EXPLORATORY STUDY OF IONOPHORIC SPIROETHERS AND SPIROKETALS
DISSERTATION
Presented in Partial Fulfillment of the Requirements for
the Degree Doctor of Philosophy in the Graduate
School of The Ohio State University
By
Peter Rajan Selvaraj
*****
The Ohio State University 2006
Dissertation Committee: Approved by Professor Leo A. Paquette, Advisor
Professor Christopher M. Hadad ______Professor Jon Parquette Advisor Graduate Program in Chemistry
ABSTRACT Abstract
Bipolar disorder, also known as manic-depressive illness, is a brain disorder that can be treated, and people with this illness can be treated successfully with lithium salts.
Lithium ionophores can be used to construct a Li+ ion selective electrode, which can in turn be used for effective monitoring of lithium levels in blood. Lithium ionophores synthesized previously in the group employing tetrahydrofuran units have been found to be good lithium ion specific ionophores. However, there have been problems with the solubility of these complexes. Consequently, two new molecules were designed by introducing oxygen atoms at strategic positions to enhance the solubility of the complexes formed with lithium. Methods to synthesize these compounds have been explored and described.
The area of biphasic complexation has also been explored by synthesizing compounds with hydroxyethyl and alkoxyethyl side chains as ligating sites for metal ions. Desired compounds were synthesized starting from inositol in short and efficient routes. Complexation studies were performed in the solution phase and gas phase using picrate extraction studies and mass spec, respectively.
En route to the synthesis of spiroether lithium ionophores some interesting properties were discovered. Cyclohexanones with spiroether units in the α and β position were found to equilibrate. Corresponding cyclopentanones were also found to exhibit this ii behavior. Influence of ring size of the equilibrium was investigated by synthesizing
cyclopentanones containing a combination of five and six membered spiroether
functionality.
Oxonium ion-initiated pinacolic ring expansion reaction has been previously
reported by our group. This discovery, which constitutes an extension of the long
established Wagner-Meerwin and pinacol rearrangements, takes advantage of the fact
that ketone adducts of metalated vinyl ethers are amenable to conversion to oxonium ions
under acid-catalyzed conditions. This results in a diastereoselective ring expansion and
spiroketone formation. Our next advance into spirocyclic chemistry involves application
of pinacolic ring expansion methodology in the synthesis of 1,6-dioxaspiro[4.5]decane
frameworks. Subsequent transformations result in the conversion of spiroketones formed
to spiroketal frameworks.
AL-2 and lissoketal are two naturally occurring spiroketals. Efforts were made to
apply the pinacol ring expansion methodology in the synthesis of AL-2 and lissoketal. In
order to arrive at 6.12, homologation was attempted to no avail via displacement of
iodide 6.11 and ring opening of epoxides 6.6 and 6.7 utilizing various methods. Attention
was then focused on initiating the synthesis with the desired chain length in place.
Synthesis of lactone 6.8 was investigated and resolved.
With an efficient synthesis of 6.19 in hand, attention was focused on alkylation at
C3 position. However, alkylation was thwarted. The final approach has given rise to a
strategy that involves construction of the unsaturated pyran ring from known spiroketal
6.26 and has allowed for the synthesis of Olefin 6.31. With Olefin 6.31 in hand, synthesis of lissoketal might be realized through more transformations.
iii
Dedication Dedicated to my parents
iv ACKNOWLEDGMENTS Acknowledgments
I wish to express my sincere gratitude and respect to my advisor, Dr. Leo A.
Paquette, for his guidance and encouragement during my stay at The Ohio State
University. Without his dedication, much of the research discussed in the dissertation
would not have possible.
I wish to thank Dr. Hadad and Dr. Parquette for serving on my dissertation committee. I also thank Rebecca Martin and Donna Rothe for their invaluable assistance
to our research group. I would like to thank all the Paquette group members for their help
and support. I would like to thank my lab mates Dr. Jiyoung Chang, Zhenjiao Tian, Dr.
Adam Preston, and Dr. Marshall Stepanian for their companionship and help. In
particular, I am thankful to Dr. Matthew Kreilein and Dr. Amy Hart for being excellent
colleagues and helping proof read my thesis and proposal.
I would like to thank Shaalon Joules for being my true friend and a part of my life
for the last couple of years. Life would not have been so great without her support and
understanding. I would also like to thank Mr. Leo Solomon, Mr. Kutralanathan, Mr.
Karthik Venkatachalam, Dr. Mike Chang and Mr. Amresh Maadhava Raao for their
friendship during my stay at The Ohio State University.
This section would not be complete without thanking my parents and family.
Whatever I am today is all because of your love and sacrifices. Thank you for giving me
v this opportunity. Finally, I thank God for guiding and blessing me to accomplish this in the year of 2006.
vi VITA Vita
June 30, 1976 ...... Born – Madras, India
September 1999 ...... M.Sc. Indian Institute of Technology Madras, India
September 2001 ...... M.S. Eastern Michigan University, Michigan
2001 – 2006...... Graduate Teaching/Research Asst. The Ohio State University.
PUBLICATIONS
Research Publications
1. Paquette, L. A.; Hilmey, D. G.; Selvaraj, P. R., Direct access to heteropolycyclic spiroketones. 1,3-dichloroacetone as a cyclopropanone equivalent. Heterocycles 2005, 66, 57-60.
2. Paquette, L. A.; Selvaraj, P. R.; Keller, K. A.; Brodbelt, J. S., Is potential coordination of alkali metal ions to stereodefined polyoxygenated cyclohexanes an adequate driving force for fostering the adoption of axial conformers? Tetrahedron 2005, 61, (1), 231-240.
3. Hilmey, D.G.; Selvaraj, P.R.; Paquette, L.A. “Synthesis and Lewis Acid-Induced Isomerization of Mono-, Di-, and Trispiro α-Keto Tetrahydrofurans and –Pyrans” Can. J. Chem. Accepted for publication.
4. Chang, S.-K.; Selvaraj, P. “Copper(II) Hexafluoroantimonate” Electronic Encyclopedia of Reagents for Organic Synthesis, 2005, John Wiley and Sons.
FIELDS OF STUDY
Major Field: Chemistry
vii TABLE OF CONTENTS
Page Abstract...... ii
Dedication...... iv
Acknowledgments...... v
Vita...... vii
List of Schemes...... xi
List of Tables ...... xiv
List of Figures...... xv
List of Abbreviations ...... xvii
Chapters:
1. Introduction ...... 1
1.1 Background ...... 1
1.2 General structural features of ionophores ...... 3
1.3 Naturally occurring polyether ionophores...... 5
1.4 Applications of ionophores ...... 9
2. Efforts directed toward the multiple spiroketalization of cyclohexane...... 16
2.1 Background ...... 16
2.2 Efforts towards the synthesis of the 1,3,5-trispiro system 2.3 ...... 18
2.2.1 First generation synthesis ...... 18
viii 2.2.2 Second generation synthesis...... 21
2.2.3 Third generation synthesis...... 25
2.3 Efforts towards the synthesis of the hexaspiro system 2.4...... 27
2.3.1 First generation synthesis ...... 27
2.3.2 Second generation synthesis...... 28
2.3.3 Third generation synthesis...... 29
2.4 Conclusion...... 33
3. Stereodefined polyoxygenated cyclohexanes as possible ionophores...... 34
3.1 Background ...... 34
3.2 Synthesis of the polyoxygenated cyclohexanes ...... 39
3.3 Solution phase complexation studies ...... 43
3.4 Electrospray ionization-mass spectrometry measurements...... 46
3.5 Conclusion...... 52
4. Synthesis and Lewis acid-induced equilibration of dispiro α-keto ethers...... 53
4.1 Background ...... 53
4.2 Synthesis...... 55
4.3 Stereoselectivity Considerations ...... 58
4.4 Lewis acid-induced isomerizations ...... 61
4.5 Conclusion...... 65
5. Efforts towards the total synthesis of AL - 2...... 66
5.1 Background ...... 66
5.2 Synthetic approaches to AL-2 ...... 68
5.2.1 Synthesis plan...... 68
5.2.2 Mukai’s total synthesis of AL-2...... 69
5.3 First generation synthesis ...... 69 ix 5.3.1 Synthesis plan...... 69
5.3.2 Attempted synthesis of spirocyclic core...... 70
5.4 Second generation synthesis...... 74
5.4.1 Synthesis plan...... 74
5.4.2 Attempted synthesis of the spirocyclic core...... 74
5.5 Third generation synthesis ...... 76
5.5.1 Synthesis plan...... 76
5.5.2 Synthesis of 5.31 - First attempt...... 76
5.5.3 Synthesis of 5.31 - Second attempt ...... 82
5.6 Conclusions ...... 83
6. Efforts towards total synthesis of Lissoketal...... 84
6.1 Background ...... 84
6.2 First generation synthesis ...... 85
6.2.1 Synthesis plan...... 85
6.2.2 First generation synthesis of 6.4...... 85
6.2.3 Second generation synthesis of 6.4 ...... 88
6.2.4 Efforts to synthesize 6.2 ...... 91
6.3 Second generation synthesis...... 93
6.3.1 Synthesis of 6.31 ...... 94
6.4 Conclusion and future work ...... 95
7. Experimental Details ...... 96
References and Notes...... 148
Appendix A: Proton NMR Spectra...... 157
x LIST OF SCHEMES List of Schemes
Scheme Page
1.1 Pinacolic ring expansion...... 7
1.2 Spiroketal synthesis using pinacolic ring expansion ...... 8
2.1 Synthesis of 2.7...... 19
2.2 Failed synthesis of 2.3...... 21
2.3 Synthesis of 2.12 and 2.13 ...... 22
2.4 Synthesis of 2.19...... 25
2.5 Synthesis of 2.22...... 27
2.6 Failed synthesis of 2.4...... 29
2.7 Synthesis of 2.31...... 30
2.8 Synthesis of 2.34...... 30
2.9 Synthesis of 2.37...... 31
2.10 Synthesis of 2.40...... 32
2.11 Failed attempt to synthesize target 2.4...... 33
3.1 Synthesis of 3.17 and 3.18 ...... 40
3.2 Synthesis of 3.23 and 3.24 ...... 41
3.3 Synthesis of 3.28...... 42
3.4 Synthesis of 3.31...... 42
4.1 Synthesis of 4.9...... 56 xi 4.2 Synthesis of 4.14...... 56
4.3 Synthesis of 4.17 and 4.18 ...... 57
4.4 Synthesis of 4.19 - 4.22...... 58
4.5 Formation of syn and anti isomers...... 59
5.1 Proposed spiroketal synthesis using pinacolic ring expansion ...... 67
5.2 Retrosynthetic analysis ...... 68
5.3 Total synthesis of AL-2 ...... 69
5.4 Spiroketal core synthesis plan...... 70
5.5 Second generation synthesis plan ...... 74
5.6 Synthesis of 5.26...... 75
5.7 Attempted synthesis of 5.29...... 75
5.8 Third generation synthesis plan ...... 76
5.9 Synthesis of 5.35...... 77
5.10 Synthesis of 5.37...... 77
5.11 Synthesis of 5.38...... 79
5.12 Attempts to synthesize 5.40 from 5.36...... 81
5.13 Attempted synthesis of 5.43...... 81
5.14 Synthesis of 5.48...... 82
5.15 Failed synthesis of 5.45...... 83
6.1 First generation synthesis plan...... 85
6.2 Synthesis of 6.6 and 6.7 ...... 86
6.3 Synthesis of 6.11...... 87
6.4 Synthesis of 6.15...... 89
6.5 Deoxygenation of 6.15...... 89
6.6 Deiodination of 6.18 ...... 90 xii 6.7 Synthesis of 6.19...... 91
6.8 Attempted conditions for alkylation of 6.19...... 92
6.9 Synthesis of 6.23...... 92
6.10 Attempted condition for synthesis of 6.25...... 93
6.11 Revised synthesis plan ...... 94
6.12 Synthesis of 6.31...... 94
6.13 Future steps ...... 95
xiii LIST OF TABLES List of Tables
Table Page
2.1 Synthesis of 2.7...... 20
2.2 Attempted conditions for the synthesis of 2.14 ...... 23
2.3 Attempted conditions for the synthesis of 2.15 ...... 24
2.4 Attempted conditions for the synthesis of 2.20 ...... 26
2.5 Failed attempt to synthesize 2.23...... 28
3.1 Association constants (Ka) determined by picrate extraction ...... 43
3.2 Signal abundance ratios, (L+2M+Cl)+/(L+M)+ by ESI-MS ...... 49
4.1 BF3•OEt2 induced isomerizations ...... 62
4.2 MM3-derived steric energies ...... 64
5.1 Ketalization conditions and results ...... 71
5.2 Reaction with acid chlorides...... 72
5.3 Nucleophilic displacement conditions ...... 73
5.4 Attempts to alkylate 5.35 and 5.37 ...... 78
5.5 Attempts to alkylate ketal 5.38 ...... 80
xiv LIST OF FIGURES List of Figures
Figure Page
1.1 K+ transport by valinomycin...... 1
1.2 Naturally occurring ionophores ...... 2
1.3 K+ transport by pore-forming ionophore ...... 3
1.4 Representative ionophore metal complex...... 4
1.5 Polyspiroethers...... 6
1.6 Synthetic spiro ethers...... 6
1.7 Naturally occurring spiroketals...... 8
1.8 Acid-catalyzed equilibration of 1.13 and 1.15...... 9
1.9 Spirotetrahydrofuran ionophores ...... 12
1.10 Spiroketal ionophores ...... 13
1.11 Conformations of 1.20 and 1.21 ...... 14
1.12 Complexation of 1.22 and 1.24 with metal ions in the gas phase...... 15
2.1 Spirotetrahydrofuran ionophores ...... 17
2.2 Spiroketal ionophores ...... 18
3.1 Conformations of 3.1 and 3.2 ...... 35
3.2 Homoditopic ionophore 3.3 ...... 35
3.3 Muellitol a natural product with axial peripheral hydroxyl groups ...... 36
3.4 Ring inversion achieved by introducing bulky silyl protecting groups ...... 37 xv 3.5 Complexation of 3.9 and 3.11 with metal ions in the gas phase...... 38
1 3.6 H NMR of 3.16 with different concentrations of LiClO4...... 44
13 3.7 C NMR of 3.16 with different concentrations of LiClO4...... 45
3.8 ESI-MS for equimolar solutions in 19:1 chloroform/methanol...... 47
3.9 Collisionally activated dissociation ...... 50
3.10 ESI-MS for equimolar solutions in 19:1 chloroform/methanol...... 51
4.1 Acid-catalyzed equilibration of 4.1 and 4.2...... 54
4.2 Possible ring expansion pathways ...... 60
4.3 Lowest energy conformations...... 63
5.1 Steroidal saponins and sapogenins...... 66
5.2 Spiroketal AL-2 ...... 67
6.1 Structure of lissoketal ...... 84
xvi LIST OF ABBREVIATIONS List of Abbreviations
α alpha
[α] specific rotation
Ac acetyl
br broad (IR and NMR)
β beta
n-Bu normal-butyl
t-Bu tert-butyl
Bz benzoyl
°C degrees Celsius
calcd calculated
CSA (1S)-(+)-10-camphorsulfonic acid
δ chemical shift in parts per million downfield from tetramethylsilane
d doublet (spectra); day(s)
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DMAP 4-(N,N-dimethylamino)pyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide xvii eq. equivalent
Et ethyl
γ gamma g gram(s) h hour(s)
IR infrared
J coupling constant in Hz (NMR) k kilo
KHMDS potassium hexamethyldisilazide
L liter(s)
LDA lithium diisopropylamide m milli; multiplet (NMR)
μ micro
M moles per liter
Mc chloromethylsulfonyl
Me methyl
MHz megahertz min minute(s) mol mole(s)
Ms methanesulfonyl
MS mass spectrometry; molecular sieves m/z mass to charge ratio (MS)
NaHMDS sodium hexamethyldisilazide xviii NMO 4-methylmorpholine N-oxide
NMR nuclear magnetic reasonance
p para
Ph phenyl
PMB p-methoxybenzyl
PMP p-methoxyphenyl
ppm parts per million
py pyridine
q quartet (NMR)
rt room temperature
s singlet (NMR); second(s)
t tertiary (tert) t triplet (NMR)
TBAF tetrabutylammonium fluoride
TBAI tetrabutylammonium iodide
TBS t-butyldimethylsilyl
TES triethylsilyl
Tf trifluoromethanesulfonyl
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
xix CHAPTER 1
INTRODUCTION
Introduction
1.1 Background
Ionophores were first recognized for their effect of stimulating energy-linked transport in mitochondria. Valinomycin isolated from Streptomyces fermentation1 was found to be a powerful decoupler of mitochondrial oxidative phosphorylation.2 When a
K+ selective electrode was inserted into the reaction medium, disappearance of K+ was
observed and was approximately equal to the quantity of hydrogen ions appearing. The
introduction of a true decoupling agent (e.g. dinitrophenol) restored the original K+ and
H+ concentration. Thus, it was deduced that valinomycin catalyzed an energy-linked ion exchange (Figure 1.1). The extreme ion selectivity was further demonstrated when Na+ proved an ineffective substitute for K+.3,4
Figure 1.1: K+ transport by valinomycin.
1 The generic term ionophore, i.e. ion carrier, was coined in order to describe the ion transport activity of valinomycin and nigericin (Figure 1.2) and to emphasize the dynamic aspects of the transport mechanism.5 Ionophores are compounds of moderate molecular weight (about 200-2000).
Nigericin Valinomycin
Figure 1.2: Naturally occurring ionophores.
Ionophores are broadly classified as small molecules, which act as either mobile ion carriers or channel formers. As mobile ion carriers, ionophores shield the charge of the ion from the surrounding environment, and thus enable transport across the hydrophobic interior of the lipid membrane. As channel formers, ionophores introduce a hydrophilic pore (Figure 1.3) into the membrane, allowing ions to pass through while avoiding contact with the membrane's hydrophobic interior.
Physical studies indicate that the complexation-decomplexation kinetics and diffusion rates of ionophores and their complexes across lipid bilayers are very favorable.
Their transport turnover numbers across biological membranes of the order of thousands per second,6 often exceed the turn over numbers of most macromolecular enzymes.
2
Figure 1.3: K+ transport by pore-forming ionophore.
Ionophores disrupt trans-membrane ion concentration gradients required for the proper functioning and survival of microorganisms, and thus have antibiotic properties.
Ionophores are produced naturally by certain microbes as part of a defense mechanism against competing microbes. Their high cation selectivity inspired consideration of ionophores as model biological carriers to increase the permeability of biological membranes, and provided the technological basis for novel series of ion selective
electrodes, which find clinical as well as laboratory applications.7-12
1.2 General structural features of ionophores
Molecular properties of ionophores facilitate their application in various investigative problems. Ionophores in general may be regarded as molecules with diverse structures containing strategically placed oxygen atoms. The backbone is capable of attaining critical conformations that orient these oxygen atoms in a ring or cavity in space into which a complexible cation may fit more or less snugly. The ligating oxygens can be part of various functional groups such as ether, alcohol, carboxyl, and amide. The neutral
3 oxygens ligate via ion-dipole interaction akin to solvation of ions in high-dielectric solvents. A representative ionophore metal complex is shown in Figure 1.4.
O O O K+ O O O
Figure 1.4: Representative ionophore metal complex.
Thus the ionophore solvates cations displacing the solvation shell of the solvent partly or completely. The polar groups of ionophore complexes orient towards the interior while the lipophilic part orients itself towards the exterior. The lipid solubility of the resulting complex can be explained by the effective shielding of the polar interior, which delocalizes the charge and by the compatibility of the complex exterior with solvents of low dielectric constant.
The ion selectivity of ionophores is a combined effect of the energy obtained on binding and energy required for the desolvation of the ion.13,14 For a relatively flexible backbone, the free energy of ionophore binding is controlled by the same considerations that determine the free energy of solvation, (i.e. the charge density of the ion); hence ion selectivity is minimal. For ionophores with rigid backbones, the free energy of complexation may be maximal for an ion of a critical ionic radius. Ionophores that form three-dimensional cages around the cation upon binding generally show superior selectivity compared to smaller more planar ionophores. The most remarkable example of
4 discrimination between two alkali ions of contiguous sizes is the 10,000:1 preference for
K+ (radius, r = 1.33Å) over Na+ (radius, r = 0.95Å) exhibited by valinomycin in both
biological and model systems.3,4,15
1.3 Naturally occurring polyether ionophores
The discovery of monensin, a polyether-containing spiroketal having ionophoric
properties, in 196716 initiated the extensive and wide-ranging interests in polyethers that
continues to this day. These ionophoric spiroketals also possess antibiotic characteristics.
Polyketide-derived polyether antibiotics produced by filamentous branching bacteria constitutes the third large class of spiroketals. Reviews of pharmacological,17 spectroscopic,18 structural,18,19 and synthetic18,20 aspects of these metabolites have been
studied. There are more than 80 polyethers that contain at least one spiroketal
substructure.
Select polyether antibiotics, (eg monensin21 and nonactin22-24) and several
synthetic tetrahydropyranoid podands have their ligating oxygens suitably preorganized
for effective coordination. Nonmacrocyclic host molecules exhibit weaker cation-binding
properties when compared to coronands and cryptands because of absence of such an
arrangement. Polyspiroethers of the type generalized by structures 1.1 and 1.2 (Figure
1.5) have ligating oxygen atoms in preorganized positions along with a rigid framework,
which can enhance cation-binding capability.
5
1.1 1.2
Figure 1.5: Polyspiroethers.
The effective binding capabilities of such host molecules are expected to be linked to the limiting conformational restrictions offered by the central belt and to the energy required to cluster the oxygens properly about the guest ion during complexation.
Knowledge of the extent to which 1.1, 1.2, and more extensively epimerized stereoisomeric arrays exhibit modified levels of cation coordination could infuse valuable insight into future synthetic design. In a program aimed at accessing these structural types, we developed ring expansion methodology which was used in the preparation of the trispiro isomers 1.3-1.5 (Figure 1.6).
1.3 1.4 1.5
Figure 1.6: Synthetic spiro ethers.
In 1990, we reported the first examples of the oxonium ion-initiated pinacolic ring expansion reaction.25 This discovery, which constitutes an extension of the long established Wagner-Meerwein26 and pinacol rearrangements,27 takes advantage of the 6 fact that ketone adducts of metalated vinyl ethers represented by 1.6 are amenable to conversion to oxonium ions such as 1.7 (Scheme 1.1) under acid-catalyzed conditions.
This first step triggers a subsequent 1,2-shift under steric and stereoelectronic control,
resulting in diastereoselective ring expansion and spiro ketone formation as exemplified
by 1.8.28
TsOH, CHCl3 O O O O OH O + H 1.6 1.7 1.8
Scheme 1.1: Pinacolic ring expansion.
The migratory aptitudes that come into play are predictably good,29 and the
differentiating elements that control product stereochemistry are reasonably well
understood.30 As a consequence, this process has seen serviceable application in the
synthesis of spirocyclic bis-C,C-glycosides,31,32 furanose and pyranose nucleosides,33 cis-
and trans-theaspirone,34 dactyloxene-B and -C,35,36 and (+)-grindelic acid.37,38
Our next advance into spirocyclic chemistry involves application of pinacolic ring
expansion methodology in the synthesis of 1,6-dioxaspiro[4.5]decane frameworks as
shown in Scheme 1.2. The adduct of lithiated dihydrofuran and cyclobutanone 1.9 is
amenable to acid-catalyzed pinacolic ring expansion. Subsequent transformations result
in the conversion of 1.11 to spiroketal 1.12.
7 O OH + O + O + H H O - H O O O
1.9 1.10 1.11 1.12
Scheme 1.2: Spiroketal synthesis using pinacolic ring expansion.
AL-2 and lissoketal (Figure 1.7) are two naturally occurring spiroketals that we
planned to synthesize using this methodology. AL-2, isolated from Artemisia lactiflora,
has been found to inhibit superoxide generation induced by a tumor promoter in
differentiated HL-60 cells.39 Lissoketal was isolated from the ascidian Lissoclinum voeltzkowi collected from sea grass blades in shallow waters in Palau. The present study will demonstrate the synthetic progress made towards the synthesis of naturally occurring spiroketals AL-239,40 and lissoketal41 via the pinacolic ring expansion pathway.
Lissoketal AL-2
Figure 1.7: Naturally occurring spiroketals.
During the synthesis of spiroethers 1.3-1.5 it was discovered that compounds 1.13 and
1.15 are amenable to equilibration via 1.14 under acid catalysis. Cyclization of the
tethered oxonium ion-enol intermediate 1.14 can occur by two pathways leading to
formation of 1.13 or 1.15 with resultant racemization (Figure 1.8).42 Rotation of either
8 terminus of the chain relative to the other chain prior to ring closure provides the means
for losing stereochemical "memory".
H O
H + H + O O O O O
O + O O
1.13 1.14 1.15
Figure 1.8: Acid-catalyzed equilibration of 1.13 and 1.15.
In order to explore the feasibility of equilibration of similar cyclopentanones under acid catalysis, it became vital that cyclopropanone replace cyclobutanone as the key building block. However, the high reactivity of cyclopropanone makes it inaccessible in preparative quantities in a laboratory setting.43,44 Alternatives45-49 previously published
were considered unfavorable in the present context. A more promising one-pot procedure
using 1,3-dichloroacetone was developed. This experimentally simple procedure offers a
versatile means for varying not only the dimensions of the central ring, but the number of
spirocycles attached thereto, as well as their individual size.50 The work to be presented
will demonstrate the successful synthesis of the desired cyclopentanones and evaluation
of their capability to equilibrate under acid catalysis.
1.4 Applications of ionophores
Some of the most chemically inert ionophores of the synthetic polyether series are
used to dissolve highly reactive compounds in to low-polarity solvents for organic 9 synthesis. Thus, the cryptands and crown ethers are capable of forming complexes with
KOH, KMnO4, and KBH4. The complexes provide solubility in organic solvents and can thereby tremendously accelerate saponification, oxidation, and reduction respectively, of
organic compounds. The enhancement of reaction rates is not only due to the increased
solubility of the reactant in the solvent but also due to increased effective radius of the
complexed cation, which discourages ion pair formation and thereby increases the
effective concentration of the reactive anion.51
Selective ion carriers are gaining increasing interest as tools for the analysis and
separation of metal ions as well as for many biological applications. Ionophores for
divalent cations and some alkali ions are well known,51-54 but thus far, very few carriers
specific for lithium ions have been described.
Gade reported in 1949 on the treatment of manic-depressive psychosis with
lithium salts.55 The efficacy of such lithium treatment was later firmly established.56
Lithium salts have since been used extensively and successfully in the treatment of manic depression and other neurological and psychiatric disorders.57 Blood normally contains only part per billion levels of lithium.58,59 Lithium is normally administered in the form of
lithium carbonate or other salts. The concentration of lithium in the blood must be
maintained over a narrow range of 0.5-1.5 mM.60 Below 0.5 mM the therapy may not be
effective, and if the concentration exceeds 1.5 mM, toxicity is manifested.61 A level of 5
mM can be lethal.62 Hence, the measurement and accurate monitoring of lithium levels is
important. A suitable technique should be capable of measuring therapeutic serum
lithium levels in the range 0.2-2 mM, in the presence of 140 mM sodium in blood.
10 Traditionally, lithium is readily measured by flame emission or flame atomic
absorption spectrometry,63,64 and results are reliable. However because of the high
instrumentation and operation costs, the bulkiness of the instrument and the desire to avoid compressed gasses and flames in the clinical laboratory, alternative measurement procedures have been investigated over the years. A major effort has been made to identify or create reagents that possess high selectivity for lithium relative to sodium.
Few are sufficiently selective to ignore the presence of sodium.
The other problem with lithium therapy is the slow penetration of lithium through the blood brain barrier and across other membranes.65,66 This results in a delayed onset of
action and necessitates the administration of relatively large doses, which may be the
cause of many undesirable side effects.
Lithium ion carriers could be potentially used in the detection and enhancement of
the uptake of lithium into the brain and other tissues. The design of lipophilic ionophores
for lithium cations is a difficult problem because the lithium ions are smaller than sodium
and potassium but strongly hydrated in aqueous solution.67 It is mainly for this reason
that few lithium ionophores have been synthesized. Examples of selective ligands for
lithium ions relative to sodium ions are the cryptands68 and spherands,69 which reached
remarkable binding selectivity. Some macrocyclic crown ethers70,71 as well as acyclic
polyethers72 and acyclic dioxa diamides73,74 which transport lithium ions in preference to
sodium ions through artificial membranes have also been synthesized. However, the ratio
of the selectivity of these carriers proved to be rather modest and did not exceed a value
of 10.70-74
11 We have previously described the synthesis and complexation properties of 1.16 and its homoditopic dimer 1.17.75-77 The rigid inositol ortho ester platform is particularly
well suited to strong ionophoric interaction with the lithium ion. This property, and
particularly the demonstrated preference of 1.16 for formation of a 2:1 complex with Li+, is shared by 1.17, which readily forms a rodlike ionic polymer upon treatment with
LiClO4 or LiBF4.
