OTBS OH OAc
Ac2O, DMAP, py, DMF, Pd(PPh3)4, NaH, o no reaction CH2Cl2, 98% adenine, PPh3, 70 C 1.8 1.44
OTBS OTBS OH NBS, THF, o PPh3, 0 C, 1 h Br 1.8 1.45
OTBS OTBS OH NCS, THF, o PPh3, 0 C, 1 h Cl 1.8 1.46
Scheme 1.16 Failed Attempts at Palladium Chemistry
28
conditions reported in the literature to synthesize alkenyl nucleosides.43 Although
acetate 1.43 was easily synthesized, no reaction was observed when it was reacted
with palladium. It was assumed that the triphenylphosphine ligands on the palladium
might be too large for the sterically hindered spirocycle or that the acetate might not
have been reactive enough. Therefore, recourse was made to synthesize allylic
bromide 1.44 and chloride 1.45, respectively.44 However, each allylic halide was extremely unstable and decomposition ensued for each of them on silica gel and in
CDCl3, which had been previously treated with basic alumina.
In conclusion, several attempts were made to synthesize the unsaturated series of nucleosides; however, since the route was plagued with so many problems, we decided to move on to the DNA and RNA series of nucleoside analogues.
29
CHAPTER 2
A HIGHLY STEREOCONTROLLED SYNTHESIS OF DNA AND RNA
SPIRO[4,4]NONANE NUCLEOSIDES
2.1 SYNTHESIS OF THE (R)-SERIES OF DNA NUCLEOSIDE ANALOGUES
Synthesis of the (R)-series of DNA nucleoside analogues started with α,β- unsaturated ketone 2.1, which was synthesized by the oxidation of allylic alcohol
1.7.45 Epoxidation of 2.1 occurred stereoselectively due to the bulky O-TBS
substituent, which blocks the upper portion of the ring from peroxide attack (Scheme
2.1).46 Epoxide 2.2 was stereoselectively opened with samarium diiodide in
OTBS OTBS OTBS
O O O H2O2, NaOH, SmI2, DMPU, THF, MeOH, 0 oC, 73% ethylene glycol, 95%
2.1 O 2.2 OH 2.3
OTBS OTBS OTBS
TBSOTf, O L-Selectride, MsCl, Et3N, 2,6-lutidine, DCM, THF, -78 oC, 99% DCM, 81% -78 oC, 92% OH OMs OTBS OTBS OTBS 2.4 2.5 2.6
Scheme 2.1 Synthesis of Mesylate 2.6
30 anhydrous THF containing ethylene glycol and DMPU by means of a reductive cleavage.47 β-Hydroxy ketone 2.3 was silylated in excellent yield under mild
conditions. If the epoxidation had occurred from the α-face of the ring, silylation of
2.3 would have been greatly impeded due to the preexisting β-TBS protecting group.
Ketone 2.4 was readily reduced with L-Selectride in THF at -78 oC to yield product
resulting only from attack on the α-face of the ring system. Again, the selectivity of
the reduction can be directly attributed to the O-TBS substituent. The O-TBS at C3'
is much closer to the carbonyl group than its counterpart at C5'. Consequently, the
C3' silyl protecting group blocks the β-face of the ring from reduction and only one
NOE
NOE OTBS TBSO H NOE TBSO H H OH O H H Dibal-H. CH Cl , 2 2 + -78 oC, 95% OH H OTBS OTBS OTBS 2.4 2.5 2.7
Scheme 2.2 NOE Proof of Compound 2.5
isomer is observed. Proof of the stereoselectivity of the reduction of 2.4 arose from
our first attempt in which DIBAL-H was used as the reductant (Scheme 2.2). The
reduction in dichloromethane led to a chromatographically separable 3:1 mixture of
isomers. The stereochemistry of the separated isomers was confirmed through the
application of NOE methods. Reduction from the top face of the ring gave compound
2.5 predominately. In compound 2.5, an NOE was observed from the C5' hydrogen
31 with both hydrogens on C3' and C1', whereas the C5' hydrogen on β-alcohol 2.7 had
an NOE interaction only with the hydrogen at C3'. This result further convinced us
that we did indeed have α-alcohol 2.5. With the issue of stereochemistry resolved,
free alcohol 2.5 was converted to mesylate 2.6 as previously discussed in 81% yield.
The SN2 reaction between mesylate 2.6 and the nucleoside bases was performed in the manner preciously described by the addition of sodium hydride and
DMF with refluxing for 2 days (Scheme 2.3). The yields observed in the coupling
OTBS OTBS B OH B
NaH, DMF, TBAF, THF base, 80 oC OMs OTBS OTBS OH 2.6 2.8 uracil, 43% 2.14 uracil, 92% 2.9 cytosine, 12% 2.15 cytosine, 84% 2.10 thymine, 27% 2.16 thymine, 73% 2.11 adenine, 60% 2.17 adenine, 93% NaOMe, MeOH, 2.12 2-amino-6-chloro- 2.18 guanine, 62% 80 oC purine, 90% SH 2.13 guanine, 87% HO
Scheme 2.3 Completion of the (R)-DNA Series of Nucleoside Analogues
reactions are based on recovered starting material. Although the percent yields for thymine and cytosine are fairly low, the other three nucleoside bases performed quite well. Protected guanine adduct 2.12 was deprotected as before to furnish the natural guanine nucleoside base by heating of sodium methoxide and 2-mercaptoethanol in methanol. The final step in the synthesis of these analogues was the double deprotection of the two tert-butyldimethylsilyl protecting groups. This was accomplished with tetra-n-butylammonium fluoride in THF. Although the yields
32 were very favorable, purification of the compounds was quite difficult due to their solubility in water, which did not allow for an aqueous extraction to remove any extra
tetra-n-butylammonium fluoride. Due to this problem, more than one column was
often necessary.
2.2 SYNTHESIS OF THE (S)-SERIES OF DNA NUCLEOSIDE ANALOGUES
Synthesis of the (S)-DNA series began by the oxidation of a mixture of
alcohols 1.24 and 1.25. The need for the oxidation was due to the fact that the
hydroxyl substituents had been installed via a borane reduction so there was not an
alkene available for epoxidation, which would lead us to the final compounds.
Therefore, the first part of the synthesis was the installation of the double bond
(Scheme 2.4). Oxidation of the mixture of alcohols under Swern conditions produced
OTBS OTBS OTBS
COCl2, DMSO, O LHMDS, TMSCl, OTMS Et3N, 80% THF, quant OH 1.24/1.25 2.19 2.20
OTBS OTBS
NBS, THF, O LiBr, Li2CO3, O o H2O, 77% DMF, 120 C, 80%
2.21 Br 2.22
Scheme 2.4 Synthesis of α,β-Unsaturated Ketone 2.22
33 ketone 2.19 in 80% yield.48 Ketone 2.19 was then deprotonated with LHMDS, where
α-deprotonation of the ketone was only seen from the less hindered methylene, and subsequently protected with TMSCl as silyl enol ether 2.20. The enol ether was added to a mixture of water, THF, and NBS, where rapid formation of α-bromo ketone 2.21 took place. Lastly, the halogen was removed via a dehydrohalogenation reaction by refluxing with lithium bromide and lithium carbonate to generate α,β- unsaturated ketone 2.22.
In much the same manner as previously discussed, the α,β-unsaturated ketone was selectively epoxidized from the bottom face by basic hydrogen peroxide in water
(Scheme 2.5). Epoxide 2.23 was opened at the α-carbon of the carbonyl to generate
OTBS OTBS
H O , NaOH, O SmI , DMPU, THF, O TBSOTf, 2,6-lutidine, 2.22 2 2 2 MeOH, 0 oC, 73% ethylene glycol, 76% DCM, -78 oC, 81%
2.23 O OH 2.24
OTBS OTBS OTBS
O L-Selectride, THF, MsCl, Et3N, -78 oC, 99% DCM, 92% OH OMs OTBS OTBS OTBS 2.25 2.26 2.27
Scheme 2.5 Synthesis of Mesylate 2.27
keto alcohol 2.24, which was subsequently protected as a silyl ether. Ketone 2.25 was then subjected to reduction with L-selectride to give alcohol 2.26, the reduction occurring only from the α-face as was the case with ketone 2.4. Free alcohol 2.26
34 was converted to mesylate 2.27 and the SN2 reactions with various bases were
initiated.
As shown in Scheme 2.6, mesylate 2.27 underwent an SN2 reaction with all
five nucleoside bases. The yields for the nucleoside adduct formation varied from
63% to 27%, based on recoverable starting material. Protected guanine adduct 2.32
was again converted to the free nucleoside base 2.33. Finally, all five adducts were
OTBS OTBS B OH B
NaH, DMF, TBAF, THF base, 80 oC OMs OTBS OTBS OH 2.27 2.28 uracil, 46% 2.34 uracil, 80% 2.29 cytosine, 40% 2.35 cytosine, 46% 2.30 thymine, 27% 2.36 thymine, 73% 2.31 adenine, 63% 2.37 adenine, 93% NaOMe, MeOH, 2.32 2-amino-6-chloro- 2.38 guanine, 62% 80 oC purine, 35% SH 2.33 guanine, 63% HO
Scheme 2.6 Completion of the (S)-DNA Series of Nucleoside Analogues
submitted to TBAF deprotection in tetrahydrofuran to give rise to the fully deprotected (S)-DNA series of nucleoside analogues.
2.3 SYNTHESIS OF THE (R)-SERIES OF RNA NUCLEOSIDE ANALOGUES
With the synthesis of both sets of DNA nucleoside analogues complete, work
was begun on the (R)-RNA series. This route likewise commenced with α,β-
unsaturated ketone 2.1. Dihydroxylation with osmium tetraoxide in the presence of pyridine, water, and acetone produced a 5:1 isomeric mixture of diols 2.39 and 2.40
with the β-diol being the major product (Scheme 2.7).49 The stereochemistry of the 35
OTBS OTBS OTBS
OH OH O OsO , py, H O, O O 4 2 + acetone; H2S, 62%
2.1 2.39 OH OH 2.40
Scheme 2.7 Dihydroxylation of α,β-Unsaturated Ketone 2.1
diols was again determined by the use of NOE methods. Due to the steric bulk around the unit of unsaturation, osmium tetraoxide was used stoichiometrically as once the osmate ester was formed cleavage was difficult until workup. Even during the workup process, when the osmate ester was stirred overnight in a saturated solution of sodium thiosulfate, no cleavage of the ester occurred. Only after bubbling dihydrogen sulfide through the reaction mixture for one hour was there complete cleavage of the ester.
The next step in the synthetic scheme was to protect the diol before reduction of the ketone. As an unprotected diol, reduction of the ketone would lead to a triol, where differentiation between the three hydroxyls would be unlikely during the subsequent protection step. Our initial idea was to use a protecting group that would be quite flexible as to not hinder nucleophilic attack of the nucleoside bases on the mesylate. The first set of conditions attempted to convert diol 2.40 into the diallylated compound (Scheme 2.8). However, although the allylated product was
36
OTBS OTBS I K2CO3, O DMF, 80% O or (i-Pr) NEt, 2 O OH OH I DMF, 80% 2.40 2.41
Scheme 2.8 Allylation Elimination
seen by TLC it underwent elimination to give α,β-unsaturated ketone 2.41. Under
both conditions, the elimination product was evident as soon as the diallylated species
was present.
Although elimination was an apparent problem, protection of the hydroxyls as
acetates was tried next (Scheme 2.9). Reaction of diol 2.40 with acetic anhydride,
MeOH, -78 oC, OTBS OTBS 1:1 mixture of isomers NaBH4, 84% O O CH2Cl2, Et3N, L-selectride 1:1 mixture of isomers Ac2O, DMAP, 98%
OH OH OAc OAc LiAlH(OtBu) 3 no reaction 2.40 2.42
Scheme 2.9 Problems with the Reduction of Diacetate 2.42
DMAP, and triethylamine gave diacetate 2.42 in 98% yield. However, reduction of
the ketone was a problem, as reduction with sodium borohydride gave a mixture of isomers, as did L-selectride. In both cases there is a large amount of possible
hydrogen bonding to the oxygen rich β-face of the molecule, which would cause
37 hydride delivery to come from the bottom face. The bulky reducing agent
50 LiAlH(OtBu)3 when dissolved in THF led to no reaction.
Since the small protecting groups were troublesome with regard to elimination and the possibility existed for reducing agents to chelate to the oxygen-rich sites, a much larger neutral protecting group was tried. The bulky protecting group tetraisopropyldisiloxy dichloride was attached to 2.40 in the presence of pyridine, silver nitrate, and THF (Scheme 2.10). Ketone 2.43 was reduced with L-selectride to
OTBS OTBS OTBS
O O TiPDSCl2, pyr, L-Selectride, AgNO3, THF, THF, 86% 100% OH O O O O OH OH 2.40 Si Si Si Si O O
2.43 2.44
OTBS
CH2Cl2, Et3N, NaH, adenine, no reaction MsCl, 98% DMF, 80 oC OMs O O
Si Si O
2.45
Scheme 2.10 Sythesis of TiPDS Protected Mesylate 2.45
generate alcohol 2.44, which was then converted to mesylate 2.45. Unfortunately the mesylate was completely unreactive when subjected to the anion of the free adenine base at 80 oC for 2 days. It was reasoned that the bulky protecting group must have hindered the approach of the nucleophile to the point of no reaction. Since the
38 reduction of the ketone was performed without incident some smaller silyl protecting
groups were also tried. Attempts at protection of diol 2.40 with both diethyldichlorosilane and dimethyldichlorosilane yielded only decomposition products (Scheme 2.11).
OTBS
diethyldichlorosilane, decomposition O pyr, AgNO3, THF
dimethyldichlorosilane, decomposition 2,6-lutidene, CH Cl OH OH 2 2 2.40
Scheme 2.11 Failed Attempts at Further Silyl Protection
Since a variety of silyl protecting groups had proven to be problematic, an
extremely versatile protecting group was needed. Diol 2.40 was reacted in neat 2,2-
dimethoxypropane in the presence of p-toluenesulfonic acid to yield acetonide 2.46 in
94% yield (Scheme 2.12). The acetonide in turn underwent a stereoselective
39 OTBS OTBS OTBS
O 2,2-dimethoxypropane, O L-Selectride, p-TsOH, 80 oC, 94% THF, -78 oC, 98% OH OH OH OO OO 2.40
2.46 2.47
OTBS
CH Cl , Et N, 2 2 3 adenine, NaH, no reaction MsCl, 0 oC, DMF, 80 0C 100% OMs OO
2.48
Scheme 2.12 Synthesis of Mesylate Acetonide 2.48
reduction with L-Selectride and the free alcohol was converted to mesylate 2.48.
However, again when the mesylate was reacted with adenine in refluxing N,N- dimethylforamide and sodium hydride, no reaction occurred.
With the failure of yet another reaction, we believed that the steric bulk of the protecting groups might have been too much for the SN2 reaction to overcome. For this reason, 2.40 was converted to carbonate 2.49 with phosgene and DMAP in dichloromethane (Scheme 2.13). Using the same reaction conditions as before, the
OTBS OTBS OTBS OTBS OH L-Selectride, o O phosgene, DMAP, O THF, -78 C, 99% + CH2Cl2,86% (1:2)
NaBH4, MeOH, OH o OH OH OO 0 C, 80% OO OO 2.40 (4:1)
2.49 O 2.50 O 2.51 O
Scheme 2.13 Different Reducing Agents Demonstrate Different Selectivities
40 carbonate was reduced with L-selectride. The reaction, however, produced a mixture
of both the α- and β-anomers. It is reasoned that due to there being less steric bulk on
the bottom side of the molecule, a molecule of L-selectride was more repelled by the
TBS substituent than the carbonate. However, when sodium borohydride in methanol
was used the selectivity was reversed and more of the α-anomer was seen. Alcohol
2.50 was converted to mesylate 2.52, which was then reacted with adenine under the
predescribed conditions only to offer decomposition after stirring for two days
(Scheme 2.14). Since carbonates are not known to be the most stable protecting
OTBS OTBS
THF, thymine, CH Cl , Et N, no reaction 2 2 3 adenine, NaH, decomposition o 0 DIAD, PPh3 MsCl, 0 C, DMF, 80 C 100% OH OMs OO OO
2.50 O 2.52 O
Scheme 2.14 Failure of both the Mitsunobu and SN2 Reactions
groups, a Mitsunobu reaction was also attempted on free alcohol 2.50. Upon stirring
for a few days, there was no reaction seen by TLC and steps were taken towards another protecting group.
Since the silyl and the acetonide protecting groups were probably too big and the carbonate was too sensitive, attempts were made to involve a benzylidine acetal.
The thought was that the benzene ring would orientate itself away from the ring
system and this would lead to less steric interactions during the SN2 step.
41 Benzylidine acetal 2.53 was synthesized with dimethoxybenzaldyhyde in the presence
of p-toluenesulfonic acid (Scheme 2.15). The reaction gave rise to only one
OTBS OTBS OTBS
O PhCH(OMe)2, O L-Selectride, p-TsOH, THF, -78 oC, 100% 100% OH OH OH OO OO 2.40 H Ph H Ph 2.53 2.54 OTBS
CH Cl , Et N, 2 2 3 adenine, NaH, no reaction MsCl, 0 oC, 89% DMF, 80 0C OMs OO
H Ph 2.55
Scheme 2.15 Synthesis of Mesylate Benzylidene Acetal 2.55
diastereomer, presumably with the phenyl ring pointing away from the molecule and not underneath, as this would lead to a large amount of steric interaction. Ketone
2.53 was reduced with L-selectride, converted to the mesylate, and reacted with adenine and sodium hydride in refluxing N,N-dimethylformamide. The reaction mixture, which was stirred for two days at 80 oC, again did not furnish the desired
adduct.
At this point, we were convinced that the smaller protecting group, the better,
so three attempts were made to synthesize the methylene acetal. Reactions with diol
42 2.40, dimethoxymethane, and p-toluenesulfonic acid, or dimethoxymethane, p-
toluenesulfonic acid, and lithium bromide,51 or dimethoxymethane and phosphorous
pentaoxide52 all resulted in the re-isolation of starting diol 2.40 (Scheme 2.16). A
OTBS (MeO)2CH2, p-TsOH
(MeO) CH , p-TsOH, O 2 2 LiBr NO (MeO)2CH2, CH2Cl2, REACTION P2O5 OH OH MOMCl, NaH, THF 2.40
Scheme 2.16 Protecting Group Failures
reaction with diol 2.40 was also attempted in which a di-MOM protected alcohol would be formed. This also resulted in no reaction.
Since protecting groups were becoming scarce, Dr. Chris Seekamp suggested the use of a triflate as the leaving group. Therefore the free alcohol of acetonide 2.47,
probably the most stable of the protected diols thus far synthesized, was converted to
triflate 2.56 with trifilic anhydride and pyridine in dichloromethane (Scheme 2.17).
OTBS OTBS
Tf2O, py, CH2Cl2, 100% OH OTf OO OO
2.47 2.56
Scheme 2.17 Synthesis of Triflate 2.56
43
When triflate 2.56 was reacted with adenine and potassium hydride in
refluxing N,N-dimethylformamide, adenosine 2.67 was synthesized in 76% yield
(Scheme 2.18). Since a triflate is a far superior leaving group than a mesylate, this
OTBS OTBS B OH B OH B
KH, DMF, TBAF, MeOH, p- base, 80 oC THF TsOH OTf OO OO OO OH OH
2.68 uracil, 82% 2.56 2.57 uracil (37% conv, 76% yield) 2.62 uracil, 60% 2.69 cytosine, 62% 2.58 cytosine (93% conv, 85% yield) 2.63 cytosine, 98% 2.70 thymine, 99% 2.59 thymine (23% conv, 83% yield) 2.64 thymine, 96% 2.71 adenine, 80% 2.60 adenine (55% conv, 97% yield) NaOMe, MeOH, 2.65 adenine, 82% 2.72 guanine, 93% 2.61 2-amino-6-chloropurine 80 oC 2.66 2-amino-6-chloro- (33% conv, 88% yield) SH purine, 100% HO 2.67 guanine, 100%
Scheme 2.18 Synthesis of the (R)-RNA Nucleoside Analogues
appeared to be the sole difference between the reactivity of the two compounds.
Triflate 2.56 was reacted with the other four nucleoside bases to generate adducts
2.58 to 2.61. The silyl protecting group was then removed with the acetonide still in place so a water workup could be possible. Lastly, the acetonide was removed with methanol in the presence of p-toluenesulfonic acid. These final transformations led to the conclusion of the (R)-RNA series of nucleoside analogues.
44 2.4 SYNTHESIS OF THE (S)-SERIES OF RNA NUCLEOSIDE ANALOGUES
Access to the (S)-RNA series was initiated much in the same away as the (R)-
series, beginning with the dihydroxylation of α,β-unsaturated ketone 2.22 (Scheme
2.19). Unlike earlier before, only one isomer of the diol was formed. Presumably
OTBS OTBS
O OsO4, py, H2O, O acetone; H2S, 66%
2.22 OH OH 2.73
Scheme 2.19 Dihydroxylation of α,β-Unsaturated Ketone 2.22
due to some steric interactions with the (S)-silylated hydroxyl substituent, attack from the osmium tetraoxide came only from the bottom face of the spirocycle.
When diol 2.73 was first synthesized attempts were still being made towards the elucidation of the right protecting group, therefore as shown in Scheme 2.20,
45 OTBS OTBS OTBS
O O TiPDSCl2, pyr, L-Selectride, AgNO3, THF, THF, 99% 98% OH O O O O OH OH 2.22 Si Si Si Si O O
2.74 2.75
OTBS
CH2Cl2, Et3N, NaH, adenine, no reaction MsCl, 88% DMF, 80 oC OMs O O
Si Si O
2.76
Scheme 2.20 The Bulky TiPDS Protected Diol is Synthesized Again
TiPDS protected diol 2.74 was synthesized, taken to the mesylate, and nonsurprisingly found to be unreactive to adenine, sodium hydride, and N,N- dimethylformamide.
At this point, the protecting group and leaving group strategy had been completed in the (R)-series and diol 2.22 was converted to the acetonide, the ketone was reduced with L-selectride, and triflate 2.79 was formed (Scheme 2.21). Unlike
46 OTBS OTBS OTBS
O 2,2-dimethoxypropane, O L-Selectride, p-TsOH, 80 oC, 99% THF, -78 oC, 98% OH OH OH OO OO 2.22
2.77 2.78
OTBS
Tf2O, py, CH2Cl2, 82% OTf OO
2.79
Scheme 2.21 Synthesis of Triflate 2.79
in the (R)-series where the triflate was an air stable white solid, this triflate was a
colorless oil and upon standing at room temperature slowly decomposed.
Triflate 2.79 was reacted with all five of the nucleoside bases to give rise to all
five adducts (Scheme 2.22). Presumably the low yields of the SN2 reaction were due
OTBS OTBS B OH B OH B
KH, DMF, TBAF, MeOH, p- base, 80 oC THF TsOH OTf OO OO OO OH OH
2.91 uracil, 88% 2.79 2.80 uracil, (60% conv, 10% yield) 2.85 uracil, 70% 2.92 cytosine, 100% 2.81 cytosine (40% conv, 61% yield) 2.86 cytosine, 93% 2.93 thymine, 90% 2.82 thymine (68% conv, 14% yield) 2.87 thymine, 92% 2.94 adenine, 85% 2.83 adenine (44% conv, 41% yield) NaOMe, MeOH, 2.88 adenine, 96% 2.95 guanine, 95% 2.84 2-amino-6-chloro-purine 80 oC 2.89 2-amino-6-chloro- (66% conv, 41% yield) SH purine, 96% HO 2.90 guanine, 72%
Scheme 2.22 Synthesis of the (S)-RNA Nucleoside Analogues
47 to the sensitivity of the triflate as its recovery from the reaction mixture was difficult.
These adducts were in turn deprotected with TBAF and guanine derivative 2.89 was
converted to unprotected guanine adduct 2.90 as seen before. Lastly all five compounds were freed of their acetonide functionalities to give rise to the final five
coumpounds in the nucleoside analogue area of research.
2.5 CONCLUSION
In conclusion, a diastereoselective synthesis of thirty-one different nucleoside
analogues has been completed, which accommodated the two different configurations
at C5'. The nucleoside bases were attached by the Mitsunobu process and SN2 displacement involving a mesylate or triflate. The later SN2 reactions allowed for the
reisolation of unconsumed starting material, which gave rise to much higher overall
yields, the removal of a deprotection step, and the ability to perform the reactions at
much higher temperatures. Various nucleoside analogues in all three series have
been sent to the NIH for biological testing.
48
CHAPTER 3
STUDIES TOWARD EPOXY CARBONATE FORMATION AND THE
SYNTHESIS OF SUITABLE PRECURSORS
3.1 BACKGROUND
In 2001, John Hofferberth, en route to taxol, attempted a reaction with an α,α'- dihydroxyketone and phosgene, where the expected product was a cyclic carbonate, resulting from a 1,2-alkyl migration (Figure 3.1). Initially, it was assumed that the
OPMB OPMB O O Phosgene, DMAP o OTBS CH2Cl2, -78 - 0 C 14 14 2 OTBS HO 2 O O H O H O HO O
via a
OPMB OPMB O O OTBS a OTBS B via b O HO O b O H O+ H (73%) O O O
Figure 3.1 Fate of a Conformationally Restricted System
49 reaction would proceed through pathway “a” to produce a carbonate; however, pathway “b” prevailed, presumably through the mechanism shown in Figure 3.1, and gave rise to the previously unknown epoxy carbonate functionality in 73% yield. A crystal structure was also determined, thereby, proving the existence of the epoxy carbonate.
Initial attention towards the synthesis of other epoxy carbonates, was given towards exocyclic α,α'-dihydroxyketones, as seen in Scheme 3.1. In all four cases
OH O O
OH O O O COCl2, DMAP, CH2Cl2, 81%
3.1 3.2
O COCl2, DMAP, O CH2Cl2, 81% HO O
HO O O 3.3 3.4 O HO O
HO O X X O O
COCl2, DMAP, CH2Cl2, 100%, O 100% O 3.5, X = H,H 3.7, X = H,H 3.6, X = O 3.8, X = O
Scheme 3.1 Conformationally Unlocked α,α'-Dihydroxyketones
50 presented, the molecular systems lacked conformational rigidity. Without this
rigidity the molecules were not forced towards the epoxy carbonate. Only simple
carbonates were formed instead. Therefore; our attention was shifted to more rigid
α,α'-dihydroxyketones where the hydroxyl substituents were conformationally bound.
In Figure 3.2 four targeted compounds are shown. Compounds 3.9 and 3.11 contain
O O HO O HO O HO OH HO OH OH OH
3.9 3.10 3.11 3.12
Figure 3.2 Target α,α'-Dihydroxyketones
hydroxyl groups trans to each other and would be expected to form the epoxy
carbonate structure, whereas compounds 3.10 and 3.12 contain the cis hydroxyl
configuration and would be expected to either give no reaction or simple carbonate
formation. When the hydroxyl substituents are orientated in a cis fashion, formation
of an epoxy carbonate would mean that either the epoxide or carbonate would have a
trans ring junction, which would be energetically unfavorable.
3.2 SYNTHESIS OF CIS-α,α'-DIHYDROXYCYCLOHEPTANONE
Trans α,α'-Dihydroxycycloheptanone 3.9 was chosen as the starting point for this project due to its presumably short synthesis. Commercially available
51 cycloheptene was oxidized with m-CPBA to give cycloheptene oxide, which
underwent ring opening with dimethyl sulfoxide in the presence of triflic acid. This
was followed by the addition of diisopropylethylamine to generate hydroxy ketone
3.14, all of which is based on a protocol developed by the Trost group (Scheme
3.2).53 The free hydroxyl was protected as a TBS ether and was further deprotonated
O O O OR TBSO OTBS 1. DMSO, TfOH; Et2Ni-Pr, 76% LHMDS, THF, 2. TBSCl, imid, TBSCl; mCPBA 68% DMAP, CH2Cl2, 95% 3.16 3.14, R = H 3.13 3.15, R = TBS
O OH HO OH HO O
TBAF, THF, + 74%
2:1 3.9 3.17
Scheme 3.2 Complete Synthesis of Dihydroxyketone 3.9
at the position α to the carbonyl, where the enolate was trapped with TMSCl.54 The trapped enolate was reacted with freshly made DMDO (dimethyldioxirane) several times where only minimal product formation was observed. Since DMDO proved less reactive toward the substrate than expected, a switch was made to mCPBA.
Reaction of the trapped enolate with mCPBA resulted in initial epoxide formation, which spontaneously rearranged to give the di-O-TBS protected diol 3.16 in 68%
yield. The diol was deprotected with three equivalents of TBAF in THF, which gave
a 2:1 mixture of the desired trans-dihydroxyketone 3.9 and its isomer 3.17
52 respectively, in an overall yield of 74%. Although the hydride shift was unexpected,
it appears to be quite common in these types of ring systems and is a common theme
throughout this research project.55
At this point, we were uncertain to whether 3.9 or 3.17 was the desired dihydroxyketone. Since we expected the structure of diol 3.9 to be properly assigned, diol 3.17 was reacted with TBSCl, which gave rise to the mono and disilylated compounds 3.18 and 3.19 (Scheme 3.3). Since neither one of the compounds was a
OH OH OTBS HO O TBSO O TBSO O
TBSCl, imid, + DMAP, CH2Cl2, 84% 1:1 3.17 3.18 3.19
Scheme 3.3 Proof 3.17 is not Desilylated 3.16
match for the previously synthesized disilyl 3.16 and that completion of the
installation of both TBS groups was difficult, diol 3.9 must be the desired compound.
In order to prove that the trans relationship of the hydroxyl groups was
present, both 3.9 and 3.16 were reduced with sodium borohydride in methanol
(Scheme 3.4). The reduction was initially only run on protected 3.16; however,
53 O O OH OTBS HO OH TBSO OTBS TBSO OTBS TBSO OH
NaBH , 4 + MeOH, 97% (2.7:1)
3.9 3.16 3.20 3.21
NaBH4, MeOH, 90% TBAF, TBAF, THF, 80% THF, 80%
OH OH HO OH HO OH
3.22 3.22
Scheme 3.4 Proof of the Trans Stereochemistry
this led to two different isomeric structures where a silyl migration had taken place.
When both alcohols 3.20 and 3.21 were treated with TBAF, only one unsymmetrical
product was observed. This proved that the compound was indeed trans, because
regardless of which face of the molecule reduction occurs from, the product is a cis,trans triol. If the starting dihydroxyketone were of cis stereochemistry, two different triols would have been observed, a cis,cis and a trans,trans isomer, both of which are symmetrical and show only four peaks in the 13C NMR. Since there was
some rearrangement duting the reduction of 3.16, diol 3.9 was also reduced, which
gave rise to the same product as the deprotection of compounds 3.20 and 3.21.
54
3.3 SYNTHESIS OF CIS-α,α'-DIHYDROXY CYCLOHEPTANONE
With the synthesis of trans-dihydroxycycloheptanone complete, our attention
was turned towards the cis isomer. The route to the cis isomer proved to be much
more difficult due the inner carbonyl of the molecule. Initial efforts, shown in
Scheme 3.5, give light to a few of the failed pathways. Diketone 3.24 was
O O O O OTBS HO OTBS O OTBS HO OTBS
LHMDS, TMSCl; IBX, DMSO, NaBH4, mCPBA, 15% THF, 68% MeOH, 95%
3.15 3.23 3.24 3.25
THF, PPh3, DIAD, PhCO2H
no reaction
Scheme 3.5 Failed Attempts Towards cis-Dihydroxycyclohetpanone
synthesized from ketone 3.15 by the reaction of the TMS silyl enol ether and
mCPBA, followed by the oxidation of free alcohol 3.23 with IBX. Reduction of the
diketone with sodium borohydride led to an unseparable mixture of diols. The free
hydroxyl of 3.23 was also subjected to Mitsunobu conditions to ascertain if the
stereochemistry could be inverted. However, no reaction was observed, which was not extremely surprising due to the low reactivity of hydroxylketones towards the
Mitsunobu reaction.
55 Attempts toward the synthesis of both the cis cycloheptanone and
cyclooctanone compounds were underway at the same time, both with little promise.
In both cases, it appeared that the inner carbonyl was responsible for the many
rearrangements and low reactivity, presumably through hydrogen bonding with the
free hydroxyl. This functionality therefore had to be removed and recourse was then
made to the Nysted reagent.56
The Nysted reagent is well known for its ability to olefinate carbonyls in the presence of free α-hydroxyl substituents. Initially, reaction with the Nysted reagent was attempted with di-O-TBS protected dihydroxy ketone 3.16. However, once the alkene (compound 3.26a is not shown) was formed, it was extremely difficult to remove only one of the TBS protecting groups. The Nysted reagent was thus used, as shown in Scheme 3.6, to olefinate ketone 3.23, where alkene 3.26 was generated.
O HO OTBS HO OTBS O OTBS Br O Br Zn Zn Nysted, IBX, TiCl4, THF, DMSO, THF, 82% Zn 31% 3.23 3.26 3.27 Nysted Reagent
O O HO OTBS HO OTBS HO OH
NaBH4, CeCl3•7H2O, O3, CH2Cl2, TBAF, MeOH, 88% PPh3, 86% THF, 46%
3.28 3.29 3.10
Scheme 3.6 Complete Synthesis of cis-Dihydroxyketone 3.10
56 Although the percent yield was only 31%, this appeared to the best achievable result.
The free hydroxyl was oxidized with IBX in DMSO and THF, followed by a Luche reduction to yield cis alcohol 3.28. The alkene was cleaved via ozonolysis, where only minimal rearrangement was seen, to produce the 1,2 diol, and the silyl group was removed with TBAF to give the final cis dihydroxyketone. Through all of these reactions, competing rearrangements were minimal, which can be attributed to the masking of the carbonyl moiety.
3.4 SYNTHESIS OF TRANS α,α'-DIHYDROXY CYCLOOCTANONE
As shown in Scheme 3.7, a previous route to trans α,α'-
OH OH KHMDS, O , -15 oC; 2 H2, 10% Pd/C, P(OEt)3, 26 % EtOH, 94% O O
3.30 OH 3.31
OH OH
LiAlH4, ether, 42% O OH
OH OH 3.11 3.32
Scheme 3.7 First Synthesis of Dihydroxy Ketone 3.11
dihydroxycyclooctanone 3.11 had been explored. In this route, commercially available 1,5-cyclooctadiene was treated in the Trost manner previously described to yield hydroxy ketone 3.30. This compound was treated with KHMDS in the presence 57 of oxygen, followed by the addition of triethyl phosphite, which gave rise to the
unsaturated trans dihydroxy ketone 3.31. However, the combined yield for the two steps was only 26% based on a 74% conversion. The olefin was then removed by hydrogenation to generate compound 3.11. As previously mentioned, in order to prove that it was the trans configuration, a reduction with lithium aluminum hydride was performed on the ketone, where only one unsymmetrical compound was seen.
Due to the low yields presented in Scheme 3.8, another pathway to diol 3.11
OH OTBS OTBS TBSCl, imid, DMAP, 10% Pd-C, CH2Cl2, 95% MeOH, 97% O O O
3.30 3.33 3.34
LHMDS, THF, LHMDS, THF, TMSCl; TBSCl; mCPBA, 60% mCPBA, 45%
HO O
OH OTBS TBAF, THF, 72% O
3.11 OH 3.35
Scheme 3.8 An Alternant Route to Dihydroxy Ketone 3.11
was needed. The free hydroxyl in 3.30 was protected with TBSCl in the presence of imidazole and DMAP to give silyl ether 3.33, where the alkene was saturated via hydrogenation in an overall yield of 92%. Reaction of the silyl enol ether of 3.34
with DMDO gave little to no percent conversion. Recourse was then again made to
mCPBA, where interestingly, when either TMSCl of TBSCl was used to trap the 58 enolate only the mono-protected diol was obtained after workup. The silyl protecting
group was then removed with TBAF to furnish compound 3.11.
3.5 SYNTHESIS OF CIS α,α'-DIHYDROXY CYCLOOCTANONE
After the synthesis of the trans-dihydroxy cyclooctanone was complete, attention was turned towards the cis isomer. The synthesis of the cis α,α'-dihydroxy cyclooctanone was initially started by Ivan Vilotijevic. Ivan initially thought the oxidation of alcohol 3.36 to diketone 3.37, followed by a stereoselective reduction with ammonium chloride and zinc dust, would yield the cis mono protected alcohol, based on steric interactions. (Scheme 3.9). However, it appeared that the innermost
HO O OO OOH
OBn OBn OBn Dess-Martin, Zn, THF, DMSO, 99% sat THF-NH4Cl (1:1), 60%
3.36 3.37 3.38
HO O Zn, sat THF- OBn NH4Cl, (1:1)
3.39
Scheme 3.9 Reduction of the Innermost Carbonyl
carbonyl underwent reduction, or the outer carbonyl was first reduced with a hydride
migration ensuing, either of which did not produce the cis α,α'-dihydroxyketone.
That free alcohol 3.38 was indeed the α,β-dihydroxyketone, was proven not only by 59 the characteristic splitting in the 1H NMR spectra but also upon hydrogenation of the benzyl protecting group, a non-symmetrical product was seen based on 1H and 13C
NMR data (Scheme 3.10).
O OH O OH HO OH HO OH
OBn OH OH OH
H2, Pd/C, NaBH4, + MeOH, 99% MeOH, 86% 3.38 3.40 3.41 3.32
Scheme 3.10 Proof of the 1,2-Hydride Shift
Therefore, the reaction product from the reduction mixture was not the correct isomer. A hydride shift or the reduction of the wrong carbonyl had occurred, to give rise to 2,3-dihydroxy cyclooctanone 3.40. Although there was some of the unrearranged product present from the reduction with ammonium chloride and zinc dust, the ratio was inconsistent, ranging from a 1:1 mixture to only the rearranged product. In order to further prove that the 1,2 diol had formed; after the benzyl protecting group was removed diol 3.40 was reduced with sodium borohydride in methanol to give a mixture of symmetrical triol 3.41 and unsymmetrical triol 3.32
(Scheme 3.10). If reduction of the wrong carbonyl had not occurred, both of the products would be symmetrical; however, since triol 3.32 was present, it was evident that the reduction had produced the wrong isomer.
60 Since the ammonium chloride and zinc dust reduction conditions led to a
mixture of isomers, two additional sets of reduction conditions were also attempted
(Scheme 3.11). However, when diketone 3.37 was subjected to reduction conditions
O O O OH
OBn OBn see below
3.37 3.38
conditions yield
NH4Cl, Zn dust 60%
Dibal-H 64%
NaBH4, MeOH 54%
Scheme 3.11 Rearrangement of a Diketone Under Reduction Conditions
with both DIBAL-H and sodium borohydride in methanol only the rearranged
product was observed. Although the α,α'-dihydroxy ketone was almost surely being
formed during the reaction, rearrangement to the α,β-dihydroxy ketone always
prevailed. Another explanation for this selectivity is that the diketone might prefer to
exist as its dios phenol tautomer under certain conditions, however, this isomer was
never seen by NMR.
In light of the rearrangements with the benzyl protected alcohol, a switch to a
silyl protecting group was attempted (Scheme 3.12). Mono-silylated 3.35 was
61 HO O O O HO O O OH
OTBS OTBS OTBS OTBS see IBX or DMP, + 90-92% below
3.35 3.42 3.43 3.44
conditions yield yield
NH4Cl, Zn dust ---- 60%
Dibal-H ---- 67%
L-Selectride ---- 89%
NaBH4, MeOH 59% 39%
TBAF, THF
HO O O OH
OH OH
+
3.12 3.40 48% 24%
Scheme 3.12 Attempts at the Reduction of Diketone 3.42
oxidized with IBX or Dess-Martin periodinane to generate diketone 3.42 in 90% and
92% yield, respectively. Reduction of the diketone was attempted with the previously mentioned reagents, along with L-selectride. Although the first three reductants produced only the rearranged product, sodium borohydride in methanol gave a reproducible 3:2 mixture of alcohols 3.43 and 3.44. Though the alcohols were separable, removal of the silyl protecting group with TBAF in THF from ketone 3.43 led to a competing α-ketol rearrangement, where the two resulting diols were inseparable.
Since reduction of the dicarbonyls proved to be too problematic, an attempt was made to synthesize the acetal of 3.42. (Scheme 3.13) This however, did not 62
OOTBS
O ethylene, glycol, no reaction PPTS, 4A MS
3.42
Scheme 3.13 Unreactivity Towards Acetal Formation
work and focus was reverted back to mono-protected dihydroxyketone 3.44. To
ensure that compound 3.44 was the α,β-dihydroxy ketone, some of it was separated
from compound 3.43 by the use of MPLC and was deprotected with TBAF in THF to
give diol 3.40 (Scheme 3.14), whose 1H NMR shows a distinct doublet (δ 4.35,
OOH OOH HO OH
OTBS OH OH TBAF, MeOH, THF, 90% NaBH4, 86%
3.44 3.40
O O O
O DMAP, DCM, Phosgene, 82%
3.45
Scheme 3.14 Formation of Carbonate 3.45
J = 2.9 Hz, 1H) for the inner carbinolic center, where the other is a doublet of triplets
(δ 4.30, J = 9.2, 3.1 Hz, 1H). This along with the mass spectral data conclusively proved that 3.40 was indeed the α,β-dihydroxyketone. Diol 3.40 was also reduced to
63 give an unfavorable 1:1 mixture of triols. Cis diol 3.40 was also converted to
carbonate 3.45 with phosgene in order to ascertain if any further rearrangements
would occur under the basic reaction conditions, which none did.
A mixture of 3.35 and 3.44 was also reacted with TBSOTf and 2,6-lutidine to ascertain if the two isomeric disilylated compounds would separate better as less polar entities. (Scheme 3.15) The reaction, however, did not proceed after two days
HO O OOH TBSO O OOTBS
OTBS OTBS OTBS OTBS 2,6-lutidine, TBSOTf, + + CH2Cl2, no reaction
3.35 3.44 3.46 3.47
Scheme 3.15 Attempted Double Protection of 3.35 and 3.44
at room temperature. This was not surprising given the fact that I was never able to
isolate disilylated α,α'-dihydroxy cyclooctanone 3.46 from a previous reaction.
In light of the findings above, a different route was needed to obtain the cis
isomer. When mCPBA is reacted with an allylic alcohol, chelation presumably takes
place and cis addition is observed. I therefore tried to synthesize the enol ether with
different protecting groups so the silyl group could be removed while still keeping the
enol ether. The several attempts however, summarized in Scheme 3.16, were not
64 OOTBS MeO OMe OOAc
DMSO, t-BuOK, THF, LHMDS; no rxn Me2SO4, 15% TBSCl
3.34 3.48 3.49 OO
Et2O, CH2N2, 53% OOTBS LHMDS, THF, Ac2Ono rxn OO 3.51 LHMDS, THF, Me2SO4 no rxn
KHMDS, THF, Me2SO4 no rxn O OTBS 3.34 t-BuOK, DMF, BnBr decomposition 3.50 THF, LHMDS; TBSCl, 54%
3.52
Scheme 3.16 Attempts at Differentiating Between Hydroxyl Groups
even remotely successful. An interesting reaction did occur when diketone 3.50 was reacted with diazomethane in ether. The expected product was the methyl enol ether, but since compound 3.50 exists as the diketone and not the diosphenol the epoxide was formed instead. This reaction spurred research into more epoxide forming reactions, which will be covered in Chapter IV. Lastly, diketone 3.50 was subjected to basic conditions and the enolate anion was trapped with TBSCl. Some of the disilylated dienol ether 3.52a (not shown) was also isolated in about 5% yield.
Compound 3.52 was then reduced with DIBAL-H and subjected to t-BuOOH and VO(acac)2 in benzene. (Scheme 3.17) After one hour, only decomposition was observed.
65 OOTBS HO OTBS
t-BuOOH, THF, decomposition DIBAL-H, 97% benzene, Vo(acac)2
3.52 3.53
Scheme 3.17 Decomposition of Alcohol 3.53, Not Epoxidation
There could have been two problems with this synthetic attempt. The first is
that the TBS protecting group could be too large for the reaction to work properly,
and the second is that the silyl enol ether might not have been entirely stable towards the reaction conditions.
As with the cycloheptanone series, attention was eventually turned towards
the Nysted reagent. The reaction of 3.35 and the Nysted reagent produced two isomeric alkenes (Scheme 3.18). Under the Lewis acidic conditions, an α-ketol
HO O HO OH
OTBS OTBS OTBS
Nysted, THF, + TiCl4
3.35 3.54 3.55 42% 14%
IBX, DMSO, IBX, DMSO, THF, 94% THF, 60% Br O Br Zn Zn O O
Zn OTBS OTBS
Nysted Reagent
3.56 3.57
Scheme 3.18 Reaction of Ketone 3.35 with the Nysted Reagent 66
rearrangement had presumably occurred during the reaction to generate both alkenes.
Although the proton attached to the free hydroxyl carbon on compound 3.55 appeared
as a doublet (δ 3.98, J = 8.4 1H)in its 1H NMR, more concrete evidence was needed
in order to move further with the route and alkene 3.54. Both isomers were oxidized
to the α,β-unsaturated ketone with IBX in DMSO and THF. At this point enone 3.57
was reduced under Luche conditions, and gave a mixture of isomeric alcohols.
Alcohol 3.55 was the same alcohol produced in Scheme 3.19, which meant the other
O OH OH
OTBS OTBS OTBS
NaBH , CeCl , O , CH Cl ; 4 3 + 3 2 2 MeOH PPh3, 100%
3.55 3.58 3.57 37% 60%
O OH O OH
OTBS OH
TBAF, THF, 90%
3.44 3.40
Scheme 3.19 Evidence Alkene 3.57 was a Product of a 1,2-Hydride Shift
alcohol must be the cis isomer. If the starting ketone was ketone 3.56, there could not
be any rearrangement possible, due to the removal of the carbonyl functionality. The olefin was transformed back into the ketone through ozonolysis, followed by subsequent removal of the silyl protecting group with TBAF, to furnish compound
3.40. Since cis diol 3.40 had previously been synthesized and characterized in
67 Scheme 3.18, this proved that alkene 3.54 was the major component of the product mixture.
With 3.54 in hand, it was time to try some old reactions again. The first conditions to be attempted were the Mitsunobu reaction. This reaction had not worked before, due to the carbonyl adjacent to the free hydroxyl substituent. This time, however, the reaction worked, but it did not go to completion. (Scheme 3.20)
OTBS
BzO THF, DIAD, OTBS PhCO2H, PPh3, 9%
HO 3.59 OTBS
O2NPhOCO 3.54 THF, DIAD, p-NO2PhCO2H, PPh3, 21% 3.60
Scheme 3.20 Unsatisfactory Attempts at the Mitsunobu Reaction
The product was apparent by 1H NMR but could not be cleanly isolated, as it was the same polarity as the starting material. Also, from the 1H NMR, the yield of product relative to the amount of starting material, was certain to be quite low. Due to the separatory problems discussed, p-nitrobenzoic acid was also used in the Mitsunobu reaction. The reaction produced 3.60 in higher yield, but the product was still not separable from the starting material. In light of this shortcoming, the path that was used to synthesize cis dihydroxy cycloheptanone 3.10, was adapted to
68 cyclooctenediol 3.54. Enone 3.56 was reduced to give exclusively free alcohol 3.61
(Scheme 3.21). However, the next two reactions were prone to rearrangement. The
O HO HO O O OH
OTBS OTBS OTBS OTBS CeCl •7H O, O , CH Cl ; 3 2 3 2 2 + NaBH4, MeOH, PPh3, 96% 93% 1 : 2.3 3.56 3.61 3.43 3.44
TBAF, THF, 70%
HO O O OH
OH OH
+
1 : 2 3.12 3.40
Scheme 3.21 Problems with Rearrangements
ozonolysis of 3.61 led to a 1:2.3 mixture of isomers, where the major isomer was the
rearranged α,β-dihydroxy ketone. Even though only a small amount of ketone 3.43
was generated, it was further deprotected with TBAF in THF, where yet another
rearrangement was observed. Again the product ratio was more weighted on the side
of the rearranged product, with a 1:2 ratio of unrearranged diol 3.12 to rearranged diol
3.40.
Interestingly, even though many rearrangements had been observed in the
cyclooctanone series, relatively few were found with cycloheptanone. Perhaps even more interesting, is that according to MM3 calculations the α,α'-dihydroxy ketones
69 are more thermodynamically stable than their 2,3-dihydroxy ketone isomers (Figure
3.3). In both the cis and trans compounds it is clear that the α,α'-dihydroxy ketones
Figure 3.3 Global Minimum Energy Conformations of the 2,8- and 2,3-Dihydroxy Cyclooctanones
are much more energetically stable than the 2,3-dihydroxy ketones. Therefore, there
must be some lowering of energy in the transition state that allows for the
rearrangement pathways to occur.
Based on the ease of rearrangement, it was decided to first remove the silyl
protecting group from compound 3.61 before the reinstallation of the carbonyl moiety
(Scheme 3.22). This pathway was chosen since the alkene will not take part in the
70 HO HO HO O O OH
OTBS OH OH OH O , CH Cl ; TBAF, 3 2 2 + THF, 70% PPh3, 96%
1 : 2 3.61 3.62 3.12 3.40
Scheme 3.22 The Final Complete Synthesis of Cis Dihydroxy Ketone 3.12
rearrangement pathway. The olefinic bond in compound 3.62 was subjected to an
ozonolysis, which gave both the wanted cis isomer 3.12 and the unwanted cis isomer
3.40 in a ratio of 1:2, respectively. Even though the route in Scheme 3.22 had one
reaction that led to rearrangement, it was overall much better than the route presented
in Scheme 3.21, where two rearrangements occurred.
The last reactions performed were to prove that the cis compound was indeed formed. Compound 3.43 was reduced with sodium borohydride in methanol to generate diol 3.63 (Scheme 3.23). Even if a rearrangement occurred, it would still
HO O HO OH HO OH
OTBS OTBS OH
MeOH, NaBH4, TBAF, 0 oC, 89% THF, 89%
3.43 3.63 3.41
Scheme 3.23 Proof of the Cis Hydroxy Ketone Structure
71 yield a cis, cis product. Diol 3.63 was desilylated with TBAF in THF, to give cis cis triol 3.41 as the only product. This product was symmetrical based on 13C NMR spectroscopy, which showed only five different carbon signals.
3.6 SYNTHESIS OF EPOXY CARBONATES
With the synthesis of the four different dihydroxy ketones complete, their reactions with phosgene and DMAP were initiated. The first reaction attempted was with trans dihydroxy ketone 3.9 (Scheme 3.24). The reaction provided epoxy
O
O O O HO OH O
phosgene, DMAP, CH2Cl2, 52% brsm
3.9 3.64 O
O O OH HO OH O O O OH
phosgene, DMAP, phosgene, DMAP, CH2Cl2, 37% CH2Cl2, 85%
3.10 3.65 3.66
O HO O O O
OH O phosgene, DMAP, CH2Cl2, 78%
3.11 3.67
HO O
OH phosgene, DMAP, unknown white precipitate CH2Cl2
3.12
Scheme 3.24 Synthesis of Two Epoxy Carbonates 72
carbonate 3.64 in 52% yield, based on recovered starting material. In order to
confirm that the epoxy carbonate was formed, the 13C NMR and IR had to be
examined. The dioxygenated spirocarbons occur between 106 to 112 ppm, where the
monooxygenated carbons occur around 70 to 90 ppm. As shown in Table 3.1, the
-1 13 Epoxy Carbonates IR (cm , film) C NMR (δ, C6D6 or CDCl3) taxol 1828 111.6, 151.5
3.50 1820 106.0, 152.4 3.53 1819 107.9, 151.0
Table 3.1 IR and 13C NMR Data of Three Epoxy Carboantes
epoxy carbonates also have a characteristic IR absorption around 1820 cm-1. In the
case of epoxy carbonate 3.64, both the IR and 13C NMR spectral data confirmed the
assumed structure. The same was also true for epoxy carbonate 3.67, which was
formed in a very reasonable yield of 78%.
Since both of the trans dihydroxy ketones formed the epoxy carbonates
without incident, the reaction next had to be attempted on the cis isomers. The cis isomers were not expected to form the epoxy carbonate, as this would give rise to a
trans epoxide or a trans carbonate. Either of these would yield a sterically strained tricyclic ring system, especially at the dioxygenated spirocarbon. When cis
dihydroxy ketone 3.10 was reacted with the said conditions, rearrangement was seen
to yield simple carbonate 3.65. This structure was proved by the missing IR and 13C
73 NMR peaks and carbonate 3.65 had already been synthesized from cis-2,3-dihydroxy
cycloheptanone, which was formed as a side product earlier in the synthesis. Finally,
cis compound 3.12 was reacted with phosgene and DMAP, where the reaction yielded a white precipitate, which was insoluble in every solvent tried. These four examples thus demonstrated the structural requirements necessary for epoxy carbonate formation and those that would not allow it.
3.7 CONCLUSION OF THE EPOXY CARBONATE PROJECT
In summary, four synthetic routes were developed to provide the cis and trans isomers of α,α'-dihydroxy cycloheptanone and cyclooctanone. It was also discovered
that in order to convert the trans compounds into their cis isomers, the Nysted reagent must be used to mask the problematic carbonyl group.
The cis and trans dihydroxy ketones were used to investigate the newly
discovered epoxy carbonate functional group. The initial studies demonstrated that
unrestrained α,α'-dihydroxy ketones, when reacted with phosgene and DMAP, would
only yield simple carbonates. When the reaction was attempted with
conformationally locked trans α,α'-dihydroxy cycloheptanone and cyclooctanone, the
epoxy carbonate was produced. However, when the reaction was attempted with the
cis derivatives, only rearrangements and uncharacterizable products were observed.
In essence, the structural requirements for epoxy carbonate formation were expanded
upon as well as the creation of four synthetic routes that led to four previously
unknown dihydroxy ketones.
74 3.8 EQUILIBRIUM OF α,α' AND α,β-DIHYDROXY KETONES IN THE
PRESENCE OF t-BuOK and TBAF
Although numerous α-hydroxy ketones have the potential for rearrangement into an isomeric α-ketol, there has not been much prior attention paid towards the effect of the desilylation of such hydroxy ketones. As the seven and eight membered medium ring α,α'-dihydroxy ketones were now readily available in our laboratory, we decided to take a look into their reactivity. As shown in Figure 3.4 when the α-
B- HO O OO O OH
OP OP OP H
Figure 3.4 Hydride Migration
hydroxyl is negatively charged, a hydride migration can occur, which when starting with an α,α'-dihydroxy ketone, will generate an α,β-dihydroxy ketone. Within our systems, we discovered a generality that when an α,α'-dihydroxy ketone was reacted with TBAF in THF, there was usually an accompanying rearrangement, whereas when an α,β-dihydroxy ketone was reacted under the same conditions no rearrangement was observed.
The first desilylation that we studied was the removal of the TBS moiety from compounds 3.16 and 3.23. In both cases a ratio of 2:1 was observed where one third
75
O O OH TBSO OTBS HO OH O OH
TBAF, THF, 74% + (2:1) 3.16 3.9 3.17
O O OH HO OTBS HO OH O OH
TBAF, THF, 86% + (2:1) 3.23 3.9 3.17
Scheme 3.25 Rearrangement of Trans α,α'-Dihydroxy Cycloheptanones
of the product had rearranged to the α,β-dihydroxy ketone. Both of the
rearrangements were stereoselective in the fact that the 1,2-hydride shift is suprafacial
as shown in Figure 3.4.
Interestingly, when the cis isomer of di-TBS protected ketone 3.16 was reacted under the same conditions with TBAF, only a ratio of 10:1 of unrearragned to rearranged was found (Scheme 3.25). As before, the rearrangement must have been
O O OH HO OTBS HO OH O OH
TBAF, + THF, 76% (10:1) 3.29 3.10 3.68
Scheme 3.26 Rearrangement of Cis α,α'-Dihydroxy Cycloheptanone
stereoselective in that only the two possible cis compounds were synthesized. 76 Shown in Scheme 3.27, when any of the mono- or di-α,β-silylated dihydroxy
OH OH O OTBS O OH
TBAF, THF, 86%
3.19 3.17
OTBS OH O OTBS O OH
TBAF, THF, 87%
3.18 3.17
OH OH O OTBS O OH
TBAF, THF, 95% 3.69 3.68
Scheme 3.27 No Rearrangement of α,β-Dihydroxy Cycloheptanones
ketones were deprotected with TBAF no rearrangement was observed within the
system. This was however unexpected, as the MM3 calculations predict that the α,α'-
dihydroxy cycloheptanone isomers should be more stable than their rearranged tautomers. Shown in Figure 3.5 are the MM3 calculations of the cycloheptanone
77
Figure 3.5 Global Minimum Energy Conformations of the α,α'- and α,β-Dihydroxy Cycloheptanones
series. In both sets of isomers, the α,α'-dihydroxy ketone is supposedly preferred to the α,β-dihydroxy ketone by over 6 kcal/mol. However, in our research we only saw the α,α'-dihydroxy ketones rearranging to the α,β-dihydroxy ketones and not vice versa.
The behavior of the cyclooctane series of hydroxylated compounds with
TBAF was also researched. In Scheme 3.28 both the cis and trans mono-silylated
78 HO O HO O
OTBS OH TBAF, THF, 72%
3.35 3.11
HO O HO O OOH
OTBS OH + OH TBAF, THF, 72% (2:1)
3.41 3.12 3.38
Scheme 3.28 Rearrangement of Cis and Trans α,α'-Dihydroxy Cyclooctanone
α,α'-dihydroxy ketones were reacted with TBAF in THF. Interestingly, the trans
compound did not exhibit the normal rearrangement that we had seen in the
cycloheptane series. However, the cis isomer delivered a 2:1 mixture of unrearranged diol 3.12 to rearranged diol 3.40.
Lastly the cis and trans mono-silylated α,β-dihydroxy cyclooctanones in
Scheme 3.29 were reacted with TBAF. As was the case in the cycloheptanone series,
OOH OOH
OTBS OH TBAF, THF, 90%
3.70 3.71
OOH OOH
OTBS OH TBAF, THF, 85%
3.44 3.40
Scheme 3.29 No Rearrangement of α,β-Dihydroxy Cyclooctanones 79 no rearrangement was observed.
In order to test monosilylated trans-2,3-dihydroxy cyclooctanone, it first had to be synthesized. The only place a compound close to this had been observed was as a byproduct from the Nysted reaction. In Scheme 3.30 compound 3.55 underwent an ozonolysis reaction followed by the removal of the silyl protecting group with TBAF
HO OTBS HO OTBS HO OH
O O
O3, DCM; TBAF, PPh3, 90% THF, 85% 3.55 3.72 3.73
Scheme 3.30 Synthesis of Silylated 3.72 and Diol 3.73
to yield 3.73 in 77% yield overall.
In all of the cases presented, the rearrangement pathway appeared to be under kinetic control, as TBAF would not be a strong enough base to force an equilibration to occur. In Scheme 3.31, when all seven of the free diols were reacted with TBAF
80 O O HO O HO O HO OH HO OH OH OH
TBAF, TBAF, THF, 100% THF, 92%
3.9 3.9 3.11 3.11
OH OH HO O HO O OOH OOH OH OH
TBAF, TBAF, THF, 97% THF, 100%
3.68 3.68 3.12 3.12 O O O OH O OH HO OH HO OH OH OH TBAF, TBAF, THF, 98% THF, 98% 3.10 3.10 3.40 3.40 O OH O OH
OH OH
TBAF, THF, 97%
3.71 3.71
Scheme 3.31 Reaction of Free Hydroxyls with TBAF
in THF the products observed were inline with what was expected. Not one of the compounds underwent rearrangement or decomposition when treated alone with
TBAF, which meant that the rearrangements were not necessarily due to TBAF itself, but to the formation of an oxygen anion, once the silyl protecting group had been cleaved.
