Innovations en Route to Muironolide A
Dissertation
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy
in the Graduate School of The Ohio State University
By
Krista Cunningham
Graduate Program in Chemistry.
The Ohio State University
2015
Dissertation Committee:
Prof. Craig J. Forsyth, Advisor
Prof. Anita M. Mattson
Prof. Psaras McGrier
Prof. Kalpana Ghoshal
Copyright by
Krista Cunningham
2015
Abstract
Muironolide A is a complex natural product that was isolated from a marine sponge
Phorbas sp. This sponge has yielded several potent anticancer drug leads, including the phorboxazoles. However, a very minute quantity of muironolide A was isolated – only 90 micrograms of purified material. Remarkably, this was sufficient for Professor T.
Molinski to propose the complete structure, which includes an unprecedented hexahydro-
1H-isoindolone skeleton, a chlorocyclopropane, and a trichlorocarbinol ester. However, the limited amount of material available has prevented evaluation of the biological activities of muironolide A. It is anticipated that the novel chemotype may have associated useful activities, given those of its natural product congeners. We are developing a convergent, biomimetic total synthesis of muironolide A and its close structural analogs to allow full evaluation of their biomedical potential. This involves the preparation of several component fragments and their successive couplings.
ii This work is dedicated to all of my teachers, both in and out of the classroom—my family, friends, and many educators who have supported and believed in me.
iii Acknowledgments
I would like to start by thanking my advisor, Professor Craig Forsyth, for all that he has done for me. Not only has he given me the opportunity to learn and grow as a scientist in his research group, but has been an incredible resource for knowledge, advice, encouragement, and support. For that, I will always be grateful.
An additional thanks goes to the muironolide A subgroup, whom have provided me with great amounts of scientific and emotional support. To Dr. Isabelle Modolo, who laid the foundation for the work described herein: your work and friendship are appreciated more than you know. I would also like to thank Charles Clay and Kedwin Rosa for their huge contributions and dedication to this project. I am also happy to have had the opportunity to work with a skilled undergraduate, Mike Hoover, and thank him for his efforts.
I have to additionally thank my research group members. I am especially grateful to
Antony Okumu and Daniel Adu-Ampratwum, who have been on this journey with me from the beginning. I have enjoyed learning from and laughing with you countless times.
To the members of my group who have already moved on, but impacted me greatly—
Drs. Matt Jackel, Sean Butler, and Ting Wang: I am grateful to have had your mentorship. I would also like to acknowledge the Forsyth group members who have always been so supportive, including Li Xiao, Jerry Casbohm, Daniel Akwaboah,
iv Olumuyiwa (MJ) Adesoye, and Nate Kenton. Additionally, a special thanks goes out to
Jen Moore, Emily Prebihalo, and Basil Jafri for making this last summer so much fun.
I cannot begin to express the gratitude I have for my many mentors in the classroom. Dr.
Peter Norris, you are the reason I decided to pursue graduate school, and you continue to be an inspiration to me as an instructor. I am additionally very thankful to have worked with Drs. Christopher Callam and Noel Paul. Your support, advice, and countless hours of chatter have molded me into the teacher I am today.
A special thanks goes out to my cheerleaders in the Stambuli and Hadad groups, namely
Chip, Ryan, Bill, Amneh, and Tom, who always made sure I had what I needed, even if it was just a laugh. To Sarah, Kendra, Krishnaja, and Oui: your support, lunch dates, and endless conversations have made these past couple of years so much more enjoyable.
To my soon-to-be-husband, Michael: “thank you” does not even begin to express my immense gratitude to have you in my life these past several years. If graduate school has taught me anything, it is that I can always count on you to love and support me, and to make me smile when I need it most. There is no way that I could have done this without you, and I could not have chosen a better person to spend my life with.
Lastly, I have to thank my incredible family—both the one I was born into and the one I will join in a few short months. You are my foundation and my rock, and all that I am is built from each and every one of you. You all mean more to me than words could ever express. Above all, I have to thank my parents, Christina and Mike Cunningham, who have molded me to be the woman I am today. Thank you for always believing in me, and teaching me not to give up.
v Vita
June 2006 ...... Boardman High School Diploma
May 2010 ...... B.S. Chemistry
Youngstown State University
September 2010 to 2015 ...... Graduate Teaching and Research Associate
The Ohio State University
Fields of Study
Major Field: Chemistry
vi Table of Contents
Abstract ...... ii!
Acknowledgments ...... iv!
Vita ...... vi!
List of Schemes ...... x!
List of Figures ...... xii!
List of Abbreviations ...... xiii!
Chapter 1 : Background ...... 1!
1.1 Introduction ...... 1!
1.2 Structure Elucidation of Muironolide A ...... 3!
1.3 Synthetic Studies Toward Muironolide A ...... 6!
1.3.1 Synthetic Studies on Muironolide A by the Molinski Group ...... 6!
1.3.2 The Mitchell Group’s Approach Towards Muironolide A ...... 10!
1.3.3 The Zakarian Group Approach to Muironolide A ...... 12!
1.4 Zakarian Total Synthesis and Structural Revision of (+)-Muironolide A ...... 16!
1.4.1 Retrosynthetic Analysis ...... 16!
1.4.2 Synthesis of Diels-Alder Reaction Substrates ...... 17
vii 1.4.3 IMDA Reactions and Synthesis of 1.5 ...... 19!
Chapter 2 : First Generation Synthetic Approach to Muironolide A ...... 24!
2.1 Retrosynthetic Analysis ...... 24!
2.2 Synthesis of Triene 2.2 ...... 26!
2.3 Progress Toward Cyclopropane 2.6 ...... 29!
2.4 Completion of Diene 2.5 ...... 31!
2.5 Problems with First Generation Route ...... 32!
Chapter 3 : Revised Approach to Muironolide A ...... 34!
3.1 Retrosynthetic Analysis ...... 34!
3.2 Revised Route to Triene 3.4 and Synthesis of (17S)-3.4 ...... 35!
3.3 Synthesis of Cyclopropane 3.5 ...... 37!
3.4 Completion of Diene 3.6 ...... 38!
3.5 Attempts at Assembly of Muironolide A ...... 39!
Chapter 4 : Current Approach and Future Directions ...... 43!
4.1 Current Retrosynthesis ...... 43!
4.2 Cyclopropane 4.5 ...... 45!
4.3 Efforts Toward Diene 4.4 ...... 46!
4.4 Future Directions ...... 48!
Chapter 5 : Experimental Section ...... 49!
viii List of References ...... 94!
Appendix A: 1H NMR Data ...... 98!
ix List of Schemes
Scheme 1.1: Synthesis of Cyclopropanes 1.9a-d ...... 5!
Scheme 1.2: Retrosynthesis of Isoindolinone Core of Muironolide A (1.5) ...... 7!
Scheme 1.3: Synthesis of Diels-Alder Reaction Precursors and Initial IMDA Reaction
Screening ...... 8!
Scheme 1.4: Optimization of Enantioselective IMDA Reaction ...... 9!
Scheme 1.5: Base-Promoted Isomerization of Alkene 1.20b ...... 10!
Scheme 1.6: First Generation Retrosynthetic Analysis of Muironolide A ...... 10!
Scheme 1.7: Attempts Toward Hemiaminal 1.27 ...... 11!
Scheme 1.8: Second Generation Retrosynthesis ...... 11!
Scheme 1.9: Synthesis of Isoindolinone Core 1.35 ...... 12!
Scheme 1.10: Muironolide A Core Retrosynthesis ...... 13!
Scheme 1.11: IMDA Reaction Studies of β-Keto Amide (4E)-1.38a ...... 14!
Scheme 1.12: Synthesis and IMDA Reaction Studies of (4Z)-1.38b ...... 15!
Scheme 1.13: Zakarian Retrosynthesis of Muironolide A ...... 17!
Scheme 1.14: Completion of Diels-Alder Reaction Substrates ...... 18!
Scheme 1.15: Initial Attempts at Completion of Muironolide A ...... 20!
Scheme 1.16: Completion of 1.5 ...... 21!
Scheme 2.1: Original Retrosynthesis of Muironolide A ...... 25
x Scheme 2.2: Synthesis of Lactones 2.17 and 2.4 ...... 27!
Scheme 2.3: Synthesis of Aldehyde 2.24 ...... 28!
Scheme 2.4: Horner-Wadsworth-Emmons Reaction of Aldehyde 2.24 ...... 29!
Scheme 2.5: Efforts Toward Cyclopropane 2.6 ...... 30!
Scheme 2.6: Alternative Route to Vinyl Chloride 2.29 ...... 30!
Scheme 2.7: Completion of Vinyl Iodide 2.8 ...... 31!
Scheme 2.8: Stille Cross-Coupling to Afford Diene Precursor 2.35 ...... 32!
Scheme 3.1: Redesigned Retrosynthesis of Muironolide A ...... 34!
Scheme 3.2: Generation of Triene 3.4 ...... 36!
Scheme 3.3: Synthesis of (17S)-3.4 ...... 36!
Scheme 3.4: Proposed Synthesis of Cyclopropane 3.5 ...... 37!
Scheme 3.5: Completion of Azide 3.6 ...... 39!
Scheme 3.6: Attempts at Saponification of Methyl Ester 3.6 ...... 40!
Scheme 3.7: Alternative Dienes 3.28 and 3.29 ...... 40!
Scheme 3.8: Attempted Mitsunobu Coupling of Alcohol 3.5 and Acid 3.29 ...... 41!
Scheme 3.9: Attempt at Amidation/IMDA Reaction Sequence of Dioxinone 3.4 with
Carbamate 3.28 ...... 41!
Scheme 4.1: Current Retrosynthesis of Muironolide A ...... 44!
Scheme 4.2: Second Generation Synthesis of Cyclopropane 4.5 ...... 45!
Scheme 4.3: Proposed Route to ent-4.5 ...... 46!
Scheme 4.4: Proposed Reductive Amination ...... 46!
Scheme 4.5: Proposed Method to Access Diene Precursor 4.20 ...... 47!
xi List of Figures
Figure 1.1: Isoindole-Containing Compounds ...... 2!
Figure 1.2: Molinski’s Proposed Structure of Muironolide A ...... 3!
Figure 1.3: Chiral Bisoxazoline Ligand for Lanthanide-Catalyzed IMDA Reaction ...... 15!
Figure 1.4: Revised Structure of (−)-Muironolide A ...... 22!
xii List of Abbreviations
1D one-dimensional
2D two-dimensional
α alpha
[α] specific rotation
Å angstrom(s)
Ac acetyl app apparent
β beta
BAIB bis(acetoxy)iodobenzene
Boc tert-butoxycarbonyl
BHT butylated hydroxytoluene br broad (NMR) n-Bu normal butyl t-Bu tertiary butyl
ºC degrees Celsius
13C carbon-13 calc’d calculated cm-1 wavenumbers (IR) d day(s); doublet (NMR) xiii dd doublet of doublets (NMR)
DIAD diisopropyl azadicarboxylate
DIBAL-H diisobutylaluminum hydride
DIPEA diisopropylethylamine
DMAP 4-(N,N-dimethylamino)pyridine
DMF N,N-dimethylformamide
DMP Dess-Martin periodinane
DMSO dimethylsulfoxide dq doublet of quartets (NMR)
DPPA diphenylphosphoryl azide dr diastereomeric ratio ee enantiomeric excess
Et ethyl
Et2O diethyl ether
ESI electrospray ionization
Fmoc 9-fluoroenylmethoxycarbonyl
FTMS Fourier transform mass spectrometry g gram(s) h hour(s)
1H proton
HPLC high-performance liquid chromatography
Hünig’s base diisopropylethylamine
xiv Hz hertz
Im imidazole
IMDA intramolecular Diels-Alder
IR infrared iso-pro isopropyl
J coupling constant in Hertz (NMR)
L liter(s)
LDA lithium diisopropylamide
LiHMDS lithium hexamethyldisilazide
µ mu; micro m meter(s); milli; multiplet (NMR)
M moles per liter; molecular ion (MS)
Me methyl min minute(s) mol mole(s)
Ms methanesulfonyl
MS molecular sieves m/z mass to charge ratio (MS)
NaHMDS sodium hexamethyldisilazide
NMR nuclear magnetic resonance obs’d observed p para
xv PDC pyridinium dichromate
Ph phenyl
Piv trimethylacetyl ppm parts per million
PPTS pyridinium para-toluenesulfonate
Py pyridine q quartet (NMR)
R rectus (latin)
Rf retention factor rt 23 °C s second(s); singlet (NMR)
S sinister (latin)
SES [2-(trimethylsilyl)ethyl]sulfonyl sex sextet (NMR) sp. species t tertiary (tert) t triplet (NMR)
TAIMDA transannular intramolecular Diels-Alder
TBAF tetra-butylammonium fluoride
TBS tert-butyldimethylsilyl td triplet of doublets (NMR)
TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl
xvi TES triethylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
Ts tosyl; p-toluenesulfonyl
TS transition state
TsOH p-toluenesulfonic acid
xvii Chapter 1: Background
1.1 Introduction
Isoindoles are a class of natural products derived from the core structure 1.1 that contain a fused benzopyrrole ring system. Several molecules in this family possess interesting biological activity and physical properties, making them targets of great interest in the synthetic community (Figure 1.1).1 One such isoindole-derived drug is thalidomide (1.2), which contains a phthalimide core. This drug was utilized in the 1950’s to prevent morning sickness in pregnant women, however its use has since been discontinued due to its link to birth defects and miscarriage. Isoindolinone-containing PD 172938 (1.3) is a dopamine D4 antagonist that demonstrates potential as an antipsychotic agent.2 In contrast, pigment yellow 185 (1.4) is a high-performance isoindoline-containing pigment used in several high performance coatings.
1
O H O N N N NH N O NH isoindole (1.1) O O thalidomide (1.2) PD 172938 (1.3)
O
H O HN HN H N O O H N H HN CN O O O O CCl3 Cl O pigment yellow 185 (1.4) H muironolide A (1.5)
Figure 1.1: Isoindole-Containing Compounds
Another member of this class of compounds is muironolide A (1.5), which contains a hexahydro-1H-isoindolinone (hereafter referred to as “isoindolinone”) core. Muironolide
A was reported in 2009 by Molinski and co-workers,3 and is the first occurrence of this structural motif. Muironolide A also contains a trichloromethylcarbinol ester, which is unprecedented in the literature. In addition, the chlorocyclopropane functionality is a rare structural feature present in 1.5. Interestingly, this particular functional group is also present in the phorbasides, another class of natural products isolated from Phorbas sp.4
Because the phorbasides demonstrate some cytotoxicity against human colon cancer cell
(HTC 116) lines, it is believed that muironolide A may demonstrate interesting biological activity. Preliminary biological screening shows weak cytotoxicity against HTC 116 lines, and also modest antifungal activity. However, only 90 µg of 1.5 were isolated, which has limited the ability to conduct a full biological screen. As such, our group set
2 out with the goal to provide a scalable and flexible synthesis of muironolide A and its structural analogs in order to gain insight into its biological potential.
1.2 Structure Elucidation of Muironolide A
The structure of muironolide A (Figure 2) was determined through use of microcryoprobe
NMR spectroscopy, Fourier transform mass spectrometry (FTMS), circular dichroism
(CD), chemical degradation, LCMS, and synthesis.3
O 9
HN H 11 27 6 4 14 25 H 26
1 17 18 O O O CCl3 21 Cl 22 19 23 O H muironolide A (1.5)
Figure 1.2: Molinski’s Proposed Structure of Muironolide A3
Both positive and negative ion electrospray ionization (ESI) FTMS were used to determine the chemical formula and degrees of unsaturation present in compound 1.5.
Together with extensive one and two-dimensional 1H and 13C NMR spectroscopic analyses, the structure of the full macrolide core of (−)-muironolide A was assigned, with the absolute configuration established by analysis of its CD spectrum.
Circular dichroism can be used to determine the chirality of complex organic molecules by measuring the differential absorption of left and right circularly polarized light. This is observed at varying wavelengths, and different chromophores present can be related by their exciton coupling.5 These data can be used along with semi-empirical methods to determine the chiral relationship between two chromophores, and this principle was used
3 to assign the absolute stereochemistry of muironolide A. The two α,β-unsaturated carbonyl chromophores of muironolide A resulted in a strong negative bisignate Cotton effect in its CD spectrum. The Molinski group then applied the Harada-Nakanishi nonempirical rule for exciton-coupled CD,6 which predicts that the negative bisignate-
Cotton effect is consistent with negative helicity present in the molecule. This resulted in the proposed stereochemistry of 5, as seen in Figure 1.2.
Given that the 1D and 2D NMR data could not definitively conclude the relative stereochemistry of the chlorocyclopropane unit, degradation, LCMS and synthesis were employed (Scheme 1.1). This began by synthesizing optically enriched alcohol 1.6,7 followed by alcohol oxidation and Reformatsky reaction with alpha-bromomethyl acetate. Diastereomeric methyl esters 1.7 were not readily separated by simple chromatography, however saponification followed by derivatization with (α)-bromo-2- acetylnaphthalene (1.8) gave a mixture of 2-acetylnaphthone esters (1.9a-d). These could then be separated by sequential chiral HPLC (Chiralpak AD, 3:7 i-PrOH/hexane) and
LCMS (Chiralpak AD-RH, single ion monitoring, SIM, m/z 355.2, M+Na+). Because the starting material was not optically pure, four cyclopropane diastereomers (1.9a-d) were obtained. The stereochemistries of the major isomers (1.9a,b) were assigned based on the known configuration of 1.6, which was determined through extensive one and two- dimensional 1H and 13C NMR analyses. This was further corroborated through use of the empirical modified Mosher’s ester method. The stereochemistries of enantiomers 1.9c and 1.9d were assigned by extensive 1H NMR and CD analyses.
4 OH OH O 1. PCC, Celite Cl Cl 2. BrCH CO CH , Zn0, THF O H 2 2 3 H 36%, 2 steps 1.6 1.7 ~85% ee dr 1:1
OH O OH O Cl R Cl R O O H H 1. LiOH, THF/H2O 1.9a 1.9b 1.7 O 2. Br OH O OH O Cl R Cl R O O H H 1.8 1.9c 1.9d R = 2-acetylnaphthone
Scheme 1.1: Synthesis of Cyclopropanes 1.9a-d3
When muironolide A was subjected to the same derivatization conditions (1. LiOH,
THF/H2O; 2. 1.8) followed by chiral LCMS, the retention time of the degradation product uniquely coeluted with compound 1.9b. This established the proposed cyclopropane stereochemistry, thus completing the complete proposed structural and stereochemical assignment of muironolide A.