1.16
1.17
Figure 1.9: Spirotetrahydrofuran ionophores.
The spirotetrahydrofuran triad is particularly conducive to lithium ion affinity.
Smaller ring sizes bind less effectively, presumably because of the differing
polarizabilities of the nonbonded electron pairs.78 However, the rodlike ionic polymer
formed upon complexation is insoluble in common solvents making them inadequate as ionophores. Solubility of these complexes can be enhanced by introduction of additional
oxygen atoms. Consequently, it was decided to substitute the spiroether with spiroketal
12 units. The current study will bring to light the efforts taken towards the synthesis of
redesigned targets 1.18 and 1.19 to address the solubility problems.
1.18 1.19
Figure 1.10: Spiroketal ionophores.
Limited success achieved previously by cyclohexane-based frameworks has
inspired their use in an exploratory study towards bifacial chelation. The concept of
bifacial chelation relates to the capacity of a single molecular entity to coordinate to a
pair of metal ions residing on opposite faces of the organic core. The structural features
built-in to this phenomenon hold fundamental interest and could potentially serve a wide
range of applications. However, the reluctance of candidate substrates to become
involved in appropriate modes of geometric alignment has considerably slowed down
progress in this area.
Previously synthesized hexamethoxycyclohexane 1.2079,80 and its hexaspiro-
tetrahydrofuran homolog 1.2181,82 (Figure 1.11) are markedly inert to alkali metal ion
chelation. The vast preference for outward projection of the C–O bonds in 1.20 and 1.21
has been attributed83 to the operation of six stabilizing gauche interactions84-86 in the all
O-equatorial conformer.
13 1.20eq 1.20ax
1.21eq 1.21ax
Figure 1.11: Conformations of 1.20 and 1.21.
Several reported discoveries have demonstrated the feasibility of projecting multiple oxygenated centers in syn-axial fashion under suitable circumstances. This has been accomplished by employing bulky substituents to induce the peripheral groups to adopt the desired axial-rich conformational bias.87,88
We have sought to extend the length of the side chains in a manner that could allow metal ion complexation to materialize at sites more distal to the interconnective ring. At issue is the capacity for binding two M+ ions (Figure 1.12) in the manner reflected in 1.23. The differing stereochemistry of 1.24 disallows comparable bifacial ligation, but could be used as a comparative test case for possible 1:1 complexation as in
1.25.
14 1.22
1.23
1.24
1.25
Figure 1.12: Complexation of 1.22 and 1.24 with metal ions in the gas phase.
The presence of solvation along with other factors could influence the formation of entities such 1.23 and 1.25. Hence the capacity of polyether of generic formula 1.22 and 1.24 to bind alkali metal ions has been evaluated in both the liquid and gas phase, the latter with the aid of electrospray ionization mass spectrometry.89-92 Electrospray ionization is sufficiently gentle that non-covalent complexes can be transferred from solution to gas phase without disruption of the binding interactions of the complexes, thereby enabling accurate measurement of binding capacities of the polyethers synthesized. The work presented here will show the progress and successful synthesis of polyethers of generic formula 1.22 and 1.24 and evaluation of their ionophoric capability in solution and the gas phase by means of extraction studies and electrospray ionization mass spectrometry.
15 CHAPTER 2
EFFORTS DIRECTED TOWARD THE MULTIPLE SPIROKETALIZATION OF
CYCLOHEXANE
Efforts directed toward the multiple spiroketalization of cyclohexane
2.1 Background
Treatment of manic-depressive psychosis with lithium salts was reported by Gade in 1949.55 Lithium administered in the form of lithium carbonate or other salts has since
been used extensively and successfully in the treatment of manic depression and other
neurological and psychiatric disorders.57
Traditionally, lithium is readily measured by flame emission or flame atomic
absorption spectrometry.63,64 However, because of the high instrumentation and operation
costs, the bulkiness of the instrument, alternative measurement procedures have been
investigated. A major effort has been made to identify or create reagents that possess high
selectivity for lithium relative to sodium. Few are sufficiently selective to ignore the
presence of sodium.
Slow penetration of lithium through the blood brain barrier and across other
membranes65,66 results in a delayed onset of action and necessitates the administration of relatively large doses, which may be the cause of many undesirable side effects.
16 Lithium ion carriers could be potentially used in the detection and enhancement of
uptake of lithium into the brain. Lithium ions are smaller than sodium and potassium but
strongly hydrated in aqueous solution.67 It is mainly for this reason that few lithium
ionophores have been synthesized. Some macrocyclic crown ethers70,71 as well as acyclic
polyethers72 and acyclic dioxa diamides73,74 which transport lithium ions in preference to
sodium ions through artificial membranes have also been synthesized. However, the ratio
of the selectivity of these carriers proved to be rather modest and did not exceed a value
of 10.70-74
We have previously described the synthesis and complexation properties of 2.1 and its homoditopic dimer 2.2 (Figure 2.1).75-77 The rigid inositol ortho ester platform is
particularly well suited to strong ionophoric interaction with the lithium ion. This
property, and particularly the demonstrated preference of 2.1 for formation of a 2:1 complex with Li+, is shared by 2.2.
2.1 2.2
Figure 2.1: Spirotetrahydrofuran ionophores.
17 The spirotetrahydrofuran triad is particularly conducive to lithium ion affinity.
Smaller ring sizes bind less effectively, presumably because of the differing
polarizabilities of the nonbonded electron pairs.78 However, the ionic polymer formed
upon complexation is insoluble in common solvents making them inadequate as
ionophores. Solubility of these complexes can be enhanced by introduction of additional
oxygen atoms. Consequently, it was decided to substitute the spiroether with spiroketal units arriving at 2.3 and 2.4 (Figure 2.2).
2.3 2.4
Figure 2.2: Spiroketal ionophores.
2.2 Efforts towards the synthesis of the 1,3,5-trispiro system 2.3
2.2.1 First generation synthesis
The synthesis of key intermediate 2.7 was the first important goal to be
accomplished en route to the trispiro system. The synthesis begins with a known protocol
established by Kishi93 (Scheme 2.1). We were interested in myo-inositol since it would form a mono orthoester but not a bis orthoester and the pendant hydroxyl groups left
behind can be differentiated easily. Treatment of myo-inositol 2.5 with triethyl
orthoformate in DMF containing p-toluenesulfonic acid affords triol 2.6 in 90% yield.
18 OH OH OH OH O OH OH O HO HC(OEt)3, p-TSA, OH HO OH OH O DMF, 100 °C (90%) HO O O O O O O 2.5 2.6 2.7
Scheme 2.1: Synthesis of 2.7.
With the orthoester functionality in place, the stage was set to install the spiroketal units. Acid-catalyzed ketalization protocols cannot be applied to install the spiroketal units due to the acid sensitive nature of the orthoester functionality. With these issues in mind, we set about attempting different reaction protocols to effect the desired transformation.
Table 2.1 summarizes conditions investigated to install the hydroxyethyl side chains necessary for installation of the ketal units. Commonly used reaction conditions were not successful in installing the side chains. Recourse was made to a two-step procedure involving alkylation with 2-benzyloxyethyl tosylate followed by hydrogenolysis to yield desired intermediate Scheme 6.5 in 87% overall yield.
19 OH OH O OH OH O OH OH O O O O O O O 2.6 2.7 Reaction Conditions Result
OO S 1. O O No reaction , NaH, DMF, 0 °C
2. Br(CH2)2OH, DBU, THF, Δ No reaction
1. AllylBr, NaH, DMF, 0 °C 3. 2. O3, MeOH, DCM, -78 °C; Decomposition NaBH4, MeOH 1. BnO(CH2)2OTs, NaH, 4. DMF, 0 °C (90%) 87 % overall yield 2. Pd/C, H2, EtOAc (97%)
Table 2.1: Synthesis of 2.7.
Installation of the side arms brought us to triol 2.7 in an expedient and chemically
straightforward method. It was decided to used a protocol that involves closure of
hydroxyl ethyl side chains to ketal units by means of photochemical oxidation with
iodobenzene diacetate initiated by iodine.94 Since no acidic reagents are used, it was expected that the ketal units would have better chances of surviving sequential installation.
The reaction could not be carried out in benzene owing to the insolubility of the triol. Recourse was made to using dichloromethane as a replacement. To our disappointment, the reaction resulted in a complex, inseparable, acid-labile mixture of compounds. The presence of multiple CH sites connected to oxygen atoms is known to
20 cause a considerable drop in yield.94 The presence of the orthoester CH, which is known
to be sensitive towards radical reaction conditions,95 can be another reason for the failure
of the reaction.
OH O OH O O O O OH PhI(OAc)2, I2, O O O DCM, hν O O O O O O O 2.7 2.3
Scheme 2.2: Failed synthesis of 2.3.
Following these frustrating results, we decided to investigate the utility of neutral
reaction conditions to install the spiroketal units starting from the corresponding ketones.
2.2.2 Second generation synthesis
Among the plethora of procedures typically established for preparation of
acetals,96,97 only a few work under fairly mild reaction conditions.98-101 It has been shown earlier by Noyori101 that dioxolanation of carbonyl compounds under aprotic conditions
can be readily achieved by 1,2-bis(trimethylsiloxy) ethane in the presence of catalytic
amounts of trimethylsilyl trifluoromethanesulfonate (TMSOTf). Recently, a systematic
study of this protocol by Hwu99 has revealed that acid-sensitive groups such as THP
ethers were relatively stable under the reaction conditions at –78 °C.
Very recently, it was discovered that ketalization of carbonyl compounds can be
accomplished under neutral and aprotic conditions using iodine as a catalyst.102,103
21 Furthermore, the method tolerates a range of functional groups such as phenolic esters, and acid-sensitive THP and TBDMS ethers. Consequently, it was decided to use this protocol to install the spiroketal units starting from respective ketone precursors.
Selective protection of an equatorial hydroxyl group in 2.6 was accomplished by treatment with tert-butyldimethylsilyl chloride in DMF to yield diol 2.8 in 50% yield
(Scheme 2.3). Mono- and diprotection of the diol was accomplished by alkylation with benzyl bromide in DMF to yield benzyl ethers 2.9 and 2.10 in 85% and 70% yield, respectively. Dibenzyl ether 2.9 was treated with TBAF in THF to effect desilylation to form alcohol 2.11 in 83% yield. Alcohols 2.10 and 2.11 were then independently oxidized using the Swern oxidation protocol to provide ketones 2.12 and 2.13 in 88% and
84% yield, respectively.
OH OH OH O O O 2.6
TBSCl, Imid, DMF, 0 °C (50%)
OH OH O OH OBn OBn BnBr, NaH, DMF, (COCl)2, DMSO, OTBS OTBS OTBS 0 °C (70%) NEt , DCM, -78 °C O O 3 O O O O O (88%) O O 2.8 2.10 2.12
BnBr, NaH, DMF, 0 °C (85%)
OBn OBn OBn O OBn OBn OBn TBAF, THF, (COCl)2, DMSO, OTBS OH 0 °C (83%) NEt , DCM, -78 °C O O 3 O O O O O (84%) O O 2.9 2.11 2.13
Scheme 2.3: Synthesis of 2.12 and 2.13. 22 Attempted ketalizations of ketones 2.12 & 2.13 were unsuccessful with a variety of reaction conditions (Table 2.2 & 2.3). Mild conditions afforded no reaction while the more vigorous and forcing ones resulted in decomposition of the ketones.
O O OBn OBn OTBS O OTBS O O O O O O 2.12 2.14
Reaction Conditions Result
1. I2, TMSOCH2CH2OTMS, DCM, rt No reaction
2. I2, TMSOCH2CH2OTMS, DCM, reflux No reaction
3. I2, HOCH2CH2OH, DCM, rt Decomposition
4. I2, HOCH2CH2OH, DCM, reflux Decomposition
TMSOTf, TMSOCH CH OTMS, 5. 2 2 No reaction DCM, -78 °C, 6 h TMSOTf, TMSOCH CH OTMS, 23 % yield of TBS 6. 2 2 DCM, -60 °C, 6 h deprotected ketone TMSOTf, TMSOCH CH OTMS, 7. 2 2 Decomposition DCM, -50 °C, 2 h TMSOTf, TMSOCH CH OTMS, 8. 2 2 Decomposition DCM, -40 °C, 1 h
9. p-TSA, PhH, HOCH2CH2OH, reflux Decomposition
10. PPTS, PhH, HOCH2CH2OH, reflux No reaction
Table 2.2: Attempted conditions for the synthesis of 2.14.
23 O OBn O OBn OBn OBn O O O O O O O 2.13 2.15 Reaction Conditions Result
1. I2, TMSOCH2CH2OTMS, DCM, r.t. No Reaction
2. I2, TMSOCH2CH2OTMS, DCM, reflux No Reaction
3. I2, HOCH2CH2OH, DCM, r.t. No Reaction
4. I2, HOCH2CH2OH, DCM, reflux No Reaction
TMSOTf, TMSOCH CH OTMS, 5. 2 2 No Reaction DCM, -78 °C 6 h
TMSOTf, TMSOCH CH OTMS, 6. 2 2 Decomposition DCM, -60 °C 6 h
TMSOTf, TMSOCH CH OTMS, 7. 2 2 Decomposition DCM, -50 °C 2 h
TMSOTf, TMSOCH CH OTMS, 8. 2 2 Decomposition DCM, -40 °C 1 h
9. p-TSA, Benzene, HOCH2CH2OH, reflux Decomposition
PPTS, Benzene, HOCH CH OH, 10. 2 2 No reaction HC(OEt)3, reflux
11. PPTS, Benzene, HOCH2CH2OH, reflux No reaction
12. PPTS, Toluene, HOCH2CH2OH, reflux No reaction
Table 2.3: Attempted conditions for the synthesis of 2.15.
24 Following these disappointing results, it was decided to install the orthoester functionality at a later stage owing to the rigidity and acid sensitivity imparted by its
presence.
2.2.3 Third generation synthesis
Beginning with the previously synthesized alcohol 2.11, alkylation with allyl
bromide in the presence of sodium hydride in DMF afforded allyl ether 2.16 in 87% yield
(Scheme 2.4). The orthoester functionality was removed by treatment with p-
toluenesulfonic acid in methanol to yield a triol, which was subsequently treated with
methyl iodide in presence of sodium hydride in DMF to form trimethyl ether 2.17 in 72%
yield. The allyl group was cleaved by treating 2.17 with p-toluenesulfonic acid and
palladium on charcoal in methanol at reflux to afford alcohol 2.18 in 83% yield. Ensuing
oxidation of the alcohol 2.18 was accomplished successfully using the Swern protocol to
provide ketone 2.19 in 52% yield. The stage was set for installation of the first ketal unit.
OAllyl OBn OBn OBn OBn MeO OMe AllylBr, NaH, DMF, 1. p-TSA, MeOH, Δ OH OAllyl 0 °C (87%) 2. MeI, NaH, DMF O O BnO OBn O O O O (72%) OMe 2.11 2.16 2.17 OH O MeO OMe MeO OMe Pd/C, p-TSA, (COCl)2, DMSO,
MeOH, Δ, 0 °C (83%) Et3N, DCM, -78 °C BnO OBn BnO OBn (52%) OMe OMe 2.18 2.19
Scheme 2.4: Synthesis of 2.19.
25 A variety of methods were used in attempts to install the spiroketal unit starting
from ketone 2.19 (Table 2.4). To our disappointment we were unsuccessful in all attempts. Use of mild conditions resulted in no reaction while use of harsher conditions
resulted in decomposition of ketone 2.19. Unfortunately, synthesis of the desired trispiroketal could not be attained by the routes described herein.
O O O MeO OMe MeO OMe
BnO OBn BnO OBn OMe OMe 2.19 2.20 Reaction Conditions Result
1. I2, TMSOCH2CH2OTMS, DCM, rt No Reaction I , TMSOCH CH OTMS, DCM, 2. 2 2 2 No Reaction reflux
3. I2, HOCH2CH2OH, DCM, rt No Reaction
4. I2, HOCH2CH2OH, DCM, reflux No Reaction TMSOTf, TMSOCH CH OTMS, 5. 2 2 No Reaction DCM, -78 °C, 6 h TMSOTf, TMSOCH CH OTMS, 6. 2 2 No Reaction DCM, -60 °C, 6 h TMSOTf, TMSOCH CH OTMS, 7. 2 2 No Reaction DCM, -50 °C, 2 h TMSOTf, TMSOCH CH OTMS, 8. 2 2 Slow decomposition DCM, -40 °C, 1 h
9. p-TSA, PhH, HOCH2CH2OH, reflux Decomposition PPTS, PhH, HOCH CH OH, 10. 2 2 No reaction HC(OEt)3, reflux
11. PPTS, PhH, HOCH2CH2OH, reflux No reaction PPTS, Toluene, HOCH CH OH, 12. 2 2 No reaction reflux
Table 2.4: Attempted conditions for the synthesis of 2.20. 26 2.3 Efforts towards the synthesis of the hexaspiro system 2.4
2.3.1 First generation synthesis
2,6-Dibenzylidenecyclohexanone104 2.21 was synthesized by the condensation of benzaldehyde with cyclohexanone in the presence of sodium hydroxide in methanol
(Scheme 2.5). Treatment of unsaturated ketone 2.21 with ethane-1,2-diol in the presence of pyridinium p-toluenesulfonate gave the spiroacetal 2.22 in high yield based on recovered starting material (60% prod, 35% sm).
O H O O O O
NaOH, MeOH (70%) Ph Ph PPTS, (CH2OH)2, Ph Ph + PhMe Δ (95%)
2.21 2.22
Scheme 2.5: Synthesis of 2.22.
In order to generate the diketone 2.23, the doubly unsaturated ketal 2.22 was subjected to various conditions to oxidatively cleave the benzylidene units. To our surprise and disappointment, this reaction was unsuccessful under a variety of conditions as summarized in Table 2.5.
27 O O O O OO Ph Ph
2.22 2.23
Reaction Conditions Results
1. O3, MeOH, DCM, -78 °C Decomposition
2. O3, Pyridine, -78 °C Decomposition
3. OsO4, NaIO4, DMF Decomposition
4. m-CPBA, DCM; HIO4, THF, H2O, Δ No reaction
5. KMnO4/Al2O3, DCM Decomposition
Table 2.5: Failed attempt to synthesize 2.23.
After these disappointing attempts, recourse was made to a route in which the target hexaspiroketal would hopefully be synthesized in a single maneuver from the corresponding hexaketone.
2.3.2 Second generation synthesis
Self-condensation of glyoxal under alkaline conditions followed by in situ aerial oxidation afforded disodium salt of tetrahydroxyquinone 2.24 in 60% yield (Scheme
2.6).105 Further oxidation of 2.24 using 25% aqueous nitric acid resulted in formation of hexaketone 2.25 as an octahydrate.106 Attempts to ketalize hexaketone using various conditions failed largely due to its complete insolubility in organic solvents commonly used in ketalization reactions. Consequently, it was decided to use a more unconventional protocol.
28 O O O O O O NaO OH O O CHO Na CO , NaHCO , 25 % HNO in H O 2 3 3 3 2 O O CHO Air, H2O, 40 - 45 °C (80%) O O HO ONa O O (60%) OO OO O O 2.24 2.25 2.4
Scheme 2.6: Failed synthesis of 2.4.
The closure of hydroxyl ethyl side chains to ketal units by means of
photochemical oxidation using iodobenzene diacetate initiated by iodine94 does not
employ acidic reagents, therefore it was expected that the ketal units would have better
chances of surviving sequential installation.
2.3.3 Third generation synthesis
For this route, methyl α-D-glucopyranoside 2.26 was selected as the ideal
precursor. Commercially available methyl α-D-glucopyranoside was converted to glucopyranoside 2.27 in a two-step maneuver in 90% and 88% yield, respectively
(Scheme 2.7). Removal of the trityl group under mildly acidic conditions afforded alcohol 2.29, which was subjected to iodination according to a modification of Garegg’s method107 to yield the corresponding iodide 2.30. Upon treatment with sodium hydride in dimethyl formamide at room temperature the iodide 2.30 under went dehydroiodination the required olefin 2.31 in excellent yield.
29 OH OTr OTr O OMe O OMe O OMe TrCl, Et3N, DMAP, NaH, BnBr, DMF PPTS, MeOH, DMF, rt (90%) 0 °C (88%) DCM (1:1) (94%) HO OH HO OH BnO OBn OH OH OBn 2.26 2.27 2.28 OH I O OMe O OMe O OMe PPh3, Imid, I2, NaH, DMF (90%) PhH (95%) BnO OBn BnO OBn BnO OBn OBn OBn OBn 2.29 2.30 2.31
Scheme 2.7: Synthesis of 2.31.
With olefin 2.31 in hand, we examined its behavior towards mercury(II) chloride in aqueous acetone. Ferrier’s carbocyclic ring closure108 of the perbenzylated hex-5-
enopyranoside 2.31 gave β-hydroxy ketone 2.32 in good yield (Scheme 2.8). Treatment
of β-hydroxyl ketone 2.32 with ethane-1,2-diol in the presence of p-toluenesulfonic acid
gave the spiroacetal 2.33 in high yield.108 Alkene 2.34 was obtained from spiroacetal 2.33
by elimination of the corresponding mesylate under basic conditions.
O O OMe OOH OH 1. HgCl , Acetone, 1. (CH OH) , PTSA, 2 2 2 O H2O (1:1) (78%) PhH, Δ (92%) BnO OBn BnO OBn BnO OBn OBn OBn OBn 2.31 2.32 2.33
1. MsCl, Et3N, THF, O 0 °C (quant) O 2. KOtBu, THF, BnO OBn 0 °C (90%) OBn 2.34
Scheme 2.8: Synthesis of 2.34.
30 The olefin 2.34 was subsequently treated with OsO4/NMO to give diol 2.35 in
70% yield (Scheme 2.9). The diol was converted to the diallyl derivative 2.36 by alkylation with allyl bromide in 78% yield. Ozonolysis followed by a reductive workup with sodium borohydride afforded diol 2.37 in 83% yield.
OH O O O O OH O O OsO4, NMO, MsNH2, O AllylBr, NaH, DMF, O (CH3)2CO, H2O (70%) 0 °C (78%) BnO OBn BnO OBn BnO OBn OBn OBn OBn
2.34 2.35 OH 2.36 O 1. O , MeOH, DCM, O 3 O (1:1), -78 °C; O OH NaBH4, MeOH, BnO OBn DCM, -78 °C (83%) OBn 2.37
Scheme 2.9: Synthesis of 2.37.
Diol 2.37 was then subjected to photochemical ring closure by irradiating it in the presence of iodobenzene diacetate with iodine as an initiator (Scheme 2.10). Trispiroketal
2.38 was obtained in a very modest yield. The low yield could be potentially explained by the presence of numerous methylene fragments connected to oxygen which could b prone to participating in the ring closure. The benzyl ethers of the trispiroketal 2.38 were then removed under standard conditions to afford triol 2.39 in 90% yield. The triol was converted to the triallyl derivative 2.40 by alkylation with allyl bromide in 74% yield.
31 OH OH
O O OO O OO O O O O PhI(OAc)2, I2, O Pd/C, EtOAc O O O O PhH, hν (10%) H2, (90%) BnO OBn BnO OBn HO OH OBn OBn OH 2.37 2.38 2.39
O OO O
AllylBr, NaH, DMF, O O 0 °C (74%) AllylO OAllyl OAllyl 2.40
Scheme 2.10: Synthesis of 2.40.
Ozonolysis of 2.40 followed by a reductive workup with sodium borohydride afforded triol 2.41 in 77% yield (Scheme 2.11). An attempt was then made to install three ketals simultaneously by subjecting triol 2.41 to the previously employed photochemical ring closure used in the simultaneous installation of two spiroketals. To our disappointment, this maneuver could not be accomplished. The reaction resulted in a complex inseparable mixture of compounds with composition of the mixture changing with time, possibly indicating the extreme sensitivity of products formed. It was suspected that acetic acid formed in the reaction could be causing the decomposition of the hexaspiroketal. Attempts were made to perform the reaction in the presence of reagents which could remove any acid formed (such as calcium carbonate, sodium bicarbonate and propylene oxide). Unfortunately, these modifications did not change the end results of the reaction. Many other routes pursued in the quest for hexaspiroketal were less successful than those detailed here.
32 O O O O O O O O 1. O3, MeOH, DCM, O O O O 1. PhI(OAc) , I , O O (1:1), -78 °C; O O 2 2 O O NaBH4, MeOH, PhH, hν O O AllylO OAllyl DCM, -78 °C (77%) O O OO OO OAllyl O
OH OH HO 2.40 2.41 2.4
Scheme 2.11: Failed attempt to synthesize target 2.4.
2.4 Conclusion
Unfortunately, the syntheses of tri and hexaspiroketals were unattainable by the
routes described herein. Due to the apparent instability of the spiroketal functionality,
attention was diverted towards the design and synthesis of targets with polyoxygenated side chains as ligating sites.
33 CHAPTER 3
STEREODEFINED POLYOXYGENATED CYCLOHEXANES AS POSSIBLE
IONOPHORES
Stereodefined polyoxygenated cyclohexanes as possible ionophores
3.1 Background
The concept of bifacial chelation relates to the capacity of a single molecular entity to coordinate to a pair of metal ions residing on opposite faces of the organic core.
The structural features built-in to this phenomenon hold fundamental interest and could
potentially serve a wide range of applications. However, the reluctance of candidate
substrates to become involved in appropriate modes of geometric alignment has
considerably slowed down progress in this area.
For example, the all-trans hexamethoxycyclohexane 3.179,80 and its hexaspiro-
tetrahydrofuran homolog 3.281,82 are markedly inert to alkali metal ions. The vast
preference for outward projection of the C–O bonds in 3.1 and 3.2 has been ascribed83 to
the operation of six stabilizing gauche interactions84-86 in the all O-equatorial conformer.
Analogous vicinal stereoelectronic contributions are absent in the axial counterparts.
Energetic cost associated with multiple projection of alkoxy groups axially on the same
face of a cyclohexane (ca. 2 kcal/mol for each 1,3- interaction)83 is the other deterrent.
The inability to gain access to the all O-axial arrangements dismisses any possibility of
coordination to metal ions.
34 3.1-eq 3.1-ax
3.2-eq 3.2-ax
Figure 3.1: Conformations of 3.1 and 3.2.
One way to evade this complication is to lock in the proper conformational features as exemplified by 3.3.75,109,110 This is possible by taking advantage of a rigid
inositol orthoester platform, followed by linking both halves into a dimeric
arrangement.75,76 Much like its monomeric building block, 3.3 binds Li+ ions very
strongly. In addition, this homoditopic ionophore exhibits a strong preference for 2:1
stoichiometry and an inclination for conversion to a rodlike supramolecular ionic
polymer. This reactivity conforms to expectations for a bifacial ligand.
3.3
Figure 3.2: Homoditopic ionophore 3.3.
35 Despite these successes, the appeal offered by multifunctionalized cyclohexanes remains a siren call for more detailed investigation. The feasibility of projecting multiple oxygenated centers in syn-axial fashion under the proper circumstances has been demonstrated by several reported discoveries.
The first of these involves the natural product muellitol (3.4). Its three prenyl substituents are adequate to influence the peripheral hydroxyl groups to adopt the desired axial-rich conformational bias.87,88
3.4
Figure 3.3: Muellitol a natural product with axial peripheral hydroxyl groups.
Introduction of bulky silyl protecting groups can also help achieve ring inversion in this manner as shown in Figure 3.3. This phenomenon, known to occur already at the simple trans-1,2-cyclohexanediol level (as 3.5→3.6),111,112 is presently recognized to be operational as well in select scyllo-inositol derivatives represented by 3.7 and 3.8.113
36 3.5 3.6
3.7 3.8
Figure 3.4: Ring inversion achieved by introducing bulky silyl protecting groups.
These effects are in contrast to the state of affairs encountered in the
corresponding alkyl ethers and have, on the basis of detailed MM3 calculations, been
attributed to differences in repulsive and attractive steric interactions.112 There is thus
some degree of variability in the consequences of interactions between vicinal electron
pairs or polar bonds upon the relative stability of cyclohexyl conformations.
In the present exploratory study, we have sought to extend the length of the side
chains in a manner that could allow metal ion complexation to materialize at sites more
distal to the interconnective ring. At issue is the capacity for binding to two M+ ions in the manner reflected in 3.10. The differing stereochemistry of 3.11 disallows comparable bifacial ligation, but could possibly serve as a comparative test case for possible 1:1 complexation as in 3.12. Alternatively, a number of factors such as solvation forces could conspire to preclude the formation of entities such as 3.10 and 3.12. For this reason, we have evaluated the capacity of polyethers of generic formula 3.9 and 3.11 to bind to alkali metal ions both in solution and in the gas phase, the latter by electrospray ionization mass spectrometry.89-92
37 3.9
3.10
3.11
3.12
Figure 3.5: Complexation of 3.9 and 3.11 with metal ions in the gas phase.