The final set of reactions involved treatment of eight of the unprotected dihydroxy ketones with t-BuOK in methanol (Scheme 3.32). Since t-BuOK is a
81 O OH HO OH O OH
KOt-Bu KOt-Bu 3.9 + 3.17 CH3OH CH3OH 91% (2 : 1) 94% 3.9 3.17
O OH HO OH OOH
KOt-Bu KOt-Bu 3.10 + 3.55 CH3OH CH3OH 89% (8 : 1) 92% 3.10 3.55
HO O O OH
OH OH KOt-Bu KOt-Bu 3.12 + 3.38 CH3OH CH3OH 100% (1 : 1) 92% 3.12 3.38 HO O O OH
OH OH KOt-Bu KOt-Bu 3.11 + 3.58 CH3OH (2 : 1) CH3OH 93% 94% 3.11 3.58
Scheme 3.32 Reaction of Free Hydroxyls with t-BuOK
strong enough base to deprotonate free hydroxyls in solution, if there was a thermodynamic equilibrium that could occur, t-BuOK would induce it. The addition of t-BuOK caused all eight of the dihydroxy ketones to equilibrate into fairly similar ratios of their α,α'-diols to α,β-diols as had been observed during their desilylation reactions with TBAF. It is again somewhat interesting that these rearrangements would occur, since the MM3 calculations show that the α,α' isomers are more stable that their α,β counterparts, yet there must be an underlying factor that drives these molecules to the ratios seen.
82 3.9 CONCLUSION OF THE FLOURIDE ION PROMOTED α-KETOL
REARRANGEMENT PROJECT
In summary, a new strategy for performing α-ketol rearrangements under mild
conditions has been presented. It has been shown that α,α'-dihydroxy ketones readily
undergo rearrangement when deprotected with TBAF; however, their α,β-dihydroxy
ketone tautomers do not. Proof was also given that TBAF itself was not responsible for the rearrangements, but rather the formation of the oxygen anion created during the removal of the TBS substituent. This hypothesis was further confirmed by the equilibrating conditions enforced by the addition of t-BuOK.
83
CHAPTER 4
I. EPOXY KETONE FORMATION WITH DIAZOMETHANE AND
POLYKETONES
II. O- VERSUS C-ALKYLATION IN MEDIUM RING α,β-UNSATURATED
HYDROXY KETONES
4.1 BACKGROUND
Previously, towards the synthesis of epoxy carbonates, we stumbled upon a relatively unknown reaction whereby a 1,2 diketone, when subjected to diazomethane, could be converted into an epoxy ketone. The epoxy ketone functional group has several reactive sites and is of considerable use in organic synthesis.
Usually, this functionality is synthesized by an alkaline peroxidation of an α,β- unsaturated ketone.57 In this manner of synthesis, the oxygen atom is introduced last.
However, there are certain instances where the addition of the carbon atom in last
position would be more beneficial.
The addition of diazomethane to polycarbonyl functional groups has not
received much attention and the little it has, does not cover the scope of its synthetic
potential.58 The majority of the literature dedicated to this transformation, is focused
on the addition of diazomethane to keto esters, shown in Scheme 4.1, although this
59 too is limited.
84 O O
OMe CH2N2 OMe R ether R 68-100% O O 4.1 4.2
(R = Ph, Ph2CH, 2-thienyl)
O O
CH2N2 ether 79% OH OMe
Br Br 4.3 4.4
Scheme 4.1 The Reaction of Diazomethane with Diketones versus Diosphenols
A compound, which exists as a true dicarbonyl, when reacted with diazomethane, will react through the less hindered π-system or the system with the most polarization. In this case diazomethane will act as a nucleophile, attacking the partial positive center of the carbonyl carbon. However, when there is an elevated enol content in the starting material, as is the case with bromide 4.3, a simple methylation of the enol oxygen atom will ensue, where diazomethane acts as an electrophile towards the enolic oxygen atom.
85 4.2 EPOXY KETONE FORMATION WITH DIAZOMETHANE AND
POLYKETONES
In order to gain a larger understanding of the structural and electronic properties necessary for the formation of an epoxy ketone, we tested various polyketones. The reaction conditions employed for all of the reactants in this section is as follows: 10 equivalents of diazomethane in ether was added to the starting material, along with silica, and the reaction mixture was stirred until conversion to product was complete by TLC. The first set of substrates to be tested consisted of various acyclic systems, as shown in Table 4.1. When symmetrical
86 Reactant Product Yield, %
O O
Me Me Me Me 54
O O 4.5 4.6
O O
Ph Ph Ph Ph 87
O O 4.7 4.8
O O
H H 40 Ph Ph
O O 4.9 4.10
O O O O
80 Ph Ph Ph Ph
O O 4.11 4.12
O O O O
81
O O O O 4.13 4.14
Table 4.1 Acyclic Systems
diketones 4.5 and 4.7 were reacted with diazomethane only one epoxide was formed.
This is because once the conjugation between two or more π-systems has been removed due to epoxide formation, the resultant product is now unreactive towards any extra diazomethane present in the medium. Therefore, when the system only contains two conjugated ketones, only one epoxide is formed. Stereoelectronic effects also play an important role in the reactivity with diazomethane, as is apparent
87 with aldehyde 4.9. In this case, diazomethane only reacts with the aldehyde, as it is more sterically accessible and is much more reactive due to one less electron donating methyl substituent. Again, with triketone 4.11 sterics, stereoelectronic effects, or both could determine which carbonyl is attacked by diazomethane. As both sterics and stereoelectronic effects make the inner ketone the most reactive, reaction is only observed at this site. The last compound to be reacted in the acyclic series was tetraketone 4.13, whose reaction with diazomethane afforded diepoxide 4.14. With tetraketone 4.13, it does not matter which ketone is epoxidized, since there are still two ketones left in conjugation with each other, which are free to react with another molecule of diazomethane. Of course, as mentioned before, the inner ketones are more reactive and reaction only occurs at these centers.
The next system reacted with diazomethane were those in which the diketone moiety was contained in a simple unstrained ring system. Both the eight and twelve membered ring systems were reacted with diazomethane to produce the epoxy ketones shown in Table 4.2. Each ring system proceeded smoothly to generate the
88 Reactant Product Yield, %
O O O O
53
4.15 4.16
O O
O O
69
4.17 4.18
Table 4.2 Unstrained Cyclic Systems
expected epoxy ketone in good yield.
The reactant group tested were ring systems in which the ring was much more rigid than in the previous examples (Table 4.3). The first rigid ring system that was
89 Reactant Product Yield, %
O O
77 O O
4.19 4.20
OMe O
O 84 +
O O OMe 4.21 4.22 4.23
O O 92
O O 4.24 4.25
O O
no rxn 0
4.26
Table 4.3 Rigid Cyclic Systems
treated with diazomethane was diketone 4.19, which gave epoxide 4.20 in 77% yield.
Camphorquinone 4.21 was then reacted with diazomethane and underwent an interesting ring expansion to give methylated enol ethers 4.22 and 4.23 in a ratio of
73 : 27, respectively. Shown in Figure 4.1 is the mechanistic rational for the
90 O O OMe O
-N CH2N2 C N2 2 + H2 O O O OMe 4.21 4.22 4.23
Figure 4.1 Ring Expansion Mechanism
observed selectivity and rearrangement. Once a molecule of diazomethane has attacked one of the carbonyls, probably the least hindered, a ring expansion ensues.
The expansion gives rise to the 1,3 diketone, which can tautomerize to its enol isomer and react with another molecule of diazomethane. Isomer 4.22, as the enolate is further away from the bridgehead methylene, is less sterically hindered towards methylation and this is seen in the product distribution. This result demonstrates that
the strain within camphorquinone 4.21 is enough to halt advancement of the system towards epoxide formation. Interestingly, when diketone 4.24 is reacted with diazomethane, no ring expansion was observed, just the normal epoxide formation.
Lastly, although the diketone in compound 4.26 is situated outside the ring system, the unsaturation inside the ring plays a very important role regarding the reactivity of the diketone. There was no reaction observed with diketone 4.26,
presumably due to the stronger tendency of the inner ketone to be in conjugation with
the alkene rather than the other ketone. Therefore, the α,β-unsaturation within the
inner ketone from the olefin renders it useless to be in conjugation with the other
ketone and the system is therefore not activated towards methylene addition.
91 The next set of reactions attempted involved the diketone moiety flanked by
aromatic rings on either side. In Table 4.4, the reactions of three different aryl-fused
Reactant Product Yield, %
O O O O
88 brsm
4.27 4.28
O O O O
96 brsm
4.29 4.30
O O O O
53 brsm
4.31 4.32
Table 4.4 Aryl-fused Diketones
diketones with diazomethane are shown. All three reacted quite well under the
previously stated reaction conditions; however, the addition of silica gel, which acts
as a Lewis acid and can coordinate to one or both of the ketones, thereby making the carbon center even more electropositive, led to higher product yields. The lower reactivity of the aryl-fused diketones can be attributed to the aromatic rings that are in
conjugation with the ketones. Since the ketones can have some conjugation with the
92 aromaticity of the rings, they are less conjugated to each other, thereby lowering their
reactability with diazomethane. Diketones 4.27 and 4.31 are symmetrical; however,
diketone 4.29 is not and as observed before, attack of a molecule of diazomethane
occurs at the least hindered ketone to give epoxide 4.30.
The last set of diketones reacted with diazomethane were a variety of
cyclobutene-1,2-diones. Interestingly, all three substrates, upon reaction with
diazomethane, underwent spontaneous rearrangement to the respective cyclopentene-
1,3-dione adduct (Table 4.5). Dimethyl squarate 4.37 gave quite messy results
Reactant Product Yield, % O
Ph O Ph 58
Ph O Ph O 4.33 4.34
O
PhS O PhS 69
PhS O PhS O 4.35 4.36 O
MeO O MeO 28
MeO O MeO O 4.37 4.38
Table 4.5 Cyclobutene-1,2-dione as Reactants
93 compared to compounds 4.33 and 4.37. Due to the strained nature of the cyclobutane
ring, the system would not allow for epoxide formation. However, unlike with
camphorquinone, the cyclobutene-1,2-diones, once rearranged, did not react further to
afford the methylated enol ethers. Formation of the enol is less energetically
favorable in cyclopentene-1,3-dione ring systems because of the antiaromatic
properties which can arise.
4.3 CONCLUSION OF THE DIAZOMETHANE REACTION WITH
POLYCARBONYLS
In conclusion, diazomethane has been shown to react with a wide variety of
multicarbonyl functionalities on various scaffolds. The reactivity of diazomethane
has been shown to be dependent on the steric environment around the ketones and the
stereoelectronics involved. Also, when strained ring systems are involved the rings
will undergo ring expansion to reduce the strain and will react with another
equivalent of diazomethane if possible.
4.4 BACKGROUND FOR O- VERSUS C-ALKYLATION PROJECT
In 2003, it was discovered in our group that deprotonation of 2-hydroxy
cyclooctanone followed by the addition of an allylic or benzylic halide resulted in C-
alkylation.60 However, when a unit of unsaturation is introduced between C5 and C6
O-alkylation dominates. This crossover in kinetic preference is attributed to the
94 olefinic system’s inability to adopt a conformation conducive to proton abstraction at
C2. The inability to adopt a certain conformation forces the unsaturated compound to undergo O-alkylation.
As seen in Figure 4.2, 2-hydroxycyclooctanone can adopt three different low
Figure 4.2 The Three Lowest Energy Conformations of 2-Hydroxy Cyclooctanone
energy conformations, based on MM3 calculations, where conformation A has an
O=C-C-H dihedral angle of 106.7o, when viewed through a Newman projection. This
dihedral angle value is quite close to the value deemed ideal for maximum
stereoelectronic overlap.61 Conformations B and C have lost the hydrogen bonding
constraint, where B would lead to the more highly strained E-enolate and in conformer C, the atoms are not in correct alignment for proton abstraction from the hydroxyl carbon.
When an olefin is resident within the molecule, there is a dramatic change in the conformational topology of the system. In Figure 4.3, conformations D, E, and F
95
Figure 4.3 The Three Lowest Energy Conformations of 2-Hydroxy-Cyclooct-5-enone
are shown. In all three of the minimized structures, the dihedral angle is not close enough to allow proton abstraction from C2 and O-alkylation predominates.
In Table 4.6 some of the results are shown for the reaction of 2-hydroxy
96 OH CH2R NaH, DMF, OH -15 oC, O RCH X O 4.39 2
Trial Halide Prodcut yield, %
1 CH2=CHCH2Br R = CH=CH2 56
2R = CH=CMe2 60 Br
Br 3 40
R =
CH2Br
4 R = 45
Table 4.6 Alkylation Products from 4.39
cyclooctanone 4.39 with NaH, and an allylic or benzylic halide in DMF at -15 oC. In all of the cases presented, only C-alkylation was observed. When 2-hydroxycyclooct-
5-enone 4.40 was reacted according to the predescribed conditions, only O-alkylation ensued. A select few of the results found are shown in Table 4.7. Due to the
97 OH CH2R NaH, DMF, -15 oC, O RCH X O 4.40 2
Trial Halide Prodcut yield, %
1 C6H5CH2Br R = C6H5 50
- 2RR = p-CF3C6H4CH2Br = p-CF3C6H4 51
Br 3 43
R =
CH2Br
4 R = 69
Table 4.7 Alkylation Products from 4.40
interesting change in selectivity when a unit of unsaturation was added within the ring system, we set out to ascertain if O- or C-alkylation would persist as the olefin linkage was moved around the cyclooctane ring system.
98 4.5 O- VERSUS C-ALKYLATION IN MEDIUM RING α,β-UNSATURATED
HYDROXY KETONES, HYDROXY KETONE 4.42
In order to answer the question of selectivity of alkylation, the first compound
we wished to test was 2-hydroxycyclooct-7-enone. Based on the previously
discussed publication by the Trost group, this compound was expected to be quite
easy to synthesize. However, when epoxide 4.41 was oxidized with DMSO and
triflic acid, neither hydroxy ketones 4.42 or 4.43 were produced (Scheme 4.2). The
O O OH HO O HO OH
DMSO, or TfOH, Eti-Pr2N
4.41 neither were produced 25% 4.42 4.43 4.44
Scheme 4.2 Synthesis of trans Diol 4.44
only product isolated was trans diol 4.44 in 25% yield. Interestingly, in the Trost
publication it was mentioned that some of the diol was sometimes recovered,
although as a minor product.
In an attempt to synthesize 4.42 and or 4.43, diol 4.44 was reacted with IBX
in the hope that one hydroxyl could be oxidized over the other, or at least the two isomeric dihydroxyketones would be separable. Unfortunately, oxidation of diol 4.44 with IBX was unselective and it appeared that once a hydroxyketone was synthesized it was far more susceptible to oxidation than the starting diol (Scheme 4.3). Due to
99 HO OH O OH HO O O O
IBX, DMSO, THF, 68% + +
4.44 4.42 4.43 4.45 (4%) (4%) (91%)
Scheme 4.3 Oxidation to a Mixture of Isomers
these circumstances, the reaction conditions produced a 1:1:20 ratio of products, where diketone 4.45 was the major product and the isomeric hydroxyketones were inseparable from each other.
By stirring the reaction mixture of diol 4.44 and IBX for longer times, complete formation of the diketone was achieved (Scheme 4.4). The diketone was
HO OH O O O OH HO O
IBX, DMSO, THF, EtOH, NaBH , 4 + 68% CeCl3·7H2O
4.44 4.45 4.42 4.43 no selectivity
Scheme 4.4 Reduction Gives a 1:1 Isomeric Mixture
then subjected to Luche conditions in the hope that only the α,β-unsaturated ketone would be reduced, which would give rise to only hydroxyketone 4.43. This, however, was not the case, and a 1:1 ratio of products was observed.
Since we were unable to selectively reduce one carbonyl group over the other, the following attempt was made to selectively protect one alcohol over the other.
100 Due to the lack of structural complexity, we did not expect any selectivity in which
alcohol would be protected and none was observed (Scheme 4.5). There was
HO OH TBSO OH HO OTBS TBSO O O OTBS
DMAP, imid, CH Cl , IBX, DMSO, 2 2 + + TBSCl, 18% THF, 100%
4.44 4.46 4.47 4.48 4.49 no selectivity THF, HF·pyridine TBAF, 87% THF, 100%
O OH HO O HO OH
TBAF, THF decomposition +
4.42 4.43 4.44
Scheme 4.5 Use of the TBS Protecting Group
however, a slight difference in polarity between the monoprotected alcohols.
Unfortunately, alcohols 4.46 and 4.47 were unseparable; therefore, the mixture of
alcohols was oxidized to give 4.48 and 4.49, which were also unseparable.
Previously, when a mixture of hydroxy ketones was encountered, there was a slight
possibility that separation could be possible. However, when a 1:1 mixture of α,β-
unsaturated hydroxyketones was synthesized by removal of the TBS protecting
group, separation was impossible. Interestingly, when the mixture of silyl ethers 4.48
and 4.49 were reacted with TBAF in THF, reduction to trans diol 4.44 was observed.
However, when HF•pyridine was used as the desilylating reagent, the desired
hydroxy ketones were recovered in 87% yield as an inseparable mixture of isomers
and were the only products. Out of general curiosity, we sought to find out if α,β- 101 unsaturated hydroxyketones 4.42 and 4.43, when subjected to TBAF, would be
unreactive or be reduced. To our surprise, upon the addition of TBAF, immediate
decomposition ensued.
The previous attempts had focused on the synthesis of two isomeric hydroxy
ketones, where hopefully they would be individually distinguishable by TLC. Since
this was not the case, we focused our efforts on α,β-unsaturated hydroxy
cyclooctanone 4.42 exclusively, as shown in Scheme 4.6. The first attempt at enone
O O
PhSeCl, Et2O, SO2Cl2; NaHCO3, 46%
4.50 4.51 O OH
LHMDS, THF, TMSCl, LHMDS, THF, NBS, CH Cl , 82% 2 2 TMSCl, m-CPBA, CH2Cl2, 72%
O Br O 4.42
LiBr, Li2CO3, DMF, 85%
4.52 4.51
Scheme 4.6 Synthesis of α,β-Unsaturated Hydroxy Cyclooctanone 4.42
4.51 was begun with cyclooctanone, which was reacted with phenylselenyl chloride,
followed by the addition of thionyl chloride.62 The selenium reaction gave 46% on small scale; however, when larger quantities were used the reaction was quite problematic, where only a yield of 8% was the highest ever obtained. Due to the difficulties with the selenium chemistry, and the expense of phenyl selenyl chloride, a 102 more simple approach was undertaken. The enone of ketone 4.50 was trapped as the
TMS silyl enol ether, followed by the addition of NBS. The ketone of bromide 4.52 was again trapped as the TMS silyl enol ether, followed by the addition of mCPBA to yield hydroxy ketone 4.42 as a single isomer and in 50% yield over three steps.
Since some of hydroxy ketone 4.42 still existed as the TMS ether, simply stirring the reaction mixture in 10% HCl for one hour was efficient enough to liberate the trimethyl silyl protecting group. When TBAF was used to remove the TMS group, reduction to the unsaturated trans diol was observed, as previously mentioned.
Hydroxyketone 4.42 was then reacted with sodium hydride and benzyl bromide in DMF at -15 oC to see whether O- or C-alkylation would dominate.
However, the only product produced was diketone 4.45 (Scheme 4.7). Presumably, a
O OH O OH O O Ph DMF, NaH, BnBr, -15 DMF, NaH, BnBr, -15 o o C, Ar, 20% C, O2, 100%
4.53 4.42 4.45
Scheme 4.7 Oxidation with Molecular Oxygen and Sodium Hydride
reaction had occurred between the substrate and a molecule of oxygen to produce diketone 4.45. Thereby, when all three substances used in the reaction were efficiently degassed with argon, the reaction exclusively generated C-alkylated compound 4.53.
103 Since large amounts of hydroxy ketone 4.42 were now accessible, undergraduate Phil Mahr completed the reactions of hydroxyketone 4.42 with various allyl and benzyl halides (Table 4.8). Phil was able to increase the yield of C-benzyl
O OH O OH O O R R
DMF, NaH, RCH2Br, -15 oC +
4.42 trial electrophile yield, % yield, %
Br 1440
21316Br
Br 3200
MeO
OMe
4100
Br
Table 4.8 O- versus C-Alkylation with Hydroxy Ketone 4.42
adduct 4.53 from 20% to 44%. Except for the reaction of hydroxy ketone 4.42 with allyl bromide, all three bromides gave way to exclusive C-alkylation. This was interesting since only O-alkylation was observed when the olefin was between C5 and
C6 of the cyclooctane ring system. Since allyl bromide is a better electrophile than
104 the other bromides tested, its reactivity could have overcome the selectivity of the reaction.
4.6 O- VERSUS C-ALKYLATION IN MEDIUM RING α,β-UNSATURATED
HYDROXY KETONES, HYDROXY KETONE 4.43
Phil’s work with hydroxy ketone 4.42 completed one of the hydroxy ketone isomers. The next step was conversion of hydroxy ketone 4.42 into its isomer. The first attempt was to protect the free hydroxyl as an acetate (Scheme 4.8). Acetate
O OH O OAc HO OAc AcO OH
CH2Cl2, Et3N, Ac2O, MeOH, NaBH4, + DMAP, 70% CeCl3·7H2O
4.42 4.54 4.55 4.56
Scheme 4.8 Acetate Migration During Reduction
4.54 was then reduced under Luche conditions, which led to an inseparable mixture of isomers, due to a migration of the acetate. Since the acetate migrated under the reduction conditions, the less labile pivolate ester was the next protecting group tried.
However, after three separate attempts utilizing the same conditions used to form acetate 4.54, only decomposition was observed. Reaction of hydroxy ketone 4.42 with PMB imidate possibly produced the PMB ether; however, both NMRs were to
105 cluttered to know for sure. This being the case, the impure ketone was reduced, under
Luche conditions, but no product was found with a PMB ether.
The next protecting group used was TBDPS. This reaction yielded the
protected product, but the yield was lower than expected and the reaction was messy,
so a switch to TBS was made. In Scheme 4.9, TBS ether 4.57 was synthesized in
O OH O OTBS HO OTBS
DMAP, imid, CH2Cl2, MeOH, NaBH4, o TBSCl, 50% 0 C,CeCl3·7H2O, 66% 4.42 4.57 4.58
Et3N, Ac2O, DMAP, CH2Cl2, 97%
HH RO OR' AcO OTBS
24 h TBAF, THF, THF, HF·py 80% ?
4.44 R = H, R' = Ac 4.59 R = Ac, R' = H 1:1
Scheme 4.9 The TBS Route
50% yield. Interestingly, although the reaction went to completion by TLC, after
column chromatography the yield was never more than 50% of compound 4.57.
Ketone 4.57 was then reduced under Luche conditions and the free alcohol was protected, to furnish acetate 4.59. At this point the idea was to remove the TBS protecting group, oxidize the free hydroxyl, and remove the acetate to give the final product. However, when the TBS ether was cleaved with TBAF in THF, the initial 106 product was a mixture of acetate isomers and if the reaction was allowed to run overnight, the product was trans diol 4.44. However, when HF•pyridine was used as the deprotecting agent, a more polar spot was observed in which no acetate, TBS protecting group, or alkene was present.
Due to the rearrangement of the acetate, under basic conditions, a switch was again made to the pivolate ester (Scheme 4.10). Reaction of free hydroxyl 4.58 with
HO OTBS PivO OTBS RO OR'
Et3N, PivCl, TBAF, THF or DMAP, CH2Cl2, 90% THF, HF·py 4.58 4.60 R = H, R' = Piv R = Piv, R' = H 1:1
Scheme 4.10 Rearrangement of Pivolate 4.60
pivaloyl chloride, DMAP, and triethylamine afforded pivolate ester 4.60 in 90% yield. However, again when the TBS ether was removed, with either TBAF or
HF•pyridine, the product was a mixture of isomers. At this point the efforts towards hydroxy ketone 4.43 were halted.
4.7 O- VERSUS C-ALKYLATION IN MEDIUM RING α,β-UNSATURATED
HYDROXYKETONES, HYDROXYKETONE 4.63 AND HYDROXY KETONE
4.64
107 The next set of isomers whose synthesis was attempted, were hydroxy ketones
4.63 and 4.64. To begin this synthesis, 1,3-cyclooctadiene was converted to its 1,4-
cyclooctadiene isomer 4.62, according to a literature procedure (Scheme 4.11).63
OH O O OH 1. NBS, AIBN; + AgOAc, AcOH 2. LiAlH4, Et2O 1. mCPBA, 4.61 4.62 CH2Cl2, 59% 4.63 4.64 2. TfOH, DMSO; Et2NiPr, 50% OH OH
4.65
Scheme 4.11 Conversion of Diene 4.62 into Diol 4.65
Diene 4.62 was then epoxidized with mCPBA to yield the mono-epoxide, which was
reacted according to the Trost protocol. Unfortunately, the reaction led to formation
of diol 4.65 in 50% yield without the observance of any hydroxy ketone present.
Since the previous attempts to convert a diol into a hydroxy ketone proved fruitless,
this route was halted.
Another avenue attempted towards this isomer, was to utilize dithiane
chemistry and use Grubbs ring closing methodology to form the cyclooctene ring system (Scheme 4.12). Dithiane 4.66 was reacted with n-BuLi and allyl bromide,
108
THF, n-BuLi, 17% (84% THF, n-BuLi, allyl SS brsm) SS bromide, 86% SS OHC(CH2)4CH=CH2
4.66 OH 4.67 4.68
Grubs II, 2,6-lutidine, CH Cl , 2 2 CH2Cl2, or TBSOTf, 84% toluene SS Grubs II, CH Cl , or no reaction 2 2 toluene OTBS no reaction 4.69
Scheme 4.12 Attempts at Dithiane Chemistry and Grubbs Ring Closing Metathesis
which afforded adduct 4.67. This adduct was again reacted with n-BuLi and hex-5-
enal to afford diene 4.68. The first attempt to cyclize via Grubbs methodology gave
no reaction after a few days with Grubbs second generation catalyst.64 On this system
there was no reaction, not even when the reaction solvent was changed to toluene.65
Since the free alcohol could be the cause of some of the problems, it was protected as a TBS ether and compound 4.69 was again subjected to ring closing metathesis in dichloromethane, followed by toluene, both of which resulted in recovered starting material. Due to the complete unreactivity of the system towards the Grubbs catalyst, the dithiane must have acted as a poison, rendering the catalyst useless. Attempts to remove the dithiane led to product decomposition and the reaction pathway was halted.
109 4.8 CONCLUSION OF THE O- VERSUS C-ALKYLATION PROJECT
Although many of the routes attempted in the synthesis of various hydroxy ketones ended in defeat, there were many positive results. A route was developed for the synthesis of hydroxy ketone 4.42, which Phil reacted with various benzyl and allyl bromides. These reactions showed predominately C-alkylation and provided valuable insight into the effect the olefin has in different positions around the ring system. Current research is being undertaken to finish the project with the synthesis of different medium-ring hydroxy ketones.
110
CHAPTER 5
TOWARDS THE TOTAL SYNTHESIS OF SALICIFOLINE
5.1 BACKGROUND AND RETROSYNTHESIS
During the past 30 years, plants from the genus Euphorbia have been the
focus of many chemical and pharmacological studies as a consequence of the
extensive range of biological activities the natural products exhibit. These
pharmacological properties include, but are not limited to antiviral, antitumor, protein
kinase C activating, and various vascular effects.66 In 2001, the Hohmann group published the isolation and structure elucidation of two novel diterpene polyesters from the plant Euphorbia saliciforia, one of which was salicifoline (Figure 5.1).67
O AcO O O
O Pri H AcO OAc AcO HO AcO OAc Salicifoline
Figure 5.1 Natural Product Salicifoline
111 Salicifoline is one of a new class of diterpenes, which possess a tricyclic skeleton and are cembrene cation-derived. The host plant was collected in Budapest, Hungary and the structure was elucidated using various NMR techniques.
Retrosynthetically, salicifoline is an extremely interesting molecule to try to synthesize. The core structure contains two fused 8-membered rings, a feature that is quite unique in the realm of natural products. Additionally, salicifoline has seven ester functionalities attached to its core structure. These considerations and the structural complexity of the natural product are more than sufficient cause to warrant an attempt at its total synthesis.
Shown in Figure 5.2 is the retrosynthetic route in which we will try to
112 O O AcO O AcO O O RCM & O epoxidation O AD (H3C)2HC (H3C)2HC H H AcO OAc AcO OAc AcO HO AcO O AcO OAc TES AcO OAc Salicifoline 5.1
PMBO PMBO O O PMBO O O O O RCM OPMB & BnO AD BnO AD OTBDPS H H BnO AcO OAc AcO AcO O AcO HO AcO H TES AcO OAc AcO OH OTBS 5.2 5.3 5.4
PMBO O O OPMB OPMB zirconium-mediated ring contraction BnO NHK + BnO OTBDPS CHO MeO O I AcO 5.6 5.7 OTBS 5.5
Figure 5.2 Retrosynthesis of Salicifoline
synthesize salicifoline. The final transformation in the synthesis of salicifoline will be the epoxidation of olefin 5.1, which will likely proceed from the less hindered exo surface. The lone carbonyl in compound 5.2 will be introduced via a four-step sequence involving a ring closing metathesis reaction followed by a Sharpless dihydroxylation, with ensuing protection and oxidation.68 Diene 5.2 will be synthesized in much the same way as ketone 5.1, with a ring closing metathesis reaction followed by a Sharpless dihydroxylation. For the synthesis of diene 5.3, another Sharpless dihydroxylation reaction will be used to install the bridgehead hydroxyl, whereafter, one double bond will be synthesized via a Wittig reaction and 113 the second through a dehydration.69 The initial core of salicifoline, represented by
5.4, will be synthesized through application of a Nozaki-Hiyama Kishi reaction
between vinyl iodide 5.5 and aldehyde 5.6 in the presence of catalytic chromium and
nickel.70 Finally, aldehyde 5.6 will be realized from a zirconium-mediated ring
contraction of 5.7, which is synthesized from commercially available methyl α,D- glucopyranoside.71
5.2 EFFORTS TOWARDS THE SYNTHESIS OF VINYL IODIDE 5.5
Vinyl iodide 5.5 was to be synthesized by coupling of vinyl bromide 5.8 with
aldehyde 5.9 (Figure 5.3). The route towards salicifoline thus began with the
PMBO O O PMBO OHC + Br OTBDPS OTBDPS I 5.8 5.9 OTBS 5.5
Figure 5.3 Coupling of 5.8 and 5.9 to Synthesize Vinyl Iodide 5.5
synthesis of aldehyde 5.9. The first attempt at 5.9 began with monoprotection of
ethylene glycol with TBDPSCl, followed by reaction of the free hydroxyl in an SN2 reaction with iodine and triphenylphosphine (Scheme 5.1). These reactions gave 5.11
114 OH TBDPSCl, imid, OTBDPS PPh3, I2, imid, OTBDPS HO DMAP, DCM, 90% HO THF, 0 oC, 87% I 5.10 5.11
NC
LiNEt , OTBDPS 2 isobutyronitrile 5.12 1 eq isobutyronitrile = 10% 3 eq isobutyronitrile = 11%
Scheme 5.1 First Attempt at Cyano Compound 5.12
in high yield. However, when the isobutyronitrile anion was treated with iodide 5.11, the reaction was sluggish at best. Even when larger amounts of the base and nucleophile were used, little improvement was observed and almost all of the starting material was recovered. Although the results were unsatisfactory, they demonstrated that the steric bulk of the gem-dimethyl and TBDPS protecting groups, when forced into a small locale, would not allow for the ready formation of nitrile 5.12.
Although the reaction between isobutyronitrile and iodide 5.11 probably could have been pushed to completion by a large excess of the anion, this would have been wasteful. Therefore, an alternative route was envisioned whereby 5.12 would be synthesized. This new approach would be one step longer, but the bulky isobutyronitrile anion would be introduced in the first step (Scheme 5.2). To
115 NC NC LiNEt , 99% O , DCM; CN 2 3 Ph P, 99% Br 3 O
5.13 5.14 5.15
DCM, NaBH4, 99%
OHC NC NC
DIBAL-H, TBDPSCl, Et3N, THF, 99% OTBDPS OTBDPS CH2Cl2, 80% OH
5.17 5.12 5.16
Scheme 5.2 Second Route to Cyanide 5.12
commence the synthesis on the second route, isobutyronitrile was again deprotonated, except this time it was reacted with allyl bromide. This reaction produced 5.14 in
almost quantitative yield. The acquisition of 5.14 was followed by ozonolysis and
subsequent reduction to form 5.16 in 98% overall yield. Finally the free hydroxyl
was protected with TBDPSCl to generate 5.12. This new synthetic route proceeded
in an overall yield of almost 80%, where the overall yield of the previous route was only 9%. Aldehyde 5.17 was obtained by the reduction of nitrile 5.12 with DIBAL-
H. As 5.17 is somewhat unstable, material was kept as the cyanide stage until vinyl bromide 5.8 was ready for the coupling reaction.
The synthesis of 5.8 was initiated with the protection of commercially available (S)-2-methyl-3-hydroxypropionate with PMB imidate (Scheme 5.3). The
116
HO PMBO PMBO CSA, CH Cl , LiAlH4, Et2O, 2 2 o PMBimid, 80% 0 C, 95% CO2Me CO2Me OH
5.18 5.19 5.20
Scheme 5.3 Synthesis of Alcohol 5.20
PMB protection of 5.18 was followed by reduction of the methyl ester to generate
5.20.
Oxidation of 5.20 under Swern conditions generated aldehyde 5.21, which was subjected to a Corey-Fuchs reaction to produce dibromide 5.22 (Scheme 5.4).72
PMBO
PMBO PMBO Swern, 93% CBr4, PPh3, Et3N, CH2Cl2, 83% OH O Br Br 5.20 5.21 5.22
B-bromo-9-BBN, AcOH, PMBO no reaction; only PMB NaOH, H2O2 n-BuLi, THF, 80% deprotection and decomposition NaI, TMSCl, H2O, CH3CN
5.23
Scheme 5.4 Decomposition During Vinyl Halide Synthesis
117 Dibromide 5.22 was subsequently transformed into alkyne 5.23 with n-BuLi in THF.
At this point two different halovinylation reactions were attempted.73 In both cases;
however, the PMB protecting group was cleaved. This system is apparently
somewhat sensitive towards acid. Removal of the PMB in the first reaction was not
surprising given that it was quenched with acetic acid. Although only a small amount
of HI is generated in the second reaction with sodium iodide, cleavage of the PMB
ether rather than formation of the vinyl iodide was again noted.
Since formation of the vinyl halide was so problematic, we searched the
literature for an alternative route. Although we would have liked to develop our own
route towards the synthesis of the vinyl halide, two publications which detailed the
synthesis of this desired compound were discovered (Scheme 5.5).74 The published
HO PMBO PMBO PMBimidate MeONHMe·HCl CSA AlMe3, CH2Cl2 CO2Me CO2Me O MeON 5.17 5.18 Me 5.24
PMBO PMBO n-BuLi, i-Pr NH, MeLi, THF; Br 2 OTf THF, Bu3SnH, CuCN; LHMDS, THF, CH2Cl2, NBS PhN(SO2CF3)2 5.26 5.25
Scheme 5.5 A Published Route for Vinyl Bromide 5.2674
procedures allowed for easy access to vinyl bromide 5.26 in very good overall yield.
In the new route PMB ester 5.19 was converted into the Weinreb amide and reacted
with methyllithium, where the enolate anion was trapped with N-phenyl triflimide.
118 The enol triflate is then subjected to two exchange reactions, first to the vinyl tin
species and then to desired vinyl bromide 5.26.
As 5.26 was now quite easy to synthesize, cyanide 5.12 was reduced to the
aldehyde with DIBAL-H in preparation for the coupling reaction. Coupling of the
two minor fragments generated the major backbone of 5.5. Reaction of the substrates
with n-BuLi in THF produced a 3:1 diastereomeric ratio of alcohols 5.27 and 5.28
(Scheme 5.6).75 The isomeric alcohols proved separable by column chromatography.
PMBO OH PMBO OH Et O, t-BuLi; 50% PMBO 2 + Br OHC
OTBDPS OTBDPS OTBDPS 5.26 5.17 top spot, major product 36% bottomspot, minor product 14% 5.27 5.28
Sharpless, 0 oC or CH2Cl2, TBHP, Vo(acac)2, rt, 75%
PMBO OH
O
OTBDPS
5.29
Scheme 5.6 Coupling of Aldehyde 5.17 and Vinyl Bromide 5.26
The more polar of the two isomers was the major product and was used for the
following reactions. Alcohol 5.27 was then subjected to a Sharpless epoxidation reaction at 0 oC, where after about a week, only one product was formed in 15%
119 yield. Since the Sharpless epoxidation reaction of 5.27 was extremely slow and
inefficient, the alcohol was also epoxidized with VO(acac)2, which gave the same
epoxide.76 The absolute configuration of the stereogenic centers are inconsequential at this point because the centers are later removed and do not influence any other stereocenters generated throughout the synthesis.
Although the stereochemistries of the free alchol and epoxide are irrelevant, it is not appropriate to leave stereocenters ambiguously defined. Epoxide 5.29 was therefore reacted with TBAF in THF to remove the TBDPS protecting group in the hope that a crystalline solid would be formed. However, the product proved to be a colorless oil (Scheme 5.7). Diol 5.30 was therefore reacted with 3,5-dinitrobenzoyl
PMBO OH PMBO OH TBAF, THF, 3,5-dinitrobenzoyl chloride, O O 79% DMAP, Et3N, CH2Cl2, 79%
OTBDPS OH
5.29 5.30
O NO2
PMBO OH PMBO O
O 3,5-dinitrobenzoyl chloride, O pyr, DMAP, 81% NO2 O O O O
5.31 5.32
O2N NO2 O2N NO2
Scheme 5.7 Unsuccessful Attempts at Crystallization
120 chloride to afford nitro compound 5.31. This substrate was again not a solid. Lastly,
one more 3,5-dinitrobenzoate was added onto the scaffold of compound 5.31, but
again, only an oil was produced. Since we were unable to form a crystalline solid,
work was shifted toward completing the synthesis of vinyl iodide 5.5.
The plan was to open the terminal epoxide with the anion of a THP-protected
propargyl alcohol in the presence of BF3•OEt2. When the reaction was performed, a more polar spot was seen by TLC.77 However, what was thought to be the result of addition of the alkyne was in fact the more substituted epoxide, which wasdue to a
Payne rearrangement (Scheme 5.8). The mass spectral data showed the presence of
PMBO OH PMBO OH OH
O BF3OET2, n-BuLi, THF, 98%
OTBDPS OTHP OTBDPS THPO 5.29 > 1%
5.33
+
PMBO PMBO O O
2,2-dimethoxypropane p-TsOH, 86% O OTBDPS HO OTBDPS MeO 5.35 5.34
Scheme 5.8 An Interesting Payne Rearrangement
some of the desired adduct; however, this was minor relative to epoxide 5.34. The
latter was reacted with 2,2-dimethoxypropane in the hope that there was more of diol 121 5.33 in the mixture than expected. Unfortunately only methyl acetal 5.35 was found by both NMR and mass spectrometry.
With the knowledge that the free hydroxyl could pose a problem with nucleophilic addition of the alkyne, a search for proper conditions for its protection and alkyne addition to the epoxide was undertaken. The first conditions consisted of pivaloyl chloride as the protecting agent. There was no reaction as this was probably too large of a protecting group to be alpha to the gem dimethyl group (Scheme 5.9).
PivCl, DMAP, Et3N, PMBO no reaction OH CH2Cl2
O
OTBDPS PMBO OEE 5.29 CH2Cl2, PPTS, vinyl ethylether, 90% O
OTBDPS
5.36
Scheme 5.9 Protecting Groups and Problems
The next attempt involved the EE (ethoxy ethyl) protecting group. This protection
did proceed. However, the yield was low and the protecting group has a racemic
center, which caused problems during characterization and purification. Although
the yield of EE protected compound 5.36 was low, it was reacted with the lithiated
alkyne (Scheme 5.10). Temperatures ranging from -78 oC to reflux yielded no
122 PMBO OEE THF, n-BuLi, BF ·Et O, O 3 2 no reaction rt-reflux THPO OTBDPS 5.36
PMBO OH PMBO OBz
O py, DMAP, O THF, n-BuLi, BF3·Et2O, BzCl, 92% rt-reflux 5.29 OTBDPS OTBDPS THPO 5.29 5.37
Scheme 5.10 Two Failed Protecting Groups
product and the starting material was completely recovered. Alcohol 5.29 was also
protected as a benzoate. However, when benzoate 5.37 was reacted with the alkynyl anion, cleavage of the protecting group was observed to afford 5.29. When the reaction was performed anywhere between -78 oC and 0 oC, no reaction was
observed, but when it was allowed to warm to room temperature the benzoate was
cleaved.
The next protecting group that was attempted was a MOM ether.
Unfortunately, under a variety of different reaction conditions the MOM ether
product was unable to be installed. When NaH was used as a base, the TBDPS
protecting group was lost and when MOMCl, NaI, DIPEA, and THF were used, only
decomposition was observed. A change was then made to use the MTM (O-methoxy
thiomethyl) protecting group (Scheme 5.11). Under both sets of conditions presented
123 PMBO OH PMBO O DMSO, Ac O, 84% O 2 O
DMSO, Ac2O, OTBDPS AcOH, 50% OTBDPS 5.29 5.38
PMBO OH PMBO OBOM BOMCl, DIPEA, Bu NI, CH Cl , 4 THF, n-BuLi, BF ·Et O, O 4 2 2 O 3 2 no reaction days, 63% rt-reflux OTBDPS OTBDPS THPO 5.29 5.39
PMBO OH PMBO OTBS
TBSOTf, CH Cl , THF, n-BuLi, BF ·Et O, O 2 2 O 3 2 no reaction 2,6-lutidine, 98% rt-reflux OTBDPS OTBDPS THPO 5.29 5.40
Scheme 5.11 BOM and TBS Protecting Groups and Oxidation
in Scheme 5.11, oxidation to the ketone, not protection, was observed.78 The
conditions presented are the same as those used to oxidize alcohols to ketones;
however, with a little acid present the reaction is supposed to stop as the MTM
protecting stage. This did not happen in our case. Next, BOM protected 5.39 was
synthesized, where the reaction took 4 days at room temperature and still only yielded
63% of the desired product. When the alkynyl anion was added to the epoxide no
change was seen by TLC, even after refluxing overnight. The same was true with
TBS-protected 5.40, where no reaction was observed, even after refluxing. At this
point, the only time that any reaction had been observed between the epoxide and
alkynyl anion was when the hydroxyl group was unprotected, where the major
product was due to a Payne rearrangement. It is interesting that none of the previous reactions have shown any reaction with the alkynyl anion. One reason for this is that 124 the site of attack at the epoxide is too hindered, but that does not seem very probable.
Another reason for the lack of reaction could be that the secondary hydroxyl of 5.29
could first undergo a Payne rearrangement followed by protection of the new primary
alcohol. In any case, either of the protected compounds would be virtually
indistinguishable from its isomeric structure.
Assuming that there was too much steric hindrance around the site of attack,
we attempted to dihydroxylate the double bond, where the primary alcohol could be
protected as a mesylate, the remaining hydroxyls would be protected as an acetonide,
and the alkynyl anion could displace the mesylate. In Scheme 5.12, three failed
PMBO OH PMBO OH OH
HO OTBDPS OTBDPS 5.27 5.41
trial conditions time equivalents of osmium reaction outcome
1 Ad-mix-b, K2CO3, K3Fe(CN)6, t- 2 days 0.02 no reaction BuOH, H2O
2 H2O, acetone, py, OsO4 2 days 1.1 no reaction
3 CH2Cl2, TMEDA, OsO4 7 days 1.2 no reaction
Scheme 5.12 Attempts at Dihydroxylation
attempts at dihydroxylation are shown. Three attempts were made, where only
starting material was recovered after varying the reaction conditions, length of time, and equivalents of osmium. Even under the most forcing conditions for the third trial, no product was formed after seven days.79
125 Since the dihydroxylation reactions did not work, an alternative way to obtain
the triol would be to open the α-hydroxy epoxide with base. When a strong aqueous
base is reacted with a primary epoxide, a diol is often formed. However, in our
system, when a strong aqueous base was used, a Payne rearrangement occurred to
yield a relatively hindered epoxide, which halted any further reaction (Scheme
5.13).80 The reaction presented in Scheme 5.13 was performed at 70 oC for 24 hours.
PMBO PMBO OH O
O H2O, t-BuOH, 3M NaOH, 100% HO OTBDPS OTBDPS 5.29 5.34
Scheme 5.13 Payne Rearrangement over Epoxide Opening
After 24 hours 100% of 5.34 was recovered.
As it appeared that formation of the desired triol was not going to be possible,
we envisioned that the nucleophile might be more reactive toward a ketone.
Therefore, as shown in Scheme 5.14, alkene 5.27 was reacted with ozone to give
126 PMBO OH PMBO OH PMBO OP
O3, CH2Cl2; PPh3, 45% O O OTBDPS OTBDPS OTBDPS 5.27 5.42
trial conditions reaction outcome
1 CH2Cl2, 2,6-lutidine, TBSOTf decomposition
2 2,2-dimethoxy propane, p-TsOH decomposition
3 TBSCl, imid, DMAP, CH2Cl2 no reaction
Scheme 5.14 Ozonolysis, but Failed Protections
5.42. Three attempts thereafter to protect the hydroxyl substituent were met with failure. The first two conditions tried both led to decomposition, where the last one gave no reaction at all. It was at this point that I finished my contributions towards vinyl halide 5.5.
5.3 SYNTHESIS OF ALDEHYDE 5.6 THROUGH ACYCLIC CHEMISTRY
The first route towards the synthesis of aldehyde 5.6 was to generate zirconocene-mediated ring contraction precursor 5.7 from readily available methacrolein. Methacrolein first underwent a Wittig olefination with the methyl
(triphenylphosphoranylidene) acetate to generate methyl ester 5.44 (Scheme 5.15).
127 O H PPh CHCO Me, CH Cl , CO2Me 3 2 2 2 LiAlH4, Et2O, OH 63% 63%
5.43 5.44 5.45
Scheme 5.15 Synthesis of Diene 5.45
The resulting methyl ester was reduced with lithium aluminum hydride to afford
alcohol 5.25 in 63% overall yield. In both reactions, the products were somewhat
volatile, which could account for the moderate yields.
Alcohol 5.45 was reacted under Sharpless epoxidation conditions to generate epoxy alcohol 5.46 (Scheme 5.16),81 which was silylated with TBSCl in 95% yield,
128 O (+)-DET, 4A MS, CH2Cl2, OH Ti(O-iPr)4, t-BuOOH, OH Me2S, 57% DMAP, CH2Cl2, TBSCl, imid, 95% 5.45 5.46
O OH PMBBr, KHMDS, L-selectride, THF, 99% OTBS THF, 85% overall yield, 80% selectivity OTBS 5.48 5.47
OH OPMB OPMB
ADmix-b, K3(CN)6, K2CO3, t-BuOH:H2O OTBS (1:1), 89% HO OTBS ????
5.49 5.50
OH OPMB
O OTBS 5.51
Scheme 5.16 Synthesis of Hydroxy Aldehyde 5.51
where the epoxide was selectively opened with L-Selectride. The epoxide opening
occurred with 80% selectively and in 99% overall yield, where 19% of the product was the 1,3-monoprotected alcohol 5.48a (not shown). Alcohol 5.48 was protected by PMBBr in THF to give 5.49, which was subsequently dihydroxylated using the
Sharpless asymmetric dihydroxylation procedure with AD mix-β to yield 5.50 in 89% yield and with 78% diastereoselectivity. Unfortunately, the diastereomers, although easily seen by NMR, were unable to be separated by column chromatography. At this point it was assumed that eventually a transformation would occur in which there would be enough of a difference in polarity between the diastereomers that they could
129 be separated. The next step in the synthesis was to oxidize the primary alcohol to the aldehyde. This was more difficult than originally anticipated. The highest yield obtained (70%) materialized under Swern conditions. In Scheme 5.17, several
OH OH OPMB OPMB
HO OTBS O OTBS 5.50 5.51
Swern not complete
IBX not complete
Dess Martin not complete
PCC decomposition
Scheme 5.17 Various Oxidation Conditions
different oxidation conditions were tried, none of which led to complete conversion to aldehyde 5.51.
Although some of aldehyde 5.51 was synthesized, there was also an appreciable amount (usually a 1:1 ratio of 5.51 to 5.52) of aldehyde 5.52 present.
Aldehyde 5.52 results from a silyl migration of the TBS moiety during the oxidation reaction (Scheme 5.18). Unfortunately, aldehydes 5.51 and 5.52 were inseparable by
130 OH OH OH OPMB o IBX, CH3CN, 70 C, 72% OPMB OPMB + swern, 70% HO OTBS O OTBS TBSO O
5.50 5.51 1:1 5.52
Scheme 5.18 Silyl Rearrangement During Oxidation
column chromatography. Since silyl migration was a problem, a change from the
TBS to the pivalate protecting group was undertaken. The free alcohol in compound
5.50 was protected as an acetate and the TBS was removed with TBAF to furnish diol
5.53 (Scheme 5.19). The free primary alcohol of 5.53 was protected as a pivalate
OH OH OH OPMB OPMB OPMB 1. CH2Cl2, Ac2O, 1. PivCl, Et3N, Et3N, DMAP CH2Cl2, DMAP 2. TBAF, THF 2. LiOH, MeOH HO OTBS AcO OH HO OPiv
5.50 5.53 5.54
Scheme 5.19 Changing of Protecting Groups
and the acetate was removed to give diol 5.54. With desired 5.54 in hand, oxidation
with IBX ensued. In this case, the reaction worked well, but yielded aldehyde 5.55 in
only 40% yield (Scheme 5.20). The next reaction was to protect the aldehyde as an
131 OH OH OPMB OPMB IBX, DMSO, HOCH2CH2OH, p- THF, rt, 40% TsOH, PhH PMBO OH HO OPiv O OPiv 5.54 5.55
Scheme 5.20 Oxidation to Aldehyde 5.55
acetal. When p-TsOH and ethylene glycol were added to aldehyde 5.55, the mono
PMB-protected ethylene glycol resulted.
Since the change in protecting groups allowed for the synthesis of 5.55, a new synthesis was begun where the pivalate would be installed in place of the previous
TBS moiety. The new route began again with the epoxide synthesized earlier via the
Sharpless reaction (Scheme 5.21). Alcohol 5.46 was protected as the TBS ether and
O O PivCl, DMAP, CH2Cl2, Et3N, 99% OH OPiv 5.46 5.56
1. TBSCl, imid DIBAL-H 2. DIBAL-H -78 oC, THF
some 1,3 reduction and Reduction of migration of the TBS epoxide and ester
Scheme 5.21 Problems with the Protecting Groups
the epoxide was opened with DIBAL-H. The reaction with DIBAL-H gave rise to a
mixture of products due to TBS migration. When 5.46 was protected as the pivalate
132 and further reacted with DIBAL-H, reduction of the pivalate ester ensued. Since the
epoxide opening, with various protecting groups was a problem, we decided to make
some slight modifications in the route as a result of a publication by the Kishi
group.82 In this publication, Kishi demonstrated that one can open an epoxide alpha to a free alcohol to selectively give the 1,2 diol, if the reaction is performed in benzene. The reaction worked on the first attempt and produced only diol 5.57
(Scheme 5.22). Since the diol was extremely water soluble, continuous extraction
O OH O benzene, DIBAL-H, rt; p-anisaldehyde, continous extraction, CSA, DMF, 81% PMP 77% OH OH O 5.46 5.57 5.58
CH2Cl2, DIBAL-H, 92% OH OPMB OPMB OPMB AD-mix-β, K2CO3, Et3N, DMAP, t-BuOH, H2O, PivCl, CH2Cl2, HO OPiv OPiv OH K3Fe(CN)6, 63% 99% 5.54 5.60 5.59
Scheme 5.22 New Route to 5.54
had to be performed to remove the product from the water layer. Diol 5.57 was then
protected as a PMP acetal, which was subsequently opened in a selective manner with
DIBAL-H to give primary alcohol 5.59 along with a trace amount of its isomer 5.59a
(not shown). Although this reaction on small scale was high yielding, upon scale-up
the yields took a dramatic hit. Alcohol 5.59 was first protected with TBSCl, but this
133 led to rearrangement, so it was then protected as a pivalate ester. PMB ether 5.60 was further dihydroxylated under Sharpless conditions to give diol 5.54 in a diastereomeric ratio of 4:1.
At this point, the primary alcohol needed to be oxidized and protected as an acetal and the tertiary alcohol needed to be protected as a benzyl ether. Since the free tertiary alcohol could hinder future reactions, we decided to protect it before oxidationto the aldehyde. The primary hydroxyl of diol 5.54 was protected as the acetate, where an attempt to protect alcohol 5.61 was now undertaken (Scheme 5.23).
OH OH OH OPMB OPMB DMF, NaH, BnBr, OPMB O CH2Cl2, Et3N, DMAP, Bu4NI Ac2O, 100% or Bn HO OPiv AcO OPiv KH, THF, BnBr O OPiv 5.54 5.61 5.62
Scheme 5.23 Benzylation of an Acetate
However, when compound 5.61 was reacted with benzyl bromide and base, deprotonation of the acetate ensued, which in turn attacked the benzyl bromide to give compound 5.62. Diol 5.54 was also oxidized under Swern conditions to the aldehyde, but the yield was low and since other problems within the scheme had appeared this pathway was halted.
At this point in the synthesis, there were a few issues that needed to be addressed. In the initial route, where the primary alcohol had been protected as a
TBS ether, there was migration upon oxidation to an aldehyde. This problem was remedied by a change in protecting group to a pivalate ester. However, with this
134 change it was extremely difficult to obtain a high yield of diol 5.57, due to its miscibility in water, and the Sharpless dihydroxylation still produced a 4:1 inseparable mixture of isomers.
It was envisioned that if a TBDPS protecting group could be used instead of a
TBS or pivalate, due to its sheer size, the Sharpless dihydroxylation would give better selectivity and the PMB acetal opening step could be removed. Therefore, some of the excess 5.45 from Scheme 5.22 was treated with DMAP and TBDPSCl in the presence of triethylamine to furnish protected olefin 5.63 (Scheme 5.24).
O O O
Et3N, DMAP, CH2Cl2, L-selectride, TBDPSCl, 85% THF, 99% OH OTBDPS OTBDPS
5.45 5.63 5.64
Scheme 5.24 Attempt at a Higher Yield Leads to 1,4-Reduction
Unfortunately, when compound 5.63 was reacted with L-Selectride to selectively open the epoxide, 1,4-reduction occurred. If the primary hydroxyl was protected with
TBS chloride, one could achieve selective epoxide opening. However, when the protecting group was much more bulky, attack occurred at the carbon β to the epoxide. Therefore, the previous route in Scheme 5.22, although low yielding, had to be used if TBDPS was chosen as the protecting group. Therefore, once the PMB acetal was selectively opened, alcohol 5.59 was protected with TBDPSCl, where the olefin was dihydroxylated under Sharpless conditions (Scheme 5.25). Unfortunately, 135
OH OPMB OPMB (DHQD)2PHAL, OPMB Et3N, DMAP, CH2Cl2, K2OsO2(OH)4, K2CO3, TBDPSCl, 83% K3Fe(CN)6, t-BuOH, H O, 56% OH OTBDPS 2 HO OTBDPS 5.59 5.65 5.66
Scheme 5.25 Failed Attempt at Better Selectivity Through a Larger Protecting Group
the diastereomeric ratio was still 4:1. Since immediate improvement was at hand,
diol 5.66 was further oxidized by reacting it with DMSO, THF, and IBX to furnish aldehyde 5.67, where no migration of the TBDPS was observed (Scheme 5.26).
OH OH OPMB OPMB TMSO(CH ) OTMS, I , IBX, THF, 2 2 2 decomposition DMSO, 49% CH2Cl2 HO OTBDPS O OTBDPS 5.66 5.67
TBAF, THF, 77%
OH OPMB DDQ, CH Cl , 2 2 decomposition H2O HO O 5.68
Scheme 5.26 The End of the Road for this Route Towards Compound A
Interestingly, although the starting material was a mixture of diastereomers, only one
of them reacted, as only a single aldehyde isomer was observed. However, even
136 under mild acetal forming conditions the PMB group was removed with ensuing decomposition.84 As this route also seemed to be a lost cause, two final reactions were performed. Removal of the TBDPS protecting group resulted in quick conversion to pyran 5.68. However, when pyran 5.68 was reacted with DDQ in dichloromethane and water to remove the PMB ether, decomposition ensued.
Therefore, based on all of the problems from the three previous routes and the fact that the product before the purposed ring contraction held many characteristics of a sugar derivative, we envisioned that the next synthetic route should start with a cheap and readily accessible sugar or sugar derivative.
5.4 SYNTHESIS OF ALDEHYDE 5.6 THROUGH SUGAR CHEMISTRY
The new route to aldehyde 5.6 began with commercially available methyl-α-
D-glucose 5.69. Although a PMP acetal was the desired protecting group, the synthesis of compounds 5.70 through 5.73 was known and was where we began our new synthetic route. Methylated glucose 5.69 was protected as a benzylidene acetal,85 where the C2 hydroxyl was selectively protected as benzoate 5.71 (Scheme
5.27).86 The alcohol was then treated with thiocarbonyl diimidazole, which yielded
137 HO O Ph O Ph O HO O Bu SnO; O PhCH(OMe)2, p-TsOH, O 2 O HO 100% BzBr, 79% HO HO OH OH OMe OBz OMe OMe 5.69 5.70 5.71
SC(imid)2; AIBN, 67%
Ph O Ph O Ph O O O NH , MeOH, O O DMSO, O 3 O 98% Ac2O, 86%
O OH OBz OMe OMe OMe 5.74 5.73 5.72
Scheme 5.27 The New Sugar Route
two isomeric Barton deoxygenation precursors (thiocarbonyl adducts 5.71a (59%) and 5.71b (7%) not shown), followed by treatment with AIBN and tributyltin hydride to removed the C3 alcohol.87 The benzoate group in 5.72 was then removed by stirring in saturated methanolic ammonia solution and heated to 50 oC for 12 hours in a sealed heavy walled flask. Finally, 5.73 was oxidized to ketone 5.74 with DMSO and acetic anhydride.88 However, compound 5.74 exists as the structure shown and its hydrate. This is a problem because when a water workup is used 5.74 is converted to the hydrate, which is water soluble. Another problem with this reaction is residual acetic acid and DMSO remain when the reaction is complete. Since the hydrated form of ketone 5.74 is fairly water soluble, a water extraction to remove the DMSO and AcOH leads to much lower yields, and the use of distillation to remove the
138 solvent leads to decomposition. Only on small scale can one achieve a yield over
80%.
The ketone was then reacted with methyllithium, where the majority of nucleophilic attack occurred from the axial direction to generate a ratio of 6:1 in favor of tertiary alcohol 5.76 (Scheme 5.28). Alcohol 5.76 was protected with benzyl
Ph O Ph O OH Ph O O O O O O O MeLi, Et2O, 52% + O OH OMe OMe OMe 5.74 5.75 5.76
BnBr, Bu4NI, DMF, 83%
PMP O HO Ph O O O O O HO O p-anisaldehyde dimethylacetal, pTsOH, toluene, p-TsOH, 99% MeOH, 90% OBn OBn OBn OMe OMe OMe 5.79 5.78 5.77
Scheme 5.28 First Synthesis of PMP Acetal 5.79
bromide to generate 5.77, where the benzylidene acetal was removed and the diol was reprotected as a PMP acetal.
Since the synthetic route at this juncture was fairly problem free, Scheme 5.27 was adapted to the PMP acetal protected derivative. In Scheme 5.29, the reactions
139 HO O PMP O PMP O HO MeO-PhCH(OMe) , p- O Bu SnO; O 2 O 2 O HO TsOH, 100% BzBr, 79% HO HO OH OH OMe OBz OMe OMe 5.69 5.80 5.81
SC(imid)2; AIBN, 50%
PMP O PMP O PMP O O O NH , MeOH, O O acetonitrile, O 3 O IBX, 90% 94%
O OH OBz OMe OMe OMe 5.84 5.83 5.82
MeLi, Et2O, 60%
PMP O PMP O O O O BnBr, Bu4NI, O DMF, 83% OH OBn OMe OMe 5.85 5.79
Scheme 5.29 Second Synthesis of PMP Acetal 5.79
presented paralleled those in Scheme 5.27 with the exception that when carbinol 5.83
was oxidized to ketone 5.84, the conditions used were IBX in warm acetonitrile and
the methylation of ketone 5.84 produced only one isomer. The oxidation of 5.83 is
quite delicate. If the acetonitrile is at room temperature no reaction occurs.