Ultimately, the initially proposed stereochemistry of muironolide A was determined to be inaccurate, which is discussed further in Section 1.4.8 Both the absolute configurational assignment of the macrolide core based upon the CD analysis and the stereochemical assignment of the cyclopropane-containing fragment proved to be incorrect. According to
Zakarian’s reassignment of stereochemistry (cf. Figure 1.4), the natural product’s degradation-derivatization fragment had the stereochemistry assigned to 1.9c, not 1.9b.
The structure of Molinski’s 1.9b and 19c were misassigned with respect to the absolute configuration of the cyclopropane moiety, tracing back to 1.6. But the absolute configuration at the adjacent C21 carbinol was correctly assigned using the modified
5 Mosher’s ester method. These misassignments could be due to several factors, including the misapplication of the semi-empirical (Harada-Nakanishi) model.
1.3 Synthetic Studies Toward Muironolide A
Since its discovery, muironolide A has gathered interest from the synthetic community.
This has resulted in several synthetic studies and one completed total synthesis of the unnatural (+)-muironolide A to date. As is the case with other isoindole natural products,1 the core of the molecule is generally thought to arise from an intramolecular Diels-Alder
(IMDA) reaction. Studies have been published that explore this hypothesis, and these will be discussed in further detail throughout the following sections. It should be noted that our group was also exploring this possibility at the time of their publication.
1.3.1 Synthetic Studies on Muironolide A by the Molinski Group
In 2011, Molinski and co-workers highlighted their efforts toward assembly of the isoindolinone core of 1.5 via an asymmetric IMDA reaction (Scheme 1.2).9 They hypothesized that the core of muironolide A (1.10) could be accessed from amide 1.11 following alkene isomerization and sidechain elaboration at R2. Intermediate 1.11 could arise from an IMDA reaction of precursor aldehyde 1.12. Finally, 1.12 would be synthesized by amidation of commercially available pentadienoic acid (1.14a) or sorbic acid (1.14b) with amines 1.15a and 1.15b.
6 HO R2 O O amidation O H O 1.14a R2 = H P1 N H P1 N 1.14b R2 = CH P1 N 3 H R2 R2 OAc 3 O OP O CCl3 R1 O OP3 P1HN P2 1 1.10 1.11 1.12 R1 = CHO 1.15a P = PMB 1 1 1.13 R = CH2OAc 1.15b P = DMB P1–P3 = protecting groups; PMB = 4-methoxybenzyl; DMB = 2,4-dimethoxybenzyl
Scheme 1.2: Retrosynthesis of Isoindolinone Core of Muironolide A (1.5)9
Amidation of acids 1.14a and 1.14b with amines 1.15a or 1.15b proceed smoothly to provide a variety of substrates (1.13a-c) to study the key IMDA reaction (Scheme 1.3).
Subjecting 1.13a to thermal conditions in the presence of disulfide 1.17 provided racemic lactam 1.18a in a 1:2 ratio of exo:endo products. Notably, when the product mixture was redissolved in ethanol and heated to 120 °C, the desired exo Diels-Alder reaction product
1.18a was isolated in a >30:1 diastereomeric ratio, albeit in racemic form. At this time, conditions were tested for an asymmetric IMDA reaction.
7 O OMe 1. (i-Pr) NEt, 1.16 2 2 R N N CH Cl , rt N HO R1 2 2 2. 1.15a or 1.15b R1 MeO N Cl O OAc OAc 1.16 1.14a R1 = H 1.14b R1 = CH 1 2 3 R2HN 1.13a R = H, R = PMB; 73% 1.13b R1 = CH , R2 = PMB; 80% 1.15a R2 = PMB 3 1.13c R1 = CH , R2 = DMB; 96% 1.15b R2 = DMB 3
O H O H (±)-1.18a µwave, 200 °C, C6H5Cl PMBN PMBN µwave, 120 °C, 1.13a >30:1 exo:endo 50 ppm 1.17 EtOH 91% 1:2 exo:endo 86% OAc OAc S (±)-endo-1.18a (±)-exo-1.18a
HO t-Bu 2 1.17
Scheme 1.3: Synthesis of Diels-Alder Reaction Precursors and Initial IMDA Reaction Screening9
In order to conduct the asymmetric Diels-Alder reaction using chiral iminium catalysis, it was necessary to convert the acetate of substrates 1.13a-c to the corresponding α,β- unsaturated aldehydes 1.12a-c. Upon exposure of these intermediates to MacMillan organocatalysts 1.19a-c,10 the optimal substrate for this transformation was found to be
PMB substituted amide 1.12b (Scheme 1.4).
8 O O R2 2 R 1. K2CO3, CH3OH, rt N O N 2. MnO2, CH2Cl2, rt R1 Ph 1 N R HN H •HCl OAc O 1.19a 1.13a R1 = H, R2 = PMB 1.12a R1 = H, R2 = PMB; 53% O 1 2 1 2 1.13b R = CH3, R = PMB 1.12b R = CH3, R = PMB; 82% 1.13c R1 = CH , R2 = DMB 1.12c R1 = CH , R2 = DMB; 70% Ph 3 3 N HN •HClO4 t-Bu 1.19b O H O OH 1.12a cat. 1.19a-c 2 Ph 1.12b R N N 20 mol% CH CN, 1 HN 1.12c 3 R •HX 2% H2O H O 1.19c X = Cl, ClO4, CO2CF3 1.20a R1 = H, R2 = PMB; ~4% 1 2 1.20b R = CH3, R = PMB; 73% 1 2 1.20c R = CH3, R = DMB; 67%
Scheme 1.4: Optimization of Enantioselective IMDA Reaction9
Aldehyde 1.12b was utilized to optimize the conditions for this transformation. It was found that 20 mol% of the perchloric acid salt of catalyst 1.19c provided the best enantio- and diastereoselectivities when the reaction was run at 0 °C for 84 h. This provided compound 1.20b, which was subjected to 1,8-diazabicycloundec-7-ene (DBU) for base- promoted isomerization of the double bond (Scheme 1.5). While this process affected both stereocenters at C4 and C8, the double bond did not isomerize under these conditions. It was suggested that the isoindolinone core prefers to adopt the half-chair conformation present in lactam 1.20b, which cannot be achieved by lactam 1.21.
However, the difficulty in alkene isomerization is not fully understood, as the α,β- unsaturated lactam is calculated to be more thermodynamically stable.9
9 O H O H O
PMB N 8 DBU PMB N PMB N 4 C6D6 23 °C H O H O H O (4S,8R)-1.20b (4R,8S)-1.20b 1.21, not observed
Scheme 1.5: Base-Promoted Isomerization of Alkene 1.20b9
1.3.2 The Mitchell Group’s Approach Towards Muironolide A
Similarly, Mitchell and co-workers set out to assemble the core of muironolide A via an
IMDA reaction.11 Their original retrosynthetic plan (Scheme 1.6) involves cleavage at the ester linkages and the C12-C13 double bond. This provides phosphonate 1.22, isoindolinone 1.23, and cyclopropane 1.24. Intermediate 1.23 could be accessed from amination and Wittig olefination of 1.25, which would result from the key IMDA reaction of amide 1.26. Precursor 1.26 would be the product of reduction of 1.28 followed by methylenation of the latent aldehyde and N-acylation.
Horner-Wadsworth O lactamization O Diels-Alder 9 Emmons olefination EtO O reaction EtO P HN H O O CbzN H O O 6 4 H 14 25 Et3Si H H O CCl3 CbzN O Mitsunobu 1 17 1.22 1.23 O O O CCl3 Wittig 1.25 Cl olefination 21 O 23 macrolactonization OH O H Cl 1.5 O H 1.24 O O OH O O O NCbz O O N O NCbz 1.27 O Cbz acylation 1.28 1.26 H2C=PPh3
Scheme 1.6: First Generation Retrosynthetic Analysis of Muironolide A11
10 Following the synthesis of lactam 1.28, reduction conditions were screened to obtain hemiaminal 1.27 (Scheme 1.7). Upon exposure to a variety of reducing conditions
(DIBAL-H, LiAlH4, LiBHEt3, LiAlH(Ot-Bu)3), hemiaminal 1.27 was not observed, and only the conjugate reduction product 1.29 was isolated in a 38% yield as a mixture of diastereomers. Decomposition was observed upon treatment of 1.29 with NaBH4 and
CeCl3 and as such, the retrosynthesis was redesigned.
O O reduction O OH O O conditions H O O O NCbz NCbz NCbz
H 1.28 1.27 1.29
Scheme 1.7: Attempts Toward Hemiaminal 1.2711
The redesigned retrosynthetic plan can be found in Scheme 1.8. Revision of the isoindolinone core to 1.30 would allow for Diels-Alder reaction product 1.31 to come from diene 1.32 and dienophile 1.33. It should be noted that such a revision alters the key
Diels-Alder reaction from an intramolecular to an intermolecular process.
O Diels-Alder O reaction BocN H O 1.5 1.22 1.24 BocN H O H 1.30 O H O OH 1.31
O O H O or N Ph BocN O
1.33 O 1.32 1.34
Scheme 1.8: Second Generation Retrosynthesis11
11 Imidazolidinone 1.19a was used to catalyze initial Diels-Alder reaction attempts between
1.32 and 1.33. A variety of solvents were screened, but reactions conducted at 23 °C did not proceed and only decomposition was observed at elevated temperatures.
O O O BHT (20 mol%) toluene BocN H H N Ph O BocN 100 °C, 6 d O 76% N 1.32 O 1.34 Ph 1.35 (dr >19:1)
Scheme 1.9: Synthesis of Isoindolinone Core 1.3511
As a result of these observations, dienophile 1.34 was used in the intermolecular Diels-
Alder reaction (Scheme 1.9). The reaction proceeded best under thermal conditions for six days in the presence of butylated hydroxytoluene (BHT) as a radical inhibitor.
Although 1.35 is not easily elaborated to form 1.5, this method allows access to the isoindolinone core of muironolide A, and avoids the difficult alkene isomerization observed by Molinski and co-workers.
1.3.3 The Zakarian Group Approach to Muironolide A
Zakarian and co-workers designed an alternative approach to the core of muironolide A
(Scheme 1.10).12 They set out to synthesize isoindolinone 1.36, the fully elaborated core of 1.5. Their strategy involved a β-keto amide precursor for an intramolecular Diels-
Alder reaction.
12 amidation intramolecular O O O O 9 O H Diels-Alder reaction PMBN PMBN PMBN 6 4 14 4 25
1 O O OR O OR OR
1.36a (R = CH2CH3) 1.37a (R = CH2CH3) (4E)-1.38a (R = CH2CH3) 1.36b (R = CH3) 1.37b (R = CH3) (4Z)-1.38b (R = CH3)
O NHPMB O O O 1.40 O or NHPMB 1.39
1.41
Scheme 1.10: Muironolide A Core Retrosynthesis12
It was proposed that 1.36 could be synthesized from the reduction of ketone 1.37, followed by elimination of the intermediate alcohol. The β-keto amide 1.37 would result from the IMDA reaction of the enol tautomer of amide 1.38, which is formed by amidation of dioxinone 1.39 with either amine 1.49 or 1.41. This IMDA strategy utilizing the enolic form of a β-keto acyl moiety is well-precedented, most noteably in the Evans’ synthesis of salvinorin A.13 Utilization of two different amine fragments allows for the synthesis of both the (4E) and (4Z) alkene isomers of 1.38. This was done in order to investigate the diastereoselectivity of the IMDA reactions.
With fragments 1.39 and 1.40 hand, the amidation reaction was performed under thermal conditions to provide (4E)-1.38a (Scheme 1.11). Following intramolecular Diels-Alder reaction, the ketone and ester of substrate 1.42 were reduced, followed by selective oxidation of the allylic alcohol to generate aldehyde 1.43. Epimerization at C4 gave aldehyde 1.44, the stereochemistry of which was confirmed by NOE analysis. This is the
13 result of the expected endo transition state, which benefits from a proposed hydrogen- bonding interaction between the ketone enol and amide carbonyl.
O O O O O O PMBN H O PhMe, reflux PPTS, PhMe PMBN 110 °C, 3 h 5 mol% BHT 4 1.39 62% 61%, dr >30:1 O O NHPMB O O OR O 1.40 (4E)-1.38a 1.42
OH OH O H O H piperidinium 1. NaBH , CeCl , CH OH 4 3 3 PMBN trifluoroacetate, PMBN –78 °C, 100% PhMe, 75 °C 1.42 4 2. DIBAL-H 80% 3. MnO2, 79% (2 steps) dr >20:1
O H O H 1.44 1.43
Scheme 1.11: IMDA Reaction Studies of β-Keto Amide (4E)-1.38a12
To investigate the reactivity of the Z-isomer of 1.38b, amidation of dioxinone 1.39 with amine 1.41 was carried out to yield amide 1.45 (Scheme 1.11). The terminal olefin underwent an olefin cross-metathesis reaction14 with methyl acrylate to afford (4Z)-
1.38b. Upon heating in toluene, the IMDA reaction proceeded with similar yield and diastereoselectivity to the (4E)-isomer. Reduction of the ketone followed by mesylation and elimination in the presence of DBU was reported to provide isoindolinone 1.36b. It was later discovered, however, that this elimination provided the unconjugated C9-C10 alkene, rather than the reported C8-C9 double bond.
14 O O O O O O O O PMBN 1.39 PPTS, PhMe PMBN 110 °C, 3 h O 62% 10 mol% HGII NHPMB catalyst 81% O 1.45 O (4Z)-1.38b 1.41
O N N O H
PMBN Cl PhMe, reflux Ru (4Z)-1.38b Cl 60%, dr >30:1 O
O O HGII catalyst 1.37b
O 9 8 10 1. NaBH4, CeCl3, CH3OH PMBN 2. CH3SO2Cl, NEt3, CH2Cl2, 23 °C 1.37b 3. DBU, PhMe, 85 °C, 6 h 64% O O 1.36b
Scheme 1.12: Synthesis and IMDA Reaction Studies of (4Z)-1.38b12 (Note: 1.36b was not obtained as shown above)
In addition, the Zakarian group set out to investigate the possibility of an enantioselective
IMDA reaction involving the use of lanthanide-terpyridine catalysts.15 The studies were performed with (4Z)-1.38b as the Diels-Alder reaction precursor. In short, the best enantiomeric excess (% ee) obtained was 50% in the presence of catalytic La(OTf)3, bisoxazoline ligand 1.46 (Figure 1.3) and triethylamine.
O O N N N
1.46
Figure 1.3: Chiral Bisoxazoline Ligand for Lanthanide-Catalyzed IMDA Reaction15
15 Utilization of these reaction conditions could allow the reaction to be conducted at a lower temperature (45 °C) for 24 h. The authors propose that this is due to lanthanide catalyst-accelerated enolization of the β-keto amide. This results in generation of a more electron-rich enolic diene that is electronically compatible for the Diels-Alder reaction process. Alternatively, the amine may facilitate enolization while the lanthanide chelates to stabilize the resulting enolate. Facial selectivity of the Diels-Alder reaction would then result from the local chirality of the enolate, thus providing the Diels-Alder reaction product.
1.4 Zakarian Total Synthesis and Structural Revision of (+)-
Muironolide A
Shortly after Zakarian and co-workers reported the lanthanide-catalyzed intramolecular
Diels-Alder reaction process, the first total synthesis and structural revision of muironolide A was described.8 The structure assigned by Molinski and co-workers (1.5) was originally synthesized. Upon comparison of the NMR data to those of the authentic sample, several inconsistencies led to its structural revision (Section 1.4.3). The retrosynthesis and synthetic methods will be further discussed in the following sections.
1.4.1 Retrosynthetic Analysis
The retrosynthetic analysis designed by Zakarian and co-workers involved the utilization of the methods described in their previous work.12, 15 As such, 1.5 was cleaved at the ester linkages to provide isoindolinone-containing fragment 1.47 and chlorocyclopropane 1.48
(Scheme 1.13). It was envisioned that 1.47 would come from the reduction and elimination of 1.49, which would be formed as a result of the lanthanide-catalyzed IMDA
16 reaction of precursor 1.50.15 Amine 1.41 from their previous work12 would be combined with a derivative of β-(+)-citronellene to access β-keto amide 1.51.
O
O PMBN 9 intramolecular O O H Diels-Alder HN H reaction 8 6 4 14 PMBN H 25 RO O BOMO CCl3
1 17 1.47 O O O CCl3 Cl 21 RO O BOMO CCl3 23 O OH OtBu H acylation Cl 1.49 1.5 O H 1.48
[Ln] O O O O PMBN PMBN
O BOMO CCl3 O BOMO CCl OR 3 OR 1.51 1.50
Scheme 1.13: Zakarian Retrosynthesis of Muironolide A8
The retrosynthetic analysis does allow for some flexibility with regard to the order of esterification of intermediate 1.47. The ability to acylate the trichloromethyl carbinol followed by the cyclopropyl alcohol, or vice versa, is a key feature highlighted in the described synthesis.
1.4.2 Synthesis of Diels-Alder Reaction Substrates
The synthesis of amide 1.47 began with (+)-β-citronellene (Scheme 1.14). Ozonolysis of the trisubstituted double bond followed by trichloromethyl anion addition to the resulting aldehyde led to an epimeric mixture of alcohols at C17. The resultant alcohols were subjected to Swern oxidation, followed by stereoselective reduction of the 17 trichloromethyl ketone under transfer hydrogenation conditions.16 Benzyloxymethylation provided acetal 1.53, which underwent olefin cross-metathesis14 with methacrolein to afford α,β-unsaturated aldehyde 1.54. A Horner-Wadsworth-Emmons reaction with dioxinone 1.55 gave triene 1.56.
O O H steps H
3 mol% HGII, CHCl3 BOMO CCl3 65 °C, 10:1 E:Z 38% from 1.52 BOMO CCl3 1.52 1.53 1.54
O O O O O PMBHN P(OEt) O O PMBN O 2 1.55 1.41 1.54 O NaH, THF, 23 °C PPTS, PhMe, 110 °C 79%, >20:1 E:Z 93%
BOMO CCl3 BOMO CCl3 1.56 1.57
O O
PMBN CH2=CHCO2R, 5-7 mol% HGII, CH Cl , 45 °C 1.57 2 2
O BOMO CCl3 OR
1.51a (R = CH3, 89%, E:Z >20:1) 1.51b (R = OtBu Cl O H 64%, >20:1 E:Z)
Scheme 1.14: Completion of Diels-Alder Reaction Substrates8
Amidation of dioxinone 1.56 with amine 1.41 proceeded smoothly. The terminal alkene subsequently underwent olefin metathesis with either methyl acrylate or the acylation product of 1.48 with methyl acrylate. This led to formation of the desired Diels-Alder reaction substrates 1.51a and 1.51b.