The use of electrospray ionization mass spectrometry (ESI-MS)114 for the study of
host–guest complexation and molecular recognition has expanded greatly over the past
decade,89-92,115-120 in large part because electrospray ionization is sufficiently gentle that non-covalent complexes can be transferred from the solution to the gas phase without disruption of the binding interactions of the complexes. Characterization of the binding properties and selectivities of new ligands has traditionally been undertaken by well established NMR, potentiometric, spectrophotometric, and microcalorimetric methods,121 but ESI-MS has gained popularity due to its sensitivity, low sample consumption, ability to give unambiguous information about the stoichiometries of complexes, and compatibility with a wide range of solvents.115-120 Moreover, ESI provides a natural
means to bridge the solution to gas-phase transition, thus giving a novel way to screen the
38 binding properties of new ligands, to evaluate solvent effects, and to probe self-assembly
strategies. The strengths and limitations of ESI-MS for applications related to molecular
recognition,110,122-135 have been mapped and we report the examination of the binding
selectivities and stoichiometries of inositol derivatives here.
3.2 Synthesis of the polyoxygenated cyclohexanes
In contemplating workable routes to the target systems, pathways originating
from the known inositol orthoesters 3.13 and 3.19136 came to be regarded as most feasible. Threefold alkylation of the hydroxyl groups resident in 3.13 with 2-
(benzyloxy)ethyl tosylate137 in a DMF solution containing sodium hydride provided 3.14
efficiently (Scheme 3.1). This maneuver, in parallel with the like conversion of 3.15 to
3.16 had the purpose of proper chain elongation with positioning of a readily removable
benzyl protecting group at the end of all six pendant β-alkoxy ethyl groups. Subsequent
exhaustive hydrogenolysis of 3.16 could then be accomplished in a manner that
conveniently averted the problem of bringing 3.17 into contact with water, a medium in
which it is freely soluble. Under the conditions adopted for the generation of 3.17, it
proved necessary only to remove the palladium catalyst by filtration and to evaporate the
methanol in vacuo. The formation of hexaacetate 3.18 was routinely achieved by direct
acylation of the solid so isolated.
39 OBn OBn OBn
OH OH O O OH BnOCH CH OTs O OH 2 2 OBn p - TSA O BnOCH2CH2OTs NaH, DMF MeOH HO O NaH, DMF OH O (95%) O (92%) O OBn (90%) O O O O OBn
3.133.13 3.143.14 3.153.15
OBn OH OAc OBn OH OAc
O O Ac O, Et N O O Pd/C(10%), H2(1atm) O 2 3 O CH CN O O MeOH O O 3 O O O O O O OBn (99%) O OH (92%) O OAc OBn OH OAc OBn BnO OH HO OAc AcO 3.163.16 3.173.17 3.183.18
Scheme 3.1: Synthesis of 3.17 and 3.18.
A parallel approach with triol epimer 3.19 proceeded with essentially identical
efficiency at each of the five steps (Scheme 3.2). The capping of inositol by way of these
symmetrical intermediates was unmistakingly diagnosed at each stage by 13C NMR spectroscopy. Evidence that hydrolysis of the orthoester subunit in 3.14 and 3.20 was accompanied by conformational ring inversion was derived by comparison of 1H NMR spectra. The most notable diagnostic is the appreciably deshielded nature of the cyclohexyl methine protons in 3.20 (4.28–4.47 ppm) relative to those in 3.21 (3.90–3.97 ppm).138 Similarly, the conversion of 3.14 to 3.15 was accompanied by wholesale shifting
of all six methine protons to higher field (as 4.19–4.41 to 3.49–3.64 ppm, respectively).
40 OBn OBn OBn BnO OH O O HO OH BnOCH CH OTs O 2 2 p - TSA O OBn BnOCH2CH2OTs NaH, DMF OH O MeOH HO OH NaH, DMF O (90%) O (90%) O (84%) O O O O OBn
3.193.19 3.203.20 3.21 3.21
OBn OH OAc OBn OH OAc OH O O O O O Ac O, Et N O O OBn Pd/C(10%), H2(1atm) O 2 3 O OAc O MeOH O CH3CN O O O O O (96%) O (91%) O OBn OH OAc OBn BnO OH HO OAc AcO 3.22 3.23 3.24
Scheme 3.2: Synthesis of 3.23 and 3.24.
The stage was now set to proceed to the hexamethoxy derivatives 3.28 and 3.31.
To take advantage of the ready availability of triallyl orthoester 3.25,139 this heavily
functionalized system was subjected to sequential acid hydrolysis and chain extension as before (Scheme 3.3). Once 3.26 became available, recourse was made to ozonolysis to degrade the allyl subunits. Direct reduction of the trialdehyde with sodium borohydride gave rise to an intermediate that could be processed without difficulty as in the conversion to polyether 3.27. The route to 3.28 was completed uneventfully.
41 OBn
OAllyl OAllyl OAllyl O AllylO OBn 1. O , NaBH , MeOH OAllyl 1. p-TSA, MeOH O O 3 4 O 2. BnOCH2CH2OTs AllylO 2. Me2SO4, NaH, DMF O O (70%) NaH, DMF (92%) OBn 3.253.25 3.263.26
OBn OMe OMe OMe
O O O O O OMe O OMe O 1. Pd/C, H2 (1 atm), MeOH O O O O 2. Me2SO4, NaH, THF O OMe OMe (82%) OBn BnO OMe MeO
3.273.27 3.283.28
Scheme 3.3: Synthesis of 3.28.
The convenience associated with distributing side chain introduction into two distinctively separate operations offers some advantages. However, a shorter means for accomplishing a comparable goal in a stereoisomeric series is available as illustrated in
Scheme 3.4. In this instance, the chain extensions were performed with 2-methoxyethanol tosylate.140 By this means, tribenzyl ether 3.29141 could be transformed into 3.31 by way of only four discrete steps. No yields reported herein are considered to be optimized.
OMe OMe OMe OBn OBn OBn O OBn O O 1. p-TSA, MeOH BnO O 1. Pd/C, H2 (1 atm), MeOH O O OBn O 2. MeOCH CH OTs O 2 2 O OMe 2. MeOCH2CH2OTs O OMe O O OMe OMe NaH, DMF (90%) NaH, THF (40%) OMe MeO 3.293.29 3.303.303.31 3.31
Scheme 3.4: Synthesis of 3.31. 42 3.3 Solution phase complexation studies
The solution-phase association constants (Ka) were determined for six of the
+ + + polyethers defined above relative to Li , Na , and K picrates in a H2O–CHCl3 solvent mixture according to Cram’s extraction protocol.142 The pair of polyols 3.17 and 3.23
proved to be too insoluble in the organic phase to allow measurements. The data
compiled in Table 3.1 were conservatively determined with relatively high concentrations
of picrate salts and normalized to the level of 1:1 complexes only.
+ - + - [M ]aq + [Pic ]aq + [host]org ' [M Pic host]org
Host Li+ Na+ K+ 1. All-trans series 3.16 2.38 1.17 0.53 3.17 a 3.18 0.55 0.27 0.83 3.31 0.93 0.48 0.28
2. cis,trans series 3.22 1.65 0.18 0.23 3.23 a 3.24 0.96 1.40 0.10 3.28 0.61 0.56 0.06
a This host exhibits extremely limited solubility in CHCl3, thus precluding data collection.
Table 3.1: Association constants (Ka) determined by picrate extraction
from chloroform at 20 °C (× 104).
43 From the outset, it became clear that the ability of the benzyl and methyl ethers as
well as the acetates to extract any of the picrate salts was low. Compound 3.16 was
defined as exhibiting a very modest capability to complex lithium ions. However, a Ka value of 2.38×10-4 represents a chelating ability roughly three orders of magnitude lower
than that exhibited by 3.3. At least in solution therefore, little tendency is seen for any of
the alkali metal ions to position themselves comfortably in a binding pocket of the type
represented by 3.10 or 3.12. This conclusion is corroborated by NMR spectroscopy.
1 Figure 3.6: H NMR of 3.16 with different concentrations of LiClO4.
44 The latter technique is recognized to be a powerful tool for dissecting changes in conformation brought on by ligation. In the present study, 3.16 dissolved in
CDCl3/CH3CN (1:1) was titrated with 0.25 M equiv of lithium perchlorate until an equimolar level had been reached. At each incremental stage, the 1H and 13C spectra of the resulting solution were recorded (Figure 3.6 & 3.7).
13 Figure 3.7: C NMR of 3.16 with different concentrations of LiClO4.
45 Only very minor changes in carbon chemical shifts were noted at the maximum level of lithium salt. The same was true for the 1H spectra except for the six equivalent protons on the cyclohexane ring which migrated upfield from δ 2.90 to 2.69. This singlet also underwent some slight line broadening. These observations are viewed as confirmatory of the absence of significant complexation of 3.16 to Li+. The response of
3.22, a key member of the cis,trans series, proved to be entirely comparable.
3.4 Electrospray ionization-mass spectrometry measurements
Mass spectrometry studies were performed in the laboratory of Dr. Jennifer S.
Brodbelt at the University of Texas. The metal complexation properties of each potential ligand were assessed by analyzing solutions containing one host and one metal salt in
19:1 chloroform/methanol. This solvent mixture was employed to provide the closest possible correlation with binding affinity/selectivity determinations performed using conventional solution methods. Using this solvent, solutions containing KCl but no added
NaCl produced signals consistent with complexation of sodium rather than potassium.
Sodium is ubiquitous on glassware and in infusion tubing, and as a result sodium cationized species are often observed in electrospray experiments even when no sodium is added.
For comparison, 1:1 mixtures of ligand and metal salt were also analyzed in methanol, and potassium complexes were readily observed in this solvent. In the presence of added NaCl or LiCl, the polyethers produced abundant complexes from the 19:1 chloroform/ methanol solvent mixture. Electrospray spectra acquired for 3.17 and 3.23 under these conditions are shown in Figure 3.8.
46 The most abundant ions in these spectra are the metal-cationized ligands, (L+M)+ where L=inositol ligand and M=metal, which suggests that the 1:1 stoichiometry is preferred for both ligand isomers.
3.17 + NaCl 3.23 + NaCl
3.17 + LiCl 3.23 + LiCl
Figure 3.8: ESI-MS for equimolar solutions in 19:1 chloroform/methanol.
Other stoichiometries were also observed at somewhat lower abundance,
including the interesting bimetallic complexes of the general formula (L+2M+Cl)+. In the all-axial conformation, the ligands potentially present two metal binding ‘cavities’, so the
1:2 ligand/metal stoichiometry was expected as a possibility. The observed retention of
Cl- counterions in these species is rationalized because the presence of the counterion
reduces coulombic repulsion within the complex and should thereby improve its gas phase stability. Ions of the general formulae (2L+M)+ and (2L+2M+Cl)+ are also
47 observed in Figure 3.8 A–D, indicating that complexes containing two ligand moieties exist for 3.17 and to a somewhat lesser extent for 3.23.
The other inositol ethers produced a smaller number of distinct complexes than
3.17 and 3.23. The (L+M)+ ions were still the major species formed in the presence of both sodium and lithium, indicating that the 1:1 stoichiometry is again preferred. In many cases (L+2M+Cl)+ ions were also major species. The (2L+M)+ ions were far less
significant for these ligands, and the (2L+2M+Cl)+ ions were not observed at all. This
suggests that steric hindrance prevents the formation of the 2:1 and 2:2 ligand/metal
complexes in the analogs containing ether or ester groups at the end of each pendant arm.
The signal abundance ratios for (L+2M+Cl)+ to (L+M)+ complexes observed upon
ESI-MS of both the 19:1 chloroform/methanol and 100% methanol solutions were
estimated for each ligand/metal combination, and the results are given in Table 3.2.
Inspection of this data (also echoed in Fig. 3.8) shows that the bimetallic (L+2M+Cl)+ ions were generally more abundant for the all-trans ligands than for the cis,trans ligands.
In fact, the enhancement ranges from a factor of 2 to 6 for the all-trans ligands versus the cis,trans ligands in chloroform/methanol (19:1) up to an enhancement factor of 25 for
3.16 versus 3.22 in methanol.
The greater (L+2M+Cl)+/(L+M)+ ratios for the all-trans ligands suggests that the
three up–three down arrangement of chelating arms enhances the formation of the bimetallic complexes. The initial solvent environments also seem to influence the formation of the bimetallic complexes.
The exaggeration of the (L+2M+Cl)+/(L+M)+ intensity ratios for the methanol
solutions relative to the chloroform/ methanol solutions suggests an increased
48 stabilization of the bimetallic complexes in the more polar solvent. Furthermore, the
(L+2M+Cl)+ ions were observed with greater relative signal intensities for M=Na over
M=Li, which implies that bimetallic coordination is less favored for smaller more charge-
dense cations. Tight binding of a metal ion in one cavity may distort the cyclohexane ring in such a way as to disfavor coordination of a second metal ion.
Ligand Solvent = 19:1 Solvent = methanol chloroform/methanol
M=Na M=Li M=K M=Na M=Li 3.16 1.0 0.5 0.8 0.25 0.03 3.22 0.2 0.25 0.03 0.01 0.01 3.18 0.3 0.1 1.2 0.2 0.15 3.24 0.1 0.03 0.1 0.03 0.03 3.17 0.6 0.3 0.4 0.25 0.05 3.23 0.1 0.1 0.3 0.05 0.1 3.31 0.4 0.8 0.15 0.1 0.3 3.28 0.1 0.3 0.3 0.02 0.1
Table 3.2: Signal abundance ratios, (L+2M+Cl)+/(L+M)+ by ESI-MS.
To further characterize the ligand–alkali metal interactions, many of the
complexes were individually isolated and subjected to collisionally activated dissociation
(CAD). Typical results are shown in Figure 3.9 for the (L+2Na+Cl)+ and (2L+2Na+Cl)+ ions observed for 3.17. For the (L+2Na+Cl)+ parent species, two major fragmentation
pathways are possible: loss of Cl- to yield the doubly charged (L+2Na)+2 ion, and loss of
NaCl to yield the singly charged (L+Na)+ ion. The spectrum in Figure 3.9A illustrates
49 that the latter pathway is followed exclusively, which lends support to notion that
coulombic effects destabilize (L+2M)+2 species.
(3.17+2Na+Cl)+
(2×3.17+2Na+Cl)+
Figure 3.9: Collisionally activated dissociation.
The same result was obtained for all other (L+2M+Cl)+ ions probed by CAD,
regardless of the identity of either the ligand or the metal. For the (2L+2Na+Cl)+ parent ions, several fragmentation pathways might be expected to give observable products, including loss of Cl-, loss of NaCl, loss of L, and possibly loss of (L+NaCl)0. Of these, only loss of one ligand was observed (Fig. 3.9B).
These CAD results shed some light on the structures of the gas-phase complexes.
Based on the exclusive loss of NaCl from the bimetallic (L+2Na+Cl)+ complexes, these
structures are best rationalized as ones in which one metal is strongly coordinated via
electrostatic interactions with the oxygen atoms on one face of the inositol plane, and
NaCl is more loosely bound as an ion pair on the other face of the inositol plane.
The (2L+2Na+Cl)+ ions are likely sandwich complexes in which one Na+ ion is bound between two inositol ligands, and a NaCl ion pair is loosely bound to the opposite 50 faces of one of the inositol ligands. Upon CAD, the exclusive loss of one of the inositol ligands suggests that steric factors prevent strong binding of both inositol ligands to the central metal ion.
To assess the metal dependence of ligand binding, solutions containing one inositol derivative and 1 equiv each of lithium, sodium, and potassium chloride were analyzed by ESI-MS. Results acquired for 3.17 and 3.23 are given in Figure 3.10, and clearly show that (L+Li)+ ions were the most abundant species. Similar results were obtained for all other analogs, indicating that the ligands in this series strongly prefer lithium to sodium and potassium. Neither the identity of the substituents nor the arrangement of the chelating groups on the cyclohexane core significantly altered the metal selectivity.
3.17+LiCl+NaCl+KCl 3.23+LiCl+NaCl+KCl
Figure 3.10: ESI-MS for equimolar solutions in 19:1 chloroform/methanol.
51 3.5 Conclusion
The ionophoric potential of polyethers of type 3.9 or 3.11 is obviously dependent
on recognition by the alkali metal ion of the availability of ligating sites at the termini of
the other two chains residing in a 1,3-diequatorial relationship. For the cation-binding
properties of these potential hosts to come into play in the manner defined in 3.10,
numerous solvent molecules require displacement so that a hold can be gained on
achieving proximity for the appropriate oxygen atoms. The entropic and enthalpic costs
of structural rigidification will also need to be paid. The fact that alkali metal ions, and
particularly Li+, are not well accommodated in an aqueous environment emphasizes that these entities are not conducive to orienting their side chains axially in this medium. The
ESI-MS results illustrate the enhanced ability of the all trans ligands to form bimetallic complexes of the type (L+2M+Cl)+ where L=inositol ligand and M=metal. Dissociation
of the bimetallic complexes suggests that one metal is coordinated to each face of the
inositol plane.
52 CHAPTER 4
SYNTHESIS AND LEWIS ACID-INDUCED EQUILIBRATION OF DISPIRO Α-
KETO ETHERS
Synthesis and Lewis acid-induced equilibration of dispiro α-keto ethers
4.1 Background
The feasibility of inducing epimerization in molecules consisting of two
neighboring quaternary carbon centers is seldom encountered. One way to facilitate this
process is to suitably position a heteroatom such as an ether oxygen or a divalent sulfur β
to a carbonyl group.29,143 This structural arrangement under acidic conditions allows the
operation of a push-pull fragmentation of the cycloalkanone, with subsequent reconstitution of the original but now stereochemically scrambled substrate.42
The equlibration of 4.1 with 4.2 via 4.3 under acid catalysis is illustrative of the process (Figure 4.1). Cyclization of this tethered oxonium ion-enol intermediate 4.3 can occur by two pathways leading to formation of 4.1 or 4.2 resulting in racemization that has been observed experimentally.42 Rotation of either terminus of the chain relative to
the other chain prior to ring closure provides the means for losing stereochemical
"memory".
53 H O
H + H + O O O O O
O + O O
4.1 4.3 4.3 4.2 4.2
Figure 4.1: Acid-catalyzed equilibration of 4.1 and 4.2.
Synthetic constraints have limited studies involving such molecular frameworks to di- and trispirocyclic cyclohexanone systems. In order to explore a more representative
array of congeners, it became vital that cyclopropanone replace cyclobutanone as the key
building block. However, the highly reactive nature of this compound makes it
inaccessible in preparative quantities in a standard laboratory setting.43,44 Most often,
recourse has been made to release of the three-membered cyclic ketone from its ethyl
hemiketal,45,46 1-acetoxycyclopropanol,47 or a select carbinolamine.48,49 None of these alternatives were considered to be particularly desirable in the present context.
A more promising alternative originated from reports that appeared several decades ago indicating that 1,3-dichloroacetone undergoes straightforward 1,2-addition in the presence of Grignard reagents. Subsequent exposure of these adducts to ethylmagnesium bromide and iron(III) chloride then furnished 1-substituted cyclopropanols.144,145 At a later date, Barluenga discovered that the initial Grignard
adducts are amenable to reductive cyclization when treated with MgBr2 and lithium
powder or more conveniently with lithium naphthalenide in THF.146 We have come to
favor the latter approach to reactive three-membered carbinols, and detail here the
54 advantages that materialize when this chemistry precedes application of the oxonium-ion
initiated pinacolic ring expansion.28,30 The use of 1,3-dichloroacetone in this manner
offers an experimentally simple one-pot procedure and versatile means for varying not
only the dimensions of the central ring, but the number of spirocycles attached thereto, as
well as their individual size.50
The end products obtained after oxonium-ion initiated pinacolic ring expansion
are subject to solution-phase epimerization studies in the presence of boron trifluoride
etherate. MM3 calculations have also been performed in order to gauge the relative stabilities of the isomer pairs in the gas phase, and, in combination with AM1 semi-
empirical calculations, the thermodynamically preferred geometry of the putative
oxonium ion intermediates.
4.2 Synthesis
The deprotonation of 2,3-dihydrofuran with tert-butyllithium147 proceeds
efficiently to produce the anion 4.5 whose condensation with 4.4 gives rise to alkoxide
4.6 (Scheme 4.1). Direct reductive dechlorination of 4.6 with a solution of lithium naphthalenide in THF at -78 to 20 ºC promoted conversion to cyclopropanol 4.7 after workup. Overnight stirring of 4.7 with a small quantity of Dowex-50W resin at room temperature resulted in smooth conversion to the volatile spiro ketone 4.9, which was isolated in 65% overall yield from 4.4.
55 , THF, -78 °C O + - O Li Li O O Cl Cl 4.54.5 Cl Cl Lithium naphthalenide 4.4 4.6 THF, -78 °C
Dowex - 50W OH O ether, rt O O + (65% over 2 steps) OH O 4.74.7 4.8 4.8 4.94.9
Scheme 4.1: Synthesis of 4.9.
When comparably direct use was made of 3,4-dihydropyran as the anticipated
precursor to lithiated 3,4-dihydropyran, a diverse array of products were formed in low
yield following exposure to 4.4. This situation was remedied by effecting transmetalation
instead via stannane 4.10.148 This alternative means for the generation of lithiated 3,4-
dihydropyran and its further processing as in Scheme 4.2 furnished 4.14 with an overall efficiency of 75%.
, n-BuLi, THF, -78 °C O Li+O- O OSnBu3 Cl Cl 4.10 Cl Cl Lithium naphthalenide 4.44.4 4.10 4.11 4.11 THF, -78 °C; H2O
Dowex - 50W OH O ether, rt O O + (75% over 2 steps) OH O 4.124.12 4.11 4.134.14 4.14
Scheme 4.2: Synthesis of 4.14.
56 The combination of 4.9 with 4.10 produced carbinols that proved amenable to
ring expansion in the presence of oven-dried Dowex-50W resin. Consequently,
cyclopentanones 4.17 and 4.18 were formed as a chromatographically separable mixture
in a single laboratory manipulation. The dominance of the more polar syn isomer 4.17 by
the margin of 8:1 is noteworthy.
1. , n-BuLi, THF, -78 °C O O OSnBu3 O O 4.10 O + 2. oven-dried DOWEX - 50W, O O ether ( 50% ) O 4.9 4.17 4.17( 8 : 1 ) 4.18
Scheme 4.3: Synthesis of 4.17 and 4.18.
Our attention was next directed to the acquisition of analogs characterized by the
presence of a spirotetrahydropyranyl unit β to the ketone carbonyl. The response of 4.14
to the action of 4.5b and subsequent ring expansion proceeded in a manner closely
comparable to the precedent set by 4.9. Once again, the syn isomer 4.19 was more prevalent in the product mixture (4:1, Scheme 4.3).
A striking difference in behavior was encountered following preparation of the tertiary carbinol from 1,2-addition of 4.10c to 4.14. In contrast to its congeners, this intermediate proved to be unusually sensitive to the presence of Dowex-50W. When the targeted ring enlargement could not be brought about in this manner, other promoters were sought and silica gel slurried in CH2Cl2 proved to be workable. With this catalyst,
57 isomerization proceeded slowly. After 3 days, a mixture of 4.21 and 4.22 richer in the syn
isomer was generated and chromatographically separated.
1. , THF, -78 °C O O O Li O O 4.54.5 + 2. oven-dried DOWEX - 50W, O ether ( 50% ) O
4.194.19( 4 : 1 ) 4.20 4.20
O O 4.14 1. , n-BuLi, THF, -78 °C 4.14 O O OSnBu3 O O 4.104.10 O + 2. SiO2, CH2Cl2, ( 10% ) O 4.214.21( 20 : 1 ) 4.22 4.22
Scheme 4.4: Synthesis of 4.19 - 4.22.
The diminished efficiencies of the ring expansions involving 4.14 are a likely reflection of enhanced steric congestion in the vicinity of the reaction centers. The stereochemical assignments to all of the dispiro ketones have been documented50 based on distinctive 1H NMR spectral features and polarity considerations.
4.3 Stereoselectivity Considerations
In line with ample precedent, the migratory aptitudes associated with 1,2-shifting
to the oxonium ion center strongly favor translocation of the more electron-rich
neighboring carbon atom.28-30,34-37 The end result is preferred migration of that adjacent
carbon atom which is the more highly alkylated. 58 The only restriction is the requirement that the migrating bond be capable of being properly aligned with the pπ-orbital resident at the electrophilic center. In the
present examples, the degrees of freedom are such that two modes of structural staging
are possible for each product isomer. The conformational facets of the conversion of 4.14 to 4.19 and 4.20 are exemplified in Scheme 4.5. At issue is the diastereoselectivity of oxonium ion capture, a phenomenon that holds considerable fascination.30
A. Syn isomer production
O O O O + O O H 4.234.23 4.19’4.19'
+ O O O O
O O H 4.244.24 4.19”4.19"
B. Anti isomer production
+ O O O O O O H 4.25 4.20”4.20'
O O O O + O O H 4.26 4.20’4.20"
Scheme 4.5: Formation of syn and anti isomers.
59 One sees that 4.23 and 4.24 are capable of arriving at 4.19' and 4.19", while 4.25 and 4.26 lead instead to 4.20' and 4.20", respectively. The possibility exists, of course, that the relative magnitude and direction of stereoselectivity is founded only on steric grounds, an analysis made acceptable by the kinetically irreversible nature of the conversion to products. In this connection, it is perhaps insignificant that the ratio of diastereomeric tertiary carbinols (for example, the precursors to 4.23/4.24 and 4.25/4.26) is not known with precision. The key outcome is the favored proximal placement of the methylene groups as in 4.19' or of the ether oxygen atoms as in 4.19" relative to the pair of alternatives 4.20' and 4.20" where nonbonded CH2/O interaction develops.
+ a O b H O O 4.274.27 ab
O O O O
O O 4.284.284.29 4.29
Figure 4.2: Possible ring expansion pathways.
The change from a flexible envelope arrangement having pseudorotational capability as in tetrahydrofurans to well defined axial/equatorial status in tetrahydropyrans because of the adoption of chair-like arrangements is a dramatic one. As a result, the diastereoselectivity associated with migrations involving six-membered 60 oxonium ions can be projected to be more pronounced. Thus the conversion of 4.27 to
4.28 should occur more readily and its formation not deterred as in 4.29 because of the development of boat-like features.
Calculations show149 that the oxonium functionality preferentially orients its
oxygen antiperiplanar to the hydroxyl substituent as seen in 4.24. This conformer will
then rearrange to syn isomer 4.19", which would explain in part the overall preference for more prevalent formation of dispirocyclopentanones 4.17, 4.19, and 4.21.
4.4 Lewis acid-induced isomerizations
On an allied front, the ability of the various syn/anti isomer pairs to interconvert
when heated in the presence of boron trifluoride etherate has been examined. An
important distinction to be made regarding isomerizations of the type 4.1 ' 4.2 is that now kinetic control is not operative. All of the ketones prepared in the course of this investigation were treated in a comparable manner involving chloroform as solvent. The results are compiled in Table 4.1.
Chlorinated solvents proved most well suited to these processes, with interconversion being optimal in the indicated medium. Except perhaps for the
4.15 ' 4.16 example, complete equilibration was not reached for the majority of the
isomerizations. Higher temperatures and longer reaction times only enhanced the extent
of accompanying decomposition. Under no circumstances did 4.21 and 4.22 interconvert.
Molecular mechanics (MM3) calculations were performed on four sets of
isomers. The conformational searching was performed with recourse to the Monte Carlo
simulation capability in MacroModel version 5.0. A minimum of 1,000 simulations were
61 determined per structure and involved operations featuring one bond closure (1.0-3.0 Å) in all rings. The minimum energy diagrams were visualized with Chem 3D ultra.
O O O BF3•OEt2, CHCl3 O ( 1 : 1 ) 80 % O
O 4.15a ( 1 : 1 ) 80 % 4.16a
O O O BF3•OEt2, CHCl3 O ( 1.25 : 1 ) 65 % O
O 4.17 ( 1.11 : 1 ) 57 % 4.18
O O O BF3•OEt2, CHCl3 O ( 1.13 : 1 ) 70 % O
O
4.19 ( 1.2 : 1 ) 60 % 4.20
O O O BF3•OEt2, CHCl3 O
O O
4.21 4.22
Table 4.1: BF3•OEt2 induced isomerizations. a Data provided by Dr. David Hilmey.
A conformational model of the lowest energy conformation of each of the 8 structures is illustrated in Figure 4.3, and the associated steric energy values are compiled in Table 4.2. These data reveal the cyclopentanone systems to have rather similar strain energy differences ranging from 2.6-2.8 kcal/mol.