However, if the reaction mixture is heated to reflux, decomposition ensues.
The PMP acetal was then opened with TMSCl and sodium cyanoborohydride
to produce a 1:1 mixture of PMB protected alcohols. Earlier selective methods did
not give a reaction and if the current reaction is performed over 12 hours, complete
removal of the PMB protecting group is observed (Scheme 5.30). At this point, the
140 PMP O PMBO HO O O O O TMSCl, CH3CN, HO + PMBO NaCNBH3, 85% OBn OBn OBn OMe OMe OMe 5.79 5.86 5.87
IBX, CH3CN; Ph3PCH2Br, n- OBn BuLi, 28% OPMB O PMBO OBn
MeO O OMe 5.7
Scheme 5.30 Synthesis of Zirconium-Mediated Ring Contraction Precursor 5.7
isomers were separated and desired compound 5.87 was oxidized to the aldehyde with IBX and acetonitrile and converted to the mono-substituted alkene via a Wittig reaction. These consecutive reactions produced zirconium-mediated ring contraction precursor 5.7, where the ring contraction was the next step.
The key step was performed in THF at room temperature to provide cyclopentane 5.87 in 10% yield when 14 milligrams was used (Scheme 5.31). Also
141 OBn OBn OPMB OPMB
Cp2ZrCl2, n-BuLi, THF; Bf3•OEt2, 10%
MeO O HO
5.7 5.87
OBn OPMB PMBO Cp Zr O Cp MeO O Zr Cp BnO Cp
Scheme 5.31 Zirconium Mediated Ring Contraction
shown in Scheme 5.31 is the proposed mechanism by which the ring contraction occurs. Initially a metalocene is formed, followed by alkene formation and ejection of the pyran oxygen atom prior to loss of methoxide. Lastly a Lewis acid is added and the ring contracts upon itself pushing out the zirconium species and the new ring system is formed. With the success of the ring contraction, albeit in moderate yield, the sugar route has been proven successful and this is where the project currently stands.
5.5 CONCLUSION OF THE SALICIFOLINE PROJECT
In conclusion, after eight months of work there has been reasonable headway towards the total synthesis of salicifoline. The route towards 5.5 is over halfway
142 complete with the completed synthses of 5.17 and 5.26, and the installation of the alkyne is close at hand (Scheme 5.32). The synthesis of aldehyde 5.6 is also
PMBO PMBO OH Br Et2O, t-BuLi; 50% 5.5 OHC
5.26 OTBDPS OTBDPS 5.27 5.17
HO PMP O 1. MeLi; BnBr O 1. MeO-PhCH(OMe)2 O HO 2. Bu2SnO, BzBr O 2. TMSCl, NaCNBH3 3. NH , MeOH HO 3. SC(imid)2, AIBN 3 4. IBX OH 4. NH3, MeOH O 5. Cp ZrCl ; BF •OEt OMe 5. IBX OMe 2 2 3 2 5.69 5.84
OBn OBn OPMB OPMB 1. Protection 2. Ozonolysis O HO AcO
5.87 5.6
Scheme 5.32 Current Synthetic Route
extremely close to completion,where the free hydroxyl in 5.7 will be protected as an acetate and the alkene will be cleaved by ozonolysis to yield the aldehyde. In closing, the approach to both 5.5 and 5.6 are considered to be close to completion. The reaction between them will form a major part of the scaffold of the natural product salicifoline.
143
CHAPTER 6
EXPERIMENTAL SECTION
All reactions were performed in the appropriate oven-dried glass apparatus
under a static N2 or Ar atmosphere. Solvents were reagent grade and in most cases
properly dried before use. All reagents were obtained commercially as reagent grade
and, unless otherwise noted, used without further purification. Thin-layer
chromatography was performed on precoated silica gel 60 F254 analytical plates. The
organic extracts were dried over anhydrous MgSO4. The column chromatographic
purifications were performed on silica gel (230-400 mesh).
Optical rotations were measured using a Perkin-Elmer Model 241 polarimeter
at 589 nm with a Na lamp and concentrations are reported in g/100 mL. A Perkin-
Elmer 1600 Series FT-IR spectrophotometer was used to record infrared spectra and absorptions are reported in reciprocal centimeters (cm-1). Proton (1H) and carbon
(13C) nuclear magnetic resonance spectra were recorded on Bruker DPX-250, AC-
300, DPX-400, and DPX-500 respectively. Chemical shifts are reported in parts per
million (ppm, δ) with the residual non-deuterated solvent as an internal standard; 7.26 ppm for chloroform and 7.16 for benzene. Splitting patterns are designed as follows:
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. High-resolution mass spectra
144 were recorded at The Ohio State University Campus Chemical Instrumentation
Center or at Chemistry Department Mass Spectrometry Facility.
Cl A solution of PPh3 (136 mg, 0/52 mmol, 2.0 eq) and DIAD (90
N N OTBS μL, 0.47 mmol, 1.8 eq) in THF (2 mL) was stirred for 30 min. N N The solution was added to 1.10 (70 mg, 0.26 mmol, 1 eq) in
THF (2 mL) and stirred for 30 min when DMF (1 mL) and 6-chloropurine (80 mg,
0.52 mg, 2.0 eq) were added. The reaction mixture was stirred for 24 h at rt,
quenched with aqueous saturated NaHCO3 solution, and extracted with Et2O (3 x 25
mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo, and the residue was purified by column chromatography on silica gel (10:1
hexanes:ethyl acetate) to give 1.13 as a white solid (mp 91-93 oC, 31 mg, 31%);
20 [α] D -39.8 (c 1.3, CHCl3); IR (neat) ν = 2857, 1590, 1557, 1335, 1256, 1111, 635
-1 1 cm ; H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.24 (s, 1H), 5.06-5.01 (m, 1H),
3.90 (t, J = 6.6 Hz, 1H), 2.43-1.45 (m, 12H), 0.94 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H);
13 C NMR (75 MHz, CDCl3) ppm 152.2, 152.0, 151.3, 143.8, 132.3, 79.3, 56.3, 53.2,
42.9, 36.8, 32.6, 32.5, 29.8, 26.2 (3C), 19.9, 18.4, -3.8, -4.4; ES HRMS m/z (M +
+ Na) calcd 429.1847, obsd 429.1857; Rf 0.13 (5:1 hexanes:ethyl acetate).
NH2 Into a 15 mL high-pressure vial were added MeOH (4 mL)
N N and 1.13 (31 mg, 0.08 mmol), and the solvent was saturated OTBS N N with gaseous NH3 for 0.5 h. The vial was sealed and stirred
145 at 80 oC for 24 h. Upon completion, the reaction mixture was allowed to come to rt
and concentrated in vacuo, and the residue was purified by column chromatography
on silica gel (2:1 ethyl acetate:hexanes) to give 1.14 as a white solid (mp 140-142 oC,
20 29 mg, 91%); [α] D -40.8 (c 0.8, CHCl3); IR (neat) ν = 1651, 1599, 1472, 1250,
-1 1 1111, 1065 cm ; H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 7.95 (s, 1H), 6.12 (s,
2H), 5.03-4.94 (m, 1H), 3.89 (t, J = 6.4 Hz, 1H), 2.40-1.46 (m, 12H), 0.95 (s, 9H),
13 0.10 (s, 6H); C NMR (75 MHz, CDCl3) ppm 155.3, 152.0, 15034, 139.1, 120.1,
79.4, 55.4, 53.2, 43.2, 36.8, 32.9, 32.6, 29.9, 26.2 (3C), 19.9, 18.4, -3.8, -4.3; ES
+ HRMS m/z (M + Na) calcd 410.2346, obsd 410.2333; Rf 0.18 (2:1 ethyl
acetate:hexanes).
NH2 To a solution of 1.14 (33 mg, 0.085 mmol, 1 eq) in THF (4 mL) N N OH was added a 1M solution of TBAF in THF (128 μL, 0.13 mmol, N N 1.5 eq). The reaction mixture was stirred for 18 h, and
concentrated in vacuo, and the residue was purified by column chromatography on
silica gel (9:1 dichloromethane:methanol) to give 1.15 as a white solid (mp 292-294
o 20 C, 20 mg, 87%); [α] D -16.6 (c 0.5, CHCl3); IR (neat) ν = 3375, 1478, 1231, 1063
-1 1 cm ; H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 8.20 (s, 1H), 4.99-4.97 (m, 1H),
13 3.93 (t, J = 5.1 Hz, 1H), 2.35-1.61 (series of m, 12H); C NMR (125 MHz, CDCl3)
ppm 156.3, 152.3, 149.5, 140.0, 119.4, 79.1, 55.8, 53.0, 42.5, 36.7, 32.0, 31.8, 29.5,
+ 19.6; ES HRMS m/z (M) calcd 274.1662, obsd 274.1649; Rf 0.32 (9:1
dichloromethane:methanol).
146 OTBS To a solution of 1.10 (322 mg, 1.19 mmol) in CH2Cl2 (40 mL) at
o 0 C was added Et3N (0.5 mL, 3.6 mmol, 3 eq) followed by MsCl OMs (0.28 mL, 3.6 mmol, 3 eq). The reaction mixture was allowed to warm to rt,
quenched after 3 h with saturated NaHCO3 solution, and extracted with Et2O (3 x 50
mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo, and the residue was purified by column chromatography on silica gel (10:1
20 hexanes:ethyl acetate) to give 1.16 as a colorless oil (380 mg, 91%); [α] D -21.8 (c
-1 1 1.3, CHCl3); IR (neat) ν = 1472, 1358, 1255, 1174, 1116 cm ; H NMR (500 MHz,
CDCl3) δ 5.18-5.16 (m, 1H), 3.74 (t, J = 6.7 Hz, 1H), 3.01 (s, 3H), 2.07-1.46 (series
13 of m, 12H), 0.91 (s, 9H), 0.07 (s, 6H); C NMR (125 MHz, CDCl3) ppm 85.2, 79.8,
53.0, 43.6, 38.8, 37.1, 33.6, 32.5, 29.4, 26.2 (3C), 20.1, 18.3, -3.8, -4.5; ES HRMS
+ m/z (M) calcd 371.1682, obsd 371.1662; Rf 0.14 (10:1 hexanes:ethyl acetate).
O To a stirred solution of DMF (2.5 mL) and uracil (40 mg, 0.36 NH
OTBS N O mmol, 2.5 eq) was added NaH (9 mg, 0.37 mmol, 2.6 eq) in one
portion. After 20 min, 1.16 (50 mg, 0.14 mmol) in DMF (2.5 mL) was introduced. The reaction mixture was heated to 80 oC for 12 hallowed to cool to
rt, quenched with H2O and extracted with EtOAc (3 x 20 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo, and the residue was
purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to give
o 20 1.18 as a colorless oil (mp 116 C, 20 mg, 38%); [α] D -39.2 (c 1.0, CHCl3); IR
-1 1 (neat) ν = 1686, 1463, 1376, 1257, 1112, 1067 cm ; H NMR (500 MHz, CDCl3) δ
9.14 (s, NH), 7.52 (d, J = 6.6 Hz, 1H), 6.11 (d, J = 6.6 Hz, 1H), 5.06-5.00 (m, 1H),
147 3.83 (t, J = 6.7 Hz, 1H), 2.29-1.47 (series of m, 12H), 0.94 (s, 9H), 0.098 (s, 3H),
13 0.094 (s, 3H); C NMR (125 MHz, CDCl3) ppm 163.6, 151.5, 141.0, 102.9, 79.4,
55.7, 52.9, 41.7, 36.3, 32.4, 31.2, 29.6, 26.2 (3C), 19.7, 18.4, -3.8, -4.3; ES HRMS
+ m/z (M + Na) calcd 387.2074, obsd 387.2079; Rf 0.17 (2:1 hexanes:ethyl acetate).
O To a solution of 1.18 (20 mg, 0.053 mmol) in THF (2.5 mL) was NH
OH N O added a 1M solution of TBAF in THF (161 μL, 0.16 mmol, 3 eq).
The reaction mixture was stirred for 18 h and concentrated in
vacuo, and the residue was purified by column chromatography on silica gel (4:1
o 20 ethyl acetate:hexanes) to give 1.19 as a white solid (mp 139 C, 12 mg, 90%); [α] D
-1 1 -20.5 (c 1.1, CHCl3); IR (neat) ν = 3335, 1684, 1457, 1097 cm ; H NMR (500
MHz, CDCl3) δ 9.42 (s, NH), 7.41 (d, J = 8.0 Hz, 1H), 5.76 (d, J = 8.7 Hz, 1H), 4.98-
4.96 (m, 1H), 3.92 (t, J = 6.1 Hz, 1H), 2.17-1.46 (series of m, 12H); 13C NMR (125
MHz, CDCl3) ppm 173.5, 163.8, 151.5, 141.8, 102.8, 79.8, 56.5, 52.8, 47.5, 41.7,
36.8, 32.8, 31.1, 29.9, 23.0, 20.0; EI HRMS m/z (M+) calcd 273.1209, obsd
273.1206; Rf 0.11 (4:1 ethyl acetate:hexanes).
Cl To a stirred solution of DMF (3.5 mL) and 2-amino-6- N N OTBS N chloropurine (85 mg, 0. 5 mmol, 2.5 eq) was added NaH (17 N NH2 mg, 0.7 mmol, 3.5 eq) in one portion. After 20 min, 1.16 (70
mg, 0.2 mmol) in DMF (1.5 mL) was introduced, and the reaction mixture was heated
o to 80 C for 12 h, allowed to cool to rt, quenched with H2O and extracted with EtOAc
(3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated
148 in vacuo, and the residue was purified by column chromatography on silica gel (2:1
hexanes:ethyl acetate) to give 1.20 as a white solid (mp 164-165 oC, 22 mg, 26%,
20 36% brsm); [α] D -33.1 (c 1.1, CHCl3); IR (neat) ν = 2953, 1610, 1562, 1462, 1250,
-1 1 1111 cm ; H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 5.13 (s, NH2), 4.83-4.79 (m,
1H), 3.88 (t, J = 6.4 Hz, 1H), 2.34-1.42 (series of m, 12H), 0.95 (s, 9H), 0.10 (s, 6H);
13 C NMR (125 MHz, CDCl3) ppm 159.1, 151.6, 141.0, 154.3, 126.1, 79.4, 55.4, 53.1,
42.8, 36.8, 32.6, 32.4, 29.8, 26.2 (3C), 19.9, 18.4, -3.8, -4.3; ES HRMS m/z (M + H)+ calcd 422.2137, obsd 422.2125; Rf 0.33 (2:1 hexanes:ethyl acetate).
O To a solution of 1.20 (22 mg, 0.05 mmol) in MeOH (19 mL) N NH OTBS N was added 2-mercaptoethanol (157 μL, 2.08 mmol, 40 eq) N NH2 and a 5.25 M solution of NaOMe in MeOH (409 μL, 2.13
mmol, 41 eq). The reaction mixture was heated to 60 oC for 4 h, allowed to cool to rt,
and concentrated in vacuo, and the residue was purified by column chromatography
on silica gel (9:1 dichlromethane:methanol) to give 1.21 as a white solid (mp > 300
o 20 -1 C, 20 mg, 96%); [α] D -48.6 (c 1.0, CHCl3); IR (neat) ν = 1686, 1362, 1115 cm ;
1 H NMR (500 MHz, pyridine-d5) δ 8.08 (s, 1H), 6.59 (s, NH2), 4.84-4.80 (m, 1H),
3.80 (t, J = 4.9 Hz, 1H), 2.25-1.31 (series of m, 12H), 0.92 (s, 9H), 0.07 (s, 3H), 0.06
13 (s, 3H); C NMR (125 MHz, pyridine-d5) ppm 159.3, 155.0, 152.5, 136.0, 118.8,
79.9, 55.0, 53.3, 43.1, 36.8, 33.0, 32.3, 30.0, 26.1 (3C), 20.2, 18.3, -4.0, -4.5; ES
+ HRMS m/z (M + Na) calcd 426.2295, obsd 426.2315; Rf 0.31 (9:1
dichloromethane:methanol).
149 O To a solution of 1.21 (26.5 mg, 0.07 mmol) in THF (3 mL) N NH OH N was added a 1M solution of TBAF in THF (197 μL, 0.2 N NH2 mmol, 3 eq). After 3 h, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (9:1 dichlromethane:methanol) to give 1.22 as a white solid (mp > 300 oC,
20 15.4 mg, 81%); [α] D -14.0 (c 0.7, MeOH); IR (neat) ν = 3390, 1656, 1352, 1117
-1 1 cm ; H NMR (500 MHz, pyridine-d5) δ 8.15 (s, 1H), 7.55 (s, NH2), 4.90-4.85 (m,
13 1H), 4.10 (m, 1H)), 2.58-1.45 (series of m, 12H); C NMR (125 MHz, pyridine-d5)
ppm 159.2, 155.0, 152.4, 136.2, 123.3, 78.8, 55.3, 53.4, 43.3, 37.4, 33.2, 32.5, 30.0,
+ 20.5; ES HRMS m/z (M + Na) calcd 312.1430, obsd 312.1434; Rf 0.19 (9:1
dichloromethane:methanol).
Cl Ph3P (103.5 mg, 0.4 mmol) and DIAD (69.5 μL, 0.4 mmol)
N N wre combined in 3 mL of THF and stirred for 1 h. The OTBS N N mixture was transferred to a round-bottomed flask where 1.25
(53.3 mg, 0.2 mmol) was added along with 2 mL of THF and stirred at rt for 1 h. To
this mixture 6-chloropurine (61.0 mg, 0.4 mmol) and 2.5 mL of DMF were added and
was stiring was maintained for 24 h. Upon completion the reaction mixture was
quenched with saturated NaHCO3 solution, transferred to a seperatory funnel, extracted 3 times with Et2O, dried over Na2SO4, and concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl
20 acetate) to give 1.28 as a colorless oil (63.2 mg, 42%); [α] D 12.4 (c 0.98, CHCl3);
IR (neat) ν = 1590, 1556, 1335, 1257, 1224, 1147, 1113, 836, 775 cm-1; 1H NMR
150 (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.24 (s, 1H), 5.07-5.00 (m, 1H), 3.87 (t, J = 6.8 Hz,
1H), 2.45-1.21(m, 12H), 0.87 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz,
CDCl3) ppm 151.9, 151.5, 150.9, 143.5, 131.9, 122.1, 80.0, 55.8, 52.7, 37.5, 36.2,
34.1, 32.5, 25.8 (3C), 19.5, 18.0, -4.2, -4.7; ES HRMS m/z (M + Na)+ calcd
429.1847, obsd 429.1823; Rf 0.60 (10:1 hexanes:ethyl acetate).
NH2 MeOH (4 mL) and 1.28 (55 mg, 0.14 mmol) were placed in a
N N 15 mL high-pressure vial added and the solvent was saturated OTBS N N with gaseous NH3 for 0.5 h. The vial was sealed and stirred at
80 oC for 24 h. Upon completion, the reaction mixture was allowed to cool to rt, and
concentrated in vacuo, and the residue was purified by column chromatography on
silica gel (4:1 ethyl acetate:hexanes) to give 1.29 as a white solid (mp 168-170oC, 41
20 mg, 78%); [α] D +20.7 (c 1.03, CHCl3); IR (neat) ν = 1629, 1587, 1471, 1250,
-1 1 1112, 895, 750 cm ; H NMR (300 MHz, CDCl3) δ 8.39 (s, 1 H), 7.99 (s, 1 H), 5.90
(s, 2 H), 5.04-4.97 (m, 1 H), 3.90 (t, J = 6.9 Hz, 1 H), 2.42-1.46 (m, 12 H), 0.93 (s, 9
13 H), 0.11 (s, 3 H), 0.10 (s, 3 H); C NMR (75 MHz, CDCl3) ppm 155.6, 152.6, 150.6,
139.1, 120.2, 50.6, 55.3, 53.0, 38.0, 36.7, 34.6, 33.2, 33.0, 26.2 (3C), 20.0, 18.4, -3.8,
+ -4.3; ES HRMS m/z (M + H) calcd 388.2527, obsd 388.2551; Rf 0.07 (2:1 ethyl acetate:hexanes).
151 NH2 To a round-bottomed flask containing THF (2 mL) and 1.29
N N (41 mg, 0.11 mmol) was added 1M TBAF in THF (130 μL, OH N N 0.13 mmol). The reaction mixture was stirred at rt under N2 for 24 h, quenched with saturated NaHCO3 solution, transferred to a separatory
funnel, and extracted with Et2O (3 x 15 ml) and ethyl acetate (3 x 15 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (10:1
dichloromethane:methanol) to give 1.30 as a white solid (mp > 300oC, 27 mg, 93%);
20 [α] D +19.3 (c 1.0, DMSO); IR (neat) ν = 1629, 1587, 1471, 1250, 1112, 895, 750
-1 1 cm ; H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), 8.13 (s, 1H), 7.14 (s, 2H), 4.90-
4.87 (m, 1H), 4.75 (d, J = 4.5 Hz, 1H), 3.74-3.73 (m, 1H), 2.50-1.44 (m, 12H); 13C
NMR (75 MHz, CDCl3) ppm 156.8, 152.9, 150.2, 139.9, 120.0, 79.1, 55.4, 53.6, 38.6,
+ 37.1, 35.1, 33.4, 32.3, 20.8; ES HRMS m/z (M ) calcd 274.1662, obsd 274.1663; Rf
0.46 (10:1 dichloromethane: methanol).
OTBS To a solution of 1.25 (307 mg, 1.14 mmol) in CH2Cl2 (38 mL) at 0
o C was added Et3N (0.47 mL, 3.4 mmol, 3 eq) followed by MsCl OMs (0.18 mL, 2.3 mmol, 2 eq). The reaction mixture was allowed to warm to rt, where
after 3 h it was quenched with saturated NaHCO3 solution, and extracted with Et2O (3 x 50 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo, and the residue was purified by column chromatography on silica gel (10:1
20 hexanes:ethyl acetate) to give 1.31 as a colorless oil (397 mg, 98%); [α] D +21.8 (c
-1 1 1.4, CHCl3); IR (neat) ν = 1472, 1359, 1256, 1175, 1113 cm ; H NMR (500 MHz,
152 CDCl3) δ 5.18-5.15 (m, 1H), 3.74 (t, J = 6.4 Hz, 1H), 3.01 (s, 3H), 2.39 (dd, J = 14.3,
6.5 Hz, 1H), 2.09-1.28 (series of m, 11H), 0.91 (s, 9H), 0.07 (s, 6H); 13C NMR (125
MHz, CDCl3) ppm 85.5, 80.5, 53.3, 39.2, 38.7, 37.0, 34.4, 33.5, 33.2, 26.2 (3C), 20.3,
+ 18.3, -3.9, -4.5; ES HRMS m/z (M - OMs) calcd 253.1988, obsd 253.2127; Rf 0.17
(10:1 hexanes:ethyl acetate).
O To a solution of 5-fluorouracil (130 mg, 1.0 mmol, 2.7 eq) in DMF F NH (6.5 mL) at rt and N2 atmosphere was added NaH (27 mg, 1.1 OTBS O mmol, 3 eq). The reaction mixture was stirred for 10 min prior to
the addition of 1.31 (130 mg, 0.4 mmol), stirred for 2 days at 80 oC, cooled to rt,
transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl
o 20 acetate) to yield 1.32 as a white solid (mp 137 C, 5 mg, 45% yield, 8% conv); [α] D
-1 1 +13 (c 0.2, CHCl3); IR (CH2Cl2) ν = 1717, 1699, 1654, 1471, 1259 cm ; H NMR
(500 MHz, CDCl3) δ 8.93 (s, NH), 7.49 (d, J = 6.2 Hz, 1H), 5.06-5.03 (m, 1H), 3.86
(t, J = 7.6 Hz, 1H), 2.12-1.52 (series of m, 12H), 0.94 (s, 9H), 0.12 (s, 3H), 0.11 (s,
13 3H); C NMR (125 MHz, CDCl3) ppm 157.5, 149.5, 141.5, 125.4, 80.6, 55.8, 52.1,
36.0, 35.6, 34.1, 32.4, 31.2, 25.9 (3C), 19.3, 18.1, -4.3, -4.6; ES HRMS m/z (M +
+ Na) calcd 405.1980, obsd 405.2003; Rf 0.37 (2:1 hexanes:ethyl acetate).
O F NH
OH O
153 To a solution of 1.32 (2 mg, 0.005 mmol) and THF (0.5 mL) was added a 1M
solution of TBAF in THF (21 μL, 0.02 mmol, 4 eq). The reaction mixture was stirred
for 24 h, and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (2:1 ethyl acetate:hexanes) to yield 1.33 as a white solid
o 1 (mp 283 C, 1.2 mg, 92%); H NMR (500 MHz, CDCl3) δ 8.55 (s, NH), 7.71 (d, J =
6.4 Hz, 1H), 5.04-5.01 (m, 1H), 3.95 (t, J = 6.2 Hz, 1H), 2.18-1.21 (series of m, 12H);
13 C NMR (125 MHz, CDCl3) ppm 156.5, 149.4, 141.4, 126.1, 80.2, 56.4, 52.4, 36.8,
20 + 36.0, 35.1, 33.4, 31.2, 20.0; [α] D +13 (c 0.1, CHCl3); ES HRMS m/z (M + Na)
calcd 291.1115, obsd 291.1118; Rf 0.18 (1:1 hexanes:ethyl acetate).
O To a stirred solution of MeCN (2.0 mL) and N3-benzoyluracil (45 Bz N
OTBS mg, 0.21 mmol, 1.2 eq) was added NaH (6 mg, 0.23 mmol, 1.3 eq) N O in one portion. After 20 min, 1.31 (61 mg, 0.18 mmol) dissolved
in MeCN (0.5 mL) was added to the initial solution. The reaction mixture was heated
o to 80 C for 12 h, quenched with H2O, and extracted with Et2O (3 x 20 mL). The
organic phases were combined, dried over Na2SO4, and concentrated in vacuo, and
the residue was purified by column chromatography on silica gel (5:1 hexanes:ethyl
20 acetate) to give 1.34 as a colorless oil (8 mg, 10%); [α] D +3.0 (c 0.2, CHCl3); IR
(neat) ν = 1749, 1706, 1666, 1448, 1365, 1253, 1112 cm -1; 1H NMR (500 MHz,
CDCl3) δ 7.99-7.97 (m, 2H), 7.70-7.66 (m, 1H), 7.55-7.52 (m, 3H), 5.86 (d, J = 8.2
Hz, 1H), 5.07-5.03 (m, 1H), 3.88 (t, J = 7.4 Hz, 1H), 2.17-1.45 (series of m, 12H),
13 0.97 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H); C NMR (125 MHz, CDCl3) ppm 169.4,
162.4, 150.5, 141.2, 135.3, 132.0, 130.8 (2C), 129.5 (2C), 102.7, 80.9, 56.2, 52.6,
154 36.5, 36.3, 34.5, 32.8, 31.7, 30.1, 26.3 (3C), 19.7, 18.5, -3.8, -4.2; EI m/z (M+) calcd
468.2438, obsd 468.2436; Rf 0.13 (5:1 hexanes:ethyl acetate).
O Compound 1.34 (3 mg, 0.006 mmol) was dissolved in MeOH (0.5 NH OTBS mL) and gaseous NH3 was bubbled throughout the solution for 30 N O min. The resulting solution was concentrated in vacuo and the
residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl
20 acetate) to give 1.35 as a colorless oil (2.1 mg, 95%); [α] D +5.8 (c 0.9, CHCl3); IR
-1 1 (neat) ν = 1684, 1463, 1376, 1271, 1111 cm ; H NMR (500 MHz, CDCl3) δ 7.97
(s, NH), 7.43 (d, J = 8.1 Hz, 1H), 5.74 (dd, J = 8.0, 2.4 Hz, 1H), 5.06-5.03 (m, 1H),
3.87 (t, J = 7.4 Hz, 1H), 2.14-1.44 (series of m, 12H), 0.95 (s, 9H), 0.12 (s, 3H), 0.11
13 (s, 3H); C NMR (125 MHz, CDCl3) ppm 162.9, 151.2, 141.4, 102.7, 96.5, 80.9,
55.8, 52.6, 36.5, 36.3, 34.5, 32.8, 31.7, 26.3 (3C), 19.8, 18.5, -3.8, -4.2; ES HRMS
+ m/z (M + Na) calcd 387.2074, obsd 387.2081; Rf 0.16 (2:1 hexanes:ethyl acetate).
O To a solution of 1.35 (0.6 mg, 0.002 mmol) in THF (0.5 mL) was
NH added a 1M solution of TBAF in THF (3 μL, 0.003 mmol, 1.5 eq). OH N O The reaction mixture was stirred for 18 h, and concentrated in
vacuo, and the residue was purified by column chromatography on silica gel (4:1
20 ethyl acetate:hexanes) to give to give 1.36 as a colorless oil (0.28 mg, 70%); [α] D
-1 1 +5.1 (c 1.0, CHCl3); IR (neat) ν = 3377, 1683, 1465 cm ; H NMR (500 MHz,
CDCl3) δ 8.23 (s, NH), 7.51 (d, J = 8.2 Hz, 1H), 5.76 (dd, J = 7.2, 2.3 Hz, 1H), 5.03-
4.99 (m, 1H), 3.94 (t, J = 6.0 Hz, 1H), 2.18-1.54 (series of m, 12H); 13C NMR (125
155 MHz, CDCl3) ppm 163.1, 151.2, 115.6, 102.8, 80.6, 56.7, 52.9, 37.0, 36.6, 35.4, 33.7,
+ 31.4, 20.5; ES HRMS m/z (M + Na) calcd 273.1209, obsd 273.1201; Rf 0.17 (4:1
hexanes:ethyl acetate).
Cl To a stirred solution of DMF (5.0 mL) and 2-amino-6- N N OTBS N chloropurine (58 mg, 0.35 mmol, 2 eq) was added NaH (10 N NH2 mg, 0.43 mmol, 2.5 eq) in one portion. After 20 min, 1.31
(60 mg, 0.17 mmol) in DMF (1.4 mL) was added to the initial solution. The reaction
o mixture was heated to 80 C for 12 h, allowed to come to rt, quenched with H2O and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to give 1.37 as a colorless oil
20 - (10 mg, 14%); [α] D +6.1 (c 0.3, CHCl3); IR (neat) ν = 1563, 1512, 1462, 1111 cm
1 1 ; H NMR (500 MHz, CDCl3) δ 7.94 (s, 1H), 5.06 (s, NH2), 4.86-4.83 (m, 1H), 3.90
(t, J = 6.8 Hz, 1H), 2.40-2.29 (m, 2H), 2.08-1.47 (series of m, 10H); 13C NMR (125
MHz, CDCl3) ppm 159.1, 154.2, 151.5, 141.1, 126.1, 80.5, 55.4, 53.0, 37.8, 36.7,
34.6, 33.1, 32.8, 30.1, 26.2 (3C), 20.0, 18.4, -3.8, -4.3; EI m/z (M+) calcd 421.2059,
obsd 421.2028; Rf 0.38 (1:1 hexanes:ethyl acetate).
O To a solution of 1.37 (2.5 mg, 0.006 mmol) in MeOH (2.12 N NH OTBS N mL) was added 2-mercaptoethanol (17 μL, 0.24 mmol, 40 N NH2 eq) and a 5.25 M solution of NaOMe in MeOH (47 μL, 0.24
mmol, 41 eq). The reaction mixture was heated to 60 oC for 4 h, allowed to come to
156 rt and concentrated in vacuo. The residue was purified by column chromatography
on silica gel (9:1 dichlromethane:methanol) to give 1.38 as a white solid (mp 250-251
o 20 -1 C, 2.0 mg, 84%); [α] D +37.3 (c 1.0, CHCl3); IR (neat) ν = 1686, 1362, 1115 cm ;
1 H NMR (500 MHz, CD3OD) δ 7.71 (s, 1H), 4.78-4.75 (m, 2H), 3.88 (t, J = 5.5 Hz,
1H), 2.33-1.49 (m, 12H), 0.93 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (125
MHz, CD3OD) ppm 159.1, 154.2, 152.3, 141.1, 136.3, 80.6, 54.9, 53.1, 38.1, 36.7,
+ 34.5, 33.1, 33.0, 26.3 (3C), 20.0, 18.4, -3.8, -4.3; ES HRMS m/z (M + Na) calcd
426.2295, obsd 426.2321; Rf 0.49 (9:1 dichloromethane:methanol).
O To a solution of 1.38 (1.7 mg, 0.004 mmol) in THF (0.5 mL) N NH OH N was added a 1M solution of TBAF in THF (6.3 μL, 0.006 N NH2 mmol, 1.5 eq). After 3 h, the reaction mixture was
concentrated in vacuo and the residue was purified by column chromatography on
silica gel (9:1 dichlromethane:methanol) to give 1.39 as a white solid (mp > 300 oC,
20 1.15 mg, 96%); [α] D +15.2 (c 0.8, MeOH); IR (neat) ν = 3384, 1686, 1362, 1115
-1 1 cm ; H NMR (500 MHz, CD3OD) δ 7.87 (s, 1H), 4.84-4.79 (m, 1H), 3.88 (t, J =
13 5.4 Hz, 1H), 2.36-1.41 (series of m, 12H); C NMR (125 MHz, CD3OD) ppm 159.2,
154.0, 152.4, 141.1, 136.3, 80.3, 54.8, 53.1, 38.3, 36.2, 34.5, 33.1, 33.0, 19.9; ES
+ HRMS m/z (M + Na) calcd 312.1430, obsd 312.1433; Rf 0.14 (9:1
dichloromethane:methanol).
157 OTBS A solution of 1.9 (273 mg, 0.99 mmol), DIAD (0.38 mL, O
O 1.97 mmol, 2 eq), p-nitrobenzoic acid (330 mg, 1.97
NO2 mmol, 2eq), and Ph3P (0.5 g, 1.97 mmol, 2 eq) were
combined in 10 mL of THF. The reaction mixture was stirred for 18 h and
concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 1.40 as a colorless oil (374 mg, 90%); IR
-1 1 (neat) ν = 1718, 1528, 1272, 1101 cm ; H NMR (500 MHz, CDCl3,) δ 8.33-8.30
(m, 2H), 8.25-8.21 (m, 2H), 6.22-6.19 (m, 1H), 5.99-5.95 (m, 1H), 5.93-5.90 (m, 1H),
3.89 (t, J = 2.4 Hz, 0.5 Hz), 3.81 (t, J = 4.6 Hz, 0.5H), 2.21-1.24 (series of m, 8H),
13 0.92 (s, 9H), 0.07 (s, 1.5H), 0.06 (s, 3H), 0.05 (s, 1.5H); C NMR (125 MHz, CDCl3)
ppm 165.0 (0.5C), 164.9 (0.5C), 150.9, 144.7 (0.5C), 144.5 (0.5C), 136.4, 131.0,
128.0 (0.5C), 127.9 (0.5C), 123.8, 82.6 (0.5C), 82.2 (0.5C), 61.4 (0.5C), 61.1 (0.5C),
52.3, 42.9, 42.6, 36.7, 34.5, 34.4, 30.1 (3C), 22.1, 21.6, 18.5 (0.5C), 18.4 (0.5C), -4.0,
+ -4.3 (0.5C), -4.5 (0.5C); ES HRMS m/z (M ) calcd 440.1863, obsd 440.1871; Rf
0.46 (10:1 hexanes:ethyl acetate).
OTBS Allylic alcohol 1.8 (38 mg, 0.14 mmol), DMAP (1.7 mg, 0.014 OAc mmol, 0.1 eq), and pyridine (23 μL, 0.28 mmol, 2 eq) were stirred in
CH2Cl2 (2.0 mL) at rt, at which point Ac2O (27 μL, 0.28 mmol, 2 eq) was added. The
reaction mixture was stirred for 2 h, quenched with saturated NaHCO3 solution, and
extracted with ether (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 1.44 (43 mg, 98%)
158 20 as a colorless oil; [α] D -38.7 (c 1.0, CHCl3); IR (neat) ν = 1735, 1472, 1363, 1240,
-1 1 1115 cm ; H NMR (500 MHz, CDCl3) δ 6.05 (dd, J = 5.6, 0.9 Hz, 1H), 5.77 (dd, J
= 5.6, 2.1 Hz, 1H), 5.68-5.65 (m, 1H), 3.82 (t, J = 2.5 Hz, 1H), 2.03 (s, 3H), 2.07-1.36
13 (m, 8H), 0.89 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); C NMR (125 MHz, CDCl3) ppm
170.9, 143.1, 128.282.0, 79.9, 60.5, 42.4, 35.5, 34.1, 25.8 (3C), 21.5, 21.2, 18.1, -4.5,
+ -4.8; ES HRMS m/z (M + Na) calcd 333.1856, obsd 333.1868; Rf 0.50 (10:1
hexanes:ethyl acetate).
OTBS Methanol (0.2 mL), 2.1 (0.163 g, 0.61 mmol), and 30% H2O2
O (0.13 mL, 1.84 mmol) were combined and cooled to 0 oC.
O Aqueous 1M NaOH (0.2 mL, 0.31 mmol) was added dropwise via
syringe. The reaction mixture was allowed to warm to rt and stirred for 4 h, quenched with saturated NaHCO3 solution, and extracted with ether (3 x 30 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography with silica gel (10:1 hexanes:ethyl
20 acetate) to yield 2.2 as a colorless oil (125 mg, 73%); [α] D -50.2 (c 1.1, CHCl3); IR
(neat) ν = 2955, 2857, 1751, 1471, 1408, 1362, 1255, cm-1; 1H NMR (300 MHz,
CDCl3) δ 3.87-3.84 (m, 2H), 3.36 (d, J = 2.5 Hz, 1H), 2.31-1.62 (m, 8H), 0.84 (s,
13 9H), 0.02 (s, 3H), 0.00 (s, 3H); C NMR (75 MHz, CDCl3) ppm 208.8, 80.3, 61.5,
56.5, 50.2, 42.1, 32.7, 31.1, 25.6 (3C), 19.9, 17.7, -4.5, -5.3; ES HRMS m/z (M +
+ Na) calcd 305.1543, obsd 305.1545; Rf 0.56 (10:1 hexanes:ethyl acetate).
159 OTBS To a flame dried 10 mL pear-shaped flask under Ar, a 0.1 M
O solution of SmI2 in THF (2.82 mL, 0.282 mmol), THF (2 mL),
OH DMPU (0.18 mL), ethylene glycol (0.1 mL), and 2.2 (26.5 mg,
0.095 mmol) were added at rt. The reaction mixture was stirred for 1.5 h, quenched with petroleum ether, filtered through a pad of Celite, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (3:1 hexanes:ethyl
20 acetate) to give 2.3 as a yellow oil (31 mg, 95%); [α] D +38.3 (c 1.1, CHCl3); IR
-1 1 (neat) ν = 3390, 2955, 1745, 1255, 1112, 836 cm ; H NMR (300 MHz, CDCl3) δ
4.56-4.50 (t, J = 7.6 Hz, 1H), 3.99 (m, 1H), 2.83 (s, 1H), 2.69-2.60 (m, 1H), 2.32-2.21
(m, 3H), 2.02-1.62 (m, 5H), 1.37-1.26 (m, 1H), 0.92 (s, 9H), 0.12 (s, 3H), 0.11 (s,
13 3H); C NMR (75 MHz, CDCl3) ppm 213.9, 82.7, 72.1, 55.1, 49.7, 45.5, 34.7, 27.4,
25.8 (3C), 21.2, 17.9, -4.4, -4.9; ES HRMS m/z (M + Na)+ calcd 307.1699, obsd
307.1708; Rf 0.25 (3:1 hexanes:ethyl acetate).
OTBS To a solution of 2.3 (56 mg, 0.2 mmol), CH2Cl2 (5 mL), and 2,6-
O o lutidine (114 μL, 0.98 mmol, 5 eq) under N2 at -78 C, TBSOTf
OTBS (90 μL, 0.39 mmol, 2 eq) was added and the reaction mixture was stirred for 45 min. The reaction mixture was warmed to rt where a saturated CuSO4 solution was added and the mixture was stirred for 15 min, where it was extracted with CH2Cl2 (3 x 25 mL). The combined organics phases were dried over Na2SO4 and concentrated in vacuo, and the residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 2.4 as a yellow oil (72 mg, 92%);
20 -1 1 [α] D -44.8 (c 1.12, CHCl3); IR (neat) ν = 2955, 1750, 1472, 1257, 1106 cm ; H
160 NMR (300 MHz, CDCl3) δ 4.55 (t, J = 2.2 Hz, 1H), 3.76 (t, J = 5.5 Hz, 1H) 2.57 (dd,
J = 18.3, 5.3 Hz, 1H), 2.34-1.49 (m, 9H), 0.92 (s, 9H), 0.91 (s, 9H), 0.11 (s, 3H), 0.08
13 (s, 6H), 0.05 (s, 3H); C NMR (75 MHz, CDCl3) ppm 217.9, 79.4, 72.3, 57.0, 48.5,
47.7, 33.8, 31.1, 26.19 (3C), 26.17 (3C), 20.6, 18.3 (2C), -3.8, -4.0, -4.4, -4.6; ES
+ HRMS m/z (M + Na) calcd 421.2564, obsd 421.2576; Rf 0.45 (10:1 hexanes:ethyl
acetate).
OTBS OTBS To a solution of 2.4 (42 mg, 0.106 mmol) and OH o CH2Cl2 (4 mL) under N2 at -78 C, a 1M +
OH OTBS OTBS solution of DIBAL-H in hexanes (127 μL,
0.13 mmol, 1.2 eq) was added dropwise and the reaction mixture was stirred for 45
min, quenched at -78 oC via the addition of a saturated K+,Na+ tartrate solution, and
allowed to warm to rt for 30 min at rt, extracted with CH2Cl2 (3 x 25 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl
acetate) to give (31 mg, 71%) of 2.5 and (10 mg, 26%) of 2.7, both as colorless oils.
20 For 2.5: [α] D -1.4 (c 1.02, CHCl3); IR (neat) ν = 3384, 2957, 1471, 1463,
-1 1 1361, 1256, 1116 cm ; H NMR (300 MHz, CDCl3) δ 4.40 (m, 1H), 4.24-4.22 (m,
1H) 3.55-3.54 (m, 1H), 2.16-2.13 (m, 1H), 1.92-1.28 (m, 9H), 0.93 (s, 9H), 0.91 (s,
9H), 0.14 (s, 3H), 0.12 (s, 3H), 0.06 (s, 3H), 0.04 (m, 3H); 13C NMR (75 MHz,
CDCl3) ppm 80.8, 74.5, 74.0, 60.1, 47.6, 43.9, 26.5, 26.3, 26.1 (3C), 25.9 (3C), 20.9,
18.3 (2C), -3.9, -4.0, -4.4, -4.5; ES HRMS m/z (M + Na)+ calcd 423.2721, obsd
423.2752; Rf 0.32 (10:1 hexanes:ethyl acetate).
161 20 For 2.7: [α] D +2 (c 0.8, CHCl3); IR (neat) ν = 3355, 2955, 1472, 1360,
-1 1 1255, 1119, 1062 cm ; H NMR (300 MHz, CDCl3) δ 4.47 (t, J = 6.0 Hz, 1H), 4.32-
4.30 (m, 1H), 3.91 (t, J = 7.2 Hz, 1H), 2.15-1.27 (m, 10H), 0.95 (s, 9H), 0.91 (s, 9H),
13 0.11 (s,, 6H), 0.088 (s, 3H), 0.086 (s, 3H); C NMR (75 MHz, CDCl3) ppm 80.6,
73.3, 71.6, 57.1, 46.0, 45.9, 33.3, 31.0, 26.3 (3C), 26.2 (3C), 20.3, 18.4, 18.3, -3.74, -
+ 3.75, -4.3, -4.5; ES HRMS m/z (M + Na) calcd 423.2721, obsd 423.2752; Rf 0.23
(10:1 hexanes:ethyl acetate).
OTBS To a solution of Ph3P (22.4 mg, 0.09 mmol, 2.0 eq), DIAD (15 μL,
0.08 mmol, 1.8 eq), and PhCO2H (12 mg, 0.09 mmol, 2.0 eq) in
OBz OTBS THF (1 mL) was added 2.7 (17 mg, 0.045 mmol). The reaction
mixture was stirred at rt for 24 h, where it was quenched with saturated NaHCO3 solution and extracted with Et2O (3 x 25 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (10:1 hexanes:ethyl acetate) to give (18 mg, 86%) of the
20 benzoate of 2.4 as a colorless oil; [α] D +7.7 (c 0.94, CHCl3); IR (neat) ν = 1717,
-1 1 1469, 1277, 1112 cm ; H NMR (300 MHz, CDCl3) δ 8.08 (dd, J = 8.1, 1.0 Hz, 1H),
7.58 (t, J = 6.2 Hz, 1H), 7.38 (t, J = 4.6 Hz, 1H), 5.34-5.31 (m, 1H), 4.36 (dd, J = 4.9,
1.1 Hz, 1H), 3.78 (t, J = 6.6 Hz, 1H), 2.50-2.44 (m, 1H), 2.29-2.24 (m, 1H), 2.10-2.06
(m, 1H), 1.91-1.47 (m, 7H), 0.95 (s, 9H), 0.93 (s, 9H, 0.11 (s, 3H), 0.103 (s, 3H),
13 0.101 (s, 3H), 0.09 (s, 3H); C NMR (75 MHz, CDCl3) ppm 166.8, 134.2, 133.1,
129.9, 128.6, 79.0, 74.6, 73.6, 57.6, 42.2, 42.0, 33.6, 31.0, 26.29 (3C), 26.26 (3C),
162 20.6, 18.4, 18.3, -3.7, -3.8, -4.4, -4.5; ES HRMS m/z (M + Na)+ calcd 527.2983, obsd
527.2976; Rf 0.60 (10:1 hexanes:ethyl acetate).
OTBS To a solution of 9 (60 mg, 0.15 mmol) and Et3N (63 μL, 0.45
o mmol, 3 eq) in CH2Cl2 (5 mL) at 0 C, MsCl (24 μL, 0.3 mmol, 2
OMs OTBS eq) was added dropwise. The reaction mixture was stirred for 3 h
where it was allowed to warm to rt, quenched with saturated NaHCO3 solution and
extracted with Et2O (3 x 25 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (10:1 hexanes:ethyl acetate) to give (60 mg, 81%) of 17
20 as a colorless oil; [α] D +10.4 (c 1.4, CHCl3); IR (neat) ν = 1472, 1359, 1256, 1174,
-1 1 1093 cm ; H NMR (300 MHz, CDCl3) δ 5.11-5.06 (m, 1H), 4.27 (dd, J = 5.0, 0.9
Hz, 1H), 3.71 (t, J = 6.8 Hz, 1H), 3.00 (s, 3H), 2.46-2.40 (m, 1H), 2.22-2.16 (m, 1H),
2.04-1.41 (m, 8H), 0.93 (s, 9H), 0.92 (s. 9H), 0.09 (s, 6H), 0.08 (s, 3H), 0.07 (s, 3H);
13 C NMR (75 MHz, CDCl3) ppm 80.8, 79.2, 72.8, 57.5, 42.6, 42.5, 38.8, 26.2 (3C),
26.1 (3C), 20.4, 18.37, 18.33, -3.85, -3.86, -4.5, -4.6; ES HRMS m/z (M + Na)+ calcd
501.2496, obsd 501.2508; Rf 0.25 (10:1 hexanes:ethyl acetate).
O Into a solution of NaH (6 mg, 0.25 mmol, 1.5 eq) and uracil (28
NH mg, 0.25 mmol, 1.5 eq) in DMF (5.2 mL) was added 2.6 (80 OTBS N O mg, 0.16 mmol) in DMF (1 mL). The reaction mixture was
OTBS 163 brought to 80 oC and stirred for 12 h. The reaction mixture was allowed to cool to rt,
quenched with a aqueous saturated NaHCO3 solution, and extracted with ether (3 x 30
mL. The combined organic phases were dried over Na2SO4 and concentrated in
vacuo, and the residue was purified by column chromatography on silica gel (3:1
hexanes:ethyl acetate) to give 2.8 (mp 118 oC, 13 mg, 16%, 43% brsm) as a white
20 -1 1 solid; [α] D -10.7 (c 1.0, CHCl3); IR (neat) ν = 1684, 1464, 1257, 1108 cm ; H
NMR (500 MHz, CDCl3) δ 8.47 (s, NH), 7.20 (d, J = 8.1 Hz, 1H), 5.73 (dd, J = 7.0,
2.3 Hz, 1H), 5.07-5.04 (m, 1H), 4.46 (t, J = 5.5 Hz, 1H), 3.85 (t, J = 7.0 Hz, 1H),
2.18-1.26 (series of m, 10H), 0.94 (s, 9H),0.91 (s, 9H), 0.09 (s, 6H), 0.08 (s, 3H), 0.07
13 (s, 3H); C NMR (125 MHz, CDCl3) ppm 162.8, 150.6, 1411, 102.4, 78.9, 72.0,
56.6, 54.1, 40.6, 39.6, 32.7, 30.3, 25.9 (3C), 25.7 (3C), 1937, 18.0, 17.8, -4.2 (2C), -
+ 4.81, -4.83; ES HRMS m/z (M + Na) calcd 517.2888, obsd 517.2871; Rf 0.20 (2:1
hexanes:ethyl acetate).
Into a stirred solution of DMF (7.0 mL) and cytosine (43.3 mg, NH2
N 0.39 mmol, 1.5 eq) was added NaH (9.4 mg, 0.39 mmol, 1.5 eq) in OTBS N O one portion. After 20 min, 2.6 (124 mg, 0.26 mmol) in DMF (1.6
OTBS mL) was added to the initial solution. The reaction mixture was
o heated at 80 C for 12 h, cooled to rt, quenched with H2O and extracted with EtOAc
(3 x 20 mL). The combined organics were dried over Na2SO4 and concentrated in
vacuo, and the residue was purified by column chromatography on silica gel (2:1
20 hexanes:ethyl acetate) to give 2.9 as a colorless oil (15 mg, 12%); [α] D -7.8 (c 1.1,
-1 1 CHCl3); IR (neat) ν = 1635, 1591, 1559, 1472, 1410, 1350, 1255 cm ; H NMR (500
164 MHz, CDCl3) δ 8.05 (d, J = 5.7 Hz, 1H), 6.09 (d, J = 5.6 Hz, 1H), 5.44-5.40 (m, 1H),
4.86 (s, NH2), 4.45 (t, J = 5.2 Hz, 1H), 4.15 (t, J = 7.1 Hz, 1H), 2.24-1.28 (series of
m, 10H), 0.93 (s, 9H), 0.92 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s,
13 3H); C NMR (125 MHz, CDCl3) ppm 164.9, 164.2, 157.9, 99.3, 78.8, 76.6, 74.5,
58.5, 42.4, 41.7, 26.2 (6C), 20.8, 18.4, 18.3, -3.9 (2C), -4.3, -4.4; ES HRMS m/z (M +
+ Na) calcd 516.3054, obsd 516.2900; Rf 0.23 (2:1 hexanes:ethyl acetate).
O Into a solution of NaH (12 mg, 0.5 mmol, 3.1 eq) and thymine
NH (61 mg, 0.48 mmol, 3 eq) in DMF (7 mL) was added 2.6 (80 OTBS N O mg, 0.16 mmol) in DMF (1 mL). The reaction mixture was
brought to 80 oC and stirred for 12 h. The reaction mixture was OTBS
allowed to cool to rt, quenched with a aqueous saturated NaHCO3 solution, and
extracted with ether (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 2.10 (20 mg, 25%,
20 27% brsm) as a colorless oil; [α] D -25.2 (c 1.0, CHCl3); IR (neat) ν = 1689, 1666,
-1 1 1471, 1255, 1107, 1063 cm ; H NMR (CDCl3, 500 MHz) δ 8.46 (s, NH), 6.99 (s,
1H), 5.08-5.05 (m, 1H), 4.47 (t, J = 5.9 Hz, 1H), 3.85 (t, J = 7.1 Hz, 1H) 2.19-1.28
(series of m, 10H), 1.94 (s, 3H), 0.95 (s, 9H), 0.91 (s, 9H), 0.09 (s, 6H), 0.08 (s, 3H),
13 0.07 (s, 3H); C NMR (125 MHz, CDCl3) ppm 163.4, 150.7, 136.9, 111.0, 78.7,
71.9, 56.3, 53.3, 40.7, 39.6, 32.6, 30.1, 25.9 (3C), 25.7 (3C), 19.7, 18.0, 17.8, 12.6, -
+ 4.1, -4.2, -4.8, -4.9; ES HRMS m/z (M + Na) calcd 531.3044, obsd 531.3023; Rf
0.26 (3:1 hexanes:ethyl acetate).
165
NH2 A solution of 2.6 (39 mg, 0.08 mmol), adenine (16.5 mg, 0.122
N N mmol, 1.5 eq), and NaH (3 mg, 0.122 mmol, 1.5 eq) in 3 mL of OTBS N N DMF was heated to reflux for 18 h. The reaction mixture was
OTBS then allowed to cool to rt, quenched with saturated NaHCO3 solution, and extracted with Et2O (3 x 25 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (2:1 hexanes:ethyl acetate) to give (25 mg, 60%) of 18
20 as a colorless oil; [α] D -10.58 (c 1.0, CHCl3); IR (neat) ν = 1650, 1598, 1471, 1250,
-1 1 1108, 1063 cm ; H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.87 (s, 1H), 5.14-5.10
(m, 1H), 4.62 (dd, J = 5.4, 3.9 Hz, 1H), 4.07 (t, J = 6.1 Hz, 1H), 2.50-1.42 (series of
m, 10H), 0.96 (s, 9H), 0.94 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H), 0.10 (s, 6H); 13C NMR
(75 MHz, CDCl3) ppm 155.4, 152.2, 150.4, 139.7, 120.6, 79.4, 73.5, 58.3, 53.8, 42.6,
41.0, 33.4, 31.3, 26.3 (3C), 26.2 (3C), 20.5, 18.4, 18.3, -3.8 (2C), -4.3, -4.4; ES
+ HRMS m/z (M + Na) calcd 518.3341, obsd 518.3326; Rf 0.30 (2:1 ethyl
acetate:hexanes).
Cl Into a solution of NaH (16 mg, 0.65 mmol, 3.1 eq) and 2-
N N amino-6-chloropurine (107 mg, 0.63 mmol, 3 eq) in OTBS N N NH2 DMF (9 mL) was added 2.6 (100 mg, 0.21 mmol) in
DMF (1 mL). The reaction mixture was brought to 80 OTBS o C, stirred for 12 h, allowed to cool to rt, quenched with aqueous saturated NaHCO3
solution, and extracted with ether (3 x 30 mL). The combined organic phases were
166 dried over Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 2.12 (mp > 300 oC,
20 31 mg, 27%, 90% brsm) as a white solid; [α] D -2.5 (c 0.8, CHCl3); IR (neat) ν =
-1 1 1609, 1566, 1456, 1407, 1257, 1109 cm ; H NMR (500 MHz, CDCl3) δ 7.79 (s,
1H), 5.06 (s, NH), 4.98-4.95 (m, 1H), 4.59 (t, J = 8.7 Hz, 1H), 4.26 (t, J = 4.3 Hz,
1H), 2.40-1.39 (series of m, 10H), 0.94 (s, 9H), 0.93 (s, 9H), 0.10 (s, 3H), 0.09 (s,
13 6H), 0.08 (s, 3H); C NMR (125 MHz, CDCl3) ppm 158.6, 153.6, 151.2, 141.1,
126.0, 79.0, 72.8, 57.6, 53.3, 41.6, 40.3, 32.9, 30.7, 25.9 (3C), 25.8 (3C), 20.0, 18.0,
17.9, -4.2, -4.3, -4.7 (2C); ES HRMS m/z (M + Na)+ calcd 574.2770, obsd 574.2780;
Rf 0.16 (5:1 hexanes:ethyl acetate).
O Into a solution of 2.12 (12 mg, 0.022 mmol) in MeOH
N NH (5.0 mL) was added 2-mercaptoethanol (30 μL, 0.43 OTBS N N NH2 mmol, 20 eq) and a 5.25 M solution of NaOMe in MeOH
(87 μL, 0.45 mmol, 21 eq). The reaction mixture was OTBS heated to 60 oC for 4 h, allowed to cool to rt, and concentrated in vacuo, and the residue was purified by column chromatography on silica gel (9:1 dichlromethane:methanol) to give 2.13 as a white solid (mp > 300 oC, 10 mg, 87%);
20 1 [α] D -2.5 (c 0.8, CHCl3); H NMR (500 MHz, CD3OD) δ 7.67 (s, 1H), 5.00-4.93 (m,
1H), 4.66-4.64 (m, 1H), 4.01 (t, J = 5.9 Hz, 1H), 2.38-1.46 (series of m, 10H), 0.96 (s,
9H), 0.95 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 159.6, 155.3, 152.3, 134.3, 114.4, 79.0, 73.1, 57.5, 51.9, 42.0,
40.1, 32.7, 30.5, 25.0 (3C), 24.9 (3C), 19.5, 17.5, 17.4, -5.3, -5.5, -5.8, -5.9; ES
167 + HRMS m/z (M + Na) calcd 556.3109, obsd 556.3080; Rf 0.18 (3% methanol in
dichloromethane).
O Compund 2.8 (11 mg, 0.02 mmol), a 1M solution of TBAF in
NH THF (0.13 mL, 0.13 mmol, 6 eq), and THF (1 mL) were stirred OH N O at rt for 32 h. At this point, the reaction mixture was and
concentrated in vacuo and the crude product was purified by OH column chromatography on silica gel (9:1 dichloromethane:methanol) to give 2.14
o 20 (mp 179 C, 5.4 mg, 92%) as a white solid; [α] D -9.8 (c 1.0, CHCl3); IR (neat) ν =
-1 1 3415, 1687, 1463, 1382, 1244 cm ; H NMR (500 MHz, CD3OD) δ 7.69 (d, J = 8.0
Hz, 1H), 5.70 (d, J = 8.0 Hz, 1H), 5.06-5.03 (m, 1H), 4.50 (t, J = 5.6 Hz, 1H), 3.93 (t,
13 J = 5.0 Hz, 1H), 2.22-1.36 (series of m, 10H); C NMR (125 MHz, CD3OD) ppm
164.8, 151.3, 143.1, 101.2, 79.6, 72.2, 56.4, 54.3, 39.9, 37.9, 32.5, 28.8, 19.9; ES
+ HRMS m/z (M + Na) calcd 289.1158, obsd 289.1169; Rf 0.7 (9:1
dichloromethane:methanol).
NH2 Into a solution of 2.9 (11 mg, 0.02 mmol) in THF (0.32 mL) was
N added a 1M solution of TBAF in THF (55 μL, 0.06 mmol, 2.5 eq). OH N O The reaction mixture was stirred for 18 h, and concentrated in
OH vacuo, and the residue was purified by column chromatography on
silica gel (9:1 dichloromethane:methanol) to give to give 2.15 as a white solid (mp
o 20 164-165 C, 5.0 mg, 84%); [α] D -17.3 (c 0.6, MeOH); IR (neat) ν = 3335, 3206,
-1 1 1632, 1596, 1557, 1412, 1351, 1294 cm ; H NMR (500 MHz, CDCl3) δ 7.83 (d, J =
168 6.0 Hz, 1H), 6.13 (d, J = 5.9 Hz, 1H), 5.43-5.38 (m, 1H), 4.45 (t, J = 5.9 Hz, 1H),
13 3.94 (t, J = 2.6 Hz, 1H), 2.21-1.37 (series of m, 10H); C NMR (125 MHz, CDCl3)
ppm 166.2, 164.6, 155.5, 98.9, 79.4, 75.8, 74.1, 57.5, 42.5, 40.8, 33.3, 29.8, 20.7; EI
+ HRMS m/z (M ) calcd 265.1420, obsd 265.1393; Rf 0.26 (9:1
dichloromethane:methanol).