18 1.4.3 IMDA Reactions and Synthesis of 1.5
The lanthanide-catalyzed IMDA reaction process was first conducted with precursor
1.51b, which would provide a more convergent approach to the overall synthetic plan
(Scheme 1.15). The Diels-Alder reaction was conducted to afford 1.49b, which underwent reduction and elimination to provide macrolide precursor 1.47b. These alternative conditions (DCC, CuCl)17 were necessary to access the C8-C9 alkene, as the authors state that conditions reported in their previous work12 did not give the α,β- unsaturated amide as was previously believed. It is proposed that the sodium borohydride reduction is stereoselective, and that the C8 hydrogen atom and resulting C9 alcohol have a syn relationship. A method for syn elimination is therefore required, and this can be obtained through a concerted dehydration event. This is in contrast to the previous method, which utilized an E2-type process where the C8 hydrogen and C9 alcohol are best antiperiplanar.
19 O O O H 9 PMBN PMBN 8 1. NaBH4, THF, CH3OH 1.46 (12 mol%) 1.51b –78 °C, 70% 10 mol% La(OTf)3, NEt3 2. DCC, CuCl, PhMe, EtOAc, 45 °C, 110 °C, 80-90% O O BOMO CCl3 61%, dr 3:1 O O BOMO CCl 3 Cl Cl H H O OtBu O OtBu
1.49b 1.47b
O O Cl
PMBN Cl O
Cl Cl PMBN CF CO H, CH Cl 1.59 1.47b 3 2 2 2 23 43b°C Py, PhMe, 0 °C 95% O O HO CCl3 then DMAP, 0 to 23 °C Cl 21 ~30-50% HO O HO CCl3 H O OH 1.60 1.58
Scheme 1.15: Initial Attempts at Completion of Muironolide A8
Exposure of ester 1.47b to trifluoroacetic acid (TFA) cleaved both the benzyloxymethoxyacetal and the tert-butyl ester, yielding 1.58. Attempts at macrolactonization under Yamaguchi conditions18 gave carboxylic acid 1.60, along with recovered starting material and higher order macrolactonization products. One possible explanation for this observation is β-elimination of the C21 ester.
20 O O OH H O H 8 PMBN NaBH4, THF, PMBN 1.46 (12 mol%) CH OH, –78 °C 1.51a 3 10 mol% La(OTf)3, NEt3 then separation by HPLC EtOAc, 45 °C, 73% 61%, dr 3:1 O O BOMO CCl3 O O BOMO CCl3 1.49a 1.61
O O
PMBN PMBN DCC, CuCl, PhMe CF CO H, CH Cl 1.61 3 2 2 2
110 °C, 75% 23 43b°C 95%
O O BOMO CCl3 O O HO 17 CCl3
1.47a 1.62
O
PMBN 1. 1.62, Py, PhMe, 0°C Et3Si O OH 1.59, Py, PhMe, 0 °C then DMAP, 0 to 50 °C, 55% Cl 21 1.5 O then 1.62, DMAP, 0 to 23 °C 2. DDQ, 5 equiv H2O, dioxane H 97% 1 100 °C, 90% R O O OR O CCl3 Cl 1.63 O H
1 1.64: R = SiEt3, R = CH3 LiCl, DMF, µwave 180 °C 1.65: R = R1 = H 81%
Scheme 1.16: Completion of 1.58
Upon observation that lactonization at the C21 hydroxyl was unsuccessful, the researchers decided to close the macrolide at the C17 ester (Scheme 1.16). To achieve this, the IMDA reaction was performed on methyl ester 1.51a, leading to formation of β- keto amide 1.49a. Exposure to identical conditions as seen in Scheme 1.16 ultimately provided alcohol 1.62. This substrate underwent acylation with chlorocyclopropane 1.63, followed by concomitant methyl ester cleavage and desilylation.17 Yamaguchi macrolactonization of the resulting seco acid followed by N-deprotection then afforded
1.5, the originally proposed structure of muironolide A.
21 The 1H and 13C NMR spectroscopic data of product 1.5 were compared to the data from the isolation report,3 and the spectra did not match. There were several significant chemical shift differences in the 13C NMR data of 1.5 compared to the authentic sample of muironolide A, leading the authors to believe the stereochemical assignment was incorrect. Because cyclopropane 1.63 was accessed through an enzymatic resolution, its enantiomer was readily available, and it was then taken through the final four steps in
Scheme 1.16. NMR spectroscopic analysis of the product of that process showed that the
13C NMR data again did not match; however the spectra were significantly better correlated. Seeing that the main differences in chemical shifts were related to the chlorocyclopropyl ketide unit, the C21 epimer of cyclopropane 1.63 was synthesized and similarly converted to the fully elaborated muironolide A core. 1H and 13C NMR spectral analysis showed a conclusive match, however circular dichroism (CD) analysis showed that the synthetic (+)-muironolide A was enantiomeric to the natural product. Thus, the structure of (−)-muironolide A was revised and is illustrated in Figure 1.4.
O 9
HN H
6 4 H 14 25
1 17 O O O CCl3 Cl 21 23 O H 1.66
Figure 1.4: Revised Structure of (−)-Muironolide A8
The work described in the following two chapters was conducted prior to the structural revision reported by Zakarian and co-workers. As such, it should be noted that the
22 stereochemistry of the structures described hereafter would lead to the synthesis of a diastereomer of the natural product. Due to the highly flexible syntheses described, however, these methods could be easily applicable to the synthesis of the revised (−)- muironolide A.
23 Chapter 2: First Generation Synthetic Approach to Muironolide A
This project was initiated in 2009, shortly after the original structure of muironolide A was reported.3 Dr. Isabelle Modolo initiated this research in the Forsyth group at The
Ohio State University. Her seminal contributions set the stage for continued research that is described herein.
2.1 Retrosynthetic Analysis
It was originally planned in 2009 that muironolide A (1.5) could be accessed though a transannular intramolecular Diels-Alder (TAIMDA) reaction of precursor 2.1, followed by alkene isomerization (Scheme 2.1). Cleavage of macrolide 2.1 at the C7 amide and
C17 ester bonds affords two fragments of approximately equal size and complexity— triene 2.2 and acid 2.3. Because it has been observed that macrocyclization through amidation is more facile than esterification,19 it was intended that the amide bond would be formed last. The triene fragment 2.2 would be accessed from a series of Wittig-type reactions beginning with lactone 2.4. Acid 2.3 could be further broken down into diene
2.5 and cyclopropane 2.6. The diene fragment 2.5 would be synthesized from a cross- coupling reaction of the two smaller fragments 2.7 and 2.8, both of which are accessed from propargyl alcohol. Finally, cyclopropane 2.6 could be synthesized from diol 2.9.
24 O O 9 9 amidation HN H 27 HN 27 6 6 4 14 14 25 H 26 26 O 4 1 17 1 17 O O O CCl3 O O CCl3 Cl 21 Cl 21 O 23 O 23 Steglich H H esterification
1.5 2.1
NHFmoc Wittig olefination O 6 O OH Mitsunobu 9 11 reaction O 4 O 17 CCl3 18 Cl 21 CO2H 23 26 27 H Horner-Wadsworth- Emmons olefination 2.2 2.3
NHFmoc OH O 6 O Cl 21 OTBS HO 23 4 H O 14 17 2.5 2.6 Cl3C 2.4
I
Bu3Sn OH FmocHN HO OH 2.7 2.9 2.8
Scheme 2.1: Original Retrosynthesis of Muironolide A
The originally proposed synthetic plan had several attractive features, including a great deal of flexibility in late-stage coupling. For example, macrolide 2.1 can be accessed through either a late-stage amidation or esterification of an acyclic precursor. In addition, it was hypothesized that the isoindolinone core of muironolide A is formed biosynthetically through a TAIMDA reaction of precursor 2.1. As such, this synthetic plan has the potential to provide insight into the biosynthesis of the natural product.
Finally, the high degree of convergency in this route allows for a variety of analog syntheses.
25 2.2 Synthesis of Triene 2.2
The original approach to triene 2.2 began with lactone 2.4 (Scheme 2.2), and was designed and first executed by Dr. Isabelle Modolo. Although 5-hexenoic acid (2.12) is commercially available, our group had previously synthesized this compound due to its high cost (~$61/g), and were utilizing a method that gave low yields and hindered the ability to work on a large scale.20 Alternatively, commercial 5-hexenol (2.10) is much less expensive (<$1/g), and can afford acid 2.12 through a simple two-step oxidation sequence. This involved successive Swern21 and Pinnick22 oxidation reactions.
Converting acid 2.12 to a mixed anhydride in the presence of pivaloyl chloride (PivCl) followed by introduction of oxazolidinone 2.13 provided imide 2.14. Treatment of 2.14 with sodium hexamethyldisilazide (NaHMDS) followed by introduction of methyl iodide provided alkene 2.15,23 which was oxidized to aldehyde 2.16 upon exposure to
24 ozone/triphenylphosphine (PPh3). Trichloromethyl anion addition to the aldehyde of
2.16 was followed by spontaneous lactonization to generate diastereomeric lactones
(2R,5S)-2.17 and (2R,5R)-2.4 in a 1:1 ratio. These lactones could then be separated by tedious column chromatography, and lactone 2.4 was carried forward en route to triene
2.2.
26 O O (COCl)2, DMSO NaClO2, NaH2PO4•H2O OH Et3N, CH2Cl2 H 2-methyl-2-butene OH 2.10 2.11 t-BuOH/H2O 2.12
O O O O O 2.12, PivCl, Et N, THF, N NaHMDS, CH I N O NH 3 O 3 O then 2.13, LiCl THF 42% from 2.10 2.14 77%, 15:1 dr 2.15 2.13 Ph Ph Ph
O O H O O Cl CCO H, Cl CCO Na O3, CH2Cl2 N O 3 2 3 2 O O 2.15 O DMF PPh3 quant. 2.16 65% Cl C Cl C (1:1 mixture 3 3 Ph 2.17 2.4 of diastereomers)
Scheme 2.2: Synthesis of Lactones 2.17 and 2.4
An alternative route to these lactones was also explored, albeit with little success.
Monosilylation of 1,5-pentanediol to a tert-butyldimethylsilyl (TBS) ether, followed by oxidation of the free alcohol provided the carboxylic acid. When 2.12 was replaced with this acid and subjected to an identical reaction sequence, the terminal TBS ether instead of aldehyde 2.16 was afforded.25 This strategy was designed bearing in mind that primary triethylsilyl ethers can undergo a one-step desilylation/oxidation under Swern oxidation conditions.26 When the aforementioned substrate was exposed to oxalyl chloride/DMSO in dichloromethane, only starting material was observed. It is likely that a more labile protecting group, such as triethylsilyl (TES), may be a more successful substrate for this reaction. Alternatively, the TBS ether can be subjected to other conditions to afford an
27 aldehyde, including PDC/trimethylsilyl chloride, or a Bi(OTf)3/TEMPO/hypervalent iodine (III) system.28 This has the potential to allow for the synthesis of 2.4 without use of 5-hexenoic acid, but was not pursued further.
With lactone 2.4 in hand, the synthesis of triene 2.2 began with opening of lactone 2.4 to form Weinreb amide 2.18 (Scheme 2.3). The secondary alcohol of compound 2.18 was
27 immediately silylated in the presence of silver nitrate and tert-butyldimethylsilyl chloride
(TBSCl). Diisobutylaluminum hydride (DIBAL-H) was utilized to reduce the amide to aldehyde 2.20, which was immediately reacted with stabilized ylide 2.21 to generate α,β- unsaturated ester 2.22 in exclusively the E-isomer. While reduction of ester 2.22 to alcohol 2.23 had previously been conducted at 0 °C, some conjugate addition was observed at this temperature. As a result, the temperature of the reaction was lowered to
–78 °C, providing a more consistent result of 1,2-reduction. Following ester conversion to alcohol 2.23, oxidation was performed with manganese dioxide to afford aldehyde
2.24.
O O OH O OTBS HCl•HN(OMe)Me TBSCl, AgNO O O 3 O AlMe3 N CCl3 pyridine, DMF N CCl3 THF 84%, 2 steps Cl3C 2.4 2.18 2.19
PPh3 MeO O OTBS 2.21 O OTBS DIBAL-H, THF O 2.19 - 78 °C H CCl3 toluene O CCl3 84% 92% 2.20 2.22
OTBS H OTBS DIBALH, THF MnO , CH Cl 2.22 2 2 2 - 78 °C HO CCl3 89% O CCl3 92% 2.23 2.24
Scheme 2.3: Synthesis of Aldehyde 2.24
Several different bases were screened for the Horner-Wadsworth-Emmons reaction to convert aldehyde 2.24 to alkene 2.26 (Scheme 2.4). Deprotonation of phosphonate 2.25 at low temperature with lithium hexamethyldisilazide (LiHMDS), followed by treatment with aldehyde 2.24 was performed. Under these conditions, the aldehyde starting material was never fully consumed, which was problematic due to the similarity of Rf values of
28 the starting material and product. Ultimately, treatment of phosphonate with lithium diisopropylamide (LDA), followed by introduction of aldehyde 2.24 provided the desired product 2.26. These conditions were chosen as optimal moving forward due to the >20:1
E/Z selectivity, but this reaction was not further optimized. At this stage, the triene fragment was set aside until the synthesis of acid 2.3 was completed.
O O P(OEt) O O 2 2.25 2.24 O LDA, THF –78 °C 70%, >20:1 E/Z TBSO CCl3 2.26
Scheme 2.4: Horner-Wadsworth-Emmons Reaction of Aldehyde 2.24
While triene fragment 2.2 could be generated from the route in Schemes 2.3 and 2.4, there was some room for improvement. It was observed that the manganese dioxide oxidation provided highly variable yields from the mid-40% to 90% range. This can be attributed to a variety of different factors.29 Such factors include the method of preparation and/or ability of substrate to absorb/desorb from the surface of the oxidant, along with reaction solvent, time, and temperature. As a result, it was important to optimize alternative oxidation conditions moving forward.
2.3 Progress Toward Cyclopropane 2.6
Synthesis of cyclopropane 2.6 began with known alkyne 2.27.30 The alkyne of 2.27 underwent stannylcupration31 performed by Dr. Chao Fang to form vinyl stannane 2.28.
Subsequent reaction of stannane 2.28 with copper (II) chloride provided vinyl chloride
2.29. The hydroxyl-directed cyclopropanation reaction pioneered by Shi32 could then be
29 performed to afford cyclopropane fragment 2.6. The final reaction in this sequence was performed by Charles Clay, and was able to generate fully functionalized cyclopropane fragment 2.6.
OH OH Bu3Sn(Bu)CuCNLi2 CuCl2 OH
OTBS THF Bu3Sn OTBS THF Cl OTBS 2.27 56% 2.28 76% 2.29
OH CF3COOZnCH2I Cl 2.29 OTBS CH2Cl2 51% H 2.6
Scheme 2.5: Efforts Toward Cyclopropane 2.6
An alternative to this sequence is chlorination of alkyne 2.27 followed by Red-Al reduction to give (E)-vinyl chloride 2.29 (Scheme 2.6). The vinyl chloride could then be transformed to cyclopropane 2.6 by identical Shi cyclopropanation conditions. This type of transformation is being further investigated within our group.
n-BuLi, THF OH OH OH –78 °C Red-Al, THF OTBS OTBS then (Cl3C)2 –78 °C Cl OTBS Cl 2.27 72% 2.30 89% 2.29
Scheme 2.6: Alternative Route to Vinyl Chloride 2.29
While the proposed route is successful to afford 2.6, it does have some disadvantages.
The enzymatic resolution early in this synthesis is not ideal because at least half of the material is not used directly. The stannylcupration/chlorination aspect of sequence of this sequence also provided highly variable and unreliable yields, which makes this route less attractive. Finally, it was difficult to separate the tin byproducts generated in the
30 stannylcupration from stannane 2.28. These factors combined forced us to eventually pursue alternative methods to generate fragment 2.6.
2.4 Completion of Diene 2.5
With triene precursor 2.26 in hand and cyclopropane 2.6 well underway, the focus shifted to diene 2.5. This required synthesis of vinyl iodide 2.8, which began from propargyl alcohol (Scheme 2.7). Methylcupration followed by iodination afforded primary alcohol
2.32, which was converted to allylic mesylate 2.33. The crude mesylate was then reacted with sodium azide in dimethyl formamide (DMF) to afford volatile azide 2.34, which was carried forward without isolation. Finally, Staudinger reduction33 followed by precipitation gave the ammonium salt, which was protected as the 9-fluorenylmethyl carbamate (Fmoc) to provide vinyl iodide 2.8. It is worth noting that upon scaling up, this carbamate was often difficult to separate from other impurities introduced in the final protection step.
OH OMs 1. CuI, MeMgBr, Et O MsCl, Et N, DMAP OH 2 3 2. I2 I Et2O I 48%, 2 steps 2.31 2.32 2.33
1. PPh3, H2O, THF, 15 h then HCl(g) N3 NHFmoc NaN3, DMF 44% from 2.32 2.33 12 h, rt I I 2. iPr2NEt, Fmoc-Cl, 90% 2.34 2.8
Scheme 2.7: Completion of Vinyl Iodide 2.8
To move forward with synthesis of diene 2.5, known stannane 2.7 was prepared from propargyl alcohol.34 Subsequent cross-coupling under Stille reaction conditions35
31 afforded diene precursor 2.34, which could be oxidized to the desired carboxylic acid oxidation state of diene 2.5 (Scheme 2.8).
FmocHN
I FmocHN 2.8 Bu3Sn OH 20 mol % Pd(CH3CN)2Cl2 OH 2.7 DMF, 50 °C 2.35 75% Scheme 2.8: Stille Cross-Coupling to Afford Diene Precursor 2.35
One attractive feature to the route in Scheme 2.7 is the minimal use of column chromatography. From alcohol 2.31 to vinyl iodide 2.8, purification is only necessary in the first and final steps. This allows for access to vinyl iodide 2.8, however the necessity to work with volatile intermediates and costly, harmful reagents in the coupling process ultimately caused the exploration of other alternatives.