62 O O O O
O O 4.15 4.16
O O O O
O O 4.17 4.18
O O O O
O O
4.19 4.20
O O O O
O O
4.21 4.22
Figure 4.3: Lowest energy conformations.a a Energy calculations were performed by Dr. David Hilmey
63 Compound ESteric (kcals/mol) Compound ESteric (kcals/mol) ΔE (kcals/mol)
O O O O
O 57.5 54.8 -2.7 O 4.15 4.16
O O O O
O 52.1 49.3 -2.8 O 4.17 4.18
O O O O
O 46.7 44.1 -2.6 O
4.19 4.20
O O O O O 51.9 49.3 -2.6 O
4.21 4.22
Table 4.2: MM3-derived steric energies.a a Energy calculations were performed by Dr. David Hilmey
These values indicate the anti isomers to be thermodynamically stable to the
extent of 95:5 at rt. 4.16 has both of its heteroatoms oriented pseudoaxially. Isomer 4.15
projects its alpha C-O bond in a pseudoequatorial fashion. The latter preference persists
when the α-spirocycle is expanded to the tetrahydropyranyl level as seen in 4.17. We conclude that the [4,4] and [4,5] dispiro systems, including 4.19/4.20 and 4.21/4.22, have lower energy when the capability exists to orient the α- and β-heteroatoms pseudoaxially.
In the mixed systems, the tetrahydropyranyl ring, whether situated α or β to the ketone as in 4.19 and 4.21 likewise prefers to adopt a pseudoaxial orientation placing the 64 tetrahydrofuranyl ring in a seemingly less favorable equatorial position. This
conformational dominance by the six-membered heterocycle is noteworthy.
At the experimental level, the acid-catalyzed equilibrations of pure samples of
4.15-4.20 gave rise to product mixtures approximating 1:1. In light of the energy
differences determined in the gas phase for these syn/anti isomer pairs, these distributions
appear not to be controlled by ground state energetics. We can hypothesize, though, that
the final distribution is influenced by solvent effects, and more strongly by coordination
with the one equivalent of BF3•OEt2. This latter association is likely leveling the
energetic differences seen between syn and anti isomers, either through altered
conformation or by steric and electronic factors. On the other hand, the epimerizations
have proven quite useful as a means for funneling one stereoisomer into another. The
initial experiments, which were performed with catalytic levels of BF3•OEt2, fared poorly. Subsequently, the use of catalytic quantities was abandoned in favor of a full equivalent of Lewis acid, despite the possibility that such high levels of promoter could play a role in leveling the relative amounts of isomers in each subset.
4.5 Conclusion
In conclusion, the isomerization of 4.15-4.20 with stoichiometric amounts of
Lewis acid does not adhere to thermodynamic control largely due to acid coordination and solvent effects. 4.21 and 4.22 are unresponsive to these conditions. The energetic preference is biased in favor of the anti relationship of the C-O bonds with one exception.
The tetrahydrofuran and tetrahydropyran spirocycles favor axial oxygen orientations in the dispiro examples regardless of ring size.
65 CHAPTER 5
EFFORTS TOWARDS THE TOTAL SYNTHESIS OF AL - 2
Efforts towards the total synthesis of AL - 2
5.1 Background
Spiroketals enjoy widespread occurrence as substructures of naturally occurring substances from many sources. The increasing importance of compounds containing spiroketal assemblies has triggered immense interest in both their synthesis and reactivity. The earliest examples of spiroketal structure in nature are the steroidal saponins and sapogenins. These compounds were isolated from plants found in the
United States and Mexico during the 1930s and 1940s. At that time, the steroid nucleus of these compounds was of more interest to synthetic chemists and the spiroketal fragment was neglected. The two most common spiroketal substructures are illustrated in
5.1 and 5.2.
O O O H H
O O H H H H H H H H HO HO H H Hecogenin Sarsasapogenin 5.1 5.2
Figure 5.1: Steroidal saponins and sapogenins.
66 AL-2 (Figure 5.2) falls under the class of naturally occurring spiroketals. AL-2,
isolated from Artemisia lactiflora, has been found to inhibit superoxide generation
induced by a tumor promoter in differentiated HL-60 cells.39 The most noteworthy
feature in the structure of AL-2 is the presence of [4.5] spiroketal system.
AL-2 Figure 5.2: Spiroketal AL-2.
Discovery of the oxonium ion-mediated pinacolic ring expansion reaction by our group led to the synthesis of spirocyclic bis-C,C-glycosides,31,32 furanose and pyranose
nucleosides,33 cis- and trans-theaspirone,34 dactyloxene- B and -C,35,36 and (+)-grindelic
acid.37,38 Our next advance into spirocyclic chemistry involved application of the
pinacolic ring expansion methodology in the synthesis of 1,6-dioxaspiro[4.5]decane
frameworks as shown in Scheme 5.1. The adduct of lithiated dihydrofuran and
cyclobutanone, viz 5.3, is amenable to acid-catalyzed pinacolic ring expansion.
Subsequent transformations were expected to result in the conversion of 5.5 to spiroketal
5.6.
O OH + O + O + H H O - H O O O
5.3 5.4 5.5 5.6
Scheme 5.1: Proposed spiroketal synthesis using pinacolic ring expansion.
67 5.2 Synthetic approaches to AL-2
5.2.1 Synthesis plan
The first total synthesis of AL-2 was accomplished by Miyakoshi and Mukai150 in
2003. Their synthesis strategy revolves around the palladium(II)-catalyzed formation of
spiroketal 5.8 from the corresponding 1-yn-4-enone 5.11 reported by Kato and Akita very
recently.151,152 Thus, ketone 5.11, prepared from diethyl L-tartrate, would be expected to
undergo a one-pot construction of the core framework of the natural product (Scheme
5.2). This transformation involves palladium(II)-catalyzed formation of intermediate 5.10
and/or the hemiacetal species 5.10'. This is followed by capture of transient oxonium ion
species 5.10 by the hydroxyl group, and/or nucleophilic attack by the hemiacetal hydroxyl group on the activated triple bond of 5.10'. Finally the palladium-mediated carbon monoxide insertion reaction occurs leading to the 1,6-dioxaspiro[4.5]decane skeleton 5.8 having an (E)-alkoxycarbonylmethylidene moiety.
R3 R3 R3 R1O O R1O O R1O O CO O O 4 O R2O R2O R OH R2O
4 R O2C LnPd(II) 5.7 5.8 5.9
3 3 R R R3 1 1 R O HO R O O HO R1O OH and/or 2 O 2 OH EtO2C R O R O CO Et R2O O 2 OH LnPd(II) LnPd(II) diethyl L-tartrate 5.10 5.10’ 5.11
Scheme 5.2: Retrosynthetic analysis.
68 5.2.2 Mukai’s total synthesis of AL-2
Mukai was able to prepare the precursor for the one-pot installation of the core
starting from diethyl L-tartrate in eleven steps (Scheme 5.3). The key transformation of
constructing the spiroketal core 5.13 from acyclic ynone system 5.12 occurred in 41%
yield. Further, the synthesis of AL-2 from spiroketal 5.13 was accomplished in nine
steps.
TBSO BnO O OH OBn 1. p-TsOH, THF, 11 Steps H2O, rt EtO2C TBDPSO CO Et O 2 2. Pd2(dba)3.CHCl3, TBDPSO OH O CO, MeOH, MeO2C diethyl L-tartrate 5.12 benzoquinone, rt 5.13 (41%) O O 9 Steps O
AL-2
Scheme 5.3: Total synthesis of AL-2.
5.3 First generation synthesis
5.3.1 Synthesis plan
We sought to provide an efficient route to AL-2 by rapid formation of the [4.5] spirocyclic core prior to peripheral functionalization. Scheme 5.4 illustrates our strategy, beginning with the adduct of lithiated dihydrofuran and cyclobutanone 5.3. This step would be followed by pincolic ring expansion initiated by formation of a bromonium ion.
The racemic ketone 5.16 will then be resolved followed by ring expansion by way of
Baeyer-Villiger oxidation to form the core spiroketal framework. The lactone portion of 69 the molecule was then to be transformed to the six-membered cyclic ether part of the molecule to form 5.15. The furan ring was then to be transformed into the cyclic enol
ether part of the molecule.
O O Br O O O O O
O 5.14 5.15 AL-2
O Br Ring Expansion
O O OH 5.16 5.3
Scheme 5.4: Spiroketal core synthesis plan.
5.3.2 Attempted synthesis of spirocyclic core
Bromoketone 5.16 was synthesized from the adduct of lithiated dihydrofuran and
cyclobutanone by means of pinacol rearrangement initiated by bromonium ion
formation.153 Attempts were made to resolve the bromoketone by means of ketalization
with optically pure (S)-mandelic acid to afford diastereotopic ketals 5.17 and 5.17', which
can then be separated by column chromatography. More commonly used conditions were
attempted and proved to be unsuccessful. Use of forcing conditions resulted in
racemization of bromoketone 5.16 presumably by formation of the oxonium ion.
70 O Ph Ph O
Br Br Br O O O O O Ph O Conditions + + HO OH O O O ( +_ ) 5.16 5.17 5.17’
Conditions Results
1. PPTS, PhH, Reflux No Reaction 2. PPTS, PhMe, Reflux No Reaction 3. PTSA, PhH, Reflux Racemization 4. PTSA, PhMe, Reflux Racemization
5. HC(OEt)3, PPTS, PhH, Reflux No Reaction HC(OEt) , PPTS, PhMe, 6. 3 No Reaction Reflux
7. HC(OEt)3, PhMe, Reflux Racemization/ Decomposition
Table 5.1: Ketalization conditions and results.
We then proceeded to reduce the bromoketone to the corresponding alcohol.
Luche conditions154 were used to carry out this maneuver, which is known to proceed
stereoselectively,153 maintaining a syn relationship between the bromide and resultant
alcohol functionality. Attempts were made to resolve the bromoalcohol by forming esters
with optically pure (S)-2-acetoxy-2-phenylacetyl chloride and camphanic acid chloride
(Table 5.2). The reaction with (S)-2-acetoxy-2-phenylacetyl chloride155 proceeded smoothly to afford mixture of esters which were inseparable. The reaction with camphanic acid chloride156 was sluggish resulting in recovery of starting material.
Following these frustrating results, attention was turned to use of the Mitsunobu protocol
to produce a separable mixture of compounds.
71 Br Br Br O OH R*COO CeCl3. 7H2O, NaBH4, Conditions MeOH (85%) O O O 5.16 5.18 5.19 Conditions Results
O Ph 1. , Et3N, DMAP, DCM, 0 °C Inseparable mixture of esters. Cl OAc
O 2. , Et3N, DMAP, DCM, 0 °C No reaction, starting material recovered O O Cl
O More than 90% starting material 3. , Py, DMAP, 0 °C → rt recovered O O Cl
Table 5.2: Reaction with acid chlorides.
Attempts to use the Mitsunobu protocol to form the esters accompanied by
inversion of stereochemistry of the alcohol center were unsuccessful due to lack of reactivity on the part of the alcohol even under forcing conditions. Attempts made to displace the bromide by anions of optically active carboxylic acids were also
unsuccessful presumably due to steric hindrance (Table 5.3).
72 Br OOCR* OH OH Conditions O O 5.16 5.20 Conditions Results
O Ph 1. ,K2CO3, 18-C-6, THF, Δ No reaction HO OH
O 2. ,K2CO3, 18-C-6, THF, Δ No reaction O O OH
O 3. ,K2CO3, DMF, 70 °C Elimination O O OH Br Br OH R*COO Conditions
O O 5.16 5.21
O Ph ,DIAD, PPh , THF, 1. 3 No reaction HO OH 0 °C → rt
,DIAD, PPh , THF, 2. O 3 No reaction 0 °C → rt O O OH
Table 5.3: Nucleophilic displacement conditions.
Following the failure of attempts to resolve spiroketone 5.16, attention was turned to other means to construct the spiroketal core starting from readily available optically pure starting materials.
73 5.4 Second generation synthesis
5.4.1 Synthesis plan
Scheme 5.5 shows the modified strategy designed based on photochemical ring
closure methodology94 to construct the spiroketal framework. The target AL-2 was
considered to be synthesized from 5.22 by epoxidation followed by Wittig or Petasis
chemistry to install the ene-diyne functionality. Lactone 5.23 can be prepared from
readily available L – glutamic acid.
O
O O OH O O O O O
AL-2 5.22 5.23
Scheme 5.5: Second generation synthesis plan.
5.4.2 Attempted synthesis of the spirocyclic core
The synthesis starts with nitrous acid-mediated deamination of readily available
L-glutamic acid, which occurs with retention of configuration (Scheme 5.6).157,158
Reduction of the deaminated acid with BH3•SMe2 while maintaining the temperature
below 15 °C produces alcohol 5.24 in 70% yield.159,160 Alcohol 5.24 was then converted
to tosylate 5.25 in 90% yield.161 Tosylate 5.25 was subsequently converted to
corresponding iodide 5.26 in 95% yield.
74 1. NaNO2, HCl, HOOC 0 °C (50%) TsCl, Et3N, DMAP,
2. BH3.SMe2, THF, OCHO 2OH THF, 0 °C (90%) OCHO 2OTs H2NCOOH 10 - 15 °C (70%) L-Glutamic acid 5.24 5.25
NaI, (CH3)2CO, Δ (95%) OCHO 2I
5.26
Scheme 5.6: Synthesis of 5.26.
The iodide was subjected to tin based radical chemistry to afford olefin 5.27 in
80% yield (Scheme 5.6). Hydroboration followed by oxidative workup resulted in the
formation of lactone 5.28 in 87% yield. The lactone was then subjected to photochemical
ring closure conditions.94 Unfortunately, the reaction resulted in the formation of an
inseparable and complex mixture of compounds. Following this disappointing result, the strategy of photochemical ring closure was set aside for a more conventional means to install the pyran ring.
OH
1. BH3•THF, THF,
AllylSnBu3, AIBN 0 °C
PhH, Δ (80%) 2. NaBO3•4H2O, OCHO 2I O O O O H2O (87%) 5.26 5.27 5.28
PhI(OAc)2, I2, PhH, hν O O O 5.29
Scheme 5.7: Attempted synthesis of 5.29.
75 5.5 Third generation synthesis
5.5.1 Synthesis plan
The modified synthesis plan is shown in Scheme 5.8. Target AL-2 can in
principle be synthesized from 5.30 by means of an epoxidation followed by manipulation
of the side arm to install the ene-diyne functionality. Spiroketal 5.30 might be
synthesized from 5.31 by means of a bromonium ion-initiated ring-closure followed by
elimination of HBr. Dihydrofuran 5.31 was to be synthesized from lactone 5.32 which
arises from readily available L – glutamic acid.
O
O O OH O O O OP OP AL-2 5.30 5.31
O O L - Glutamic Acid 5.32 OP
Scheme 5.8: Third generation synthesis plan.
5.5.2 Synthesis of 5.31 - First attempt
Commencing with previously synthesized alcohol 5.24, reaction with freshly
prepared benzyl imidate under acidic conditions results in formation of corresponding
benzyl ether 5.33162 in 90% yield (Scheme 5.9). The lactone was partially reduced with
DIBAL to form a lactol which was acetylated, followed by heating in DMSO at 190 °C in the presence of NaHCO3 to afford enol ether 5.35 in 78% yield. 76 1. DIBAL, DCM, -78 °C
BnIm, TfOH, DCM, 2. Ac2O, Et3N, DCM
OCHO 2OH -78 °C, (90%) OCHO 2OBn3. NaHCO3, DMSO, O CH2OBn 190 °C (78%) 5.24 5.33 5.35
Scheme 5.9: Synthesis of 5.35.
With the enol ether in hand, it was time to install the side arm that will form the pyran of the spiroketal. Attempts to alkylate the C3 position of dihydrofuran 5.35 failed.
The benzyl group was suspected to be the cause of the problem. Consequently, the enol ether was synthesized with a TBS group as a replacement for the benzyl protecting group
(Scheme 5.10).
1. DIBAL, DCM, -78 °C
TBSCl, Im, DCM 2. Ac2O, Et3N, DCM
OCHO 2OH 0 °C, (92%) O O 3. NaHCO3, DMSO, O OTBS 190 °C (80%) OTBS 5.24 5.36 5.37
Scheme 5.10: Synthesis of 5.37.
Attempts were made to alkylate enol ether 5.37163 by varying both the equivalents
of base and the electrophiles used. To our disappointment, the reaction failed again. To
understand possible reasons for the failure of the reaction, each step involved was
investigated (Table 5.4). In order to enhance the lifetime of t-BuLi, ether was used as a
solvent instead of THF. The extent of deprotonation of the enol ether was investigated
using simple electrophiles such as methyl iodide and tributyltin chloride. The products
expected from successful reaction with these electrophiles were formed in minute 77 quantities or were not observed at all. Therefore, it was decided to install the side arm prior to formation of the enol ether functionality.
Conditions R R O E O
Substrate Conditions Result
1. R = OBn, 5.35 t-BuLi, TESO(CH2)4I No reaction
2. R = OBn, 5.35 t-BuLi, MeI No reaction
3. R = OBn, 5.35 t-BuLi, Bu3SnCl No reaction
4. R = OTBS, 5.37 t-BuLi, TESO(CH2)4I No reaction
5. R = OTBS, 5.37 t-BuLi, MeI No reaction
6. R = OTBS, 5.37 t-BuLi, Bu3SnCl No reaction
7. R = OTBS, 5.37 t-BuLi, AllylBr No reaction
Table 5.4: Attempts to alkylate 5.35 and 5.37.
The reaction profile of mixed ketals formed with sulfenic acid serves our needs very well in this aspect. These mixed ketals are known to undergo alkylation at lower temperatures under basic conditions. The alkylated ketals are also known to eliminate spontaneously when the temperature is raised which will result in the formation of
78 alkylated enol ether functionality.164 The lactol obtained on reduction of lactone 5.36 was
treated with phenylsulfenic acid to form ketal 5.38 in 82% yield (Scheme 5.11).
1. DIBAL, DCM, -78 °C
O O 2. PhSO2H, DCM, PhO2S O CaCl (82%) 5.36 OTBS 2 5.38 OTBS
Scheme 5.11: Synthesis of 5.38.
Unfortunately, attempts to alkylate ketal 5.38 under various conditions proved
unsuccessful (Table 5.5). No reaction was observed at – 78 °C. However, when the
temperature was raised to 0 °C the ketals eliminated spontaneously to form enol ethers.
The deprotonation of ketal 5.38 is confirmed by the spontaneous elimination that ensues.
The presence of additives such as TMEDA did not have any effect on the outcome.
Ketals of similar structure are known to react moderately with sp2 centers. A
detailed literature search revealed that reactions are sluggish when sp3 centers are involved presumably due to the steric congestion.165 Hence, it was decided to swap roles
and use the side arm precursor as a nucleophile.
79 Conditions OTBS R PhO2S O R O 5.38
Conditions Result
1. KHMDS, TESO(CH2)4I Elimination without alkylation
2. n-BuLi, TESO(CH2)4I No reaction
3. n-BuLi, CH2=CH(CH2)2Br No reaction
4. KHMDS, CH2=CH(CH2)2Br Elimination without alkylation
5. n-BuLi, TMEDA, CH2=CH(CH2)2Br Elimination without alkylation
6. KHMDS, 18-C-6, CH2=CH(CH2)2Br Elimination without alkylation
Table 5.5: Attempts to alkylate ketal 5.38.
The strategy was to perform nucleophilic attack on the lactone to form the lactol, which can then be transformed into the alkylated enol ether. Morpholinamides are known to react with nucleophiles to form stable intermediates, resulting in formation of the corresponding ketones upon workup.166 Lactone 5.36 was converted to the corresponding morpholinamide by heating with neat morpholine at 70 °C to afford amide 5.39 in 80% yield (Scheme 5.12). The amide was then reacted with a suitable nucleophile.
Unfortunately, this led to formation of products arising from both single and double addition along with unreacted starting material.
80 OTBS Morpholine 70 °C OH NO O O O (80%) OH OTBS OTBS O 5.36 5.39 5.40
Scheme 5.12: Attempts to synthesize 5.40 from 5.36.
Following this result, it was decided to use a Weinreb amide to accomplish this task. Lactone 5.36 was converted to the corresponding Weinreb amide using trimethylaluminum and N,O-dimethylhydroxylamine hydrochloride. Weinreb amides of a similar structure are known to reform the lactone under mildly acidic or basic conditions.167 In order to prevent this, the alcohol was trapped as a silyl ether using
TMSCl to form amide 5.41 in 85% yield. Reaction of the Weinreb amide with suitable nucleophile proceeded smoothly to afford 5.42 as a single product. We were, however, disappointed to find out that it was the open ketone form and not the lactol as expected.
Attempts to convert ketone 5.42 to dihydrofuran 5.43 by means of an acid-catalyzed dehydration failed.
1. AlMe3, MeONMeH2Cl OTBS 1. CH2=CH(CH2)3I, OTBS DCM, 0 °C; OTMS t-BuLi, ether, -78 °C OH N O O O O 2. TMSCl, Et3N, DCM 2. K2CO3, MeOH (84%) O OTBS 0 °C (85%) 5.36 5.41 5.42
O OTBS 5.43
Scheme 5.13: Attempted synthesis of 5.43. 81 5.5.3 Synthesis of 5.31 - Second attempt
The second attempt towards the synthesis of 5.31 starts with the Horner-
Wadsworth-Emmons reaction of previously synthesized lactol 5.44 with
(carbomethoxy)methylenetriphenyl phosphorane to form α,β - unsaturated ester 5.45 in
90% yield (Scheme 5.14). Reduction of α,β-unsaturated ester with excess DIBAL affords
diol 5.46 in 95% yield. Iodoetherification in the presence of NaHCO3 affords iodide 5.47 in 81% yield. Benzoylation of 5.47 affords the corresponding benzoate 5.48 in 88% yield.
Ph3P=CHCOOMe DIBAL, DCM I2, NaHCO3, THF HO O HO HO DCM, rt, (90%) -78 °C (95%) H2O, rt (81%) OTBS OTBS OTBS O OMe HO 5.44 5.45 5.46
I BzCl, Et3N, DMAP I O DCM, -78 °C (88%) O OTBS OTBS HO 5.47BzO 5.48
Scheme 5.14: Synthesis of 5.48.
With the iodide 5.48 in hand, elimination of HI followed by isomerization of the
resultant double bond was attempted using DBU (Scheme 5.15). The reaction
unfortunately failed to produce the desired product. A double elimination occurred
instead of the planned single elimination to produce diene 5.49 in 70% yield. As a result
of these frustrating results, the enol ether based strategy was set aside.
82 I DBU, THF, Δ (70%) O O O OTBS OTBS OTBS BzO BzO 5.45 5.48 5.49
Scheme 5.15: Failed synthesis of 5.45.
5.6 Conclusions
Unfortunately, the total synthesis of AL-2 could not be attained by the routes described above. Attempts to alkylate the C3 position of dihydrofuran intermediates were unsuccessful. Alternate routes with modified substrates did not change the outcome.
Hence, the enantioselective synthesis of AL-2 was abandoned.
83 CHAPTER 6
EFFORTS TOWARDS TOTAL SYNTHESIS OF LISSOKETAL
Efforts towards total synthesis of Lissoketal
6.1 Background
Although alkaloids constitute a major part of natural products isolated from ascidians,168 a small but significant number of acetogenins have been found. A new acetogenin, lissoketal was isolated from specimens of the ascidian Lissoclinum
voeltzkowi.41 The encrusting grey ascidian Lissoclinum voeltzkowi was collected from sea
grass blades in shallow waters off the coast of Palau. It showed no activity in simple
antimicrobial or brine shrimp toxicity assays.
Lissoketal
Figure 6.1: Structure of lissoketal.
Notable structural features are the spiroketal functionality and the unsaturated
pyran ring as part of the framework.
84 6.2 First generation synthesis
6.2.1 Synthesis plan
The synthesis of lissoketal can be envisioned from olefin 6.2 by means of ring closing metathesis. Olefin 6.2 can be synthesized from dihydrofuran 6.3 by means of bromonium ion formation followed by attack of an alcohol with the desired chain length.
Dihydrofuran 6.3 can be prepared from lactone 6.4 which in turn can be obtained from readily available L-glutamic acid.
O PO
O O O OH O OP O OP
6.1 6.2 6.3
L - Glutamic Acid O O OP
6.4
Scheme 6.1: First generation synthesis plan.
6.2.2 First generation synthesis of 6.4
The synthesis begins with readily available L – glutamic acid, which is transformed into tosylate 6.5 in three steps as outlined in Section 5.4.2. Tosylate 6.5 was treated with potassium carbonate in methanol to form methyl ester 6.6 in 89% yield
(Scheme 6.2). The corresponding benzyl ester 6.7 was prepared in a similar procedure using benzyl alcohol in 80% yield.
85 NaH, BnOH, THF K2CO3, MeOH,THF BnOOC MeOOC 0 °C (80%) OCHO 2OTs 0 °C (89%) O O 6.7 6.5 6.6
Scheme 6.2: Synthesis of 6.6 and 6.7.
Attempts were made to synthesize butyrolactone 6.8 with an elongated side arm by opening epoxides 6.6 and 6.7 with suitable nucleophiles followed by cyclization.
Unfortunately, these attempts failed, primarily due to the reactivity of product butyrolactone to conditions used for chain elongation (Table 6.1).
Conditions ROOC OOBnO O 6.6, 6.7 6.8 Substrate Reaction Condition Result
1. 6.6 Bu3SnCH2OBn, n-BuLi, CuCN, THF -78 °C Decomposition
Bu3SnCH2OBn, n-BuLi, CuCN, 2. 6.6 Decomposition BF3•OEt2, THF -78 °C
3. 6.6 Bu3SnCH2OBn, n-BuLi, CuI, THF -78 °C Decomposition
Bu3SnCH2OBn, n-BuLi, CuI, 4. 6.6 Decomposition BF3•OEt2, THF -78 °C
5. 6.7 Bu3SnCH2OBn, n-BuLi, CuCN, THF -78 °C Decomposition
Bu3SnCH2OBn, n-BuLi, CuCN, 6. 6.7 Decomposition BF3•OEt2, THF -78 °C
7. 6.7 Bu3SnCH2OBn, n-BuLi, CuI, THF -78 °C Decomposition
Bu3SnCH2OBn, n-BuLi, CuI, 8. 6.7 Decomposition BF3•OEt2, THF -78 °C
Table 6.1: Conditions attempted to extend the side arm.
86 Following the failure of attempts to directly synthesize butyrolactone 6.8 having
the extended side chain, it was decided to mask the lactone in the form of a cyclic ketal in
order to eliminate the possibility of further reaction. The synthesis of iodoketal 6.11 was
initiated from previously synthesized iodide 6.9 by reducing it with DIBAL to form lactol
6.10 in a quantitative yield (Scheme 6.3). Acid-catalyzed ketalization with benzyl alcohol
resulted in formation of ketal 6.11 in 98% yield.
DIBAL, DCM BnOH, p-TSA, OCHO 2I -78 °C (95%) HOO CH2I DCM, 0 °C (83%) BnOO CH2I 6.9 6.10 6.11
Scheme 6.3: Synthesis of 6.11.
The ketal was then subjected to different conditions in order to effect the elongation (Table 6.2). Unfortunately, these conditions proved unsuccessful in achieving chain extension resulting in no change of starting material 6.11.
87 Conditions I BnO O BnOO OBn 6.11 6.12 Substrate Reaction Condition Result
Bu3SnCH2OBn, n-BuLi, 1. 6.11 No reaction CuCN, THF -78 °C
Bu3SnCH2OBn, n-BuLi, 2. 6.11 No reaction CuI, THF -78 °C
3. 6.11 CH2=CHLi, THF -78 °C No reaction
4. 6.11 CH2=CHCH2Li, THF -78 °C No reaction
Table 6.2: Conditions attempted to extend the side arm of 6.11.
6.2.3 Second generation synthesis of 6.4
Following the failure of chain elongation strategies pursued thus far, it was
decided to change the strategy and start from a substrate with the required chain length
built in. Consequently, we designed a route that begins with readily available D –
glucose. Benzylidene protection of glucose under acid catalysis provides benzylidene
acetal 6.13 in 70% yield (Scheme 6.4).169 The aldehyde formed upon periodate cleavage
of 6.13 was not isolated, but rather treated in situ with the appropriate Horner-
Wadsworth-Emmons reagent to afford α,β-unsaturated ester 6.14 in 80% yield.170
Rhodium catalyzed hydrogenation of the unsaturated ester 6.14 afforded methyl ester
6.15 in quantitative yield.
