Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A
Bioactive Cardenolide
A thesis presented
by
Hans Renata
to
The Scripps Research Institute Graduate Program
in partial fulfillment of the requirements
for the degree of
Doctor of Philosophy
in the subject of
Chemistry
for
The Scripps Research Institute
La Jolla, California
February 2013
UMI Number: 3569793
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! ii! ACKNOWLEDGEMENTS
To Phil, thank you for taking me under your wing, the past five years have been a wonderful learning experience. You truly are a fantastic teacher, both in and out of the fumehood and your unbridled enthusiasm, fearlessness and passion for chemistry are second to none. In the words of Kurt Cobain, I am “forever indebted to your priceless advice.”
To the members of the Baran lab, in the words of Kurt Cobain, “Our little (?) group has always been and always will until the end.” See what I did there? Oh well, whatever, nevermind.
To my committee members, Prof. K. C. Nicolaou, Prof. Floyd Romesberg, and Prof. Jin-
Quan Yu, thank you for overseeing my graduate education for the past five years.
To Prof. Breslow and Prof. Katz, thank you for introducing me to the wonderful world of organic chemistry, you both were fabulous teachers to me, especially in the field of physical organic chemistry. Tristan, thank you for letting me join your lab as one of your first students when you started. Scott, thank you for agreeing to serve as my external committee member and the various advices that you have given to me.
To the early members of the Baran lab, I am grateful for the opportunity to learn from you guys as a naïve first year student. You guys played an influential role in establishing a superb lab culture and showed me what hard work really means. Your passion for chemistry is truly contagious. I will always regard Baran lab as the Eames office (Charles and Ray Eames anyone?) equivalent of organic chemistry and you guys definitely play a big part in establishing that notion for me.
! iii! To the Worrell household (Williams and B), thank you for your nonpareil hospitality and provision of various alternative entertainments. Being one of the founding fathers of
O’Briens Wednesday is probably one of my proudest achievements in grad school, next to spelling the alphabets backwards. And don’t worry, from the scale of 1 to 10, I’m still a 6.
To Dane, thank you for watching A Serbian Film with me and for having a similar taste in music (although I still maintain that War All The Time is better than Full Collapse).
To Aaron Sather, thank you for inviting me to your place on multiple occasions to watch sports on TV. I wish you and Lupita all the best.
Danny Wansen, thank you for initiating Don Diego’s Monday and for always having bottomless supply of candies whenever we need one. Brosen, thank you for taking turns to carpool to O’Briens and Don Diego’s. I hope you find a great future project that’s better than quassin, but also with the funding. PEmily, thank you for your hospitality during Thanksgiving for the past few years. Taycoh, the lab will be forever grateful for the Jelly Belly machine you got. JG, thank you for being such an enabler when it comes to beers.
To Qianghui, I am very grateful to have you as my teammate in the ouabagenin project.
Thank you for your help and valuable scientific discussions throughout the project. I wish you all the best for your future career.
To Ian Young and Sarah Tully, thank you for being such great friends during the ‘dark
Cheetah’s days’ of the Baran lab, and for the many Papa John’s pizzas and Sour Patch
Kids. Thank you for Per Se too! I eagerly wait to be driven around in your (future) R8.
! iv! To my parents, you guys recently made a passing comment to me, “Never did we imagine we would have a Ph.D. graduate in the family.” Well, neither did I. But I am really thankful for your love and support throughout my education.
The following non-scientists have played a huge role in coloring my worldview: Mark
Rothko, Richard Serra, Joseph Beuys, Le Corbusier, Dieter Rams, Robert Mapplethorpe,
Rick Owens, Yohji Yamamoto, Andrei Tarkovsky, and Béla Tarr. Their creative output has been a wellspring of inspiration for me. As Beuys once said, “Creativity is not limited to people practicing one of the traditional forms of art, and even in the case of artists, creativity is not confined to the exercise of their art.”
! v! Dieter Rams: ten principles for good design
Good design is innovative
Good design makes a product useful
Good design is aesthetic
Good design makes a product understandable
Good design is unobtrusive
Good design is honest
Good design is long-lasting
Good design is thorough down to the last detail
Good design is environmentally-friendly
Good design is as little design as possible
! vi! Decades
Here are the young men, the weight on their shoulders
Here are the young men, well where have they been?