2.5 Problems with First Generation Route
While each of the three main fragments or their immediate precursors were synthesized according to the previous routes, the original synthetic route required revisions. As mentioned above, a method to access the diene intermediate that does not involve environmentally unfriendly tin reagents was desired. In addition, a more reliable sequence for the vinyl chloride synthesis was needed due to the unreliability of the stannylcupration/chlorination process. In regards to the diene fragment, it would be preferable to avoid the use of costly transition metals, and also to utilize methods that allow for easier purification.
32 Perhaps most instrumental in the synthetic redesign was the work of Molinski and co- workers, which highlighted difficulty with olefin isomerization upon the key IMDA reaction.9
33 Chapter 3: Revised Approach to Muironolide A
3.1 Retrosynthetic Analysis
Research into the literature suggested that a β-keto amide may be a better substrate for the intramolecular Diels-Alder reaction.12,13,36 The retrosynthesis resulting from this realization is illustrated in Scheme 3.1.
intramolecular amidation Diels-Alder O O O O OH 9 reaction 9 HN 9 HN H HN 14 6 6 4 14 6 4 14 H H 25 25 25 17 26 4 O TBSO CCl3 1 17 1 17 1 O O O CCl3 O O HO CCl3 O O 21 21 Cl Cl Cl 21 23 O 23 O H macrolactonization H H O OH 1.5: muironolide A 3.1 3.2
N3 6 Mitsunobu Wittig olefination OH O N O 3 6 O reaction O O OTBS Cl 4 21 19 O 1 14 1 O O 9 17 O O CCl3 H 4 Cl 21 3.5 3.6 23 O HWE H olefination 3.4 3.3
O
O 14 17 Cl3C 2.4
Scheme 3.1: Redesigned Retrosynthesis of Muironolide A
34 It was intended that muironolide A would be afforded from the elimination of a β- hydroxyamide, which could be accessed from reduction of ketone 3.1. The lactonization at C19 could be achieved through a Steiglich esterification or alternatively, a Mitsunobu reaction of the C17 alcohol (Section 3.2). Diels-Alder adduct 3.1 would be produced from precursor 3.2, which is the result of amidation of the ketene derived in situ from dioxinone 3.4 with the amine resulting from Staudinger reduction of azide 3.3. In retrospect, a primary amine at the stage of 3.3 may be prone to undergo an intramolecular
β-addition upon the tethered dienoate. A primary amine derived from the azide of 3.3 is formed after Staudinger reduction33 of the Mitsunobu product37 between the acid derived from ester 3.6 with alcohol 3.5. Once again, the triene fragment would be accessed from lactone 2.4.
Key advantages of this redesigned route are avoiding the difficult alkene isomerization and amide protecting group, as well as alleviating the need for a late-stage alteration of the oxidation state at C19.
3.2 Revised Route to Triene 3.4 and Synthesis of (17S)-3.4
To access triene 3.4, lactone 2.4 was once again converted to aldehyde 2.24 (Scheme
3.2). Horner-Wadsworth-Emmons reaction with the phosphonate anion of 1.55 would generate triene 3.4. This intermediate was utilized for several amidation screenings, which will be discussed in greater detail in Section 3.5.
35 O O O O O O P(OEt) H OTBS O 2 O steps O 1.55 O CCl3 NaH, THF 17 Cl3C 69% TBSO CCl 2.4 2.24 >20:1 E:Z 3 3.4
Scheme 3.2: Generation of Triene 3.4
In addition to the synthesis of dioxinone 3.4, its C17 epimer (17S)-3.4 was also synthesized (Scheme 3.3).
O O OH O OTBS AgNO3, TBSCl, Py HN(OMe)Me•HCl O O O N CCl DMF N CCl AlMe 3 3 17 3 92%, 2 steps Cl C THF 3 3.7 3.8 2.17 O
Ph3P O OTBS O O OTBS OTBS DIBAL-H 2.21 DIBALH 3.8 THF H CCl3 toluene O CCl3 THF, - 78 °C HO CCl3 96%, 2 steps 89% 3.9 3.10 3.11
O O O
P(OEt)2 H OTBS O O O OTBS DMP, NaHCO3 1.51 3.11 17 CH2Cl2 O CCl3 NaH, THF O CCl3 89% 46%, >20:1 E:Z 3.12 (17S)-3.4
Scheme 3.3: Synthesis of (17S)-3.4
This sequence was performed in the event that a Mitsunobu reaction was more practical for the final macrolactonization step. It is widely accepted that the mechanism of the
Mitsunobu reaction involves activation of the alcohol, followed by nucleophilic displacement with an acidic nucleophile.37, 38 It is anticipated that upon desilylation of the
C17 silyl ether, the strongly electron-withdrawing trichloromethyl group at C17 will enhance the electrophilicity of the activated alcohol. As such, the carboxylate anion nucleophile should more readily displace the activated alcohol.
36 3.3 Synthesis of Cyclopropane 3.5
With respect to cyclopropane 3.5, the main goal was to have the C21 configuration set early on. It was recognized that the two ester functional groups of (D)-dimethyl malate
(3.9) could be individually manipulated.39 This would allow for the material-costly enzymatic resolution to be avoided, and would also have the correct oxidation state at
C19.
OH O OH O TBSO O HO acetyl chloride O TBSCl, Im O 21 19 OH MeOH, rt O DMF O O 91% O 0 to 23 °C O 3.13 3.14 87% 3.15
TBSO O DIBAL-H, MgBr •OEt CrCl , CHCl TBSO O 3.15 2 2 H 2 3 O THF, 50 °C CH2Cl2, -78 °C Cl O 55% O 62% 3.16 3.17
OH O TBAF OH O CF CO ZnCH I 3.17 3 2 2 Cl THF O Cl O CH2Cl2 0 to 23 °C 0 to 23 °C H 3.18 3.5
Scheme 3.4: Proposed Synthesis of Cyclopropane 3.5
The synthesis of cyclopropane 3.5 began with conversion of (D)-malic acid to the bis- methyl ester 3.14 (Scheme 3.4). Silylation of the secondary alcohol provided silyl ether
3.15, the desired substrate for selective reduction of the proximal methyl ester. A similar regioselective reduction was reported with the benzyl ether of alcohol 3.14, presumably due to a 5-membered magnesium chelate between the ethereal oxygen and the ester.39
This chelate makes the proximal ester more active to 1,2-reduction by DIBAL-H.
However, being that silyl ethers are poorly coordinating,40 it was unknown if similar regioselectivity would be observed.
37 Upon exposure of ester 3.15 to DIBAL-H in the presence of magnesium bromide diethyl etherate (MgBr2•OEt2), aldehyde 3.16 was afforded, along with the fully reduced diol.
The resulting aldehyde was reacted under Takai olefination conditions41 to yield (E)- vinyl chloride 3.17. Desilylation followed by Shi cyclopropanation would generate cyclopropane 3.5. Forsyth research group members Kedwin Rosa and Charles Clay have successfully completed this sequence to provide the desired target 3.5.
3.4 Completion of Diene 3.6
Synthesis of diene 3.6 gained momentum with the discovery of differentiated diol 3.19 in the literature.42 It is known that alcohol 3.19 can be accessed from commercially available propargyl alcohol 2.31 (Scheme 3.5).42 Alcohol 3.19 was prepared according to literature procedure, and then oxidized to provide volatile aldehyde 3.20. Wittig olefination of aldehyde 3.20 led to formation of acetal 3.22. Methanolysis of the acetal followed by mesylation of the resulting alcohol 3.23 afforded mesylate 3.24, which was reacted with sodium azide to afford the fully elaborated diene fragment 3.6. A one step
Mitsunobu protocol with diphenylphosphorylazide (DPPA), triphenylphosphine (PPh3), and diisopropylazodicarboxylate (DIAD) was also employed,43 however the desired product was inseparable from the byproduct of this reaction under the conditions attempted.
38 THPO THPO steps SO •py, DMSO O HO 3 NEt , CH Cl OH 3 2 2 H 2.31 3.19 3.20
O PPh3 O THPO HO 3.21 O PPTS O 3.20 CH2Cl2 MeOH 75% from 3.14 O 80% O 3.22 3.23
MsO N MsCl, NEt O NaN 3 O 3.23 3 3 DMF O O 3.24 3.6
Scheme 3.5: Completion of Azide 3.6
Several observations were made en route to optimization of diene 3.6. Conversion of alcohol 3.19 to ester 3.22 was attempted under several different conditions. Oxidation by
MnO2 resulted in isomerization of the (Z)-olefin. While a one-step process involving
MnO2 and ylide 3.21 did provide the desired product 3.20, isomerization of the (Z)-olefin was again observed. As a result, Parikh-Doering conditions were used to oxidize the alcohol to aldehyde 3.20, and the resulting aldehyde was directly subjected to the ylide without concentration. This method gave acetal 3.22 in a scalable and reliable manner, and was used moving forward.
3.5 Attempts at Assembly of Muironolide A
With triene fragment 3.4 in hand, the focus shifted to intermediate 3.3, the structure of which is shown in Scheme 3.1. This required that the methyl ester of diene fragment 3.6 be saponified. Exposure to mild saponification conditions (lithium hydroxide•H2O/methanol) only afforded decomposition products, and acid 3.20 was not observed. It is hypothesized that the highly reactive azide functionality caused this decomposition to occur (Scheme 3.6). 39
N N 3 O LiOH•H2O 3 O CH OH O 3 OH 3.6 3.26
Scheme 3.6: Attempts at Saponification of Methyl Ester 3.6
As a result of these observations, alternative methods to introduce the amine functional group were explored. Attempts at SN2 reaction of the allylic mesylate with a variety of amines were unsuccessful. Consequently, alternative Mitsunobu conditions were explored. Hart and co-workers describe the use of tert-butyl [[2-
(trimethylsilyl)ethyl]sulfonyl]carbamate (SES carbamate) as a useful nitrogen source in
Mitsunobu reactions.44 These conditions were used to convert alcohol 3.23 to sulfonamide 3.27 (Scheme 3.7). To prove that the SES group could be cleaved under mild tetra-n-butylammonium fluoride (TBAF) conditions, a small TLC scale reaction was conducted and proceeded smoothly, and it was concluded that carbamate 3.28 could be accessed via this method.
BocHN TBAF O THF 84% O HO Boc(SES)N 3.28 O HN(SES)Boc O DIAD, PPh3 O THF O 3.23 84% 3.27 LiOH•H2O CH3OH Boc(SES)N 55% O OH 3.29
Scheme 3.7: Alternative Dienes 3.28 and 3.29
The carboxylic acid of 3.27 was synthesized by mild hydrolysis of the methyl ester. The acid 3.29 was then subjected to Mitsunobu conditions in the presence of alcohol 3.5
40 (Scheme 3.8). Desired product 3.30 was not observed, but only the product of elimination was detected by mass spectrometry. This result was reiterated in Zakarian’s recently published work.8 Thus the C19 functionality should remain as a protected alcohol, which could be accessed by ester reduction and alcohol protection of 3.5. This is discussed further in Chapter 4.
Boc(SES)N SES(Boc)N O O OH OH O 3.29 O Cl O O Cl 19 O O PPh3, DIAD Cl H THF O H H 3.5 0 to 23 °C 3.31 3.30
Scheme 3.8: Attempted Mitsunobu Coupling of Alcohol 3.5 and Acid 3.29
Additionally, preliminary screening of the amidation conditions was performed (Scheme
3.9). It was proposed that heating carbamate 3.28, dioxinone 3.4 and BHT to reflux in toluene would afford either amide product 3.32, or the IMDA reaction product. Instead, only decomposition of the dioxinone to methyl ketone 3.33 was observed.
BocHN O
O O O O O OTBS 3.28 Boc O OTBS N O CCl3 BHT, toluene CCl3 110 °C 3.4 TBSO CCl3 3.33 O 3.32 O
Scheme 3.9: Attempt at Amidation/IMDA Reaction Sequence of Dioxinone 3.4 with Carbamate 3.28
This decomposition pathway is known to occur due to water intercepting the ketene intermediate followed by decarboxylation, and only occurs when the nucleophile is too
41 weak for amidation to occur.36 This led to the conclusion that a primary or electron-rich secondary amine should be used for amidation under these conditions.
42 Chapter 4: Current Approach and Future Directions
4.1 Current Retrosynthesis
Issues discussed in Section 3.5 necessitated alterations to the diene fragment and coupling strategies. This is detailed in Scheme 4.1. Because it has been demonstrated that polyketide 1.5 is the incorrect structure of the natural product,8 the current route targets macrolide 1.66. The natural product 1.66 was envisioned to come from the macrolactonization at trichloromethyl carbinol of 4.1. Following desilylation of the silyl ethers of macrolide precursor 4.1, lactonization could be achieved under oxidative conditions, and catalyzed by (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and bis- acetoxyiodobenzene (BAIB).45 It is hypothesized that the primary alcohol at C19 will be more readily oxidized than the electron-poor C17 trichloromethylcarbinol. The C19 alcohol would be converted to an aldehyde, which could be intercepted by the trichloromethylcarbinol. This would form a hemiacetal, which could then be further oxidized under the given conditions to yield the desired macrolide.
43
amidation intramolecular O O O Diels-Alder O OH 9 reaction 9 DMBN 9 HN H DMBN 14 6 6 4 14 6 4 14 H H 25 25 25 17 26 4 O TBSO CCl3 1 17 1 17 1 O O O CCl3 O O HO CCl3 O 21 21 Cl Cl Cl 21 23 O oxidative 23 OTBS H macrolactonization H H OH 1.66: muironolide A 4.1 4.2
DMBHN 6 Wittig olefination OH DMBHN O esterification 6 O O O OTBS 4 Cl 1 23 21 OTBS 14 1 O OH O 9 17 CCl3 H 4 Cl 21 4.5 4.6 23 OTBS HWE H olefination 4.4 4.3
O
O 14 17 Cl3C 4.7
Scheme 4.1: Current Retrosynthesis of Muironolide A
It was apparent from the work of Molinski9 and Zakarian8, 12 that a strongly electron donating group, such as (2,4)-dimethoxybenzyl (DMB) or (3,4)-DMB, would be beneficial on the nitrogen atom of intermediate 4.3. This will allow for the nucleophilic nitrogen to engage the ketene generated from thermolysis of dioxinone 3.4, thus generating amide 4.2. Dioxinone 4.4 would be prepared by a method similar to that in
Section 3.2, by beginning from the lactone 4.7. Cyclopropane-containing fragment 4.3 could result from acylation of secondary alcohol 4.5 with acid 4.6. Cyclopropane 4.5 could be generated from methods used to product intermediate 3.5 (Scheme 3.8) by
44 instead beginning with (L)-malic acid. Finally, diene 4.6 could be accessed from functional group manipulations of alcohol 3.23.
4.2 Cyclopropane 4.5
Synthesis of cyclopropane 4.5 could be achieved by using (L)-malic acid as a starting material for the transformations depicted in Scheme 3.4. Similar functional group manipulations could afford cyclopropane 4.8. Reduction of the C19 methyl ester to the corresponding alcohol followed by desilylation could afford diol 4.9 (Scheme 4.2).
Regioselective monosilylation would provide the desired cyclopropane fragment 4.5.
OH O OH TBSCl, Im, OH DIBAL-H DMAP Cl Cl Cl 21 O OH 23 OTBS H H H 4.8 4.9 4.5
Scheme 4.2: Second Generation Synthesis of Cyclopropane 4.5
An alternative to this process is currently being explored with some success, albeit on the enantiomer of the desired target (Scheme 4.3). Conversion of aldehyde 3.16 to a geminal dichloroolefin46 followed by protecting group manipulations provides alcohol 4.11. Base- generated elimination of hydrogen chloride affords chloroalkyne 4.12.47
45 1. PPh , CCl TBSO O 3 4 TBS CH Cl Cl OH H 2 2 Cl O 1. TBAF, THF O 2. DIBAL-H, CH2Cl2 2. TBSCl, Py, CH2Cl2 Cl OTBS O Cl OH –78 to 25 oC 3.16 4.10 4.11
OH LiHMDS, THF Red-Al, THF OH 4.11 OTBS 0 to 25 °C –78 to 25 oC Cl OTBS Cl 4.12 2.29
steps OH 2.29 Cl OTBS H 2.6
Scheme 4.3: Proposed Route to ent-4.5
In the presence of sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al), the alkyne
4.12 can be reduced to provide exclusively the (E)-vinyl chloride 2.29.48 This substrate may be subjected to Shi cyclopropanation conditions to afford cyclopropane 2.6. By beginning with (L)-malic acid, the desired cyclopropane 4.5 could be accessed.
4.3 Efforts Toward Diene 4.4
Small changes were required to the previously utilized route in order to access diene 4.6.
It was recognized that alcohol 3.23 could act as a precursor to an aldehyde substrate for a reductive amination with the desired amine. Initial attempts for this process can be found in Scheme 4.4.
O NH2 HO H O O 4.14 DMBHN O SO3•py, DMSO O O NEt3, CH2Cl2 O O NaBH(OAc)3 O 3.23 4.13 4.15 DMB N O O 4.16
Scheme 4.4: Proposed Reductive Amination
46
With alcohol 3.23 in hand, Parikh-Doëring oxidation was carried out to generate unsaturated aldehyde 4.13. Reductive amination was performed under mild conditions49 with the intent of gaining access to amine 4.15. Although thin-layer chromatography analysis showed essentially spot to spot conversion, further study of the 1H NMR spectrum suggests formation of pyrrole 4.16. This may occur due to the strong nucleophilicity of the (3,4)-DMB amine. Presumably, the desired product is indeed formed, but then undergoes amine 1,4-conjugate addition onto the β-position of the unsaturated ester. A series of deprotonation/reprotonation sequences would allow for aromatization to occur. Additional data are currently being collected in order to confirm this hypothesis.
It is hypothesized that altering the oxidation state of the ester of acetal 3.22 may allow this process to be circumvented (Scheme 4.5). Reduction of the methyl ester followed by protection of the primary allylic alcohol of alcohol could afford protected diol 4.17.
Protecting group manipulations could provide allylic alcohol 4.18, which could be oxidized and then exposed to reductive amination conditions. This would provide a useful diene precursor that could be later oxidized at C1 for further elaboration.
THPO THPO PPTS HO O 1. LiAlH4, THF 2. + PG CH3OH O OPG OPG 3.22 4.17 4.18
O NH2 H O DMBHN SO3•py, DMSO O 4.14 4.18 NEt , CH Cl 3 2 2 1 OPG NaBH(OAc)3 OPG 4.19 4.20
Scheme 4.5: Proposed Method to Access Diene Precursor 4.20
47 4.4 Future Directions
This project has several goals moving forward. First and foremost, we strive to complete the total synthesis of muironolide A employing an intramolecular Diels-Alder reaction.