88 OOH OOH1. NaIO , NaHCO , EtOAc, OH HO O 4 3 O PhCH(OMe)2, p-TSA, H2O, 0 °C to rt
HO OH DMF, 70 °C (70%) Ph OOH2. Ph3P=CHCOOMe, Ph O OH OH EtOAc (80% over 2 steps) OMe D - Glucose 6.13 6.14 O
OH O Rh/C, H2, EtOAc rt (quant) Ph O OMe 6.15 O
Scheme 6.4: Synthesis of 6.15.
Removal of the secondary hydroxyl group of 6.15 was necessary (Scheme 6.5).
Xanthate derivative 6.16 was exposed to radical conditions employing n-Bu3SnH in the
presence of AIBN to afford deoxy derivative 6.17 in 85% yield. As a consequence of low
yields encountered in generating xanthate 6.16 and contamination of deoxygenated
product with tin byproducts, alternate routes to accomplish deoxygenation were
investigated.
OH O SMe O O O NaH, CS , MeI Bu SnH, AIBN, 2 S 3 Ph O THF 0 °C (60%) Ph O PhH, Δ (85%) Ph O OMe OMe OMe 6.15 6.16 6.17 O O O
Scheme 6.5: Deoxygenation of 6.15.
Alcohol 6.15 was converted to the corresponding iodide 6.18 using classical conditions in 80% yield (Scheme 6.6). Deiodination using stoichiometric quantities of 89 tributyltin hydride was successful in generating 6.17 in 80% yield. However, difficulties
were encountered in isolating 6.17 free of tin byproducts. Consequently, a recently
reported protocol that employs in situ generation of tributyltin hydride from tributyltin
chloride and sodium cyanoborohydride was attempted.171 This method was successful in
generating 6.17 free of tin byproducts in quantitative yield.
OH I O O O PPh3, Imid, I2, iPr2NEt Bu3SnCl, NaBH3CN,
Ph O THF Δ (80%) Ph O THF, MeOH, Δ (quant) Ph O OMe OMe OMe 6.15 6.18 6.17 O O O
Scheme 6.6: Deiodination of 6.18.
Methyl ester 6.17 was then subjected to conditions known to effect reductive cleavage of the benzylidene acetal (Table 6.3). Among protocols attempted, a combination of trifluoroacetic acid, trifluoroacetic anhydride, and triethylsilane proved successful in generating butyrolactone 6.8 in 85% yield.
90 O Conditions Ph O OOBnO OMe 6.17 6.8 O Conditions Result
1. TFA, NaBH3CN, THF, 0 °C to rt Decomposition
2. CSA, Et3SiH, THF, Δ Reduction of methyl ester
3. TFA, Et3SiH, DCM, -10 °C 60% yield of desired product
4. TFA, TFAA, Et3SiH, -20 °C 85% yield of desired product
Table 6.3: Attempted conditions for synthesis of 6.8.
The benzyl protected butyrolactone 6.8172 was then reduced with DIBAL to form
the lactol, which was then treated with acetic anhydride to form the corresponding acetate
(Scheme 6.7). The acetate was thermolyzed in DMSO in the presence of sodium
bicarbonate to afford dihydrofuran 6.19 in 80% yield.
1. DIBAL, DCM, -78 °C;
2. Ac2O, Et3N, DCM 0 °C; OOBnO 3. NaHCO3, DMSO, 190 °C O OBn (80% over 3 steps) 6.8 6.19
Scheme 6.7: Synthesis of 6.19.
6.2.4 Efforts to synthesize 6.2
With the dihydrofuran 6.19 in hand, attempts were made to alkylate at C3.
Conditions attempted were however unsuccessful in accomplishing the required
91 transformation (Scheme 6.8). Taking note of results obtained under similar conditions in
the AL-2 synthesis, we pursued this reaction no further.
t-BuLi, n-Bu3SnCl t-BuLi, AllylBr O OBn Bu3Sn O OBn ether, -78 °C O OBn ether, -78 °C 6.20 6.19 6.21
Scheme 6.8: Attempted conditions for alkylation of 6.19.
A role reversal of the components involved was planned to avoid the generation of a C3 anion. The benzyl protecting group was replaced with a TBS group in a two step sequence to form lactone 6.22. The strategy involves reaction of a nucleophile with lactone 6.22 to form a lactol which will then be subjected to elimination under suitable conditions to afford the desired alkylated dihydrofuran. This was realized by converting lactone 6.22173 to a Weinreb amide using trimethylaluminum and the hydroxyl group
released was trapped as a silyl ether to form 6.23 (Scheme 6.9).
1. Pd/C, H2, MeOH, rt 1. AlMe3, MeONMeH2Cl, OTBS (quant) DCM, 0 °C OTMS OOBnO 2. TBSCl, Imid, DCM OOTBSO 2. TMSCl, Et3N, DCM, N O DCM 0 °C (86%) 0 °C (83% over 2 steps) O 6.8 6.22 6.23
Scheme 6.9: Synthesis of 6.23.
With the Weinreb amide 6.23 in hand, nucleophilic addition was investigated
(Scheme 6.10). Unfortunately, addition of nucleophiles resulted in the formation of 92 ketone 6.24, which is the open form of the desired lactol. Taking into account results
obtained under similar conditions in the AL-2 project, we did not pursue this reaction
further. Following the failure of attempts to generate the desired dihydrofuran 6.25,
attention was turned to designing a strategy free of the complications encountered thus
far.
OTBS 1. BuLi, CH2=CH(CH2)2Br, OTBS ether, - 78 °C OTMS OH N O 2. K2CO3, MeOH, rt O O OBn (65% over 2 steps) O 6.23 6.24 6.25
Scheme 6.10: Attempted condition for synthesis of 6.25.
6.3 Second generation synthesis
6.3.1 Synthesis plan
The new strategy involves a major deviation from the disconnection approach
previously pursued. The strategy involves introduction of the unsaturated pyran ring of
lissoketal in a masked form (Scheme 6.11). Spiroketal 6.26 has been previously
synthesized.174 Aldehyde 6.27 can be obtained from methyl ester 6.17, which has been successfully prepared from D – glucose as shown in Scheme 6.6.
93 O
O O O O O OH + Ph O HO OP OO OMe 6.27 6.17 O
6.26
D - Glucose
Scheme 6.11: Revised synthesis plan.
6.3.1 Synthesis of 6.31
Synthesis of 6.31 begins with reduction of previously synthesized 6.17 with
DIBAL to afford alcohol 6.28 in 95% yield. Attempts to eliminate the tosyl derivative of
6.29 under various conditions failed to afford 6.31. Recourse was made to converting the tosylate 6.29 to selenide 6.30 in 90% yield. Elimination proceeded smoothly to afford
olefin 6.31 in 93% yield (Scheme 6.12).
O O O DIBAL, DCM TsCl, Et3N, DMAP Ph O -78 °C (95%) Ph O DCM 0 °C (90%) Ph O 6.17 OMe 6.28 OH 6.29 OTs O
O O (PhSe)2, NaBH4, NaIO4, THF, H2O EtOH, 0 °C (90%) Ph O rt, (93%) Ph O 6.30 SePh 6.31
Scheme 6.12: Synthesis of 6.31.
94 Future steps will involve reductive cleavage of the benzylidene acetal followed by
trapping of the alcohol so released as a silyl ether to form 6.32. Ozonolysis of olefin 6.32
will yield aldehyde 6.33 which can then be couple with spiroketal 6.26 to form 6.34, which can then be transformed into lissoketal in the steps that ensue.
O - O 1. Et SiH, TFA, TFAA BnO O3, MeOH, DCM BnO 3 + 2. TBSCl, Imid -78 ºC; PPh3 Ph O TBSO TBSO O O 6.31 6.32 6.33 O PO OBn O OTBS 6.26 Lissoketal OO
6.34
Scheme 6.13: Future steps.
6.4 Conclusion and future work
Unfortunately, the total synthesis of lissoketal could not be completed by the
routes described above. We were, however, able to develop a route for quick and efficient
synthesis of functionalized dihydrofuran analogs. The prospects of completion of the
synthesis based on the latest route appear to be reasonably plausible.
95 CHAPTER 7
Experimental Details
General Methods. All reactions were performed in flame-dried glassware under a nitrogen (N2) or Argon (Ar) atmosphere. All solvents were reagent greade and pre-dried
over 4 Å molecular sieves prior to distillation, and, if necessary, stored over 4 Å
molecular sieves under nitrogen (N2). Benzene (PhH), tetrahydrofuran (THF), and diethyl
ether (Et2O) were distilled from sodium/benzophenone ketyl. Acetonitrile (CH3CN), chlorotrimethylsilane (TMSCl), dichloromethane (CH2Cl2), diisopropylamine (i-Pr2NH),
diisopropylethylamine (Hünig’s base), N,N-dimethylformamide (DMF), dimethyl
sulfoxide (DMSO) and triethylamine (Et3N) were individually distilled over calcium hydride under nitrogen (N2) atmosphere. Pyridine was distilled over potassium hydroxide
prior to use. All reagents were purchased as reagent grade and, unless otherwise noted, used without further purification. The combined organic extracts were dried over anhydrous magnesium sulfate (MgSO4) or sodium sulfate (Na2SO4) as noted. Thin-layer chromatography was performed on precoated silica gel 60 F254 aluminum sheets and the
column chromatographic separations were performed with silica gel (40-63 μm).
96 A Perkin-Elmer 1600 series FT-IR spectrometer was used to record infrared spectra and absorptions are reported reciprocal centimeters (cm-1). Optical rotations were measured by a Perkin-Elmer Model 241 Polarimeter at 589 nm with a sodium lamp and concentrations are reported in g/100 mL. Melting points were measured on a Thomas
Hoover (Uni-melt) capillary melting point apparatus. Brucker AC-300, DPX-400 and
DRX-500 NMR spectrometers were used to record proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectra. Chemical shifts are reported in parts per million
(ppm, δ) with the residual non-deutrated solvent as an internal standard. Splitting patters are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Hgih-resolution mass spectra were recorded at The Ohio State University Campus
Chemical Instrumentation Center or at Chemistry Department Mass Spectrometry
Facility.
97 2-[8,9-Bis-(2-hydroxyethoxy)-2,4,10-trioxatricyclo[3.3.1.13,7]dec-6-yloxy]ethanol
OBn OH O OBn O OH O O OBn Pd/C, H2, EtOAc OH O O (97%) O O O O O O 3.20 2.7 Palladium on charcoal (10%, 300 mg) was added to a solution of 3.20 (1.36 g, 2.29
mmol) in ethyl acetate (30 mL) and hydrogen was purged through the system followed by
stirring under an atmosphere of hydrogen for 8 h. The mixture was filtered through a
Celite plug and the solvent was removed in vacuo to afford triol 2.7 (0.72 g, 97%) as a
-1 1 colorless oil: IR (film, cm ) 3414, 2940, 1164; H NMR (300 MHz, CDCl3) δ 5.5 (s, 1H),
5.28 (s, 1H), 4.48 – 4.46 (m, 1H), 4.39 – 4.37 (m, 2H), 4.29 – 4.27 (m, 2H), 3.89 (s, 1H),
13 3.75 – 3.51 (m, 14H); C NMR (75 MHz, CDCl3) δ 103.0, 74.8, 71.5, 70.6, 69.9, 68.1,
+ 67.5, 61.8, 61.4; ES HRMS m/z (C13H22O9Na ) calcd 345.1162, obsd 345.1159.
6-Allyloxy-8,9-dibenzyloxy-2,4,10-trioxatricyclo[3.3.1.13,7]decane
OBn OBn OBn OBn AllylBr, NaH, DMF, OH OAllyl 0 °C (87%) O O O O O O 2.11 2.16
A solution of 2.11 (4.15 g, 11.2 mmol) in anhydrous DMF (150 mL) at 0 °C was treated
with sodium hydride (60% in oil, 1.02 g, 25.0 mmol), followed by allyl bromide (2.00
mL, 22.4 mmol) after 30 min. The mixture was stirred overnight, quenched with satd.
NH4Cl solution (10 mL) followed by water (300 mL), and extracted with ether (3×100
mL). The combined organic layers were dried and concentrated to leave a residue that
was purified by chromatography on silica gel (elution with 20% ethyl acetate in hexanes) 98 to afford 2.16 (4.00 g, 87%) as a colorless oil; IR (film, cm-1) 2920, 1167, 1001; 1H
NMR (300 MHz, CDCl3) δ 7.35 – 7.26 (m, 10H), 6.05 – 5.92 (m, 1H), 5.53 (s, 1H), 5.32
(d, J = 17 Hz, 1H), 5.21 (d, J = 10 Hz, 1H), 4.69 (d, J = 11.6 Hz, 2H), 4.57 (d, J = 11.6
Hz, 2H), 4.48 – 4.40 (m, 1H), 4.39 – 4.31 (m, 4H), 4.11 (d, J = 5.7 Hz, 2H), 4.0 (s, 1H);
13 C NMR (75 MHz, CDCl3) δ 137.6, 134.5, 128.4, 127.8, 127.6, 117.6, 103.2, 74.1, 71.7,
+ 70.5, 68.0, 67.4; ES HRMS m/z (C24H26O6Na ) calcd 433.1627, obsd 433.1630.
(1R, 2R, 3S, 4R, 5R, 6S)-5-Allyloxy-2,4,6-trimethoxy-1,3-dibenzyloxycyclohexane
OAllyl OBn OBn MeO OMe 1. p-TSA, MeOH, Δ OAllyl 2. MeI, NaH, DMF O BnO OBn O O (72%) OMe 2.16 2.17 A solution of 2.16 (4.00 g, 9.76 mmol) in MeOH (100 mL) was treated with p – TsOH
(25.1 mg, 1.32 mmol) added and heated at reflux for 2 h. After being cooled to room
temperature, the reaction mixture was evaporated in vacuo. The residue was dissolved in
anhydrous DMF (150 mL), cooled to 0 °C, and treated with sodium hydride (60% in oil,
1.6 g, 40 mmol), followed by methyl iodide (2.8 mL, 45 mmol) after 30 min. The mixture
was stirred overnight, quenched with saturated NH4Cl solution (10 mL) followed by
water (300 mL), and extracted with ether (3×100 mL). The combined organic layers were
dried and concentrated to leave a residue that was purified by chromatography on silica
gel (elution with 20% ethyl acetate in hexanes) to afford 2.17 (3.14 g, 72%) as a colorless
-1 1 oil; IR (film, cm ) 2905, 1102, 1050; H NMR (300 MHz, CDCl3) δ 7.46 – 7.27 (m,
10H), 5.95 – 6.08 (m, 1H), 5.39 – 5.31 (m, 1H), 5.25 – 5.20 (m, 1H), 4.91 (d, J = 10.7
Hz, 2H), 4.83 (dd, J = 10.7 Hz, 2H), 4.37 – 4.34 (m, 2H), 4.09 (t, J = 2.2 Hz, 1H), 3.86 99 (t, J = 9.4 Hz, 2H), 3.68 (s, 3H), 3.52 (s, 6H), 3.17 (t, J = 9.2 Hz, 1H), 3.08 (dd, J = 9.8,
13 2.2 Hz, 2H); C NMR (75 MHz, CDCl3) δ 139.2, 135.7, 128.3, 128.1, 127.7, 127.5,
+ 116.7, 85.4, 82.9, 81.8, 75.7, 73.2, 72.4, 61.4, 58.5; ES HRMS m/z (C26H34O6Na ) calcd
465.2253, obsd 465.2256.
(1R,2R,3S,4R,5R,6S)-5-Hydroxy-2,4,6-trimethoxy-1,3-dibenzyloxycyclohexane
OAllyl OH MeO OMe MeO OMe Pd/C, p-TSA, MeOH, Δ, 0 °C (83%) BnO OBn BnO OBn OMe OMe 2.17 2.18
To a solution of 2.17 (3.14 g, 7.11 mmol) in MeOH/H2O (4:1, 100 mL), 10% Pd/C (300
mg) and p – TsOH (133 mg, 0.70 mmol) were added in advance of heating at reflux for 2
h. After cooling to room temperature, the reaction mixture was filtered through Celite and
evaporated in vacuo. The residue was extracted with ethyl acetate, washed with H2O,
brine, dried, and evaporated to leave a residue which was purified by column
chromatography (elution with 30 % ethyl acetate in hexanes) to afford 2.18 (1.94 g,
83%) as a white solid, mp 100 – 102 °C; IR (film, cm-1) 3433, 2977, 1155; 1H NMR (300
MHz, CDCl3) δ 7.44 - 7.27 (m, 10H), 4.86 (d, J = 10.7 Hz, 2H), 4.82 (d, J = 10.7 Hz,
2H), 4.33 (t, J = 2.7 Hz, 1H), 3.82 (t, J = 9.5 Hz, 2H), 3.68 (s, 3H), 3.55 (s, 6H), 3.19 -
13 3.10 (m, 3H); C NMR (75 MHz, CDCl3) δ 138.9, 128.4, 128.1, 127.6, 84.9, 81.9, 81.3,
+ 75.8, 66.2, 61.5, 58.5; ES HRMS m/z (C23H30O6Na ) calcd 425.1940, obsd 425.1943.
100 (2R,3S,4S,5R,6S)-3,5-Dibenzyloxy-2,4,6-trimethoxycyclohexanone
OH O MeO OMe MeO OMe (COCl)2, DMSO,
Et3N, DCM, -78 °C BnO OBn BnO OBn (52%) OMe OMe 2.18 2.19
To stirred solution of (COCl)2 (1.3 mL, 15 mmol) in dry CH2Cl2 (50 mL), Me2SO (1.4 mL, 20 mmol) was added at −78 °C under argon. After 30 min, a solution of alcohol 2.18
(1.94 g, 4.82 mmol) in dry CH2Cl2 (10 mL) was added dropwise to the reaction mixture at −78 °C. After 30 min, triethylamine (3.5 mL, 25 mmol) was added dropwise to the above mixture, and stirring was continued for 5 min. The reaction mixture was poured into NaHCO3 solution (10%, 200mL), extracted with CH2Cl2, washed with brine and
water, dried, and evaporated to give a residue which was purified by column
chromatography (15 % ethyl acetate in hexanes) to afford 2.19 (1.01 g, 52%) as a
-1 1 colorless oil; IR (film, cm ) 2966, 1750, 1013; H NMR (300 MHz, CDCl3) δ 7.42 - 7.30
(m, 10H), 4.85 (d, J = 10.7 Hz, 2H), 4.76 (d, J = 10.7 Hz, 2H), 3.91 (d, J = 9.6 Hz, 2H),
13 3.69 (s, 3H), 3.55 (s, 6H), 3.45 (d, J = 9.3 Hz, 2H); C NMR (75 MHz, CDCl3) δ 202.2,
138.2, 128.4, 128.2, 127.9, 86.2, 83.9, 81.6, 75.9, 61.7, 59.7; ES HRMS m/z
+ (C23H28O6Na ) calcd 423.1784, obsd 423.1786.
101 6,10-Dibenzylidene-1,4-dioxa-spiro[4.5]decane
O O O
Ph Ph PPTS, (CH2OH)2, Ph Ph PhMe Δ (95%)
2.21 2.22
A stirred mixture of 2.21 (10.03 g, 36.6 mmol), PPTS (0.92 g, 3.70 mmol), and ethylene
glycol (20 mL) in toluene (100 mL) was heated under reflux under a Dean- Stark
apparatus for 8 h. The mixture was then cooled, quenched with satd. NaHCO3 solution
(50 mL) and extracted with ether (3×100 mL). The combined organic layers were dried and concentrated to leave a residue that was purified by chromatography on silica gel neutralized with triethylamine (elution with 2% ethyl acetate, 1% triethylamine in hexanes) to afford 2.22 (7.02 g, 60%) as a white solid and unreacted 2.21 (3.05 g, 35%) ;
-1 1 IR (film, cm ) 2935, 2883, 1098, 701; H NMR (300 MHz, CDCl3) δ 7.24 – 7.38 (m,
10H), 6.9 (t, J = 8 Hz, 2H), 4.1 (s, 4H), 2.73 (t, J = 6 Hz, 4H), 1.62 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 140.9, 137.5, 129.0, 128.0, 126.5, 122.1, 108.7, 64.5, 27.1; ES
+ HRMS m/z (C22H22O2Na ) calcd 341.1512, obsd 341.1519.
(6S,7R,8S,9R,10S)-8,9,10-Tris(benzyloxy)-1,4-dioxaspiro[4.5]decane-6,7-diol
OH O O OH O OsO4, NMO, MsNH2, O (CH3)2CO, H2O (88%) BnO OBn BnO OBn OBn OBn 2.34 2.35
Olefin 2.34 (1.00 g, 2.18 mmol) was dissolved in acetone (40 mL) containing water (10
mL) and treated with osmium tetroxide (110 mg, 0.43 mmol), methanesulfonamide (0.62
102 g, 6.50 mmol) and NMO (2.56 g, 21.8 mmol). After 18 h of stirring, H2S was bubbled
through the solution for 15 min, during which time a black precipitate formed. This
mixture was purged with N2 for 10 min, filtered through a pad of Celite, which was rinsed with ethyl acetate. The filtrate was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried and concentrated to leave a residue that was purified by chromatography on silica gel (elution with 25% ethyl acetate in hexanes) to afford
0.95 g (88%) of 2.35 as a colorless oil; IR (film, cm-1) 3439, 2897, 1100; 1H NMR (300
MHz, CDCl3) δ 7.25 – 7.33 (m, 15H), 4.99 – 4.90 (m, 2H), 4.82 – 4.79 (m, 3H), 4.74 –
4.70 (m, 1H), 4.2 – 4.0 (m, 2H), 4.02 – 3.91 (m, 3H), 3.73 – 3.68 (m, 4H), 2.44 (s, 1H),
13 2.31 (s, 1H); C NMR (75 MHz, CDCl3) δ 138.6, 138.6, 138.6, 128.5, 128.3, 127.8,
127.8, 127.5, 127.5, 108.5, 82.4, 81.6, 81.0, 76.1, 75.6, 75.4, 73.0, 71.1, 67.1, 65.4; ES
+ HRMS m/z (C29H32O7Na ) calcd 515.2046, obsd 515.2031.
(5R,6S,7S,8S,9R,10S)-6,7-Bis(allyloxy)-8,9,10-tris(benzyloxy)-1,4- dioxaspiro[4.5]decane
OH O O O OH O O AllylBr, NaH, DMF, O 0 °C (74%) BnO OBn BnO OBn OBn OBn 2.35 2.36
A solution of 2.35 (1.8 g, 3.7 mmol) in anhydrous DMF (20 mL) at 0 °C was treated with
sodium hydride (60% in oil, 0.4 g, 10 mmol), followed by allyl bromide (0.91 mL, 10.5 mmol) after 30 min. The mixture was stirred overnight, quenched with satd. NH4Cl
solution (5 mL) followed by water (50 mL), and extracted with ether (3×25 mL). The
103 combined organic layers were dried and concentrated to leave a residue that was purified
by chromatography on silica gel (elution with 11% ethyl acetate in hexanes) to afford
2.36 (1.54 g, 74%) as a colorless oil; IR (film, cm-1) 2898, 1453, 1070; 1H NMR (300
MHz, CDCl3) δ 7.37 – 7.24 (m, 15H), 6.01 – 5.90 (m, 2H), 5.37 – 5.33 (m, 1H), 5.30 –
5.26 (m, 3H), 5.25 – 5.18 (m, 2H), 4.94 – 4.89 (m, 1H), 4.35 – 4.32 (m, 2H), 4.18 – 4.11
(m, 4H), 4.03 – 3.89 (m, 4H), 3.66 – 3.58 (m, 2H), 3.52 – 3.48 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 139.0, 138.8, 135.4, 135.0, 128.2, 127.9, 127.7, 127.7, 127.3, 127.3,
116.7, 116.5, 109.1, 82.7, 81.6, 81.3, 77.3, 75.9, 75.8, 75.6, 73.1, 71.7, 66.7, 65.2; ES
+ HRMS m/z (C35H40O7Na ) calcd 595.2666, obsd 595.2643.
(5R,6S,7S,8R,9R,10S)-6,7-Bis(2-hydroxyethoxy)-8,9,10-tris(benzyloxy)-1,4-
dioxaspiro[4.5]decane
OH O O O 1. O , MeOH, DCM, O O 3 O O (1:1), -78 °C; O OH NaBH4, MeOH, BnO OBn BnO OBn DCM, -78 °C (83%) OBn OBn 2.36 2.37
Ozone was bubbled through a solution of 2.36 (1.05 g, 1.83 mmol) in
methanol/dichloromethane mixture (9:1, 50 mL) at -78 °C followed by the addition of sodium borohydride (0.69 g, 18.3 mmol) after reaction was complete by TLC. The mixture was stirred for 3 h and allowed to gradually warm to rt prior to quenching by
slow addition of saturated NH4Cl solution and extraction with ether (3×100 mL). The
organic extracts were combined, dried, and freed of solvent to afford pure 2.37 (0.9 g,
-1 1 83%) as a colorless oil; IR (film, cm ) 3424, 2926, 1053; H NMR (300 MHz, CDCl3) δ
104 7.37- 7.25 (m, 15H), 5.28 (d, J = 4 Hz, 1H), 4.91 – 4.77 (m, 6H), 4.17 – 3.99 (m, 2H),
13 4.00 – 3.86 (m, 5H), 3.78 – 3.59 (m, 10H); C NMR (75 MHz, CDCl3) δ 138.7, 138.5,
138.4, 128.3, 128.2, 127.8, 127.7, 127.6, 127.5, 127.4, 108.8, 82.5, 81.4, 81.2, 80.5, 80.0,
+ 76.0, 75.8, 75.7, 74.7, 73.2, 67.0, 65.3, 62.1, 61.4; ES HRMS m/z (C33H40O9Na ) calcd
603.2565, obsd 603.2567.
Triketal 2.38
OH OH
O O OO O O O PhI(OAc)2, I2, O O O PhH, hν (10%) BnO OBn BnO OBn OBn OBn 2.37 2.38
A solution of 2.37 (150 mg, 0.25 mmol) in anhydrous benzene (30 mL) was treated with
iodobenzene diacetate (0.24 g, 0.76 mmol) and iodine (0.13 g, 0.50 mmol). The mixture
was irradiated with light from a 250W tungsten lamp for 1 h. It was then cooled to rt,
quenched with a mixture of satd. NaHCO3 and satd. Na2S2O3 solutions (2:1) and
extracted with ether (3×50 mL). The organic layers were combined, dried over Na2SO4 and evaporated in vacuo to afford a residue that was purified by chromatography on silica gel neutralized with triethylamine (elution with 50% ethyl acetate, 1% triethylamine in hexanes) to afford (15 mg, 10%) of 2.38 as a colorless oil; IR (film, cm-1) 2866, 1122; 1H
NMR (300 MHz, CDCl3) δ 7.32 – 7.20 (m, 15H), 4.87 – 4.77 (m, 6H), 4.25 – 4.17 (m,
13 5H), 4.06 – 3.99 (m, 5H), 3.92 – 3.83 (m, 5H); C NMR (75 MHz, CDCl3) δ 139.0,
138.8, 128.1, 127.9, 127.3, 127.2, 109.5, 107.6, 82.3, 81.1, 76.0, 75.9, 68.1, 66.8, 65.7;
+ ES HRMS m/z (C33H36O9Na ) calcd 599.2252, obsd 599.2245. 105 Triol 2.39
O OO O OO O O
O Pd/C, EtOAc O O O H2, (90%) BnO OBn HO OH OBn OH 2.38 2.39
To a solution of 2.38 (0.17 g, 0.30 mmol) in ethyl acetate (10 mL) was added palladium
on charcoal (10%, 50 mg) and hydrogen was purged through the system followed by
stirring under an atmosphere of hydrogen for 8 h. The mixture was filtered through a
Celite plug and the solvent was removed in vacuo to afford pure triol 2.39 (81 mg, 90%)
-1 1 as a colorless oil; IR (film, cm ) 3425, 1188; H NMR (300 MHz, CDCl3) δ 4.87 (s, 3H),
4.16 – 4.03 (m, 4H), 4.00 – 3.90 (m, 4H), 3.63 – 3.53 (m, 4H), 3.34 – 3.31 (m, 3H); 13C
NMR (75 MHz, CDCl3) δ 110.5, 109.7, 74.8, 73.9, 69.0, 68.3, 68.1, 67.2; ES HRMS m/z
+ (C12H18O9Na ) calcd 329.0843, obsd 329.0838.
Triketal 2.40
O OO O OO O O
O AllylBr, NaH, DMF, O O O 0 °C (74%) HO OH AllylO OAllyl OH OAllyl 2.39 2.40
A solution of 2.39 (89 mg, 0.29 mmol) in anhydrous DMF (5 mL) at 0 °C was treated with sodium hydride (60% in oil, 118 mg, 2.94 mmol), followed by allyl bromide (0.10 mL, 1.18 mmol) after 30 min. The mixture was stirred overnight, quenched with satd.
NH4Cl solution (5 mL) followed by water (20 mL), and extracted with ether (3×10 mL).