We knocked on the doors of hell’s darker chamber
Pushed to the limit, we dragged ourselves in
Watched from the wings as the scenes were replaying
We saw ourselves now as we never had seen
Potrayal of the trauma and degeneration
The sorrows we suffered and never were free
Where have they been?
Weary inside, now our heart’s lost forever
Can’t replace the fear, or the thrill of the chase
Each ritual showed up the door for our wanderings
Open then shut, then slammed in our face
Where have they been?
Ian Curtis
L.W.T.U.A., 07/15/56–05/18/80
! vii! Table of contents
Chapter 1 Introduction: Historical background of the cardiac glycosides ...... 1
1.1. Structure, history and bioactivity of the cardiac glycosides and related natural
product ...... 2
1.2. Syntheses of cardenolides, bufadienolides and the batrachotoxins ...... 5
1.3. Recent semisyntheses of other complex, bioactive steroidal natural products .... 18
1.4. Other polyoxygenated steroids ...... 24
1.5. References ...... 25
Chapter 2 A scalable synthesis of ouabagenin ...... 30
2.1. Synthesis planning part 1: additional lessons from literature ...... 31
2.2. Synthesis planning part 2: cyclase-oxidase approach ...... 33
2.3. C19 methyl oxidation literature ...... 36
2.4. Norrish photochemistry ...... 40
2.5. Cyclobutanol fragmentation and diepoxide synthesis ...... 43
2.6. Diepoxide fragmentation and synthesis of protected ouabageninone ...... 46
2.7. Model study development for butenolide attachment ...... 51
2.8. Back to the real system ...... 54
2.9. Reinventing your exit ...... 57
2.10. Conclusion and future direction ...... 58
2.11. Distribution of credit ...... 61
2.12. References ...... 62
2.13. Supplementary information ...... 67
Appendix 1: Spectra ...... 109
! viii! Appendix 2: X-ray crystal structures ...... 196
Appendix 3: Curriculum Vitae ...... 214
! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !
! ix! List of Figures and Schemes
Figure 1-1. Selected examples of cardiotonic steroid natural products ...... 2
Scheme 1-1. Wiesner’s synthesis of digitoxigenin from testosterone ...... 6
Scheme 1-2. Kabat’s formal synthesis of digitoxigenin ...... 7
Scheme 1-3. Stork’s total synthesis of digitoxigenin ...... 8
Scheme 1-4. Yoshii’s synthesis of strophanthidol ...... 9
Scheme 1-5. Jung’s total synthesis of rhodexin A ...... 10
Scheme 1-6. Deslongchamps’ total synthesis of ouabagenin ...... 11
Scheme 1-7. Synthesis of batrachotoxinin A by Wehrli and co-workers ...... 13
Scheme 1-8. Total synthesis of batrachotoxinin A by Kishi and co-workers ...... 14
Scheme 1-9. Sondheimer’s synthesis of bufalin and resibufogenin ...... 15
Scheme 1-10. Wiesner’s synthesis of bufalin ...... 16
Scheme 1-11. Yoshii’s synthesis of bufalin via Sondheimer’s intermediate ...... 18
Scheme 1-12. Baran’s synthesis of cortistatin A from prednisone ...... 19
Scheme 1-13. Shair’s synthesis of cephalostatin 1 ...... 20
Scheme 1-14. Giannis’ synthesis of cyclopamine ...... 22
Scheme 1-15. Gademann’s synthesis of withanolide A ...... 23
Figure 1-2. Other examples of bioactive polyoxygenated steroids ...... 24
Scheme 2-1. Overman’s Heck annulation strategy towards ouabagenin ...... 31
Scheme 2-2. Jung’s synthesis of the fully elaborated A/B ring of ouabagenin ...... 32
Figure 2-1. Facile formation of ouabain-borate complex ...... 33
Scheme 2-3. Utilization of the “two-phase” approach in the total synthesis of the eudesmane family ...... 34
! x! Figure 2-2. Initial strategic considerations towards accessing C19 oxidation ...... 35
Scheme 2-4. Attempted direct C19 functionalization with iron porphyrin catalysis ...... 37