Once that has been accomplished, both structural and stereochemical analogs of the natural product will be synthesized. This will allow for the biological profile of muironolide A to be fully assessed, and may also provide new information into the relationship between the structure of the natural product and its biological activity. Based on that information, new targets may be designed to further improve the biological properties of muironolide A.
48 Chapter 5: Experimental Section
General Methods.
All reactions were carried out under argon atmosphere in oven-dried glassware using standard syringe, cannula, and septa techniques, unless otherwise noted. All commercial reagents were purchased as reagent grade and used without further purification. Organic solvents, such as tetrahydrofuran (THF), diethyl ether (Et2O), dichloromethane (CH2Cl2), toluene, and dimethyl formamide (DMF), were obtained from an Innovative Technology
PureSolvMD solvent system and presumed to be dry. Dimethyl sulfoxide (DMSO) was stored over freshly activated molecular sieves, and triethylamine, diisopropylethylamine, diisopropylamine, and pyridine were freshly distilled from CaH2. Methanol was distilled from magnesium prior to use. Solutions of diisobutylaluminum hydride (DIBAL-H), trimethylaluminum (TMA), methyllithium (CH3Li), and n-butyllithium (n-BuLi) were purchased from Sigma Aldrich. Lipase AK Amano was received from Amano Enzyme
Co. as a gift. Flash chromatography was performed using SiliaFlash® P60 (40-63 µm) and the indicated solvent systems. Thin-layer chromatography was performed using
Silicycle Glass Backed TLC Extra Hard Layer 60Å, 250 µm, F-254 TLC plates, and was visualized with UV light (254 nm), or p-anisaldehyde and potassium permanganate stains. Reactions were typically stirred continuously using Teflon coated magnetic stir
49 bars in round-bottom borosilicate glass flasks. Melting points were measured using a
Mel-Temp II apparatus. Optical rotations were measured at 589 nm with a Perkin-Elmer
Model 241 Polarimeter with a sodium lamp, and concentrations are reported in g/100 mL.
A Shimadzu IRAffinity-1 FT-IR spectrophotometer was used to record infrared spectral data, and absorptions are reported in cm-1. All IR spectra were obtained using a solution cell and solutions were prepared in dichloromethane, unless otherwise noted. Proton (1H) and carbon (13C) Nuclear Magnetic Resonance (NMR) spectra were obtained using
Bruker AVIII-400 and AVIII-600 NMR spectrometers. Residual solvent peak signals for
1 13 CHCl3 were set at 7.26 ppm in the H NMR and 77.16 ppm in the C NMR spectra, respectively. High-resolutions mass spectrometric data were obtained using a Bruker
MicroTOF (ESI) Mass Spectrometer in positive ion mode.
50 O O N O
Ph
(R)-4-Benzyl-3-(hex-5-enoyl)oxazolidin-2-one (2.14).
A solution of 5-hexenoic acid (1.7 g, 14 mmol) and Et3N (5.3 mL, 38 mmol) in THF (75 mL) was cooled to −10 °C. Pivaloyl chloride (1.8 mL, 15 mmol) was added dropwise over 5 min and the reaction was allowed to stir for 1 h. (R)-4-Benzyl-2-oxazolidinone
(2.51 g, 14.9 mmol) and LiCl (691.4 mg, 16.31 mmol) were added and the ice bath was removed. The reaction was stirred for 12 h at 23 °C, at which point it was quenched with saturated aqueous NaHCO3 (25 mL) and diluted with ethyl acetate (75 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (3 x 10 mL).
Combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (7:1 hexanes/ethyl acetate) to give 2.14 (3.6743 g, 13.452 mmol, 90%) as a colorless oil, with
50 NMR data that correlates to previously reported data. Rf 0.33 (7:1 hexanes/ethyl
1 acetate); H NMR (CDCl3, 600 MHz) δ 1.81 (m, 2H), 2.16 (m, 2H), 2.76 (dd, J = 9.7,
13.3 Hz, 1H), 2.95 (m, 2H), 3.30 (dd, J = 3.2, 12.4 Hz, 1H), 4.18 (m, 2H), 4.67 (m, 1H),
5.00 (m, 1H), 5.06 (m, 1H), 5.82 (m, 1H), 7.21 (m, 2H), 7.28 (m, 1H), 7.35 (m, 2H);
+ + HRMS (ESI) calcd for C16H19NNaO3 m/z 296.1257 [M+Na ], found m/z 296.1252.
51 O O N O
Ph
(R)-4-Benzyl-3-((R)-2-methylhex-5-enoyl)oxazolidin-2-one (2.15).
A solution of acylated oxazolidinone 2.14 (3.77 g, 13.8 mmol) in THF (20 mL) was added dropwise to NaHMDS (1 M in THF, 20.7 mL, 20.7 mmol) at −78 °C. The reaction was stirred for 1.5 h at −78°C, followed by dropwise addition of methyl iodide (4.3 mL,
68.9 mmol). After 1 h, the reaction was quenched with saturated aqueous NH4Cl (25 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 x 10 mL). Combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (6:1 hexanes/ethyl acetate) to give 2.15 (3.37 g, 11.7 mmol, 85%) as a
50 20 1 colorless oil. Rf 0.49 (5:1 hexanes/ethyl acetate); [α] D −71.3° (c 1.40, CHCl3); H
NMR (CDCl3, 400 MHz) δ 1.23 (d, J = 6.9 Hz, 3H), 1.51 (m, 1H), 1.88 (m, 1H), 2.06-
2.11 (m, 2H), 2.77 (dd, J = 9.6, 13.4 Hz, 1H), 3.26 (dd, J = 3.2, 13.3 Hz, 1H), 3.73 (sex, J
= 6.9 Hz, 1H), 4.16-4.20 (m, 2H), 4.67 (m, 1H), 4.95 (m, 1H), 5.00 (dq J = 1.7 Hz, 17.1
Hz, 1H), 5.79 (m, 1H), 7.22 (m, 2H), 7.28-7.35 (m, 3H); HRMS (ESI) calcd for
+ + C17H21NNaO3 m/z 310.1414 [M+Na ], found m/z 310.1410.
52 O O H N O O
Ph
(R)-5-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-4-methyl-5-oxopentanal (2.16).
A solution of alkene 2.15 (3.12 g, 10.9 mmol) in CH2Cl2 (360 mL) was prepared and cooled to − 78 °C. Ozone was bubbled through until the solution turned a deep blue, at which point Ar was bubbled through until the blue color disappeared.
Triphenylphosphine (5.6960 g, 21.716 mmol) was then added and the reaction was allowed to warm to 23 °C and stirred 12 h. Saturated aqueous NaHCO3 (300 mL) was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2
(5 x 25 mL) and combined extracts were dried over Na2SO4, filtered, and concentrated to a yellow solid. This was dissolved in toluene and purified by flash column chromatography (10:1→1:1 hexanes/ethyl acetate) to give 2.16 (3.14 g, 10.9 mmol,
20 quant.). Rf 0.29 (3:1 hexanes/ethyl acetate); [α] D −15.9° (c 1.41, CHCl3); IR (NaCl)
-1 1 cm 1389, 1705, 1782, 2932, 2986, 3032, 3055; H NMR (CDCl3, 400 MHz) δ 1.30 (d, J
= 6.9 Hz, 3H), 1.87 (m, 1H), 2.12 (m, 1H), 2.55 (td, J = 1.4, 7.4 Hz, 2H), 2.82 (dd, J =
9.5, 13.4 Hz, 2H), 3.79 (sex, J = 6.8 Hz, 1H), 4.21-4.31 (m, 2H), 4.72 (m, 1H), 7.24-7.40
13 (m, 5H), 9.80 (t, J = 1.4 Hz, 1H); C NMR (CDCl3, 400 MHz) δ 17.53, 25.50, 37.28,
38.11, 41.61, 55.42, 66.35, 127.55, 129.11, 129.57, 135.36, 153.36, 176.46, 201.58;
+ + HRMS (ESI) calcd for C16H19NNaO4 m/z 312.1206 [M+Na ], found m/z 312.1217.
53 O O
O O
Cl3C Cl3C
(3R,6R)-3-Methyl-6-(trichloromethyl)tetrahydro-2H-pyran-2-one (2.4) and (3R,6S)-
3-methyl-6-(trichloromethyl)tetrahydro-2H-pyran-2-one (2.17)
A solution of aldehyde 2.16 (3.0756 g, 10.742 mmol) in DMF (15.5 mL) was prepared and cooled to 0 °C. Trichloroacetic acid (2.4572 g, 15.038 mmol) was added and the reaction stirred for 1 min, followed by addition of sodium trichloroacetate (2.7881 g,
15.038 mmol). The ice bath was removed and the reaction stirred for 2 h at 23 °C, at which point it was quenched with water (15 mL) and diluted with Et2O (25 mL). The organic phase was separated and the aqueous phase extracted with Et2O (5 x 10 mL).
Combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated to a yellow oil. The crude product was purified by flash column chromatography (10:1 hexanes/ethyl acetate) to give 2.4 (793.2 mg, 3.426 mmol, 32%), and 2.17 (649.0 mg, 2.803 mmol, 26%), both as white solids. (3R,6R)-2.4: mp 48.5 °C; Rf
20 -1 0.32 (5:1 hexanes/ethyl acetate); [α] D −47° (c 1.72, CHCl3); IR (NaCl) cm 1173,
1 1759, 2878, 2947, 2978; H NMR (CDCl3, 400 MHz) δ 1.29 (d, J = 6.8 Hz, 3H), 1.71 (m,
1H), 2.02-2.22 (m, 2H), 2.43 (m, 1H), 2.67 (m, 1H). 4.74 (dd, J = 4.1, 10.6 Hz, 1H); 13C
NMR (CDCl3, 400 MHz) δ 16.42, 22.64, 24.82, 33.46, 85.64, 98.63, 172.93; HRMS
+ + (ESI) calcd for C7H9Cl3NaO2 m/z 252.9560 [M+Na ], found m/z 252.9568; (3R,6S)-
20 2.17: mp 74.2 °C; Rf 0.36 (5:1 hexanes/ethyl acetate); [α] D +6.6° (c 1.23, CHCl3); IR
-1 1 (NaCl) cm 1165, 1751, 2878, 2940, 2970; H NMR (CDCl3, 400 MHz) δ 1.32 (d, J =
7.0 Hz, 3H), 1.64 (m, 1H), 1.95 (m, 1H), 2.10 (m, 1H), 2.45-2.55 (m, 2H). 4.78 (dd, J =
13 4.5, 11.0 Hz, 1H); C NMR (CDCl3, 400 MHz) δ 17.08, 25.30, 26.81, 36.13, 87.72,
54 + + 99.46, 171.84; HRMS (ESI) calcd for C7H9Cl3NaO2 m/z 252.9560 [M+Na ], found m/z
252.9563.
55 O OTBS O N CCl3
(2R,5R)-5-((tert-Butyldimethylsilyl)oxy)-6,6,6-trichloro-N-methoxy-N,2- dimethylhexanamide (2.19).
N,O-Dimethylhydroxylamine hydrochloride (385.6 mg, 3.953 mmol) in THF (7.2 mL) was cooled to 0 °C. Trimethylaluminum (2 M in hexanes, 2.0 mL, 4.0 mmol) was added dropwise over 5 min before the solution was warmed to 23 °C and stirred for 20 min. The solution was then cooled to 0 °C with dropwise addition of the lactone 2.4 (305.0 mg,
1.318 mmol) in THF (6.5 mL) over 5 min. The reaction was warmed to 23 °C and stirred for 1 h, at which time it was cooled to 0 °C and quenched very carefully with pH 7 aqueous phosphate buffer (15 mL). The mixture was then diluted with CH2Cl2 (25 mL) and stirred for 1 h, followed by extraction with CH2Cl2. Combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated to provide (2R,5R)-5-
(hydroxy)-6,6,6-trichloro-N-methoxy-N,2-dimethylhexanamide (2.18) as a colorless oil, which was taken directly forward to the next transformation. Rf 0.41 (1:1 hexanes/ethyl acetate).
Crude alcohol 2.18 (ca. 1.3175 mmol) was dissolved in DMF (4.4 mL). Pyridine (85 µL,
11 mmol) was added to the 23 °C solution, followed by AgNO3 (895.0 mg, 5.270 mmol).
The reaction mixture was stirred at 23 °C until the AgNO3 dissolved, followed by addition of tert-butyldimethylsilyl chloride (724.3 mg, 5.270 mmol). The flask was covered in aluminum foil and allowed to stir at 23 °C for 24 h. Following dilution with
Et2O (10 mL), the reaction mixture was filtered through Celite. The filtrate was washed with water (25 mL) and the resulting aqueous layer extracted with Et2O (5 x 10 mL).
56 Combined organic fractions were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (5:1—1:2 hexanes/ethyl acetate) to give of 2.19 (407.5 mg, 1.002 mmol, 76% from lactone 2.4) as a
20 colorless oil. Rf 0.41 (5:1 hexanes/ethyl acetate); [α] D +9.5° (c 1.16, CHCl3); IR (NaCl)
-1 1 cm 787, 1389, 1651, 2862, 2940; H NMR (CDCl3, 400 MHz) δ 0.15 (s, 3H), 0.17 (s,
3H), 0.92 (s, 9H), 1.13 (d, J = 6.9 Hz, 3H), 1.71 (m, 3H), 2.00 (m, 1H), 2.84 (m, 1H),
13 3.17 (s, 3H), 3.68 (s, 3H), 4.02 (m, 1H); C NMR (CDCl3, 400 MHz) δ −3.93, −3.30,
17.50, 18.57, 26.13, 30.73, 32.19, 35.59, 61.59, 84.13, 103.92, 177.37; HRMS (ESI)
+ + calcd for C15H30Cl3NNaO3Si m/z 428.0953 [M+Na ], found m/z 428.0941.
57 O OTBS
O CCl3
(4R,7R,E)-Methyl 7-((tert-butyldimethylsilyl)oxy)-8,8,8-trichloro-2,4-dimethyloct-2- enoate (2.22).
A solution of amide 2.19 (457.2 mg, 1.124 mmol) in THF (28 mL) was prepared and cooled to − 78 °C. DIBAL-H (1 M in toluene, 4.5 mL, 4.5 mmol) was added dropwise over 45 min. The reaction was then allowed to stir for 2.5 h at − 78 °C. Acetone (5 mL) was then added, followed by aqueous sodium potassium tartrate (Rochelle’s salt, 30 mL) and CH2Cl2 (30 mL). The resulting mixture was stirred 1 h at 23 °C, followed by extraction with CH2Cl2 (5 x 10 mL). Combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude aldehyde (4R,7R,E)-7-((tert- butyldimethylsilyl)oxy)-8,8,8-trichloro-2,4-dimethyloct-2-enal 2.20 was taken forward directly to the subsequent transformation. Rf 0.51 (10:1 hexanes/ethyl acetate).
Crude aldehyde 2.20 (ca. 1.1238 mmol) was dissolved in toluene (5.6 mL). To this 23 °C solution was added (carbethoxyethylidene)triphenylphosphorane (2.1598 g, 5.6190 mmol). The reaction was stirred for 12 h at 23 °C, followed by concentration and purification by flash column chromatography (10:1 hexanes/ethyl acetate) to give 2.22
(431.6 mg, 1.033 mmol, 92% from 2.19) as a colorless oil. Rf 0.34 (20:1 hexanes/ethyl
20 -1 acetate); [α] D +7.1° (c 1.53, CHCl3); IR (NaCl) cm 787, 1288, 1713, 2862, 3048,
1 3063; H NMR (CDCl3, 400 MHz) δ 0.14 (s, 3H), 0.18 (s, 3H), 0.94 (s, 9H), 1.03 (d, J =
6.6 Hz, 3H), 1.43 (m, 1H), 1.70 (m, 2H), 1.85 (d, J = 1.3 Hz, 3H), 1.98 (m, 1H), 2.48 (m,
1H), 3.74 (s, 3H), 4.02 (dd, J = 2.9, 6.7 Hz, 1H), 6.54 (dd, J = 1.3, 10.0 Hz, 2H); 13C
NMR (CDCl3, 400 MHz) δ −3.91, −3.39, 12.76, 18.58, 19.94, 26.12, 32.28, 33.52, 33.61,
58 + 51.85, 84.10, 103.87, 126.98, 147.26, 168.82; HRMS (ESI) calcd for C17H31Cl3NaO3Si m/z 439.1000 [M+Na+], found m/z 439.0962.
59 OTBS
HO CCl3
(4R,7R,E)-7-((tert-Butyldimethylsilyl)oxy)-8,8,8-trichloro-2,4-dimethyloct-2-en-1-ol
(2.23).
A solution of ester 2.22 (100.0 mg, 239.0 µmol) in CH2Cl2 (1 mL) was prepared and cooled to −78 °C. DIBAL-H (1 M in toluene, 500 µL, 500 µmol) was then added dropwise and the reaction mixture was allowed to stir 1 h at −78 °C. Acetone (1 mL) was added and the reaction mixture was stirred for 5 min. Rochelle’s salt (sat’d aq, 5 mL) and
CH2Cl2 (5 mL) were then added and the reaction mixture was stirred until two clear layers had formed. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (5 x 5 mL). Combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (5:1 hexanes/ethyl acetate) to give 2.23 (89.0 mg, 228 µmol, 96%) as a
20 colorless oil. Rf 0.48 (15:1 hexanes/ethyl acetate); [α] D +19° (c 0.70, CHCl3); IR (NaCl)
-1 1 cm 787, 1134, 1381, 2862, 2932, 3603; H NMR (CDCl3, 600 MHz) 0.14 (s, 3H), 0.19
(s, 3H), 0.94 (s, 9H), 0.98 (d, J = 6.7 Hz, 3H), 1.23 (t, J = 6.1 Hz, 1H), 1.33 (m, 1H),
1.60-1.70 (m, 5H), 2.02 (m, 1H), 2.37 (m, 1H), 4.01 (m, 3H), 5.19 (dd, J = 1.2, 9.5 Hz,
13 1H); C NMR (CDCl3, 400 MHz) δ −3.90, −3.35, 14.08, 18.60, 20.93, 26.13, 32.30,
32.45, 34.37, 69.05, 84.34, 104.07, 131.95, 134.23; HRMS (ESI) calcd for
+ + C16H31Cl3NaO2Si m/z 411.1051 [M+Na ], found m/z 411.1029.