The combined organic layers were dried and concentrated to leave a residue that was 106 purified by chromatography on silica gel (elution with 20% ethyl acetate in hexanes) to
afford 2.40 (92 mg, 74%) as a colorless oil; IR (film, cm-1) 2905, 1114, 730; 1H NMR
(300 MHz, CDCl3) δ 5.96 – 5.87 (m, 3H), 5.26 – 5.06 (m, 6H), 4.27 – 4.15 (m, 12H),
13 4.02 – 3.97 (m, 6H), 3.56 (s, 3H); C NMR (75 MHz, CDCl3) δ 135.5, 116.0, 115.6,
+ 109.3, 81.5, 80.8, 74.5, 74.5, 68.0, 67.0, 66.7, 65.6; ES HRMS m/z (C21H30O9Na ) calcd
449.1782, obsd 449.1793.
Triketal 2.41
O O O O O O 1. O3, MeOH, DCM, O O O O (1:1), -78 °C; O O NaBH4, MeOH, AllylO OAllyl DCM, -78 °C (77%) O O OAllyl O
OH OH HO 2.40 2.41
Ozone was bubbled through a solution of 2.40 (92 mg, 0.2 mmol) in MeOH/CH2Cl2 mixture (9:1, 10 mL) at -78 °C followed by the addition of sodium borohydride (41 mg,
1.1 mmol) after reaction was complete. The mixture was stirred for 3 h and allowed to gradually warm to rt prior to quenching by slow addition of saturated NH4Cl solution (2
mL) followed by water (10 mL), and extracted with ether (3×10 mL). The organic
extracts were combined, dried, and freed of solvent to afford a residue that was purified
by chromatography on silica gel (elution with 50% ethyl acetate in hexanes) to afford
2.41 (73 mg, 77%) as a colorless oil; IR (film, cm-1) 3466, 2966, 1087; 1H NMR (300
MHz, CDCl3) δ 7.32 – 7.20 (m, 15H), 4.87 – 4.77 (m, 6H), 4.25 – 4.17 (m, 5H), 4.06 –
13 3.99 (m, 5H), 3.92 – 3.83 (m, 5H); C NMR (75 MHz, CDCl3) δ 119.1, 107.9, 65.5,
107 + 65.6, 65.2, 65.3, 61.4, 63.0, 71.3, 62.4, 72.8, 72.7; ES HRMS m/z (C18H30O12Na ) calcd
461.1635, obsd 461.1639.
6,8,9-Tris-(2-benzyloxyethoxy)-2,4,10-trioxatricyclo[3.3.1.13,7]decane
OBn OBn
OH OH O O OH BnOCH CH OTs O 2 2 OBn NaH, DMF O (95%) O O O O O
3.13 3.14
To triol 3.13 (0.62 g, 3.2 mmol) dissolved in dry DMF (25 mL) was added sodium
hydride (60% in oil, 0.80 g, 19 mmol) followed by 2-(benzyloxy)ethyl tosylate (5.97 g,
19.5 mmol) at 0 ºC. The mixture was stirred overnight with allowance for warming to rt,
carefully quenched with saturated NH4Cl solution, and extracted with ether (4×75 mL).
The combined organic layers were washed with brine (4×100 mL), dried, and
concentrated to leave a residue that was purified by chromatography on silica gel (elution
with 20% ethyl acetate in hexanes) to afford 1.84 g (95%) of 3.14 as a colorless oil; IR
-1 1 (film, cm ) 1602, 1584, 1496; H NMR (300 MHz, CDCl3) δ 7.27–7.24 (m, 6H), 7.17–
7.12 (m, 6H), 7.08–7.03 (m, 3H), 5.65 (s, 1H), 4.35 (q, J = 2.9 Hz, 3H), 4.32 (s, 6H),
4.21 (q, J = 2.9 Hz, 3H), 3.45–3.41 (m, 6H), 3.38–3.34 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 139.1, 128.2, 127.5, 127.3, 103.4, 73.8, 72.9, 69.7, 68.9, 68.8; ES HRMS m/z
+ (C34H40O9Na ) calcd 615.2564, obsd 615.2510.
108 2,4,6-Tris-(2-benzyloxyethoxy)cyclohexane-1,3,5-triol
OBn OBn OBn
O O O OH OBn p - TSA O MeOH HO O OH O (92%) O OBn O O OBn
3.14 3.15
A solution of 3.14 (2.2 g, 3.7 mmol) and p-toluenesulfonic acid (0.04 g, 0.19 mmol) in methanol (75 mL) was refluxed for 4 h. The solvent was reduced to about 10 mL and the reaction mixture was quenched with saturated sodium carbonate solution (50 mL) and water (75 mL), and extracted with ether (3×100 mL). The organic extracts were combined, dried, and evaporated. The residue was purified by chromatography on silica gel (elution with 40% hexanes in ethyl acetate) to afford 3.15 as a colorless oil (2.0 g,
-1 1 92%); IR (film, cm ) 3428, 1496, 1453; H NMR (300 MHz, CDCl3) δ 7.34–7.26 (m,
15H), 4.58 (s, 6H), 3.99 (t, J = 4.7 Hz, 6H), 3.64 (t, J = 4.7 Hz, 6H), 3.61 (t, J = 9.4 Hz,
13 6H), 3.52 (t, J = 9.4 Hz, 3H); C NMR (75 MHz, CDCl3) δ 137.6, 128.4, 127.9, 127.8,
+ 83.9, 73.7, 73.1, 72.2, 69.6; ES HRMS m/z (C33H42O9Na ) calcd 605.2721, obsd
605.2712.
1,2,3,4,5,6-Hexakis-(2-benzyloxyethoxy)cyclohexane
OBn OBn OBn OH O O BnOCH2CH2OTs O HO O NaH, DMF O O OH O O OBn (90%) O OBn OBn OBn OBn BnO 3.15 3.16
Triol 3.15 (2.52 g, 4.32 mmol) was dissolved in dry DMF (100 mL), treated with sodium hydride (60% in oil, 0.86 g, 22 mmol), and cooled to 0 ºC. 2-(Benzyloxy)ethyl tosylate
109 (5.30 g, 17.3 mmol) was introduced and the mixture was stirred overnight, quenched with
methanol (10 mL), and poured into an ice–water mixture prior to extraction with ether
(3×100 mL). The combined organic extracts were dried and freed of solvent to afford a
residue that was purified by chromatography on silica gel (elution with 33% ethyl acetate
in hexanes) to afford 3.84 g (90%) of 3.16 as a colorless oil that crystallized in the cold,
-1 1 mp 77–79 ºC; (film, cm ) 1497, 1454, 1357; H NMR (300 MHz, CDCl3) δ 7.36–7.26
(m, 30H), 4.54 (s, 12H), 4.06–4.03 (m, 12H), 3.62–3.58 (m, 12H), 3.28 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 138.5, 128.3, 127.7, 127.5, 83.1, 73.0, 72.9, 70.0; ES HRMS m/z
+ (C60H72O12Na ) calcd 1007.4916, obsd 1007.4913.
1,2,3,4,5,6-Hexakis-(2-hydroxyethoxy)cyclohexane
OBn OH OBn OH O O O Pd/C(10%), H2(1atm) O O O MeOH O O O O O OBn (99%) O OH OBn OH OBn BnO OH HO 3.16 3.17
To a solution of 3.16 (0.60 g, 0.61 mmol) in methanol (10 mL) was added palladium on
charcoal (10%, 20 mg) and hydrogen was purged through the system followed by stirring
under an atmosphere of hydrogen for 6 h. The mixture was filtered through a Celite plug
and the solvent was removed in vacuo to afford polyol 3.17 in almost quantitative yield
(0.27 g, 99%) as a white solid, mp 260 ºC dec. Further purification was not required; IR
-1 1 (film, cm ) 3373, 1458, 1355; H NMR (300 MHz, CDCl3) δ 4.56 (t, J = 5.4 Hz, 6H),
3.70 (t, J = 5.1 Hz, 12H), 3.50 (q, J = 5.1 Hz, 12H), 3.05 (s, 6H); 13C NMR (75 MHz,
+ CDCl3) δ 82.2, 74.5, 60.8; ES HRMS m/z (C18H36O12Na ) calcd 467.2099, obsd
467.2098. 110 1,2,3,4,5,6-Hexakis-(2-acetoxyethoxy)cyclohexane
OH OAc OH OAc O O O Ac2O, Et3N O CH CN O O 3 O O O O O OH (92%) O OAc OH OAc OH HO OAc AcO 3.17 3.18
A suspension of 3.17 (0.88 g, 2.0 mmol) in acetonitrile (25 mL) was cooled to 0 ºC and
treated with triethylamine (1.8 mL, 13 mmol) followed by acetic anhydride (1.15 mL, 12
mmol). The mixture was allowed to warm gradually to rt, freed of acetonitrile, and
purified by flash chromatography on silica gel (15% methanol in ethyl acetate) to afford
3.18 (1.26 g, 92%) as a white solid, mp 157–159 ºC; IR (film, cm-1) 1738, 1464, 1384; 1H
NMR (300 MHz, CDCl3) δ 3.89 (t, J = 4.7 Hz, 12H), 3.50 (t, J = 4.9 Hz, 12H), 3.32 (s,
13 18H), 3.12 (s, 6H); C NMR (75 MHz, CDCl3) δ 83.1, 72.6, 72.2, 58.7; ES HRMS m/z
+ (C30H48O18Na ) calcd 719.2733, obsd 719.2738.
6,8,9-Tris-(2-benzyloxyethoxy)-2,4,10-trioxatricyclo[3.3.1.13,7]decane
OBn OBn BnO OH O OH BnOCH2CH2OTs O OH NaH, DMF O O (90%) O O O O O
3.19 3.20
A solution of 3.19 (0.5 g, 2.6 mmol) in DMF (20 mL) was added dropwise to a stirred
suspension of sodium hydride (60% in oil, 0.4 g, 10 mmol) in DMF (30 mL) at 0 ºC. the
reaction mixture was stirred for 20 min prior to dropwise addition of solution of
benzyloxyethyl tosylate (3.22 g, 10.5 mmol) in DMF (25 mL), stirred overnight with
warming to rt, and quenched by careful addition of water (100 mL) followed by 111 extraction with ether (3×50 mL). The combined organic extracts were washed with brine,
dried, and evaporated to leave a residue which was purified by flash chromatography on
silica gel (5:1, hexanes/ethyl acetate) to afford 3.20 (1.40 g, 90%) as a colorless oil; IR
-1 1 (film, cm ) 1498, 1453, 1166; H NMR (300MHz, CDCl3) δ 7.36–7.24 (m, 15H), 5.53
(d, J = 1.2 Hz, 1H), 4.57 (s, 2H), 4.49 (s, H), 4.47–4.46 (m, 1H), 4.39–4.37 (m, 2H), 4.30
(t, J = 3.5 Hz, 2H), 3.94 (d, J = 1.5 Hz, 1H), 3.80–3.62 (m, 8H), 3.56 (t, J = 4.7 Hz, 4H);
13 C NMR (75 MHz, CDCl3) δ 138.2, 138.1, 128.9, 128.2, 127.7, 127.6, 127.5, 103.9,
+ 74.8, 73.2, 73.1, 70.4, 69.6, 69.4, 69.1, 69.0, 68.7, 67.9; ES HRMS m/z (C34H40O9Na ) calcd 615.2565, obsd 615.2551.
2,4,6-Tris-(2-benzyloxyethoxy)cyclohexane-1,3,5-triol
OBn OBn OBn BnO O O O HO p - TSA O OBn O MeOH HO OH O (90%) O O O OBn
3.20 3.21
A solution of 3.20 (2.90, 4.89 mmol) and p-toluenesulfonic acid (7.6 mg, 0.04 mmol) in
100 mL of methanol was refluxed for 4 h and evaporated to leave a residue that was
purified by chromatography on silica gel (elution with 1:1 ethyl acetate in hexanes).
There was isolated 2.56 g (90%) of 3.21 as a colorless oil; IR (film, cm-1) 3446, 1276,
1 1114; H NMR (300 MHz, CDCl3) δ 7.34–7.25 (m, 15H), 4.57–4.56 (m, 6H), 3.97–3.90
(m, 6H), 3.86 (s, 1H), 3.63–3.58 (m, 6H), 3.47–3.42 (m, 5H), 3.13 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 137.4, 137.3, 128.2, 128.1, 127.6, 127.5, 83.4, 81.0, 74.2, 72.9, 72.6,
+ 72.1, 69.5, 69.4; ES HRMS m/z (C33H42O9Na ) calcd 605.2721, obsd 605.2669.
112 1,2,3,4,5,6-Hexakis-(2-benzyloxyethoxy)cyclohexane
OBn OBn OBn
O O HO O O OBn BnOCH2CH2OTs O OBn HO OH NaH, DMF O O O (84%) O OBn OBn OBn BnO 3.21 3.22
To triol 3.21 (2.56 g, 4.40 mmol), dissolved in dry DMF (100 mL) was added sodium
hydride (60% in oil, 1.2 g, 30 mmol) followed by 2-(benzyloxy)ethyl tosylate (6.74 g, 22
mmol) at 0 ºC. The mixture was stirred overnight, allowed to warm up gradually to rt,
quenched with saturated NH4Cl solution, and extracted with ether (4×100 mL). The
combined organic layers were washed with brine (4×100 mL), dried, and concentrated to
leave a residue that was purified by chromatography on silica gel (elution with 50% ethyl
acetate in hexanes) to afford 3.61 g (84%) of 3.22 as a colorless oil; IR (film, cm-1) 1602,
1 1496, 1453; H NMR (300 MHz, CDCl3) δ 7.40–7.26 (m, 30H), 4.60 (s, 2H), 4.54–4.53
(m, 10H), 4.05–3.97 (m, 9H), 3.81–3.58 (m, 19H), 3.24–3.16 (m, 3H); 13C NMR (75
MHz, CDCl3) δ 138.8, 138.5, 138.4, 128.3, 128.2, 127.6, 127.5, 127.4, 127.3, 99.7, 83.9,
82.0, 81.3, 76.4, 73.1, 72.9, 72.8, 72.85, 72.75, 72.5, 72.3, 70.4, 70.1, 70.0, 69.91, 69.88;
+ ES HRMS m/z (C69H72O12Na ) calcd 1007.4916, obsd 1007.4834.
113 1,2,3,4,5,6-Hexakis-(2-hydroxyethoxy)cyclohexane
OBn OH OBn OH OH O O O O O OBn Pd/C(10%), H2(1atm) O O MeOH O O O O (96%) O OBn OH OBn BnO OH HO 3.22 3.23
To a solution of 3.22 (3.61 g, 3.66 mmol) in methanol (100 mL) was added palladium on
charcoal (10%, 150 mg) and hydrogen was purged through the system followed by
stirring under 1 atm for 6 h. The mixture was filtered through a Celite plug, solvent
removed in vacuo, and the residue was purified by recrystallization (50% methanol in ethylacetate) to afford 1.57 g (96%) of 3.23 as a white solid, mp 104–106 ºC; IR (film,
-1 1 cm ) 3386, 1461, 1361; H NMR (300 MHz, CDCl3) δ 4.60–4.52 (m, 5H), 4.32 (t, J =
5.6 Hz, 1H), 3.93 (s, 1H), 3.70–3.31 (m, 26H), 3.17–3.13 (m, 2H), 2.99 (t, J = 9.0 Hz,
13 1H); C NMR (75 MHz, CDCl3) δ 94.8, 83.0, 81.2, 80.1, 75.2, 74.5, 74.3, 73.9, 71.8,
+ 60.84, 60.78, 60.7, 60.6; ES HRMS m/z (C18H36O12Na ) calcd 467.2099, obsd 467.2098.
1,2,3,4,5,6-Hexakis-(2-acetoxyethoxy)cyclohexane
OH OAc OH OAc OH O O O Ac O, Et N O O 2 3 O OAc O CH3CN O O O O (91%) O OH OAc OH HO OAc AcO 3.23 3.24
A suspension of 3.23 (100 mg, 0.22 mmol) in dry acetonitrile (50 mL) was treated with
triethylamine (0.4 mL, 2.70 mmol) and DMAP (2.7 mg, 0.02 mmol), and cooled to 0 ºC.
Following the addition of acetic anhydride (0.3 mL, 2.70 mmol), the reaction mixture
was stirred for 2 h, quenched with saturated bicarbonate solution (30 mL), and extracted 114 with CH2Cl2 (3×50 mL). The combined organic layers were dried and freed of solvent.
The residue was chromatographed on silica gel (elution with 75% ethyl acetate in hexanes) to afford 142 mg (91%) of 3.24 as a white solid, mp 57–59 ºC; (film, cm-1)
1 1739, 1440, 1382; H NMR (300 MHz, CDCl3) δ 4.11–4.01 (m, 12H), 3.85–3.63 (m,
12H), 3.47 (t, J = 9.4 Hz, 2H), 2.98–2.90 (m, 3H), 1.92 (s, 18H); 13C NMR (75 MHz,
CDCl3) δ 170.63, 170.58, 83.2, 81.3, 80.7, 76.2, 71.1, 70.9, 70.7, 69.8, 63.9, 63.8, 63.53,
+ 63.47, 20.7, 20.6; ES HRMS m/z (C30H48O17Na ) calcd 719.2733, obsd 719.2738.
1,3,5-Trisallyloxy-2,4,6-tris-(2-benzyloxyethoxy)cyclohexane
OBn
OAllyl OAllyl OAllyl O AllylO OBn OAllyl 1. p-TSA, MeOH O O O 2. BnOCH2CH2OTs AllylO O O NaH, DMF (92%) OBn 3.25 3.26
A solution of 3.25 (2.64 g, 8.51 mmol) and p-toluenesulfonic acid (80 mg, 0.05 mmol) in methanol (150 mL) was refluxed for 4 h. The solvent was removed and the residue was dissolved in dry DMF (150 mL), cooled to 0 ºC and treated with sodium hydride (60% in oil, 1.36 g, 34.0 mmol). 2-(Benzyloxy)ethyl tosylate (9.12 g, 29.77 mmol) was introduced and the reaction mixture was stirred overnight, quenched with methanol (10 mL), poured
into an ice–water mixture, and extracted with ether (3×100 mL). The combined organic
extracts were dried and evaporated. The residue was purified by chromatography on
silica gel (elution with 25% ethyl acetate in hexanes) to afford 5.50 g (92% over two
steps) of 3.26 as a colorless oil; IR (film, cm-1) 1496, 1454, 1354; 1H NMR (300 MHz,
CDCl3) δ 7.37–7.26 (m, 15H), 6.04–5.89 (m, 3H), 5.30–5.07 (m, 6H), 4.59–4.57 (m, 6H),
4.36–4.34 (m, 5H), 4.00–3.97 (m, 3H), 3.78–3.58 (m, 13H), 3.17–3.11 (m, 3H); 13C 115 NMR (75 MHz, CDCl3) δ 138.5, 138.4, 136.0, 135.8, 128.5, 128.4, 128.3, 127.8, 127.6,
127.5, 116.4, 116.2, 84.3, 81.7, 81.2, 74.4, 74.2, 73.3, 73.2, 73.0, 72.9, 71.4, 70.5; ES
+ HRMS m/z (C42H54O9Na ) calcd 725.3660, obsd 725.3684.
1,3,5-Tris-(2-methoxyethoxy)-2,4,6-tris-(2-benzyloxyethoxy)cyclohexane
OBn OMe OBn O O OAllyl OMe O O AllylO OBn O 1. O , NaBH , MeOH O O O 3 4 O OMe AllylO 2. Me2SO4, NaH, DMF OBn BnO (70%) OBn 3.26 3.27
Ozone was bubbled through a solution of 3.26 (5.50 g, 7.83 mmol) in
methanol/dichloromethane mixture (9:1, 100 mL) at -78 ºC followed by the addition of
sodium borohydride (1.48 g, 38.1 mmol) after reaction was complete. The mixture was
stirred for 3 h and allowed to gradually warm to rt prior to quenching by slow addition of
saturated NH4Cl solution and extraction with ether (3×100 mL). The organic extracts
were combined, dried, and freed of solvent to afford a residue that was dissolved in dry
DMF (100 mL). The resulting solution was treated first with sodium hydride (60% in oil,
1.25 g, 31.3 mmol) at -10 ºC and then slowly with dimethyl sulfate (3 mL, 31.3 mmol).
After overnight stirring, the reaction mixture was quenched with methanol (10 mL), poured into water (200 mL), and extracted with ether (3×100 mL). The organic extracts were combined, dried, and freed of solvent to afford crude product that was
chromatographed on silica gel (elution with 60% ethyl acetate in hexanes) to afford 3.27
(4.15 g, 70% over three steps) as a colorless oil; IR (film, cm-1) 1453, 1354, 1094; 1H
NMR (300 MHz, CDCl3) δ 7.33–7.24 (m, 15H), 4.56 (s, 2H), 4.53 (s, 4H), 4.00–3.97 (m,
116 2H), 3.93–3.84 (m, 7H), 3.76–3.71 (m, 4H), 3.68–3.59 (m, 8H), 3.53–3.52 (m, 6H), 3.32
13 (s, 3H), 3.29 (s, 6H), 3.16– 3.08 (m, 3H); C NMR (75 MHz, CDCl3) δ 138.6, 138.4,
128.3, 128.2, 127.6, 127.53, 127.50, 127.4, 83.4, 82.1, 81.3, 76.2, 73.1, 72.9, 72.7, 72.4,
+ 72.2, 72.0, 70.4, 70.2, 69.9, 58.8, 58.7; ES HRMS m/z (C42H60O12Na ) calcd 779.3977,
obsd 779.3958.
1,2,3,4,5,6-Hexakis-(2-methoxyethoxy)cyclohexane
OBn OMe OMe OMe
O O O O O OMe O OMe O 1. Pd/C, H2 (1 atm), MeOH O O O O 2. Me2SO4, NaH, THF O OMe OMe (82%) OBn BnO OMe MeO
3.27 3.28
Compound 3.27 (2.0 g, 2.4 mmol) was dissolved in ethyl acetate (75 mL) followed by
palladium on charcoal (10%, 200 mg). The mixture was purged with hydrogen and stirred
in this atmosphere for 3 h. The catalyst was removed by filtration through a cotton plug
and the filtrate was evaporated. The residue so obtained was dissolved in THF, treated
with sodium hydride (60% in oil, 0.37 g, 9.25 mmol), and cooled to -20 ºC prior to the
addition of dimethyl sulfate (1.0 mL, 10.57 mmol). This mixture was stirred for 4 h,
allowed to warm gradually, and quenched with methanol (5 mL). Solvent was removed in
vacuo and the residue was purified by chromatography on silica gel (elution with 5%
methanol in ethyl acetate) to afford 3.28 as a colorless oil (1.2 g, 82%); IR (film, cm-1)
1 1454, 1356, 1267; H NMR (300 MHz, CDCl3) δ 3.89–3.78 (m, 10H), 3.71–3.63 (m,
3H), 3.56 (t, J = 9.6 Hz, 1H), 3.50–3.43 (m, 12H), 3.30–3.29 (m, 19H), 3.08–3.01 (m,
13 3H); C NMR (75 MHz, CDCl3) δ 83.9, 81.9, 81.3, 76.0, 72.5, 72.3, 72.2, 72.1, 71.9,
117 + 70.2, 58.8, 58.7, 58.7, 58.6; ES HRMS m/z (C24H48O12Na ) calcd 551.3038, obsd
551.3037.
6,8,9-Trisbenzyloxy-2,4,10-trioxatricyclo[3.3.1.13,7]decane
OH OH OBn OBn OH OBn 1. BnBr, NaH, DMF O 0 C (88%) O O O O O
3.13 3.29
Triol 3.13 (4.0 g, 21.0 mmol) dissolved in anhydrous DMF (100 mL) at 0 ºC was treated
with sodium hydride (60% in oil, 3.0 g, 75.0 mmol), followed by benzyl bromide (8.35
mL, 70 mmol) after 30 min. The mixture was stirred overnight, quenched with saturated
NH4Cl solution (200 mL), and extracted with CH2Cl2 (3×100 mL). The combined
organic layers were dried and concentrated to leave a residue that was purified by
chromatography on silica gel (elution with 5% ethyl acetate in hexanes) to afford 8.55 g
(88%) of 3.29 as a white solid, mp 117–119 ºC; IR (film, cm-1) 1497, 1453, 1167; 1H
NMR (300 MHz, CDCl3) δ 7.28–7.17 (m, 5H), 5.55 (s, 1H), 4.66 (s, 6H), 4.59 (dd, J =
13 4.2, 3.0 Hz, 3H), 4.37 (dd, J = 4.2, 3.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 137.8,
+ 128.1, 127.7, 127.4, 103.1, 72.5, 71.2, 68.6; ES HRMS m/z (C28H28O6Na ) calcd
438.1778, obsd 483.1764.
118 1,3,5-Trisbenzyloxy-2,4,6-tris-(2-methoxyethoxy)cyclohexane
OMe
OBn OBn OBn OBn O 1. p-TSA, MeOH BnO O OBn O 2. MeOCH2CH2OTs O OMe O O OMe NaH, DMF (90%) 3.29 3.30
A solution of 3.29 (2.4 g, 5.2 mmol) and p-toluenesulfonic acid (0.05 g, 0.26 mmol) in methanol was refluxed for 3 h, cooled, and freed of solvent. The crude residue was dissolved in dry DMF (75 mL) followed by the addition of sodium hydride (60% in oil,
0.73 g, 18.24 mmol) and cooling to 0 ºC. 2-Methoxyethanol tosylate (4.20 g, 18.2 mmol) was introduced and the reaction mixture was allowed to warm gradually during overnight stirring, quenched with methanol (10 mL) and water (100 mL), and extracted with ether
(3×100 mL). The organic extracts were combined, dried, and evaporated to afford a residue that was purified on silica gel (elution with 25% ethyl acetate in hexanes) to afford 3.30 (2.95 g, 90%) as a white solid, mp 95–97 ºC; IR (film, cm-1) 1454, 1356,
1198; 1H NMR (300 MHz, CDCl3) δ 7.46–7.26 (m, 15H), 4.90 (s, 6H), 3.99–3.95 (m,
6H), 3.55–3.48 (m, 9H), 3.35 (s, 9H), 3.27 (t, J = 9.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.9, 128.4, 128.2, 127.6, 83.4, 82.5, 75.8, 73.0, 72.3, 59.0; ES HRMS m/z
+ (C36H48O9Na ) calcd 647.3191, obsd 647.3205.
119 1,2,3,4,5,6-Hexakis-(2-methoxyethoxy)cyclohexane
OMe OMe OMe OBn O O O BnO O 1. Pd/C, H2 (1 atm), MeOH O O OBn O O OMe 2. MeOCH2CH2OTs O OMe OMe OMe NaH, THF (40%) OMe MeO 3.30 3.31
A solution of 3.30 (2.4 g, 3.84 mmol) in methanol (75 mL) containing palladium on
charcoal (10%, 100 mg) was stirred under an atmosphere of H2 for 3 h. The catalyst was
removed by filtration through a cotton plug, the solvent was evaporated, and the residue
was dissolved in dry THF (75 mL) and treated with sodium hydride (60% in oil, 0.46 g,
11.5 mmol) at 0 ºC. 2-Methoxyethanol tosylate (2.65 g, 11.52 mmol) was introduced and
the mixture was stirred overnight with gradual warming to rt, quenched with methanol
(10 mL) followed by water (100 mL), and filtered. The filtrate was evaporated in vacuo
to afford a residue that was purified on silica gel (elution with 10% methanol in ethyl
acetate) to afford 3.31 (0.82 g, 40%) as a colorless oil; IR (film, cm-1) 1487, 1462, 1358;
1 H NMR (300 MHz, CDCl3) δ 3.90–3.87 (m, 12H), 3.52–3.48 (m, 12H), 3.32 (s, 18H),
13 3.12 (s, 6H); C NMR (75 MHz, CDCl3) δ 83.0, 72.6, 72.2, 58.1; ES HRMS m/z
+ (C24H48O12Na ) calcd 551.3038, obsd 551.3048.