Scheme 2-5. Attempted alkylative dearomatization of estrone ...... 37
Scheme 2-6. Attempted oxidative dearomatization of estrone derivatives ...... 38
Figure 2-3. Final retrosynthesis of ouabagenin ...... 39
Scheme 2-7. Norrish type II photochemistry for the C19 functionalization ...... 40
Scheme 2-8A. Application of Norrish type II photochemistry on 2-43 ...... 41
Scheme 2-8B. Attempted oxidative fragmentation with Pb(OAc)4 ...... 41
Scheme 2-9. Selected precedents for solid-state photochemistry ...... 42
Scheme 2-10. Attempts at oxidative fragmentation of cyclobutanol 2-44 ...... 43
Scheme 2-11. Mechanistic reasoning for the proposed fragmentation with hypervalent iodine reagent ...... 43
Scheme 2-12. Mechanistic proposal for the formation of acetate 2-55 ...... 44
Scheme 2-13. Oxidative fragmentation of 2-44 and synthesis of diepoxide 2-62 ...... 45
Scheme 2-14. Proposed mechanism for NIS-assisted oxidative fragmentation ...... 45
Scheme 2-15. Attempted dehydrogenation of 2-63 with IBX or HIO3 ...... 46
Scheme 2-16. Attempted hydrogenation of diepoxide 2-62 and its acetate derivative ..... 47
Scheme 2-17A. Attempted reduction of free triol 2-66 ...... 48
Scheme 2-17B. Outcome of attempted protection of triol 2-66 ...... 48
Scheme 2-18. Completion of the synthesis of ouabagenin ketonic core ...... 49
Scheme 2-19. Final route for the synthesis of protected ouabageninone (2-84) ...... 51
Scheme 2-20. Synthesis of estrone model system using Stille coupling ...... 52
! xi! Scheme 2-21. Preparation of alkyl iodide 2-91 and attempted radical and nickel cross- coupling reactions ...... 53
Scheme 2-22. Preparation of furan derivative 2-97 via C-H activation, its use in hydrazone-boronic acid cross-coupling and completion of estrone model system ...... 54
Scheme 2-23. Attempts at effecting hydrazone-boronic acid cross-coupling on protected ouabageninone ...... 55
Scheme 2-24. Proposed mechanism for the formation of 2-103 ...... 56
Scheme 2-25. Completion of the synthesis of ouabagenin (2-1) ...... 56
Figure 2-4A. Radical fluorination of 2-83 ...... 59
Figure 2-4B. Comparison with previous semisynthesis efforts ...... 59
Figure 2-5. Selected examples of semisynthetic corticosteroids ...... 61
! xii! List of abbreviations
Ac acetyl
Acac acetylacetonate
AIBN azobis(isobutyronitrile)
BAIB (diacetoxyiodo)benzene
BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diazaphosphorine
Bn benzyl
BTMG 2-tert-butyl-1,1,3,3-tetramethylguanidine
Bu n-butyl tBu tert-butyl c concentration (for optical rotation) calc’d calculated (for mass spectrometry analysis)
CDI 1,1’-carbonyldiimidazole cod cyclooctadiene
CSA camphorsulfonic acid
Cum cumene
CuTC copper(I) thiophene-2-carboxylate
DBU 1.8-diazabicycloundec-7-ene
DCB dichlorobenzene
DIBAL diisobutylaluminum hydride
DIPEA diisopropylethylamine
DMF dimethylformamide
! xiii! DMP Dess-Martin periodinane
DMSO dimethylsulfoxide dppb 1,2-bis(diphenylphosphino)butane dtbpy 4,4’-di-tert-butyl-bipyridine
ESI-TOF electrospray ionization-time of flight
Et ethyl
Fur furyl
HMDS hexamethyldisilazane
HMPA hexamethylphosphoramide hν light
IBX 2-iodoxybenzoic acid
Im imidazole
IR infrared
KHMDS potassium hexamethyldisilazide
LCMS liquid chromatography-mass spectrometry
LDA lithium diisopropylamide
LHMDS lithium hexamethyldisilazide mCPBA meta-chloroperoxybenzoic acid
Me methyl
MOM methoxymethyl
MPO methoxypyridine-N-oxide
Ms methanesulfonyl (mesyl)
NBS N-bromosuccinimide
! xiv! NCS N-chlorosuccinimide
NIS N-iodosuccinimide
NMP 1-methyl-2-pyrrolidinone
NMR nuclear magnetic resonance ox oxalate
PCC pyridinium chlorochromate