60 O OTBS
H CCl3
(4R,7R,E)-7-((tert-Butyldimethylsilyl)oxy)-8,8,8-trichloro-2,4-dimethyloct-2-enal
(2.24).
A solution of alcohol 2.23 (299.8 mg, 769.0 µmol) in CH2Cl2 (7.7 mL) was prepared and cooled to 0 °C. NaHCO3 (129.2 mg, 1.538 mmol) was added, followed by Dess-Martin periodinane (489.0 mg, 1.153 mmol). The reaction was allowed to warm to 23 °C and stirred 1 h. The reaction mixture was diluted with CH2Cl2 (10 mL), saturated aqueous
Na2S2O3 (10 mL) and saturated aqueous NaHCO3 (10 mL) were added. After 15 min of stirring, the organic layer was separated and the aqueous layer extracted with CH2Cl2 (5 x
5 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. The resulting crude product was purified by flash column chromatography (20:1 hexanes/ethyl acetate) to give 2.24 (276.5 mg, 712.9 µmol, 93%) as a colorless oil. Rf
20 -1 0.44 (10:1 hexanes/ethyl acetate); [α] D +25.2° (c 3.27, CHCl3); IR (NaCl) cm 779,
1 1134, 1682, 2986, 3048, 3063; H NMR (CDCl3, 600 MHz) δ 0.13 (s, 3H), 0.18 (s, 3H),
0.93 (s, 9H), 1.10 (d, J = 6.7 Hz, 3H), 1.48 (m, 1H), 1.72-1.79 (m, 5H), 1.98 (m, 1H),
2.68 (m, 1H), 4.03 (dd, J = 3.1, 6.7 Hz, 1H), 6.24 (dd, J = 1.3, 9.9 Hz, 1H), 9.40 (s, 1H);
13 C NMR (CDCl3, 600 MHz) δ −3.91, −3.39, 9.60, 18.54, 19.76, 26.07, 32.16, 33.31,
+ 33.83, 83.91, 103.70, 138.61, 159.06, 195.43; HRMS (ESI) calcd for C16H29Cl3NaO2Si m/z 409.0895 [M+Na+], found m/z 409.0876.
61 O OTBS
O CCl3
(2E,4E,6E,8R,11R)-Methyl 11-((tert-butyldimethylsilyl)oxy)-12,12,12-trichloro-6,8- dimethyldodeca-2,4,6-trienoate (2.26)
A solution of i-Pr2NEt (20 µL, 0.20 mmol) in THF (1.6 mL) was prepared at 0 °C. n-
BuLi (2.5 M in hexanes, 50 µL, 0.13 mmol) was added dropwise and the reaction was stirred for 10 min at 0 °C, then cooled to −78 °C. A solution of trans-triethyl 4- phosphonocrotonate (32.8 mg, 139 µmol) in THF (280 µL) was then added dropwise, resulting in a yellow color. The reaction mixture was stirred for 5 min, followed by dropwise addition of aldehyde 2.24 (24.5 mg, 63.2 µmol) in THF (630 µL). The reaction was warmed to 0 °C and stirred for 4.5 h before being quenched with saturated aqueous
NH4Cl (0.5 mL). The organic layer was separated, and the aqueous extracted with ethyl acetate (5 x 5 mL). Combined organic extracts were dried (MgSO4), filtered, and concentrated. Following flash column chromatography (15:1 hexanes/ethyl acetate), 2.26 was isolated (20.7 mg, 44.0 µmol, 70%) as a colorless oil. Rf 0.48 (10:1 hexanes/ethyl
20 acetate); [α] D −2.5° (c 1.66, CHCl3); IR (NaCl) 1334, 1427, 1613, 1705, 2862, 2963,
-1 1 2989 cm ; H NMR (CDCl3, 600 MHz) δ 0.14 (s, 3H), 0.18 (s, 3H), 0.94 (s, 9H), 1.02 (d,
J = 6.7 Hz, 3H), 1.39 (m, 1H), 1.64-1.73 (m, 2H), 1.80 (d, J = 1.1 Hz, 3H), 2.00 (m, 1H),
2.51 (m, 1H), 3.75 (s, 3H), 4.01 (dd, J = 2.9, 6.8 Hz, 1H), 5.48 (d, J = 9.7 Hz, 1H), 5.88
(d, J = 15.2 Hz, 1H), 6.25 (dd, J = 11.2, 15.2 Hz, 1H), 6.56 (d, J = 15.2 Hz, 1H), 7.34 (dd,
13 J = 11.1, 15.3 Hz, 1H); C NMR (CDCl3, 600 MHz) δ −3.91, −3.36, 12.73, 18.58, 20.69,
26.12, 32.32, 33.44, 34.13, 51.60, 84.16, 103.92, 119.56, 124.32, 133.07, 143.89, 145.68,
62 + + 146.20, 167.87; HRMS (ESI) calcd for C21H35Cl3NaO3Si m/z 491.1313 [M+Na ], found m/z 491.1304.
63 OH
OTBS
(R)-5-((tert-Butyldimethylsilyl)oxy)pent-1-yn-3-ol (2.27).
To a solution of racemic alcohol 5-((tert-butyldimethylsilyl)oxy)pent-1-yn-3-ol51 (1.290 g, 6.017 mmol) in hexanes (50 mL) was added 1.5 g of 4 Å molecular sieves. Vinyl acetate (3.33 mL, 36.1 mmol) was added, followed by lipase AK amano (1.290 g). The reaction was stirred for 48 h at 23 °C, at which point 1H NMR analysis showed a 1:1 mixture of acetate:alcohol. The lipase was filtered off and washed several times with hexanes (5 x 10 mL). The filtrate was concentrated and purified by flash column chromatography (10:1 hexanes/ethyl acetate) to give 2.27 (0.4631 g, 2.160, 36%) as a
30 20 1 colorless oil. Rf 0.32 (8:1 hexanes/ethyl acetate); [α] D +14.8° (c 1.59, CHCl3); H
NMR (CDCl3, 400 MHz) δ 0.09 (d, J = 3.1 Hz, 6H), 0.90 (s, 9H), 1.83-1.91 (m, 1H),
1.98-2.06 (m, 1H), 2.46 (d, J = 2.2 Hz, 1H), 3.47 (d, J = 6.1 Hz, 1H), 3.84 (m, 1H), 4.06
13 (m, 1H), 4.62 (m, 1H); C NMR (CDCl3, 400 MHz) δ −5.39, 18.31, 26.00, 38.70, 61.14,
+ + 61.88, 72.93, 84.64; HRMS (ESI) calcd for C11H22NaO2Si m/z 237.1281 [M+Na ], found m/z 237.1281.
64 OH
Bu3Sn OTBS
(R,E)-5-((tert-Butyldimethylsilyl)oxy)-1-(tributylstannyl)pent-1-en-3-ol (2.28).
To a stirred suspension of CuCN (125 mg, 1.40 mmol) in THF (1.4 mL) at −42 °C was added n–BuLi (2.4 M in hexanes, 1.16 mL, 2.79 mmol) dropwise. The reaction mixture was stirred for 15 min at −42 °C, followed by dropwise addition of n-Bu3SnH (750 µL,
2.8 mmol). After 20 min, the reaction was cooled to −78 °C with dropwise addition of alkyne 2.27 (200 mg, 930 µmol) in THF (1.86 mL). The suspension was stirred at −78 °C for 1 h, then quenched with saturated aqueous ammonium chloride (2 mL) and warmed to
23 °C. Following dilution with ethyl acetate (5 mL), the organic and aqueous layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude stannane was purified by flash column chromatography (100:2 hexanes/ethyl acetate—100:1—30:1) to give 2.28 (263.8 mg, 521.9 µmol, 56%) as a colorless oil.* Rf
20 0.47 (hexanes-ethyl acetate, 10:1, v/v); [α] D +2.7° (c 5.6, CHCl3); IR (neat): 3448,
-1 1 2955, 2927, 2856, 1602, 1464, 1378, 1176, 1096 cm ; H NMR (CDCl3, 500 MHz): δ
6.20 (dd, J = 1.0, 19.0 Hz, 1H), 6.02 (dd, J = 5.0, 19.5 Hz, 1H), 4.32 (m, 1H), 3.87 (m,
1H), 3.80 (m, 1H), 3.22 (d, J = 4.0 Hz, 1H), 1.80 (m, 1H), 1.73 (m, 1H), 1.48 (m, 6H),
13 1.31 (m, 6H), 0.90 (m, 24H), 0.07 (s, 3H), 0.07 (s, 3H); C NMR (CDCl3, 125 MHz): δ
150.5, 127.3, 74.8, 62.1, 38.5, 29.4, 29.3, 27.7, 27.5, 26.1, 18.3, 13.9, 9.6, −5.4, −5.4;
+ HRMS (ESI+) calcd for C23H50NaO2SiSn (M+Na) 529.2498, found 529.2485.
*Data obtained by Dr. Chao Fang 2013, The Ohio State University
65 OH
Cl OTBS (R,E)-5-((tert-Butyldimethylsilyl)oxy)-1-chloropent-1-en-3-ol (2.29).
Method A: A solution of stannane 2.28 (263.8 mg, 522.0 µmol) in THF (5 mL) was added to a suspension of CuCl2 (281 mg, 2.09 mmol) in THF (1.75 mL). The reaction was allowed to stir 1.5 h at 23 °C before it was quenched with saturated aqueous sodium bicarbonate (5 mL), then diluted with ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (5 x 10 mL). Combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The resulting yellow oil was purified by flash column chromatography (50:1 hexanes/ethyl acetate—30:1—5:1) to afford 2.29 (100 mg, 399 µmol, 76%) as a colorless oil. Rf 0.46 (5:1 hexanes/ethyl
20 -1 acetate); [α] D +2.4 (c 1.13, CHCl3); IR (NaCl) cm 841, 903, 1180, 2862, 3048, 3063,
1 3472, 3603; H NMR (CDCl3, 400 MHz) δ 0.08 (s, 6H), 0.90 (s, 9H), 1.69-1.83 (m, 2H),
3.56 (d, J = 3.2 Hz, 1H), 3.81 (m, 1H), 3.90 (m, 1H), 4.42 (m, 1H), 5.97 (dd, J = 5.7, 13.2
13 Hz, 1H), 6.27 (dd, J = 1.5, 13.2 Hz, 1H); C NMR (CDCl3, 400 MHz) δ −5.43, −5.40,
18.26, 25.98, 38.29, 61.97, 71.09, 119.46, 135.80; HRMS (ESI) calcd for
+ + C11H23ClNaO2Si m/z 273.1048 [M+Na ], found m/z 273.1047.
Method B: A solution of alkyne 2.27 (84 mg, 0.34 mmol) in ether (850 µL) was prepared and cooled to 0 °C. A solution of Red-Al (60 wt% in toluene, 260 µL, 777 µmol) in Et2O
(1 mL) was added dropwise, and the reaction was stirred for 3 h at 0 °C. The reaction was quenched with 10% aqueous NaOH until gas evolution ceased. Following dilution with
Et2O (5 mL), the suspension was stirred until two layers formed. Immediate extraction
66 with Et2O (5 x 1 mL) was followed by drying (Na2SO4), filtering, and concentrating. The resulting crude product was purified by flash column chromatography (5:1 hexanes/ethyl acetate) to provide vinyl chloride 2.29 (75.5 mg, 89%) as a colorless oil. Data obtained for this compound matched those that were reported above.
67 I
HO
(Z)-3-Iodo-2-methylprop-2-en-1-ol (2.32).
The iodide was prepared according to the literature.52 A suspension of CuI (170.0 mg,
891.9 µmol) and propargyl alcohol (500 µL, 9 mmol) in THF (14.9 mL) was prepared and cooled to − 5 °C. CH3MgBr (3 M in ether, 8.9 mL, 27 mmol) was added dropwise and the reaction was stirred for 2.5 h, followed by addition of I2 (2.2640 g, 8.9190 mmol) in THF (29 mL). After 24 h at 23 °C, the reaction was quenched with saturated aqueous
NH4Cl (10 mL). The resultant emulsion was filtered over Celite and extracted with Et2O
(5 x 10 mL). The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Following flash column chromatography (5:1 hexanes/ethyl acetate), 1.07 g of 2.32 was recovered (5.40 mmol, 60%) as a colorless oil. Spectroscopic data agreed
1 with that of the literature. Rf 0.29 (5:1 hexanes/ethyl acetate); H NMR (CDCl3, 400
MHz) δ 1.88 (s, 1H), 1.97 (s, 3H), 4.23 (s, 2H), 5.97 (s, 1H).
68 I
H3N Cl
(Z)-3-Iodo-2-methylprop-2-en-1-ammonium chloride (S1).
A solution of alcohol 2.32 (937.5 mg, 4.735 mmol) in Et2O (72 mL) was cooled to 0 °C.
DMAP (cat.) was then added, followed by triethylamine (1.32 mL, 9.47 mmol) and methanesulfonyl chloride (0.40 mL, 5.2 mmol). The reaction was stirred for 30 min at 0
°C and then warmed to 23 °C for 1.5 h. The salts were filtered off and rinsed with ether
(3 x 10 mL). The organic layer was then washed with water and saturated aqueous
NaHCO3, dried over MgSO4, filtered and concentrated to an orange oil. The crude (Z)-3- iodo-2-methylallyl methanesulfonate (2.33, 1.0570 g, 3.8285 mmol) was used directly in the next transformation. Rf 0.51 (2:1 hexanes/ethyl acetate).
Sodium azide (371.0 mg, 5.707 mmol) was added to a solution of crude 2.33 (ca. 3.8285 mmol) in DMF (38 mL) at 23 °C. The reaction was stirred for 24 h, then cooled to 0 °C and treated with 0 °C H2O (20 mL) and saturated aqueous NaHCO3 (40 mL). The reaction mixture was diluted with Et2O (40 mL), and the aqueous later was separated and extracted with Et2O (2 x 30 mL). Combined organic layers were washed with H2O and brine, then dried with MgSO4 and concentrated to 2 mL of a solution of azide 2.34. Rf
0.95 (5:1 hexanes/ethyl acetate).
To the crude azide (ca. 3.8285 mmol) was added THF (38 mL), PPh3 (997.0 mg, 3.801 mmol), and water (103 µL, 5.72 mmol). The reaction flask was covered in aluminum foil and allowed to stir for 24 h. Et2O (50 mL) was added, and the organic phase was washed with 0 °C H20 (40 mL). An extraction was performed with Et2O (2 x 30 mL). Combined organic phases were washed with brine, dried (MgSO4), and filtered into an Erlenmeyer
69 flask. HCl(g) was bubbled through the solution until the appearance became cloudy, then for 1 min longer, at which time a vibrant yellow color was observed. The flask was allowed to stand at 23 °C for 15 min, then cooled to 0 °C for 10 min. The solid was collected by filtration and washed with Et2O (5 mL) and hexanes (5 mL). Following extensive drying under reduced pressure, S1 was isolated as a yellow solid (482.7 mg,
2.067 mmol, 44%) and was used without further purification. The ammonium chloride salt was not visible on TLC under any of the attempted conditions. mp 196.7 °C; IR
-1 1 (NaCl) cm 1427, 1605, 1736, 2986, 3048, 3603; H NMR (CD3)2SO, 600 MHz) δ 1.96
13 (d, J = 1.4 Hz, 3H), 3.53 (s, 2H), 6.48 (s, 1H), 8.37 (s, 3H); C NMR (CD3)2SO, 600
+ MHz) δ 21.45, 45.52, 81.49, 140.01; HRMS (ESI) calcd for C23H37Cl3NaO4Si m/z
197.9774 [M], found m/z 197.9772.
70 I Fmoc N H
(9H-Fluoren-9-yl)methyl (Z)-(3-iodo-2-methylallyl)carbamate (2.8).
To a suspension of S1 (75 mg, 0.32 mmol) in CH2Cl2 (3.2 mL) was added N,N- diisopropylethylamine (120 µL, 710 µmol). The mixture was cooled to 0 °C with slow addition of Fmoc-OSu (119.2 mg, 353.3 µmol) in CH2Cl2 (1.8 mL) to follow. The reaction was stirred at 23 °C for 36 h, at which point it was cooled to 0 °C and quenched slowly with 5% aqueous HCl (1 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (5 x 5 mL). Combined organic extracts were washed twice with water and concentrated. Following chromatography (1:1 hexanes/ethyl acetate), 2.8 was isolated as a white solid (121.8 mg, 290.5 µmol, 90%). mp 158.6 °C; Rf 0.14 (10:1 hexanes/ethyl acetate); IR (NaCl) cm-1 725, 1450, 1512, 1728, 2963, 3441; 1H NMR
(CDCl3, 400 MHz) δ 1.82 (s, 3H), 3.89 (d, J = 6.1 Hz, 3H), 4.15 (app t, J = 6.6, 1H), 4.38
(d, J = 6.7 Hz, 2H), 4.80 (br s, 1H), 5.95 (s, 1H), 7.24 (td, J = 0.9, 7.4 Hz, 2H), 7.33 (t, J
13 = 7.4 Hz, 2H), 7.52 (d, J = 7.4 Hz, 2H), 7.69 (d, J = 7.5 Hz, 2H); C NMR (CDCl3, 400
MHz) δ 22.27, 47.51, 48.25, 66.96, 76.33, 120.15, 125.13, 127.21, 127.86, 141.54,
+ + 144.05, 156.72; HRMS (ESI) calcd for C19H18INNaO2 m/z 442.0274 [M+Na ], found m/z 442.0252.
71 NHFmoc
HO
(9H-Fluoren-9-yl)methyl ((2Z,4E)-6-hydroxy-2-methylhexa-2,4-dien-1-yl)carbamate
(2.35).