5-Oxaspiro[3.5]nonan-1-one
, n-BuLi, THF, -78 °C O O OSnBu3 Cl Cl 4.10 O 4.4 4.14
A solution of 4.10 (14.93 g, 40.0 mmol) in dry THF (150 mL) was blanketed with N2, cooled to -78 °C, and treated dropwise with n-butyllithium (29.2 mL of 1.3 M in pentane,
120 0.038 mol). Upon completion of the addition, the reaction mixture was stirred in the cold for 30 min prior to being added to a solution of 1,3-dichloroacetone (5.08 g, 0.040 mol) in dry THF (100 mL) at -78 °C. After 1 h at this temperature, a solution of lithium naphthalenide [from 0.69 g (0.10 mol) of lithium and 19.22 g (0.15 mol) of naphthalene] in THF (200 mL) was added. The reaction mixture was maintained at -78 °C for 2 h, quenched with water, diluted with petroleum ether (200 mL), and extracted with ether (3 x 300 mL). The organic extracts were washed with brine, treated with Dowex-50W (3 g), and stirred for 3 h. The resin was separated by filtration, the solvent was removed by fractional distillation, and the residue was purified by chromatography on silica gel
(elution with 4:1 petroleum ether/ether) to furnish 4.0 g (75%) of 4.14 as a colorless,
-1 1 volatile oil: IR (neat, cm ) 1732, 1464, 1282; H NMR (300 MHz, CDCl3) δ 4.18-4.10
(m, 1 H), 3.65-3.59 (m, 1 H), 2.56-2.32 (m, 2 H), 1.90-1.80 (m, 1 H), 1.44-1.28 (m, 7 H);
13 C NMR (75 MHz, CDCl3) δ 208.3, 87.5, 64.9, 39.1, 34.2, 30.1, 29.8, 25.8, 25.4, 20.2;
ES HRMS m/z ([M+Na]+) calcd 163.0735, obsd 163.0735.
1,7-Dioxadispiro[4.0.5.3]tetradecan-12-one (syn and anti)
1. , n-BuLi, THF, -78 °C O O O O OSnBu3 4.10 O + 2. oven-dried DOWEX - 50W, O O ether ( 50% ) O 4.9 4.17( 8 : 1 ) 4.18 n-Butyllithium (29 mL of 1.54 M, 45 mmol) was added to a solution of 4.10 (18.65 g, 50 mmol) in anhydrous THF (100 mL) at -78 °C. After 30 min, the above solution was added to a solution of 4.9 (5.0 g, 39.7 mmol) in THF (50 mL) and stirring was maintained in the cold for 2 h. Water was slowly added, the products were extracted into ether, and 121 the combined organic layers were washed with brine and dried. Oven-dried Dowex-50W resin (2 g) was added and ultimately filtered off when isomerization was complete (TLC analysis). The filtrate was evaporated and the residue chromatographed on silica gel
(gradient elution with hexanes/ethyl acetate). Ketone 4.17 eluted with a 2:1 solvent mixture while 4.18 eluted with a 10:1 solvent system. There was isolated 3.33 g (40%) of
4.17 and 0.42 g (5%) of 4.18, both as colorless oils.
-1 1 For 4.17: IR (neat, cm ) 1743, 1450; H NMR (300 MHz, CDCl3) δ 4.33-4.24 (m, 1
H), 3.90-3.79 (m, 3 H), 2.45-2.32 (m, 1 H), 2.22-2.05 (m, 2 H), 1.96-1.46 (series of m, 11
13 H); C NMR (75 MHz, CDCl3) δ 216.4, 89.9, 81.4, 68.6, 64.2, 33.5, 30.3, 30.1, 26.2,
25.7, 25.3, 18.6; ES HRMS m/z ([M+Na]+) calcd 233.1148, obsd 233.1148.
-1 1 For 4.18: IR (neat, cm ) 1741, 1443; H NMR (300 MHz, CDCl3) δ 3.80-3.56 (m, 4
H), 2.30-1.99 (m, 5 H), 1.94-1.83 (m, 3 H), 1.77-1.61 (m, 3 H), 1.54-1.34 (m, 3 H); 13C
NMR (75 MHz, CDCl3) δ 215.9, 90.4, 79.8, 68.3, 64.1, 34.1, 31.4, 28.9, 26.1, 25.8, 23.0,
18.3; ES HRMS m/z ([M+Na]+) calcd 233.1148, obsd 233.1158.
1,7-Dioxadispiro[4.0.5.3]tetradecan-14-one (syn and anti)
1. , THF, -78 °C O O O O O Li 4.5 O + O 2. oven-dried DOWEX - 50W, ether ( 50% ) O O 4.14 4.19( 4 : 1 ) 4.20
A solution of 2,3-dihydrofuran (2.64 mL, 35 mmol) in anhydrous THF (100 mL) was cooled to -78 °C, treated with tert-butyllithium (17.6 mL of 1.7 M, 30 mmol), stirred in the cold for 1 h, and allowed to warm to rt for 30 min. The reaction mixture was returned 122 to -78 °C, at which point it was added to a solution of 4.14 (4.0 g, 28.5 mmol) in dry THF
(50 mL). Once TLC analysis indicated the ketone to be consumed, water was slowly
introduced and the product was extracted into ether (3 x 100 mL). The combined organic
layer was washed with brine and dried. Oven-dried Dowex-50W resin (2.5 g) was added
to the filtrate. When the reaction was complete (TLC analysis), the resin was filtered off,
the filtrate was concentrated, and the residue was chromatographed on silica gel (gradient
elution from hexane to ethyl acetate/hexane) to afford 4.19 (2.40 g, 40%) and 4.20 (0.59
g, 10%), both as colorless oils.
-1 1 For 4.19: IR (neat, cm ) 1752, 1448; H NMR (300 MHz, CDCl3) δ 4.13-3.92
(m, 2 H), 3.80 (dd, J = 10.5, 3.5 Hz, 1 H), 3.56 (dt, J = 11, 3.0 Hz, 1 H), 2.49 (ddd, J =
3.3, 9.0, 10.3 Hz, 1 H), 2.33-2.11 (m, 2 H), 2.02-1.54 (series of m, 11 H); 13C NMR (75
MHz, CDCl3) δ 216.7, 92.0, 80.3, 70.1, 62.1, 30.8, 29.0, 27.2, 25.5, 25.1, 24.0, 19.2; ES
HRMS m/z ([M+Na]+) calcd 233.1154, obsd 233.1143.
-1 1 For 4.20: IR (neat, cm ) 1750, 1446; H NMR (300 MHz, CDCl3) δ 3.88-3.54 (m, 4 H),
13 2.45-2.11 (m, 3 H), 2.04-1.72 (m, 6 H), 1.62-1.46 (m, 5 H); C NMR (75 MHz, CDCl3)
δ 216.1, 89.8, 80.5, 77.5, 77.0, 69.0, 61.6, 32.0, 27.2, 26.5, 26.1, 24.8, 18.9; ES HRMS m/z ([M+Na]+) calcd 233.1154, obsd 233.1156.
123 1,8-Dioxadispiro[5.0.5.3]pentadecan-13-one (syn and anti)
1. , n-BuLi, THF, -78 °C O O OSnBu3 O O 4.10 O + O 2. SiO2, CH2Cl2, ( 10% ) O O 4.14 4.21( 20 : 1 ) 4.22
n-Butyllithium (20.1 mL of 1.54 M in hexane, 31 mmol) was added to a solution of 4.14
(11.94 g, 32 mmol) in anhydrous THF (100 mL) at -78 °C. After being stirred for 30 min,
this solution was added to a solution of 4.14 (2.8 g, 20 mmol) in the same medium (50
mL) at the same temperature. After the disappearance of 4.14 (TLC), water was slowly
introduced, the products were extracted into ethyl acetate (3 x 200 mL), and the
combined organic layers were washed with brine and dried. The residue remaining after
solvent evaporation was dissolved in dry CH2Cl2 (250 mL). Silica gel (4 g) was added and stirring was maintained at rt for 3 days. After filtration, solvent removal, and chromatographic separation on silica gel (25-5:1 hexane/ethyl acetate), there was isolated
20 mg (0.5%) of less polar 4.22 and 400 mg (9%) of more polar 4.21.
For 4.21: colorless solid, mp 70-72 °C; IR (neat, cm-1) 1745, 1443, 1219; 1H
NMR (300 MHz, C6D6) δ 4.53 (dt, J = 2.8, 11.4 Hz, 1 H), 3.83-3.71 (m, 2 H), 3.36 (dt, J
= 2.7, 8.5 Hz, 1 H), 2.29-2.17 (m, 1 H), 2.12-2.03 (m, 1 H), 1.87-1.76 (m, 2H), 1.58 (dt, J
13 = 4.2, 12.5 H, 1 H), 1.49-1.12 (m, 10 H), 1.03-0.97 (m, 1 H); C NMR (75 MHz, C6D6)
δ 214.9, 82.6, 80.8, 63.4, 61.8, 32.4, 27.2, 25.8, 25.7,24.8, 23.8, 19.1, 18.8; ES HRMS
m/z ([M+Na]+) calcd 247.1310, obsd 247.1308.
For 4.22: colorless oil; IR (neat, cm-1) 1743, 1441, 1094; 1H NMR (300 MHz,
C6D6) δ 3.69-3.64 (m, 2 H), 3.50-3.44 (m, 1 H), 3.26 (dt, J = 11.6, 2.8 Hz, 1 H), 2.56-
124 13 2.40 (m, 1 H), 2.27-2.00 (m, 4 H), 1.77-1.21 (m, 11 H); C NMR (75 MHz, C6D6) δ
214.4, 82.3, 80.3, 63.9, 61.0, 32.6, 27.2, 26.4, 26.2, 23.7, 22.5, 19.1, 18.8; ES HRMS m/z
([M+Na]+) calcd 247.1310, obsd 247.1310.
Isomerization of 4.15 and 4.16. Prototypical procedure
Ketone 4.15 (4.5 g, 22.9 mmol) dissolved in CHCl3 (100 mL) was treated with boron
trifluoride etherate (2.9 mL, 23 mmol), refluxed for 6 h, cooled to 0 °C, and quenched
with water. The separated organic phase was dried and freed of solvent to leave a residue
that was chromatographed on silica gel. Elution with 25-50% ethyl acetate in hexane
furnished 1.7 g of 4.15 and 1.9 g (80% total) of 4.16.
An identical procedure was adopted starting from 4.16 (500 mg, 2.65 mmol) in CHCl3
(10 mL) and the subsequent introduction of boron trifluoride etherate (0.37 mL, 2.91 mmol). A parallel workup protocol furnished 206 mg of 4.15 and 1.93 mg of 4.16 (total of 80%).
(R)-5-(4-Hydroxybutyl)dihydrofuran-2(3H)-one
OH
1. BH3.THF, THF, 0°C O O O O 2. NaBO3,H2O (87%) 5.27 5.28
A solution of BH3•THF (1 M in THF, 0.7 mL, 0.7 mmol) was added to a solution of 5.27
(0.10 g, 0.71 mmol) in THF (15 mL) at 0 °C for 30 min followed by warm up to room
temperature. Upon completion of the reaction, the solution was cooled back to 0 ºC and
treated with a solution of sodium perborate (0.33 g, 2.10 mmol) in water (15 mL),
125 warmed to room temperature, and stirred for 2 h. The solution was extracted with ethyl
acetate (3×30 mL). The combined organic layers were washed with brine, dried, and concentrated to afford a residue that was purified by chromatography on silica gel
(elution with 30% ethyl acetate in hexanes) to furnish 5.28 (0.098 g, 87%) as a colorless
-1 1 oil: IR (film, cm ) 3500, 2926, 2359, 1769, 1182; H NMR (300 MHz, CDCl3) δ 4.52 –
4.43 (m, 1H), 3.63 (t, J = 6.0 Hz, 2H), 2.51 (dd, J = 9.8, 9.5 Hz, 2H), 2.31 (sextet, J = 6.6
13 Hz, 1H), 1.77 – 1.44 (m, 8H); C NMR (75 MHz, CDCl3) δ 177.3, 80.9, 62.3, 35.2, 32.2,
+ 28.8, 27.9, 21.6; ES HRMS m/z (C8H14O3Na ) calcd 181.0835, obsd 181.0833.
(S)-2-(Benzyloxymethyl)-2,3-dihydrofuran
1. DIBAL, DCM, -78 °C
2. Ac2O, Et3N, DCM
O O CH2OBn 3. NaHCO3,DMSO, O CH2OBn 190 °C (78%) 5.33 5.35 A solution of DIBAL in hexanes (1 M, 9.7 mL, 9.7 mmol) was added dropwise to a solution of 5.33 (2.0 g, 9.7 mmol) in CH2Cl2 (50 mL) at -78 °C and stirred for 2 h. The
reaction mixture was quenched at -78 °C by slowly adding methanol (5 mL) followed by
satd. Rochelle’s salt solution (50 mL), and extracted with CH2Cl2 (3×50 mL). The
combined organic layers were dried and concentrated to leave a residue that was taken up
in CH2Cl2 (50 mL), cooled to 0 °C, and treated with triethylamine (6.8 mL, 48.5 mmol)
followed by acetic anhydride (1.83 mL, 19.4 mmol). The solution was stirred for 2 h,
quenched with satd. NaHCO3 solution (50 mL), and extracted with CH2Cl2 (3×50 mL).
The combined organic layers were dried and concentrated to leave a residue that was
taken up in DMSO (50 mL). The solution was then treated with NaHCO3 (1.63 g, 19.4
126 mmol) and heated at 190 °C for 4 h. The solution was cooled to rt, poured into ice cold
water (200 mL), and extracted with ether (3×50 mL). The combined organic layers were
dried and concentrated to leave a residue that was purified by chromatography on silica
gel neutralized with triethylamine (elution with 2% ethyl acetate, 1% triethylamine in
hexanes) to afford 5.35 (1.44 g, 78%) as a colorless oil: IR (film, cm-1) 2970, 1520, 1040;
1 H NMR (300 MHz, CDCl3) δ 7.32 – 7.10 (m, 5H), 6.23 – 6.20 (m, 1H), 4.72 – 4.62 (m,
2H), 4.39 (s, 2H), 3.50 – 3.44 (m, 1H), 3.36 – 3.27 (m, 1 H), 2.46 – 2.36 (m, 1H), 2.32 –
13 2.23 (m, 1H); C NMR (75 MHz, CDCl3) δ 145.6, 139.0, 128.5, 127.7, 98.9, 80.1, 73.3,
+ 72.6, 32.0; ES HRMS m/z (C12H14O2Na ) calcd 213.0891, obsd 213.0895.
tert-Butyldimethyl(((2S)-5-(phenylsulfonyl)tetrahydrofuran-2-yl)methoxy)silane
5.36 5.38 A solution of DIBAL in hexanes (1 M, 4.3 mL, 4.3 mmol) was added dropwise to a solution of 5.33 (1.0 g, 4.3 mmol) in CH2Cl2 (50 mL) at -78 °C and stirred for 2 h. The
reaction mixture was quenched at -78 °C by the slow addition of methanol (3 mL)
followed by satd. Rochelle’s salt solution (20 mL), and extracted with CH2Cl2 (3×50
mL). The combined organic layers were dried, and concentrated to leave a residue that
was taken up in CH2Cl2 (50 mL), cooled to 0 °C, and treated with phenylsulfenic acid
(0.93 g, 6.5 mmol) followed by anhydrous CaCl2 powder (0.2 g). The suspension was
stirred for 8 h. Upon completion as indicated by TLC, the reaction mixture was quenched
by adding satd. NaHCO3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The combined
127 organic layers were dried and concentrated to leave a residue that was purified by
chromatography on silica gel (elution with 12% ethyl acetate in hexanes) to afford 5.38
-1 1 (1.28 g, 82%) as a colorless oil: IR (film, cm ) 1350, 1160; H NMR (300 MHz, CDCl3)
δ 7.97 – 7.92 (m, 2H), 6.98 – 6.93 (m, 3H), 4.71 (dd, J = 7.9, 3.7 Hz, 1H), 4.40 – 4.33 (m,
1H), 3.35 (dd, J = 11.0, 3.9 Hz, 1H), 3.23 (dd, J = 11.0, 3.9 Hz, 1H), 2.67 – 2.57 (m, 1H),
2.00 – 1.87 (m, 2H), 1.50 – 1.39 (m, 1H), 0.86 (s, 9H), -0.10 (s, 3H), -0.11 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 138.6, 133.2, 129.5, 128.8, 94.9, 83.0, 65.0, 26.7, 26.0, 25.9,
+ 18.4, -5.4, -5.5; ES HRMS m/z (C17H28O4SSiNa ) calcd 379.1375, obsd 379.1373.
(S)-5-(tert-Butyldimethylsilyloxy)-N-methoxy-N-methyl-4-
(trimethylsilyloxy)pentanamide
1. AlMe3, MeONMeH2Cl OTBS DCM, 0 °C; OTMS N O O O 2. TMSCl, Et3N, DCM O OTBS 0 °C (85%) 5.36 5.41 A suspension of N,O-dimethylhydroxylamine hydrochloride (0.93 g, 9.5 mmol) in
CH2Cl2 (20 mL) was cooled to 0 °C and treated dropwise with a solution of
trimethylaluminum in hexanes (2M, 4.34 mL, 8.7 mmol). After being stirred for 30 min,
the solution was warmed to rt and stirred for 1 h. The solution was cooled to 0 °C, treated
with a solution of 5.36 (1.0 g, 4.3 mmol) in CH2Cl2 (5 mL), and stirred overnight. The
reaction mixture was quenched with satd. solution of Rochelle’s salt (20 mL), vigorously
stirred for 2 h, and extracted with CH2Cl2 (3×25 mL). The combined organic layers were
dried and concentrated to leave a residue, which was taken up in CH2Cl2 (25 mL) and
cooled to 0 °C. The solution was then treated with triethylamine (3.0 mL, 21.7 mmol)
128 followed by trimethylsilyl chloride (1.65 mL, 13.0 mmol). After being stirred for 3 h, the
reaction mixture was stirred at rt for 1 h, quenched with satd. NaHCO3 solution (20 mL),
and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried and
concentrated to leave a residue that was purified by chromatography on silica gel (elution
with 16% ethyl acetate in hexanes) to afford 5.41 (1.35 g, 85%) as a colorless oil: IR
-1 1 (film, cm ) 1665, 1470, 740; H NMR (400 MHz, CDCl3) δ 3.93 – 3.87 (m, 1H), 3.62
(dd, J = 10.3, 5.7 Hz, 1H), 3.54 (dd, J = 10.3, 5.7 Hz, 1H), 3.08 (s, 3H), 2.88 (s, 3H), 2.54
(t, J = 7.6 Hz, 2H), 2.18 – 2.10 (m, 1H), 1.94 – 1.85 (m, 1H), 0.96 (s, 9H), 0.17 (s, 9H),
13 0.07 (s, 6H); C NMR (100 MHz, CDCl3) δ 174.1, 72.6, 67.9, 60.3, 32.0, 28.9, 27.7,
+ 26.0, 18.4, 0.3, -5.3, -5.4; ES HRMS m/z (C16H37O4NSi2Na ) calcd 386.2159, obsd
386.2144.
(S)-1-(tert-Butyldimethylsilyloxy)-2-hydroxydec-9-en-5-one
OTBS OTBS
OTMS 1. CH2=CH(CH2)3I, OH N O tBuLi, ether, -78 °C O O 2. K2CO3, MeOH (84%) 5.41 5.42
A solution of 5-bromo-1-pentene (0.73 mL, 6.2 mmol) in THF (20 mL) at -78 °C was
treated dropwise with a solution of t-BuLi in pentanes (1.7 M, 5.82 mL, 9.9 mmol). The
solution was stirred for 15 min followed by the addition of a solution of 5.41 (0.45 g, 1.2
mmol) in dry THF (5 mL). The solution was stirred for 2 h, quenched by adding water
(25 mL), and extracted with ether (3×25 mL). The combined organic layers were dried
and concentrated to leave a residue that was taken up in methanol (20 mL). The solution
was treated with K2CO3 (0.86 mg, 6.2 mmol) and stirred at rt for 1 h. The solution was
129 diluted with ether (30 mL) and filtered through a silica plug, which was rinsed with ethyl
acetate (10 mL). The filtrate and rinsings were combined and concentrated to afford a
residue that was purified by chromatography on silica gel (elution with 15% ethyl acetate
in hexanes) to afford 5.42 (0.31 mg, 84%) as a colorless oil: IR (film, cm-1) 3490, 2930,
1 1690; H NMR (300 MHz, CDCl3) δ 5.73 - 5.58 (m, 1H), 5.06 - 4.98 (m, 2H), 3.84 - 3.79
(m, 1H), 3.47 (s, 2H), 2.58 - 2.41 (m, 4H), 2.10 - 2.05 (m, 3H), 1.89 - 1.66 (m, 4H), 0.92
13 (s, 9H), 0.96 (s, 6H); C NMR (75 MHz, CDCl3) δ 210.9, 137.9, 115.2, 71.5, 65.7, 41.8,
+ 37.7, 33.0, 27.1, 25.8, 22.8, 18.0, -4.6; ES HRMS m/z (C16H32O3SiNa ) calcd 323.2018,
obsd 323.2022.
(S,E)-Methyl 7-(tert-butyldimethylsilyloxy)-6-hydroxyhept-2-enoate
5.44 5.45
A solution of 5.44 (0.74 g, 3.2 mmol) in CH2Cl2 (25 mL) was treated with
methoxycarbonylmethylidene triphenylphosphorane (1.62 g, 4.8 mmol) and stirred at rt
for 8 h. The solution was then concentrated to leave a residue that was purified by
chromatography on silica gel (elution with 25% ethyl acetate in hexanes) to afford 5.45
(0.84 g, 90%) as a colorless oil: IR (film, cm-1) 3400, 2866, 1650; 1H NMR (300 MHz,
CDCl3) δ 6.98 (td, J = 15.6, 6.9 Hz, 1H), 5.85 (td, J = 15.6, 1.6 Hz, 1H), 3.72 (s, 3H),
3.67 - 3.59 (m, 2H), 3.40 (dd, J = 8.7, 1.1 Hz, 1H), 2.47 - 2.22 (m, 2H), 1.64 - 1.47 (m,
13 2H), 0.89 (s, 9H), 0.06 (s, 6H); C NMR (75 MHz, CDCl3) δ 166.9, 148.9, 121.0, 70.8,
130 + 66.9, 51.2, 31.0, 28.2, 25.7, 18.1, -5.5, -5.6; ES HRMS m/z (C14H28O4SiNa ) calcd
311.1655, obsd 311.1648.
(S,E)-7-(tert-Butyldimethylsilyloxy)hept-2-ene-1,6-diol
5.45 5.46 A solution of DIBAL-H in hexanes (1 M, 10.3 mL, 10.3 mmol) was added dropwise to a
solution of methyl ester 5.45 (0.74 g, 2.6 mmol) in dry dichloromethane (25 mL) at -78
ºC. Upon completion of the reaction by TLC, the reaction mixture was quenched by adding methanol (3 mL) followed by satd. solution of Rochelle’s salt (25 mL), warmed up to room temperature, and stirred for 2 h. The mixture was extracted with dichloromethane (3×20 mL) and the combined organic layers were dried and concentrated to leave a residue that was purified by chromatography on silica gel (elution with 50% ethyl acetate in hexanes) to afford 5.46 (0.64 g, 95%) as a colorless oil: IR
-1 1 (film, cm ) 3440; H NMR (300 MHz, CDCl3) δ 5.75 - 5.60 (m, 2H), 4.07 (d, J = 4.2 Hz,
2H), 3.67 - 3.58 (m, 2H), 3.42 - 3.36 (m, 2H), 2.27 - 2.02 (m, 4H), 1.58 - 1.39 (m, 2H),
13 0.89 (s, 9H), 0.06 (s, 6H); C NMR (75 MHz, CDCl3) δ 132.3, 129.3, 71.1, 67.0, 63.5,
+ 32.1, 28.2, 25.8, -5.4, -5.5; ES HRMS m/z (C13H28O3SiNa ) calcd 283.1705, obsd 1696.
131 2-((5S)-5-((tert-Butyldimethylsilyloxy)methyl)tetrahydrofuran-2-yl)-2-iodoethanol
5.46 5.47 Iodine (97.5 mg, 0.4 mmol) was added to a solution of 5.46 (50 mg, 0.2 mmol) and
NaHCO3 (161 mg, 1.9 mmol) in a mixture of THF and water (2:1, 6 mL). After being stirred for 2 h in the dark, the reaction mixture was quenched by adding a mixture of satd.
NaHCO3 (10 mL) and satd. Na2S2O3 (10 mL) solutions, and extracted with ether (3×20
mL). The combined organic layers were dried and concentrated to leave a residue that
was purified by chromatography on silica gel (elution with 20% ethyl acetate in hexanes)
to afford 5.47 (60 mg, 81%) as a colorless oil: IR (film, cm-1) 3489; 1H NMR (300 MHz,
CDCl3) δ 4.26 - 4.24 (m, 2H), 4.05 - 3.97 (m, 1H), 3.90 (d, J = 6.0 Hz, 2H), 3.62 - 3.53
(m, 2H), 2.39 - 2.28 (m, 1H), 2.00 - 1.92 (m, 1H), 1.85 - 1.67 (m, 2H), 0.88 (s, 9H), 0.04
13 (s, 6H); C NMR (75 MHz, CDCl3) δ 84.0, 81.2, 68.4, 65.4, 37.7, 33.7, 27.3, 25.8, 18.2,
-5.4; mass spec data was not recorded, as the compound was too unstable.
2-((5S)-5-((tert-Butyldimethylsilyloxy)methyl)tetrahydrofuran-2-yl)-2-iodoethyl
benzoate
5.47 5.48
Benzoyl chloride (45 μL, 0.2 mmol) was added to a solution of 5.47 (75 mg, 0.2 mmol)
and diisopropylethylamine (135 μL, 0.8 mmol) in CH2Cl2 (5 mL) at 0 °C. After the
solution was stirred for 8 h, the reaction mixture was quenched by adding satd. NaHCO3
132 (5 mL), and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried
and concentrated to leave a residue that was purified by chromatography on silica gel
(elution with 8% ethyl acetate in hexanes) to afford 5.48 (84 mg, 88%) as a colorless oil:
-1 1 IR (film, cm ) 2986, 1730; H NMR (300 MHz, CDCl3) δ 8.09 - 8.06 (m, 2H), 7.61 -
7.55 (m, 1H), 7.48 - 7.43 (m, 2H), 4.68 (dd, J = 12.2, 5.0 Hz, 1H), 4.58 (dd, J = 12.2, 5.0
Hz, 1H), 4.38 - 4.31 (m, 1H), 4.22 - 4.07 (m, 2H), 3.60 (d, J = 4.5 Hz, 2H), 2.35 - 2.26
(m, 1H), 2.06 - 1.99 (m, 1H), 1.92 - 1.80 (m, 2H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H);
13 C NMR (75 MHz, CDCl3) δ 165.8, 133.0, 129.7, 129.6, 128.3, 80.7, 80.0, 67.1, 65.6,
34.9, 32.8, 27.7, 25.8, 18.2, -5.4; mass spec data was not recorded, as the compound was
too unstable.
(S)-tert-Butyldimethyl((5-vinyl-2,3-dihydrofuran-2-yl)methoxy)silane
5.48 5.49
DBU (152 μL, 1 mmol) was added to a solution of 5.48 (50 mg, 0.1 mmol) in THF (10
mL) and heated at reflux for 4 h. The solution was cooled, poured into satd. NaHCO3 solution (10 mL), and extracted with ether (3×10 mL). The combined organic layers were dried and concentrated to leave a residue that was purified by chromatography on silica gel neutralized with triethylamine (elution with 2% ethyl acetate, 1% triethylamine in hexanes) to afford 5.49 (17.2 mg, 70%) as a colorless oil: IR (film, cm-1) 2948, 2872; 1H
NMR (300 MHz, CDCl3) δ 6.16 (dd, J = 17.3, 10.9 Hz, 1H), 5.81 – 5.75 (m, 1H), 5.13 –
5.10 (m, 1H), 4.70 – 4.68 (m, 1H), 4.63 – 4.53 (m, 1H), 3.68 – 3.55 (m, 2H), 2.47 – 2.44
133 13 (m, 2H), 1.01 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); C NMR (75 MHz, CDCl3) δ 155.1,
126.1, 114.8, 99.8, 81.3, 65.2, 32.2, 25.7, 18.1, -5.5, -5.6; mass spec data was not
recorded, as the compound was too unstable.
(5S)-5-(Iodomethyl)tetrahydrofuran-2-ol
6.8 6.9 A solution of DIBAL-H in hexanes (1 M, 4 mL) was added dropwise to a solution of
iodolactone 6.8 (0.74 g, 3.27 mmol) in dry dichloromethane (20 mL) at -78 ºC. Upon
completion as determined by TLC, the reaction mixture was quenched by adding
methanol (1 mL) followed by satd. solution of Rochelle’s salt (20 mL), warmed to room
temperature, and stirred for 2 h. The mixture was extracted with dichloromethane (3×20
mL). The combined organic layers were dried, passed through a silica plug, and
concentrated to furnish 6.9 (0.74 g, 99%) as a colorless oil: IR (thin film, cm-1) 3700,
1 3600, 3010, 2990, 2870, 1730, 1460, 1420, 1280; H NMR (300 MHz, CDCl3) δ 5.64 –
5.58 (m, 1H), 4.32 – 4.16 (m, 1H), 3.77 (s, 1H), 3.39 – 3.33 (m, 1H), 3.27 – 3.20 (m, 1H),
13 2.30 – 1.79 (m, 4H); C NMR (75 MHz, CDCl3) δ 99.1, 98.9, 80.2, 77.4, 33.9, 32.7,
29.8, 29.6, 11.1, 10.1; mass spec data was not recorded, as the compound was too unstable.