PDC pyridinium dichlorochromate
Ph phenyl
PIDA (diacetoxyiodo)benzene
PIFA [bis(trifluoroacetoxy)iodo]benzene
Pin pinacol
PMB para-methoxybenzyl ppm parts per million
PPTS pyridinium p-toluenesulfonate
PTAD 4-phenyl-1,2,4-triazole-3,5,-dione pyr pyridine
R.E. reductive elimination
Ra-Ni Raney-nickel
Salen N,N’-ethylenebis(salicylimine)
SDS sodium dodecyl sulfate
TASF tris(dimethylamino)sulfonium difluorotrimethylsilicate
TBAF tetra-n-butylammonium fluoride
TBCHD 2,4,4,6-tetrabromocyclohexa-2,4-dienone
! xv! TBD triazabicyclodecene
TBDPS tert-butyldiphenylsilyl
TBHP tert-butyl hydroperoxide
TBS tert-butyldimethylsilyl
TEMPO (2,2,6,6,-tetramethyl-piperidin-1-yl)oxyl
Tf trifluoromethanesulfonyl (triflyl)
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
THP tetrahydropyranyl
TLC thin-layer chromatography
TMG 1,1,3,3-tetramethylguanidine
TMS trimethylsilyl
TPAP tetrapropylammonium perruthenate
TPP tetraphenylporphyrin
Tris triisopropylbenzenesulfonyl
Ts toluenesulfonyl (tosyl)
! xvi! ABSTRACT
The cardiotonic steroids are a family of steroidal natural products with unusual cis
A/B and C/D ring fusions as well as lactone ring system at the C17 position. Possessing the capability to increase the cardiac output through the inhibition of the membrane- bound sodium pump (NA+/K+ -ATPase), some members of this family have been utilized in the treatment of congestive heart failure, a progressive condition that currently affects approximately two million people in the United States alone. The use of these molecules, however, is complicated by an extremely narrow therapeutic index. Thus a synthesis that would allow versatile topological diversification could lead to the development of further analogs potentially possessing a wider therapeutic window as safer alternatives. Herein we describe a scalable synthesis of ouabagenin, one of the most oxygenated members of the family with an unusual take on the age-old practice of steroid semisynthesis. The incorporation of both redox and stereochemical relays during the design of this synthesis resulted in efficient access to more than 500 milligrams of a key precursor toward ouabagenin and the discovery of innovative methods for carbon- hydrogen and carbon-carbon activation. Some of the highlights of the current route include (i) the application of solid-state Norrish type II photochemistry in natural product synthesis; (ii) chemoselective cyclobutanol fragmentation; (iii) implementation of an “on- water” epoxide fragmentation; (iv) highly diastereoselective Mukaiyama hydration to furnish the requisite C/D ring junction of ouabagenin; (v) chemoselective dienoate reduction; and (vi) robustness and scalability of the route in an academic setting.
! xvii!
This is the way,
step inside…
! xviii!
Chapter 1
Introduction: Historical Background of the Cardiac Glycosides
! 1 1.1. Structure, history and bioactivity of the cardiac glycosides and related natural
products
O O O O
O O O O OH OH Me Me OH Me Me 17 HO Me HO HO H Me H HO H Me H 14 HO O 5 H OH H OH H OH H OH HO HO HO O HO OH H H OH H HO ouabagenin (1-1) digitoxigenin (1-2) ouabain (1-3) digoxigenin (1-4) O O O O O O Me O N OH Me Me HO OH Me HO OMe HO HO Me OH O Me H O O O H Me H OH H OH H OH O O O O HO HO H OH H OH Me O batrachotoxinin A (1-5) strophanthidol (1-6) rubellin (1-7) bryotoxin C (1-8)
O O O O O O O
O Me Me Me Me HO S OH O O OH H Me H H H HN O H OH H OH H OH H OH Me O O HO HO O H H H scilliglaucosidin (1-9) helleborogenone (1-10) UNBS 1450 (1-11) rostafuroxin (1-12) Figure 1-1. Selected examples of cardiotonic steroid natural products and semisynthetic medicinal derivatives.