A solution of carbamate 2.8 (56 mg, 0.13 mmol) and stannane 2.7 (100.0 mg, 228.1
µmol) in DMF (1.5 mL) was added to a flask containing Pd(CH3CN)2Cl2 (6.0 mg, 24
µmol). The reaction was heated to 50 °C for 2.5 h, then was subsequently cooled to 23 °C and cold water (1.5 mL) was added. The aqueous layer was then extracted with CH2Cl2
(5 x 5 mL), then dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (4:1 hexanes/ethyl acetate→1:1 hexanes/ethyl
acetate) to afford 2.35 as a white solid (35.1 mg, 100 µmol, 77%). mp 99.2 °C; Rf 0.24
(3:1 hexanes/ethyl acetate); IR (NaCl) cm-1 1450, 1512, 1721, 2924, 3048, 3063, 3449,
1 3603; H NMR (CDCl3, 400 MHz) δ 1.40 (m, 1H), 1.81 (s, 3H), 3.94 (d, J = 5.7 Hz, 2H),
4.22 (m, 3H), 4.43 (d, J = 6.8 Hz, 2H), 4.73 (br s, 1H), 5.80 (dt, J = 5.8, 14.7 Hz, 1H),
5.97 (d, J = 11.0 Hz, 1H), 6.54 (m, 1H), 7.31 (td, J = 1.1, 7.5 Hz, 2H), 7.40 (t, J = 7.4 Hz,
13 2H), 7.59 (d, J = 7.4 Hz, 2H), 7.77 (d, J = 7.6 Hz, 2H); C NMR (CDCl3, 600 MHz) δ
22.07, 29.84, 41.61, 47.44, 63.54, 66.83, 120.13, 125.14, 126.34, 127.18, 127.91, 132.22,
+ 134.77, 141.48, 144.07, 156.67; HRMS (ESI) calcd for C22H23NNaO3 m/z 372.1570
[M+Na+], found m/z 372.1560.
72 O O OTBS
O CCl3
6-((1E,3E,5R,8R)-8-((tert-Butyldimethylsilyl)oxy)-9,9,9-trichloro-3,5-dimethylnona-
1,3-dien-1-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (3.4).
A suspension of sodium hydride (60% in mineral oil, 21.0 mg, 524 µmol) in THF (2.6 mL) was prepared and cooled to 0 °C. A solution of phosphonate (152.8 mg, 549.1 µmol) in THF (1.1 mL) was added dropwise, and the resulting yellow solution was stirred for 30 min at 0 °C. Dropwise addition of a solution of the aldehyde 2.24 (96.8 mg, 250 µmol) in
THF (0.5 mL) followed, and the reaction was allowed to stir 24 h at 23 °C before a saturated aqueous solution of NH4Cl (5 mL) was added. The organic layer was separated and the aqueous phase extracted with CH2Cl2 (5 x 5 mL). Combined organic extracts were dried (Na2SO4), filtered and concentrated. Following flash column chromatography
(15:1 hexanes/ethyl acetate), 3.4 was isolated (88.3 mg, 172 µmol, 69%) as a pale yellow oil. It should be noted that the ketal is acid sensitive, and should not be stored for long
20 periods of time. Rf 0.29 (8:1 hexanes/ethyl acetate); [α] D +24°.5 (c 1.13, CHCl3); IR
-1 1 (NaCl) cm 779, 1281, 1628, 1713, 2986, 3048, 3063; H NMR (CDCl3, 600 MHz) δ
0.14 (s, 3H), 0.19 (s, 3H), 0.94 (s, 9H), 1.03 (d, J = 6.7 Hz, 3H), 1.65-1.73 (m, 9 H), 1.81
(d, J = 1.1 Hz, 3H), 2.01 (m, 1H), 2.54 (m, 1H), 4.01 (dd, J = 2.9, 6.8 Hz, 1H), 5.32 (s,
1H), 5.64 (d, J = 9.7 Hz, 1H), 5.90 (d, J = 15.6 Hz, 1H), 6.95 (d, J = 15.6 Hz, 1H); 13C
NMR (CDCl3, 400 MHz) δ −3.88, −3.38, 12.57, 18.58, 20.53, 25.27, 26.12, 32.29, 33.66,
34.02, 84.14, 94.08, 103.86, 106.34, 117.83, 132.37, 143.02, 146.78, 162.22, 164.15;
+ + HRMS (ESI) calcd for C23H37Cl3NaO4Si m/z 533.1419 [M+Na ], found m/z 533.1406.
73 O OTBS O N CCl3
(2R,5S)-5-((tert-Butyldimethylsilyl)oxy)-6,6,6-trichloro-N-methoxy-N,2- dimethylhexanamide (3.8).
N,O-Dimethylhydroxylamine hydrochloride (254.9 mg, 2.613 mmol) in THF (4.7 mL) was cooled to 0 °C. Trimethylaluminum (2 M in hexanes, 1.3 mL, 2.6 mmol) was added dropwise over 5 min before the solution was warmed to 23 °C and stirred for 20 min. The solution was then cooled to 0 °C with dropwise addition of lactone 2.17 (201.6 mg, 870.8
µmol) in THF (4.4 mL) over 5 min. The reaction was warmed to 23 °C and stirred for 1 h, at which time it was cooled to 0 °C and quenched very carefully with pH 7 aqueous phosphate buffer (5 mL). The mixture was then diluted with CH2Cl2 (10 mL) and stirred for 1 h, followed by extraction with CH2Cl2 (5 x 5 mL). Combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated to provide (2R,5S)-5-
(hydroxy)-6,6,6-trichloro-N-methoxy-N,2-dimethylhexanamide (3.7) as a colorless oil, which was taken directly forward to the next transformation. Rf 0.36 (1:1 hexanes/ethyl acetate).
Crude alcohol 3.7 (ca. 870.8 µmol) was dissolved in DMF (2.9 mL), followed by addition of pyridine (590 µL, 7.0 mmol), followed by AgNO3 (591.6 mg, 3.483 mmol). The reaction mixture was stirred until the AgNO3 dissolved (ca. 5 min), followed by addition of tert-butyldimethylsilyl chloride (525.0 mg, 3.483 mmol). The flask was covered in aluminum foil and allowed to stir at 23 °C for 24 h. Following dilution with Et2O (10 mL), the reaction mixture was filtered over Celite. The organic layer was washed with water and the resulting aqueous layer extracted with Et2O (5 x 10 mL). Combined
74 organic fractions were washed with brine, dried over MgSO4, filtered, and concentrated.
The crude product was purified by flash column chromatography (5:1—1:2 hexanes/ethyl acetate) to give 3.8 (313.0 mg, 769.3 µmol, 88% from lactone) as a colorless oil. Rf 0.37
20 -1 (5:1 hexanes/ethyl acetate); [α] D −15.3° (c 1.11, CHCl3); IR (NaCl) cm 787, 1389,
1 1651, 2862, 2940; H NMR (CDCl3, 400MHz) δ 0.16 (d, 3H), 0.18 (s, 3H), 0.93 (s, 9H),
1.14 (d, J = 6.9 Hz, 3H), 1.50 (m, 1H), 1.67 (m, 1H), 2.01 (m, 2H), 2.86 (m, 1H), 3.18 (s,
13 3H), 3.68 (s, 3H), 4.04 (dd, J = 2.9, 6.8 Hz, 1H); C NMR (CDCl3, 400 MHz) δ −3.99,
−3.45, 17.52, 18.55, 26.11, 30.78, 32.33, 35.33, 61.61, 84.10, 104.01, 177.29; HRMS
+ + (ESI) calcd for C15H30Cl3NNaO3Si m/z 428.0953 [M+Na ], found m/z 428.0918.
75 O OTBS
O CCl3
(4R,7S,E)-methyl 7-((tert-Butyldimethylsilyl)oxy)-8,8,8-trichloro-2,4-dimethyloct-2- enoate (3.10).
A solution of amide (769.0 mg, 1.890 mmol) in THF (47 mL) was prepared and cooled to
− 78 °C. DIBAL-H (1 M in toluene, 7.6 mL, 7.6 mmol) was added dropwise over 45 min.
The reaction was then allowed to stir for 2.5 h at − 78 °C. Acetone (10 mL) was then added, followed by a saturated aqueous solution Rochelle’s salt (50 mL) and CH2Cl2 (50 mL). The resulting mixture was stirred at 23 °C until two clear layers had formed, followed by extraction with CH2Cl2 (5 x 20 mL). Combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Crude aldehyde
(4R,7S,E)-7-((tert-butyldimethylsilyl)oxy)-8,8,8-trichloro-2,4-dimethyloct-2-enal (3.9) was taken forward directly to the subsequent transformation. Rf 0.53 (10:1 hexanes/ethyl acetate).
The crude aldehyde 3.9 (ca. 1.8901 mmol) was dissolved in toluene (9.5 mL). To this 23
° C solution was added (carbethoxyethylidene)triphenylphosphorane (3.62 g, 9.45 mmol).
The reaction was stirred 12 h at 23 °C, followed by concentration and purification by flash column chromatography (10:1 hexanes/ethyl acetate) to give 3.10 (759.6 mg, 1.818
20 mmol, 96% from 3.8) as a colorless oil. Rf 0.44 (10:1 hexanes/ethyl acetate); [α] D
-1 1 −28.9° (c 1.34, CHCl3); IR (NaCl) cm 787, 1281, 1713, 2863, 3048, 3063; H NMR
(CDCl3, 400 MHz) δ 0.14 (s, 3H), 0.19 (s, 3H), 0.93 (s, 9H), 1.04 (d, J = 6.6 Hz, 3H),
1.61 (m, 2H), 1.85 (d, J = 1.4 Hz, 3H), 2.02 (m, 1H), 2.48 (m, 1H), 3.74 (s, 3H), 4.00 (dd,
13 J = 3.0, 6.7 Hz, 1H), 6.53 (dd, J = 1.4, 10.1 Hz, 1H); C NMR (CDCl3, 400 MHz) δ
76 −3.86, −3.45, 12.78, 18.57, 20.14, 26.10, 32.45, 33.48, 33.82, 51.85, 84.14, 103.93,
+ 127.10, 147.13, 168.80; HRMS (ESI) calcd for C17H31Cl3NaO3Si m/z 439.1000
[M+Na+], found m/z 439.0974.
77 OTBS
HO CCl3
(4R,7S,E)-7-((tert-Butyldimethylsilyl)oxy)-8,8,8-trichloro-2,4-dimethyloct-2-en-1-ol
(3.11).
A solution of ester 3.10 (759.6 mg, 1.818 mmol) in CH2Cl2 (18 mL) was prepared and cooled to 0 °C. DIBAL-H (1 M in toluene, 3.8 mL, 3.8 mmol) was then added dropwise and the reaction was allowed to stir 1 h. Acetone (5 mL) was added and the reaction mixture was stirred for 5 min. A saturated aqueous solution of Rochelle’s salt (20 mL) and CH2Cl2 (20 mL) were then added, and the reaction mixture was stirred until two clear layers had formed. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (5 x 10 mL). Combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (5:1 hexanes/ethyl acetate) to give 3.11 (631.7 mg, 1.620 mmol, 89%) as
20 a colorless oil. Rf 0.48 (5:1 hexanes/ethyl acetate); [α] D −11° (c 0.95, CHCl3); IR
-1 1 (NaCl) cm 787, 1126, 1381, 2862, 2955, 3610; H NMR (CDCl3, 400 MHz) δ 0.15 (s,
3H), 0.19 (s, 3H), 0.93 (s, 9H), 0.98 (d, J = 6.6 Hz, 3H), 1.26 (t, J = 6.0 Hz, 1H), 1.45-
1.52 (m, 2H), 1.61-1.70 (m, 4H), 2.01 (m, 1H), 2.38 (m, 1H), 4.00 (m, 3H), 5.17 (dd, J =
13 1.3, 9.6 Hz, 1H); C NMR (CDCl3, 400 MHz) δ −3.85, −3.41, 14.09, 18.60, 21.19,
26.14, 32.29, 32.41, 34.46, 69.07, 84.25, 104.16, 131.79, 134.42; HRMS (ESI) calcd for
+ + C16H31Cl3NaO2Si m/z 411.1051 [M+Na ], found m/z 411.1022.
78 O OTBS
H CCl3
(4R,7S,E)-7-((tert-Butyldimethylsilyl)oxy)-8,8,8-trichloro-2,4-dimethyloct-2-enal
(3.12).
A solution of alcohol 3.11 (613.7 mg, 1.574 mmol) in CH2Cl2 (16 mL) was prepared and cooled to 0 °C. NaHCO3 (264.5 mg, 3.148 mmol) was added, followed by Dess-Martin periodinane (1.00 g, 2.36 mmol). The reaction was allowed to warm to 23 °C and stirred
1 h. The reaction mixture was diluted with CH2Cl2 (25 mL), and saturated aqueous
Na2S2O3 (25 mL) and saturated aqueous NaHCO3 (25 mL) were added. After 15 min of stirring, the organic layer was separated and the aqueous layer extracted with CH2Cl2 (5 x
10 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. The resulting crude product was purified by flash column chromatography (20:1 hexanes/ethyl acetate) to give 3.12 (542.5 mg, 1.399 mmol, 89%) as a colorless oil. Rf
20 -1 0.47 (10:1 hexanes/ethyl acetate); [α] D −8.3 (c 1.32, CHCl3); IR (NaCl) cm 787, 1134,
1 1458, 1682, 2932, 2963, 3055; H NMR (CDCl3, 600 MHz) δ 0.14 (s, 3H), 0.19 (s, 3H),
0.93 (s, 9H), 1.11 (d, J = 6.7 Hz, 3H), 1.60-1.69 (m, 3H), 1.79 (d, J = 1.4 Hz, 3H), 2.01-
2.07 (m, 1H), 2.66-2.73 (m, 1H), 4.02 (m, 1H), 6.23 (dd, J = 1.3, 10.0 Hz, 1H), 9.40 (s,
13 1H); C NMR (CDCl3, 600 MHz) δ −3.83, −3.42, 9.63, 18.55, 20.02, 26.07, 32.32,
33.55, 33.76, 83.89, 103.73, 138.76, 158.97, 195.45; HRMS (ESI) calcd for
+ + C16H29Cl3NaO2Si m/z 409.0895 [M+Na ], found m/z 439.0875.
79 O O OTBS
O CCl3
6-((1E,3E,5R,8S)-8-((tert-Butyldimethylsilyl)oxy)-9,9,9-trichloro-3,5-dimethylnona-
1,3-dien-1-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (17S-3.4).
A suspension of sodium hydride (60% in mineral oil, 223.8 mg, 5.596 mmol) in THF (28 mL) was prepared and cooled to 0 °C. A solution of phosphonate (1.635 g, 5.875 mmol) in THF (12 mL) was added dropwise, and the resulting yellow solution was stirred for 30 min at 0 °C. Dropwise addition of the aldehyde (542.5 mg, 1.399 mmol) in THF (3 mL) followed, and the reaction was allowed to stir 24 h before a saturated aqueous solution of
NH4Cl (10 mL) was added. The organic layer was separated and the aqueous phase extracted with CH2Cl2 (5 x 15 mL). Combined organic extracts were dried (Na2SO4), filtered and concentrated. Following flash column chromatography (15:1 hexanes/ethyl acetate), (17S)-3.4 was isolated (331.3 mg, 647.1 µmol, 46%). Rf 0.27 (8:1 hexanes/ethyl
20 -1 acetate); [α] D −35.0° (c 1.09, CHCl3); IR (NaCl) cm 779, 1281, 1605, 1728, 2986,
1 3048, 3063; H NMR (CDCl3, 600 MHz) δ 0.14 (s, 3H), 0.19 (s, 3H), 0.93 (s, 9H), 1.03
(d, J = 6.6 Hz, 3H), 1.54 (m, 2 H), 1.66 (m, 1H), 1.72 (d, J = 3.0 Hz, 6H), 1.81 (d, J = 1.1
Hz, 3H), 2.02 (m, 1H), 2.54 (m, 1H), 4.01 (dd, J = 2.9, 7.1 Hz, 1H), 5.32 (s, 1H), 5.62 (d,
13 J = 9.8 Hz, 1H), 5.90 (d, J = 15.6 Hz, 1H), 6.94 (d, J = 15.6 Hz, 1H); C NMR (CDCl3,
400 MHz) δ −3.82, −3.41, 12.59, 18.57, 20.77, 25.23, 26.11, 32.34, 33.52, 34.12, 84.06,
94.07, 103.89, 106.35, 117.81, 132.49, 143.00, 146.61, 162.21, 164.14; HRMS (ESI)
+ + calcd for C23H37Cl3NaO4Si m/z 533.1419 [M+Na ], found m/z 533.1425.
80 TBS O O O O O
Dimethyl (R)-2-((tert-Butyldimethylsilyl)oxy)succinate (3.15).
53 The title compound (3.15) was prepared according to literature procedure. Rf 0.19 (20:1
20 -1 1 hexanes/ethyl acetate); [α] D +48.2° (c 2.09, CHCl3); IR (NaCl) cm ; H NMR (CDCl3,
400 MHz) δ 0.08 (s, 3 H), 0.08 (s, 3H), 0.87 (s, 9H), 2.70 (dd, J = 8.0, 15.4 Hz, 1H), 2.80
(dd, J = 4.6, 15.4 Hz, 1H), 3.69 (s, 3H), 3.73 (s, 3H), 4.64 (dd, J = 4.6, 8.0 Hz, 1H); 13C
NMR (CDCl3, 400 MHz) δ −5.39, −4.81, 18.32, 25.73, 40.30, 51.90, 52.21, 69.35,
+ + 170.91, 172.86; HRMS (ESI) calcd for C12H24NaO5Si m/z 299.1285 [M+Na ], found m/z 299.1276.
81 TBS O O H O O
Methyl (R)-3-((tert-Butyldimethylsilyl)oxy)-4-oxobutanoate (3.16).
To a solution of ester 3.15 (5.00 g, 18.1 mmol) in CH2Cl2 (250 mL) was added
MgBr2•OEt2 (5.28 g, 20.4 mmol), and the resulting suspension was stirred for 1 h. The reaction mixture was cooled to −78 °C with dropwise addition of DIBAL-H (1 M in hexanes, 31 mL, 31 mmol). After 1 h, methanol (30 mL) was added to quench, followed by dilution with ether (250 mL). Rochelle’s salt (250 mL) was added, and the suspension was stirred until two layers formed. The aqueous layer was separated and extracted with
CH2Cl2 (5 x 25 mL), and combined organic extracts were then dried (MgSO4), filtered, and concentrated. The crude aldehyde was purified by flash column chromatography
(10:1 hexanes/ethyl acetate) to afford 3.16 (2.4322 g, 9.8718 mmol, 55%) as a colorless
20 -1 oil. Rf 0.41 (5:1 hexanes/ethyl acetate); [α] D +56.2° (c 1.89, CHCl3); IR (NaCl) cm
1 1281, 1366, 1736, 2855, 2955; H NMR (CDCl3, 400 MHz) δ 0.08 (s, 3H), 0.12 (s, 3H),
0.90 (s, 9H), 2.64 (dd, J = 6.9, 15.7 Hz, 1H), 2.73 (dd, J = 4.7, 15.6 Hz, 1H), 3.69 (s, 3H),
13 4.38 (dd, J = 4.7, 6.9 Hz, 1H), 9.69 (s, 1H); C NMR (CDCl3, 400 MHz) δ −4.94, −4.60,
+ 18.20, 25.76, 38.55, 52.01, 74.47, 170.72, 202.69; HRMS (ESI) calcd for C11H22NaO4Si m/z 269.1180 [M+Na+], found m/z 269.1182.