O Compound 2.10 (20 mg, 0.04 mmol), a 1M solution of TBAF
NH in THF (0.24 mL, 0.24 mmol, 6 eq), and THF (1.8 mL) were OH N O stirred at rt for 5 h. The reaction mixture was concentrated in
vacuo and the crude product was purified by column OH chromatography on silica gel (9:1 dichloromethane:methanol) to give 2.16 (mp > 300
o 20 1 C, 8 mg, 73%) as a white solid; [α] D -12.3 (c 0.7, C5H5N); H NMR (500 MHz,
CDCl3) δ 7.50 (d, J = 1.2 Hz, 1H), 5.05-5.02 (m, 1H), 4.51 (t, J= 6.7 Hz, 1H), 3.94 (t,
J = 5.3 Hz, 1H), 2.23-1.39 (series of m, 10H), 1.95 (3H); 13C NMR (125 MHz,
CDCl3) ppm 165.0, 151.5, 138.8, 110.2, 79.6, 72.1, 56.3, 53.9, 39.9, 37.8, 32.5, 28.7,
+ 19.5, 12.6; ES HRMS m/z (M + Na) calcd 303.1315, obsd 303.1296; Rf 0.08 (3%
methanol in dichloromethane).
To a solution of 2.11 (32 mg, 0.06 mmol) in THF (0.9 mL) was NH2
N N added a 1M solution of TBAF in THF (154 μL, 0.15 mmol, 2.5 OH N N eq). The reaction mixture was stirred for 18 h, and concentrated
OH in vacuo, and the residue was purified by column
chromatography on silica gel (9:1 dichloromethane:methanol) to give 2.17 as a white
169 o 20 solid (mp > 300 C, 17 mg, 93%); [α] D -3.0 (c 1.0, MeOH); IR (neat) ν = 3321,
-1 1 1478, 1415, 1203 cm ; H NMR (500 MHz, CD3OD) δ 8.20 (s, 1H), 8.20 (s, 1H),
5.20-5.15 (m, 1H), 4.58 (m, 1H), 4.06 (t J = 5.0 Hz, 1H), 2.61-2.55 (m, 1H), 2.28-
2.19 (m, 3H), 2.04-1.94 (m, 2H), 1.84-1.80 (m, 1H), 1.72-1.65 (m, 2H), 1.54-1.49 (m,
13 1H); C NMR (125 MHz, CD3OD) ppm 156.3, 152.2, 149.4, 140.5, 119.7, 80.2,
72.9, 57.5, 53.7, 41.6, 40.2, 32.6, 29.7, 20.2; ES HRMS m/z (M+) calcd 289.1533,
obsd 289.1502; Rf 0.19 (9:1 dichloromethane:methanol).
O Compound 2.13 (6.1 mg, 0.01 mmol), a 1M solution of N NH OH TBAF in THF (57 μL, 0.06 mmol, 6 eq), and THF (0.5 N N NH2 mL) were stirred at rt for 32 h. The reaction mixture was
OH concentrated in vacuo and the crude product was purified
by column chromatography on silica gel (9:1 dichloromethane:methanol) to give 2.18
o 20 1 (mp > 300 C, 2.1 mg, 62%) as a white solid; [α] D -5.7 (c 0.2, C5H5N); H NMR
(500 MHz, C5D5N) δ 8.10 (s, 1H), 5.16 (t, J = 5.6 Hz, 1H), 4.72 (t, J = 5.4 Hz, 1H),
13 4.24-4.25 (m, 1H), 2.71-1.30 (series of m, 10H); C NMR (125 MHz, C5D5N) ppm
158.5, 157.2, 154.5, 143.4, 119.0, 79.9, 72.7, 57.6, 52.3, 42.5, 41.6, 33.8, 29.8, 20.9;
+ ES HRMS m/z (M + Na) calcd 328.1380, obsd 328.1395; Rf 0.54 (15% methanol in
dichloromethane).
OTBS A solution of oxalyl chloride (17 μL, 0.195 mmol, 1.5 eq) and
O o CH2Cl2 (1 mL) was cooled to -78 C and DMSO (28 μL, 0.39
mmol, 5 eq) was added dropwise. After 15 min of stirring 1.24/1.25 (35.1 mg, 0.13
170 mmol) in 1 mL of CH2Cl2 was added dropwise. The reaction mixture was stirred for
1 h, where Et3N (54 μL, 0.39 mmol, 5 eq) was added. The solution was allowed to
come to rt, quenched with saturated NaHCO3 solution, transferred to a seperatory
funnel, and extracted (3 x Et2O). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by column
20 chromatography on silica gel to give 2.19 as a colorless oil (27.7 mg, 79%); [α] D
-1 1 +43.1 (c 1.22, CHCl3); IR (neat) ν = 1745, 1472, 1406, 1252, 1124 cm ; H NMR
(300 MHz, CDCl3) δ 3.83 (t, J = 6.9 Hz, 1H), 2.54-2.48 (m, 1H), 2.26-2.23 (m, 2H),
13 1.93-1.52 (m, 9H), 0.85 (s, 9H), 0.02 (s, 6H); C NMR (75 MHz, CDCl3) ppm 219.8,
79.4, 51.1, 45.0, 37.6, 34.8, 32.8, 32.6, 25.6 (3C), 19.5, 17.8, -4.3, -5.1; ES HRMS
+ m/z (M + Na) calcd 291.1750, obsd 291.1770; Rf 0.34 (20:1 hexanes:ethyl acetate).
OTBS A solution of 2.19 (67 mg, 0.25 mmol) in THF (1.5 mL) was
O cooled to -78 oC and a 1M solution of LHMDS in THF (300 μL,
0.3 mmol, 1.2 eq) was added and the reaction mixture was Br stirred for 1 h, when TMSCl (44 μL, 0.35 mmol, 1.4 eq) was added and the reaction
mixture was stirred for an addition 1 h as it was allowed to warm to rt. The reaction
mixture was quenched with a saturated NaHCO3 solution and extracted with ether (3
x 15 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The crude product was redissolved in a mixture of THF and H2O (5:1, 3 mL),
where NBS (134 mg, 0.75 mmol, 3 eq) was added and stirring was maintained at rt
for 4 h. Upon completion of the reaction, the mixture was quenched with saturated
NaHCO3 solution and extracted with ether (3 x 15 mL). The combined organic
171 phases were dried over Na2SO4, and concentrated in vacuo, and the residue was
purified by column chromatography on silica gel (hexanes:ethyl acetate 10:1) to give
2.21 as a colorless oil (67 g, 77%); IR (neat) ν = 1750, 1471, 1257, 1158, 1131,
-1 1 1066, 873, 836, 777 cm ; H NMR (300 MHz, CDCl3) δ 4.4 (s, 1H), 4.00 (t, J = 6.9
Hz, 1H), 2.41-1.54 (m, 10H), 0.84 (s, 9H), 0.24 (s, 3H), 0.15 (s, 3H); 13C NMR (75
MHz, CDCl3) ppm 210.5, 81.0, 57.3, 34.4, 33.4, 32.0, 28.1, 26.1 (3C), 22.7, 20.2,
+ 18.3, -3.9, -4.7; ES HRMS m/z (M + Na) calcd 369.0855, obsd 369.0862; Rf 0.36
(10:1 hexanes:ethyl acetate).
OTBS A solution of 2.21 (1.12 g, 3.23 mmol), LiBr (489 mg, 5.49
O mmol, 1.7 eq), and Li2CO3 (597 mg,, 8.07 mmol, 2.5 eq) in
DMF (62 mL) was heated to 120-130 oC for 2h. The reaction
mixturte was quenched with saturated NaHCO3 solution and extracted with ether (3 x
15 mL). The combined organic phases were dried with Na2SO4 and concentrated in vacuo, and the residue was purified by column chromatography on silica gel
20 (hexanes:ethyl acetate 10:1) to give 2.20 as a colorless oil (18 mg, 44%); [α] D -94.6
-1 1 (c 0.89, CHCl3); IR (neat) ν = 1716, 1472, 1401, 1255 cm ; H NMR (300 MHz,
CDCl3) δ 7.33 (d, J = 5.6 Hz, 1H), 6.12 (d, J = 5.6 Hz, 1H), 4.02 (t, J = 8.1 Hz, 1H),
2.79 (d, J = 18.1 Hz, 1H), 2.20-1.52 (m, 6H), 1.94 (d, J = 18.1 Hz, 1H), 0.84 (s, 9H),
13 0.03 (s, 3H), -0.01 (s, 3H); C NMR (75 MHz, CDCl3) ppm 210.4, 169.9, 134.1,
77.9, 57.1, 42.1, 35.3, 33.4, 26.0 (3C), 20.2, 18.3, -4.2, -4.5; ES HRMS m/z (M +
+ Na) calcd 289.1594, obsd 289.1604; Rf 0.18 (10:1 hexanes:ethyl acetate).
172 OTBS Methanol (0.2 mL), 2.22 (0.163 g, 0.61 mmol), and 30% H2O2
O (0.13 mL, 1.84 mmol) were combined and cooled to 0 oC.
O Aqueous 1M NaOH (0.2 mL, 0.31 mmol) was added dropwise
via syringe, the reaction mixture was allowed to warm to rt, and stirred for 4 h. The
reaction mixture was quenched with saturated NaHCO3 solution, and extracted with
ether (3 x 15 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the residue was purified by column chromatography on silica gel (hexanes:ethyl acetate 10:1) to give 2.23 as a colorless oil (130 mg, 78%);
20 [α] D +8.4 (c 0.5, CHCl3); IR (neat) ν = 1720, 1445, 1360, 1320, 1192, 1128, 1091,
-1 1 1069 cm ; H NMR (300 MHz, CDCl3) δ 4.03 (t, J = 7.8 Hz, 1H), 3.56 (d, J = 2.3
Hz, 1H), 3.36 (d, J = 2.4 Hz, 1H), 2.40-1.59 (m, 8H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04
13 (s, 3H); C NMR (75 MHz, CDCl3) ppm 208.7, 142.0, 77.3, 66.2, 38.9, 32.8, 32.0,
29.7, 25.9 (3C), 20.1, 18.2, -4.0, -4.7; ES HRMS m/z (M + Na)+ calcd 305.1543,
obsd 305.1519; Rf 0.29 (10:1 hexanes:ethyl acetate).
OTBS To a flame-dried 10 mL pear-shaped flask a 0.1 M solution of
O SmI2 in THF (2.82 mL, 0.282 mmol), THF (2 mL), DMPU (0.18
OH mL), ethylene glycol (0.1 mL), and 2.23 (26.5 mg, 0.095 mmol)
were added at rt under Ar. The reaction mixture was stirred for 1.5 h, quenched with
petroleum ether, filtered through a pad of Celite, and concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (3:1 hexanes:ethyl
20 acetate) to give 2.24 as a yellow oil (18.3 mg, 68%); [α] D +22.0 (c 1.3, CHCl3); IR
-1 1 (neat) ν = 3390, 2955, 1745, 1255, 1112, 836 cm ; H NMR (300 MHz, CDCl3) δ
173 4.56-4.50 (t, J = 7.6 Hz, 1H), 3.99 (m, 1H), 2.83 (s, 1H), 2.69-2.60 (m, 1H), 2.32-2.21
(m, 3H), 2.02-1.62 (m, 5H), 1.37-1.26 (m, 1H), 0.92 (s, 9H), 0.12 (s, 3H), 0.11 (s,
13 3H); C NMR (75 MHz, CDCl3) ppm 213.9, 82.7, 72.1, 55.1, 49.7, 45.5, 34.7, 27.4,
25.8 (3C), 21.2, 17.9, -4.4, -4.9; ES HRMS m/z (M + Na)+ calcd 307.1699, obsd
307.1708; Rf 0.25 (3:1 hexanes:ethyl acetate).
OTBS A solution of 2.24 (197 mg, 0.7 mmol), 2,6-lutidine (0.4 mL, 3.5 O o mmol, 5 eq), and CH2Cl2 (20 mL) was cooled to – 78 C, where OTBS TBSOTf (0.32 mL, 1.4 mmol, 2 eq) was added. The reaction mixture was stirred for
1 h, allowed to warm to rt, quenched with aqueous saturated NaHCO3 solution,
transferred to a separatory funnel, and extracted with Et2O (3 x 50 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl
20 acetate) to give to give 2.25 as a colorless oil (224 mg, 81%); [α] D +40.0 (c 1.4,
-1 1 CHCl3); IR (neat) ν = 1748, 1472, 1255, 1115 cm ; H NMR (CDCl3, 500 MHz) δ
4.10 (t, J = 5.8 Hz, 1H), 3.94 (t, J = 7.4 Hz, 1H), 2.57-1.42 (series of m, 10H), 0.88
(s, 9H), 0.85 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H), 0.03 (s, 6H); 13C NMR (125 MHz,
CDCl3) ppm 216.7, 76.6, 74.4, 56.3, 47.8, 43.9, 34.0, 29.5, 26.14 (3C), 26.11 (3C),
19.8, 18.3, 18.2, -3.6, -3.9, -4.61, -4.64; ES HRMS m/z (M + Na)+ calcd 421.2564,
obsd 421.2582; Rf 0.8 (20:1 hexanes:ethyl acetate).
174 OTBS Compound 2.25 (30 mg, 0.08 mmol) and THF (1 mL) were cooled to
-78 oC, where L-selectride (83 μL, 0.08 mmol, 1.1 eq) was added and OH OTBS the reaction mixture was stirred for 10 min, quenched with saturated
NaHCO3 solution and extracted with ether (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the residue was
purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give
o 20 2.26 (mp 65-66 C, 30 mg, 99%) as a white solid; [α] D 42.5 (c 1.0, CHCl3); IR
-1 1 (CH2Cl2) ν = 3394, 1472, 1256, 1107 cm ; H NMR (500 MHz, CDCl3) δ 4.22 (t, J
= 6.2 Hz, 1H), 3.83 (t, J = 4.0 Hz, 1H), 3.71 (t, J = 7.0 Hz, 1H), 2.41-1.44 (series of
m, 8H), 0.91 (s, 9H), 0.88 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H), 0.04 (s, 3H), 0.03 (s,
13 3H); C NMR (125 MHz, CDCl3) ppm 79.7, 78.2, 73.4, 58.1, 43.9, 40.7, 33.4, 31.5,
25.83 (3C), 25.82 (3C), 19.8, 18.0, 17.9, -4.1, -4.4, -5.0, -5.02; ES HRMS m/z (M +
+ Na) calcd 423.2721, obsd 423.2724; Rf 0.13 (10:1 hexanes:ethyl acetate).
OTBS To a solution of 2.26 (335 mg, 0.84 mmol) in CH2Cl2 (29 mL) at 0
o C was added Et3N (0.35 mL, 2.5 mmol, 3 eq) followed by MsCl OMs OTBS (0.2 mL, 2.5 mmol, 3 eq). The reaction mixture was allowed to
warm to rt, where after 3 h it was quenched with saturated NaHCO3 solution, and
extracted with Et2O (3 x 50 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 2.27 as a colorless
20 oil (0.37 g, 92%); [α] D 28 (c 1.1, CHCl3); IR (CH2Cl2) ν = 1472, 1361, 1257, 1174,
-1 1 1115 cm ; H NMR (500 MHz, CDCl3) δ 5.09-5.04 (m, 1H), 3.78-3.72 (m, 2H),
175 2.99 (s, 3H), 2.47-1.26 (series of m, 8H), 0.91 (s, 9H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06
13 (s, 3H), 0.05 (s, 6H); C NMR (125 MHz, CDCl3) ppm 80.4, 76.6, 75.0, 41.8, 38.3,
36.8, 33.5, 29.1, 25.8 (3C), 25.7 (3C), 19.7, 17.9 (2C), -4.0, -4.2, -4.9 (2C); ES
+ HRMS m/z (M + Na) calcd 501.2496, obsd 501.2499; Rf 0.23 (10:1 hexanes:ethyl
acetate).
O To a solution of NaH (6.3 mg, 0.26 mmol, 2.1 eq) and uracil (28
NH mg, 0.253 mmol, 2 eq) in DMF (4.0 mL) was added 2.27 (60 mg, OTBS N O 0.13 mmol) in DMF (1.0 mL). The reaction mixture was brought
to 80 oC, stirred for 12 h, allowed to cool to rt, quenched with OTBS
aqueous saturated NaHCO3 solution, and extracted with ether (3 x 30 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (3:1 hexanes:ethyl
o 20 acetate) to give 2.28 (mp 140 C, 12 mg, 19%, 46% brsm) as a white solid; [α] D
-1 1 +26.0 (c 1.0, CHCl3); IR (CH2Cl2) ν = 1688, 1471, 1257, 1111 cm ; H NMR (500
MHz, CDCl3) δ 8.41 (s, NH), 7.37 (d, J = 8.1 Hz, 1H), 5.73 (dd, J = 8.0, 2.2 Hz, 1H),
5.21-5.18 (m, 1H), 4.06 (t, J = 6.6 Hz, 1H), 3.91 (t, J = 8.5 Hz, 1H), 2.06-1.26 (series of m, 8H), 0.92 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.06 (s,
13 3H); C NMR (125 MHz, CDCl3) ppm 162.8, 150.7, 141.3, 102.5, 75.1, 56.9, 52.8,
40.0, 34.5, 32.9, 28.8, 25.9 (3C), 25.7 (3C), 19.2, 18.1, 17.9, -4.0, -4.1, -4.6, -4.9; ES
+ HRMS m/z (M + Na) calcd 517.2888, obsd 517.2897; Rf 0.27 (3:1 hexanes:ethyl
acetate).
176 NH2 To a solution of NaH (8 mg, 0.33 mmol, 2.1 eq) and cytosine (35
N mg, 0.3 mmol, 2 eq) in DMF (4.5 mL) was added 2.27 (74 mg, OTBS N O 0.16 mmol) in DMF (1.5 mL). The reaction mixture was brought
to 80 oC, stirred for 12 h, and allowed to cool to rt, where it was OTBS
transferred to a separatory funnel, quenched with an aqueous saturated NaHCO3
solution, and extracted with ether (3 x 30 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 2.29 (mp 139 oC, 9
20 mg, 12%, 40% brsm) as a white solid; [α] D +22.2 (c 0.9, CHCl3); IR (CH2Cl2) ν =
-1 1 3315, 3178, 1631, 1591, 1560, 1411, 1112 cm ; H NMR (500 MHz, CDCl3) δ 8.02
(d, J = 5.7 Hz, 1H), 6.10 (d, J = 5.7 Hz, 1H), 5.34-5.30 (m, 1H), 4.93 (s, NH2), 4.11
(t. J = 8.3 Hz, 1H), 3.88 (t, J = 7.0 Hz, 1H), 2.10-1.26 (series of m, 8H), 0.89 (s, 9H),
13 0.86 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 6H); C NMR (125 MHz, CDCl3) ppm 164.6, 157.0, 149.7, 139.3, 76.5, 74.7, 73.8, 56.6, 40.7, 36.2, 33.8, 28.3, 25.88
(3C), 25.84 (3C), 20.1, 18.0, 17.9, -4.0, -4.09, -4.8, -4.9; ES HRMS m/z (M + Na)+ calcd 516.3048, obsd 516.3061; Rf 0.19 (3:1 hexanes:ethyl acetate).
O To a solution of NaH (12 mg, 0.5 mmol, 3.1 eq) and thymine (61
NH mg, 0.48 mmol, 3 eq) in DMF (6 mL) was added 2.27 (80 mg, OTBS N O 0.16 mmol) in DMF (2 mL). The reaction mixture was brought
to 80 oC, stirred for 12 h, and allowed to cool to rt, where it was OTBS
transferred to a separatory funnel, quenched with an aqueous saturated NaHCO3
solution, and extracted with ether (3 x 30 mL). The combined organic phases were
177 dried over Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 2.30 (mp 160-162
o 20 C, 20 mg, 25%, 27% brsm) as a white solid; [α] D +26.2 (c 1.4, CHCl3); IR
-1 1 (CH2Cl2) ν = 1687, 1471, 1255, 1114 cm ; H NMR (500 MHz, CDCl3) δ 8.51 (s,
NH), 7.07 (d, J = 1.1 Hz, 1H), 5.23-5.16 (m, 1H), 4.09 (t, J = 7.0 Hz, 1H), 3.91 (t, J =
7.3 Hz, 1H), 2.02-1.24 (series of m, 8H), 1.94 (s, 3H), 0.93 (s, 9H), 0.91 (s, 9H), 0.11
13 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H); C NMR (125 MHz, CDCl3) ppm
163.4, 150.8, 136.8, 111.1, 76.6, 74.6, 56.8, 52.2, 39.7, 34.3, 32.8, 28.2, 25.9 (3C),
25.8 (3C), 19.2, 18.0, 17.9, 12.5, -3.8, -4.1, -4.8, -4.9; ES HRMS m/z (M + Na)+ calcd
531.3044, obsd 531.3070; Rf 0.18 (5:1 hexanes:ethyl acetate).
To a solution of NaH (9 mg, 0.32 mmol, 2.1 eq) and adenine NH2
N N (41 mg, 0.3 mmol, 2 eq) in DMF (4.5 mL) was added 2.27 OTBS N N (72 mg, 0.15 mmol) in DMF (1.5 mL). The reaction mixture
was brought to 80 oC, stirred for 12 h, and allowed to cool to OTBS rt, where it was transferred to a separatory funnel, quenched with aqueous saturated
NaHCO3 solution, and extracted with ether (3 x 30 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo, and the residue was
purified by column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give
o 20 2.31 (mp 142 C, 28 mg, 37%, 63% brsm) as a white solid; [α] D +40.2 (c 0.9,
-1 1 CHCl3); IR (CH2Cl2) ν = 3316, 3159, 1643, 1599, 1471, 1250, 1110 cm ; H NMR
(500 MHz, CDCl3) δ 8.36 (s, 1H), 7.91 (s, 1H), 5.84 (s, NH2), 5.13-5.10 (m, 1H), 4.29
(t, J = 7.0 Hz, 1H), 3.96 (t, J = 7.3 Hz, 1H), 2.37-1.41 (series of m, 8H), 0.91 (s, 9H),
178 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 155.3, 152.5, 150.0, 138.8, 119.9, 76.6, 74.5, 57.1, 51.5, 41.0,
36.0, 33.2, 28.4, 25.8 (6C), 19.5, 18.0, 17.9, -4.0, -4.1, -4.7, -4.9; ES HRMS m/z (M +
+ Na) calcd 540.3160, obsd 540.3154; Rf 0.29 (1:1 hexanes:ethyl acetate).
Cl To a solution of NaH (7 mg, 0.29 mmol, 2.1 eq) and 2-
N N amino-6-chloropurine (48 mg, 0.28 mmol, 2 eq) in DMF OTBS N N NH2 (4 mL) was added 2.27 (67 mg, 0.14 mmol) in DMF (1.4
mL). The reaction mixture was brought to 80 oC, stirred OTBS for 12 h, and allowed to cool to rt, where it was transferred to a separatory funnel,
quenched with aqueous saturated NaHCO3 solution, and extracted with ether (3 x 30
mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo, and the residue was purified by column chromatography on silica gel (3:1
hexanes:ethyl acetate) to give 2.31 (mp 200 oC, 15 mg, 20%, 35% brsm) as a white
20 solid; [α] D +29.9 (c 0.8, CHCl3); IR (neat) ν = 1609, 1566, 1456, 1407, 1257, 1109
-1 1 cm ; H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 5.06 (s, NH), 4.98-4.95 (m, 1H),
4.26 (t, J = 6.8 Hz, 1H), 3.96 (t, J = 7.3 Hz, 1H), 2.32-1.41 (series of m, 10H), 0.92
(s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (3C); 13C NMR
(125 MHz, CDCl3) ppm 158.6, 153.6, 151.1, 141.1, 126.0, 76.6, 74.6, 57.1, 51.8,
40.6, 35.6, 33.2, 28.4, 25.9 (3C), 25.8 (3C), 19.5, 18.07, 18.01, -3.9, -4.1, -4.7, -4.8;
+ ES HRMS m/z (M + Na) calcd 574.2770, obsd 574.2795; Rf 0.4 (3:1 hexanes:ethyl
acetate).
179 O To a solution of 2.31 (8.7 mg, 0.016 mmol, 1 eq) in
N NH MeOH (3.6 mL) was added 2-mercaptoethanol (27.4 μL, OTBS N N NH2 0.31 mmol, 20 eq) and a 5.25 M solution of NaOMe in
MeOH (63 μL, 0.33 mmol, 21 eq). The reaction mixture OTBS was heated to 60 oC for 4 h and concentrated in vacuo, and the residue was purified
by column chromatography on silica gel (9:1 dichlromethane:methanol) to give 2.32
o 20 1 as a white solid (mp > 300 C, 5.3 mg, 63%); [α] D +48.6 (c 0.5, MeOH); H NMR
(500 MHz, CD3OD) δ 7.72 (s, 1H), 4.97-4.91 (m, 1H), 4.31 (t, J = 6.9 Hz, 1H), 4.02
(t, J = 7.2 Hz, 1H), 2.32-1.46 (series of m, 10H), 0.94 (s, 9H), 0.90 (s, 9H), 0.13 (s,
13 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H); C NMR (125 MHz, CDCl3) ppm 158.8,
153.5, 151.5, 135.9, 116.6, 77.0, 74.8, 57.2, 51.3, 39.9, 36.3, 33.3, 28.4, 25.0 (3C),
24.9 (3C), 19.4, 17.4 (2C), -5.2, -5.3, -5.8, -6.0; ES HRMS m/z (M + Na)+ calcd
556.3109, obsd 556.3104; Rf 0.18 (3% methanol in dichloromethane).
O Compound 2.28 (12 mg, 0.024 mmol), a 1M solution of TBAF
NH in THF (0.5 mL, 0.15 mmol, 6eq), and THF (1.0 mL) were OH N O stirred for 7 h. The reaction mixture was concentrated in vacuo
and the crude material was purified by column chromatography OH on silica gel (10% MeOH in dichloromethane) to give 2.34 (mp 156 oC, 5.1 mg, 80%)
20 1 as a white solid. Spectral data of 2.34: [α] D +17.0 (c 0.7, CHCl3); H NMR (500
MHz, CD3OD) δ 7.83 (d, J = 8.1 Hz, 1H), 5.70 (d, J = 8.1, Hz, 1H), 5.17-5.13 (m,
1H), 4.07 (t, J = 5.5 Hz, 1H), 3.93 (t, J = 7.1 Hz, 1H), 2.14-1.40 (series of m, 8H); 13C
NMR (125 MHz, CD3OD) ppm 164.8, 151.4, 143.1, 101.2, 76.6, 75.1, 56.6, 53.7,
180 38.2, 34.4, 32.6, 29.3, 19.4; ES HRMS m/z (M + Na)+ calcd 289.1158, obsd
289.1155; Rf 0.27 (9:1 dichloromethane:methanol).
NH2 Compound 2.29 (14 mg, 0.0274 mmol), a 1M solution of TBAF
N in THF (0.16 mL, 0.16 mmol, 6eq), and THF (1.0 mL) were OH N O stirred for 48 h. The reaction mixture was concentrated in vacuo
and the crude material was purified by column chromatography OH on silica gel (10% MeOH in dichloromethane) to give 2.35 (mp 156 oC, 6.6 mg, 86%)
20 1 as a white solid; [α] D +15.3 (c 0.6, CHCl3); H NMR (500 MHz, CD3OD) δ 7.83
(d, J = 5.9 Hz, 1H), 6.13 (d, J = 5.9, Hz, 1H), 5.35-5.33 (m, 1H), 4.037 (t, J = 7.1 Hz,
1H), 3.89 (t, J = 5.8 Hz, 1H), 2.13-1.41 (series of m, 8H); 13C NMR (125 MHz,
CD3OD) ppm 165.8, 164.5, 155.5, 98.5, 76.0, 74.5, 73.7, 58.1, 40.2, 36.1, 32.4, 28.4,
+ 19.7; ES HRMS m/z (M + Na) calcd 288.1318, obsd 288.1313; Rf 0.27 (9:1
dichloromethane:methanol).
O Compound 2.30 (11 mg, 0.021 mmol), a 1M solution of TBAF
NH in THF (0.13 mL, 0.13 mmol, 6eq), and THF (1.0 mL) were OH N O stirred for 48 h. The reaction mixture was concentrated in vacuo
and the crude material was purified by column chromatography OH on silica gel (10% MeOH in dichloromethane) to give 2.36 (mp 218 oC, 4.3 mg, 73%)
20 1 as a white solid; [α] D +23.5 (c 0.4, CHCl3); H NMR (500 MHz, CD3OD) δ 7.67
(s, 1H), 5.16-5.13 (m, 1H), 4.09 (t, J = 5.5 Hz, 1H), 3.93 (t, J = 7.1 Hz, 1H), 2.12-
13 1.53 (series of m, 8H), 1.90 (s, 3H); C NMR (125 MHz, CD3OD) ppm 165.0, 151.6,
181 138.8, 110.2, 76.6, 75.0, 56.6, 53.3, 38.1, 34.3, 32.6, 29.3, 19.6, 11.0; ES HRMS m/z
+ (M + Na) calcd 303.1315, obsd 303.1325; Rf 0.22 (9:1 dichloromethane:methanol).
Compound 2.31 (27 mg, 0.05 mmol), a 1M solution of TBAF NH2
N N in THF (0.3 mL, 0.3 mmol, 6eq), and THF (2.5 mL) were OH N N stirred for 7 h. The reaction mixture was concentrated in
vacuo and the crude material was purified by column OH chromatography on silica gel (10% MeOH in dichloromethane) to give 2.37 (mp 178-
o 20 1 180 C, 14 mg, 93%) as a white solid; [α] D +31.1 (c 1.0, CHCl3); H NMR (500
MHz, CD3OD) δ 8.30 (s, 1H), 8.20 (s, 1H), 5.23-5.20 (m, 1H), 4.15 (t, J = 5.1 Hz,
1H), 3.98 (t, J = 6.7 Hz, 1H), 2.43-1.41 (series of m, 8H); 13C NMR (125 MHz,
CD3OD) ppm 155.9, 151.9, 150.3, 140.1, 119.0, 76.6, 75.1, 57.3, 52.8, 39.9, 35.6,
+ 32.8, 29.5, 19.8; ES HRMS m/z (M + Na) calcd 312.1430, obsd 312.1428; Rf 0.18
(10% methanol in dichloromethane).
O Compound 2.33 (5.3 mg, 0.01 mmol), a 1M solution of
N NH TBAF in THF (60 μL, 0.06 mmol, 6eq), and THF (0.75 OH N N NH2 mL) were stirred for 48 h. The reaction mixture was
concentrated in vacuo and the crude material was OH purified by column chromatography on silica gel (10% MeOH in dichloromethane) to
o 20 give 2.38 (mp > 300 C, 1.8 mg, 62%) as a white solid; [α] D +82.0 (c 0.1, MeOH);
1 H NMR (500 MHz, CD3OD) δ 7.88 (s, 1H), 5.18-5.15 (m, 1H), 4.18 (t, J = 5.1 Hz,
1H), 3.97 (t, J = 6.7 Hz, 1H), 2.33-2.01 (series of m, 8H); 13C NMR (125 MHz,
182 CD3OD) ppm 158.0, 153.7, 151.4, 136.7, 116.5, 76.4, 74.8, 56.9, 51.8, 39.7, 35.8,
+ 32.7, 29.1, 19.6; ES HRMS m/z (M + Na) calcd 305.1488, obsd 305.1492; Rf 0.09
(10% methanol in dichloromethane).
Compound 2.1 (0.62 g, 2.3 mmol), H O (6.34 OTBS OTBS 2
OH OH O O mL), acetone (63.4 mL), pyridine (0.38 mL, +
OH OH 4.7 mmol, 2 eq), and OsO4 (0.65 g, 2.6 mmol,
1.1 eq) were combined and stirred for 2 h. Gaseous H2S was bubbled through the solution until reduction of the osmate ester was complete by TLC. The solution was filtered through a pad of celite, where the mother liquor was quenched with saturated
NaHCO3 solution, and extracted with ether (3 x 150 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo, and the crude product was
purified by column chromatography on silica gel (5:1 hexanes:ethyl acetate) to give
2.39 (mp 84-85 oC, 0.34 g, 50%) and 2.40 (mp 105 oC, 90 mg, 12%) both as white
solids.
20 Spectral data of 2.39: [α] D -38.5 (c 1.1, CHCl3); IR (CH2Cl2) ν = 3557,
-1 1 1751, 1471, 1382, 1217, 1111 cm ; H NMR (500 MHz, CDCl3) δ 4.49 (dd, J = 4.6,
1.6 Hz, 1H), 4.35 (d, J = 4.5 Hz, 1H), 3.91 (t, J = 5.8 Hz, 1H), 2.32-1.51 (series of m,
13 8H), 0.89 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); C NMR (125 MHz, CDCl3) ppm
216.1, 80.7, 78.0, 71.7, 51.1, 43.0, 33.1, 31.2, 25.8 (3C), 19.8, 17.9, -4.3, -4.9; ES
+ HRMS m/z (M + Na) calcd 323.1649, obsd 323.1655; Rf 0.07 (5:1 hexanes:ethyl
acetate).
183 20 Spectral data of 2.40: [α] D +7.7 (c 1.0, CHCl3); IR (CH2Cl2) ν = 3555, 1754,
-1 1 1471, 1401 cm ; H NMR (500 MHz, CDCl3) δ 4.33 (d, J = 3.8 Hz, 1H), 4.20 (m,
1H), 4.15 (t, J = 4.8 Hz, 1H), 2.36-1.45 (series of m, 8H), 0.91 (s, 9H), 0.12 (s, 6H);
13 C NMR (125 MHz, CDCl3) ppm 215.2, 80.1, 78.2, 75.0, 49.5, 42.4, 33.8, 32.4, 25.6
(3C), 20.2, 17.8, -4.3, -5.1; ES HRMS m/z (M + Na)+ calcd 323.1649, obsd 323.1653;
Rf 0.10 (5:1 hexanes:ethyl acetate).
OTBS Compound 2.40 (40 mg, 0.13 mmol), DMAP (0.9 mg, 0.013
O mmol, 0.1 eq), and Et3N (39 μL, 0.28 mmol, 2.1 eq) were stirred in
OAcOAc CH2Cl2 (1.0 mL) at rt, where Ac2O (32 μL, 0.34 mmol, 2.5 eq) was
added. The reaction mixture was stirred for 2 h, quenched with saturated NaHCO3
solution, and extracted with ether (3 x 30 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 2.42 (50
20 mg, 98%) as a colorless oil; [α] D -13.5 (c 1.7, CHCl3); IR (CH2Cl2) ν = 1753,
-1 1 1471, 1372, 1247, 1121 cm ; H NMR (500 MHz, CDCl3) δ 5.75 (dd, J = 5.1, 1.2
Hz, 1H), 5.70 (d, J = 5.0 Hz, 1H), 3.95 (t, J = 5.9 Hz, 1H), 2.41-1.54 (series of m,
8H), 2.10 (s, 3H), 2.09 (s, 3H), 0.92(s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 209.4, 170.0, 169.4, 80.4, 75.8, 73.1, 50.7, 43.6, 32.8, 31.5, 25.7
(3C), 20.6, 20.2, 19.5, 17.8, -4.3, -5.1; ES HRMS m/z (M + Na)+ calcd 407.1860,
obsd 407.1867; Rf 0.24 (5:1 hexanes:ethyl acetate).
184 OTBS Compound 2.40 (64 mg, 0.22 mmol), pyridine (139 μL, 1.7
O mmol, 8 eq), and AgNO3 (146 mg, 0.86 mmol, 4 eq) were
O O Si Si stirred in THF (11.6 mL) in the dark for 1 h, where TiPDSCl2 O (137 μL, 0.43 mmol, 2 eq) was added in one portion. The reaction mixture was stirred for 2 h and filtered through a pad of celite. The organic phases were transferred to a separatory funnel and extracted with saturated NaHCO3 solution and
ether (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 2.43 (116 mg, 100%) as a colorless oil;
20 -1 1 [α] D -47.2 (c 1.2, CHCl3); IR (CH2Cl2) ν = 1765, 1464, 1251, 1095 cm ; H NMR
(500 MHz, CDCl3) δ 4.68-4.64 (m, 2H), 3.83 (dd, J = 5.5, 4.1 Hz, 1H), 2.26-1.44 (m,
8H), 1.12-0.90 (m, 28H), 0.89 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 212.4, 80.8, 79.7, 75.2, 52.0, 43.4, 33.9, 32.5, 25.7 (3C), 19.7,
17.8, 17.4-12.8 (12C), -4.2, -4.9; ES HRMS m/z (M + Na)+ calcd 565.3171, obsd
565.3191; Rf 0.28 (10:1 hexanes:ethyl acetate).
OTBS Compound 2.43 (116 mg, 0.21 mmol) and THF (2.8 mL) were
cooled to -78 oC, where L-selectride (235 μL, 0.23 mmol, 1.1 OH O O Si Si eq) was added and the reaction mixture was stirred for 10 min, O quenched with saturated NaHCO3 solution, and extracted with ether (3 x 30 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo,
and the residue was purified by column chromatography on silica gel (20:1
20 hexanes:ethyl acetate) to give 2.44 (100 mg, 86%) as a colorless oil; [α] D -0.5 (c
185 -1 1 1.3, CHCl3); IR (CH2Cl2) ν = 3574, 1464, 1250, 1153, 1116 cm ; H NMR (500
MHz, CDCl3) δ 4.47 (d, J = 4.4 Hz, 1H), 4.26 (t, J = 4.4 Hz, 1H), 4.03 (dd, J = 11.4,
6.0 Hz, 1H), 3.73 (t, J = 7.1 Hz, 1H), 2.34-1.35 (m, 8H), 1.12-1.06 (m, 28H), 0.89 (s,
13 9H), 0.05 (s, 6H); C NMR (125 MHz, CDCl3) ppm 80.8, 77.2, 74.5, 71.2, 54.5,
43.2, 33.8, 32.3, 25.8 (3C), 19.6, 17.9, 17.5-13.0 (12C), -4.3, -4.9; ES HRMS m/z (M
+ + Na) calcd 567.3327, obsd 567.3316; Rf 0.14 (20:1 hexanes:ethyl acetate).
OTBS To a solution of 2.44 (54 mg, 0.1 mmol) in CH2Cl2 (3.4 mL) at
o 0 C was added Et3N (42 μL, 0.3 mmol, 4 eq) followed by MsCl OMs O O Si Si (23 μL, 0.3 mmol, 4 eq). The reaction mixture was allowed to O
warm to rt, where after 6 h it was quenched with saturated NaHCO3 solution, and
extracted with Et2O (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 2.45 as a colorless
20 oil (56 mg, 90%); [α] D -4.8 (c 1.7, CHCl3); IR (CH2Cl2) ν = 1464, 1360, 1250,
-1 1 1178, 1102 cm ; H NMR (500 MHz, CDCl3) δ 4.88 (dd, J = 10.8, 6.4 Hz, 1H), 4.49
(d, J = 4.3 Hz, 1H), 4.35 (t, J = 4.4 Hz, 1H), 3.75 (t, J = 7.6 Hz, 1H), 2.99 (s, 3H),
2.41-1.20 (series of m, 8H), 1.12-1.08 (m, 28H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s,
13 3H); C NMR (125 MHz, CDCl3) ppm 80.9, 79.8, 76.3, 73.1, 54.4, 39.6, 38.2, 32.5,
31.2, 25.8 (3C), 19.6, 17.9, 17.5-17.1 (8C), 13.5, 13.4, 13.1, 13.0, -4.3, -4.8; ES
+ HRMS m/z (M + Na) calcd 645.3103, obsd 645.3121; Rf 0.09 (10:1 hexanes:ethyl
acetate).
186 OTBS Compound 2.40 (32 mg, 0.11 mmol), 2,2-dimethoxypropane (2
O mL), and p-TsOH (2 mg, 0.011 mmol, 0.1 eq) were combined and
OO heated to 80 oC. The reaction mixture was stirred for 2 h, allowed
to come to rt, quenched with saturated NaHCO3 solution, and
extracted with ether (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo, and the crude product was purified by column
chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 2.46 (34 mg, 94%)
20 as a colorless oil; [α] D -106.5 (c 1.0, CHCl3); IR (CH2Cl2) ν = 1759, 1472, 1271,
-1 1 1250, 1102, 1064 cm ; H NMR (500 MHz, CDCl3) δ 4.65 (d, J = 5.4 Hz, 1H), 4.28
(d, J = 5.4 Hz, 1H), 3.85 (t, J = 7.8 Hz, 1H), 2.76-1.54 (series of m, 8H), 1.44 (s, 3H),
13 1.37 (s, 3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); C NMR (125 MHz, CDCl3) ppm 212.6, 110.9, 81.4, 79.9, 79.3, 50.4, 43.9, 31.9, 28.5, 26.8, 25.8 (3C), 19.1, 17.9,
+ -4.6, -5.1; EI HRMS m/z (M ) calcd 340.2064, obsd 340.2097; Rf 0.24 (20:1
hexanes:ethyl acetate).
OTBS A solution of 2.46 (34 mg, 0.1 mmol) and THF (1.4 mL) was cooled to
-78 oC, where L-selectride (0.11 mL, 0.11 mmol, 1.1 eq) was added. OH OO The reaction mixture was stirred for 20 min, when it was quenched
with saturated NaHCO3 solution. The mixture was transferred to a separatory funnel
and extracted with ether (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (20:1 hexanes:ethyl acetate) to yield 2.47 as a colorless
20 oil (33 mg, 98%); [α] D -33.7 (c = 1.2, CHCl3); IR (neat) ν = 3543, 1472, 1371,
187 -1 1 1251, 1210 cm ; H NMR (500 MHz, CDCl3) δ 4.53 (d, J = 5.6 Hz, 1H), 4.45 (t, J =
5.7 Hz, 1H), 4.21-4.16 (m, 1H), 3.82 (t, J = 7.2 Hz, 1H), 2.05-1.38 (series of m, 8H),
1.49 (s, 3H), 1.38 (s, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 109.9, 81.3, 80.8, 79.5, 70.4, 52.8, 43.0, 29.9, 26.1, 25.8 (3C);
24.2, 20.2, 17.8, -4.1, -5.0; ES HRMS m/z (M + Na)+ calcd 365.2118, obsd
365.2117; Rf 0.12 (10:1 hexanes:ethyl acetate).
OTBS o To a solution of 2.47 (20 mg, 0.06 mmol) in CH2Cl2 (2 mL) at 0 C
was added Et3N (25 μL, 0.18 mmol, 3 eq) followed by MsCl (14 μL, OMs OO 0.18 mmol, 3 eq). The reaction mixture was allowed to warm to rt
when, after 3 h, it was quenched with saturated NaHCO3 solution, and extracted with
Et2O (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo, and the residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 2.48 as a colorless oil (24 mg, 100%);
20 -1 1 [α] D -50.1 (c 1.3, CHCl3); IR (neat) ν = 1457, 1360, 1252, 1211, 1178 cm ; H
NMR (500 MHz, CDCl3) δ 5.11-5.07 (m, 1H), 4.64 (t, J = 5.4 Hz, 1H), 4.51 (d, J =
5.4 Hz, 1H), 3.87 (t, J = 7.6 Hz, 1H), 3.07 (s, 3H), 2.20 (t, J = 11.9 Hz, 1H), 2.08-
1.35 (series of m, 7H), 1.50 (s, 3H), 1.36 (s, 3H), 0.91 (s, 9H), 0.11 (s, 3H), 0.07 (s,
13 3H); C NMR (125 MHz, CDCl3) ppm 110.7, 81.1, 80.6, 78.5, 78.0, 52.3, 38.9, 38.7,
33.4, 29.3, 26.1, 25.8 (3C), 24.4, 19.8, 17.7, -4.2, -5.0; ES HRMS m/z (M + Na)+ calcd 443.1894, obsd 443.1897; Rf 0.29 (5:1 hexanes:ethyl acetate).
188 OTBS Diol 2.40 (20 mg, 0.07 mmol) and DMAP (82 mg, 0.7 mmol, 10
O eq) were dissolved in CH2Cl2 (2 mL). The solution was brought
OO to 0 oC and a 1M solution of phosgene in toluene (0.6 mL, 0.6
O mmol, 0.75 eq) was added and the reaction mixture was stirred for
16 h and allowed to warm to rt. The reaction mixture was slowly quenched with
saturated NaHCO3 solution, and extracted with Et2O (3 x 20 mL). The combined
organic phases were dried over Na2SO4 and concentrated in vacuo, and the residue
was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to
20 give 2.49 as a colorless oil (17 mg, 80%); [α] D -134.8 (c 1.3, CHCl3); IR (neat) ν =
-1 1 1825, 1804, 1766, 1471, 1254, 1147, 1070 cm ; H NMR (500 MHz, CDCl3,) δ 5.15
(d, J= 6.7 Hz, 1H), 4.67 (d, J = 6.8 Hz, 1H), 3.93 (t, J = 8.5 Hz, 1H), 2.78 (d, J = 18.3
Hz, 1H), 2.23 (d, J = 18.4 Hz, 1H), 2.19-1.65 (series of m, 6H), 0.86 (s, 9H), 0.05 (s,
13 3H), 0.01 (s, 3H); C NMR (125 MHz, CDCl3) ppm 205.5, 153.8, 81.7, 80.4, 78.1,
52.4, 43.5, 31.5, 27.8, 25.7 (3C), 19.0, 17.8, -4.6, -5.2; ES HRMS m/z (M + Na)+ calcd 349.1441, obsd 349.1434; Rf 0.28 (10:1 hexanes:ethyl acetate).
OTBS OTBS A solution of 2.49 (41 mg, 0.13 mmol) and OH o + MeOH (4 mL) was cooled to 0 C and NaBH4 OH OO OO (4.8 mg, 0.13 mmol, 1 eq) was added. The
O O reaction mixture was quenched after 5 min with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted
with CH2Cl2 (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vauco, and the residue was purified by column chromatography on
189 silica gel (5:1 hexanes:ethyl acetate) to give 2.50 (26 mg, 63%) and 2.51 (7 mg,
17%), both as colorless oils;
20 For 2.50; [α] D -35.7 (c 1.8, CHCl3); IR (neat) ν = 3420, 1804, 1471, 1364,
-1 1 1256, 1164, 1098 cm ; H NMR (500 MHz, CDCl3) δ 5.00 (d, J = 6.6 Hz, 1H), 4.87
(t, J = 6.2 Hz, 1H), 4.46-4.42 (m, 1H), 3.89 (t, J = 7.7 Hz, 1H), 2.11-1.50 (series of m,
13 8H), 0.90 (s, 9H), 0.087 (s, 3H), 0.082 (s, 3H); C NMR (125 MHz, CDCl3) ppm
154.8, 82.0, 81.1, 80.8, 71.3, 54.4, 33.8, 31.5, 29.9, 25.8 (3C), 20.2, 17.7, -4.1, -5.0;
+ ES HRMS m/z (M + Na) calcd 351.1598, obsd 351.1599; Rf 0.27 (5:1 hexanes:ethyl
acetate).
20 -1 For 2.51; [α] D +13.5 (c 1.5, CHCl3); IR (neat) ν = 3512, 1794, 1471 cm ;
1 H NMR (500 MHz, CDCl3) δ 5.05-4.99 (m, 1H), 5.03 (d, J= 4.7 Hz, 1H), 4.20 (d, J
= 4.8 Hz, 1H), 3.87 (t, J = 5.1 Hz, 1H), 2.29-1.45 (series of m, 8H), 0.91 (s, 9H),
13 0.107 (s, 3H), 0.105 (s, 3H); C NMR (125 MHz, CDCl3) ppm 154.9, 82.3, 80.3,
78.8, 74.2, 54.5, 40.3, 3.3, 27.8, 25.8 (3C), 21.2, 17.9, -4.3, -4.9; ES HRMS m/z (M +
+ Na) calcd 351.1598, obsd 351.1601; Rf 0.33 (5:1 hexanes:ethyl acetate).
OTBS To a solution of 2.50 (26 mg, 0.08 mmol) in CH2Cl2 (3.3 mL) at 0
o C was added Et3N (33 μL, 0.24 mmol, 3 eq) followed by MsCl OMs OO (19 μL, 0.24 mmol, 3 eq). The reaction mixture was allowed to
O warm to rt, where after 3 h it was quenched with saturated
NaHCO3 solution, and extracted with Et2O (3 x 20 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo, and the residue was
purified by column chromatography on silica gel (3:1 hexanes:ethyl acetate) to give
190 20 2.52 as a colorless oil (28 mg, 87%); [α] D -71.4 (c 1.4, CHCl3); IR (neat) ν = 1810,
-1 1 1471, 1362, 1260, 1179 cm ; H NMR (500 MHz, CDCl3) δ 5.30-5.26 (m, 1H), 5.07
(t, J = 6.0 Hz, 1H), 4.97 (d, J = 6.5 Hz, 1H), 3.94 (t, J = 7.7 Hz, 1H), 3.12 (s, 3H),
2.20-1.54 (series of m, 8H), 0.91 (s, 9H), 0.13 (s, 3H), 0.09 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 154.3, 81.37, 81.32, 78.8, 75.7, 54.2, 38.7, 38.2, 33.2, 29.1, 25.7
(3C), 19.9, 17.7, -4.2, -5.0; ES HRMS m/z (M + Na)+ calcd 429.1373, obsd
429.13919; Rf 0.33 (3:1 hexanes:ethyl acetate).
OTBS A solution of 2.40 (40 mg, 0.13 mmol) and p-TsOH (2.5 mg, 0.01
o O mmol, 0.1 eq) in neat PhCH(OMe)2 (0.5 mL) was stirred at 80 C
OO for 1 h. The reaction mixture was cooled to rt, quenched with
H Ph saturated NaHCO3 solution, and extracted with Et2O (3 x 20 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo, and
the residue was purified by column chromatography on silica gel (30:1 hexanes:ethyl
20 acetate) to give 2.53 as a colorless oil (50 mg, 99%); [α] D -68.9 (c 1.3, CHCl3); IR
-1 1 (neat) ν = 1737, 1461, 1365, 1215, 1159, 1054 cm ; H NMR (500 MHz, CDCl3) δ
7.47-7.45 (m, 2H), 7.41-7.37 (m, 3H), 5.86 (s, 1H), 4.76 (d, J = 5.7 Hz, 1H), 4.43 (d,
J = 5.7 Hz, 1H), 3.90 (t, J = 7.9 Hz, 1H), 2.85 (d, J = 18.0 Hz, 1H), 2.28-1.58 (series
13 of m, 7H), 0.89 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); C NMR (125 MHz, CDCl3) ppm
211.2, 136.1, 129.6, 128.3 (2C), 126.8 (2C), 105.0, 81.5, 81.2, 80.0, 50.7, 44.0, 31.9,
28.4, 25.8 (3C), 19.1, 17.9, -4.5, -5.1; ES HRMS m/z (M + Na)+ calcd 411.1962,
obsd 411.1950; Rf 0.07 (20:1 hexanes:ethyl acetate).
191 OTBS Ketone 2.53 (23 mg, 0.06 mmol, 1 eq) and THF (1 mL) were
combined and cooled to -78 oC, where a 1M solution of L- OH OO selectride in THF (66 μL, 0.066 mmol, 1.1 eq) was added. The
H Ph reaction mixture was stirred for 20 min, where it was quenched
with saturated NaHCO3 solution and warmed to rt. The mixture was transferred to a
separatory funnel and washed with Et2O (3 x 15 mL). The combined organic phases
were dried over Na2SO4 and concentrated in vacuo, and the residue was purified by
column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 2.54 as a
o 20 white solid (mp 66 C, 23 mg, 100%); [α] D -5.8 (c 1.0, CHCl3); IR (neat) ν = 3565,
-1 1 1460, 1402, 1252, 1093 cm ; H NMR (500 MHz, CDCl3) δ 7.55-7.53 (m, 2H),
7.43-7.42 (m, 3H), 5.82 (s, 1H), 4.61 (d, J = 5.9 Hz, 1H), 4.55 (t, J = 5.9 Hz, 1H),
4.35-4.30 (m, 1H), 3.89 (t, J = 7.6 Hz, 1H), 2.19-1.49 (series of m, 8H), 0.93 (s, 9H),
13 0.10 (s, 3H), 0.08 (s, 3H); C NMR (125 MHz, CDCl3) ppm 136.5, 129.7, 128.4
(2C), 126.9 (2C), 104.0, 82.7, 81.0, 80.4, 70.8, 53.1, 43.4, 34.0, 30.0, 22.9 (3C), 20.2,
+ 17.8, -4.1, -5.0; ES HRMS m/z (M + Na) calcd 413.2118, obsd 413.2117; Rf 0.17
(10:1 hexanes:ethyl acetate).
OTBS To a solution of 2.54 (7.0 mg, 0.02 mmol) in CH2Cl2 (1.0 mL) at
o 0 C was added Et3N (15 μL, 0.11 mmol, 6 eq) followed by MsCl
OMs OO (8.4 μL, 0.11 mmol, 6 eq). The reaction mixture was allowed to
H Ph warm to rt, stirred for 36 h, quenched with saturated NaHCO3
solution, and extracted with Et2O (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
192 chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 2.55 as a colorless oil
20 (8 mg, 96%); [α] D -43.3 (c 1.0, CHCl3); IR (neat) ν = 1470, 1360, 1256, 1178,
-1 1 1089 cm ; H NMR (500 MHz, CDCl3) δ 7.55 (dd, J = 6.7, 3.8 Hz, 2H), 7.43-7.40
(m, 3H), 5.80 (s, 1H), 5.25-5.20 (m, 1H), 4.73 (t, J = 5.7 Hz, 1H), 4.59 (d, J = 5.8 Hz,
1H), 3.93 (t, J = 8.1 Hz, 1H), 3.02 (s, 3H), 2.41-1.21 (m, 8H), 0.94 (s, 9H), 0.15 (s,
13 3H), 0.10 (s, 3H); C NMR (125 MHz, CDCl3) ppm 136.3, 129.7, 128.3 (2C), 127.1
(2C), 104.6, 82.2, 81.2, 79.0, 78.1, 52.6, 38.7, 33.4, 31.5, 25.8 (3C), 22.6, 19.9, 17.8, -
+ 4.1, -5.0; ES HRMS m/z (M + Na) calcd 491.1894, obsd 491.1902; Rf 0.18 (10:1 hexanes:ethyl acetate).
OTBS A solution of 2.47 (259 mg, 0.76 mmol) and CH2Cl2 (2.2 mL) was
cooled to 0 oC, where pyridine (0.12 mL, 1.5 mmol, 2 eq) and
OTf OO triflic anhydride (0.15 ml, 0.9 mmol, 1.2 eq) were added. The
reaction mixture was stirred for 40 min, quenched with water,
transferred to a separatory funnel, and extracted with dichloromethane (3 x 30 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to yield 2.56 as a white solid (decomposition upon heating, 370 mg, 100%);
20 -1 1 [α] D -29.3 (c 0.7, CHCl3); IR (neat) ν = 1415, 1246, 1210, 1148, 1091 cm ; H
NMR (500 MHz, CDCl3) δ 5.29-5.25 (m, 1H), 4.64 (t, J = 5.5 Hz, 1H), 4.49 (d, J =
5.3 Hz, 1H), 3.87 (t, J = 8.4 Hz, 1H), 2.34-1.32 (series of m, 8H), 1.51 (s, 3H), 1.38
13 (s, 3H), 0.91 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); C NMR (125 MHz, CDCl3) ppm
193 111.2, 85.2, 81.2, 80.4, 78.4, 52.5, 38.7, 32.9, 28.8, 26.0, 25.7 (3C), 24.4, 19.7, 17.7, -
4.1, -5.2 (CF3 not seen); Rf 0.30 (20:1 hexanes:ethyl acetate).
O To a solution of uracil (74 mg, 0.66 mmol, 5.4 eq) and DMF (10
NH mL) at rt under N2 was added KH (30 mg, 0.74 mmol, 6 eq). The OTBS N O mixture was stirred for 10 min prior to the addition of 2.56 (60
mg, 0.12 mmol). The reaction mixture was stirred for 48 h, OO quenched with water, transferred to a separatory funnel, and
extracted with ether (3 x 30 mL). The combined organic phases were dried over
Na2SO4. The residue was purified by column chromatography on silica gel (2:1
o 20 hexanes:ethyl acetate) to yield 2.57 as a white solid (mp 185 C, 7 mg, 13%); [α] D -
-1 1 47.8 (c 0.7, CHCl3); IR (neat) ν = 1684, 1457, 1379, 1250, 1065 cm ; H NMR
(500 MHz, CDCl3) δ 8.46 (s, NH), 7.17 (d, J = 8.1 Hz, 1H), 5.73 (dd, J = 8.0, 2.2 Hz,
1H), 4.77 (d, J = 6.7 Hz, 1H), 4.69-4.65 (m, 2H), 3.81 (t, J = 7.4 Hz, 1H), 2.30-1.27
(series of m, 8H), 1.56 (s, 3H), 1.33 (s, 3H), 0.94 (s, 9H), 0.09 (s, 6H); 13C NMR (125
MHz, CDCl3) ppm 162.7, 150.4, 141.8, 113.5, 102.5, 82.5, 78.7, 78.3, 62.7, 52.9,
39.3, 32.2, 30.4, 26.7, 25.8 (3C), 25.0, 19.4, 18.0, -4.2, -4.9; ES HRMS m/z (M +
+ Na) calcd 459.2285, obsd 459.2274; Rf 0.08 (2:1 hexanes:ethyl acetate).
NH2 A solution of DMF (3 mL) and cytosine (18 mg, 0.16 mmol, 2.7
N eq) was stirred under N2. KH (7.5 mg, 0.18 mmol, 3 eq) was OTBS N O added in one portion and after 5 min followed by 2.56 (30 mg,
OO
194 0.06 mmol, 1 eq). The reaction mixture was stirred at rt for 48 h, quenched with H2O, transferred to a separatory funnel, and diluted with saturated NaHCO3 solution. The
mixture was extracted with CH2Cl2 (3 x 30 mL), at which point the organic phases
were combined, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to give
20 2.58 as a colorless oil (11 mg, 40%, 93% brsm); [α] D -33.1 (c 1.0, CHCl3); IR
(neat) ν = 3343, 3192, 1633, 1593, 1558, 1408, 1372, 1058 cm -1; 1H NMR (500
MHz, CDCl3) δ 8.07 (d, J = 5.7 Hz, 1H), 6.09 (d, J = 5.7 Hz, 1H), 5.17-5.15 (m, 1H),
4.89 (s, NH2), 4.84 (d, J = 6.1 Hz, 1H), 4.59 (d, J = 6.0 Hz, 1H), 4.23-4.22 (m, 1H),
2.23-1.43 (series of m, 8H), 1.51 (s, 3H), 1.33 (s, 3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.05
13 (s, 3H); C NMR (125 MHz, CDCl3) ppm 164.6, 157.7, 110.3, 99.2, 85.5, 82.6, 81.7,
60.3, 57.6, 39.9, 34.1, 32.0, 26.5, 25.8 (3C), 24.2, 21.0, 20.6, 18.0, -4.3, -4.9; ES
+ HRMS m/z (M + Na) calcd 458.2476, obsd 458.2445; Rf 0.17 (2:1 hexanes:ethyl
acetate).