The term “cardiac glycosides”–often used interchangeably with “cardiotonic steroids”– refers to a class of natural products exhibiting positive inotropic activity.1
These molecules possess the capacity to increase the cardiac output by increasing the force of contraction of the heart muscle. This ability is believed to have arisen from their inhibitory interaction1c with the extracellular surface of the membrane-bound sodium pump (NA+/K+ -ATPase) through stabilization of the latter in the E2-P transition state.
This inhibition results in the increase of intracellular sodium concentration, leading to the inhibition of another membrane protein, NCX, and the build-up of intracellular calcium concentration in the sarcoplasmic reticulum, which in turn leads to more powerful contraction of the mycocyte.
! 2 Cardiac glycosides possess several characteristic structural features (Fig. 1-1): i) glycosylation, if any, is found at the C3 position of the steroidal framework; ii) in contrast to common steroidal framework,2 both their A/B and C/D rings are of cis configuration; iii) a β-configured tertiary alcohol is present at the C14 (and often C5) and; iv) an unsaturated lactone ring system is found at the C17 position. The C17 lactone domain further defines the subclass of cardiac glycosides: those with unsaturated butyrolactone moiety–typically afforded by plant sources–are called cardenolides and those with unsaturated 2-pyrone moiety–typically afforded by animal sources–are called bufadienolides.3
As early as 1785,4 this class of natural products has found application in medical literature; pioneering work by William Withering had prescribed the use of Digitalis purpurea extract, whose main bioactive components are digitoxin and digoxin (their aglycones are shown as 1-2 and 1-4 respectively), for treatment of heart failure. In 1998, digoxin was approved for medication of heart failure by the Food and Drug
Administration (FDA) following a series of studies and clinical trials, although its use in patients with heart failure is currently on the decline.
In 1888, a highly oxidized member of the cardenolide family, ouabain (1-3), was isolated by Arnaud5 from the roots and barks of the African ouabio tree. Its aglycone, ouabagenin (1-1), was later isolated for the first time in 1942 by Mannich and Siewert,6 who also proposed the correct structure for the aglycone and the parent glycoside. These molecules have attracted considerable attention due to the discovery of the natural occurrence of ouabain (or ouabain-like compound) in mammals that acts as endogenous digitalis as proposed by Szent-Gyorgyi.7 Aside from inhibiting the Na+/K+ -ATPase,
! 3 endogenous ouabain also acts as a signal transducer and activator for the transcription factor NF-kB,8 which mediates the activation of several genes involved in vascular physiology. Recently, build-up of endogenous ouabain has been proposed as one genetic- molecular mechanism for hypertension in animal models,9 suggesting that a novel anti- hypertension agent may arise from the pursuit of a molecule possessing an antagonistic effect to ouabain. This hypothesis has led to the development of rostafuroxin (1-12),10 an antihypertensive digitoxigenin derivative currently undergoing clinical development.
The bufadienolides could be found in the skin secretions of toads such as Bufo gargarizans Cantor and Bufo melanostictus Schneider and form the main constituents of the traditional Chinese medicine Ch’an Su.11 In addition, numerous other bufadienolides have been found to be bioactive, exhibiting a range of activities including cardiotonic, antineoplastic and cytotoxic. For example, bryotoxin C (1-8),12 whose structure is confirmed by single crystal X-ray analysis, was identified as the main cytotoxic component of B. pinnatum and exhibited significant cytotoxicity in KB cells (ED50= 14 ng/mL), human lung carcinoma A-549 cells (ED50= 10 ng/mL) and colon HCT-8 tumor cells (ED50= 30 ng/mL). On the other hand, rubellin (1-7)13 was shown to be the toxic principle of U. rubella capable of eliciting death in mammalian test subjects.