82 TBS O O
Cl O
Methyl (R,E)-3-((tert-Butyldimethylsilyl)oxy)-5-chloropent-4-enoate (3.17).
A suspension of CrCl2 (6.64 g, 54.0 mmol) was prepared in THF (11 mL) at 23 °C.
Chloroform (1.6 mL, 20 mmol) was added to the resulting green slurry, and the reaction was heated to 65 °C for 10 min. The aldehyde (2.22 g, 9.00 mmol) was added as a solution in THF (45 mL) and the reaction was stirred at 65 °C for 12 h. The reaction was cooled to 23 °C and then saturated aqueous ammonium chloride (10 mL) was added. The aqueous layer was separated and extracted with Et2O (5 x 10 mL), and combined organic fractions were dried (Na2SO4), filtered, and concentrated. Following chromatography (8:1 hexanes/ethyl acetate), 3.17 (1.5646 g, 5.6109 mmol, 62%) was isolated as a colorless oil.
20 -1 Rf 0.50 (5:1 hexanes/ethyl acetate); [α] D +4.2° (c 0.78, CHCl3); IR (NaCl) cm 833,
1 1165, 1249, 1265, 1736, 2855, 2955; H NMR (CDCl3, 400 MHz) δ 0.05 (s, 6H), 0.86 (s,
9H), 2.46 (dd, J = 5.5, 14.9 Hz, 1H), 2.56 (dd, J = 7.7, 14.9 Hz, 1H), 3.67 (s, 2H), 4.61
(m, 1H), 5.96 (dd, J = 6.6, 13.3 Hz, 1H), 6.21 (dd, J = 1.1, 13.3 Hz, 1H); 13C NMR
(CDCl3, 400 MHz) δ −5.01, −4.37, 18.14, 25.79, 43.46, 51.72, 68.87, 119.82,
+ + 135.49.171.02; HRMS (ESI) calcd for C12H23ClNaO3Si m/z 301.0997 [M+Na ], found m/z 301.0986.
83 THPO
OH
(Z)-3-Methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-en-1-ol (3.19).
42 The allylic alcohol 3.19 was prepared according to literature procedure. Rf 0.19 (5:1
1 hexanes/ethyl acetate); H NMR (CDCl3, 600 MHz) δ 1.52-1.63 (m, 4H), 1.69-1.74 (m,
2H), 1.80 (s, 3H), 2.26 (t, J = 5.9 Hz, 1H), 3.54-3.57 (m, 1H), 3.8203.86 (m, 1H), 4.04-
4.19 (m, 4H), 4.66 (t, J = 3.3, 1H), 5.74 (t, J = 7.4, 1H); HRMS (ESI) calcd for
+ + C10H18NaO3 m/z 209.1148 [M+Na ], found m/z 209.1151.
84 THPO O
O
Methyl (2E,4Z)-5-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)hexa-2,4-dienoate
(3.22).
To a solution of alcohol 3.19 (920 mg, 4.9 mmol), in CH2Cl2 (50 mL) was added Et3N
(3.4 mL, 25 mmol) and DMSO (12.5 mL). The solution was cooled to 0 °C, followed by addition of SO3!py (2.36 g, 14.8 mmol). After 30 min, the reaction was quenched with saturated aqueous ammonium chloride (25 mL), followed by extraction with CH2Cl2 (5 x
10 mL). Combined organic layers were washed with brine, dried (MgSO4), and filtered to provide a solution of volatile aldehyde (Z)-3-methyl-4-((tetrahydro-2H-pyran-2- yl)oxy)but-2-enal (3.20), which was taken directly forward without concentration. Rf 0.5
(3:1 hexanes/ethyl acetate).
To a solution of crude 3.20 (ca. 4.9 mmol) in CH2Cl2 was added methyl
(triphenylphosphoranylidene)acetate (4.96 g, 14.8 mmol). The reaction was allowed to stir 12 h, followed by concentration and purification by column chromatography (3:1 hexanes/ethyl acetate) to afford 3.22 (891.5 mg, 3.710 mmol, 76% from alcohol 3.19) as
-1 a colorless oil. Rf 0.49 (3:1 hexanes/ethyl acetate); IR (NaCl) cm 1173, 1721, 2878,
1 2947, 3048, 3063; H NMR (CDCl3, 600 MHz) δ 1.49-1.52 (m, 2H), 1.55-1.60 (m, 2H),
1.67-1.72 (m, 1H), 1.79-1.83 (m, 1H), 1.92 (s, 3H), 3.52 (m, 1H), 3.71 (s, 3H), 3.85 (m,
1H), 4.25 (d, J = 12.4 Hz, 1H), 4.59 (app. t, J = 3.5 Hz, 1H), 5.79 (d, J = 15.2 Hz, 1H),
13 6.09 (d, J = 11.7 Hz, 1H), 7.65 (dd, J = 11.7, 15.2 Hz); C NMR (CDCl3, 400 MHz) δ
19.42, 22.48, 25.50, 30.59, 51.44, 62.26, 65.64, 98.04, 120.30, 126.43, 139.91, 144.88,
85 + + 167.68; HRMS (ESI) calcd for C13H20NaO4 m/z 263.1254 [M+Na ], found m/z
263.1252.
86 HO O
O
Methyl (2E,4Z)-6-hydroxy-5-methylhexa-2,4-dienoate (3.23).
Pyridinium p-toluenesulfonate (178.8 mg, 711.6 µmol) was added to a solution of acetal
3.22 (855.0 mg, 3.558 mmol) in CH3OH (44 mL). After 12 h, the reaction was quenched with saturated aqueous NaHCO3 (50 mL) and concentrated. The resulting residue was dissolved in Et2O (50 mL), and organic and aqueous layers were separated. The organic layer was washed with H2O and brine, and these aqueous layers were combined and extracted with Et2O (5 x 10 mL). Organic fractions were combined, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes/ethyl acetate) to provide 3.23 as a white solid (498.6 mg,
-1 3.192 mmol, 90%). mp 50.8 °C; Rf 0.44 (5:1 hexanes/ethyl acetate); IR (NaCl) cm
1 1219, 1713, 2947, 3055, 3611; H NMR (CDCl3, 600 MHz) δ 1.43 (t, J = 5.9 Hz, 1H),
1.58 (s, 1H), 1.97 (s, 3H), 3.75 (s, 3H), 4.37 (d, J = 5.8 Hz, 2H), 5.84 (d, J = 15.1 Hz,
13 1H), 6.08 (d, J = 11.8 Hz, 1H), 7.62 (dd, J = 11.8, 15.1 Hz, 1H); C NMR (CDCl3, 400
MHz) δ 22.04, 51.65, 61.80, 120.60, 125.66, 139.43, 147.02, 167.80; HRMS (ESI) calcd
+ + for C8H12NaO3 m/z 179.0679 [M+Na ], found m/z 179.0674.
87 N 3 O
O
Methyl (2E,4Z)-6-azido-5-methylhexa-2,4-dienoate (3.6).
A solution of alcohol 3.23 (198.5 mg, 1.272 mmol) in diethyl ether (18 mL) was prepared and cooled to 0 °C. DMAP (cat.) was added, followed by triethylamine (350 µL, 2.5 mmol) and dropwise addition of methanesulfonyl chloride (110 µL, 1.4 mmol). The reaction was then warmed to 23 °C and stirred for 24 h. The resulting solid was filtered off and washed several times with Et2O (5 x 10 mL). The organic layer was then washed with water and saturated sodium bicarbonate. The crude (2E,4Z)-methyl 5-methyl-6-
((methylsulfonyl)oxy)hexa-2,4-dienoate 3.24 was taken directly forward following drying (MgSO4), filtering, and concentrating. Rf 0.24 (3:1 hexanes/ethyl acetate).
To a solution of crude mesylate 3.24 (ca. 1.2716 mmol) in DMF (13 mL) was added sodium azide (124.0 mg, 1.907 mmol). After 24 h, the reaction was diluted with water
(15 mL). Saturated sodium bicarbonate (15 mL) and Et2O (30 mL) were added, and aqueous and organic layers were separated. The aqueous layer was extracted with Et2O (5 x 10 mL), and combined organic extracts were washed with water and brine, dried
(Na2SO4), filtered, and concentrated. The crude azide was purified by flash column chromatography (5:1 hexanes/ethyl acetate) to provide 3.6 (111.3 mg, 0.6143 mmol,
-1 48%) as a colorless oil. Rf 0.47 (10:1 hexanes/ethyl acetate); IR (NaCl) cm 1157, 1227,
1 1713, 2261, 2855, 2924, 2955; H NMR (CDCl3, 400 MHz) 2.00 (m, 3H), 3.76 (s, 3H),
4.23 (s, 2H), 5.90 (d, J = 15.1 Hz, 2H), 6.11 (m, 1H), 7.53 (dd, J = 11.8, 15.1 Hz, 1H);
13 C NMR (CDCl3, 400 MHz) δ 22.50, 42.64, 51.74, 122.04, 127.73, 138.50, 142.67,
88 + + 167.45; HRMS (ESI) calcd for C8H11N3NaO2 m/z 204.0743 [M+Na ], found m/z
204.0748.
89 Boc(SES)N O
O
Methyl (2E,4Z)-6-((N-(tert-butoxycarbonyl)-2-(trimethylsilyl)ethyl)sulfonamido)-5- methylhexa-2,4-dienoate (3.27).
A solution of alcohol 3.23 (498.6 mg, 3.1925 mmol) and tert-butyl ((2-
(trimethylsilyl)ethyl)sulfonyl)carbamate (1.0782 g, 3.8310 mmol) in THF (11 mL) was prepared and cooled to 0 °C. Triphenylphosphine (1.0049 g, 3.8310 mmol) was added, followed by dropwise addition of diisopropylazodicarboxylate (40 wt. % in toluene, 1.7 mL, 3.8 mmol). Following stirring at 23 °C for 12 h, H2O (10 mL) was added, followed by dilution with EtOAc (20 mL). The aqueous phase was extracted with EtOAc (5 x 5 mL), and combined organic phases were dried (MgSO4), filtered, and concentrated.
Purification by flash column chromatography (5:1 hexanes/ethyl acetate) gave 3.27 (1.12 g, 2.7 mmol, 84%) as a white solid. mp 80.6 °C; Rf 0.52 (3:1 hexanes/ethyl acetate); IR
-1 1 (NaCl) cm 1281, 1350, 1612, 1643, 1721, 2955, 3063; H NMR (CDCl3, 400 MHz) δ
0.07 (s, 9H), 0.96 (m, 2H), 1.49 (s, 9H), 1.92 (br s, 3H), 3.43 (m, 2H), 3.74 (s, 3H), 4.56
(br s, 2H), 5.83 (d, J = 15.1 Hz, 1H), 6.09 (d, J = 11.8 Hz, 1H), 7.62 (dd, J = 11.8, 15.1
13 Hz, 1H); C NMR (CDCl3, 400 MHz) δ −1.88, 10.58, 21.82, 28.11, 28.16, 47.49, 50.89,
51.61, 84.92, 120.63, 125.73, 139.44, 143.81, 151.83, 167.77; HRMS (ESI) calcd for
+ + C18H33NNaO6SSi m/z 442.1690 [M+Na ], found m/z 442.1674.
90 BocHN O
O
Methyl (2E,4Z)-6-((tert-butoxycarbonyl)amino)-5-methylhexa-2,4-dienoate (3.28).
Sulfonamide 3.27 (113 mg, 269 µmol) was placed in THF (27 mL).
Tetrabutylammonium fluoride (1 M in THF, 810 µL, 810 µmol) was added. The reaction was stirred 1h, then diluted with Et2O (50 mL). The organic layer was washed with water
(4 x 10 mL), saturated aqueous sodium bicarbonate, dried (MgSO4), and concentrated in vacuo. Following flash column chromatography (3:1 hexanes/ethyl acetate), 3.28 (57.8 mg, 226 mmol, 84%) was isolated as a white solid. mp 70.0 °C; Rf 0.44 (3:1 hexanes/ethyl acetate); IR (NaCl) cm-1 1157, 1713, 2986, 3048, 3063, 3449; 1H NMR
(CDCl3, 400 MHz) δ 1.45 (s, 9H), 1.90 (s, 3H), 3.74 (s, 3H), 3.98 (app s, 2H), 4.53 (br s,
1H), 5.82 (d, J = 15.1 Hz, 1H), 6.07 (d, J = 11.9 Hz, 1H), 7.57 (dd, J = 11.8 15.0 Hz,
13 1H); C NMR (CDCl3, 400 MHz) δ 22.49, 28.54, 41.27, 51.64, 120.74, 126.09, 139.30,
+ + 145.32, 156.07, 167.72; HRMS (ESI) calcd for C13H21NNaO4 m/z 278.1363 [M+Na ], found m/z 278.1356.
91 Boc(SES)N O
OH
(2E,4Z)-6-((N-(tert-Butoxycarbonyl)-2-(trimethylsilyl)ethyl)sulfonamido)-5- methylhexa-2,4-dienoic acid (3.29).
A solution of ester 3.27 (116 mg, 0.276 mmol) in THF/CH3OH (14 mL/14 mL) was cooled to 0 °C. Water (7 mL) was added, followed by LiOH•H2O (232.0 mg, 5.528 mmol). After 12 h at 23 °C, the reaction was cooled to 0 °C and acidified with 1N HCl.
The aqueous layer was extracted with Et2O (5 x 5 mL), then CH2Cl2 (5 x 5 mL).
Combined organic extracts were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (2:1 hexanes/ethyl acetate) to afford 3.29 (61.8 mg, 0.152 mmol, 55%) as a white solid. mp 159.6 °C; Rf 0.33 (2:1 hexanes/ethyl acetate); IR (NaCl) cm-1 1350, 1612, 1643, 1721, 2955, 3055, 3503, 3595;
1 H NMR (CDCl3, 400 MHz) δ 0.08 (s, 9H), 0.96 (m, 2H), 1.50 (s, 9H), 1.95 (s, 3H), 3.44
(m, 2H), 4.56 (s, 2H), 5.84 (d, J = 15.1 Hz, 1H), 6.13 (d, J = 11.8 Hz, 1H), 7.70 (dd, J =
13 11.9, 15.0 Hz, 1H); C NMR (CDCl3, 400 MHz) δ −1.87, 10.55, 21.98, 28.14, 47.41,
50.85, 85.05, 119.77, 125.65, 141.45, 145.15, 151.77, 171.08; HRMS (ESI) calcd for
+ + C18H33NNaO6SSi m/z 442.1690 [M+Na ], found m/z 428.1519.
92 H O O
O
Methyl (2E,4Z)-5-methyl-6-oxohexa-2,4-dienoate (4.13).
DMSO (8 mL) and DIPEA (2.8 mL, 16 mmol) were added to a solution of alcohol (504.2 mg, 3.228 mmol) in CH2Cl2 (32 mL). The resulting solution was cooled to 0 °C, and
SO3•py (1.5124 g, 9.6849 mmol) was added. After 12 h, the reaction was quenched with saturated aqueous ammonium chloride (15 mL). Following extraction with CH2Cl2 (5 x
10 mL), combined organic layers were washed with water and brine, and then dried
(Na2SO4). Filtration and concentration provided the crude aldehyde, which was purified by flash column chromatography (5:1 hexanes:ethyl acetate) to provide 4.13 as a bright yellow solid (353.7 mg, 2.294 mmol, 71%). mp 82.7 °C; Rf 0.45 (5:1 hexanes/ethyl
-1 1 acetate); IR (NaCl) cm 1165, 1435, 1682, 1713, 2986, 3048, 3063; H NMR (CDCl3,
600 MHz) δ 1.94 (s, 3H), 3.80 (s, 3H), 6.10 (d, J = 15.6 Hz, 1H), 6.99-7.02 (m, 1H), 8.15
13 (dd, J = 12.4, 15.0 Hz, 1H), 10.39 (s, 1H); C NMR (CDCl3, 400 MHz) δ 17.00, 52.10,
+ 126.90, 135.90, 140.86, 141.74, 166.63, 189.94; HRMS (ESI) calcd for C8H10NaO3 m/z
177.0522 [M+Na+], found m/z 177.0523.
93
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97 Appendix A: 1H NMR Data
98
99
1H NMR Spectrum of Acylated Oxazolidinone 2.14
2.15
100
1H NMR Spectrum of Alkene 2.15
2.16
101
1H NMR Spectrum of Aldehyde 2.16
2.17
102
1H NMR Spectrum of Lactone 2.17
2.4
1
03
1H NMR Spectrum of Lactone 2.4
2.19
104
1H NMR Spectrum of Weinreb Amide 2.19
2.22
105
1H NMR Spectrum of Ester 2.22
2.23
106
1H NMR Spectrum of Alcohol 2.23
2.24
107
1H NMR Spectrum of Aldehyde 2.24
2.26
108
1H NMR Spectrum of Ester 2.26
2.27
109
1H NMR Spectrum of Alcohol 2.27
2.29
110
1H NMR of Vinyl Chloride 2.29
2.8
111
1H NMR Spectrum of Iodide 2.8
2.35
112
1H NMR Spectrum of Alcohol 2.35
3.4
113
1H NMR of Dioxinone 3.4
3.8
114
1H NMR Spectrum of Amide 3.8
3.10 115
1H NMR Spectrum of Ester 3.10
3.11
116
1H NMR Spectrum of Alcohol 3.11
3.12
117
1H NMR Spectrum of Aldehyde 3.12
(17S)-3.4
118
1H NMR of Dioxinone (17S)-3.4
3.15
119
1H NMR Spectrum of Bis-Ester 3.15
3.16
120
1H NMR Spectrum of Aldehyde 3.16
3.17
121
1H NMR Spectrum of Vinyl Chloride 3.17
3.19
122
1H NMR Spectrum of Alcohol 3.19
3.22
123
1H NMR of Acetal 3.22
3.23
124
1H NMR Spectrum of Alcohol 3.23
3.6
125
1H NMR of Azide 3.6
3.28
126
1H NMR of Carbamate 3.28
3.27
127
1H NMR of Sulfonamide 3.27
3.29
128
1H NMR of Acid 3.29
4.13
129
1H NMR Spectrum of Aldehyde 4.13