O To a solution of thymine (84 mg, 0.66 mmol, 5.4 eq) and DMF
NH (10 mL) at rt under a nitrogen atmosphere was added KH (30 mg, OTBS N O 0.74 mmol, 6 eq). The mixture was stirred for 10 min prior to the
OO addition of 2.56 (60 mg, 0.12 mmol, 1 eq). The reaction mixture
was stirred for 48 h, where it was quenched with water,
transferred to a separatory funnel, and extracted with ether (3 x 30 mL). The
combined organic phases were dried over Na2SO4 and concentrated iin vacuo. The
residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl
195 o 20 acetate) to yield 2.59 as a white solid (mp 205 C, 3.5 mg, 6%); [α] D -36.8 (c 0.6,
-1 1 CHCl3); IR (neat) ν = 1682, 1471, 1373, 1250, 1066 cm ; H NMR (500 MHz,
CDCl3) δ 8.19 (s, NH), 6.98 (s, 1H), 4.77 (d, J = 6.3 Hz, 1H), 4.70-4.66 (m, 2H), 3.80
(t, J = 7.6 Hz, 1H), 2.30-1.27 (series of m, 8H), 2.06 (s, 3H), 1.56 (s, 3H), 1.33 (s,
13 3H), 0.95 (s, 9H), 0.10 (s, 6H); C NMR (125 MHz, CDCl3) ppm 163.2, 150.5,
137.7, 113.4, 111.0, 82.5, 78.7, 78.3, 62.2, 52.8, 39.3, 32.1, 30.4, 26.7, 25.8 (3C),
25.0, 19.4, 18.0, 12.4, -4.1, -4.9; ES HRMS m/z (M + Na)+ calcd 473.2442, obsd
473.2435; Rf 0.15 (2:1 hexanes:ethyl acetate).
A solution of DMF (6 mL) and adenine (45 mg, 0.33 mmol, NH2
N N 2.7 eq) was stirred under N2. KH (15 mg, 0.37 mmol, 3 eq) OTBS N N was added in one portion and after 5 min 2.56 (60 mg, 0.12
mmol) was added. The reaction mixture was stirred at rt for OO
48 h, quenched with H2O, transferred to a separatory funnel,
and diluted with saturated NaHCO3 solution. The reaction mixture was extracted with
CH2Cl2 (3 x 30 mL), the combined organics were dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 2.60 as a colorless oil (30 mg, 52%, 97%
20 brsm); [α] D -37.3 (c 1.1, CHCl3); IR (neat) ν = 3325, 3174, 1649, 1598, 1472,
-1 1 1372, 1249, 1068 cm ; H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.83 (s, 1H),
5.77 (s, NH2), 5.00 (dd, J = 7.4, 6.1 Hz, 1H), 4.94 (d, J = 7.6 Hz, 1H), 4.76-4.71 (m,
1H), 3.85 (t, J = 7.8 Hz, 1H), 2.35-1.33 (series of m, 8H), 1.57 (s, 3H), 1.33 (s, 3H),
13 0.95 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); C NMR (125 MHz, CDCl3) ppm 155.4,
196 152.7, 150.2, 139.5, 120.3, 113.5, 83.8, 78.9, 77.9, 60.9, 53.3, 40.6, 32.3, 30.3, 26.7,
25.8 (3C), 24.9, 19.4, 18.0, -4.2, -5.0; ES HRMS m/z (M + Na)+ calcd 482.2557,
obsd 482.2576; Rf 0.34 (2:1 ethyl acetate:hexanes).
Cl To a solution of 2-amino-6- N N NH2 N N OTBS OTBS N chloropurine (95 mg, 0.6 N N N NH2 Cl + mmol, 2.7 eq) in DMF (10 mL)
OO OO at rt and under N2 was added
KH (26 mg, 0.62 mmol, 3 eq). The mixture was stirred for 10 min prior to the
addition of 2.56 (100 mg, 0.2 mmol). The reaction mixture was stirred for 48 h,
quenched with water, transferred to a separatory funnel, and extracted with ether (3 x
30 mL). The combined organic phases were dried over Na2SO4 and the residue was
purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to yield
and isomeric 2.61 as a clear oil (10 mg, 4%) and 2.61 as a white solid (mp 166 oC, 44
mg, 42%).
20 Spectral data for isomeric 2.61: [α] D -23.2 (c 1.0, CHCl3); IR (neat) ν =
-1 1 3329, 3201, 1587, 1402, 1253, 1208, 1068 cm ; H NMR (500 MHz, CDCl3) δ 7.50
(s, 1H), 4.98 (t, J = 1.7 Hz, 1H), 4.91 (d, J = 7.6 Hz, 1H), 4.65-4.60 (m, 1H), 3.83 (t, J
= 8.3 Hz, 1H), 2.60 (t, J = 12.6 Hz, 1H), 2.34-2.29 (m, 1H), 1.92-1.23 (series of m,
7H), 1.57 (s, 3H), 1.33 (s, 3H), 0.96 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR
(125 MHz, CDCl3) ppm 158.6, 156.7, 152.3, 140.8, 135.0, 113.3, 83.6, 78.8, 77.8,
59.8, 53.2, 40.7, 32.4, 30.3, 26.5, 25.9 (3C), 25.0, 22.6. 19.4. 18.1. -4.2. -4.9; ES
197 + HRMS m/z (M + Na) calcd 516.2168, obsd 516.2160; Rf 0.24 (2:1 hexanes:ethyl
acetate).
20 Spectral data for 2.61: [α] D -23.1 (c 1.1, CHCl3); IR (neat) ν = 3317, 3205,
-1 1 1613, 1561, 1464, 1207, 1070 cm ; H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H),
5.10 (s, NH2), 4.98-4.96 (m, 1H), 4.91 (d, J = 7.7 Hz, 1H), 4.64-4.58 (m, 1H), 3.84 (t,
J = 8.2 Hz, 1H), 2.66 (t, J = 12.7 Hz, 1H), 2.34-2.29 (m, 1H), 1.93-1.30 (series of m,
6H), 1.57 (s, 3H), 1.34 (s, 3H), 0.97 (s, 9H), 0.10 (s, 6H); 13C NMR (125 MHz,
CDCl3) ppm 158.6, 153.7, 151.4, 141.6, 126.0, 113.7, 83.2, 78.6, 77.7, 60.9, 53.1,
40.1, 32.2, 30.2, 26.6, 25.9 (3C), 24.9, 19.3, 18.1, -4.1, -4.9; ES HRMS m/z (M +
+ Na) calcd 516.2168, obsd 516.2157; Rf 0.31 (2:1 hexanes:ethyl acetate).
O To a solution of 2.57 (31 mg, 0.069 mmol) and THF (1 mL)
NH was added a 1M solution of TBAF in THF (0.2 mL, 0.21 mmol,
OH N O 3 eq). The reaction mixture was stirred for 24 h, quenched with
brine, transferred to a separatory funnel, and extracted with
OO dichloromethane (4 x 30 mL). The combined organic phases
were dried over Na2SO4 and the residue was purified by column chromatography on
silica gel (6% methanol in dichloromethane) to yield 2.62 as a white solid (mp 217
o 20 C, 20 mg, 91%); [α] D -24.3 (c 1.0, CHCl3); IR (neat) ν = 3274, 1681, 1462, 1379,
-1 1 1065 cm ; H NMR (500 MHz, CDCl3) δ 8.87 (s, NH), 7.85 (d, J = 8.1 Hz, 1H),
5.73 (d, J = 8.0 Hz, 1H), 4.86 (d, J = 6.7 Hz, 1H), 4.80-4.72 (m, 2H), 3.96 (t, J = 6.9
Hz, 1H), 2.47-1.55 (series of m, 8H), 1.53 (s, 3H), 1.30 (s, 3H); 13C NMR (125 MHz,
CDCl3) ppm 163.2, 151.0, 143.6, 112.9, 102.4, 83.7, 79.5, 78.7, 62.3, 53.2, 40.0,
198 32.2, 31.3, 26.9, 25.2, 19.9; ES HRMS m/z (M + H)+ calcd 345.1420, obsd 345.1438;
Rf 0.06 (6% methanol in dichloromethane).
NH2 To a solution of 2.58 (9.7 mg, 0.02 mmol) in THF (1 mL) was
N added a 1 M solution of TBAF in THF (132 μL, 0.12 mmol, 6 OH N O eq). The reaction mixture was stirred at rt for 7 h, quenched with
OO H2O, transferred to a separatory funnel, and diluted with brine.
The product was extracted into CH2Cl2 (4 x 30 mL), where the
organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (3% methanol in
o 20 CH2Cl2) to give 2.63 as a white solid (mp 149 C, 7 mg, 98%); [α] D -11.4 (c 0.8,
-1 1 CHCl3); IR (neat) ν = 3354, 1632, 1597, 1555, 1407, 1048 cm ; H NMR (500
MHz, CDCl3) δ 8.05 (d, J = 5.9 Hz, 1H), 6.15 (d, J = 5.7 Hz, 1H), 5.22 (d, J = 5.6 Hz,
1H), 5.10 (s, NH2), 4.70 (d, J = 5.3 Hz, 1H), 4.59 (dd, J = 5.5, 1.7 Hz, 1H), 4.09 (t, J
= 7.4 Hz, 1H), 2.32-1.22 (series of m, 8H), 1.48 (s, 3H), 1.33 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 164.8, 163.7, 157.6, 109.6, 99.9, 81.5, 81.3, 79.7, 55.5, 52.2, 39.9,
33.0, 31.6, 26.4, 25.1, 24.1; ES HRMS m/z (M + Na)+ calcd 344.1565, obsd
344.1580; Rf 0.22 (4:1 ethyl acetate:hexanes).
O To a solution of 2.59 (13 mg, 0.03 mmol) and THF (0.5 mL)
NH was added a 1M solution of TBAF in THF (0.1 mL, 0.11 mmol, OH N O 4 eq). The reaction mixture was stirred for 24 h, quenched with
OO 199 brine, transferred to a separatory funnel, and extracted with dichloromethane (4 x 30
mL). The combined organic phases were dried over Na2SO4 and the residue was
purified by column chromatography on silica gel (6% methanol in dichloromethane)
o 20 to yield 2.64 as a white solid (mp 256 C, 9.0 mg, 96%); [α] D -34.3 (c 1.0, CHCl3);
-1 1 IR (neat) ν = 3445, 3274, 1683, 1652 cm ; H NMR (500 MHz, CDCl3) δ 8.96 (s,
NH), 7.06 (d, J = 1.2 Hz, 1H), 4.90 (dd, J = 7.0, 5.4 Hz, 1H), 4.828 (d, J = 7.1 Hz,
1H), 4.45-4.40 (m, 1H), 3.94 (t, J = 6.1 Hz, 1H), 2.30-1.39 (series of m, 8H), 1.93
13 (dd, J 1.0 Hz, 3H), 1.56 (s, 3H), 1.34 (s, 3H); C NMR (125 MHz, CDCl3) ppm
163.7, 150.7, 139.7, 113.2, 111.0, 82.9, 80.0, 79.7, 65.4, 54.2, 39.4, 32.6, 30.7, 26.7,
+ 25.0, 19.9, 12.3; ES HRMS m/z (M + Na) calcd 359.1577, obsd 359.1574; Rf 0.14
(2:1 ethyl acetate:hexanes).
NH2 To a solution of 2.60 (30 mg, 0.065 mmol) in THF (3 mL)
N N OH was added a 1M solution of TBAF in THF (0.39 mL, 0.39 N N mmol, 6 eq). The reaction mixture was stirred for 3 h,
OO quenched with brine, transferred to a separatory funnel, and
extracted with dichloromethane (4 x 30 mL). The combined
organic phases were dried over Na2SO4 and the residue was purified by column
chromatography on silica gel (10% methanol in dichloromethane) to yield 2.65 as a
o 20 1 white solid (mp > 300 C, 18 mg, 82%); [α] D -29.7 (c 0.6, CHCl3); H NMR (500
MHz, CD3OD) δ 8.26 (s, 1H), 8.21 (s, 1H), 5.08 (t, J = 7.0 Hz, 1H), 4.94 (d, J = 7.1
Hz, 1H), 4.93-4.86 (m, 1H), 3.90 (t, J = 6.4 Hz, 1H), 2.48-1.41 (series of m, 8H), 1.57
13 (s, 3H), 1.34 (s, 3H); C NMR (125 MHz, CD3OD) ppm 155.9, 152.1, 149.1, 140.2,
200 113.1, 84.1, 79.8, 78.1, 60.8, 53.8, 40.5, 31.7, 30.1, 25.7, 23.8, 19.1, 12.4; ES HRMS
+ m/z (M + H) calcd 346.1873, obsd 346.1875; Rf 0.09 (10% methanol in
dichloromethane).
Cl To a solution of 2.61 (41 mg, 0.083 mmol) in THF (3
N N mL) was added a 1M solution of TBAF in THF (0.33 mL, OH N N NH2 0.33 mmol, 4 eq). The reaction mixture was stirred for
24 h, quenched with brine, transferred to a separatory OO funnel, and extracted with dichloromethane (4 x 30 mL).
The combined organic phases were dried over Na2SO4 and the residue was purified
by column chromatography on silica gel (10% methanol in dichloromethane) to yield
o 20 1 2.66 as a white solid (mp > 300 C, 30 mg, 100%); [α] D -48 (c 1.6, py); H NMR
(500 MHz, C5D5N) δ 8.44 (s, 1H), 5.32-5.29 (m, 2H), 5.03-4.99 (m, 1H), 4.06 (t, J =
6.2 Hz, 1H), 2.69-1.44 (series of m, 8H), 1.59 (s, 3H), 1.30 (s, 3H); 13C NMR (125
MHz, C5D5N) ppm 160.6, 154.6, 151.0, 141.8, 125.4, 112.9, 84.2, 80.1, 77.6, 60.8,
54.1, 40.8, 33.2, 30.8, 26.8, 24.9, 20.0; ES HRMS m/z (M + H)+ calcd 402.1303,
obsd 402.1297; Rf 0.63 (10% methanol in dichloromethane).
A mixture of 2.66 (30 mg, 0.082 mmol), MeOH (10 mL), O
N NH 2-mercaptoethanol (0.11 mL, 1.64 mmol, 20 eq), and a OH N N NH2 5.25 M solution of NaOMe in methanol (0.33 mL, 1.7
mmol, 21 eq) was stirred at 80 oC for 4 h. The reaction OO
201 mixture was quenched with saturated NaHCO3 solution, transferred to a separatory
funnel, and extracted with dichloromethane (3 x 30 mL). The combined organic
phases were dried over Na2SO4 and the residue was purified by column chromatography on silica gel (10% methanol in dichloromethane) to yield 2.67 as a
o 20 1 white solid (mp > 300 C, 29 mg, 100%); [α] D -23.5 (c 1.5, DMSO); H NMR (500
MHz, (CD3)2SO) δ 7.86 (s, 1H), 6.81 (s, NH2), 4.90-4.80 (m, 3H), 4.61-4.56 (m, 1H),
2.79-1.23 (series of m, 8H), 1.44 (s, 3H), 1.23 (s, 3H); 13C NMR (125 MHz,
(CD3)2SO) ppm 157.2, 153.9, 151.5, 136.1, 127.8, 112.7, 84.1, 79.5, 77.0, 60.0, 53.8,
41.6, 32.7, 30.5, 27.0, 25.3, 19.8; ES HRMS m/z (M + H)+ calcd 384.1642, obsd
384.1635; Rf 0.16 (10% methanol in dichloromethane).
O To a solution of 2.62 (20 mg, 0.062 mmol) in MeOH (2.0 mL)
NH was added p-TsOH (11.8 mg, 0.062 mmol, 1 eq). The reaction OH N O mixture was stirred for 24 h and concentrated in vacuo. The
residue was purified by column chromatography on silica gel HO OH (15% methanol in dichloromethane) to yield 2.68 as a white solid (mp > 300 oC, 14
20 1 mg, 82%); [α] D -39.6 (c 1.4, pyridine); H NMR (500 MHz, C6D5N) δ 7.95 (d, J =
8.0 Hz, 1H), 5.84 (d, J = 7.9 Hz, 1H), 5.54-5.48 (m, 1H), 5.10-5.08 (m, 1H), 4.88 (d,
J = 4.8 Hz, 1H), 4.30 (t, J = 5.6 Hz, 1H), 2.73-1.33 (series of m, 8H); 13C NMR (125
MHz, C6D5N) ppm 164.6, 152.6, 143.0, 102.0, 79.8, 75.5, 72.9, 62.2, 54.0, 37.7, 33.0,
+ 32.0, 20.2; ES HRMS m/z (M + Na) calcd 305.1107, obsd 305.1115; Rf 0.46 (15%
methanol in dichloromethane).
202 To a solution of 2.63 (40 mg, 0.14 mmol) in MeOH (2.0 mL) NH2 was added p-TsOH (32 mg, 0.17 mmol, 1 eq). The reaction N OH mixture was stirred for 24 h and concentrated in vacuo. The N O residue was purified by column chromatography on silica gel
HO OH (15% methanol in dichloromethane) to yield 2.69 as a white
o 20 1 solid (mp > 300 C, 21 mg, 62%); [α] D -20.0 (c 0.8, pyridine); H NMR (500
MHz, C5D5N) δ 8.05 (d, J = 3.8 Hz, 1H), 7.75 (s, NH2), 6.43-6.41 (m, 1H), 5.86-5.84
(m, 1H), 4.98-4.97 (m, 2H), 4.28 (m, 1H), 2.69-1.53 (series of m, 8H); 13C NMR
(125 MHz, C5D5N) ppm 166.1, 154.6, 143.3, 99.8, 82.5, 79.3, 78.4, 74.8, 55.4, 41.2,
+ 33.6, 32.4, 20.8; ES HRMS m/z (M + Na) calcd 304.1267, obsd 304.1256; Rf 0.22
(15% methanol in dichloromethane).
To a solution of 2.64 (9 mg, 0.03 mmol) in MeOH (0.5 mL) O
NH was added p-TsOH (5 mg, 0.03 mmol, 1 eq). The reaction
OH N O mixture was stirred for 24 h and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
HO OH (15% methanol in dichloromethane) to yield 2.70 as a white
o 20 1 solid (mp > 300 C, 7.8 mg, 99%); [α] D -36.0 (c 0.8, methanol); H NMR (500
MHz, CD3OD) δ 7.47 (s, 1H), 4.70-4.64 (m, 1H), 4.40-4.37 (m, 1H), 4.06 (d, J = 5.0
Hz, 1H), 3.90 (t, J = 5.4 Hz, 1H), 2.18-1.37 (series of m, 8H), 1.86 (s, 3H); 13C NMR
(125 MHz, CD3OD) ppm 163.6, 150.4, 138.0, 108.4, 77.9, 72.7, 70.6, 60.5, 51.9,
34.7, 30.3, 29.5, 17.7, 9.41; ES HRMS m/z (M + Na)+ calcd 319.1264, obsd
319.1254; Rf 0.39 (15% methanol in dichloromethane).
203
To a solution of 2.65 (10 mg, 0.03 mmol) in MeOH (2.0 NH2
N mL) was added p-TsOH (5.5 mg, 0.03 mmol, 1 eq). The N OH reaction mixture was stirred for 24 h and concentrated in N N vacuo. The residue was purified by column
HO OH chromatography on silica gel (15% methanol in
o 20 dichloromethane) to yield 2.71 as a white solid (mp > 300 C, 7 mg, 80%); [α] D -40
1 (c 0.7, pyridine); H NMR (500 MHz, C6D5N) δ 8.55 (s, 1H), 8.48 (s, 1H), 8.14 (s,
NH2), 5.75-5.25 (not seen, 1H), 4.94 (d, J = 3.9 Hz, 1H), 4.49-4.44 (m, 2H), 2.77-
13 1.61 (series of m, 8H); C NMR (125 MHz, C6D5N) ppm 157.0, 152.6, 150.0, 140.9,
128.0, 80.0, 76.8, 73.6, 61.3, 54.8, 38.7, 32.8, 32.1, 20.1; ES HRMS m/z (M + Na)+ calcd 328.1380, obsd 328.1377; Rf 0.33 (15% methanol in dichloromethane).
O To a solution of 2.67 (33 mg, 0.1 mmol) in MeOH
N NH (3.7 mL) was added p-TsOH (19 mg, 0.1 mmol, 1 eq). OH N N NH2 The reaction mixture was stirred for 24 h and
concentrated in vacuo. The residue was purified by
HO OH column chromatography on silica gel (15% methanol
o 20 in dichloromethane) to yield 2.72 as a white solid (mp > 300 C, 13 mg, 93%); [α] D
1 -42.2 (c 0.5, DMSO); H NMR (500 MHz, (CD3)2SO) δ 7.78 (s, 1H), 7.48 (s, NH2),
4.76-4.75 (m, 1H), 4.49 (m, 1H), 3.99-3.96 (m, 1H), 3.81 (d, J = 4.5 Hz, 1H), 2.09-
13 1.23 (series of m, 8H); C NMR (125 MHz, (CD3)2SO) ppm 157.3, 153.7, 152.0,
204 136.1, 114.3, 78.8, 75.8, 72.2, 58.1, 53.6, 32.6, 32.0, 31.4, 19.9; ES HRMS m/z (M +
+ Na) calcd 344.1329, obsd 344.1313; Rf 0.16 (15% methanol in dichloromethane).
OTBS Compound 2.22 (0.14 g, 0.5 mmol), H2O (1.39 mL), acetone (13.9
O mL), pyridine (82 μL, 1.0 mmol, 2 eq), and OsO4 (0.14 g, 0.56
OH OH mmol, 1.1 eq) were combined and stirred for 2 h. Gaseous H2S
was bubbled through the solution until reduction of the osmate ester was complete by
TLC. The solution was filtered through a pad of Celite, at which point the mother
liquor was quenched with saturated NaHCO3 solution, and extracted with ether (3 x
150 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by column chromatography on silica gel (3:1
o 20 hexanes:ethyl acetate) to give 2.73 (mp 102 C 0.1 g, 66%) as a white solid; [α] D
-1 1 +14.7 (c 1.6, CHCl3); IR (CH2Cl2) ν = 3552, 1750, 1109 cm ; H NMR (500 MHz,
CDCl3) δ 4.41 (dd, J = 4.5, 1.6 Hz, 1H), 4.00-3.97 (m, 2H), 2.74-1.49 (series of m,
13 8H), 0.83 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); C NMR (125 MHz, CDCl3) ppm
216.7, 78.3, 77.4, 76.7, 51.0, 39.0, 33.6, 32.1, 25.7 (3C), 19.6, 17.8, -4.0, -5.1; ES
+ HRMS m/z (M + Na) calcd 323.1649, obsd 323.1647; Rf 0.15 (3:1 hexanes:ethyl
acetate).
OTBS Compound 2.22 (93 mg, 0.31 mmol), DMAP (2.1 mg, 0.03 mmol,
O 0.1 eq), and Et3N (92 μL, 0.66 mmol, 2.1 eq) were stirred in CH2Cl2
OAcOAc (2.3 mL) at rt when Ac2O (74 μL, 0.78 mmol, 2.5 eq) was added.
The reaction mixture was stirred for 1 h, quenched with saturated NaHCO3 solution,
205 and extracted with ether (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 2.22 acetate (mp 75
o 20 C, 100 mg, 84%) as a colorless oil; [α] D +7.3 (c 0.8, CHCl3); IR (CH2Cl2) ν =
-1 1 1750, 1372, 256, 1110 cm ; H NMR (500 MHz, CDCl3) δ 5.66 (dd, J = 5.0, 1.1 Hz,
1H), 5.37 (d, J = 4.5 Hz, 1H), 4.13 (t, J = 7.6 Hz, 1H), 2.76 (d, J = 18.9 Hz, 1H),
2.25-1.56 (series of m, 7H), 2.08 (s, 3H), 2.06 (s, 3H), 0.85 (s, 9H), 0.14 (s, 3H), 0.08
13 (s, 3H); C NMR (125 MHz, CDCl3) ppm 209.3, 170.1, 169.6, 78.2, 77.9, 75.2, 50.3,
40.1, 33.3, 32.5, 25.6 (3C), 20.6, 20.3, 19.2, 17.7, -4.0, -5.2; ES HRMS m/z (M +
+ Na) calcd 407.1860, obsd 407.1856; Rf 0.25 (5:1 hexanes:ethyl acetate).
OTBS Compound 2.22 (338 mg, 1.13 mmol), pyridine (0.73 mL, 9.04
O mmol, 8 eq), and AgNO3 (0.76 mg, 4.52 mmol, 4 eq) were
O O Si Si stirred in THF (61 mL) in the dark for 1 h, where TiPDSCl O 2 (0.72 mL, 2.26 mmol, 2 eq) was added in one portion. The reaction mixture was stirred for 2 h and filtered through a pad of Celite. The meaction mixture was transferred to a separatory funnel, quenched with saturated NaHCO3 solution, and
extracted with ether (3 x 100 mL). The combined organic phases were dried over Na-
2SO4 and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 2.74 (0.6 g, 98%) as
20 a colorless oil; [α] D -8.8 (c 1.1, CHCl3); IR (CH2Cl2) ν = 1765, 1464, 1252, 1144,
-1 1 1095 cm ; H NMR (500 MHz, CDCl3) δ 4.60 (d, J = 4.4 Hz, 1H), 4.24 (d, J = 4.3
Hz, 1H), 3.97 (t, J = 7.0 Hz, 1H), 2.64-1.45 (m, 8H), 1.12-0.99 (m, 28H), 0.86 (s,
206 13 9H), 0.06 (s, 3H), 0.05 (s, 3H); C NMR (125 MHz, CDCl3) ppm 212.6, 79.7, 79.5,
77.9, 51.6, 39.1, 33.9, 32.8, 25.7 (3C), 19.4, 17.8, 17.5-12.8 (12C), -3.9, -5.1; ES
+ HRMS m/z (M + Na) calcd 565.3171, obsd 565.3159; Rf 0.18 (20:1 hexanes:ethyl
acetate).
OTBS Compound 2.74 (0.6 g, 1.1 mmol) and THF (15 mL) were
cooled to -78 oC, where L-selectride (1.2 mL, 1.2 mmol, 1.1 eq) OH O O Si Si was added and the reaction mixture was stirred for 10 min, O
quenched with saturated NaHCO3 solution, and extracted with ether (3 x 100 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl
20 acetate) to give 2.75 (598 mg, 86%) as a colorless oil; [α] D +27.2 (c 1.0, CHCl3);
-1 1 IR (CH2Cl2) ν = 1464, 1250, 1165, 1101, 1065 cm ; H NMR (500 MHz, CDCl3) δ
4.29 (t, J = 4.4 Hz, 1H), 4.04-4.02 (m, 1H), 3.98 (d, J = 3.9 Hz, 1H), 3.77 (t, J = 8.4
Hz, 1H), 2.37-1.28 (series of m, 8H), 1.09-1.06 (m, 28H), 0.89 (s, 9H), 0.05 (s, 3H),
13 0.03 (s, 3H); C NMR (125 MHz, CDCl3) ppm 77.5, 77.3, 76.3, 70.6, 55.1, 37.7,
31.6, 31.2, 25.8 (3C), 19.3, 17.9, 17.6-12.9 (12C), -4.2, -5.0; ES HRMS m/z (M +
+ Na) calcd 567.3327, obsd 567.3314; Rf 0.25 (20:1 hexanes:ethyl acetate).
OTBS To a solution of 2.75 (0.6 g, 1.1 mmol) in CH2Cl2 (37 mL) at 0
o C was added Et3N (0.61 mL, 4.4 mmol, 4 eq) followed by OMs O O Si Si MsCl (0.43 mL, 5.5 mmol, 5 eq). The reaction mixture was O allowed to warm to rt, quenched after 6 h with saturated NaHCO3 solution, and
207 extracted with Et2O (3 x 100 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 2.76 as a colorless
20 oil (0.6 g, 88%); [α] D +10.2 (c 1.1, CHCl3); IR (CH2Cl2) ν = 1464, 1361, 1251,
-1 1 1178, 1104 cm ; H NMR (500 MHz, CDCl3) δ 4.87-4.85 (m, 1H), 4.41-4.40 (m,
1H), 4.03 (d, J = 3.4 Hz, 1H), 3.79 (t, J = 8.1 Hz, 1H), 3.00 (s, 3H), 2.46-1.29 (series
of m, 8H), 1.12-1.06 (m, 28H), 0.91 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR
(125 MHz, CDCl3) ppm 79.5, 78.2, 77.4, 75.5, 55.1, 38.1, 34.8, 31.7, 31.6, 25.8
(3C)19.4, 17.9, 17.5-12.9 (12C), -4.1, -5.0; ES HRMS m/z (M + Na)+ calcd
645.3103, obsd 645.3109; Rf 0.25 (10:1 hexanes:ethyl acetate).
OTBS Compound 2.22 (94 mg, 0.32 mmol), 2,2-dimethoxypropane (4.5 O mL), and p-TsOH (6 mg, 0.03 mmol, 0.1 eq) were combined and
OO heated to 80 oC. The reaction mixture was stirred for 2 h, allowed to
come to rt, quenched with saturated NaHCO3 solution, and extracted with ether (3 x
30 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by column chromatography on silica gel (20:1
20 hexanes:ethyl acetate) to give 2.77 (104 mg, 99%) as a colorless oil; [α] D -77.6 (c
-1 1 1.7, CHCl3); IR (CH2Cl2) ν = 1758, 1251, 1086 cm ; H NMR (500 MHz, CDCl3) δ
4.37 (d, J = 5.0 Hz, 1H), 4.27 (d, J = 5.0 Hz, 1H), 3.95 (t, J = 8.1 Hz, 1H), 2.48-1.39
(series of m, 8H), 1.39 (s, 3H), 1.33 (s, 3H), 0.82 (s, 9H), 0.02 (s, 3H), 0.06 (s, 3H);
13 C NMR (125 MHz, CDCl3) ppm 213.3, 111.1, 85.3, 79.6, 79.0, 50.3, 40.7, 32.0,
208 30.8, 26.9, 25.6 (3C), 25.0, 19.6, 17.8, -4.1, -5.0; ES HRMS m/z (M + Na)+ calcd
363.1962, obsd 363.1967; Rf 0.14 (20:1 hexanes:ethyl acetate).
OTBS A solution of 2.77 (104 mg, 0.3 mmol) and THF (4 mL) was cooled
o OH to -78 C, when L-selectride (0.34 mL, 0.34 mmol, 1.1 eq) was added.
OO The reaction mixture was stirred for 20 min, quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with ether (3 x 30
mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (20:1
20 hexanes:ethyl acetate) to yield 2.78 as a colorless oil (100 mg, 98%); [α] D +29.9 (c
-1 1 1.7, CHCl3); IR (neat) ν = 3495, 1471, 1372, 1251, 1043 cm ; H NMR (500 MHz,
CDCl3) δ 4.46 (t, J = 5.7 Hz, 1H), 4.14-4.11 (m, 1H), 4.06 (d, J = 5.5 Hz, 1H), 3.64 (t,
J = 5.7 Hz, 1H), 2.26-1.34 (series of m, 8H), 1.49 (s, 3H), 1.34 (s, 3H), 0.89 (s, 9H),
13 0.04 (s, 6H); C NMR (125 MHz, CDCl3) ppm 110.4, 85.4, 79.3, 78.0, 70.9, 54.3,
37.8, 33.3, 30.1, 26.0, 25.8 (3C), 24.3, 20.2, 17.9; ES HRMS m/z (M + Na)+ calcd
365.2118, obsd 365.2102; Rf 0.08 (20:1 hexanes:ethyl acetate).
OTBS A solution of 2.78 (83 mg, 0.24 mmol) and CH2Cl2 (1 mL) was
cooled to 0 oC, when pyridine (39 μL, 0.5 mmol, 2 eq) and triflic OTf
OO anhydride (50 μl, 0.3 mmol, 1.2 eq) were added. The reaction
mixture was stirred for 15 min, quenched with water, transferred to a separatory
funnel, and extracted with dichloromethane (3 x 30 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified
209 by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to yield 2.79 as
20 a colorless oil (97 mg, 82%); [α] D -10.3 (c 0.7, CHCl3); IR (neat) ν = 1415, 1246,
-1 1 1209, 1148 cm ; H NMR (500 MHz, CDCl3) δ 5.25-5.21 (m, 1H), 4.61 (t, J = 5.5
Hz, 1H), 4.17 (d, J = 5.1 Hz, 1H), 3.76 (t, J = 7.2 Hz, 1H), 2.40-1.54 (series of m,
8H), 1.50 (s, 3H), 1.34 (s, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR
(125 MHz, CDCl3) ppm 111.8, 86.3, 85.7, 78.8, 78.1, 53.5, 35.0, 32.5, 30.5, 25.9,
25.6 (3C), 24.7, 19.6, 17.8, -4.3, -5.0 (CF3 not seen); Rf 0.45 (10:1 hexanes:ethyl
acetate).
O To a solution of uracil (123 mg, 1.1 mmol, 2.7 eq) in DMF (20
NH mL) at rt under N2 was added KH (50 mg, 1.2 mmol, 3 eq). The OTBS N O reaction mixture was stirred for 10 min prior to the addition of
2.79 (200 mg, 0.4 mmol) quenched after 48 h with water, OO transferred to a separatory funnel, and extracted with ether (3 x
30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1
20 hexanes:ethyl acetate) to yield 2.80 as a colorless oil (10 mg, 5%); [α] D +3.7 (c 0.9,
-1 1 CHCl3); IR (neat) ν = 1691, 1461, 1380, 1250 cm ; H NMR (500 MHz, CDCl3) δ
8.48 (s, NH), 7.22 (d, J = 8.1 Hz, 1H), 5.73 (dd, J = 8.0, 2.4 Hz, 1H), 4.77-4.67 (m,
2H), 4.68 (d, J = 5.9 Hz, 1H), 3.95 (t, J = 6.9 Hz, 1H), 1.98-1.26 (series of m, 8H),
1.55 (s, 3H), 1.31 (s, 3H), 0.92 (s, 9H), 0.10 (s, 3H) 0.08 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 162.7, 150.5, 142.0, 113.6, 102.5, 83.0 (2C), 79.2, 62.4, 53.8,
210 35.2, 32.2, 29.6, 26.5, 25.8 (3C), 25.0, 19.9, 18.0, -4.2, -4.7; ES HRMS m/z (M +
+ Na) calcd 459.2285, obsd 459.2316; Rf 0.33 (1:1 hexanes:ethyl acetate).
NH2 To a solution of cytosine (64 mg, 0.58 mmol, 2.7 eq) in DMF
N (10 mL) at rt under N2 was added KH (26 mg, 0.64 mmol, 3 OTBS N O eq). The reaction mixture was stirred for 10 min prior to the
addition of 2.79 (104 mg, 0.2 mmol), stirred for 48 h,
OO quenched with water, transferred to a separatory funnel, and extracted with ether (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to yield 2.81 as a white solid
o 20 (mp 143 C, 22 mg, 23%, 61% brsm); [α] D +29.2 (c 1.0, CHCl3); IR (neat) ν =
-1 1 3341, 3108, 1665, 1595, 1411 cm ; H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 5.7
Hz, 1H), 6.05 (d, J = 5.7 Hz, 1H), 5.27-5.24 (m, 1H), 4.85 (s, NH2), 4.65 (d, J = 6.4
Hz, 1H), 4.14 (d, J = 6.5 Hz, 1H), 3.93-3.92 (m, 1H), 2.24-1.24 (series of m, 8H),
1.48 (s, 3H), 1.29 (s, 3H), 0.79 (s, 9H), 0.05 (s, 3H), -0.01 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 164.7, 164.6, 157.6, 111.2, 99.1, 85.6, 83.2, 80.0, 78.0, 57.6, 34.7,
33.2, 29.4, 26.3, 25.7 (3C), 24.5, 20.2, 17.9, -4.2, -5.0; ES HRMS m/z (M + Na)+ calcd 458.2445, obsd 458.2442; Rf 0.21 (2:1 hexanes:ethyl acetate).
O To a solution of thymine (86 mg, 0.68 mmol, 2.7 eq) in DMF
NH (12 mL) at rt under N2 was added KH (31 mg, 0.76 mmol, 3 OTBS N O
211
OO eq). The reaction mixture was stirred for 10 min prior to the addition of 2.79 (123
mg, 0.25 mmol), stirred for 48 h, quenched with water, transferred to a separatory
funnel, and extracted with ether (3 x 30 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to yield 2.82 as a white solid
o 20 (mp 142 C, 5 mg, 14% yield, 68% conv); [α] D +3.5 (c 0.4, CHCl3); IR (neat) ν =
-1 1 1688, 1469, 1379, 1250, 1064 cm ; H NMR (500 MHz, CDCl3) δ 8.12 (s, NH),
7.01 (d, J = 0.9 Hz, 1H), 4.76-4.68 (m, 2H), 4.39 (d, J = 7.1 Hz, 1H), 3.96 (t, J = 7.1
Hz, 1H), 2.42-1.23 (series of m, 8H), 1.94 (s, 3H), 1.55 (s, 3H), 1.32 (s, 3H), 0.93 (s,
13 9H), 0.11 (s, 3H), 0.09 (s, 3H); C NMR (125 MHz, CDCl3) ppm 163.2, 150.5,
137.8, 113.6, 111.0, 82.89, 82.87, 79.1, 61.9, 53.6, 35.0, 32.2, 29.4, 26.5, 25.8 (3C),
25.1, 19.9, 18.0, 12.4, -4.1, -4.8; ES HRMS m/z (M + Na)+ calcd 473.2442, obsd
473.2440; Rf 0.25 (2:1 hexanes:ethyl acetate).
NH2 To a solution of adenine (97 mg, 0.53 mmol, 2.7 eq) in
N N DMF (10 mL) at rt under N2 was added KH (24 mg, 0.6 OTBS N N mmol, 3 eq). The reaction mixture was stirred for 10 min
prior to the addition of 2.79 (97 mg, 0.2 mmol), stirred for OO an additional 48 h, quenched with water, transferred to a
separatory funnel, and extracted with ether (3 x 30 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to yield 2.83 as a
o 20 white solid (mp 198 C, 17 mg, 18%, 41% brsm); [α] D +15.5 (c 1.7, CHCl3); IR
212 -1 1 (neat) ν = 3320, 3165, 1647, 1598, 1066 cm ; H NMR (500 MHz, CDCl3) δ 8.32 (s,
1H), 8.01 (s, NH), 7.84 (s, 1H), 5.81 (s, NH2), 5.02 (dd, J = 7.5, 5.5 Hz, 1H), 4.80-
4.75 (m, 1H), 4.53 (d, J = 7.5 Hz, 1H), 4.00 (t, J = 6.7 Hz, 1H), 2.10-1.41 (series of
m, 8H), 1.55 (s, 3H), 1.30 (s, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H); 13C NMR
(125 MHz, CDCl3) ppm 155.5, 152.7, 150.2, 139.5, 120.3, 113.8, 84.1, 82.9, 79.0,
60.4, 54.3, 36.7, 32.5, 29.3, 26.5, 25.7 (3C), 24.9, 20.1, 18.0, -4.1, -4.9; ES HRMS
+ m/z (M + Na) calcd 482.2557, obsd 482.2530; Rf 0.39 (2:1 hexanes:ethyl acetate).
Cl To a solution of 2-amino-6-chloropurine (222 mg, 1.3
N N mmol, 2.7 eq) in DMF (23 mL) at rt under N2 was OTBS N N NH2 added KH (60 mg, 1.4 mmol, 3 eq), stirred for 10 min
prior to the addition of 2.79 (237 mg, 0.5 mmol, 1 OO eq). The reaction mixture was stirred for 48 h, quenched with water, transferred to a separatory funnel, and extracted with ether (3 x
30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1
20 hexanes:ethyl acetate) to yield 2.84 as a clear oil (52 mg, 22%, 38% brsm); [α] D -
-1 1 19.5 (c 1.2, CHCl3); IR (neat) ν = 3317, 3204, 1612, 1563, 1462, 1207 cm ; H
NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 5.19 (s, NH2), 4.95-4.92 (m, 1H), 4.67-4.62
(m, 1H), 4.49 (d, J = 7.5 Hz, 1H), 3.99-3.97 (m, 1H), 2.81-1.23 (series of m, 8H),
1.54 (s, 3H), 1.30 (s, 3H), 0.91 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 158.8, 153.7, 151.3, 141.6, 125.9, 113.9, 83.5, 82.7, 78.8, 60.5,
213 54.0, 36.0, 32.4, 29.2, 26.5, 25.8 (3C), 24.9, 20.0, 18.0, -4.1, -4.9; ES HRMS m/z (M
+ + Na) calcd 516.2168, obsd 516.2163; Rf 0.27 (2:1 hexanes:ethyl acetate).
O To a solution of 2.80 (10 mg, 0.023 mmol) in THF (1 mL) was
NH added a 1M solution of TBAF in THF (0.1 mL, 0.1 mmol, 4 OH N O eq). The reaction mixture was stirred for 24 h, quenched with
brine, transferred to a separatory funnel, and extracted with
OO dichloromethane (4 x 30 mL). The combined organic phases
were dried over Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (6% methanol in dichloromethane) to yield 2.85
20 as a colorless oil (5 mg, 70%); [α] D -3 (c 0.5, CHCl3); IR (neat) ν = 3400, 3173,
-1 1 1679, 1381, 1209, 1060 cm ; H NMR (500 MHz, CDCl3) δ 9.01 (s, NH), 7.36 (d, J
= 8.1 Hz, 1H), 5.74 (d, J = 7.9 Hz, 1H), 4.81 (t, J = 5.7 Hz, 1H), 4.61-4.57 (m, 1H),
4.39 (d, J = 6.9 Hz, 1H), 4.01 (t, J = 5.5 Hz, 1H), 2.50-1.57 (series of m, 8H), 1.55 (s,
13 3H), 1.32 (s, 3H); C NMR (125 MHz, CDCl3) ppm 163.2, 150.7, 143.2, 113.3,
102.4, 83.6, 83.3, 78.77, 64.7, 54.5, 34.9, 32.8, 30.6, 26.7, 25.0, 20.4; ES HRMS m/z
+ (M + H) calcd 345.1420, obsd 345.1417; Rf 0.27 (10% methanol in
dichloromethane).
NH2 To a solution of 2.81 (21 mg, 0.05 mmol) in THF (2 mL) was
N added a 1M solution of TBAF in THF (0.2 mL, 0.2 mmol, 4 OH N O eq). The reaction mixture was stirred for 24 h, quenched with
OO 214 brine, transferred to a separatory funnel, and extracted with dichloromethane (4 x 30
mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (10%
methanol in dichloromethane) to yield 2.86 as a white solid (mp 273 oC, 14 mg,
20 93%); [α] D +13.4 (c 1.0, CHCl3); IR (neat) ν = 3338, 3213, 1635, 1596, 15558,
-1 1 1409, 1042 cm ; H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 5.7 Hz, 1H), 6.08 (d, J
= 5.7 Hz, 1H), 5.39 (s, NH2), 5.15-5.14 (m, 1H), 4.58 (d, J = 5.6 Hz, 1H), 4.03 (d, J =
5.5 Hz, 1H), 3.84 (d, J = 5.7 Hz, 1H), 2.11-1.47 (series of m, 8H), 1.79 (s, 3H), 1.61
13 (s, 3H); C NMR (125 MHz, CDCl3) ppm 164.9, 164.1, 157.5, 110.3, 99.8, 85.2,
83.9, 80.7, 76.5, 59.1, 33.9, 33.6, 30.0, 26.3, 24.0, 22.0; ES HRMS m/z (M + H)+ calcd 344.1580, obsd 344.1588; Rf 0.47 (10% methanol in dichloromethane).
O To a solution of 2.82 (3.5 mg, 0.008 mmol) in THF (0.5 mL)
NH was added a 1M solution of TBAF in THF (31 μL, 0.03 mmol, OH N O 4 eq). The reaction mixture was stirred for 24 h, quenched
with brine, transferred to a separatory funnel, and extracted
OO with dichloromethane (4 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 ethyl acetate:hexanes) to yield 2.87 as a
o 20 1 white solid (mp 248 C, 2.4 mg, 92%); [α] D -5.5 (c 0.2, CHCl3); H NMR (500
MHz, CDCl3) δ 8.48 (s, NH), 7.13 (d, J = 0.9 Hz, 1H), 4.83 (dd, J = 6.8, 5.4 Hz, 1H),
4.57-4.53 (m, 1H), 4.39 (d, J = 6.9 Hz, 1H), 4.02 (t, J = 5.8 Hz, 1H), 2.51-1.19
(series of m, 8H), 1.94 (d, J = 0.8 Hz, 3H), 1.56 (s, 3H), 1.32 (s, 3H); 13C NMR (125
215 MHz, CDCl3) ppm 163.4, 150.1, 139.1, 113.4, 110.9, 83.6, 83.2, 78.9, 64.5, 54.5,
35.0, 32.9, 30.6, 29.7, 26.7, 25.0, 12.3; ES HRMS m/z (M + Na)+ calcd 359.1577, obsd 359.1580; Rf 0.11 (2:1 ethyl acetate:hexanes).
NH2 To a solution of 2.83 (15 mg, 0.03 mmol) in THF (1.5
N N mL) was added a 1M solution of TBAF in THF (130 μL, OH N N 0.13 mmol, 4 eq). The reaction mixture was stirred for 24
h, quenched with saturated NaHCO3 solution, transferred OO to a separatory funnel, and extracted with dichloromethane
(4 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography on silica gel (6%
methanol in dichloromethane) to yield 2.88 as a white solid (mp > 300 oC, 11 mg,
20 1 96%); [α] D -36.2 (c 1.0, py); H NMR (500 MHz, C5D5N) δ 8.68 (s, NH), 8.63 (s,
1H), 8.61 (s, 1H), 8.18 (s, NH2), 5.33 (1H not seen), 5.19-5.15 (m, 1H), 4.72 (d, J =
7.1 Hz, 1H), 4.21 (t, J = 4.8 Hz, 1H), 3.19-1.33 (series of m, 8H), 1.61 (s, 3H), 1.33
13 (s, 3H); C NMR (125 MHz, C5D5N) ppm 157.1, 153.0, 150.3, 140.1, 120.5, 112.9,
85.0, 84.0, 77.9, 60.9, 55.6, 36.6, 33.3, 30.4, 26.6, 24.8, 20.9; ES HRMS m/z (M +
+ Na) calcd 368.1693, obsd 368.1684; Rf 0.41 (10% methanol in dichloromethane).
Cl To a solution of 2.84 (49 mg, 0.01 mmol) in THF (5
N N mL) was added a 1M solution of TBAF in THF (0.4 OH N N NH2 mL, 0.4 mmol, 4 eq). The reaction mixture was
OO 216 stirred for 24 h, quenched with brine, transferred to a separatory funnel, and extracted
with dichloromethane (4 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10% methanol in dichloromethane) to yield 2.89 as a
20 1 white foam (35 mg, 96%); [α] D -1.5 (c 1.6, py); H NMR (500 MHz, C5D5N) δ
8.63 (s, 1H), 7.60 (s, NH2), 5.22 (dd, J = 6.6, 4.5 Hz, 1H), 5.03-4.99 (m, 1H), 4.59 (d,
J = 6.8 Hz, 1H), 4.11 (s, 1H), 3.06-3.01 (m, 1H), 2.38-1.62 (series of m, 7H), 1.59 (s,
13 3H), 1.32 (s, 3H); C NMR (125 MHz, C5D5N) ppm 160.6, 154.7, 150.8, 141.8,
125.3, 112.6, 85.0, 84.1, 77.4, 60.7, 56.0, 35.9, 33.5, 30.3, 26.7, 24.8, 20.9; ES
+ HRMS m/z (M + H) calcd 402.1303, obsd 402.1280; Rf 0.43 (6% methanol in
dichloromethane).
O A solution of 2.89 (35 mg, 0.092 mmol), MeOH (12
N NH mL), 2-mercaptoethanol (0.13 mL, 1.84 mmol, 20 OH N N NH2 eq), and a 5.25 M solution of NaOMe in methanol
(0.37 mL, 1.93 mmol, 21 eq) was stirred at 80 oC for OO 4 h. The reaction mixture was quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with
dichloromethane (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10% methanol in dichloromethane) to yield 2.90 as a white solid (mp > 300
o 20 1 C, 24 mg, 72%); [α] D +2.4 (c 1.0, DMSO); H NMR (500 MHz, (CD3)2SO) δ
7.89 (s, 1H), 6.48 (s, NH2), 4.87 (dd, J = 7.2, 5.1 Hz, 1H), 4.72 (d, J = 4.4 Hz, 1H),
217 4.60-4.56 (m, 1H), 4.35 (d, J = 7.3 Hz, 1H), 2.95-1.45 (series of m, 8H), 1.43 (s, 3H),
13 1.22 (s, 3H); C NMR (125 MHz, (CD3)2SO) ppm 157.2, 153.9, 151.5, 136.1, 117.2,
112.8, 84.7, 83.4, 77.6, 58.5, 55.1, 38.0, 33.0, 26.8, 25.2, 21.0; ES HRMS m/z (M +
+ H) calcd 384.1642, obsd 384.1625; Rf 0.15 (10% methanol in dichloromethane).
To a solution of 2.85 (4 mg, 0.012 mmol) in MeOH (2.0 mL) O was added p-TsOH (0.5 mg, 0.002 mmol, 0.2 eq). The NH OH reaction mixture was stirred for 24 h, and concentrated in N O vacuo, and the residue was purified by column
HO OH chromatography on silica gel (15% methanol in
o 20 dichloromethane) to yield 2.91 as a white solid (mp > 300 C, 3 mg, 88%); [α] D -
1 14.3 (c 0.3, DMSO); H NMR (500 MHz, (CH3)2SO) δ 7.76 (d, J = 8.0 Hz, 1H),
5.62 (d, J = 8.0 Hz, 1H), 4.83-4.76 (m, 2H), 4.59 (d, J = 4.2 Hz, 1H), 3.49 (t, J = 4.3
13 Hz, 1H), 1.87-1.36 (series of m, 8H); C NMR (125 MHz, (CH3)2SO) ppm 163.6,
151.9, 142.7, 101.8, 77.4, 76.8, 74.9, 59.6, 53.3, 33.2, 32.6, 32.1, 19.9; ES HRMS
+ m/z (M + Na) calcd 305.1107, obsd 305.1118; Rf 0.34 (15% methanol in
dichloromethane).
NH2 To a solution of 2.86 (14 mg, 0.04 mmol) in MeOH (1.0 mL)
N was added p-TsOH (11 mg, 0.05 mmol, 1 eq). The reaction OH N O mixture was stirred at 80 oC for 2 h, cooled to rt, and
concentrated in vacuo, and purified by column
HO OH
218 chromatography on silica gel (15% methanol in dichloromethane) to yield 2.92 as a
o 20 1 white solid (mp > 300 C, 12 mg, 100%); [α] D -27.4 (c 1.2, py); H NMR (500
MHz, C5D5N) δ 8.06 (d, J = 3.8 Hz, 1H), 7.68 (s, NH2), 6.26 (d, J = 3.9 Hz, 1H),
5.91-5.86 (m, 1H), 4.85 (t, J = 5.4 Hz, 1H), 4.31 (d, J = 5.8 Hz, 1H), 4.24 (t, J = 6.2
13 Hz, 1H), 2.73-1.53 (series of m, 8H); C NMR (125 MHz, C5D5N) ppm 166.4, 156.8,
114.3, 99.5, 82.5, 77.6, 77.4, 76.3, 54.9, 34.5, 33.4, 31.4, 20.4; ES HRMS m/z (M +
+ Na) calcd 304.1267, obsd 304.1275; Rf 0.51 (20% methanol in dichloromethane).
O To a solution of 2.87 (1.3 mg, 0.004 mmol) in MeOH (0.5
NH mL) was added p-TsOH (0.2 mg, 0.001 mmol, 0.3 eq). The
OH o N O reaction mixture was stirred at 80 C for 2 h, cooled to rt, and
concentrated in vacuo, and the residue was purified by column
HO OH chromatography on silica gel (15% methanol in
o 20 dichloromethane) to yield 2.93 as a white solid (mp > 300 C, 1.1 mg, 99%); [α] D -
1 7.8 (c 0.14, methanol); H NMR (500 MHz, CD3OD) δ 7.72 (d, J 1.0 Hz, 1H), 4.93-
4.88 (m, 1H), 4.34 (dd, J = 9.0, 6.9 Hz, 1H), 3.88 (t, J = 7.2 Hz, 1H), 3.71 (d, J = 4.9
Hz, 1H) 2.06-1.52 (series of m, 8H), 1.90 (d, J 1.0 Hz, 3H); 13C NMR (125 MHz,
CD3OD) ppm 165.0, 152.1, 139.1, 110.0, 77.8, 76.9, 74.9, 60.7, 53.5, 32.4, 31.5,
+ 31.3, 19.2, 11.0; ES HRMS m/z (M + Na) calcd 319.1264, obsd 319.1275; Rf 0.45
(15% methanol in dichloromethane).
219 NH2 To a solution of 2.88 (11 mg, 0.03 mmol) in MeOH (1.1
N N mL) was added p-TsOH (6 mg, 0.03 mmol, 1 eq). The OH N N reaction mixture was stirred for 24 h, and concentrated in
vacuo and the residue was purified by column HO OH chromatography on silica gel (15% methanol in dichloromethane) to yield 2.94 as a
o 20 1 white solid (mp > 300 C, 8.3 mg, 86%); [α] D -36.4 (c 1.0, py); H NMR (500
MHz, C5D5N) δ 8.60 (s, 1H), 8.53 (s, 1H), 8.17 (s, NH2), 5.48-5.42 (m, 1H), 5.22 (dd,
J = 8.5, 4.3 Hz, 1H), 4.27 (t, J = 6.5 Hz, 1H), 4.24 (d, J = 4.3 Hz, 1H), 3.96-1.13
13 (series of m, 8H); C NMR (125 MHz, C5D5N) ppm 157.1, 153.0, 150.3, 140.1,
120.5, 112.9, 85.0, 84.0, 77.9, 60.9, 55.6, 36.6, 33.3, 30.4, 26.6, 24.8, 20.9, 13.4; ES
+ HRMS m/z (M + Na) calcd 328.1380, obsd 328.1368; Rf 0.10 (10% methanol in
dichloromethane).
O To a solution of 2.90 (28 mg, 0.08 mmol) in MeOH
N NH (2.5 mL) was added p-TsOH (4.4 mg, 0.02 mmol, 0.3 OH N o N NH2 eq). The reaction mixture was stirred at 80 C for 2 h,
cooled to rt, and concentrated in vacuo, and the HO OH residue was purified by column chromatography on
silica gel (15% methanol in dichloromethane) to yield 2.95 as a white solid (mp > 300
o 20 1 C, 23 mg, 95%); [α] D -14.1 (c 0.5, DMSO); H NMR (500 MHz, (CD3)2SO) δ
7.79 (s, 1H), 6.63 (s, NH2), 4.93 (d, J = 11.1, 5.1 Hz, 1H), 4.65 (d, J = 4.1 Hz, 1H),
4.33-4.29 (m, 1H), 3.55 (t, J = 4.3 Hz, 1H), 2.05-1.23 (series of m, 8H); 13C NMR
(125 MHz, (CD3)2SO) ppm 157.3, 152.7, 150.2, 140.7, 121.0, 77.7, 77.6, 75.1, 61.3,
220 55.1, 45.7, 34.0, 32.4, 20.7; ES HRMS m/z (M + Na)+ calcd 344.1329, obsd
344.1323; Rf 0.13 (15% methanol in dichloromethane).
O To a stirred solution of 3.14 (0.59g, 4.6 mmol), imidazole (0.47 g, 6.91 OTBS
mmol), and DMAP (56 mg, 0.46 mmol) in CH2Cl2 (25 mL), TBSCl
(1.04 g, 6.91 mmol) was added in one portion. The reaction mixture
was heated to reflux and stirred for 24 h, allowed to come to rt, quenched with
saturated NaHCO3 solution, transferred to a seperatory funnel, and extracted with
CH2Cl2 (3 x 25mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 3.15 as a colorless oil (1.11 g, 98); IR (neat)
-1 1 ν = 1710, 1472, 1253, 1114 cm ; H NMR (300 MHz, CDCl3) δ 4.26 (dd, J = 7.1,
2.4 Hz, 1 H), 2.66 (dt, J = 15.4, 6.5 Hz, 1 H), 2.39-2.29 (m, 1 H), 1.92-1.56 (m, 7 H),
1.39-1.32 (m, 1 H), 0.90 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3H); 13C NMR (75 MHz,
CDCl3) ppm 213.7, 79.0, 40.3, 33.7, 28.2, 25.7, 24.9 (3C), 22.7, 18.1, -5.0, -5.1; ES
+ HRMS m/z (M + Na) calcd 265.1594, obsd 265.160; Rf 0.60 (10:1 hexanes:ethyl
acetate).
O To a solution of 3.15 (11.46 g, 47.4 mmol) and THF (320 mL) at -
TBSO OTBS 78 oC, a 1M solution of LHMDS in THF (56.8 mL, 56.9 mmol)
was added, stirred for 1 h, and followed by the addition of TBSCl
(9.97 g, 66.4 mmol) at -78 oC. The reaction mixture was warmed to rt, quenched with
saturated NaHCO3 solution, extracted with Et2O (3 x 200 mL), dried over Na2SO4,
221 and concentrated in vacuo. The crude product was redisolved in CH2Cl2 (573 mL),
cooled to 0 oC, and mCPBA (12.78 g, 56.9 mmol) was added. The reaction mixture was stirred for 2 h, allowed to come to rt, quenched with 1M solution of NaOH (700 mL), and extracted with CH2Cl2 (2 x 400 mL). The combined organic phases were washed once with saturated NaHCO3 solution, dried over Na2SO4, and concentrated
in vacuo, and the residue was purified by column chromatography on silica gel (10:1
hexanes:ethyl acetate) to give 3.16 as a yellow oil (11.65 g, 66%); IR (neat) ν =
-1 1 1728, 1472, 1255, 1106, 1037, 836, 777 cm ; H NMR (300 MHz, CDCl3) δ 4.53 (t,
J = 4.4 Hz, 2 H), 1.98-1.43 (m, 8 H), 0.90-0.83 (m, 18 H), 0.11-0.00 (m, 12 H); 13C
NMR (75 MHz, CDCl3) ppm 211.9, 76.8 (2C), 33.6 (2C), 25.7 (6C), 21.4 (2C), 18.2
+ (2C), -4.99 (2C), -5.26 (2C); ES HRMS m/z (M + Na) calcd 395.2408, obsd
395.2402; Rf 0.67 (10:1 hexanes:ethyl acetate).
O OH To a solution of 3.16 (3.0 g, 8.07 mmol) and HO OH O OH
THF (90 mL) under N2, 1M solution of TBAF + in THF (17.7 mL, 17.7 mmol) was added and
the reaction mixture was stirred for 18 h, quenched with saturated NaHCO3 solution,
and extracted with Et2O (3 x 90 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 3.9 (0.93 g, 80%)
and 3.10 (0.11 g, 10%) both as a yellow oils; IR (neat) ν = 3414, 1710, 1452, 1270,
-1 1 1085, 1008 cm ; H NMR (300 MHz, CDCl3) δ 4.25 (dd, J = 9.8, 2.9 Hz, 2H), 3.10
(s, 2 OH), 2.12-2.04 (m, 2H), 1.98-1.90 (m, 2H), 1.79-1.25 (m, 4H); 13C NMR (75
222 + MHz, CDCl3) ppm 214.2, 77.4 (2C), 32.2 (2C), 26.9 (2C); ES HRMS m/z (M + Na) calcd 167.1678, obsd 167.0674; Rf 0.15 (3:1 hexanes:ethyl acetate).
For 3.10; IR (neat) ν = 3418, 1703, 1647, 1451, 1402, 1347, 1264 cm-1; 1H
NMR (300 MHz, CDCl3) δ 4.45 (d, J = 1.5 Hz, 1H), 4.26-4.22 (m, 1H), 2.75-2.69 (m,
1H), 2.53-2.46 (m, 1H), 2.23-2.18 (m, 1H), 1.99-1.93 (m, 1H), 1.88-1.79 (m, 2H),
13 1.74-1.61 (m, 2H); C NMR (75 MHz, CDCl3) ppm 212.2, 80.8, 73.1, 41.0, 34.2,
+ 23.0, 22.9; ES HRMS m/z (M + Na) calcd 167.1678, obsd 167.0669; Rf 0.26 (1:1
hexanes:ethyl acetate).
OH OTBS To a stirred solution of 3.17 (1.0g, 7.0 mmol), O OTBS O OTBS imidazole (0.72 g, 10.6 mmol), and DMAP + (86 mg, 70 mmol) in CH2Cl2 (38 mL), TBSCl
(1.59 g, 10.6 mmol) was added in one portion. The reaction mixture was heated to
reflux, stirred for 48 h, allowed to come to rt, quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 20 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel to give give (26
mg, 42%) of 3.18 and (38 mg, 40%) of 3.19, both as colorless oils.