In 1969, Daly and Witkop14 isolated the neurotoxic constituents of the skins of
Colombian poison-arrow frogs and named the alkaloid batrachotoxin. Not only does this molecule produce cardiotoxic effects similar to the cardiac glycosides, it also shares some common structural features with them, notably the steroidal framework, the cis A/B and
C/D ring junctures, and the hydroxyl groups at C3 and C14 in a β-orientation. Unique to the batrachotoxins are the existence of the seven-membered oxazapane bridging ring
! 4 across the C/D ring juncture and the hemiketal moiety at C3. To date, the batrachotoxins are one of the most potent neurotoxins15 (LD50 in mice 2 µg/kg, approximately ten times more potent than tetrodotoxin) isolated from animals. This neurotoxicity is derived from its ability to depolarize the nerve and muscle membranes by irreversible stabilization of the sodium ion channels in the active, open form, thus allowing increased flow of sodium ions into cells. As such, batrachotoxins have become particularly useful chemical agents to probe the voltage-dependent sodium ion transport in the body.
Despite their approval by the FDA, cardiotonic steroid drugs are complicated by an extremely narrow therapeutic index.1b The therapeutic plasma concentration for digoxin ranges from 0.8–2.0 ng mL-1, above which acute poisoning could occur.16 In fact, patients are often treated with 60% of the toxic dose to obtain a therapeutic response. In light of this problem, a de novo synthesis is desirable as it would allow versatile topological diversification, leading to the development of novel analogs and new scaffolds that could potentially possess a wider therapeutic window as safer alternatives.17
1.2. Synthesis of cardenolides, bufadienolides, and the batrachotoxins
1.2.1. Wiesner’s synthesis of digitoxigenin
Synthesis of digitoxigenin from testosterone (Scheme 1-1) by Wiesner and co- workers18 represents a landmark achievement in the field of cardenolide synthesis owing to its practical and creative strategy for the construction of the D-ring topology. The issues of introduction of 17β butenolide and the 14β tertiary hydroxyl moieties were addressed by the use of furan as a butenolide surrogate. Thus, lithiofuran addition onto
! 5 the C17 ketone moiety of 1-14 proceeded preferentially from the α face. The resulting allylic alcohol 1-15 was acetylated and subjected to a Claisen rearrangement to furnish alcohol 1-16. Following hydrogenation of the C16-C17 olefin, the furan moiety was converted to butenolide via treatment with mCPBA and reduction with NaBH4. Finally, alcohol dehydration, bromohydrin formation and excision of the extraneous bromide group afforded the protected form of digitoxigenin, and the synthesis was completed by removal of the benzyl protecting group.
O OH OH Me O Me Me O Li Me H Me H Me H
H H H H (93%) H H O BnO BnO 1-13 H 1-14 H 1-15 1. Ac2O, pyr (87%) O 2. CaCO3 O O O
Me OH Me H2, Me mCPBA Pd/CaCO3 Me H Me H Me H (92%)
H H OH H H OH H H OH BnO BnO BnO H 1-18 H 1-17 H 1-16
NaBH4 (87%) O O O 1. O O O O Me NHBr MeSO2Cl, Me pyr Me HOAc Me
Me H (85%) Me H 2. Ra-Ni, Me H KOAc 3. H , H H OH H 2 H OH Pd/C BnO BnO HO H H (73% over H 1-19 1-20 3 steps) digitoxigenin (1-2) Scheme 1-1. Wiesner's synthesis of digitoxigenin from testosterone.
Extension of this organolithium addition approach led to synthesis of bufalin19 as well as various analogs of digitoxigenin possessing various heterocyclic domains, such as thiophene and pyridine, at C17. A similar approach starting from testosterone was undertaken by Kabat20 in 1995 to complete a formal synthesis of digitoxigenin (Scheme
! 6 1-2). Instead of lithiofuran, he utilized a silylated vinyl lithium species to attack the C17 ketone moiety and the resulting diene 1-22 was doubly-epoxidized to generate 1-24 via the intermediacy of a C17 allene oxide species. Condensation with Bestmann phosphoranylidene ketene completed the formal synthesis.21
O OH OH Me Li Me Me O 1. tBuOOH, TMS TMS Me H TMS Me H VO(acac)2 Me H O H H (91%) H H 2. mCPBA H H THPO THPO (75% THPO H H over 2 steps) H 1-21 1-22 1-23 1. TFAA (28% over 2 steps) O O 2. TBAF
O O OH O MeSO2Cl, 1. H2, Pd/C Me pyr Me 2.Ph3P C C O Me
Me H Me H Me H (53%)
H H H OH H H OH THPO THPO THPO H 1-26 H 1-25 H 1-24
Scheme 1-2. Kabat's formal synthesis of digitoxigenin.