134 (5S)-2-(Benzyloxy)-5-(iodomethyl)tetrahydrofuran
6.9 6.10 Benzyl alcohol (1.10 g, 10.2 mmol) and p – TsOH (0.22 g, 1.05 mmol) were added to a
solution of 6.9 (0.74 g, 3.24 mmol) in dichloromethane (10 mL) at rt and stirred
overnight. Upon completion, the reaction mixture was quenched by adding satd. NaHCO3 solution (10 mL) and extracted with dichloromethane (3×15 mL). The combined organic layers were dried and concentrated to leave a residue that was purified by chromatography on silica gel (elution with 2% ethyl acetate in hexanes) to furnish 6.10
(1.03 g, 98%) as a colorless oil: IR (thin film, cm-1) 2913, 1452, 1348, 1199, 1018, 955;
1 H NMR (300 MHz, CDCl3) δ 7.38 – 7.28 (m, 5H), 5.33 (dd, J = 11.0, 4.4 Hz, 1H), 4.78
(dd, J = 13.2, 12.2 Hz,1H), 4.50 (dd, J = 11.7, 3.9 Hz, 1H), 4.41 – 4.15 (m, 1H), 3.42 –
13 3.19 (m, 2H), 2.31 – 1.61 (m, 4H); C NMR (75 MHz, CDCl3) δ 138.1, 137.9, 128.4,
128.3, 127.9, 127.8, 127.6, 127.5, 103.9, 103.7, 80.3, 68.9, 68.9, 33.5, 32.1, 29.8, 29.6,
11.2, 10.3; mass spec data was not recorded, as the compound was too unstable.
Methyl 3-((2R,4S,5R)-5-Hydroxy-2-phenyl-1,3-dioxan-4-yl)propanoate
OH O
Ph O OMe
O 6.13 6.12 Rhodium on carbon (10%, 1 g) was added to a solution of 6.13 (9.50 g, 3.60 mmol) in
ethyl acetate (250 mL). The mixture was purged with hydrogen and stirred in an
atmosphere of hydrogen overnight. The solution was filtered through a Celite® pad upon
135 completion of reaction as determined by TLC. Evaporation of filtrate afforded 6.12 (9.57
g) in quantitative yield as a colorless oil: IR (thin film, cm-1) 3440, 1730; 1H NMR (300
MHz, CDCl3) δ 7.48 - 7.44 (m, 2 H), 7.40 - 7.33 (m, 3 H), 5.46 (s, 1 H), 4.25 (dd, J =
2.6, 8.7 Hz, 1 H), 3.67 (s, 3 H), 3.61 - 3.56 (m, 3 H), 3.06 (d, J = 4 Hz, 1 H), 2.69 - 2.58
(m, 1 H), 2.55 - 2.44 (m, 1 H), 2.30 - 2.19 (m, 1 H), 2.05 - 1.91 (m, 1 H); 13C NMR (75
MHz, CDCl3) δ 174.8, 137.6, 128.8, 128.1, 126.0, 100.8, 80.8, 70.9, 65.0, 51.7, 29.0,
+ 26.3; ES HRMS m/z (C14H18O5Na ) calcd 289.1052, obsd 289.1064.
Methyl 3-((2R,4S,5R)-5-(Methylthiocarbonothioyloxy)-2-phenyl-1,3-dioxan-4- yl)propanoate
6.13 6.14 Sodium hydride (60% in oil, 0.27 g, 6.8 mmol) was added to a solution of 6.13 (1.5 g, 5.6
mmol) and carbon disulfide (2.1 mL, 28 mmol) in dry THF (50 mL) at 0° C. The solution was stirred for 3 h and allowed to warm up gradually to rt over 3 h. The solution was then
cooled back to 0°C and treated dropwise with methyl iodide (2.3 mL, 28 mmol). The
reaction mixture was carefully quenched with water (50 mL) upon completion as
determined by TLC and extracted with ethyl acetate (3×30 mL). The combined organic
layers were washed with brine, dried, and concentrated to leave a residue that was
purified by chromatography on silica gel (elution with 6% ethyl acetate in hexanes) to
afford xanthate 6.14 (1.2 g, 60%) as a pale yellow oil: IR (thin film, cm-1) 1740, 1270
1 1150; H NMR (300 MHz, CDCl3) δ 7.50 - 7.47 (m, 2H), 7.39 - 7.35 (m, 3H), 5.63 (dt, J 136 = 5.4, 9.8 Hz, 1H), 5.54 (s, 1H), 4.57 (dd, J = 5.3, 10.7 Hz, 1H), 4.02 (dt, J = 3.0, 9.1 Hz,
1H), 3.71 - 3.64 (m, 4H), 2.59 - 2.50 (m, 5H), 2.21 - 2.10 (m, 1H), 1.98 - 1.85 (m, 1H);
13 C NMR (75 MHz, CDCl3) δ 215.2, 173.4, 137.1, 129.0, 128.1, 126.0, 101.1, 77.7, 74.1,
+ 66.9, 51.5, 29.2, 26.9, 19.3; ES HRMS m/z (C16H20O5S2Na ) calcd 379.0650, obsd
379.0676.
Methyl 3-((2R,4S,5S)-5-Iodo-2-phenyl-1,3-dioxan-4-yl)propanoate
6.13 6.16 Iodine (19.1 g, 75.1 mmol) was added in three portions to a solution of 6.13 (10.0 g, 37.6
mmol), triphenyphosphine (19.7 g, 75.1 mmol) and imidazole (5.11 g, 75.1 mmol) in dry
THF (250 mL), cooled to 0 °C, and stirred for 1 h. The solution mixture was treated with
diisopropylethylamine (13.1 mL, 75.1 mmol) and heated at reflux overnight. After being
cooled to rt, the reaction mixture was quenched using a mixture of satd. NaHCO3, satd.
Na2S2O3 and water (1:1:1), and extracted with ethyl acetate (3×150 mL). The organic
layers were combined, washed with brine, dried, and evaporated in vacuo to afford a
residue that was purified by chromatography on silica gel (elution with 14% ethyl acetate
in hexanes) to afford 6.16 (11.4 g, 80%) as colorless oil: IR (thin film, cm-1) 1725; 1H
NMR (300 MHz, CDCl3) δ 7.56 - 7.52 (m, 2H), 7.42 - 7.35 (m, 3H), 5.54 (s, 1H), 4.46
(dd, J = 1.4, 12.8 Hz, 1H), 4.34 (dd, J = 1.4, 12.8 Hz, 1H), 4.18 (q, J = 1.5 Hz, 1H), 3.67
(s, 3H), 3.08 (ddd, J = 1.6, 4.2, 8.4 Hz, 1H), 2.48 (q, J = 6.9 Hz, 2H), 2.11 - 1.99 (m, 1H),
13 1.82 - 1.71 (m, 1H); C NMR (75 MHz, CDCl3) δ 173.4, 137.6, 129.1, 128.2, 126.3, 137 + 102.2, 77.4, 74.2, 51.6, 33.4, 32.5, 28.6; ES HRMS m/z (C14H17O4Na ) calcd 399.0069, obsd 399.0061.
Methyl 3-((2R,4S)-2-Phenyl-1,3-dioxan-4-yl)propanoate
6.16 6.15 Tributyltin chloride (0.80 mmol, 0.22 mL) was added to a solution of 6.16 (30.0 g, 80 mmol), sodium cyanoborohydride (10.02 g, 160 mmol), and AIBN (1.30 g, 8 mmol) in a mixture of methanol and tetrahydrofuran (1:1 v/v, 500 mL), and heated overnight at reflux. After the reaction was judged to be complete by TLC, satd. NaHCO3 solution was added and the mixture was extracted with ethyl acetate (3×200 mL). The organic layers were combined, washed with brine, dried and evaporated in vacuo to afford a residue purified by column chromatography (elution with 25% ethyl acetate in hexanes) to afford
6.15 (19.0 g, 95%) as a colorless oil: IR (thin film, cm-1) 1735; 1H NMR (300 MHz,
CDCl3) δ 7.39 - 7.35 (m, 2H), 7.29 - 7.22 (m, 3H), 5.40 (s, 1H), 4.15 (ddd, J = 1, 4.9,
11.4 Hz, 1H), 3.86 (dt, J = 2.6, 12.0 Hz, 1H), 3.81 - 3.74 (m, 1H), 3.55 (s, 3H), 2.41 (dt, J
= 3.0, 7.4 Hz, 2H), 1.83 (q, J = 7.3 Hz, 2H), 1.74 - 1.64 (m, 1H), 1.47 - 1.41 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 173.8, 138.7, 128.6, 128.1, 125.9, 100.9, 75.9, 51.5, 46.5, 31.1,
+ 30.9, 29.6; ES HRMS m/z (C14H18O4Na ) calcd 273.1103, obsd 273.1120.
138 (S)-5-(2-(Benzyloxy)ethyl)dihydrofuran-2(3H)-one
6.15 6.16 Trifluoroacetic acid (14.8 mL, 24 mmol) was added dropwise to a solution of 6.15 (10.0
g, 40.0 mmol), triethylsilane (32.0 mL, 200 mmol) and trifluoroacetic anhydride (16.7
mL, 120 mmol) in anhydrous dichloromethane (100 mL) under an atmosphere of
nitrogen at -20 ºC. The reaction mixture was stirred overnight and quenched at -20 ºC
with satd. NaHCO3 solution (20 mL), and extracted with dichloromethane (3×100 mL).
The combined organic layers were dried and concentrated to leave a residue that was
purified by chromatography on silica gel (elution with 25% ethyl acetate in hexanes) to
afford 6.16 (7.50 g, 85%) as a colorless oil: IR (thin film, cm-1) 2361, 2336, 1772; 1H
NMR (300 MHz, CDCl3) δ 7.38 - 7.27 (m, 5 H), 4.75 - 4.66 (m, 1 H), 4.55 - 4.46 (m, 2
H), 3.65 - 3.61 (m, 2 H), 2.56 - 2.51 (m, 2 H), 2.35 (sextet, J = 6.4 Hz, 1 H), 2.06 - 1.84
13 (m, 3 H); C NMR (75 MHz, CDCl3) δ 176.9, 137.9, 128.2, 127.5, 127.4, 78.0, 72.9,
66.0, 35.5, 28.6, 27.9; known compound.
139 (S)-2-(2-(Benzyloxy)ethyl)-2,3-dihydrofuran
1. DIBAL, DCM, -78 °C;
2. Ac2O, Et3N, DCM 0 °C; O O OBn 3. NaHCO3, DMSO, 190 °C O OBn (80% over 3 steps) 6.16 6.17 A solution of DIBAL in hexanes (1 M, 3.00 mL, 3.30 mmol) was added dropwise to a
solution of 6.16 (0.67 g, 3.04 mmol) in CH2Cl2 (20 mL) at -78 °C and stirred for 2 h. The
reaction mixture was quenched at -78 °C by slowly adding methanol (1 mL) followed by
satd. Rochelle’s salt solution (20 mL), and extracted with CH2Cl2 (3×20 mL). The
combined organic layers were dried and concentrated to leave a residue that was taken up
in CH2Cl2 (20 mL), cooled to 0 °C, and treated with triethylamine (2.33 mL, 16.7 mmol)
followed by acetic anhydride (1.08 mL, 8.4 mmol). The solution was stirred for 2 h,
quenched with satd. NaHCO3 solution (20 mL), and extracted with CH2Cl2 (3×25 mL).
The combined organic layers were dried and concentrated to leave a residue that was
taken up in DMSO (20 mL). This solution was treated with NaHCO3 (1.28 g, 15.3
mmol), heated at 190 °C for 4 h, cooled to rt, poured in to cold water (50 mL), and
extracted with ether (3×30 mL). The combined organic layers were dried and concentrated to leave a residue that was purified by chromatography on silica gel neutralized with triethylamine (elution with 3% ethyl acetate, 1% triethylamine in hexanes) to afford 6.17 (0.5 g, 80%) as a colorless oil: IR (film, cm-1) 2967, 1530, 1045;
1 H NMR (300 MHz, CDCl3) δ 7.32 - 7.12 (m, 5H), 6.22 (q, J = 2.4 Hz, 1H), 4.69 (q, J =
2.4 Hz, 1H), 4.34 (s, 2H), 3.58 - 3.42 (m, 3H), 2.53 - 2.43 (m, 1H), 2.13 - 2.04 (m, 1H),
13 2.03 - 1.92 (m, 1H), 1.82 - 1.74 (m, 1H); C NMR (75 MHz, CDCl3) δ 145.0, 138.9,
140 128.1, 127.3, 127.2, 98.5, 78.3, 72.7, 66.7, 59.7, 36.4, 34.7, 13.8; ES HRMS m/z
+ (C13H16O2Na ) calcd 227.1048, obsd 227.1057.
(S)-5-(2-(tert-Butyldimethylsilyloxy)ethyl)dihydrofuran-2(3H)-one
6.16 6.20 A solution of 6.16 (2.0 g, 9.1 mmol) in methanol (30 mL) was purged with nitrogen for
30 min. Palladium on charcoal (10%, 0.1 g) was added in a single portion and the mixture
was purged with hydrogen for 15 min. After being stirred under an atmosphere of
hydrogen for 4 h, the mixture was purged with nitrogen followed by filtration through a
Celite® plug, which was rinsed with methanol after filtration. The filtrate was
concentrated to afford a residue that was taken up in CH2Cl2 (30 mL) and treated with imidazole (1.24 g, 18.2 mmol) and TBSCl (2.05 g, 13.6 mmol). After being stirred for 4 h, the reaction mixture was quenched with satd. NaHCO3 solution (30 mL) and extracted with DCM (3×30 mL). The combined organic layers were dried and concentrated to leave a residue that was purified by chromatography on silica gel (elution with 20% ethyl acetate in hexanes) to afford 6.20 (1.91 g, 86%) as a colorless oil: IR (film, cm-1) 1740,
1 1170; H NMR (300 MHz, CDCl3) δ 4.23 – 4.14 (m, 1H), 3.56 – 3.42 (m, 2H), 1.99 –
1.77 (m, 2H), 1.57 – 1.33 (m, 3H), 1.18 – 1.05 (m, 1H), 0.92 (s, 9H), 0.01 (s, 3H), 0.00
13 (s, 3H); C NMR (75 MHz, CDCl3) δ 175.4, 76.7, 59.2, 38.5, 28.1, 27.6, 25.8, 18.1, -5.7;
+ ES HRMS m/z (C12H24O3SiNa ) calcd 267.1392, obsd 267.1401.
141 (S)-6-(tert-Butyldimethylsilyloxy)-N-methoxy-N-methyl-4-
(trimethylsilyloxy)hexanamide
6.20 6.21 A suspension of N,O-dimethylhydroxylamine hydrochloride (0.21 g, 2.2 mmol) in
CH2Cl2 (10 mL) was cooled to 0 °C and treated dropwise with a solution of
trimethylaluminum in hexanes (2M, 0.98 mL, 2.0 mmol). After being stirred for 30 min
the mixture was warmed to rt, stirred for 1 h, cooled to 0 °C, treated with solution of 6.20
(0.24 g, 1.0 mmol) in CH2Cl2 (5 mL), and stirred overnight. The reaction mixture was
quenched with satd. solution of Rochelle’s salt (10 mL), vigorously stirred for 2 h, and
extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried and
concentrated to leave a residue, which was taken up in CH2Cl2 (15 mL) and cooled to 0
°C. This solution was treated with triethylamine (0.55 mL, 3.9 mmol) followed by
trimethylsilyl chloride (0.25 mL, 2.0 mmol). After 3 h, the reaction mixture was stirred at
rt for 1 h, quenched with satd. NaHCO3 solution (10 mL), and extracted with CH2Cl2
(3×15 mL). The combined organic layers were dried and concentrated to leave a residue that was purified by chromatography on silica gel (elution with 20% ethyl acetate in hexanes) to afford 6.21 (0.31 g, 83%) as a colorless oil: IR (film, cm-1) 2855, 1650, 1432;
1 H NMR (400 MHz, CDCl3) δ 4.08 – 4.02 (m, 1H), 3.75 – 3.64 (m, 2H), 3.08 (s, 3H),
2.89 (s, 3H), 2.52 (t, J = 7.4, 2H), 2.10 – 2.02 (m, 1H), 1.98 – 1.89 (m, 1H), 1.81 – 1.66
(m, 2H), 0.99 (s, 9H), 0.19 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (100 MHz,
142 CDCl3) δ 174.1, 68.7, 60.3, 59.8, 40.6, 32.1, 32.0, 27.8, 25.9, 18.2, 0.3, -5.3, -5.4; ES
+ HRMS m/z (C17H39O4NSi2Na ) calcd 400.2315, obsd 400.2326.
(S)-10-(tert-Butyldimethylsilyloxy)-8-(trimethylsilyloxy)dec-1-en-5-one
6.21 6.22
A solution of 4-bromo-1-butene (60 μL, 0.6 mmol) in THF (4 mL) at -78 °C was treated dropwise with a solution of t-BuLi in pentane (1.7 M, 0.62 mL, 1.1 mmol). The solution was stirred for 15 min followed by addition of a solution of 6.21 (50 mg, 0.1 mmol) in dry THF (1 mL). The solution was stirred for 2 h, quenched with water (5 mL) and extracted with ether (3×5 mL). The combined organic layers were dried and concentrated to leave a residue that was taken up in methanol (5 mL). The solution was treated with
K2CO3 (73 mg, 0.5 mmol), stirred at rt for 1 h, diluted with ether (10 mL) and filtered
through a silica plug, which was rinsed with ethyl acetate (3 mL). The filtrate and
rinsings were combined and concentrated to afford a residue that was purified by
chromatography on silica gel (elution with 10% ethyl acetate in hexanes) to afford 6.22
-1 1 (26 mg, 65%) as a colorless oil: IR (film, cm ) 2920, 1640; H NMR (400 MHz, CDCl3)
δ 5.70 – 5.59 (m, 1H), 4.99 – 4.92 (m, 2H), 3.43 (dd, J = 9.9, 4.0 Hz, 1H), 3.32 (dd, J =
10.2, 6.9 Hz, 1H), 2.29 (q, J = 6.3 Hz, 2H), 1.99 (t, J = 7.4 Hz, 2H), 1.91 – 1.83 (m, 2H),
13 1.76 – 1.52 (m, 6H), 0.90 (s, 9H), -0.01 (s, 6H); C NMR (100 MHz, CDCl3) δ 209.0,
138.2, 114.9, 71.2, 67.6, 41.6, 38.6, 33.2, 26.9, 25.8, 22.9, 18.2, -5.5, -5.6; ES HRMS m/z
+ (C16H32O3SiNa ) calcd 323.2018, obsd 323.2008.
143 3-((2R,4S)-2-Phenyl-1,3-dioxan-4-yl)propan-1-ol
6.15 6.26 A solution of DIBAL in hexanes (1 M, 32.0 mL, 32.0 mmol) was added to a solution of
6.15 (2.0 g, 8.0 mmol) in CH2Cl2 (100 mL) at -78 °C and stirred for 2 h. The reaction
mixture was quenched by addition of methanol (5 mL) followed by satd. Rochelle’s salt
solution (50 mL), vigorously stirred for 2 h, and extracted with CH2Cl2 (3×50 mL). The
combined organic layers were dried and concentrated to leave a residue that was purified
by chromatography on silica gel (elution with 50% ethyl acetate in hexanes) to afford
-1 1 6.26 (1.69 g, 95%) as a colorless oil: IR (film, cm ) 3440; H NMR (400 MHz, CDCl3) δ
7.52 – 7.50 (m, 2H), 7.41 – 7.33 (m, 3H), 5.54 (s, 1H), 4.30 (ddd, J = 11.5, 5.0, 1.0 Hz,
1H), 3.99 (dt, J = 12.1, 2.0 Hz, 1H), 3.91 – 3.88 (m, 1H), 3.67 (t, J = 5.5 Hz, 2H), 2.04 (s,
1H), 1.88 (dq, J = 12.5, 5.1 Hz, 1H), 1.79 – 1.68 (m, 4H), 1.57 – 1.52 (m, 1H) ; 13C NMR
(100 MHz, CDCl3) δ 138.6, 128.8, 128.3, 126.0, 101.3, 77.24, 67.1, 62.7, 32.6, 31.3,
+ 28.6; ES HRMS m/z (C13H18O3Na ) calcd 241.1154, obsd 241.1166.
3-((2R,4S)-2-Phenyl-1,3-dioxan-4-yl)propyl 4-methylbenzenesulfonate
6.26 6.27 TsCl (2.29 g, 12.0 mmol) was added to a solution of 6.26 (1.78 g, 8.0 mmol),
triethylamine (3.35 mL, 24.0 mmol) and DMAP (98 mg, 0.8 mmol) in CH2Cl2 (50 mL) at
144 0 °C. The solution was stirred for 1 h at 0 °C and 1 h at rt, quenched by adding satd.
NaHCO3 solution (20 mL), and extracted with CH2Cl2 (3×30 mL). The combined organic
layers were dried and concentrated to leave a residue that was purified by
chromatography on silica gel (elution with 20% ethyl acetate in hexanes) to afford 6.27
-1 1 (2.72 g, 90%) as a colorless oil: IR (film, cm ) 1366, 1097; H NMR (400 MHz, CDCl3)
δ 7.81 – 7.79 (m, 2H), 7.48 – 7.45 (m, 2H), 7.37 – 7.33 (m, 5H), 5.47 (s, 1H), 4.26 (ddd,
J = 11.4, 5.0, 1.1 Hz, 1H), 4.17 – 4.03 (m, 2H), 3.94 (dt, J = 12.0, 2.6 Hz, 1H), 3.83 –
3.76 (m, 1H), 2.45 (s, 3H), 1.96 – 1.74 (m, 3H), 1.67 – 1.62 (m, 2H), 1.50 – 1.46 (m, 1H);
13 C NMR (100 MHz, CDCl3) δ 144.7, 138.7, 133.1, 129.9, 128.7, 128.2, 127.9, 126.0,
+ 101.1, 76.2, 70.5, 66.9, 31.8, 31.2, 24.7, 21.6; ES HRMS m/z (C20H24O5SNa ) calcd
399.1242, obsd 399.1266.
(2R,4S)-2-Phenyl-4-(3-(phenylselanyl)propyl)-1,3-dioxane
O O (PhSe)2,NaBH4, Ph O EtOH, 0 °C (90%) Ph O OTs SePh 6.27 6.28 Sodium borohydride (1.62 g, 5.2 mmol) was added to a solution of diphenyl diselenide
(0.39 g, 10.4 mmol) in ethanol (20 mL) at 0 °C and stirred for 1 h. After the yellow color
disappeared, a solution of 6.27 (1.78 g, 4.7 mmol) in ethanol (5 mL) was added and
allowed to warm up gradually. The reaction mixture was quenched by adding mixture of
satd. NH4Cl solution and water (1:1, 20 mL), and extracted with ethyl acetate (3×30 mL).
The combined organic layers were washed with brine, dried, and concentrated to leave a
residue that was purified by chromatography on silica gel (elution with 6% ethyl acetate
145 in hexanes) to afford 6.28 (1.48 g, 90%) as a colorless oil: IR (film, cm-1) 2982, 1507; 1H
NMR (400 MHz, CDCl3) δ 7.37 – 7.32 (m, 4H), 7.24 – 7.18 (m, 3H), 7.12 – 7.09 (m,
3H), 5.34 (s, 1H), 4.12 (dd, J = Hz, 1H), 3.80 (dt, J = 12.0, 1.9 Hz, 1H), 3.72 – 3.66 (m,
1H), 2.85 – 2.80 (m, 2H), 1.86 – 1.76 (m, 1H), 1.75 – 1.51 (m, 4H), 1.37 – 1.32 (m, 1H);
13 C NMR (100 MHz, CDCl3) δ 138.8, 132.6, 130.3, 129.0, 128.7, 128.2, 126.7, 126.0,
+ 101.1, 76.6, 67.0, 36.0, 31.3, 27.8, 25.7; ES HRMS m/z (C19H22O2SeNa ) calcd
385.0683, obsd 385.0668.
(2R,4S)-4-Allyl-2-phenyl-1,3-dioxane
O O NaIO4,THF,H2O Ph O rt, (93%) Ph O SePh 6.28 6.29
A solution of sodium periodate (0.58 g, 2.7 mmol) and NaHCO3 (0.45 g, 5.4 mmol) in water (20 mL) was added to a solution of 6.28 (0.33 g, 0.9 mmol) in THF (20 mL) at 0
°C. The solution was warmed to rt, stirred for 4 h, and extracted with ethyl acetate (3×20
mL). The combined organic layers were washed with brine, dried, and concentrated to
leave a residue that was taken up in THF (20 mL), treated with NaHCO3 (0.45 g, 5.4
mmol), and heated at reflux for 4 h. The solution was cooled to rt and concentrated to
leave a residue that was purified by chromatography on silica gel (elution with 5% ethyl
acetate in hexanes) to afford 6.29 (0.17 g, 93%) as a colorless oil: IR (film, cm-1) 2910,
1 910; H NMR (400 MHz, CDCl3) δ 7.55 – 7.52 (m, 2H), 7.42 – 7.35 (m, 3H), 5.98 – 5.87
(m, 1H), 5.55 (s, 1H), 5.20 – 5.11 (m, 2H), 4.31 (ddd, J = 11.3, 5.0, 1.3 Hz, 1H), 3.99 (dt,
J = 12.1, 2.5 Hz, 2H), 2.55 – 2.47 (m, 1H), 2.39 – 2.31 (m, 1H), 1.91 – 1.81 (m, 1H), 1.61
146 13 – 1.56 (m, 1H); C NMR (100 MHz, CDCl3) δ 138.8, 133.9, 128.7, 128.2, 126.1, 117.4,
+ 101.2, 67.1, 40.5, 30.8; ES HRMS m/z (C13H16O2Na ) calcd 227.1048, obsd 227.1060.
147 References and Notes
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Appendix A: Proton NMR Spectra
Proton NMR Spectra
157 2.7
H NMR spectrum of 1
158 2.16
H NMR spectrum of 1
159 2.17
H NMR spectrum of 1
160 2.18
H NMR spectrum of 1
161 2.19
H NMR spectrum of 1
162 2.22
H NMR spectrum of 1
163 2.35
H NMR spectrum of 1
164 2.36
H NMR spectrum of 1
165 2.37
H NMR spectrum of 1
166 2.38
H NMR spectrum of 1
167 2.39
H NMR spectrum of 1
168 2.40
H NMR spectrum of 1
169 2.41
H NMR spectrum of 1
170 3.14
H NMR spectrum of 1
171 3.15
H NMR spectrum of 1
172 3.16
H NMR spectrum of 1
173 3.17
H NMR spectrum of 1
174 3.18
H NMR spectrum of 1
175 3.20
H NMR spectrum of 1
176 3.21
H NMR spectrum of 1
177 3.22
H NMR spectrum of 1
178 3.23
H NMR spectrum of 1
179 3.24
H NMR spectrum of 1
180 3.26
H NMR spectrum of 1
181 3.27
H NMR spectrum of 1
182 3.28
H NMR spectrum of 1
183 3.29
H NMR spectrum of 1
184 3.30
H NMR spectrum of 1
185 3.31
H NMR spectrum of 1
186 4.14
H NMR spectrum of 1
187 4.17
H NMR spectrum of 1
188 4.18
H NMR spectrum of 1
189 4.19
H NMR spectrum of 1
190 4.20
H NMR spectrum of 1
191 4.21
H NMR spectrum of 1
192 4.22
H NMR spectrum of 1
193 5.28
H NMR spectrum of 1
194 5.35
H NMR spectrum of 1
195 5.38
H NMR spectrum of 1
196 5.41
H NMR spectrum of 1
197 5.42
H NMR spectrum of 1
198 5.45
H NMR spectrum of 1
199 5.46
H NMR spectrum of 1
200 5.47
H NMR spectrum of 1
201 5.48
H NMR spectrum of 1
202 5.49
H NMR spectrum of 1
203 6.10
H NMR spectrum of 1
204 6.11
H NMR spectrum of 1
205 6.15
H NMR spectrum of 1
206 6.16
H NMR spectrum of 1
207 6.18
H NMR spectrum of 1
208 6.17
H NMR spectrum of 1
209 6.8
H NMR spectrum of 1
210 6.19
H NMR spectrum of 1
211 6.22
H NMR spectrum of 1
212 6.23
H NMR spectrum of 1
213 6.24
H NMR spectrum of 1
214 6.28
H NMR spectrum of 1
215 6.29
H NMR spectrum of 1
216 6.30
H NMR spectrum of 1
217 6.31
H NMR spectrum of 1
218