For 8; IR (neat) ν = 3460, 1705, 1472, 1397, 1256, 1098, cm-1; 1H NMR (300
MHz, CDCl3) δ 4.40 (s, 1H), 4 20 (d, J = 5.3 Hz, 1H), 4.08 (s, OH), 2.73-2.72 (m,
1H), 2.44-2.37 (m, 1H), 2.08-2.03 (m, 1H), 1.98-1.92 (m, 1H), 1.86-1.58 (m, 4H),
13 0.87 (s, 9H), 0.06 (s, 6H); C NMR (75 MHz, CDCl3) ppm 211.6, 81.2, 74.8, 40.9,
223 35.9, 26.1 (3C), 23.4, 22.9, 18.4, -4.4, -4.6; ES HRMS m/z (M + Na)+ calcd 281.1543,
obsd 281.1533; Rf 0.28 (10:1 hexanes:ethyl acetate).
For 9; IR (neat) ν = 1723, 1472, 1252, 1126, 1078, 1030, 954 cm-1; 1H NMR
(300 MHz, CDCl3) δ 4.35 (s, 1H), 3.92-3.90 (m, 1H), 2.57-2.38 (m, 2H), 2.08-1.97
(m, 2H), 1.79-1.46 (m, 4H), 0.95 (s, 9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H), 0.07
13 (s, 6H); C NMR (75 MHz, CDCl3) ppm 211.3, 84.9, 75.8, 41.6, 35.3, 26.3 (3C),
25.7 (3C), 23.8, 22.8, 18.8, 18.5, -4.2, -4.4, -4.6, -4.8; ES HRMS m/z (M + Na)+ calcd
395.2408, obsd 395.2435; Rf 0.75 (10:1 hexanes:ethyl acetate).
OH OTBS Into a solution of 3.16 (42 mg, 0.106 TBSO OTBS TBSO OH
mmol) and CH2Cl2 (4 mL) under N2 at - + 78 oC, a 1M solution of DIBAL-H in
hexanes (127 μL, 0.13 mmol, 1.2 eq) was added dropwise and the reaction mixture
was stirred for 45 min, quenched at -78 oC with saturated K+,Na+ tartarate solution,
and allowed to warm to rt. After 30 min, the reaction mixture was extracted with
CH2Cl2 (3 x 25 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give (31 mg, 71%) of 3.20 and (10 mg, 26%) of
3.21, both as colorless oils.
For 3.20: IR (neat) ν = 3468, 2930, 2858, 1472, 1361, 1254, 1132, 1102 cm-1;
1 H NMR (300 MHz, CDCl3) δ 3.94-3.91 (m, 1H), 3.88-3.86 (m, 1H), 3.83-3.81 (m,
224 1H), 1.92-1.42 (m, 8H), 0.96 (s, 9H), 0.93 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H), 0.09 (s,
13 3H), 0.08 (s, 3H); C NMR (75 MHz, CDCl3) ppm 79.1, 72.0, 71.8, 30.2, 29.3, 26.25
(3C), 26.20 (3C), 22.6, 20.3, 18.48, 18.40, -4.0, -4.3, -4.4 (2C); ES HRMS m/z (M +
+ Na) calcd 397.2564, obsd 397.2587; Rf 0.48 (10:1 hexanes:ethyl acetate).
For 3.21: IR (neat) ν = 3355, 2955, 1472, 1360, 1255, 1119, 1062 cm-1; 1H
NMR (300 MHz, CDCl3) δ 4.07-4.05 (m, 1H), 3.88-3.83 (m, 1H), 3.58 (d, J = 7.2 Hz,
1H), 2.03-1.46 (m, 8H), 0.96 (s, 9H), 0.93 (s, 9H), 0.13 (s, 6H), 0.11 (s, 3H), 0.08 (s,
13 3H); C NMR (75 MHz, CDCl3) ppm 82.1, 74.4, 72.8, 33.1, 32.7, 26.3 (3C), 26.2
(3C), 23.8, 22.1, 18.5 (2C), -3.5, -4.2, -4.3, -4.4; ES HRMS m/z (M + Na)+ calcd
397.2564, obsd 397.2559; Rf 0.44 (10:1 hexanes:ethyl acetate).
OH Into a solution of 3.20 (3.0 g, 8.07 mmol) and THF (90 mL) under N2, HO OH at 0 oC, 1M solution of TBAF in THF (17.7 mL, 17.7 mmol) was
added and the reaction mixture was stirred for 12 h, quenched with
saturated NaHCO3 solutiond, transferred to a separatory funnel, and extracted with
Et2O (3 x 90 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 3.22 as a yellow oil (0.93 g, 80%); IR (neat) ν
-1 1 = 3394, 2930, 1454, 1030 cm ; H NMR (300 MHz, CDCl3) δ 4.12-4.11 (m, 1H),
3.82-3.78 (m, 1H), 3.53 (dd, J = 8.5, 3.3 Hz, 1H), 1.98-1.93 (m, 1H), 1.84-1.41 (m,
13 7H); C NMR (75 MHz, CDCl3) ppm 79.1, 71.9, 70.8, 33.2, 30.7, 24.0, 21.5; ES
HRMS m/z (M + Na)+ calcd 169.0835, obsd 169.0827; Rf 0.17 (10:1
dichloromethane:methanol).
225
O A solution of 3.15 (1.65 g, 6.82 mmol) in THF (8.17 mL) was cooled HO OTBS to 0 oC, where a 1M solution of LHMDS in THF (47.1 mL, 47.1
mmol, 1.2 eq) was added and the mixture was stirred for 1 h at rt.
The reaction mixture was cooled to 0 oC, treated with TMSCl (1.21 mL, 9.55 mmol,
1.4 eq), and stirred for 12 h as it warmed to rt. Upon completion, the reaction mixture
was quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and
extracted with ether (3 x 100 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The crude product was redissolved in CH2Cl2
(138 mL) and K2CO3 (0.94 g, 6.82 mmol, 1 eq) was added. The mixture was cooled
to 0 oC, where mCPBA (2.08 g, 8.17 mmol, 1.2 eq) was added and stirred for 4 h.
Upon completion, the reaction mixture was allowed to warm rt, quenched with
saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with
Et2O (3 x 50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 3.23 as a colorless oil (264 mg, 15%); IR
-1 1 (neat) ν = 3492, 1712, 1471, 1254 cm ; H NMR (300 MHz, CDCl3) δ 4.64 (dd, J =
5.5, 2.5 Hz, 1H), 4.55 (dd, J = 6.6, 1.5 Hz, 1H) 2.30-2.24 (m, 1H), 1.95-1.91 (m, 2H),
1.76-1.65 (m, 4H), 1.57-1.50 (m, 1H), 0.96 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H); 13C
NMR (75 MHz, CDCl3) ppm 215.0, 77.9, 74.7, 34.4, 32.0, 26.0 (3C), 25.0, 23.7,
18.4, -4.5, -4.9; ES HRMS m/z (M + Na)+ calcd 281.1543, obsd 281.1531; Rf 0.31
(10:1 hexanes:ethyl acetate).
226 O A solution of 3.23 (108 mg, 0.42 mmol) and IBX (140 mg, 0.5 mmol, O OTBS 1.2 eq) in an 8:1 solution of THF and DMSO (2.25 ml) was stirred at
rt for 7 h. Upon completion, the reaction mixture was quenched with
saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with
Et2O (3 x 50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 3.24 as a colorless oil (68 mg, 60%); IR
-1 1 (neat) ν = 1722, 1472, 1255, 1110, 1050 cm ; H NMR (300 MHz, CDCl3) δ 4.39
(dd, J = 6.6, 1.4 Hz, 1H), 2.61-2.44 (m, 2H), 2.12-2.04 (m, 2H), 1.94-1.88 (m, 2H),
1.78-1.71 (m, 1H), 1.50-1.47 (m, 1H), 0.90 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H); 13C
NMR (75 MHz, CDCl3) ppm 207.3, 206.8, 77.0, 39.1, 35.0, 26.0 (3C), 23.8, 23.2,
+ 18.4, -4.6, -4.9; ES HRMS m/z (M + Na) calcd 279.1386, obsd 279.1385; Rf 0.16
(10:1 hexanes:ethyl acetate).
To a flame-dried round-bottomed flask under N2, a 20% suspension TBSO OTBS of Nysted reagent in THF (14.7 g, 6.45 mmol, 1.5 eq) was added
along with 12 mL of THF. The suspension was cooled to 0 oC and neat TiCl4 (0.71 mL, 6.45 mmol, 1.5 eq) was added dropwise followed by the addition of 3.16 (1.17 g, 4.3 mmol) in THF (8 mL). The reaction mixture was stirred at rt for 24 h, where it was quenched by the addition of 10% HCl solution (100 mL).
The reaction mixture was transferred to a separatory funnel and extracted with ether
(3 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica
227 gel (hexanes) to give 3.26a (140 mg, 12%) as a colorless oil; IR (neat) ν = 2857,
-1 1 2361, 1472, 1360, 1252, 1094, 1050 cm ; H NMR (300 MHz, CDCl3) δ 5.06 (s,
2H), 4.48 (t, J = 5.2 Hz, 2H), 1.91-1.89 (m, 2H), 1.64-1.57 (m, 4H), 1.47-1.42 (m,
13 2H), 0.93 (s, 18H), 0.09 (s, 6H), 0.07 (s, 6H); C NMR (75 MHz, CDCl3) ppm
155.9, 110.6, 73.2 (2C), 38.7 (2C), 26.3 (6C), 24.4 (2C), 18.6 (2C), -4.3 (2C), -4.5
+ (2C); ES HRMS m/z (M + Na) calcd 393.2615, obsd 393.2625; Rf 0.26 (hexanes).
To a flame dried round-bottomed flask under N2, a 20% suspension TBSO OH of Nysted reagent in THF (4.23 g, 1.9 mmol, 1.5 eq) was added
along with 3.5 mL of THF. The suspension was cooled to 0 oC and neat TiCl4 (0.21 mL, 1.9 mmol, 1.5 eq) was added dropwise followed by the addition of 3.16 (0.32 g, 1.24 mmol) in THF (2.4 mL). The reaction mixture was stirred at rt for 24 h when it was quenched by the addition of 10% HCl soution (100 mL). The reaction mixture was transferred to a separatory funnel and extracted with ether (3 x
100 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (20:1
hexanes:ethyl acetate) to give 3.26 (74 mg, 23%) as a colorless oil; IR (neat) ν =
-1 1 3400, 2856, 1472, 1255, 1049 cm ; H NMR (300 MHz, CDCl3) δ 5.16 (d, J = 5.9
Hz, 2H), 4.49-4.44 (m, 2H), 2.18-2.15 (m, 1H), 1.91-1.86 (m, 1H), 1.73-1.30 (m, 6H),
13 0.92 (s, 9H), 0.09 (s, 3H), 0.07 s, 3H); C NMR (75 MHz, CDCl3) ppm 156.9, 111.8,
73.2, 72.4, 39.5, 36.7, 26.2 (3C), 25.3, 24.1, 18.5, -4.3, -4.5; ES HRMS m/z (M +
+ Na) calcd 279.1750, obsd 279.1757; Rf 0.34 (10:1 hexanes:ethyl acetate).
228 A solution of 3.26 (74 mg, 0.29 mmol) and IBX (97 mg, 0.35 mmol, TBSO O 1.2 eq) in an 8:1 solution of THF and DMSO (1.6 ml) was stirred at rt
for 12 h, when the reaction mixture was quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with Et2O (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (20:1
hexanes:ethyl acetate) to give 3.27 (61 mg, 82%) as a colorless oil; IR (neat) ν =
-1 1 2857, 1693, 1472, 1253, 1080 cm ; H NMR (300 MHz, CDCl3) δ 5.95 (d, J = 1.9
Hz, 1H), 5.38 (s, 1H), 4.62 (d, J = 7.0 Hz, 1H), 2.81-2.75 (m, 1H), 2.58-2.53 (m, 1H),
2.09-1.29 (series of m, 6H), 0.92 (s, 9H), 0.09 (s, 3H), 0.04 (s, 3H); 13C NMR (75
MHz, CDCl3) ppm 203.8, 152.2, 121.7, 73.8, 43.8, 38.9, 26.1 (3C), 25.4, 24.7, 18.5, -
+ 4.5, -4.7; ES HRMS m/z (M + Na) calcd 277.1594, obsd 277.1594; Rf 0.53 (10:1
hexanes:ethyl acetate).
A solution of 3.27 (61 mg, 0.24 mmol) and CeCl3•7H2O (89 mg, TBSO OH 0.24 mmol, 1 eq) in MeOH (1.1 mL) was cooled to 0 oC where
NaBH4 (9 mg, 0.24 mmol, 1 eq) was added in one portion. The
reaction mixture was stirred for 10 min, allowed to warm to rt, quenched with
saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with
ether (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 3.28 (54 mg, 88%) as a colorless oil; IR
-1 1 (neat) ν = 3437, 2856, 1472, 1254, 1041 cm ; H NMR (300 MHz, CDCl3,) δ 5.08
229 (d, J = 7.7 Hz, 2H), 4.49 (t, J = 5.4 Hz, 1H), 4.35 (dd, J = 7.3, 5.6 Hz, 1H), 2.00-1.94
(m, 1H), 1.90-1.77 (m, 3H), 1.74-1.59 (m, 2H), 1.53-1.46 (m, 1H), 1.43-1.36 (m, 1H),
13 0.94 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); C NMR (75 MHz, CDCl3) ppm 154.2,
112.9, 76.4, 75.3, 38.4, 37.5, 26.2 (3C), 24.8, 24.5, 18.4, -4.4, -4.5; ES HRMS m/z (M
+ + Na) calcd 279.1750, obsd 279.1757; Rf 0.36 (10:1 hexanes:ethyl acetate).
O OH A solution of 3.28 (82 mg, 0.32 mmol) and CH2Cl2 TBSO OH TBSO O o (27 mL) was cooled to -78 C where O3 was bubbled +
through until a faint blue color persisted. O2 was then
bubbled through until the solution became clear where Ph3P (101 mg, 0.39 mmol, 1.2
eq) was added and the reaction mixture was allowed to warm to rt and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (10:1
hexanes:ethyl acetate) to give 3.29 (60 mg, 73%) and 3.69 (4.6 mg, 6%), both as
clear oils.
For 3.29; IR (neat) ν = 3482, 1722, 1472, 1255, 1121, 1023 cm -1; 1H NMR
(300 MHz, CDCl3) δ 4.43 (dd, J = 7.9, 4.1 Hz, 1H), 4.29 (m, 1H), 1.99-1.30 (series
13 of m, 8H), 0.93 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H); C NMR (75 MHz, CDCl3) ppm
212.8, 75.4, 75.2, 34.7, 33.6, 26.1 (3C), 24.9, 24.8, 18.7, -4.2, -4.7; ES HRMS m/z (M
+ Na)+ calcd 281.1543, obsd 281.1548; Rf 0.26 (10:1 hexanes:ethyl acetate).
For 3.69; IR (neat) ν = 3494, 1712, 1471, 1255, 1094 cm -1; 1H NMR (300
MHz, CDCl3) δ 4.64 (d, J = 3.0 Hz, 1H), 4.55 (dd, J = 6.5, 1.2 Hz, 1H), 3.63 (s,
1OH), 2.30-2.24 (m, 1H), 1.95-1.91 (m, 2H), 1.79-1.51 (series of m, 5H), 0.96 (s,
13 9H), 0.13 (s, 3H), 0.09 (s, 3H); C NMR (75 MHz, CDCl3) ppm 215.0, 77.9, 74.7,
230 34.4, 32.0, 26.0 (3C), 25.0, 23.7, -4.5, -4.9; ES HRMS m/z (M + Na+) calcd 281.1543,
obsd 281.1552; Rf 0.23 (20:1 hexanes:ethyl acetate).
O A solution of 3.29 (25 mg, 0.09 mmol) and THF (2.6 mL) was cooled HO OH to 0 oC where a 1M solution of TBAF in THF (0.1 mL, 0.1 mmol, 1.2
eq) was added. The reaction mixture was stirred at rt for 30 min when
it was quenched with saturated NaHCO3 solution, transferred to a separatory funnel,
and extracted with ether (3 x 15 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 3.10 as a white solid
(mp 87 oC, 6 mg, 46%); IR (neat) ν = 3406, 1711, 1451 cm -1; 1H NMR (300 MHz,
CDCl3) δ 4.41 (dd, J = 7.6, 4.5 Hz, 2H), 3.39 (s, 2OH), 2.06-2.00 (m, 2H), 1.83-1.76
13 (m, 2H), 1.69-1.59 (m, 4H); C NMR (75 MHz, CDCl3) ppm 214.9, 74.9 (2C), 33.7
+ (2C), 24.8 (2C); ES HRMS m/z (M + Na) calcd 167.0678, obsd 167.0684; Rf 0.23
(1:1 hexanes:ethyl acetate).
OOTBS To a stirred solution of 3.30 (1.0g, 7.0 mmol), imidazole (0.72 g, 10.6
mmol), and DMAP (86 mg, 70 mmol) in CH2Cl2 (38 mL), TBSCl (1.59
g, 10.6 mmol) was added in one portion. The reaction mixture was heated to reflux and stirred for 24 h. Upon completion, the solution was allowed to come to rt, quenched with saturated NaHCO3 solution, transferred to a separatory
funnel, and extracted with CH2Cl2 (3 x 100 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
231 chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 3.33 as a colorless
oil (1.71 g, 95%); IR (neat) ν = 1710, 1471, 1254, 1108, 1040, 836 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.73-5.60 (m, 2H), 4.20 (dd, J = 5.9, 2.1 Hz, 1H), 3.34-3.20 (m,
1H), 3.08-3.02 (m, 1H), 2.78-2.66 (m, 1H), 2.28-2.18 (m, 1H), 2.03-1.94 (m, 1H),
1.87-1.55 (m, 3H) 0.96 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz,
CDCl3) ppm 216.2, 131.1, 131.0, 78.1, 44.0, 32.9, 25.7 (3C), 20.7, 19.6, 18.0, -4.5, -
+ 5.6; ES HRMS m/z (M + Na) calcd 277.1594, obsd 277.1589; Rf 0.56 (10:1
hexanes:ethyl acetate).
OOTBSTo a stirred solution of 2-hydroxycyclooctanone (1.0g, 7.0 mmol),
imidazole (0.72 g, 10.6 mmol), and DMAP (86 mg, 70 mmol) in
CH2Cl2 (38 mL), TBSCl (1.59 g, 10.6 mmol) was added in one
portion. The reaction mixture was heated to reflux and stirred for 24 h. Upon
completion, the solution was allowed to come to rt, quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 100 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 3.34 as a colorless oil (0.7 g, 68%); IR (neat) ν = 1706, 1464, 1254,
-1 1 1111, 1052 cm ; H NMR (300 MHz, CDCl3) δ 4.19-4.18 (m, 1H), 2.76-2.67 (m,
1H), 2.24-1.51 (m, 11H), 0.90 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz,
CDCl3) ppm 218.2, 78.1, 39.2, 35.4, 27.2, 25.7 (3C), 25.2, 25.1, 20.8, 18.1, -5.0, -5.1;
+ ES HRMS m/z (M + Na) calcd 279.1750, obsd 279.1753; Rf 0.65 (10:1
hexanes:ethyl acetate).
232
TBSO O A solution of 3.34 (0.91 g, 3.55 mmol, 1eq) in THF (25 mL) was
o OH cooled to 0 C, where a 1M solution of LHMDS in THF (4.26
mL, 4.26 mmol, 1.2 eq) was added and the mixture was stirred for
1 h. TMSCl (0.75 g, 4.97 mmol, 1.4 eq) was then added and stirred for an additional
1 h as the reaction mixture was allowed to warm to rt. Upon completion, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with ether (3 x
50 mL). The combined organic phases were dried over Na2SO4 and concentrated in
o vacuo. The crude product was redissolved in CH2Cl2 (72 mL) and cooled to 0 C
where mCPBA (1.08 g, 4.26 mmol, 1.2 eq) was added. The reaction mixture was stirred for 4 h, allowed to warm to rt, quenched with saturated NaHCO3 solution,
transferred to a separatory funnel, and extracted with Et2O (3 x 50 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl
acetate) to give 3.35 as a colorless oil (56 mg, 60%); IR (neat) ν = 3489, 1702, 1471,
-1 1 1359, 1253, 1116, 838 cm ; H NMR (300 MHz, CDCl3) δ 4.51 (dd, J = 5.2, 2.3 Hz,
1H), 4.48 (dd, J = 5.8, 2.2 Hz, 1H), 3.59 (s, OH), 2.96-2.90 (m, 1H), 2.01-1.34 (m,
13 9H), 0.95 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H); C NMR (75 MHz, CDCl3) ppm 219.6,
77.7, 74.6, 39.4, 27.6, 26.0 (3C), 24.8, 21.9, 19.1, 18.3, -4.4, -4.9; ES HRMS m/z (M
+ + Na) calcd 295.1699, obsd 295.1682; Rf 0.19 (10:1 hexanes:ethyl acetate).
233 OOH A solution of 3.38 (25 mg, 0.10 mmol), 10% Pd/C (2.5 mg, 0.1 eq), and
OH MeOH (2 mL) was stirred under H2 for 1 day. The reaction mixture
was filtered through a pad of Celite and washed with Et2O (25 mL).
The combined organic phases were concentrated in vacuo, and the residue was purified by column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give
3.40 as a white solid (mp 79 oC, 16 mg, 90%); IR (neat) ν = 3391, 1700 cm -1; 1H
NMR (300 MHz, CDCl3) δ 4.49-4.39 (m, 1H), 4.44 (d, J = 3.5 Hz, 1H), 2.67 (ddd, J
= 14.3, 10.7, 3.6 Hz, 1H), 2.50-2.46 (m, 1H), 2.00-1.68 (m, 6H), 1.50-1.41 (m, 1H),
13 1.03-0.96 (m, 1H); C NMR (75 MHz, CDCl3) ppm 213.1, 79.6, 70.9, 38.6, 31.6,
+ 28.1, 26.5, 22.6; ES HRMS m/z (M + Na) calcd 181.0835, obsd 181.0839; Rf 0.09
(1:1 hexanes:ethyl acetate).
HO OH To a solution of 3.40 (11.4 mg, 0.04 mmol) in THF (1 mL), a 1M
OH solution of TBAF in THF (44 μL, 0.044 mmol, 1.05 eq) was added.
The reaction mixture was stirred for 30 min, when it was concentrated in vacuo and the residue was purified by column chromatography on silica gel (10:1 dichloromethane:methanol) to give 3.41 as white solid (mp 84-85 oC, 6.0 mg, 89); IR
-1 1 (neat) ν = 3614, 1477, 1236, 1040 cm ; H NMR (300 MHz, CDCl3) δ 4.03-3.99
(m, 2H), 3.96 (t, J = 2.5 Hz, 1H), 2.37 (s, OH), 2.10-2.04 (m, 2H), 1.92-1.80 (m 4H),
13 1.71-1.34 (m, 4H); C NMR (75 MHz, CDCl3) ppm 77.6, 76.1 (2C), 32.6 (2C), 29.1,
+ 22.9 (2C); ES HRMS m/z (M + Na) calcd 183.0991, obsd 183.0993; Rf 0.23 (10:1
dichloromethane:methanol).
234 TBSO O A solution of 3.35 (50 mg, 1.82 mmol) and IBX (608 mg, 2.18
O mmol, 1.2 eq) in 8:1 THF:DMSO (2.25 ml) was stirred at rt for 4 h,
when the reaction mixture was quenched with saturated NaHCO3
solution, transferred to a separatory funnel, and extracted with Et2O (3 x 50 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl
acetate) to give 3.42 as a colorless oil (46 mg, 92%); IR (neat) ν = 1707, 1464, 1253,
-1 1 1145 cm ; H NMR (300 MHz, CDCl3) δ 4.66 (dd, J = 8.8, 4.9 Hz, 1H), 2.94-2.80
(m, 1H), 2.40-2.34 (m, 1H), 2.09-1.41 (seies of m, 8H), 0.94 (s, 9H), 0.15 m(s, 3H),
13 0.08 (s, 3H); C NMR (75 MHz, CDCl3) ppm 210.6, 208.5, 75.9, 40.0, 31.9, 27.3,
26.1 (3C), 21.2, 20.3, 18.7, -4.4, -5.0; ES HRMS m/z (M + Na+) calcd 293.1543, obsd
293.1532; Rf 0.36 (10:1 hexanes:ethyl acetate).
O A solution of 3.40 (15 mg, 0.1 mmol), DMAP (113 mg, 1.0 mmol, 10
O O o eq), and CH2Cl2 (6.3 mL) was cooled to -78 C, where a 1M solution of
O phosgene in toluene (0.6 mL, 0.6 mmol, 5 eq) was added. The reaction
mixture was allowed to warm to rt, and stirred for 2 days, quenched with
H2O, and extracted with ether (3 x 15 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 3.45 as a colorless oil
(15 mg, 82%); IR (neat) ν = 1798, 1718, 1465, 1359, 1181, 1065 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.30 (d, J = 8.5 Hz, 1H), 4.97-4.93 (m, 1H), 2.62-2.59 (m, 2H),
13 1.98-1.29 (series of m, 8H); C NMR (75 MHz, CDCl3) ppm 205.9, 153.9, 80.0,
235 79.6, 43.5, 28.7, 27.4, 23.8, 23.3; ES HRMS m/z (M + Na)+ calcd 184.0676, obsd
184.0736; Rf 0.22 (1:1 hexanes:ethyl acetate).
MeO OMe A solution of DMSO (62.5 mL) and t-BuOK (1.4 g, 12.5 mmol, 3.2 eq)
were cooled to 0 oC and 3.34 (1 g, 3.91 mmol) was added dropwise.
After 10 min, the reaction mixture was a deep orange and dimethyl
sulfate (1.26 ml, 13.3 mmol, 3.4 eq) was added. The reaction mixture was stirred for
15 min, quenched with saturated NaHCO3 solution, transferred to a separatory funnel,
and extracted with Et2O (3 x 100 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 3.48 as a colorless
-1 1 oil (98 mg, 15%); IR (neat) ν = 1711, 1466, 1105 cm ; H NMR (300 MHz, CDCl3)
δ 4.75 (t, J = 8.6 Hz, 1H), 4.25 (dd, J = 9.6, 4.9 Hz, 1H), 3.57 (s, 3H), 3.34 (s, 3H),
13 2.27-1.27 (series of m, 10H); C NMR (75 MHz, CDCl3) ppm 155.2, 98.6, 77.5,
57.0, 54.8, 34.6, 32.2, 27.4, 24.7, 24.2; ES HRMS m/z (M + Na)+ calcd 179.1042, obsd 179.1043; Rf 0.34 (10:1 hexanes:ethyl acetate).
TBSO O TBSO OTBS A solution of 3.50 (85 mg, 0.61 mmol) in THF (4.3 mL)
o + was cooled to 0 C, where a 1M solution of LHMDS in
THF (0.88 mL, 0.88 mmol, 1.5 eq) was added. The reaction mixture was stirred at 0 oC for 15 min, warmed to rt for 45 min, and cooled
again to 0 oC where TBSCl (128 mg, 0.85 mmol, 1.4 eq) was added. After 2 h, the
reaction mixture was quenched with saturated NaHCO3 solution, transferred to a
236 separatory funnel, and extracted with ether (2 x 25 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give both
3.52 (96 mg, 62 %) and 3.52a (13 g, 6 %) as yellow oils.
For 3.52; IR (neat) ν = 2856, 1672, 1251, 1167, 839 cm -1; 1H NMR (300
MHz, CDCl3) δ 5.91 (t, J = 9.1 Hz, 1H), 2.82 (t, J = 7.4 Hz, 2H), 2.59-2.54 (m, 2H),
13 1.80-1.55 (m, 6H), 0.98 (s, 9H), 0.17 (s, 6H); C NMR (75 MHz, CDCl3) ppm 199.0,
125.8, 121.7, 41.5, 26.2 (3C), 25.6, 24.8, 23.8, 22.8, 18.9, -4.2 (2C); ES HRMS m/z
+ (M + Na) calcd 277.1594, obsd 277.159; Rf 0.29 (20:1 hexanes:ethyl acetate).
For 3.52a; IR (neat) ν = 2856, 1642, 1255, 1231, 1176, 1150 cm -1; 1H NMR
(300 MHz, CDCl3) δ 5.13 (t, J = 8.3 Hz, 2H), 2.18-1.72 (series of m, 6H), 1.20-1.10
13 (m, 2H), 0.96 (s, 18H), 0.15 (s, 12H); C NMR (75 MHz, CDCl3) ppm 147.0, 113.1,
26.3, 26.2 (6C), 25.0 18.6 (2C), -4.0 (4C); ES HRMS m/z (M + Na)+ calcd 391.2459,
obsd 391.2478; Rf 0.90 (10:1 hexanes:ethyl acetate).
TBSO OH A solution of 3.52 (82 mg, 0.32 mmol) and THF (4 mL) was cooled to 0
oC where DIBAL-H (390 μL, 0.39 mmol, 1.2 eq) was added. After 10
min, the reaction mixture was warmed to rt, quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with Et2O (3 x 25 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (10:1
hexanes:ethyl acetate) to give 3.53 as a colorless oil (80 mg, 97%); IR (neat) ν =
-1 1 3474, 1662, 1462, 1407, 1243, 1174, 1055 cm ; H NMR (300 MHz, CDCl3) δ 4.80
237 (t, J = 8.6 Hz, 2H), 4.57-4.53 (m, 1H), 2.56 (d, J = 8.8 Hz, 1H), 2.09-1.35 (series of
13 m, 9H), 0.98 (s, 9H), 0.26 (s, 3H), 0.25 (s, 3H); C NMR (75 MHz, CDCl3) ppm
151.3, 103.6, 68.5, 38.1, 31.6, 26.7, 26.1 (3C), 24.4 (2C), 18.5, -3.9, -4.2; ES HRMS
+ m/z (M + Na) calcd 279.1750, obsd 279.1762 Rf 0.39 (10:1 hexanes:ethyl acetate).
TBSO TBSO OH To a flame dried round-bottomed flask under N2 , a
OH
+ 20% suspension of Nysted reagent in THF (14.7 g,
6.45 mmol, 1.5 eq) was added along with 12 mL of
o THF. The suspension was cooled to 0 C and neat TiCl4 (0.71 mL, 6.45 mmol, 1.5
eq) was added dropwise followed by the addition of 3.35 (1.17 g, 4.3 mmol) in THF
(8 mL). The reaction mixture was stirred at rt for 24 h when it was quenched by the
addition of 10% of HCl (100 mL, transferred to a separatory funnel, and extracted
with ether (3 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give (468 mg, 42%) of 3.54 and (157 mg, 14%) of
3.55, both as colorless oils.
For 3.54; IR (neat) ν = 3435, 2856, 1471, 1253, 1068 cm -1; 1H NMR (300
MHz, CDCl3) δ 5.21 (s, 1H), 5.18 (d, J = 0.6 Hz, 1H), 4.48 (dd, J = 9.2, 4.7 Hz, 1H)
4.37 (dd, J = 8.4, 4.6 Hz, 1H), 2.04-1.99 (m, 1H), 1.83-1.38 (m, 9H), 0.91 (s, 9H),
13 0.08 (s, 3H), 0.05 (s, 3H); C NMR (75 MHz, CDCl3) ppm 157.0, 113.5, 73.6, 71.7,
36.8, 35.3, 26.2 (3C), 26.1, 22.4, 21.7, 18.4, -4.2, -4.4; ES HRMS m/z (M + Na)+ calcd 293.1907, obsd 193.1901; Rf 0.29 (10:1 hexanes:ethyl acetate).
238 For 3.55; IR (neat) ν = 3581, 2857, 2358, 1462, 1253, 1066 cm -1; 1H NMR
(300 MHz, CDCl3) δ 5.24 (s, 1H), 5.09 (s, 1H), 3.98 (d, J = 8.4 1H), 3.61 (dt, J = 9.0,
3.3, 1H), 2.41-2.29 (m. 2H), 1.84-1.50 (m, 8H), 0.96 (s, 9H), 0.18 (s, 3H), 0.16 (s,
13 3H); C NMR (75 MHz, CDCl3) ppm 149.4, 114.8, 79.1, 78.2, 34.3, 32.8, 27.3, 26.1
(3C), 26.1, 22.8, 18.4, -3.6, -4.2; ES HRMS m/z (M + Na)+ calcd 293.1907, obsd
293.1902; Rf 0.52 (10:1 hexanes:ethyl acetate).
TBSO A solution of 3.54 (162 mg, 0.6 mmol) and IBX (200 mg, 0.72 mmol,
O 1.2 eq) in an 8:1 solution of THF and DMSO (3.1 ml) was stirred at rt
for 12 h when the reaction mixture was quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with Et2O (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (20:1
hexanes:ethyl acetate) to give 3.56 (150 mg, 94%) as a colorless oil; IR (neat) ν =
-1 1 2858, 1689, 1471, 1253, 1089, 1066 cm ; H NMR (300 MHz, CDCl3) δ 5.84 (d, J
= 0.8 Hz, 1H), 5.64 (t, J = 1.6 Hz, 1H), 4.75 (dd, J = 9.3, 4.8 Hz, 1H), 2.68-2.60 (m,
2H), 1.93-1.29 (m, 8H), 0.95 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz,
CDCl3) ppm 206.5, 153.0, 119.2, 71.6, 41.1, 40.3, 28.1, 27.2, 26.2 (3C), 23.1, 18.6, -
+ 4.4, -4.6; ES HRMS m/z (M + Na) calcd 291.1750, obsd 291.1763; Rf 0.53 (10:1 hexanes:ethyl acetate).
239 TBSO O A solution of 3.55 (62 mg, 0.23 mmol) and IBX (77 mg, 0.28 mmol,
1.2 eq) in an 8:1 solution of THF and DMSO (1.2 ml) was stirred at rt
for 12 h when the reaction mixture was quenched with saturated
NaHCO3 solution, transferred to a separatory funnel and extracted with Et2O (3 x 30
mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (20:1
hexanes:ethyl acetate) to give 3.57 (36 mg, 60%) as a colorless oil; IR (neat) ν =
-1 1 2857, 1688, 1606, 1463, 1254, 1112, 1045 cm ; H NMR (300 MHz, CDCl3) δ 5.72
(d, J = 2.0 Hz, 1H), 5.26 (s, 1H), 4.53 (dd, J = 6.6, 3.8 Hz, 1H), 3.26-3.20 (m, 1H),
2.41-2.36 (m, 2H), 1.95-1.54 (m, 8H), 0.93 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz,
CDCl3) ppm 208.6, 150.1, 122.5, 78.4, 38.3, 30.5, 29.7, 26.1 (3C), 25.6, 20.8, 18.6, -
+ 4.6, -4.7; ES HRMS m/z (M + Na) calcd 291.1750, obsd 291.1763; Rf 0.53 (10:1 hexanes:ethyl acetate).
TBSO OH TBSO OH A solution of 3.57 (30 mg, 0.11 mmol, 1 eq), MeOH
+ (0.5 mL) and CeCl3•H2O (42 mg, 0.11 mmol, 1 eq)
o was cooled to 0 C where NaBH4 (4.3 mg, 0.11
mmol, 1 eq) was added. After 5 min, the reaction mixture was quenched by the
addition of 30 ml of H2O. The solution was transferred to a separatory funnel and extracted with ether (3 x 30 mL). The combined organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (10:1 hexanes:ethyl acetate) to give (11 mg, 37%) of
3.58 and (18 mg, 60%) of 3.55, both as colorless oils; For 3.58; IR (neat) ν = 3456,
240 -1 1 2929, 1462, 1253, 1065 cm ; H NMR (300 MHz, CDCl3) δ 5.19 (s, 1H), 4.99 (s,
1H), 4.27 (s, 1H), 4.01-3.97 (m, 1H), 2.50-2.45 (m, 1H), 2.12-2.07 (m, 1H), 1.98-1.91
(m, 1H), 1.85-1.77 (m, 1H), 1.69-1.43 (m, 6H), 0.95 (s, 9H), 0.15 (s, 3H), 0.14 (s,
13 3H); C NMR (75 MHz, CDCl3) ppm 148.3, 113.0, 77.2, 75.0, 31.9, 30.8, 28.4, 26.5,
26.2 (3C), 23.7, 18.5, -4.1, -4.4; ES HRMS m/z (M + Na)+ calcd 293.1907, obsd
293.1909; Rf 0.52 (10:1 hexanes:ethyl acetate).
TBSO A solution of 3.56 (85 mg, 0.32 mmol) and CeCl3•7H2O (119 mg,
OH o 0.32 mmol, 1 eq) in MeOH (1.4 mL) was cooled to 0 C where NaBH4
(12 mg, 0.32 mmol, 1 eq) was added in one portion. The reaction mixture was stirred for 10 min, allowed to warm to rt, quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with ether (3 x 15
mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (10:1
hexanes:ethyl acetate) to give 3.61 (79 mg, 93%) as a colorless oil; IR (neat) ν =
-1 1 3395, 2857, 1461, 1253, 1116, 1085, 1031, 909 cm ; H NMR (300 MHz, CDCl3) δ
5.15 (s, 2H), 4.36 (dd, J = 8.5, 5.7 Hz, 1H), 4.28 (dd, J = 9.2, 4.5 Hz, 1H), 2.07-1.27
13 (m, 10H), 0.93 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); C NMR (75 MHz, CDCl3) ppm
152.7, 114.5, 77.0, 75.6, 36.9, 35.5, 27.4, 26.2 (3C), 22.4, 22.3, 18.4, -4.4, -4.5; ES
+ HRMS m/z (M + Na) calcd 293.1907, obsd 193.1901; Rf 0.24 (10:1 hexanes:ethyl
acetate).
241 TBSO O OOH A solution of 3.61 (48 mg, 0.175 mmol) in MeOH
OH OTBS o + (2.0 mL) was cooled to 0 C, where NaBH4 (6.5 mg,
0.175 mmol, 1 eq) was added. The reaction mixture
was stirred for 1 h, allowed to warm to rt, quenched with saturated NaHCO3 solution,
transferred to a separatory funnel, and extracted with ether (3 x 15 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl
acetate) to give (28 mg, 59%) of 3.43 and (19 mg, 39%) of 3.44, both as colorless
oils.
For 3.43; IR (neat) ν = 3447, 1717, 1472, 1252, 1142 cm -1; 1H NMR (300
MHz, CDCl3) δ 4.51 (dd, J = 9.2, 4.1 Hz, 1H), 4.27 (dd, J = 7.6, 4.4 Hz, 1H), 2.30-
1.26 (series of m, 10H), 0.93 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz,
CDCl3) ppm 216.2, 74.9, 74.2, 36.1, 31.3, 26.1 (3C), 24.2, 22.2, 21.8, 18.7, -4.2, -4.6;
+ ES HRMS m/z (M + Na) calcd 295.1699, obsd 295.1692; Rf 0.29 (5:1 hexanes:ethyl
acetate).
For 3.44; IR (neat) ν = 3487, 1702, 1472, 1255, 1114, 1078 cm -1; 1H NMR
(300 MHz, CDCl3) δ 4.35 (d, J = 2.9 Hz, 1H), 4.30 (dt, J = 9.2, 3.1 Hz, 1H), 2.59-
2.51 (m, 2H), 2.01-1.89 (m, 3H), 1.70-1.29 (series of m, 5H), 0.94 (s, 9H), 0.15 (s,
13 3H), 0.12 (s, 3H); C NMR (75 MHz, CDCl3) ppm 213.0, 79.5, 73.9, 40.1, 31.2, 27.9
(3C), 24.4, 20.5, 18.5, -4.3, -4.4; ES HRMS m/z (M + Na)+ calcd 295.1699, obsd
295.1713; Rf 0.32 (5:1 hexanes:ethyl acetate).
242 HO O A solution of 3.43 (22 mg, 0.14 mmol, 1 eq) in CH2Cl2 (12 mL) was
OH o cooled to -78 C where O3 was bubbled through until a faint blue color
persisted. O2 was then bubbled through the solution until it became
clear, when Ph3P (44.5 mg, 0.17 mmol, 1.2 eq) was added and the reaction mixture
was allowed to warm to rt, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 3.12 (mp
120-121 oC, 7.5 mg, 30%) and 3.40 (15 mg, 60%) both as white solids; For 3.12; IR
-1 1 (neat) ν = 3693, 1705, 1246, 1120, 1036 cm ; H NMR (300 MHz, CDCl3) δ 4.41
(dd, J = 7.7, 3.7 Hz, 2 H), 3.26 (s, 2 OH), 2.33-2.27 (m, 2H), 1.97-1.90 (m, 2H),
13 1.84-1.66 (m, 4H), 1.48-1.40 (m, 2H); C NMR (75 MHz, CDCl3) ppm 218.2, 74.1
(2C), 33.4 (2C), 24.6, 21.9 (2C); ES HRMS m/z (M + Na)+ calcd 181.0835, obsd
181.0829; Rf 0.24 (1:1 hexanes:ethyl acetate).
HO A solution of 3.61 (57.5 mg, 0.21 mmol) and THF (2.5 mL) was
OH cooled to 0 oC where a 1M solution of TBAF in THF (0.26 mL, 0.26
mmol, 1.2 eq) was added. The reaction mixture was stirred at rt for 30
min, when it was quenched with saturated NaHCO3 solution, transferred to a
separatory funnel, and extracted with ether (3 x 15 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 3.62 (mp
96-98 oC, 23 mg, 70%) as a white solid; IR (neat) ν = 3506, 2860, 2248, 1460, 1444,
-1 1 1255, 1029, 1007 cm ; H NMR (300 MHz, CDCl3) δ 5.24 (s, 2H), 4.37 (dd, J = 8.9,
5.2 Hz, 2H), 2.46 (s, 2 OH), 2.08-2.02 (m, 2H), 1.89-1.82 (m, 2H), 1.78-1.70 (m, 2H),
243 13 1.61-1.47 (m, 2H), 1.40-1.32 (m, 2H); C NMR (75 MHz, CDCl3) ppm 154.1, 113.9,
75.3 (2C), 35.8 (2C), 26.9, 22.4 (2C); ES HRMS m/z (M + Na)+ calcd 179.1042, obsd
179.1036; Rf 0.16 (1:1 hexanes:ethyl acetate).
TBSO OH A solution of 3.43 (13.3 mg, 0.05 mmol) in MeOH (0.5 mL) was
OH o cooled to 0 C, where NaBH4 (1.9 mg, 0.05 mmol, 1 eq) was added.
The reaction mixture was stirred for 20 min, allowed to warm to rt,
quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with ether (3 x 15 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (5:1 hexanes:ethyl acetate) to give 3.63 as a colorless oil
(11.9 mg, 89%); IR (neat) ν = 3467, 1471, 1253, 1075, 1028 cm -1; 1H NMR (300
MHz, CDCl3) δ 4.14 (t, J = 8.1 Hz, 1H), 3.87-3.80 (m, 2H), 3.06 (s, 2 OH), 2.13-1.29
(series of m, 10H), 0.94 (s, 9H), 0.16 (s, 3H), 0.13 (s, 3H); 13C NMR (75 MHz,
CDCl3) ppm 78.3, 75.8, 71.8, 33.9, 32.6, 29.3, 22.6 (3C), 22.9, 22.6, 18.2, -4.2, -4.5;
+ ES HRMS m/z (M + Na) calcd 297.1856, obsd 297.1863; Rf 0.19 (5:1 hexanes:ethyl
acetate).
O A solution of 3.9 (368 mg, 2.6 mmol) and DMAP (3.11 g, 25.5 mmol) in O O O o CH2Cl2 (80 mL) was cooled to -78 C and a 1M solution of phosgene in
toluene (12.75 mL) was added. The reaction mixture was stirred for 2 d, washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (10:1
244 hexanes:ethyl acetate) to give 3.64 as a clear oil (39 mg, 9%, 52% brsm); IR (neat) ν
-1 1 = 1820, 1257, 1163 cm ; H NMR (300 MHz, CDCl3) δ 4.88 (d, J = 2.0 Hz, 1H),
4.31 (d, J = 7.5 Hz, 1H), 2.64-2.61 (m, 2H), 2.19-1.54 (m, 6H); 13C NMR (75 MHz,
CDCl3) ppm 152.4, 106.0, 92.4, 69.9, 40.9, 31.7, 23.5, 23.4; ES HRMS m/z (M +
+ Na) calcd 193.0471, obsd 193.0480; Rf 0.24 (3:1 hexanes:ethyl acetate).
O A solution of 3.66 (3.0 mg, 0.021 mmol), DMAP (25.4 mg, 0.21 mmol,
O o O O 10 eq), and CH2Cl2 (1.2 mL) was cooled to -78 C, where 1M phosgene
in toluene (0.1 mL, 0.1 mmol, 5 eq) was added. The reaction mixture
was allowed to warm to rt, stirred for 1 d, and concentrated in vacuo. Theresidue was
purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to give
3.65 as a white solid (mp 150 oC, 1.3 mg, 37%); IR (neat) ν = 1815, 1738, 1450,
-1 1 1163 cm ; H NMR (300 MHz, CDCl3) δ 5.21 (dd, J = 9.3, 0.7 Hz, 1H), 5.04-5.00
(m, 1H), 2.82-2.76 (m, 1H), 2.54-2.51 (m, 1H), 1.98-1.94 (m, 2H), 1.90-1.83 (m, 2H),
13 1.78-1.72 (m, 2H); C NMR (75 MHz, CDCl3) ppm 203.6, 153.6, 82.0, 75.6, 39.6,
+ 31.3, 25.4, 22.4; ES HRMS m/z (M + Na) calcd 193.0471, obsd 193.0473; Rf 0.32
(1:1 hexanes:ethyl acetate); .
O A solution of 3.11 (77 mg, 0.49 mmol), DMAP (0.6 g, 4.9 mmol, 10 eq),
O O o and CH2Cl2 (33 mL) was cooled to -78 C, where 1M phosgene in toluene O (2.45 mL, 2.45 mmol, 5 eq) was added. The reaction mixture was allowed
to warm to rt, stirred for 2 d, quenched with H2O, and extracted with ether
(3 x 15 mL). The combined organic phases were dried over Na2SO4 and concentrated
245 in vacuo. The residue was purified by column chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 3.67 as a colorless oil (130 mg, 78%); IR (neat) ν =
-1 1 3442, 1819, 1260, 1104, 1077, 1027 cm ; H NMR (300 MHz, CDCl3) δ 4.95 (d, J =
11.3 Hz, 1H), 4.34 (dd, J = 9.7, 5.4 Hz, 1H), 2.09-0.91 (series of m, 10H); 13C NMR
(75 MHz, CDCl3) ppm 151.0, 107.9, 91.1, 71.2, 33.6, 30.9, 27.7, 25.5, 21.9; ES
+ HRMS m/z (M + MeOH + Na) calcd 239.0889, obsd 239.0904; Rf 0.13 (3:1
hexanes:ethyl acetate).
TBSO OH A mixture of 3.55 (206 mg, 0.76 mmol) and CH2Cl2 (63 mL) was
O o cooled to -78 C where O3 was bubbled through until a faint blue color
persisted. O2 was then bubbled through until the solution became clear where Ph3P (240 mg, 0.92 mmol, 1.2 eq) was added and the reaction mixture was
allowed to warm to rt, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (10:1 hexanes:ethyl acetate) 3.72 (184 mg,
90%) as a clear oil; IR (neat) ν = 3467, 1702, 1471, 1255, 1107, 1071 cm -1; 1H
NMR (500 MHz, CDCl3) δ 4.17 (d, J = 5.9 Hz, 1H), 3.88-3.85 (m, 1H), 3.57 (s,
1OH), 3.12-3.07 (m, 1H), 2.37-2.32 (m, 1H), 1.95-1.90 (m, 2H), 1.78-1.69 (m, 4H),
1.44-1.40 (m, 1H), 1.33-1.29 (m, 2H), 1.18-1.15 (m, 1H), 0.96 (s, 9H), 0.17 (s, 3H),
13 0.14 (s, 3H); C NMR (125 MHz, CDCl3) ppm 215.7, 80.4, 76.2, 38.8, 32.2, 27.4,
26.2 (3C), 25.5, 21.1, 18.4, -4.3, -4.4; ES HRMS m/z (M + Na)+ calcd 295.1705,
obsd 295.1712; Rf 0.39 (10:1 hexanes:ethyl acetate).
246 HO OH A mixture of 3.72 (80 mg, 0.29 mmol) and THF (8 mL) was cooled to 0
O oC where a 1M solution of TBAF in THF (0.31 mL, 0.31 mmol, 1.05 eq)
was added. The reaction mixture was stirred at rt for 30 min, when it
was quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and
extracted with ether (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 3.73 (40 mg, 85%) as
a colorless oil; IR (neat) ν = 3394, 1703, 1468, 1051 cm -1; 1H NMR (300 MHz,
CDCl3) δ 4.28 (t, J = 8.2 Hz, 1H), 3.38 (d, J = 8.7 Hz, 1H), 3.31-3.26 (m, 1H), 3.18
(s, 2 OH), 2.72-2.66 (m, 1H), 2.51-2.44 (m, 1H), 2.11-2.04 (m, 1H), 1.93-1.80 (m,
2H), 1.67-1.57 (m, 2H), 1.54-1.47 (m, 1H), 1.02-0.94 (m, 1H); 13C NMR (75 MHz,
+ CDCl3) ppm 213.7, 79.7, 77.6, 41.6, 29.2, 28.2, 21.0, 20.7; ES HRMS m/z (M + Na) calcd 181.0835, obsd 181.0841; Rf 0.20 (1:1 hexanes:ethyl acetate).
O Into a flask containing KOH (0.6 g), H O (2 mL) and Et O (5mL) was O 2 2 placed N-nitrosomethylurea (0.5 g, 4.8 mmol). The resultant yellow
ether layer was withdrawn with a pipet (the tip had previously been
flame-polished) and dried over KOH (0.4 g). The dried ether-diazomethane solution
was added to a solution of 4.17 (72.5 mg, 0.37 mmol) in ether (5 mL). The reaction
mixture was stirred for 12 h and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 4.18 (53.4 mg, 69%, 80% based on recovered starting material) as a colorless oil; IR (neat) ν =
-1 1 1704, 1470 cm ; H NMR (500 MHz, CDCl3,) δ 2.82 (d, J = 5.1 Hz, 1H), 2.77 (d, J
247 13 = 5.4 Hz, 1H), 2.07-0.90 (series of m, 20H); C NMR (125 MHz, CDCl3) ppm 211.2,
63.5, 50.9, 36.1, 31.6, 27.5, 26.7, 25.9, 24.5, 24.4, 23.8, 23.0, 22.8; HRMS m/z (M +
+ Na) calcd 233.1511, obsd 233.1531; Rf 0.39 (10:1 hexanes:ethyl acetate).
O To a flask containing KOH (0.6 g), H2O (2 mL), and Et2O (5mL) was O added N-nitrosomethylurea (0.38 g, 3.7 mmol). The resultant yellow
ether layer was withdrawn with a pipet (the tip had previously been flame polished) and dried over KOH (0.4 g). The dried ether-diazomethane solution was added to a solution of 4.27 (67 mg, 0.37 mmol) in CH2Cl2 (10 mL). The reaction
mixture was stirred for 12 h and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to give 4.28 (mp 145
oC, 36 mg, 50%, 88% based on recovered starting material) as a white solid; IR
-1 1 (neat) ν = 1731, 1248, 1273 cm ; H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 8.2 Hz,
1H), 8.09 (d, J = 7.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 8.1, 7.0 Hz, 1H),
7.72 (dd, J = 8.4, 7.0 Hz, 1Hz), 7.46 (d, J = 6.9 Hz, 1H), 3.75 (d, J = 6.6 Hz, 1H),
13 3.62 (d, J = 6.6 Hz, 1H); C NMR (125 MHz, CDCl3) ppm 198.6, 143.2, 132.9,
132.5, 132.0, 130.8, 128.9, 128.7, 121.5, 122.5, 119.1, 61.1, 54.9, 32.0, 14.6; HRMS
+ m/z (M + Na) calcd 219.0416, obsd 219.0425; Rf 0.54 (2:1 hexanes:ethyl acetate).
O To a flask containting KOH (0.6 g), H2O (2 mL) and Et2O (5mL) O was added N-nitrosomethylurea (0.38 g, 3.7 mmol). The resultant
248 yellow ether layer was withdrawn with a pipet (the tip had previously been flame polished) and dried over KOH (0.4 g). The dried ether-diazomethane solution was added to a solution of 4.29 (86 mg, 0.37 mmol) in CH2Cl2 (10 mL). The reaction
mixture was stirred for 12 h and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (5:1 hexanes:ethyl acetate) to give 4.30 (mp 180
oC, 46 mg, 51%, 96% based on recovered starting material) as a white solid; IR
-1 1 (neat) ν = 1710, 1216, 1210 cm ; H NMR (500 MHz, CDCl3) δ 9.17 (d, J = 8.6 Hz,
1H), 8.77 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.82 (t, J = 7.3
Hz, 1H), 7.71-7.64 (m, 2H), 7.41 (t, J = 6.6 Hz, 1H), 3.81 (d, J = 6.6 Hz, 1H), 3.67 (d,
13 J = 6.7 Hz, 1H); C NMR (125 MHz, CDCl3) ppm 198.1, 145.0, 133.7, 133.6, 133.2,
130.1, 129.7, 128.6, 128.4, 127.8, 127.2, 126.6, 125.6, 125.1, 118.6, 61.0, 54.4;
+ HRMS m/z (M + Na) calcd 269.0572, obsd 269.0565; Rf 0.32 (5:1 hexanes:ethyl
acetate).
O To a flask containing KOH (0.6 g), H2O (2 mL), and Et2O (5mL) was PhS added N-nitrosomethylurea (0.38 g, 3.7 mmol). The resultant yellow PhS O ether layer was withdrawn with a pipet (the tip had previously been flame
polished) and dried over KOH (0.4 g). The dried ether-diazomethane solution was
added to a solution of 4.33 (110 mg, 0.37 mmol) and SiO2 (30 mg) in CH2Cl2 (5 mL).
The reaction mixture was stirred for 12 h and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to give
4.34 as a white solid (mp 101-103 oC, 79 mg, 69%); IR (neat) ν = 1703, 1219 cm -1;
1 13 H NMR (500 MHz, CDCl3) δ 7.35-7.29 (m, 10H), 3.08 (s, 2H); C NMR (125 MHz,
249 CDCl3) ppm 192.8 (2C), 153.0 (2C), 133.0 (4C), 129.3 (4C), 129.1 (2C), 128.9 (2C),
+ 43.1; HRMS m/z (M + Na) calcd 312.0273, obsd 312.0267; Rf 0.57 (2:1
hexanes:ethyl acetate).
HO OH A water-cooled solution of DMSO (134 mL) and TfOH (12.5 mL, 141
mmol, 1 eq) was added slowly to a solution of 4.41 (17.5 g, 141 mmol)
and DMSO (44 mL). The reaction mixture was stirred at rt for 2 h,
o CH2Cl2 (254 mL) was added, and the reaction mixture was cooled to -78 C. At this
temperature i-Pr2NEt (35 mL, 202 mmol, 5 eq) was added and the mixture was
allowed to warm to rt, quenched with saturated NaHCO3 solution, transferred to a
separatory funnel, and extracted with CH2Cl2 (3 x 100 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 4.44 as a white solid (mp 78 oC, 5.68 g, 29%); IR (neat) ν = 3368, 2929, 2358, 1446, 1041 cm
-1 1 ; H NMR (500 MHz, CDCl3) δ 5.62-5.51 (m, 2H), 4.35 (t, J = 7.7 Hz, 1H), 3.47-
13 3.43 (m, 1H), 2.22-1.31 (series of m, 8H); C NMR (125 MHz, CDCl3) ppm 131.9,
129.9, 75.6, 73.1, 31.9, 27.2, 26.1, 20.6; ES HRMS m/z (M + Na)+ calcd 165.0885,
obsd 165.0885; Rf 0.36 (1:1 hexanes:ethyl acetate).
A solution of 4.44 (25 mg, 0.18 mmol), IBX (123 mg, 0.44 mmol, 2.5 eq), O O THF (0.44 mL), and DMSO (30 μL) was stirred at rt for 16 h, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (5:1 hexanes:ethyl aceate) to give 4.45 as a colorless oil
250 (23 mg, 95%); IR (neat) ν = 1706, 1652, 1472, 1288 cm -1; 1H NMR (500 MHz,
CDCl3) δ 6.80-6.74 (m, 1H), 6.30 (d, J = 11.5 Hz, 1H), 26.0-2.57 (m, 2H), 2.49-2.45
13 (m, 2H), 1.98-1.92 (m, 2H), 1.74-1.69 (m, 2H); C NMR (125 MHz, CDCl3) ppm
209.8, 197.2, 147.7, 131.7, 38.9, 25.1, 24.2, 19.3; ES HRMS m/z (M + Na)+ calcd
138.0675, obsd 138.0658; Rf 0.23 (5:1 hexanes:ethyl acetate).
A solution of 4.44 (0.2 g, 1.4 mmol), DMAP (17 mg, 0.14 mmol, 0.1 TBSO OH eq), imidazole (143 mg, 2.11 mmol, 1.5 eq), and TBSCl (0.23 g, 1.55
mmol, 1.1 eq) in CH2Cl2 (5.2 mL) was stirred at rt for 12 h, quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted
with CH2Cl2 (3 x 50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 4.47 as a colorless oil (360 mg, 81%); IR
-1 1 (neat) ν = 3490, 1471, 1252, 1082 cm ; H NMR (500 MHz, CDCl3) δ 5.56-5.44
(m, 2H), 4.29 (dd, J = 14.3, 6.0 Hz, 1H), 3.42-3.35 (m, 1H), 2.78-1.30 (series of m,
13 8H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); C NMR (125 MHz, CDCl3) ppm 133.4,
128.8, 75.2, 74.7, 30.6, 27.4, 26.0, 25.8 (3C), 20.6, 18.0, -4.0, -4.9; Rf 0.47 (20:1
hexanes:ethyl acetate).
TBSO O A solution of 4.47 (150 mg, 1.07 mmol) and IBX (628 mg, 2.25 mmol,
2.1 eq) in 8:1 THF:DMSO (2.83 ml) was stirred at rt for 12 h, quenched
with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted
with Et2O (3 x 50 mL). The combined organic phases were dried over Na2SO4 and
251 concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 4.48 as a colorless oil (100 mg, 62%); IR
-1 1 (neat) ν = 1720, 1471, 1253, 1107, 1072 cm ; H NMR (500 MHz, CDCl3) δ 5.70-
5.64 (m, 1H), 5.54-5.51 (m, 1H), 4.88 (dd, J = 5.6, 1.5 Hz, 1H), 2.66-1.47 (series of
13 m, 8H), 0.90 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); C NMR (125 MHz, CDCl3) ppm
211.7, 130.9, 129.2, 76.3, 39.9, 27.0, 25.7 (3C), 25.7, 22.9, 18.3, -4.8, -5.0; ES
+ HRMS m/z (M + Na) calcd 277.1594, obsd 277.1582; Rf 0.07 (40:1 hexanes:ethyl
acetate).
A solution of 4.42 (23 mg, 0.16 mmol) in DMF (0.8 mL) was O OH deoxygenated with argon. To the said mixture was added a
deoxygenated solution of NaH (5.1 mg, 0.21 mmol, 1.3 eq) and
DMF (0.8 mL) followed by the addition of BnBr (26 μL, 0.21 mmol, 1.3 eq), also
deoxygenated with argon. The solution was stirred at rt for 12 h, quenched with
saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with
CH2Cl2 (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 4.53 (9 mg, 20%) as a colorless oil; IR (neat)
-1 1 ν = 3477, 1687, 1451, 1168, 1097 cm ; H NMR (500 MHz, CDCl3) 7.38-7.37 (m,
2H), 7.31-7.25 (m, 1H), 7.17-7.15 (m, 2H), 6.24-6.21 (m, 1H), 5.90-5.86 (m, 1H),
3.76 (d, J = 1.8 Hz, 1H), 2.86 (d, J = 13.6 Hz, 1H), 2.79 (d, J = 13.6 Hz, 1H), 2.39-
13 1.28 (series of m, 8H); C NMR (125 MHz, CDCl3) ppm 212.1, 140.2, 135.1, 130.2
252 (2C), 128.5, 128.1 (2C), 126.9, 124.3, 81.6, 47.2, 32.8, 30.6, 23.2, 22.0; ES HRMS
+ m/z (M + Na) calcd 253.1198, obsd 253.1189; Rf 0.22 (10:1 hexanes:ethyl acetate).
O OAc A solution of 4.42 (46 mg, 0.33 mmol), DMAP (2.2 mg, 0.03 mmol, 0.1
eq), Et3N (50 μL, 0.36 mmol, 1.1 eq), and Ac2O (33 μL, 0.35 mmol, 1.05
eq), in CH2Cl2 (2 mL) was stirred at rt for 12 h, quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x
20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 4.54 (42 mg, 70%) as a colorless oil; IR (neat) ν =
-1 1 1745, 1679, 1242, 1052 cm ; H NMR (500 MHz, CDCl3) 6.47-6.42 (m, 1H), 6.19
(dd, J = 12.4, 2.1 Hz, 1H), 5.96 (dd, J = 9.7, 7.1 Hz, 1H), 2.66-1.54 (series of m, 8H),
13 2.14 (s, 3H); C NMR (125 MHz, CDCl3) ppm 198.1, 170.2, 142.2, 132.8, 77.0,
28.8, 28.2, 23.1, 21.2, 20.7; ES HRMS m/z (M + Na)+ calcd 205.0835, obsd
205.0830; Rf 0.25 (5:1 hexanes:ethyl acetate).
O OTBS A solution of 4.42 (200 mg, 1.4 mmol), DMAP (9.5 mg, 0.14 mmol, 0.1
eq), imidazole (0.26 g, 2.1 mmol, 1.5 eq), and TBSCl (0.32 g, 2.1 mmol,
1.5 eq) in CH2Cl2 (14 mL) was stirred at reflux for 7 h, quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x
40 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 4.57 (183 mg, 50%) as a colorless oil; 1H NMR (500
253 MHz, CDCl3) 6.34-6.29 (m, 1H), 6.06 (dd, J = 12.6, 1.5 Hz, 1), 4.65 (dd, J = 8.0, 5.9
Hz, 1H), 2.53-1.56 (series of m, 8H), 0.92 (s, 9H), 0.13 (s, 3H), 0.05 (s, 3H); 13C
NMR (125 MHz, CDCl3) ppm 204.4, 140.6, 131.2, 77.0, 32.8, 29.1, 25.8 (3C), 23.1,
22.0, 18.3, -4.6, -5.3; IR (neat) ν = 1727, 1395, 1288, 1095 cm -1; ES HRMS
molecular ion too fleeting for accurate mass spectroscopic analysis; Rf 0.39 (20:1
hexanes:ethyl acetate).
HO OTBS A solution of 4.57 (127 mg, 0.5 mmol) and CeCl3•7H2O (204 mg, 0.55
o mmol, 1.1 eq) in MeOH (2 mL) was cooled to 0 C. NaBH4 (76 mg, 2.0
mmol, 4 eq) was added and the reaction mixture was stirred for 30 min, allowed to
warm to rt, quenched with saturated NaHCO3 solution, transferred to a separatory
funnel, and extracted with CH2Cl2 (3 x 30 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 4.58 (127 mg, 98%)
as a colorless oil; IR (neat) ν = 3480, 1422, 1252, 1063 cm -1; 1H NMR (500 MHz,
CDCl3) 5.64-5.49 (m, 2H), 4.35 (t, J = 7.5 Hz, 1H), 3.44 (dt, J = 3.3, 8.2 Hz, 1H),
2.26-1.32 (series of m, 8H), 0.93 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 131.3, 129.8, 77.3, 73.0, 32.7, 27.0, 26.1, 25.8 (3C), 20.5, 18.0, -
4.2, -4.7; ES HRMS molecular ion too fleeting for accurate mass spectroscopic
analysis; Rf 0.30 (20:1 hexanes:ethyl acetate).
254 AcO OTBS A solution of 2.58 (84 mg, 0.33 mmol), DMAP (2.2 mg, 0.03 mmol,
0.1 eq), Et3N (50 μL, 0.36 mmol, 1.1 eq), and Ac2O (32 μL, 0.34 mmol,
1.05 eq) in CH2Cl2 (3.3 mL) was stirred at reflux for 7 h, quenched
with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted
with CH2Cl2 (3 x 40 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 2.59 (93 mg, 95%) as a colorless oil; IR
-1 1 (neat) ν = 1745, 1368, 1237, 1082 cm ; H NMR (500 MHz, CDCl3) 5.78 (dd, J =
18.2, 8.2 Hz, 1H), 5.63 (t, J = 7.9 Hz, 1H), 5.36-5.33 (m, 1H), 3.85-3.81 (m, 1H),
2.07 (s, 3H), 2.39-1.28 (series of m, 8H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (125
MHz, CDCl3) ppm 170.3, 132.6, 128.7, 75.8, 74.1, 32.9, 28.8, 27.8, 25.6 (3C), 21.4,
+ 21.3, 17.9, -4.7 (2C); ES HRMS m/z (M + Na) calcd 321.1856, obsd 321.1868; Rf
0.30 (20:1 hexanes:ethyl acetate).
PivO OTBS A solution of 4.58 (37 mg, 0.14 mmol), Et3N (22 μL, 0.16 mmol, 1.1
eq), PivCl (18 μL, 0.15 mmol, 1.05 eq) and DMAP (1 mg, 0.01 mmol,
0.1 eq) in CH2Cl2 (1.4 mL) was stirred for 12 h, quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 30 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (20:1 hexanes:ethyl acetate) to
give 4.60 as a yellow oil (43 mg, 90%); IR (neat) ν = 1730, 1461, 1157 cm -1; 1H
NMR (500 MHz, CDCl3) 5.83-5.78 (m, 1H), 5.59 (t, J = 7.8 Hz, 1H), 5.28 (dd, J =
10.8, 7.6 Hz, 1H), 3.96-3.93 (m, 1H), 2.39-1.58 (series of m, 8H), 1.22 (s, 9H), 0.89
255 13 (s, 9H), 0.07 (s, 6H); C NMR (125 MHz, CDCl3) ppm 178.2, 133.0, 129.1, 76.0,
73.8, 38.6, 32.6, 28.4, 28.1 (3C), 27.3 (3C), 21.6, 18.0, -4.6 (2C); ES HRMS m/z (M
+ + Na) not performed; Rf 0.5 (20:1 hexanes:ethyl acetate).
OH A solution of TfOH (1.05 mL, 11.8 mmol, 1 eq) in DMSO (3 mL) was OH added to a stirred solution of 4.62 (1.14 g, 1.8 mmol) in DMSO (8.9 mL). The reaction mixture was stirred for 10 min, diluted with CH2Cl2 (100mL),
o cooled to -78 C, and quenched with Et2Ni-Pr (10.3 mL, 56 mmol, 5 eq). The
reaction mixture was allowed to warm to rt, transferred to a separatory funnel, treated
with H2O (200 mL), and extracted with CH2Cl2 (3 x 40 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:ethyl acetate) to give 4.65 as a colorless oil
-1 1 (0.66 g, 50%); IR (neat) ν = 3394, 1456, 1052 cm ; H NMR (500 MHz, CDCl3)
5.72-5.67 (m, 1H), 5.63-5.57 (m, 1H), 3.90-3.86 (m, 1H), 3.82 (dd, J = 8.8, 2.8 Hz,
1H), 3.22 (s, OH), 3.18 (s, OH), 2.48-2.42 (m, 1H), 2.26-2.03 (m, 4H), 1.77-1.71 (m,
13 1H), 1.49-1.42 (m, 2H); C NMR (125 MHz, CDCl3) ppm 132.3, 125.8, 74.0, 73.2,
+ 30.6, 30.5, 26.5, 25.6; ES HRMS m/z (M + Na) not performed; Rf 0.17 (2:1
hexanes:ethyl acetate).
A solution of 4.67 (0.53 g, 3.56 mmol) in THF (34 mL) was cooled
SS o OH to 0 C, where a 1.2 M solution of n-BuLi in hexanes (3.0 mL, 3.6 mmol, 1 eq) was added. The reaction mixture was stirred for 5
256 min and hex-5-enal (0.2 g, 3.6 mmol, 1 eq) in THF (5 mL) was added. The reaction
mixture was allowed to warm to rt, stirred for 12 h, quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 30 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (20:1 hexanes:ethyl acetate) to
give 4.68 as a yellow oil (156 mg, 17%, 84% brsm); IR (neat) ν = 3479, 1638, 1423,
-1 1 1274, 910 cm ; H NMR (500 MHz, CDCl3) 6.03-5.95 (m, 1H), 5.87-5.67 (m, 1H),
5.13-4.94 (series of m, 4H), 3.96 (d, J = 9.7 Hz, 1H), 2.98-1.40 (series of m, 14H);
13 C NMR (125 MHz, CDCl3) ppm 138.6, 133.2, 118.1, 114.5, 71.9, 58.1, 38.9, 33.6,
29.7, 26.9, 26.0, 25.1, 24.3; ES HRMS m/z (M + O + Na)+ calcd 297.0953, obsd
297.0954; Rf 0.15 (20:1 hexanes:ethyl acetate)
A solution of 4.68 (79 mg, 0.3 mmol), CH2Cl2 (8 mL), and 2,6-
SS o OTBS lutidine (71μL, 0.6 mmol, 2 eq) was cooled to -78 C and
TBSOTf (0.1 mL, 0.5 mmol, 1.5 eq) was added. The reaction
mixture was allowed to warm to rt, quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x
30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel(20:1 hexanes:ethyl acetate) to give 4.69 as a yellow oil (87 mg, 84%); IR (neat) ν = 1639,
-1 1 1462, 1253, 910, 835 cm ; H NMR (500 MHz, CDCl3) 6.09-6.01 (m, 1H), 5.88-
5.81 (m, 1H), 5.14-5.10 (series of m, 2H), 5.03 (dd, J = 17.1, 1.5 Hz, 1H), 4.97 (dd, J
= 10.1, 4.0, 1H), 2.84-1.44 (series of m, 14H), 0.94 (s, 9H), 0.18 (s, 3H), 0.12 (s, 3H);
257 13 C NMR (125 MHz, CDCl3) ppm 138.5, 134.6, 117.0, 114.6, 76.6, 58.5, 39.9, 33.6,
27.2, 26.2, 26.0, 25.7, 24.6, 18.6, -3.5, -3.7; ES HRMS m/z (M + Na)+ calcd
395.1869, obsd 395.1856; Rf 0.45 (20:1 hexanes:ethyl acetate).
NC A solution of 5.16 (0.5 g, 4.4 mmol), imidazole (0.45 g, 6.7
OTBDPS mmol, 1.5 eq), DMAP, (50 mg, 0.4 mmol, 0.1 eq), and TBDPSCl
(1.15 mL, 4.4 mmol, 1.0 eq), in CH2Cl2 (16 mL) was refluxed overnight, allowed to
come to rt, quenched with saturated NaHCO3 solution, transferred to a separatory
funnel, and extracted with CH2Cl2 (3 x 50 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (5:1 hexanes:ethyl acetate) to give 5.12 as a colorless oil
-1 1 (1.33 g, 80%); IR (CH2Cl2) ν = 1470, 1427, 1109 cm ; H NMR (500 MHz, CDCl3)
δ 7.73-7.72 (m, 4H), 7.48-7.42 (m, 6H), 3.91 (t, J = 6.6 Hz, 2H), 1.85 (t, J = 6.5 Hz,
13 2H), 1.40 (s, 6H), 1.11 (s, 9H); C NMR (125 MHz, CDCl3) ppm 135.6 (4C), 133.3
(2C), 129.8 (2C), 124.9 (4C), 124.9, 60.7, 42.8, 30.9, 27.2 (2C), 26.8 (3C), 19.1; EI
+ m/z (M) calcd 351.2018, obsd 351.2012; Rf 0.10 (20:1 hexanes:ethyl acetate).
PMBO Dibromide 5.22 (289 mg, 0.79 mmol) dissolved in THF (10 mL)
was brought to -78 oC, where a 1.6 M solution of t-BuLi in
hexanes (1.24 mL, 1.98 mmol, 2.5 eq) was added. The reaction mixture was stirred
for 1 h, quenched with H2O, warmed to rt, transferred to a separatory funnel, and
extracted with ether (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column
258 chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 5.23 (130 mg, 80%)
20 as a colorless oil; [α] D -0.6 (c 1.0, CHCl3); IR (neat) ν = 1613, 1513, 1247, 1173,
-1 1 1089 cm ; H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.6
Hz, 2H), 4.52 (d, J = 2.6 Hz, 1H), 3.83 (3, 3H), 3.53 (dd, J = 9.0, 6.2 Hz, 1H), 3.37
(dd, J = 9.0, 7.3 Hz, 1H), 2.77-2.73 (m, 1H), 2.09 (d, J = 2.5 Hz, 1H), 1.23 (d, J = 7.0
13 Hz, 3H); C NMR (125 MHz, CDCl3) ppm 159.2, 130.2, 129.2 (2C), 113.8 (2C),
86.5, 73.5, 72.7, 68.9, 55.2, 26.5, 17.6; HRMS m/z (M + Na)+ calcd 227.1042, obsd
227.1038; Rf 0.22 (20:1 hexanes:ethyl acetate).
PMBO OH To a solution of 5.25 (1.5 g, 5.3 mmol) in Et2O (24.4 mL)
o OTBDPS at -78 C was added a 1.5 M solution of t-BuLi in pentane
(7 mL, 10.5 mmol, 2 eq). The solution was brought to 0 oC for 10 min and returned
o to -78 C, where aldehyde 5.17 (1.86 g, 5.3 mmol, 1 eq) was added in 2.0 mL of Et2O.
The reaction mixture was stirred for 1 h, quenched at 0 oC with Rochelle’s salt,
transferred to a separatory funnel, and extracted with ether (3 x 60 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl
acetate) to give 5.27 as a crystalline solid (mp 35 oC, 0.97 g, 33%) and 5.28 as a
colorless oil (0.79 g, 27%).
20 For 5.27: top spot; [α] D +42.2 (c 1.0, CHCl3); IR (neat) ν = 3456, 1612,
-1 1 1513, 1249, 1111, 1086 cm ; H NMR (500 MHz, CDCl3) δ 7.71 (dd, J = 7.2, 0.6
Hz, 4H), 7.45-7.38 (m, 6H), 7.23 (d, J = 8.6 Hz, 2H), 6.90-6.87 (m, 2H), 5.01 (s, 1H),
4.96 (s, 1H), 4.46 (s, 2H), 3.89 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 3.6-3.78 (m, 1H),
259 3.47 (dd, J = 8.0, 5.1 Hz, 1H), 3.16 (dd, J = 9.7, 8.1 Hz, 1H), 2.77-2.72 (m, 1H), 1.84-
1.78 (m, 1H), 1.57-1.52 (m, 1H), 1.07 (s, 9H), 1.05 (d, J = 7.0 Hz, 3H), 0.89 (s, 3H),
13 0.86 (s, 3H); C NMR (125 MHz, CDCl3) ppm 159.2, 153.7, 135.6 (4C), 134.0 (2C),
129.7, 129.5 (2C), 129.3 (2C), 127.6 (4C), 113.8 (2C), 112.5, 82.4, 78.0, 73.0, 61.1,
55.2, 41.5, 37.4, 33.6, 26.8 (3C), 23.9, 23.5, 19.1, 17.0 ; ES HRMS m/z (M + Na)+ calcd 583.3214, obsd 583.3191; Rf 0.19 (10:1 hexanes:ethyl acetate).
20 For 5.28: bottom spot: [α] D +15.2 (c 0.7, CHCl3); IR PMBO OH (neat) ν = 3419, 1652, 1614, 1513, 1464, 1427 cm -1; 1H OTBDPS
NMR (500 MHz, CDCl3) δ 7.72-7.69 (m, 4H), 7.47-7.39 (m, 6H), 7.26 (d, J = 8.6
Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.18 (s, 1H), 5.08 (s, 1H), 4.45 (d, J = 5.6 Hz, 1H),
3.96 (d, J = 2.0 Hz, 1H), 3.81 (s, 3H), 3.77 (t, J = 6.0 Hz, 1H), 3.49 (dd, J = 9.1, 4.1
Hz, 1H), 3.22 (t, J = 8.6 Hz, 1H), 2.82 (d, J = 3.0 Hz, 1H), 2.42-2.38 (m, 1H), 1.83-
1.78 (m, 1H), 1.57-1.49 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 1.07 (s, 9H), 0.90 (s, 3H),
13 0.87 (s, 3H); C NMR (125 MHz, CDCl3) ppm 159.1, 153.9, 135.6 (2C), 135.5 (2C),
133.4, 133.3, 130.6, 129.7 (2C), 129.6 (2C), 129.1 (2C), 127.7 (2C), 113.7 (2C),
111.5, 80.8, 76.3, 72.7, 61.1, 55.2, 42.1, 39.0, 38.1, 26.8 (3C), 24.8, 22.5, 19.0, 16.9;
+ ES HRMS m/z (M + Na) calcd 583.3214, obsd 583.3189; Rf 0.18 (10:1
hexanes:ethyl acetate).
To a solution of 5.27 (40 mg, 0.07 mmol) and VO(acac) PMBO 2 OH O (1.9 mg, 0.007 mmol, 0.1 eq) in CH2Cl2 (1.5 mL) was OTBDPS
added a 2.6 M solution of TBHP in CH2Cl2 (0.06 mL), 0.14 mmol, 2 eq). The
resulting wine-colored reaction mixture was stirred until it became a light yellow,
260 quenched with dimethyl sulfide (0.1 mL), transferred to a separatory funnel, diluted
with saturated NaHCO3 solution, and washed with CH2Cl2 (3 x 30 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (3:1 hexanes:ethyl
20 acetate) to give 5.29 as a colorless oil (30 mg, 75%); [α] D +3.8 (c 0.8, CHCl3); IR
-1 1 (neat) ν = 3426, 1611, 1513, 1240, 1111, 1087 cm ; H NMR (500 MHz, CDCl3) δ
7.74 (d, J = 6.5 Hz, 4H), 7.47-7.40 (m, 6H), 7.27 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.6
Hz, 2H), 4.46 (q, J = 26.1, 11.7 Hz, 2H), 3.83 (s, 3H), 3.35 (d, J = 2.8 Hz, 1H), 3.28-
3.20 (m, 2H), 2.85 (d, J = 4.5 Hz, 1H), 2.79 (d, J = 4.5 Hz, 1H), 2.55-2.51 (m, 1H),
1.90-1.85 (m, 1H), 1.69-1.63 (m, 1H), 1.10 (s, 9H), 1.04 (s, 3H), 1.00 (s, 3H), 0.90 (d,
13 J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl3) ppm 159.3, 135.6 (4C), 134.0 (2C),
129.9, 129.5 (2C), 129.2 (2C), 127.6 (4C), 113.8 (2C), 77.0, 72.7, 72.0, 61.1, 60.9,
55.2, 49.8, 42.7, 37.7, 34.0, 26.9 (3C), 25.0, 24.4, 19.1, 12.2; ES HRMS m/z (M +
+ Na) calcd 599.3163, obsd 599.3140; Rf 0.06 (3:1 hexanes:ethyl acetate).
PMBO OH A solution of 5.29 (90 mg, 0.16 mmol), 1M TBAF in THF O OH (0.23 mL, 0.23 mmol, 1.5 eq), and THF (2 mL) were stirred
for 1 h at rt, transferred to a separatory funnel, diluted with saturated NaHCO3 solution, and washed with CH2Cl2 (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 5.30 as a colorless oil
20 (35 mg, 66%); [α] D +21.5 (c 1.0, CHCl3); IR (neat) ν = 3408, 1612, 1513, 1248 cm
-1 1 ; H NMR (500 MHz, CDCl3) δ 7.23 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H),
261 4.44 (dd, J = 18.1, 11.6 Hz, 2H), 3.82 (3, 3H), 3.75-3.67 (m, 2H), 3.40 (s, 1H), 3.28
(dd, J = 9.3, 4.8 Hz, 1H), 3.16 (t, J = 9.4 Hz, 1H), 2.86 (d, J = 4.4 Hz, 1H), 2.78 (d, J
= 4.4 Hz, 1H), 2.60-2.53 (m, 1H), 1.75-1.69 (m, 1H), 1.61-1.55 (m, 1H), 1.08 (s, 3H),
13 1.02 (s, 3H), 0.88 (d, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl3) ppm 159.4,
129.7, 129.2 (2C), 113.9 (2C), 77.0, 72.8, 72.1, 61.1, 59.1, 55.2, 49.8, 45.4, 37.8,
+ 26.3, 23.6, 12.0; ES HRMS m/z (M + Na) calcd 361.1985, obsd 361.1969; Rf 0.22
(1:1 hexanes:ethyl acetate).
O N PMBO 2 A solution of 5.30 (34 mg, 0.1 mmol), Et3N (15 μL, OH O NO2 0.11 mmol, 1.1 eq), DMAP (0.7 mg, 0.01 mmol, O O 0.1 eq), CH2Cl2 (0.7 mL), and 3,5-dinitrobenzoyl
chloride (35 mg, 0.15 mmol, 1.5 eq) was stirred for 2 h at rt, transferred to a
separatory funnel, diluted with saturated NaHCO3 solution, and washed with CH2Cl2
(3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography on silica gel (1:1
20 hexanes:ethyl acetate) to give 5.31 as a colorless oil (42 mg, 79%); [α] D +8.4 (c
-1 1 1.0, CHCl3); IR (neat) ν = 3491, 1730, 1546, 1345 cm ; H NMR (500 MHz,
CDCl3) δ 9.21 (t, J = 2.2 Hz, 1H), 9.14 (d, J = 2.1 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H),
6.85 (d, J = 8.6 Hz, 2H), 4.63-4.56 (m, 2H), 4.44 (q, J = 21.7, 11.7 Hz, 2H), 3.80 (s,
3H), 3.42 (d, J = 2.6 Hz, 1H), 3.37 (d, J = 2.6 Hz, 1H), 3.31 (dd, J = 9.2, 4.5 Hz, 1H),
3.13 (t, J = 9.6 Hz, 1H), 2.86 (d, J = 4.4 Hz, 1H), 2.80 (d, J = 4.4 Hz, 1H), 2.61-2.54
(m, 1H), 2.09-2.03 (m, 1H), 1.86-1.80 (m, 1H), 1.17 (s, 3H), 1.11 (s, 3H), 0.89 (d, J =
13 7.1 Hz, 3H); C NMR (125 MHz, CDCl3) ppm 162.5, 159.3, 148.6, 134.2, 129.6,
262 129.3 (2C), 129.2 (2C), 122.2, 113.8 (2C), 77.0, 72.8, 72.1, 64.5, 60.9, 55.2, 49.8,
39.0, 37.8, 33.6, 25.2, 24.2, 12.0; ES HRMS m/z (M + Na)+ calcd 555.1949, obsd
555.1963; Rf 0.16 (5:1 hexanes:ethyl acetate).
O N 2 NO2 A solution of 5.31 (27 mg, 0.05 mmol), pyridine
O N (0.5 mL), DMAP (1 mg, 0..5 mmol, 0.1 eq), and PMBO 2 O O O NO2 3,5-dinitrobenzoylchloride (24 mg, 0.1 mmol, 2 eq) O O was stirred at rt for 12 h, quenched with saturated from top spot
NaHCO3 solution, transferred to a separatory funnel, and washed with CH2Cl2 (3 x 20
mL). The combined organics were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (5:1 hexanes:ethyl
20 acetate) to give 5.32 (30 mg, 81%) as a yellow oil; [α] D +11.1 (c 1.0, CHCl3); IR
-1 1 (neat) ν = 2359, 1732, 1545, 1344, 1274 cm ; H NMR (500 MHz, CDCl3) δ 9.22
(t, J = 2.2 Hz, 1H), 9.11 (d, J = 2.2 Hz, 3H), 8.95 (d, J = 2.2 Hz, 2H), 8.63 (d, J = 4.0
Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.64 (d, J= 8.6 Hz, 2H), 4.91 (s, 1H), 4.63-4.53 (m,
2H), 4.19 (d, J= 3.6 Hz, 2H), 3.74 (s, 3H), 3.36 (dd, J= 9.4, 4.7 Hz, 1H), 3.06 (t, J=
9.5 Hz, 1H), 2.96 (d, J = 4.6 Hz, 1H), 2.85 (d, J = 4.7 Hz, 1H), 2.75-22.71 (m, 1H),
2.13-1.99 (m, 2H), 1.34 (s, 3H), 1.26 (s, 3H), 1.04 (d, J= 6.9 Hz, 3H); 13C NMR (125
MHz, CDCl3) ppm 162.4, 161.7, 159.0, 148.6, 148.3, 133.79, 133.76, 129.7, 129.3
(2C), 129.2 (2C), 128.9 (2C), 122.4, 122.1, 113.4 (2C), 81.8, 72.8, 72.5, 63.5, 58.1,
55.1, 50.9, 38.2, 37.9, 32.8, 25.1, 24.7, 12.3; ES HRMS m/z (M + Na)+ calcd
749.1912, obsd 749.1934; Rf 0.28 (5:1 hexanes:ethyl acetate).
263 PMBO O A solution of 5.29 (35 mg, 0.06 mmol), THF (2 mL),
THPOCH2CCH (42 μL, 0.3 mmol, 5 eq) and a 1.3 M HO OTBDPS solution of n-BuLi in hexanes (0.3 mL, 0.3 mmol, 5eq) was stirred for 2 h at -78 oC,
where BF3•OEt2 (0.27 mL, 0.3 mmol, 5 eq) was added. After 12 h, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with CH2Cl2 (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (5:1
20 hexanes:ethyl acetate) to give 5.34 as a colorless oil (10 mg, 24%); [α] D -0.4 (c 1.0,
-1 1 CHCl3); IR (neat) ν = 3422, 1513, 1427, 1247, 1111 cm ; H NMR (500 MHz,
CDCl3) δ 7.69 (d, J = 7.5 Hz, 4H), 7.45-7.38 (m, 6H), 7.31-7.26 (m, 2H), 6.89 (d, J =
8.5 Hz, 2H), 4.50 (d, J = 11.5 Hz, 1H), 4.45 (d, J = 11.5 Hz, 1H), 3.82 (s, 3H), 3.74
(dd, J = 12.2, 3.2 Hz, 1H), 3.59-3.51 (m, 2H), 3.36 (dd, J = 12.1, 8.9 Hz, 1H), 2.69 (s,
1H), 2.53-2.51 (m, 1H), 2.19-2.15 (m, 1H), 1.28 (s, 3H), 0.98 (s, 3H), 0.90 (d, J = 6.9
13 Hz, 3H); C NMR (125 MHz, CDCl3) ppm 159.2, 135.5 (2C), 133.8 (2C), 130.0,
129.6, 129.3, 127.6 (2C), 113.8, 72.9, 71.6, 68.8, 65.5, 62.5, 60.6, 55.2, 45.2, 33.6,
33.4, 31.9, 29.7, 29.6, 29.3, 26.8 3C), 25.6, 25.0, 22.7, 19.1, 14.14, 14.11; ES HRMS
+ m/z (M + Na) calcd 599.2809, obsd 599.2809; Rf 0.14 (5:1 hexanes:ethyl acetate).
PMBO O A solution of 5.34 (10 mg, 0.01 mmol), p-TsOH (0.3 mg,
O OTBDPS 0.001 mmol, 0.1 eq), and 2,2-dimethoxypropane (0.2 mL) MeO from top spot of o IV-REH-142 was heated to 60 C for 1 h, cooled to rt, quenched with
saturated NaHCO3 solution, and extracted with CH2Cl2 (3 x 30 mL). The combined
organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was 264 purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give
20 5.35 as a colorless oil (9 mg, 86%); [α] D -19.4 (c 0.5, CHCl3); IR (neat) ν = 1510,
-1 1 1460, 1247, 1107, 1082 cm ; H NMR (500 MHz, CDCl3) δ 7.70-7.67 (m, 4H),
7.45-7.37 (m, 6H), 7.27 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.44 (d, J= 2.7
Hz, 2H), 3.85-3.79 (m, 1H), 3.81 (s, 3H), 3.63 (dd, J = 6.2, 4.6 Hz, 1H), 3.54 (t, J =
8.4 Hz, 1H), 3.39 (d, J = 10.9 Hz, 1H), 3.33 (d, J = 11.0 Hz, 1H), 3.12 (s, 3H), 2.67
(s, 1H), 2.19-2.15 (m, 2H), 1.72 (t, J= 7.4 Hz, 2H), 1.26 (s, 6H), 1.11 (d, J = 7.1 Hz,
13 3H), 1.06 (s, 9H), 1.00 (s, 3H), 0.99 (s, 3H); C NMR (125 MHz, CDCl3) ppm
159.1, 135.5 (2C), 133.9, 130.7, 129.5, 129.2, 127.6 (2C), 113.7, 99.9, 72.6, 72.5,
68.4, 64.8, 62.4, 60.7, 55.2, 48.5, 45.1, 34.5, 33.4, 31.9, 29.7, 25.8 (3C), 25.0, 24.2,
+ 19.1, 14.8, 14.1; ES HRMS m/z (M + Na) calcd 671.3744, obsd 671.3813; Rf 0.15
(10:1 hexanes:ethyl acetate).
PMBO A solution of 5.29 (130 mg, 0.22 mmol) DMAP (2 mg, OBz O 0.02 mmol, 0.1 eq), benzoyl chloride (0.16 mL, 1.34 OTBDPS mmol, 6 eq), and pyridine (0.5 mL) was stirred at rt for 12 h, quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x
30 mL). The combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (10:1
20 hexanes:ethyl acetate) to give 5.37 as a colorless oil (140 mg, 92%); [α] D +16.2 (c
-1 1 1.0, CHCl3); IR (neat) ν = 1723, 1513, 1269, 1248, 1110 cm ; H NMR (500 MHz,
CDCl3) 8.02 (d, J = 7.1 Hz, 2H), 7.72-7.70 (m, 4H), 7.59 (t, J = 7.5 Hz, 1H), 7.50-
265 7.37 (m, 8H), 7.17 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 4.86 (s, 1H), 4.30 (d,
J = 3.9 Hz, 2H), 3.84 (t, J = 7.6 Hz, 2H), 3.82 (s, 3H), 3.27 (dd, J = 9.2, 7.2 Hz, 1H),
3.15 (dd, J = 9.3, 5.9 Hz, 1H), 2.84 (d, J = 4.9 Hz, 1H), 2.73 (d, J = 4.8 Hz, 1H),
2.68-2.64 (m, 1H), 1.92-1.78 (m, 2H), 1.15 (s, 3H), 1.14 (s, 3H), 1.09 (s, 9H), 1.03 (d,
13 J = 6.9 Hz, 3H); C NMR (125 MHz, CDCl3) ppm 165.4, 159.1, 135.6 (2C), 133.9,
133.8, 132.8, 130.4, 130.3, 129.66 (2C), 129.60 (2C) 129.0 (2C), 128.4 (2C), 128.3
(2C), 127.6 (2C), 113.7 (2C), 79.9, 72.5, 71.8, 60.5, 58.2, 55.2, 49.2, 42.2, 37.8, 33.7,
26.9 (3C), 25.15, 25.12, 19.1, 12.4; ES HRMS m/z (M + Na)+ calcd 703.3425, obsd
703.3417; Rf 0.14 (10:1 hexanes:ethyl acetate).
PMBO OBOM To a solution of 5.29 (59 mg, 0.1 mmol) in CH2Cl2 (1 O mL) was added DIPEA (108 μL, 0.6 mmol, 6 eq) and OTBDPS
Bu4NI (38 mg, 0.1 mmol, 1 eq) followed by BOMCl (44 μL, 0.31 mmol, 3 eq). The
reaction mixture was stirred for 4 d, quenched with saturated NaHCO3 solution,
transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl
20 acetate) to give 5.39 (45 mg, 63%) as a colorless oil; [α] D +22.9 (c 1.3, CHCl3);
-1 1 IR (neat) ν = 2930, 1472, 1248, 1082 cm ; H NMR (500 MHz, CDCl3) 7.69 (dd, J
= 6.3, 1.7 Hz, 4H), 7.44-7.28 (m, 11H), 7.23 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz,
2H), 4.80 (d, J = 7.1 Hz, 1H), 4.69-4.63 (m, 2H), .50 (d, J = 11.9 Hz, 1H), 4.40 (d, J
= 2.5 Hz, 2H), 3.80 (s, 3H), 3.80-3.78 (m, 1H), 3.36 (dd, J = 9.2, 6.4 Hz, 1H), 3.22
(dd, J = 7.3, 6.0 Hz, 1H), 3.18 (s, 1H), 2.75 (d, J = 5.0 Hz, 1H), 2.68 (d, J = 4.9 Hz,
266 1H), 2.54-2.53 (m, 1H), 1.86-1.82 (m, 1H), 1.78-1.74 (m, 1H), 1.57 (s, 3H), 1.06 (s,
13 9H), 1.02 (s, 3H), 0.91 (d, J = 6.9 Hz, 3H); C NMR (125 MHz, CDCl3) ppm 159.1,
137.9, 135.6 (2C), 134.0, 130.5, 129.5 (2C), 129.0 (2C), 128.4, 128.3 (2C), 127.8,
127.7 (2C), 127.6 (4C), 113.7 (2C), 94.6, 72.5, 71.8, 70.2, 60.7, 58.1, 55.2, 48.9, 42.0,
38.2, 33.4, 26.8 (3C), 25.0, 24.8, 19.1, 12.5; ES HRMS m/z (M + Na)+ calcd
719.3739, obsd 719.3737; Rf 0.1 (10:1 hexanes:ethyl acetate).
PMBO OTBS A solution of 5.29 (102 mg, 0.18 mmol), CH2Cl2 (2 mL), O OTBDPS and 2,6-lutidine (104 μL, 0.89 mmol, 5 eq) was cooled to
-78 oC and treated with TBSOTf (82 μL, 0.36 mmol, 2 eq). The reaction mixture was
stirred for 4 h as it was allowed to warm to rt, washed with saturated NaHCO3
solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 20 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl
20 acetate) to give 5.40 (120 mg, 98%) as a colorless oil; [α] D -3.4 (c 0.9, CHCl3); IR
-1 1 (neat) ν = 2931, 1472, 1111 cm ; H NMR (500 MHz, CDCl3) 7.72 (dd, J = 7.8, 1.4
Hz, 4H), 7.46-7.38 (m, 6H), 7.25 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.42
(s, 2H), 3.82 (s, 3H), 3.78 (t, J = 7.3 Hz, 2H), 3.61 (dd, J = 8.7, 5.2 Hz, 1H), 3.14-
3.10 (m, 2H), 2.71 (d, J = 5.0 Hz, 1H), 2.65-2.61 (m, 1H), 2.49 (d, J = 4.9 Hz, 1H),
1.81-1.73 (m, 2H), 1.08 (s, 9H), 0.99 (s, 6H), 0.93 (d, J = 6.9 Hz, 3H), 0.92 (s, 9H),
13 0.05 (s, 6H); C NMR (125 MHz, CDCl3) ppm 159.1, 135.6 (4C), 134.1 (2C), 130.6,
129.5 (2C), 129.0 (2C), 127.6 (4C), 113.7 (2C), 72.5, 72.4, 60.9, 59.5, 55.2, 48.2,
41.3, 38.8, 33.5, 26.8 (3C), 26.1 (3C), 25.0, 24.5, 19.1, 18.5, 12.6, -3.2, -4.9; ES
267 + HRMS m/z (M + Na) calcd 713.4027, obsd 713.4033; Rf 0.31 (10:1 hexanes:ethyl
acetate).
PMBO OH A solution of 5.27 (34 mg, 0.06 mmol) in CH2Cl2 (10
o O OTBDPS mL) was cooled to -78 C, where gaseous O3 was bubbled through until a light purple color persisted. Ph3P (39.8 mg, 0.15 mmol, 2.5
eq) was added and the solution was allowed to warm to rt. The reaction mixture was
concentrated in vacuo and purified by column chromatography on silica gel (10:1
20 hexanes:ethyl acetate) to give 5.42 as a colorless oil (15 mg, 44%); [α] D +20.6 (c
-1 1 1.0, CHCl3); IR (neat) ν = 3463, 1707, 1513, 1249, 1101 cm ; H NMR (500 MHz,
CDCl3) 7.70 (d, J = 6.6 Hz, 4H), 7.45-7.38 (m, 6H), 7.20 (d, J = 8.5 Hz, 2H), 6.87 (d,
J = 8.6 Hz, 2H), 4.45-4.39 (m, 2H), 4.18 (d, J = 3.4 Hz, 1H), 3.83 (d, J = 3.5 Hz, 1H),
3.81 (s, 3H), 3.78 (t, J= 6.8 Hz, 2H), 3.50-3.46 (m, 1H), 1.91-1.86 (m, 1H), 1.59-1.45
(m, 1H), 1.06 (s, 9H), 0.99 (d, J = 3.2 Hz, 3H), 0.97 (s, 3H), 0.93 (s, 3H); 13C NMR
(125 MHz, CDCl3) ppm 217.0, 159.3, 135.5 (4C), 133.7 (2C), 129.5 (2C), 129.4 (2C),
129.2 (2C), 127.6 (4C), 113.9 (2C), 82.9, 73.2, 73.1, 60.7, 55.2, 42.4, 41.3, 37.9, 26.8
(3C), 23.9, 23.6, 19.1, 12.8; ES HRMS m/z (M + Na)+ calcd 585.3006, obsd
585.2993; Rf 0.45 (5:1 hexanes:ethyl acetate).
O (+)-DET (30 mg, 0.15 mmol, 0.12 eq), powdered 4 Å molecular OH sieves (0.63 g), and CH2Cl2 (13.5 mL) were combined and
o cooled to -20 C, where Ti(O-i-Pr)4 (36 μL, 0.12 mmol, 0.1 eq) was added. The
reaction mixture was stirred for 20 min and 5.45 (0.12 g, 1.22 mmol) in CH2Cl2 (9
268 mL) was added. The solution was stirred for 1.5 h and a 2.6 M solution of t-BuOOH
in CH2Cl2 (1.4 mL, 3.7 mmol, 4 eq) was added. The reaction mixture was stirred
until conversion was complete by TLC (approximately 3-5 h), quenched with Me2S,
o stirred at 0 C for 1 h, filtered through a plug of Celite, extracted with Et2O (3 x 20
mL), and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 5.46 as a colorless oil
20 (80 mg, 57%); [α] D -22.1 (c 1.0, CHCl3); IR (neat) ν = 3490, 3070, 1731, 1589,
-1 1 1470, 1427, 1391, 1255, 1108 cm ; H NMR (500 MHz, CDCl3) δ 5.14 (s, 1H),
5.01 (t, J = 1.5 Hz, 1H), 3.91 (d, J = 1.6 Hz, 1H), 3.68-3.60 (m, 1H), 3.39 (d, J = 2.2
Hz, 1H), 3.14-3.12 (m, 1H), 2.67-2.69 (m, 1H), 1.63 (t, J 1.0 Hz, 1H); 13C NMR (125
+ MHz, CDCl3) ppm 140.5, 114.9, 61.5, 58.0, 57.8, 16.6; HRMS m/z (2M + Na) calcd
251.1267, obsd 251.1267; Rf 0.26 (3:1 hexanes:ethyl acetate).
O Alcohol 5.46 (40 mg, 0.35 mmol), DMAP (4 mg, 0.035 mmol, OTBS 0.1 eq), CH2Cl2 (1.26 mL), TBSCl (79 mg, 0.53 mmol, 1.5 eq),
and imidazole (36 mg, 0.53 mmol, 1.5 eq) were combined and stirred for 12 h at rt,
quenched with saturated NaHCO3 solution, transfered to a separatory funnel, and
extracted with CH2Cl2 (3 x 15 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 5.47 as a colorless
20 oil (76 mg, 95%); [α] D -5.4 (c 1.0, CHCl3); IR (neat) ν = 1646, 1471, 1361, 1255,
-1 1 1143, 1109 cm ; H NMR (500 MHz, CDCl3) δ 5.15 (t, J = 0.7 Hz, 1H), 5.01 (dd, J
= 3.0, 1.5 Hz, 1H),3.87 (dd, J = 11.9, 3.2 Hz, 1H), 3.72 (dd, J = 11.9, 4.6 Hz, 1H),
269 3.30 (d, J = 2.2 Hz, 1H), 3.08-3.06 (m, 1H), 1.66 (t, J = 1.3 Hz, 1H), 0.92 (s, 9H),
13 0.10 (s, 3H), 0.09 (s, 3H); C NMR (125 MHz, CDCl3) ppm 141.0, 114.3, 63.3, 58.2,
58.1, 25.8 (3C), 18.3, 16.7, -5.31, -5.33; HRMS m/z (M + Na)+ calcd 251.1437, obsd
251.1429; Rf 0.59 (20:1 hexanes:ethyl acetate).
OH A solution of 5.47 (2.0 g, 8.77 mmol) and OH THF (142 mL) was brought to -78 oC, + OTBS OTBS where a 1M solution of L-Selectride in
THF (17.5 mL, 17.54 mmol, 2 eq) was added. The reaction mixture was stirred for
30 min, warmed to rt, quenched with saturated NaHCO3 solution, transferred to a
separatory funnel, and extracted with CH2Cl2 (3 x 100 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to give 5.48 (1.6
g, 80%) and 5.48a (0.4 g, 20%) both as a colorless oils.
20 For 5.48: [α] D -2.8 (c 0.4, CHCl3); IR (neat) ν = 3442, 1651, 1471, 1362, 1255,
-1 1 1120, 1077 cm ; H NMR (500 MHz, CDCl3) δ 4.86 (s, 1H), 4.80 (d, J = 0.9 Hz,
1H), 3.85-3.81 (m, 1H), 3.64 (dd, J = 9.9, 3.9 Hz, 1H), 3.49 (dd, J = 9.9, 3.1 Hz, 1H),
2.19 (d, J = 6.6 Hz, 2H), 1.80 (s, 3H), 0.93 (s, 9H), 0.10 (s, 6H); 13C NMR (125 MHz,
CDCl3) ppm 142.3, 112.8, 69.6, 66.8, 41.5, 25.8 (3C), 22.5, 18.3, -5.34, -5.38;
+ HRMS m/z (M + Na) calcd 253.1594, obsd 253.1589; Rf 0.19 (20:1 hexanes:ethyl
acetate).
20 For 5.48a: [α] D -11.1 (c 1.0, CHCl3); IR (neat) ν = 3445, 1652, 1463, 1361, 1255,
-1 1 1112 cm ; H NMR (500 MHz, CDCl3) δ 4.80 (d, J = 1.5 Hz, 1H), 4.75 (d, J = 0.7
270 Hz, 1H), 3.92-3.88 (m, 1H), 3.56 (dd, J = 11.1, 3.7 Hz, 1H), 3.45 (dd, J = 11.1, 5.3
Hz, 1H), 2.25-2.23 (m, 2H), 1.76 (s, 3H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C
NMR (125 MHz, CDCl3) ppm 141.8, 113.3, 71.2, 66.0, 42.7, 25.8 (3C), 22.8, 18.0, -
+ 4.5, -4.6; HRMS m/z (M + Na) calcd 253.1594, obsd 253.1593; Rf 0.17 (20:1
hexanes:ethyl acetate).
OPMB Alcohol 5.48 (0.96 g, 4.17 mmol), THF (38 mL), and a 0.66M
solution of KHMDS in toluene (9.48 mL, 6.3 mmol, 1.5 eq) were OTBS mixed at rt and stirred for 20 min. PMBBr (1.25 g, 6.3 mmol, 1.5 eq) was then introduced in THF (19 mL), and the reaction mixture was stirred for 10 h, quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted
with Et2O (3 x 50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica
20 gel (20:1 hexanes:ethyl acetate) to give 5.49 (1.2 g, 83%) as a colorless oil; [α] D
-1 1 +4.3 (c 1.0, CHCl3); IR (neat) ν = 1653, 1615, 1514, 1472, 1249, 1085 cm ; H
NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 4.81
(dd, J = 13.6, 1.2 Hz, 2H), 4.60 (dd, J = 42.3, 11.3 Hz, 2H), 3.82 (s, 3H), 3.70-3.68
(m, 1H), 3.68-3.61 (m, 2H), 1.76 (s, 3H), 0.94 (s, 9H), 0.09 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 159.0, 142.8, 131.1, 129.2 (2C), 113.6 (2C), 112.5, 78.1, 71.8,
65.5, 55.2, 40.2, 25.6 (3C), 22.9, 18.2, -5.30, -5.37; HRMS m/z (M + Na)+ calcd
373.2169, obsd 373.2163; Rf 0.41 (10:1 hexanes:ethyl acetate).
OH OPMB 271 HO OTBS To a solution of H2O (22 mL) and t-BuOH (12 mL) was added (DHQD)2PHAL (265
mg, 0.34 mmol, 0.1 eq), K2OsO2(OH)4 (25 mg, 0.68 mmol, 0.02 eq), Ke3Fe(CN)6
(3.39 g, 10.3 mmol, 3 eq), and K2CO3 (1.42 g, 10.3 mmol, 3 eq). The mixture was
cooled to 0 oC and 5.49 (1.2 g, 3.4 mmol) was added in 12 mL of t-BuOH. The
reaction mixture was stirred for 12 h, warmed to rt, quenched with saturated NaHCO3
solution, transferred to a separatory funnel, and extracted with Et2O (3 x 50 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (1:1 hexanes:ethyl
20 acetate) to give 5.50 (1.05 g, 88%) as a colorless oil; [α] D +37.3 (c 1.0, CHCl3); IR
(neat) ν = 3435, 1613, 1515, 1464, 1251, 1112, 1038 cm -1; 1H NMR (500 MHz,
CDCl3) δ 7.28 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.79 (d, J = 10.8 Hz, 1H),
4.51 (d, J = 10.8 Hz, 1H), 3.94-3.92 (m, 1H), 3.82-3.77 (m, 1H), 3.81 (s, 3H), 3.63-
3.60 (m, 1H), 3.39 (d, J = 11.0 Hz, 1H), 3.33 (d, J = 11.0 Hz, 1H), 1.90 (dd, J = 14.9,
10.5 Hz, 1H), 1.55 (dd, J = 14.9, 2.5 Hz, 1H), 1.18 (s, 3H), 0.93 (s, 9H), 0.104 (s,
13 3H), 0.101 (s, 3H); C NMR (125 MHz, CDCl3) ppm 159.5, 129.8 (2C), 129.7,
114.0 (2C), 77.2, 72.2, 71.9, 70.9, 65.9, 60.3, 55.2, 39.0, 25.8 (3C), 24.1, 18.2, -5.3, -
+ 5.4; HRMS m/z (M + Na) calcd 407.2224, obsd 407.2215; Rf 0.5 (1:1 hexanes:ethyl
acetate).
O To a solution of 5.46 (0.6 g, 5.3 mmol), Et3N (0.8 mL, 5.8 mmol, 1.1 OPiv
eq), and DMAP (53 mg, 0.53 mol, 0.1 eq) in CH2Cl2 (35 mL) was
added pivaloyl chloride (0.97 mL, 7.9 mmol, 1.5 eq). The reaction mixture was stirred for 1 h, quenched with brine, transferred to a separatory funnel, and extracted
272 with dichloromethane (3 x 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to yield 5.56 as a colorless
20 oil (1.0g, 99%); [α] D -20.8 (c 1.9, CHCl3); IR (neat) ν = 2976, 1729, 1282, 1155
-1 1 cm ; H NMR (500 MHz, CDCl3) δ 5.16 (s, 1H), 5.04 (d, J = 1.3 Hz, 1H), 4.41 (dd,
J = 12.3, 3.2 Hz, 1H), 4.00 (dd, J = 12.2, 5.9 Hz, 1H), 3.29 (d, J = 1.2 Hz, 1H), 3.18-
13 3.16 (m, 1H), 1.66 (s, 3H), 1.24 (s, 9H); C NMR (125 MHz, CDCl3) ppm 178.1,
140.3, 114.7, 64.2, 58.2, 55.1, 38.8, 27.1 (3C), 16.7; ES HRMS m/z (M + Na)+ calcd
221.1148, obsd 221.1150; Rf 0.4 (2:1 hexanes:ethyl acetate).
OH To a solution of 5.45 (2.48 g, 21.7 mmol) in benzene (183 mL) at rt was
OH added DIBAL-H (32.6 mL, 32.6 mmol, 1.5 eq). The reaction mixture
was stirred for 20 min, cooled to 0 oC, and quenched with Rochelle’s salt. The
benzene was evaporated in vacuo and the water layer was added to a heavier than
water continuous extractor with CH2Cl2 and was extracted for 24 h. The combined
organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to give
20 5.57 as a colorless oil (1.23 g, 50%); [α] D -13.2 (c 1.0, CHCl3); IR (neat) ν = 3357,
-1 1 2362, 2344, 1457 cm ; H NMR (500 MHz, CDCl3) δ 4.83 (d, J = 35.1 Hz, 2H),
2.87 (t, J = 3.3 Hz, 1H), 3.66 (d, J = 11.0 Hz, 1H), 3.46 (dd, J = 10.9, 7.2 Hz, 1H),
13 2.17 (t, J = 5.9 Hz, 2H), 1.77 (s, 3H); C NMR (125 MHz, CDCl3) ppm 141.9, 113.4,
69.6, 66.4, 41.7, 22.4; molecular ion too fleeting for accurate mass spectroscopic
analysis; Rf 0.33 (2:1 hexanes:ethyl acetate).
273
O A solution of 5.57 (183 mg, 1.6 mmol, 1 eq), CSA (37 mg, o.16 PMP O mmol, 0.1 eq), p-anisaldehyde (230 μL, 1.9 mmol, 1.2 eq), and
DMF (4mL) were stirred at rt for 12 h. The reaction mixture was quenched with
saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with
CH2Cl2 (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica
20 gel (10:1 hexanes:ethyl acetate) to give 5.58 (300 mg, 81%) as a colorless oil; [α] D
-1 1 -9.5 (c 1.0, CHCl3); IR (neat) ν = 2360, 1614, 1516, 1248, 1078 cm ; H NMR
(500 MHz, CDCl3) δ 7.42 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.92 (s, 1H),
4.86 (s, 1H), 4.81 (s, 1H), 4.43 (t, J = 6.8 Hz, 1H), 4.26 (dd, J = 8.1, 6.2 Hz, 1H), 3.83
(s, 3H), 3.67 (dd, J = 8.1, 7.0 Hz, 1H), 2.53 (dd, J = 14.2, 7.7 Hz, 1H), 2.29 (dd, J =
13 14.3, 6.7 Hz, 1H), 1.82 (s, 3H); C NMR (125 MHz, CDCl3) ppm 160.2, 141.6,
130.5, 127.7 (2C), 113.7 (2C), 112.7, 103.1, 74.6, 70.5, 55.3, 41.4, 22.9; molecular
ion too fleeting for accurate mass spectroscopic analysis; Rf 0.32 (10:1 hexanes:ethyl
acetate).
OPMB OH To a solution of 5.58 (13 mg, 0.06 mmol) + o OH OPMB and CH2Cl2 (0.5 mL) at -78 C was added
DIBAL-H (67 μL, 0.07 mmol, 1.2 eq). After 20 min the reaction mixture was
quenched with a saturated solution of Rochelle’s salt, allowed to warm to rt,
transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
274 residue was purified by column chromatography on silica gel (3:1 hexanes:ethyl
acetate) to give 5.59 (12 mg, 92%) and 5.59a (0.4 mg, 3%) both as a colorless oils;
20 For 5.59: [α] D -23.2 (c 1.1, CHCl3); IR (neat) ν = 3428, 2360, 1699, 1652, 1515,
-1 1 1456 cm ; H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7
Hz, 2H), 4.84 (d, J = 1.5 Hz, 1H), 4.80 (d, J = 0.9 Hz, 1H), 4.62 (d, J = 11.1 Hz, 1H),
4.49 (d, J = 11.2 Hz, 1H), 3.82 (s, 3H), 3.70-3.65 (m, 2H), 3.54-3.50 (m, 1H), 2.40
(dd, J = 14.0, 5.0 Hz, 1H), 2.21 (dd, J = 14.0, 6.8 Hz, 1H), 1.78 (s, 3H); 13C NMR
(125 MHz, CDCl3) ppm 159.3, 142.0, 130.4, 129.4 (2C), 113.9 (2C), 113.1, 77.7,
71.2, 64.2, 55.2, 39.4, 22.8; ES HRMS m/z (M + Na)+ calcd 259.1304, obsd
259.1311; Rf 0.09 (3:1 hexanes:ethyl acetate).
20 -1 For 5.59: [α] D -12.1 (c 1.1, CHCl3); IR (neat) ν = 3436, 1612, 1513, 1248 cm ;
1 H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 6.7 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H),
4.83 (d, J = 30.6 Hz, 2H), 4.51 (s, 2H), 4.01-3.96 (m, 1H), 3.83 (s, 3H), 3.50 (dd, J =
9.5, 3.4 Hz, 1H), 3.37 (dd, J = 9.5, 7.2 Hz, 1H), 2.22-2.20 (m, 2H), 1.78 (s, 3H); 13C
NMR (125 MHz, CDCl3) ppm 159.3, 142.1, 130.1, 129.3 (2C), 113.8 (2C), 113.1,
73.9, 73.0, 68.2, 55.2, 41.9, 22.4; ES HRMS m/z (M + Na)+ calcd 259.1304, obsd
259.1310; Rf 0.26 (3:1 hexanes:ethyl acetate).
OTBS To a solution of 5.59a (1.22 g, 5.3 mmol) in THF (48 mL) at rt was
OPMB added a 0.66 M solution of KHMDS in toluene (12 mL, 7.9 mmol, 1.5
eq). After 20 min, PMBBr (1.6 mL, 7.9 mmol, 1.5 eq) was added in THF (24 mL).
The reaction mixture was stirred for 2 h, quenched with saturated NaHCO3 solution,
transferred to a separatory funnel, and extracted with CH2Cl2 (3x 60 mL). The
275 combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl
20 acetate) to give the diprotected diol (0.85 g, 46 %) as a colorless oil; [α] D +1.9 (c
-1 1 1.0, CHCl3); IR (neat) ν = 2359, 1699, 1558, 1248 cm ; H NMR (500 MHz,
CDCl3) δ 7.28 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 4.80 (d, J = 1.4 Hz, 1H),
4.75 (s, 1H), 4.48 (s, 2H), 4.02-3.97 (m, 1H), 3.83 (s, 3H), 3.40 (d, J = 5.4 Hz, 2H),
2.30 (dd, J = 13.6, 5.6 Hz, 1H), 2.19 (dd, J = 13.6, 6.6 Hz, 1H), 1.77 (s, 3H), 0.91 (s,
13 9H), 0.082 (s, 3H), 0.081 (s, 3H); C NMR (125 MHz, CDCl3) ppm 159.1, 142.2
130.6 (129.1 (2C), 113.7 (2C), 113.1, 74.3, 72.9, 70.2, 55.2, 43.3, 25.9 (3C), 23.0,
+ 18.2, -4.3, -4.7; ES HRMS m/z (M + Na) calcd 373.2169, obsd 373.2170; Rf 0.38
(10:1 hexanes:ethyl acetate).
OPMB A solution of 5.59 (39 mg, 0.17 mmol), Et3N (26 μL, 0.18 mmol, 1.1
OPiv eq), DMAP (1.1 mg, 0.017 mmol, o.1 eq), CH2Cl2 (1.1 mL), and pivaloyl chloride (30 μL, 0.25 mmol, 1.5 eq) was stirred for 4 h, quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with
CH2Cl2 (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica
20 gel (20:1 hexanes:ethyl acetate) to give 5.60 (41 mg, 77%) as a colorless oil; [α] D -
-1 1 6.2 (c 1.0, CHCl3); IR (neat) ν = 1731, 1613, 1514, 1248 cm ; H NMR (500 MHz,
CDCl3) δ 7.28 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 1H), 4.82 (d, J = 24.0 Hz, 2H),
4.60 (d, J = 2.2 Hz, 1H), 4.53 (d, J = 2.2 Hz, 1H), 4.23 (dd, J = 11.6, 4.0 Hz, 1H),
4.07 (dd, J = 11.6, 6.0 Hz, 1H), 3.81 (s, 3H), 3.80-3.76 (m, 1H), 2.38-2.24 (m, 2H),
276 13 1.76 (s, 3H), 1.24 (s, 9H); C NMR (125 MHz, CDCl3) ppm 178.3, 159.2, 141.8,
130.5, 129.3 (2C), 113.7 (2C), 113.3, 75.1, 71.4, 65.7, 55.2, 40.2, 38.8, 27.2 (3C),
22.8; ES HRMS m/z (M + Na)+ calcd 343.1879, obsd 343.1893; Rf 0.22 (20:1
hexanes:ethyl acetate).
OH A solution of (DHQD) PHAL (23.4 mg, 0.03 mmol, 0.1 eq), OPMB 2
HO OPiv K2OsO2(OH)4 2.2 mg, 0.006 mmol, 0.02 eq), K3Fe(CN)6 (0.3 g, 0.9
mmol, 3 eq), K2CO3 (124 mg, 0.9 mmol, 3 eq), and 1:1 t-BuOH:H2O (1.9 ml) was
o cooled to 0 C and 5.60 (96 mg, 0.3 mmol) in 1:1 t-BuOH:H2O (1.9 ml) was added.
The reaction mixture was stirred for 12 h, allowed to warm to rt, quenched with
saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with
CH2Cl2 (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to give 5.54 (64 mg, 63%) as a colorless oil (4:1
20 mixture of isomers); [α] D +29.0 (c 1.0, CHCl3); IR (neat) ν = 3445, 1731, 1515,
-1 1 1250, 1158 cm ; H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J
= 8.5 Hz, 2H), 4.70 (d, J = 10.6 Hz, 1H), 4.44 (d, J = 10.6 Hz, 1H), 4.31 (dd, J = 11.6,
4.2 Hz, 1H), 4.29-4.07 (m, 2H), 3.78 (s, 3H), 2.02-1.97 (m, 1H), 1.51 (dd, J = 14.9,
13 2.4 Hz, 1H), 1.22 (s, 9H), 1.15 (s, 3H); C NMR (125 MHz, CDCl3) ppm 178.2,
159.5, 129.9 (2C), 129.2, 114.0 (2C), 74.5, 72.1, 71.5, 70.6, 65.5, 55.2, 39.3, 38.8,
+ 27.1 (3C), 24.1; ES HRMS m/z (M + Na) calcd 377.1934, obsd 377.1923; Rf 0.37
(2:1 ethyl acetate:hexanes).
277 OH OPMB A solution of 5.54 (152 mg, 0.43 mmol), CH2Cl2 (3.3 mL), Et3N (66
AcO OPiv μL, 0.47 mmol, 1.1 eq), Ac2O (43 μL, 0.45 mmol, 1.05 eq), and
DMAP (2.9 mg, 0.04 mmol, 0.1 eq) was stirred at rt for 1 h, quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x
20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl acetate) to give 5.61 (169 mg, 100%) as a colorless oil; IR (neat) ν =
-1 1 3492, 17313, 1514, 1249 cm ; H NMR (500 MHz, CDCl3) δ 7.26 (d, J= 8.5 Hz,
2H), 6.88 (d, J = 8.5 Hz, 2H), 4.72 (t, J = 10.6 Hz, 1H), 4.46 (d, J = 10.7 Hz, 1H),
4.32 (dd, J = 11.7, 4.3 Hz, 1H), 4.10 (dd, J = 7.7, 4.3 Hz, 1H), 3.97-3.90 (m, 2H),
3.80 (s, 3H), 3.73 (s, 1H), 2.08 (s, 3H), 1.93 (dd, J = 14.7, 10.6 Hz, 1H), 1.59 (dd, J =
13 14.7, 2.4 Hz, 1H), 1.24 (s, 9H); C NMR (125 MHz, CDCl3) ppm 178.2, 170.9,
159.5, 129.8 (2C), 114.0 (2C), 74.4, 71.6, 70.9, 65.4, 55.2, 38.8, 27.2 (3C), 23.9,
+ 20.9; ES HRMS m/z (M + Na) calcd 419.2040, obsd 419.2040; Rf 0.18 (2:1
hexanes:ethyl acetate).
OH OPMB A solution of 5.54 (60 mg, 0.17 mmol, 1 eq), IBX (56 mg, 0.2 mmol,
O OPiv 1.2 eq), THF (0.4 mL), and DMSO (28 μL) was stirred at rt for 16 h.
The reaction mixture was filtered and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (2:1:0.01 hexanes:ethyl
20 aceate:triethylamine) to give the aldehyde as a colorless oil (24 mg, 40%); [α] D
-1 +12.6 (c 1.5, CHCl3); IR (neat) ν = 3491, 1726, 1612, 1514, 1249, 1154, 1034 cm ;
1 H NMR (500 MHz, CDCl3) δ 9.42 (d, J 1.0 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.87
278 (d, J = 8.7 Hz, 1H), 4.46 (d, J = 10.2 Hz, 1H), 4.26 (dd, J = 11.7, 4.6 Hz, 1H), 4.18
(d, J = 10.3 Hz, 1H), 4.02 (dd, J= 11.7, 4.6 Hz, 1H), 3.81 (s, 3H), 3.80-3.77 (m, 1H),
3.68 (s, 1H), 2.17-2.12 (m, 1H), 1.89 (dd, J = 14.5, 1.9 Hz, 1H), 1.28 (s, 3H), 1.23 (s,
13 9H); C NMR (125 MHz, CDCl3) ppm 201.5, 178.2, 159.3, 130.0 (2C), 129.5, 113.7
(2C), 75.8, 72.4, 71.4, 65.0, 55.2, 41.7, 38.8, 27.2 (3C), 23.8; Rf 0.71 (2:1
hexanes:ethyl acetate).
O A solution of 5.45 (1g, 8.8 mmol), DMAP (107 mg, 0.88
mmol, 0.1 eq), imidazole (0.89 g, 13.2 mmol, 1.5 eq), OTBDPS
TBDPSCl (3.5 mL, 13.5 mmol, 1.5 eq) in CH2Cl2 (33 mL) was heated to reflux, stirred for 12 h, cooled to rt, quenched with saturated NaHCO3 solution, transferred to
a separatory funnel, and extracted with CH2Cl2 (3 x 70 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purifed
by column chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 5.63 (2.68
20 g, 85%) as a colorless oil; [α] D +3.2 (c 1.0, CHCl3); IR (neat) ν = 1471, 1427,
-1 1 1112 cm ; H NMR (500 MHz, CDCl3) 7.72-7.70 (dt, J = 7.9, 1.6 Hz, 4H), 7.47-
7.39 (m, 6H), 5.13 (s, 1H), 5.02 (t, J = 1.5 Hz, 1H), 3.88 (dd, J = 11.8, 3.4 Hz, 1H),
3.80 (dd, J = 11.8, 4.5 Hz, 1H), 3.30 (d, J = 2.1 Hz, 1H), 3.14-3.12 (m, 1H), 1.66 (s,
13 3H), 1.09 (s, 9H); C NMR (125 MHz, CDCl3) ppm 141.0, 135.6 (2C), 135.5 (2C),
133.3, 133.2, 129.7 (2C), 129.7 (4C), 114.3, 63.9, 58.1, 58.0, 26.7 (3C), 19.2, 16.8;
+ ES HRMS m/z (M + Na) calcd 375.1750, obsd 375.1749; Rf 0.23 (20:1
hexanes:ethyl acetate).
279 OPMB A solution of 5.59 (140 mg, 0.6 mmol), DMAP (7.2 mg, 0.06
OTBDPS mmol, 0.1 eq), Et3N (0.16 mL, 1.19 mmol, 1.5 eq), TBDPSCl
(0.24 mL, 1.19 mmol, 1.5 eq), in CH2Cl2 (6 mL) was heated to reflux, stirred for 12 h,
cooled to rt, quenched with saturated NaHCO3 solution, transferred to a separatory
funnel, and extracted with CH2Cl2 (3 x 30 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (3:1 hexanes:ethyl acetate) to give 5.65 (236 mg, 83%)
20 as a colorless oil; [α] D +5.2 (c 1.0, CHCl3); IR (neat) ν = 1612, 1513, 1247, 1112
-1 1 cm ; H NMR (500 MHz, CDCl3) 7.75-7.70 (m, 4C), 7.48-7.38 (m, 7H), 7.28 (d, J
= 1.5 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 4.80 (dd, J = 13.6, 1.3 Hz, 2H), 4.62 (d, J =
11.3 Hz, 1H), 4.51 (dd, J = 11.3 Hz, 1H), 3.83 (s, 3H), 3.80-3.77 (m, 1H), 3.72-3.67
(m, 1H) 2.36 (dd, J = 14.4, 4.5 Hz, 1H), 2.29 (dd, J = 14.0, 7.4 Hz, 1H), 1.74 (s, 3H),
13 1.12 (s, 9H); C NMR (125 MHz, CDCl3) ppm 159.0, 142.7, 135.7, 135.6 (2C),
133.68, 133.64, 131.1 (2C), 129.6 (2C), 129.2 (2C), 127.69 (2C), 127.60, 127.5,
113.7 (2C), 112.6, 78.1, 71.7, 66.0, 55.2, 40.2, 26.9 (3C), 22.9, 19.2; ES HRMS m/z
+ (M + Na) calcd 497.2482, obsd 497.2487; Rf 0.4 (20:1 hexanes:ethyl acetate).
OH A mixture of 5.66 (132 mg, 0.26 mmol) and IBX (109 mg, 0.4 OPMB mmol, 1.5 eq) in THF (0.65 mL) and DMSO (44 μL) was stirred O OTBDPS for 12 h at rt, filtered through Celite and washed with ether. The combined organics were concentrated in vacuo and the residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give 5.67 (64 mg, 49%) as a colorless oil;
20 -1 1 [α] D +19.6 (c 1.1, CHCl3); IR (neat) ν = 3492, 1725, 1514, 1249, 1112 cm ; H
280 NMR (500 MHz, CDCl3) 9.48 (d, J 1.0 Hz, 1H), 7.72-7.69 (m, 4H), 7.49-7.39 (m,
6H), 7.19 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.44 (d, J = 10.5 Hz, 1H), 4.16
(d, J = 10.5 Hz, 2H), 3.82 (s, 3H), 3.74-3.64 (m, 4H), 3.14-2.09 (m, 1H), 1.97 (dd, J =
13 14.6, 1.7 Hz, 1H), 1.28 (s, 3H), 1.10 (s, 9H); C NMR (125 MHz, CDCl3) ppm
202.0, 159.2, 135.6 (4C), 133.3, 133.2, 130.0, 129.9 (2C), 129.8 (2C), 129.7, 127.7
(2C), 75.9, 75.1, 71.6, 65.8, 55.2, 41.5, 26.8 (3C), 23.8, 19.2; ES HRMS molecular
ion too fleeting for accurate mass spectroscopic analysis; Rf 0.26 (5:1 hexanes:ethyl
acetate).
OH OPMB To a solution of 5.67 (34 mg, 0.09 mmol) in THF(1 mL) was added a 1M solution of TBAF in THF (0.13 mL, 0.13 mmol, 1.5 HO O
eq). The reaction mixture was stirred for 5 h, quenched with saturated NaHCO3
solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 20 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (1:1 hexanes:ethyl
1 acetate) to give 5.68 (17 mg, 77%) as a colorless oil; H NMR (500 MHz, CDCl3)
was not able to differentiate which signals were from which isomer; 13C NMR (125
MHz, CDCl3) ppm 159.3, 129.5 (2C), 113.9 (2C), 98.2, 97.5, 71.6, 70.2, 69.7, 66.5,
55.2, 38.3, 22.6; IR (neat) ν = 3438, 1612, 1514, 1249, 1036 cm -1; ES HRMS m/z
+ (M + Na) calcd 291.1202, obsd 291.1208; Rf 0.24 (1:1 hexanes:ethyl acetate).
281 A solution of 5.71 (0.6 g, 1.54 Ph O Ph O S O O O O S OBz + O N BzO N mmol), thiocarbonyldiimidazole O N OMe OMe N (0.44 g, 2.46 mmol, 1.6 eq) and
toluene (23 mL) was refluxed for 12 h. Upon completion, toluene was removed by
distillation, and the reaction mixture was quenched with saturated NaHCO3 solution,
transferred to a separatory funnel and extracted with CH2Cl2 (3 x 30 mL). The
combined organic phases were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (2:1 hexanes:ethyl
acetate) to give 5.71a as a white solid (448 mg, 59%, mp 149 oC) and 5.71b as a
colorless oil (52 mg, 7%).
20 -1 For 5.71a: [α] D +85.1 (c 1.0, CHCl3); IR (neat) ν = 1725, 1389, 1285, 1093 cm ;
1 H NMR (500 MHz, CDCl3) 8.32 (s, 1H), 8.03 (d, J = 7.3 Hz, 2H), 7.59 (s, 1H), 7.56
(t, J = 7.4 Hz, 1H), 7.47-7.36 (m, 7H), 6.97 (s, 1H), 6.65 (t, J = 9.7 Hz, 1H), 5.60 (s,
1H), 5.42 (dd, J = 9.8, 3.7 Hz, 1H), 5.21 (d, J = 3.7 Hz, 1H), 4.41 (dd, J = 10.3, 4.8
Hz, 1H), 4.16-4.11 (m, 1H), 4.01 (t, J = 9.6 Hz, 1H), 3.90 (t, J = 10.4 Hz, 1H), 3.47
13 (s, 3H); C NMR (125 MHz, CDCl3) ppm 183.6, 165.7, 136.9, 136.6, 133.7, 130.8,
130.0 (2C), 129.2, 128.6, 128.5 (2C), 128.3 (2C), 126.1 (2C), 118.1, 101.7, 97.9,
79.2, 77.9, 71.8, 68.8, 62.4, 55.7; ES HRMS m/z (M + Na)+ calcd 519.1196, obsd
519.1203; Rf 0.27 (2:1 hexanes:ethyl acetate).
20 -1 For 5.71b: [α] D +36.0 (c 1.0, CHCl3); IR (neat) ν = 1678, 1471, 1253, 1119 cm ;
1 H NMR (500 MHz, CDCl3) 8.34 (s, 1H), 8.00 (d, J = 7.4 Hz, 2H), 7.61 (s, 1H), 7.54
(t, J = 7.6 Hz, 1H), 7.45-7.32 (m, 7H), 7.00 (s, 1H), 6.13 (t, J = 9.8 Hz, 1H), 5.70 (dd,
J = 9.8, 3.6 Hz, 1H), 5.60 (s, 1H), 5.34 (d, J = 3.7 Hz, 1H), 4.41 (dd, J = 10.4, 4.8 Hz,
282 1H), 4.13-4.08 (m, 1H), 3.97 (t, J = 9.6 Hz, 1H), 3.89 (t, J = 10.3 Hz, 1H), 3.48 (s,
13 3H); C NMR (125 MHz, CDCl3) ppm 183.4, 165.6, 136.7, 133.4, 131.0, 129.8
(2C), 129.2, 129.1, 128.4 (2C), 128.3, (2C), 126.1 (2C), 118.1, 101.7, 96.4, 79.3,
78.9, 69.2, 68.8, 62.6, 55.6; ES HRMS m/z (M + Na)+ calcd 519.1196, obsd
519.1198; Rf 0.39 (2:1 hexanes:ethyl acetate).
A solution of AIBN (54 mg, .13 mmol, 0.45 eq) and t- Ph O O O
OBz Bu3SnH (1 mL, 3.9 mmol, 5.4 eq) in 37 mL of toluene was OMe heated to reflux, where 5.71 (360 mg, 0.73 mmol) in 15 mL
of toluene was added. The reaction mixture was refluxed for 12 h, the toluene was
removed by distillation, the crude material was transferred to a separatory funnel,
quenched with saturated NaHCO3 solution, and extracted with CH2Cl2 (3 x 50 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (10:1 hexanes:ethyl
o 20 acetate) to give 5.72 as a white solid (190 mg, 73%, mp 113 C); [α] D +63.2 (c 1.0,
-1 1 CHCl3); IR (neat) ν = 1721, 1274, 1105, 1048 cm ; H NMR (500 MHz, CDCl3)
8.10 (d, J = 8.2 Hz, 2H), 7.62-7.38 (m, 8H), 5.60 (s, 1H), 5.19-5.15 (m, 1H), 4.99 (d,
J = 3.4 Hz, 1H), 4.33 (dd, J = 10.1, 4.6 Hz, 1H), 3.91-3.71 (m, 3H), 3.48 (s, 3H),
13 2.40-2.27 (m, 2H); C NMR (125 MHz, CDCl3) ppm 165.8, 137.3, 133.2, 129.8
(2C), 129.7, 129.1, 128.4 (2C), 128.3 (2C), 126.2 (2C), 101.8, 96.9, 76.4, 69.4, 69.3,
63.9, 55.2, 29.7; ES HRMS: molecular ion too fleeting for accurate mass spectroscopic analysis; Rf 0.13 (10:1 hexanes:ethyl acetate).
283 Ph O A stream of gaseous ammonia was bubbled through a O O
OH solution of 5.72 (40 mg, 0.1 mmol) and methanol (3 mL) for OMe 30 min. The high pressure reaction vessel was then fitted with a screw cap, stirred at
50 oC for 12 h, allowed to come to rt, and concentrated in vacuo. The residue was
purified by column chromatograpy on silica gel to give 5.73 as a white solid (20 mg,
o 20 71%, mp 183-184 C); [α] D +102.9 (c 1.0, CHCl3); IR (neat) ν = 1098, 1054, 915
-1 1 cm ; H NMR (500 MHz, CDCl3) 7.50 (dd, J = 7.5, 1.9 Hz, 2H), 7.41-7.35 (m, 3H),
5.54 (s, 1H), 4.70 (d, J = 3.6 Hz, 1H), 4.31 (d, J = 5.5 Hz, 1H), 3.84-3.75 (m, 1H),
3.73-3.72 (m, 1H), 3.70-3.53 (m, 1H), 3.49 (s, 3H), 2.34-2.30 (m, 1H), 2.12 (d, J =
13 11.3 Hz, 1H), 1.88 (dd, J = 23.1, 11.6 Hz, 1H); C NMR (125 MHz, CDCl3) ppm
137.3, 129.1, 128.3 (2C), 126.2 (2C), 101.7, 99.1, 76.3, 69.3, 67.6, 63.9, 55.2, 33.8;
+ ES HRMS m/z (M + Na) calcd 289.1046, obsd 289.1044; Rf 0.23 (2:1 hexanes:ethyl
acetate).
Ph O HO Ph O A solution of alcohol 5.73 (1 g, 3.8 O O O O + OH mmol), DMSO (10.5 mL), and Ac2O OMe OMe (8.6 mL) was stirred for 24 h at rt, quenched with water, transferred to a separatory funnel, and extracted with Et2O (3 x 20 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. To the crude product was added 100
mL of toluene, and the toluene was distilled off. A solution of crude 5.74 (70 mg,
o 0.26 mmol) and Et2O (2.6 mL) was cooled to 0 C and a 1.5 M solution of MeLi in
Et2O (0.28 mL, 0.4 mmol, 1.5 eq) was added. The reaction mixture was stirred for 3
h, allowed to warm to rt, quenched with saturated NaHCO3 solution, transferred to a
284 separatory funnel, and extracted with CH2Cl2 (3 x 30 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (3:1 hexanes:ethyl acetate) to give 5.75 as a white solid
(5 mg, 7%, mp 162 oC) and 5.76 as a colorless oil (34 mg, 45%).
20 -1 For 5.75: [α] D +122.0 (c 1.0, CHCl3); IR (neat) ν = 3514, 1454, 1104, 1049 cm ;
1 H NMR (500 MHz, CDCl3) 7.50 (dd, J = 7.7, 1.9 Hz, 2H), 7.40-7.35 (m, 3H), 5.58
(s, 1H), 4.31-4.27 (m, 2H), 3.95-3.90 (m, 1H), 3.85-3.80 (2H), 3.43 (s, 3H), 2.06-1.89
13 (m, 2H), 1.27 (s, 3H); C NMR (125 MHz, CDCl3) ppm 137.5, 129.0, 128.3 (2C),
126.1 (2C), 103.9, 102.0, 75.3, 72.3, 69.3, 64.1, 55.2, 37.4, 25.6; Rf 0.22 (3:1
hexanes:ethyl acetate).
20 -1 For 5.76; [α] D +111.7 (c 1.7, CHCl3); IR (neat) ν = 3514, 1452, 1115, 1052 cm ;
1 H NMR (500 MHz, CDCl3) 7.50 (dd, J = 7.5, 2.0 Hz, 2H), 7.40-7.36 (m, 3H), 5.54
(s, 1H), 4.31 (d, J = 12.5 Hz, 1H), 4.27 (d, J = 11.7 Hz, 1H), 3.76 (d, J = 7.4 Hz, 2H),
3.64-3.59 (m, 1H), 3.48 (s, 3H), 3.58 (d, J = 0.8 Hz, 1H), 2.11 (dd, J = 11.7, 4.4 Hz,
13 1H), 1.98 (t, J = 11.7 Hz, 1H), 1.40 (s, 3H); C NMR (125 MHz, CDCl3) ppm 137.4,
129.1, 128.3 (2C), 126.1 (2C), 103.3, 101.8, 76.3, 70.4, 69.4, 64.4, 55.3, 39.4, 24.3;
Rf 0.28 (3:1 hexanes:ethyl acetate).
Ph O A solution of 5.76 (18 mg, 0.06 mmol), BnBr (38 μL, 0.32 O O OBn mmol, 5 eq), NaH (13 mg, 0.32 mmol, 5 eq) and Bu4NI (24 OMe mg, 0.06 mmol, 1 eq) in DMF (0.6 mL) was heated to 60 oC, stirred for 3 h, allowed
to cool to rt, quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 30 mL). The combined organic phases were
285 dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (10:1 hexanes:ethyl acetate) to give 5.77 as a colorless oil (19 mg,
20 -1 1 83%); [α] D -37.9 (c 1.5, CHCl3); IR (neat) ν = 1454, 1377, 1096, 1053 cm ; H
NMR (500 MHz, CDCl3) 7.51 (d, J = 7.5 Hz, 2H), 7.40-7.28 (m, 6H), 5.56 (s, 1H),
4.66 (d, J = 11.3 Hz, 1H), 4.54 (d, J = 11.5 Hz, 1H), 4.51 (s, 1H), 4.30 (dd, J = 9.9,
4.4 Hz, 1H), 3.89-3.84 (m, 1H), 3.78 (t, J = 10.1 Hz, 1H), 3.73-3.68 (m, 1H), 3.48 (s,
3H), 2.28 (t, J = 11.5 Hz, 1H), 2.14 (dd, J = 11.4, 4.4 Hz, 1H), 1.50 (s, 3H); 13C NMR
(125 MHz, CDCl3) ppm 139.1, 137.4, 129.1, 128.34 (2C), 128.30 (2C), 127.39 (2C),
127.32, 126.2 (2C), 102.6, 101.9, 76.4, 75.3, 69.5, 64.4, 64.2, 55.1, 35.8, 22.9; Rf
0.14 (10:1 hexanes:ethyl acetate).
A solution of 5.77 (187 mg, 0.5 mmol) and p-TsOH (10 mL, 0.05 HO O HO OBn mmol, 0.1 eq) in MeOH (2 mL) was heated to 50 oC, stirred for 5 h, OMe allowed to cool to rt, quenched with saturated NaHCO3 solution, transferred to a
separatory funnel, and extracted with CH2Cl2 (3 x 30 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 ethyl acetate :hexanes) to give 5.78 as a colorless oil
20 (114 mg, 90%) [α] D +113.3 (c 2.2, CHCl3); IR (neat) ν = 3410, 1218, 1111, 1044
-1 1 cm ; H NMR (500 MHz, CDCl3) 7.37-7.26 (m, 5H), 4.60 (d, J = 11.3 Hz, 1H),
4.50 (d, J = 11.3 Hz, 1H), 4.48 (s, 1H), 3.87-3.74 (m, 3H), 3.57 (dd, J = 9.3, 4.2 Hz,
13 1H), 3.45 (s, 3H), 2.09-2.02 (m, 2H), 1.39 (s, 3H); C NMR (125 MHz, CDCl3) ppm
139.0, 128.3 (2C), 127.4 (2C), 127.3, 101.4, 74.9, 72.5, 65.4, 64.1, 62.7, 55.0, 39.0,
21.9; Rf 0.26 (2:1 ethyl acetate:hexanes).
286
PMP O A solution of 5.81 (0.6 g, 1.54 mmol), O O S OBz O thiocarbonyldiimidazole (0.44 g, 2.46 mmol, 1.6 eq) and N OMe N toluene (23 mL) was refluxed for 12 h. Upon completion,
toluene was removed by distillation, and the reaction mixture was quenched with
saturated NaHCO3 solution, transferred to a separatory funnel and washed with
CH2Cl2 (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica
20 gel (2:1 hexanes:ethyl acetate) to give 5.81a as a colorless oil (645 mg, 59%); [α] D
-1 1 +6.0 (c 4.0, CHCl3); IR (neat) ν = 1724, 1389, 1285, 1093 cm ; H NMR (500
MHz, CDCl3) 8.29 (s, 1H), 8.01 (dd, J = 7.8, 1.2 Hz, 2H), 7.57-7.53 (m, 2H), 7.42-
7.36 (m, 3H), 6.95 (d, J= 0.7 Hz, 1H), 6.87 (dt, J = 8.8, 2.7 Hz, 2H), 6.62 (t, J = 9.7
Hz, 1H), 5.53 (s, 1H), 5.39 (dd, J = 9.8, 3.7 Hz, 1H), 5.19 (d, J = 3.7 Hz, 1H), 4.37
(dd, J = 10.4, 4.9 Hz, 1H), 4.14-4.07 (m, 1H), 3.98 (t, J = 9.6 Hz, 1H), 3.86 (t, J =
13 10.4 Hz, 1H), 3.76 (s, 3H), 3.45 (s, 3H); C NMR (125 MHz, CDCl3) ppm 183.6,
165.7, 160.2, 136.9, 133.7, 130.8, 130.0 (2C), 129.1, 128.6, 128.5 (2C), 127.5 (2C),
118.1, 113.6 (2C), 101.6, 97.9, 79.1, 78.0, 71.8, 68.7, 62.4, 55.6, 55.2; ES HRMS
+ m/z (M + Na) calcd 549.1308, obsd 549.1312; Rf 0.16 (2:1 hexanes:ethyl acetate).
PMP O A solution of AIBN (54 mg, .13 mmol, 0.45 eq) and n- O O
OBz Bu3SnH (1 mL, 3.9 mmol, 5.4 eq) in 37 mL of toluene was OMe heated to reflux, where 5.81a (360 mg, 0.73 mmol) in 15 mL of toluene was added.
The reaction mixture was refluxed for 12 h, the toluene was removed by distillation,
287 and the crude material was transferred to a separatory funnel, quenched with saturated
NaHCO3 solution, and extracted with CH2Cl2 (3 x 50 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (5:1 hexanes:ethyl acetate) to give 5.82 as a
o 20 white solid (151 mg, 58%, mp 91 C); [α] D +78.5 (c 1.2, CHCl3); IR (neat) ν =
-1 1 1718, 1518, 1274, 1100, 1047 cm ; H NMR (500 MHz, CDCl3) 8.10 (d, J = 7.4
Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.49-7.45 (m, 4H), 6.93 (d, J = 8.6 Hz, 2H), 5.55 (s,
1H), 5.19-5.15 (m, 1H), 4.99 (d, J = 3.4 Hz, 1H), 4.31 (dd, J = 10.1, 4.7 Hz, 1H),
3.90-3.85 (m, 1H), 3.81 (s, 3H), 3.77 (t, J = 10.3 Hz, 1H), 3.73-3.68 (m, 1H), 3.47 (s,
13 3H), 2.39-2.27 (m, 2H); C NMR (125 MHz, CDCl3) ppm 165.8, 160.2, 133.3, 129.9
(2C), 129.8, 128.4 (2C), 127.5 (2C), 113.7 (2C), 101.7, 96.9, 76.3, 69.4, 69.3, 64.0,
+ 55.3, 55.2, 29.7; ES HRMS m/z (M + Na) calcd 423.1420, obsd 423.1439; Rf 0.14
(5:1 hexanes:ethyl acetate).
PMP O A stream of gaseous ammonia was bubbled through a O O OH solution of 5.82 (200 mg, 0.5 mmol) and methanol (12 mL) OMe for 30 min. The high pressure reaction vessel was then fitted with a screw cap and
stirred at 50 oC for 12 h. The reaction mixture was allowed to come to rt and
concentrated in vacuo. The residue was purified by column chromatograpy on silica
gel (2:1 hexanes:ethyl acetate) to give 5.83 as a white solid (140 mg, 94%, mp 91 oC);
20 -1 1 [α] D +96.0 (c 1.05, CHCl3); IR (neat) ν = 3320, 1612, 1214, 908 cm ; H NMR
(500 MHz, CDCl3) 7.42 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.49 (s, 1H),
4.70 (d, J = 3.6 Hz, 1H), 4.29-4.24 (m, 1H), 3.82 (s, 3H), 3.84-3.77 (m, 1H), 3.74-
288 3.68 (m, 2H), 3.56-3.51 (m, 1H), 3.49 (s, 3H), 2.33-2.29 (m, 1H), 2.08 (d, J = 2.0 Hz,
13 1H); C NMR (125 MHz, CDCl3) ppm 160.1, 129.9, 127.5 (2C), 113.7 (2C), 101.7,
99.1, 76.2, 69.3, 67.6, 63.9, 55.3, 55.2, 33.8; ES HRMS m/z (M + Na)+ calcd
319.1150, obsd 319.1153; Rf 0.16 (2:1 hexanes:ethyl acetate).
PMP O O A solution of alcohol 5.83 (100 mg, 0.34 mmol), IBX (330 O
O mg, 1.1 mmol, 3.3 eq), and CH3CN (0.7 mL) was stirred at OMe reflux for 4 h, allowed to cool to rt, filtered through a pad of Celite, and concentrated
o 20 in vacuo to give 5.84 as a white solid (100 mg, 100%, mp 124-126 C); [α] D +84.0
-1 1 (c 1.1, CHCl3); IR (neat) ν = 1614, 1464, 1248, 1099 cm ; H NMR (500 MHz,
CDCl3) 7.43 (d, J = 8.7 Hz, 2H), 6.92 (d., J = 8.8 Hz, 2H), 5.52 (s, 1H), 4.60 (s, 1H),
4.39 (dd, J = 10.5, 5.0 Hz, 1H), 4.18-4.13 (m, 1H), 3.86-3.77 (m, 2H), 3.82 (s, 3H),
13 3.51 (s, 3H), 2.98-2.87 (m, 2H); C NMR (125 MHz, CDCl3) ppm 198.8, 160.3,
129.3, 127.5 (2C), 113.7 (2C), 101.4, 100.6, 77.1, 69.0, 64.1, 55.7, 55.3, 42.7; ES
HRMS m/z (M + Na)+ calcd 317.1001, obsd 317.1002.
PMP O O A solution of alcohol 5.84 (100 mg, 0.34 mmol), IBX (330 O OH
OMe mg, 1.1 mmol, 3.3 eq), and CH3CN (0.7 mL) was stirred at
reflux for 4 h, allowed to cool to rt, filtered through a pad of Celite, and concentrated
in vacuo. The crude product was dissolved in 7 mL of Et2O:THF (1:1), cooled to 0
o C and a 1.5 M solution of MeLi in Et2O (0.34 mL, 0.5 mmol, 1.5 eq) was added.
The reaction mixture was stirred for 3 h, allowed to warm to rt, quenched with saturated NaHCO3 solution, transferred to a separatory funnel, and extracted with
289 CH2Cl2 (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (3:1
20 hexanes:ethyl acetate) to give 5.85 as a colorless oil (63 mg, 60%); [α] D +31.4 (c
-1 1 1.8, CHCl3); IR (neat) ν = 3572, 1612, 1249, 1051 cm ; H NMR (500 MHz,
CDCl3) 7.42 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.50 (s, 1H), 4.31 (s, 1H),
4.26 (d, J = 5.5 Hz, 1H), 3.81 (s, 3H), 3.74 (d, J = 7.1 Jz, 2H), 3.62-3.57 (m, 1H),
3.48 (s, 3H), 2.57 (s, OH), 2.09 (dd, J = 11.6, 4.5 Hz, 1H), 1.96 (t, J = 11.8 Hz, 1H),
13 1.39 (s, 3H); C NMR (125 MHz, CDCl3) ppm 160.1, 129.9, 127.4 (2C), 113.7 (2C),
103.3, 101.7, 76.2, 70.4, 69.3, 64.4, 60.3, 55.3, 39.5, 24.3; ES HRMS m/z (M + Na)+ calcd 333.1314, obsd 333.1314; Rf 0.13 (3:1 hexanes:ethyl acetate).
PMP O O A solution of 5.85 (73 mg, 0.23 mmol), BnBr (145 μL, 0.1.2 O OBn
OMe mmol, 5 eq), NaH (28 mg, 0.1.2 mmol, 5 eq) and Bu4NI (87
mg, 0.23 mmol, 1 eq) in DMF (0.2.4 mL) was heated to 60 oC, stirred for 3 h, and
allowed to cool to rt. The reaction mixture was quenched with saturated NaHCO3
solution, transferred to a separatory funnel, and extracted with CH2Cl2 (3 x 30 mL).
The combined organic phases were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (10:1 hexanes:ethyl acetate) to
20 give 5.79 as a colorless oil (84 mg, 83%); [α] D +55.2 (c 2.0, CHCl3); IR (neat) ν =
-1 1 1218, 1111, 1044 cm ; H NMR (500 MHz, CDCl3) 7.44 (d, J = 8.7 Hz, 2H), 7.39-
7.26 (series of m, 5H), 6.92 (d, J = 11.5 Hz, 2H), 5.53 (s, 1H), 4.66 (d, J = 11.3 Hz,
1H), 4.54 (d, J = 11.3 Hz, 1H), 4.52 (s, 1H), 4.29 (dd, J = 10.0, 4.5 Hz, 1H), 3.91-
3.83 (m, 1H), 3.82 (s, 3H), 3.77 (t, J = 10.3 Hz, 1H), 3.71-3.66 (m, 1H), 3.49 (s, 3H),
290 2.28 (t, J = 11.6 Hz, 1H), 2.13 (dd, J = 11.4, 4.5 Hz, 1H), 1.50 (s, 3H); 13C NMR (125
MHz, CDCl3) ppm 160.1, 139.1, 130.0, 128.3 (2C), 127.5 (2C), 127.4 (2C), 127.3,
113.7 (2C), 102.6, 101.9, 76.3, 75.3, 69.5, 64.4, 64.2, 55.3, 55.1, 35.8, 22.9; ES
+ HRMS m/z (M + Na) calcd 421.1991, obsd 421.1989; Rf 0.12 (10:1 hexanes:ethyl
acetate).
PMBO HO O O A solution of 5.79 (27 mg, 0.07 mmol), HO OBn + PMBO OBn
OMe OMe sodium cyanoborohydride (6 mg, 0.1
mmol, 1.5 eq), 3Å MS (5 pieces), and acetonitrile (1.3 mL) was cooled to 0 oC. To
the previously made solution was added a mixture of TMSCl (13 μL, 0.1 mmol, 1.5
eq) and acetonitrile (0.4 mL). The reaction mixture was stirred for 20 min, allowed to
warm to rt, quenched with saturated NaHCO3 solution, transferred to a separatory
funnel, and extracted with CH2Cl2 (3 x 30 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (3:1 hexanes:ethyl acetate) to give 5.86 (13 mg, 48%) and 5.87 (10 mg, 37%) both as colorless oils.
20 For 5.86: [α] D +28.8 (c 1.0, CHCl3); IR (neat) ν = 3443, 1513, 1248, 1110, 1046
-1 1 cm ; H NMR (500 MHz, CDCl3) 7.37-7.25 (series of m, 7H), 6.90 (d, J = 8.6 Hz,
2H), 4.62-4.47 (m, 5H), 3.83 (s, 3H), 3.78-3.68 (m, 2H), 3.68-3.64 (m, 2H), 3.45 (s,
13 3H), 2.09-2.01 (m, 2H), 1.39 (s, 3H); C NMR (125 MHz, CDCl3) ppm 159.3, 139.2,
129.7, 129.3 (2C), 128.2 (2C), 127.4 (2C), 127.2, 113.9 (2C), 101.4, 74.8, 73.4, 71.0,
70.6, 67.5, 64.1, 55.2, 55.0, 38.3, 22.1; Rf 0.18 (3:1 hexanes:ethyl acetate).
291 20 For 5.87: [α] D +120.5 (c 0.6, CHCl3); IR (neat) ν = 3480, 1513, 1248, 1111, 1036
-1 1 cm ; H NMR (500 MHz, CDCl3) 7.38-7.26 (series of m, 7H), 6.89 (d, J = 8.6 Hz,
2H), 4.63-4.58 (dd, J = 13.5, 11.3 Hz, 2H), 4.50 (d, J = 11.1 Hz, 1H), 4.50 (s, 1H),
4.41 (d, J = 11.1 Hz, 1H), 3.87-3.74 (m, 1H), 3.82 (s, 3H), 3.69-3.56 (series of m,
3H), 3.44 (s, 3H), 2.20 (dd, J = 11.5, 4.9 Hz, 1H), 1.91 (dd, J = 7.5, 5.4 Hz, 1H), 1.37
13 (s, 3H); C NMR (125 MHz, CDCl3) ppm 159.3, 139.1, 130.1, 129.4 (2C), 128.3
(2C), 127.4 (2C), 127.3, 113.9 (2C), 101.4, 74.9, 71.5, 71.1, 70.3, 64.1, 62.5, 55.2,
54.8, 35.6, 22.0; ES HRMS m/z (M + Na)+ calcd 423.1784, obsd 423.1794; Rf 0.12
(3:1 hexanes:ethyl acetate).
OBn A solution of crude 5.87 (40 mg, 0.1 O OPMB PMBO OBn o mmol) in 1 mL of Et2O was added at 0 C OMe MeO O
to a mixture of Ph3PMeI (80 mg, 0.2 mmol, 2 eq) and t-BuOH (22 mg, 0.2 mmol, 2
o eq) in 1.5 mL of Et2O, which had been previously stirred at 0 C for 30 min. The
reaction mixture was stirred for 12 h at rt, filtered through a pad of Celite, and
concentrated in vacuo. The residue was purified by column chromatography (10:1
hexanes:ethyl acetate) to give 5.88 as a colorless oil (11 mg, 28% over two steps);
20 -1 1 [α] D +86.6 (c 1.1, CHCl3); IR (neat) ν = 2359, 1514, 1456, 1249 cm ; H NMR
(500 MHz, CDCl3) 7.38-7.33 (m, 4H), 7.28-7.20 (m, 3H), 6.89 (d, J = 8.7 Hz, 2H),
6.02-5.96 (m, 1H), 5.46 (dt, J = 17.2, 1.5 Hz, 1H), 5.27 (dt, J = 10.5, 1.5 Hz, 1H),
4.62 (d, J = 11.2 Hz, 1H), 4.55-4.49 (m, 3H), 4.44 (d, J= 11.2 Hz, 1H), 4.07 (dd, J =
9.6, 6.1 Hz, 1H), 3.82 (s, 3H), 3.44 (s, 3H), 3.36-3.32 (m, 1H), 2.18-2.10 (m, 2H),
13 1.38 (s, 3H); C NMR (125 MHz, CDCl3) ppm 159.2, 169.2, 136.0, 130.3, 129.3
292 (2C), 128.2 (2C), 127.4 (2C), 127.2, 117.2, 113.7 (2C), 101.3, 75.6, 74.9, 71.6, 70.7,
64.0, 55.2, 54.8, 36.3, 31.9, 29.7, 29.6, 29.3, 22.7, 22.1, 14.1; ES HRMS: m/z (M +
+ Na) calcd 319.1158, obsd 319.1153; Rf 0.29 (10:1 hexanes:ethyl acetate).
293
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297 65. Spagnol, G.; Heck, M-P.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2002, 4, 1767.
66. (a) Yamamura, S.; Kosemura, S.; Ohba, S.; Ito, M.; Saito, Y. Tetrahedron Lett. 1981, 22, 5315. (b) Zheng, W. F.; Cui, Z.; Zhu, Q. Planta Med. 1998, 64, 754. (c) Nishizuka, Y. Nature 1984, 308, 693. (d) Appendino, G.; Szallasi, A. Life Sci. 1997, 60, 681. (e) Miranda, F. J.; Alabadi, J. A.; Orti, M.; Centeno, J. M.; Pinon, M.; Yuste, A.; Sanz-Cervera, J. F.; Marco, j. A.; Alborch, E. J. Pharm. Pharmacol. 1998, 50, 237.
67. Hohmann, J.; Evanics, F.; Dombi, G.; Szabó, P. Tetrahedron Lett. 2001, 42, 6581.
68. (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. (b) Hentges, S. G.; Sharpless, K. B. J. Org. Chem. 1989, 54, 2263.
69. Wittig, G.; Rieber, M. Ann. 1040, 562, 187. (b) Wittig, G.; Geissler, G. Ibid. 1953, 580, 44.
70. (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. (b) Takai, K.; Tagahira, M.; Kurada, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. (c) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Morganti, S.; Umani-Ronchi, A. Org. Lett., 2001, 3, 1153.
71. Ito, H.; Motoki, Y.; Taguchi, T.; Hanzawa, Y. J. Am. Chem. Soc. 1993, 115, 8835.
72. (a) Gibtner, T.; Hampel, F.; Gisselbrecht, J.-P.; Hirsch, A. Chem. Eur. J., 2002, 68, 408. (b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3796.
73. (a) Gras, J. L.; Nouguier, R.; Mchich, M. Tetrahedron Lett. 1987, 28, 6601- 6604. (b) Rich, R. H.; Bartlett, P. A. J. Org. Chem. 1996, 61, 3916-3919.
74. (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9335. (b) Hubbs, J. L.; Heathcock, C. H. J. Am. Chem. Soc., 2003, 125, 12836.
75. Hubbs, J. L.; Heathcock, C. H. J. Am. Chem. Soc. 2003, 125, 12836.
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81. Sharpless, B. K.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X-L. ,J. Org. Chem. 1992, 57, 2768-2771.
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299
APPENDIX
1H NMR SPECTRA
300
N
l
N
C
N N
O
S
B
T
1.13
H NMR Spectrum of Compound
1
302
N
N N
2 H
N N
O
S
B T
1.14
H NMR Spectrum of Compound 1 303
N 2 NH N N N OH
1.15
H NMR Spectrum of Compound 1 304
OMs
OTBS
1.16
H NMR Spectrum of Compound 1 305
O NH N O
OTBS
1.18
H NMR Spectrum of Compound 1 306
O NH N O
OH
1.19
H NMR Spectrum of Compound 1 307
2
NH
N N Cl
N N
OTBS
1.20
H NMR Spectrum of Compound 1
308
2
NH
N N OH
N N
OTBS
1.21
H NMR Spectrum of Compound 1 309
2
NH
N N OH
N N
OH
1.21
H NMR Spectrum of Compound 1 310
N
l
N
C
N N
O
S
B
T
1.28
H NMR Spectrum of Compound 1 311
N
N N
2
H
N N
O
S
B
T
1.29
H NMR Spectrum of Compound 1 312
N
N N
2
H
N N
O H
1.30
H NMR Spectrum of Compound 1 313
OMs
OTBS
1.31
330 H NMR Spectrum of Compound 314 1
O
H
N
N O
F
O
S
B T
1.32
H NMR Spectrum of Compound 1 315
O
H
N
N O
F
O H
1.33
H NMR Spectrum of Compound 1 316
Bz O N N O OTBS
1.34
H NMR Spectrum of Compound 1 317
O NH N O OTBS
1.35
H NMR Spectrum of Compound 1 318
O NH N O OH
1.36
H NMR Spectrum of Compound 1 319
2 NH N N Cl N N OTBS
1.37
H NMR Spectrum of Compound 1 320
2 NH N N OH N N OTBS
1.398
H NMR Spectrum of Compound 1 321
2 NH N N OH N N OH
1.39
H NMR Spectrum of Compound
1
322
2 NO
O O
OTBS
1.40
H NMR Spectrum of Compound 1 323
OAc
S
B
T O
1.44
H NMR Spectrum of Compound
1 324
O
O
O
S
B
T
2.2
H NMR Spectrum of Compound 1 325
O
H
O
O
S
B
T
2.3
H NMR Spectrum of Compound 1 326
O
S
B
T
O
O
S
B T
2.4
H NMR Spectrum of Compound 1 327
H
O
S
B
T
O
O
S
B
T
2.5
H NMR Spectrum of Compound 1 328
H
O
S
B
T
O
O
S
B
T
2.7
H NMR Spectrum of Compound 1 329
s
M
O
S B T
O
O
S
B
T
2.6
H NMR Spectrum of Compound 1 330
O
H N
N O
S
B
T
O
S
B
T O
2.8
H NMR Spectrum of Compound
1
331
O N
2 N NH
OTBS
OTBS
2.9
H NMR Spectrum of Compound
1
332
O
H N
N O
S
B
T
O
S
B
T O
2.10
H NMR Spectrum of Compound 1 333
N
N N
2
H
N N
S
B
T
O
O S B
T
2.11
H NMR Spectrum of Compound 1
334
2
H
N
N
l C N
N N
S
B
T
O
S
B
T O
2.12
H NMR Spectrum of Compound 1 335
2
H
N
H
N
N O
N N
S
B T O
SO
B 2.13
T
H NMR Spectrum of Compound 1
336
O
H
N
N O
H
O
H
O
2.14
H NMR Spectrum of Compound
1 337
O N 2 N NH OH OH
2.15
H NMR Spectrum of Compound 1 338
O
H
N
N O
H
O
H
O
2.16
H NMR Spectrum of Compound 1 339
N
2 NH N
N N
OH
OH
2.17
H NMR Spectrum of Compound 1
340
2
H
N
H
N
O N
N N
H
O
O
H
2.18
H NMR Spectrum of Compound
1 341
O
O
S
B
T
2.19
H NMR Spectrum of Compound 1 342
O
r
B
O
S
B
T
2.21
H NMR Spectrum of Compound 1 343
O
O
S
B T
2.20
H NMR Spectrum of Compound 1 344
O
O
O
S
B
T
2.23
H NMR Spectrum of Compound 1 345
O
H
O
O
S
B T 2.24
H NMR Spectrum of Compound 1
346
O 2.25 OTBS OTBS
H NMR Spectrum of Compound
1
347
H O
S B T O
O S
B T
2.26
H NMR Spectrum of Compound 1 348
s
M
O
S
B
T
O
O
S
B
T
2.27
H NMR Spectrum of Compound
1 349
O
H
N
N O
S
B
OT
S
B
OT
2.28
H NMR Spectrum of Compound 1
350
O N 2 NH N OTBS OTBS
2.29
H NMR Spectrum of Compound
1 351
O
H
N
O N
S
B
T
O
O
S
B
T 2.30
H NMR Spectrum of Compound 1 352
N
2
H
N N
N N
S
B
T
O
S
B
T O
2.31
H NMR Spectrum of Compound 1 353
2 NH N Cl N N N OTBS OTBS
2.32
H NMR Spectrum of Compound 1
354
2 NH NH N O N N OTBS 2.33 OTBS
H NMR Spectrum of Compound 1
355
O
H
N
N O
H
O
O
H
2.34
H NMR Spectrum of Compound 1
356
O
N
N N
2
H
H
O
O
H
2.35
H NMR Spectrum of Compound 1 357
N
N N
2
H
N N
H
O
O
H
2.36
H NMR Spectrum of Compound 1
358
O
O
H
O
H
O
S
B
T
2.40
H NMR Spectrum of Compound 1
359
O OH OH
O
S
B
T
2.39
H NMR Spectrum of Compound 1 360
O
c
A
O
c
A
O
O
S
B
T
2.42
H NMR Spectrum of Compound 1
361
O O Si O Si O OTBS
2.43
H NMR Spectrum of Compound 1
362
H
O
i
O
S
O
i
S
O
S
B
T
O
2.44
H NMR Spectrum of Compound 1
363
s
M
O
i
O
S
O
i
S
O
O
S
B
T
2.45
H NMR Spectrum of Compound 1 364
O
O
O
O
S
B
T
2.46
H NMR Spectrum of Compound 1
365
H
O
O
O
O
S
B
T
2.47
H NMR Spectrum of Compound
1
366
s
M
O
O
O
O
S
B
T
2.48
H NMR Spectrum of Compound 1 367
O
O
O
O
O
S
B
T
2.49
H NMR Spectrum of Compound 1
368
H
O
O
O
O
O
S
B
T
2.50
H NMR Spectrum of Compound 1 369
H
O
O
O
O
O
S
B
T
2.51
H NMR Spectrum of Compound 1
370
s
M
O
O
O
O
O
S
B
T
2.52
H NMR Spectrum of Compound 1 371
O
h
P
O
O
H
O
S
B
T
2.53
H NMR Spectrum of Compound 1 372
H
O
h
O P
H O
O
S
B
T
2.54
H NMR Spectrum of Compound 1 373
s
M
O
h
O P
H O
O
S
B
T
2.55
H NMR Spectrum of Compound 1 374
f
T
O
O
O
O
S
B
T
2.56
H NMR Spectrum of Compound 1 375
O
H
N
O N
O
O
O
S
B
T
2.57
H NMR Spectrum of Compound 1 376
O
H
N
N N
2 O
H
O
O
S
B
T
2.58
H NMR Spectrum of Compound 1 377
O
H
N
N O
O
O
O
S
B
T
2.59
H NMR Spectrum of Compound 1
378
N
N N
2
H
N N
O
O
O
S
B
T
2.60
H NMR Spectrum of Compound 1 379
2
H
N
N
l
N
C
N N
O
O
O
S
B
T
2.61
H NMR Spectrum of Compound 1 380
2
H
N
N
l
N C
N N
O
O
O
S
B
T
isomeric 2.62
H NMR Spectrum of Compound 1
381
O
H
N
N O
O
O
O
H
2.62
H NMR Spectrum of Compound 1 382
O
H
N
N N
2 O
H
O
O
H
2.63
H NMR Spectrum of Compound 1 383
O
H
N
O N O
O
O H
2.64
H NMR Spectrum of Compound
1 384
N
N N
2
H
N N
O
O
O
H
2.65
H NMR Spectrum of Compound 1 385
2
H
N
N
l
N
C
N N
O
O
O
H
2.66
H NMR Spectrum of Compound 1
386
2
H
N
H
N
O N
N N
O
O
O
H
2.67
H NMR Spectrum of Compound 1 387
O
H
N
H
N O
O
O
H
O
H
2.68
H NMR Spectrum of Compound 1 388
O
N
H
N N
O 2
H
O
H
O
H
2.69
H NMR Spectrum of Compound 1 389
O
H
N
H
O N
O
O
H
O
H
2.70
H NMR Spectrum of Compound
1 390
N
N N
2
H
H
N N
O
O
H
O
H
2.71
H NMR Spectrum of Compound 1 391
2
H
N
H
N
O N
H
N N
O
O
H
O
H
2.72
H NMR Spectrum of Compound 1
392
O
H
O
H
O
O
S
B
T
2.73
H NMR Spectrum of Compound 1 393
O
c
A
O
c
A
O
O
S
B
T
2.2 acetate
H NMR Spectrum of Compound 1 394
O O Si O Si O OTBS
2.74
H NMR Spectrum of Compound
1 395
H
O
i
O
S
O
i
S
O
O
S
B
T
2.75
H NMR Spectrum of Compound 1 396
s
M
O
i
O
S
O
i
S
O
O
S
B
T
2.76
H NMR Spectrum of Compound 1
397
O
O
O
O
S
B
T
2.77
H NMR Spectrum of Compound 1 398
H
O
O
O
O
S
B
T
2.78
H NMR Spectrum of Compound 1 399
f
T
O
O
O
O
S
B
T
2.79
H NMR Spectrum of Compound 1 400
O
H
N
O N
O
O
O
S
B
T
2.80
H NMR Spectrum of Compound 1
401
O
N
N N
O 2
H
O
O
S
B
T
2.81
H NMR Spectrum of Compound 1 402
O
H
N
O N
O
O
O
S
B
T
2.82
H NMR Spectrum of Compound
1
403
N
N N
2
H
N N
O
O
O
S
B
T
2.83
H NMR Spectrum of Compound 1 404
2
H
N
N
l
N
C
N N
O
O
O
S
B
T
2.84
H NMR Spectrum of Compound 1 405
O
H
N
N O
O
O
O
H
2.85
H NMR Spectrum of Compound
1 406
O
N
N N
O 2
H
O
O
H
2.86
H NMR Spectrum of Compound 1 407
O
H
N
O N
O
O
O
H
2.87
H NMR Spectrum of Compound 1 408
N
N N
2
H
N N
O
O
O
H
2.88
H NMR Spectrum of Compound 1 409
2
H
N
N
l
N
C
N N
O
O
O
H
2.89
H NMR Spectrum of Compound 1 410
2
H
N
H
N
O N
N N
O
O
O
H
2.90
H NMR Spectrum of Compound
1 411
O
H
N
H
O N
O
O
H
O
H
2.91
H NMR Spectrum of Compound 1
412
O
N
H
N N
O 2
H
O
H
O H
2.92
H NMR Spectrum of Compound
1 413
O
H
N
H
O N
O
O
H
O
H
2.93
H NMR Spectrum of Compound 1 414
N
N N
2 H
H
N N
O
O
H
O
H
2.94
H NMR Spectrum of Compound 1
415
2
H
N
H
N
N O
H
N N O
O H O
H
2.95
H NMR Spectrum of Compound 1 416
S
B
T
O
O
O
S
B
T
3.16
H NMR Spectrum of Compound 1 417
H
O
O
O
H
3.9
H NMR Spectrum of Compound
1
418
OH
O
HO
3.12
H NMR Spectrum of Compound 1
419
OH
OH
O
3.17
H NMR Spectrum of Compound 1
420
OTBS
OH
O
0
3-1
H NMR Spectrum of Compound 1
421
OTBS
OTBS
O
3.18
H NMR Spectrum of Compound 1 422
OTBS
HO
TBSO
3.19
H NMR Spectrum of Compound 1 423
OTBS
OTBS
HO
3.21
H NMR Spectrum of Compound 1 424
OH
HO
HO
3.22
H NMR Spectrum of Compound 1 425
OTBS
O
HO
3.23
H NMR Spectrum of Compound 1
426
TBSO
O
O
3.24
H NMR Spectrum of Compound 1
427
OH
TBSO
3.26
H NMR Spectrum of Compound 1
428
O
TBSO
3.27
H NMR Spectrum of Compound 1
429
OH
TBSO
3.28
H NMR Spectrum of Compound 1
430
OH
O
TBSO
3.29
H NMR Spectrum of Compound 1
431
O
HO
TBSO
3.29a
H NMR Spectrum of Compound 1 432
OH
O
HO
3.10
H NMR Spectrum of Compound 1
433
OTBS
O
3.34
H NMR Spectrum of Compound 1
434
OH
O
TBSO
3.35
H NMR Spectrum of Compound 1 435
O
OH
HO
3.40
H NMR Spectrum of Compound 1 436
OH
OH
HO
3.41
H NMR Spectrum of Compound 1 437
OTBS
O
O
3.42
H NMR Spectrum of Compound 1
438
OH
O
TBSO
3.43
H NMR Spectrum of Compound 1
439
O
OH
TBSO
3.44
H NMR Spectrum of Compound 1 440
O
O
O
O
3.45
H NMR Spectrum of Compound 441 1
OMe
MeO
3.48
H NMR Spectrum of Compound 1
442
O
TBSO
3.52
H NMR Spectrum of Compound 1
443
OTBS
TBSO
3.52a
H NMR Spectrum of Compound 1
444
OH
TBSO
3.53
H NMR Spectrum of Compound 1
445
OH
TBSO
3.54
H NMR Spectrum of Compound 1
446
TBSO OH
3.55
H NMR Spectrum of Compound 1 447
O
TBSO
3.56
H NMR Spectrum of Compound 1 448
TBSO O
3.57
H NMR Spectrum of Compound 1
449
OH
TBSO
3.61
H NMR Spectrum of Compound 1
450
OH
HO
3.62
H NMR Spectrum of Compound 1
451
OH
OH
TBSO
3.63
H NMR Spectrum of Compound 1 452
O O
O
O
7 1
H NMR Spectrum of Compound 1 453
O
O
O
O
3.65
H NMR Spectrum of Compound 1
454
O
O
O
O
3.67
H NMR Spectrum of Compound 1 455
O
OH
TBSO
3.72
H NMR Spectrum of Compound 1
456
O
OH
HO
3.73
H NMR Spectrum of Compound 1 457
O O 4.18 H NMR Spectrum of Compound 1
458
O O 4.28 H NMR Spectrum of Compound 459 1
O O 4.30 H NMR Spectrum of Compound 1 460
O O
PhS PhS
4.34
H NMR Spectrum of Compound
1
461
H
O
O
H
4.44
H NMR Spectrum of Compound 1
462
O
O
H NMR Spectrum of Compound dione 1 463
H
O
O
S
B T
4.47
H NMR Spectrum of Compound 1 464
O
O
S
B
T
4.49
H NMR Spectrum of Compound 1
465
Ph
H
O
O
4.53
H NMR Spectrum of Compound 1 466
c
A
O
O
4.54
H NMR Spectrum of Compound 1 467
S
B
T
O
O
4.57
H NMR Spectrum of Compound 1 468
S
B
T
O
O
H
4.58
H NMR Spectrum of Compound 1 469
S
B
T
O
O
c
A
2.59
H NMR Spectrum of Compound 1 470
S
B
T
O
O
v
i
P
4.60
H NMR Spectrum of Compound 1 471
H O
H
O
4.65
H NMR Spectrum of Compound 1 472
H
O S
S
2.68
H NMR Spectrum of Compound 1 473
S
B
T
O
S
S
4.69
H NMR Spectrum of Compound 1 474
OTBDPS NC 5.12
H NMR Spectrum of Compound
1 475
O
B
M P
5.23
H NMR Spectrum of Compound 1
476
S
P
D
B
T
O
H
O
t
o
p
S
5.27
p
o
T
O
B
M
P
H NMR Spectrum of Compound 1 477
S
P
D
B
T O
t
o H
p
O
S
m
o
t
t
o B
O 5.28
B
M P
H NMR Spectrum of Compound 1 478
S
P
D
B
T
O
t
o
p
s
p
H
o
t
O
e
h
t
m
o
r
f
O
O
B
M
P
5.29
H NMR Spectrum of Compound 1 479
S
P
D
B
T
O
f
o
2
t
4
o
1
p
-
s
H
p
E
o
t O
R
-
m
V
o
I
r
O f
H
O
B 5.34
M
P
H NMR Spectrum of Compound 1 480
S
P
D
B
T
O
f
o
2
t
4
o
1
p
-
s
H
p
E
o
t O
R
-
m
V
o
I
r
O f
O
B 5.35
M eO
P
M
H NMR Spectrum of Compound 1 481
H
O
t
H
o
p
O
s
p
o
t
e
h
t
O
m
o
r
f
O
B
M
P
5.30
H NMR Spectrum of Compound 1 482
2
O
N
N
2
O
O
t
o
p
O s
p
o
t
e
H h
t
O
m
o 5.31
r
f
O
O
B
M
P
H NMR Spectrum of Compound 1 483
2
O
N
N
2
2
O
O
O
N
O
O
f
o
2
t
4
O
o
1
p
-
s
N
H
2 p
E
o
O 5.32
t
R
-
m
O V
o
I
r
f
O
B
M
P
H NMR Spectrum of Compound 1 484
S
P
D
B
T
O
f
o
2
t
z 4
o
1
B
p
-
s
O
H
p
E
o
t
R
-
m
V
o
I
r
O
f
O
B
M
P
5.37
H NMR Spectrum of Compound 1 485
S
P
D
B
T
O
S
B
T
O
O
O
B
M
P
5.40
H NMR Spectrum of Compound 1 486
S
P
D
B
T
O
M
O
B
O
O
O
B
M
P
5.39
H NMR Spectrum of Compound 1 487
S
P
D
B
T
O
H
O
O
O
B
M
P
5.42
H NMR Spectrum of Compound 1 488
H
O
O
5.46
H NMR Spectrum of Compound 1 489
S
B
T
O
O
5.47
H NMR Spectrum of Compound
1 490
S
B
H T
O O
5.48
H NMR Spectrum of Compound 1 491
S
B
T
O
O
H
5.48a
H NMR Spectrum of Compound 1 492
B
S
B M
P T
O O
5.49
H NMR Spectrum of Compound 1 493
B
S
B M
P T
O O
O
H
O
H
5.50
H NMR Spectrum of Compound 1 494
v
i
P
O
O
5.56
H NMR Spectrum of Compound 1 495
H H
O O
5.57
H NMR Spectrum of Compound 1 496
P
M
P
O O
5.58
H NMR Spectrum of Compound 1 497
B
M
P H
O O
5.59
H NMR Spectrum of Compound 1 498
B
M
H P
O O
5.59a
H NMR Spectrum of Compound 1
499
B
v
M i
P P
O O
5.60
H NMR Spectrum of Compound 1 500
B
S
B M
T P
O O
H NMR Spectrum of Compound Diprotected Diol 1 501
B
v
M i
P P
O O
O
H
O
H
5.54
H NMR Spectrum of Compound 1 502
B
v M i
P P
O O
e
O
H O
the Aldehyd
H NMR Spectrum of Compound 1
503
S
P
D
B
T
O
O
5.63
H NMR Spectrum of Compound 1 504
S
P
B
D
B M
P T
O O
5.65
H NMR Spectrum of Compound 1 505
S
P
B
D
B M
P T
O O
O
H
O
5.67
H NMR Spectrum of Compound 1 506
B
M
P
O
O
O
H
O
H
5.68
H NMR Spectrum of Compound 1 507
z
B
e
O
M
O
O
O
O
O
S
N
h
P N
5.71a
H NMR Spectrum of Compound 1 508
N
N
S
e
O
M
O O
O O
z
O
B
h
P
5.71b
H NMR Spectrum of Compound 1
509
e
M
O z
B
O
O
O O
h P
5.72
H NMR Spectrum of Compound 1 510
e
M
O
H
O
O
O
O
h
P
5.73
H NMR Spectrum of Compound 1 511
e
H
M
O
O
O
O
O
h
P
5.76
H NMR Spectrum of Compound 1 512
e
M
O
O
O
H
O
O
h
P
5.75
H NMR Spectrum of Compound 1 513
n
e B
M
O
O
O
O
O
h
P
5.77
H NMR Spectrum of Compound 1 514
n
e B
M
O
O
O
O
H
O
H
5.78
H NMR Spectrum of Compound 1 515
z
B
e
O
M
O O
O
O
O
S
N
P
N
M
P
5.81a
H NMR Spectrum of Compound 1
516
z
B
e
O
M
O
O
O
O
P
M
P
5.82
H NMR Spectrum of Compound 1 517
e
M
O
H
O
O
O
O
P
M
P
5.83
H NMR Spectrum of Compound 1 518
e
M
O
O
O
O
O
P
M
P
5.84
H NMR Spectrum of Compound 1 519
e H M
O
O
O
O O
P M
P
5.85
H NMR Spectrum of Compound 1 520
n
e
B
M
O
O
O
O
O
P
M
P
5.79
H NMR Spectrum of Compound 1 521
n
e B
M
O
O
O
O
B
O
M
H
P
5.86
H NMR Spectrum of Compound 1 522
n
e B
M
O
O
O
O
H
O
B
M P
5.87
H NMR Spectrum of Compound 1 523
B
M
P
O
O
O
n
B
O e
M
n
e
B
M O
O
O
O
B
M
P
5.88 HNMR Spectrum of Compound 1 524