1.2.2. Stork’s first total synthesis of digitoxigenin
The first total synthesis of digitoxigenin was achieved by Stork and co-workers22 in
1996 starting from Wieland-Miescher ketone (Scheme 1-3). Functional group manipulations led to intermediate 1-27, which was then fragmented to dialdehyde 1-28.
The less-hindered formyl group was first reduced and the neopentyl aldehyde subjected to a Horner-Wadsworth-Emmons-type olefination. Swern oxidation and dithiane addition set the stage for an intramolecular Diels-Alder reaction to furnish tricycle 1-30, which was then taken through several steps to arrive at enone 1-31. Grignard addition to the carbonyl moiety was followed by a stereoselective 5-exo-dig vinyl radical cyclization23 to construct the D ring of digitoxigenin. Epoxidation and rearrangement of the subsequent epoxide delivered aldehyde moiety at C17, which was then converted to the
! 7 corresponding nitrile. Inversion of the nitrile configuration was achieved by formation of the dianion on the D ring, followed by kinetic protonation using sterically-hindered butylated hydroxytoluene (BHT). Construction of the butenolide moiety was achieved by addition of (benzyloxy)-methyllithium, debenzylation and condensation with Bestmann phosphoranylidene ketene.21 Finally, desilylation completed the first total synthesis of digitoxigenin. This work represents a landmark achievement for the stereocontrolled construction of the steroidal tetracyclic framework and the solution to the stereochemical problem of the β-disposition of the butenolide moiety at C17.
Me O 1. NaBH4 O Me Me Me OH 2. NaIO4 O 1. NaBH(OAc)3 O O 2. Me O (94%) OH O H O H P(O)Ph2 O H 1-27 1-28 (52% over 1-29 (prepared from Wieland- 2 steps) 1. Swern Miescher ketone) 2. S (61% over (EtO)2(O)P 3 steps) S 3. PhMe, 180 ºC Me Me Me Me H 1. TMS Me H Me H S MgBr O H OH H O H S 2. TBAF TBSO TBSO H (67% over H O H 1-32 2 steps) 1-31 1-30
Bu3SnH, (40%) AIBN Me Me CHO Me CN
1. mCPBA 1. NH2OH Me H 2. BF3.OEt2 Me H 2. CDI Me H
H OH H OH H OH (65%) (95%) TBSO TBSO TBSO H 1-33 H 1-34 H 1-35
LiNEt2; (73%) O BHT OH O O Me CN Me Me 1. Ph3P C C O 1. BnOCH2Li Me H Me H Me H 2. pTsOH 2. H2, Pd/C H OH H OH (85% TBSO H OH (72% over H 2 steps) TBSO over 2 steps) HO H 1-37 1-36 H 1-2 Scheme 1-3. Stork's total synthesis of digitoxigenin.
! 8 1.2.2. Yoshii’s synthesis of strophanthidol and strophanthidin
O O O Me Me Me Me Me 1. Br2, Me AcOH Me H H H O 2. LiBr O H H H (44% over AcO AcO 2 steps) AcO 1-38 Br 1-39 Br 1-40 O Zn, iPrOH-AcOH (89%) O O O Me Me Me Me Me Ph3SnH AcO HO HO H H H (82%) H H H AcO AcO AcO 1-43 1-42 1-41 (60%) 1. KHCO3 2. PCC O O O 3. H+ O O O
1. AcNHBr Me Me Me 2. Ra-Ni AcO HO HO H H H 3. KHCO3 4. H O H 2 2 H OH H OH (63%) O HO O O OH 1-44 1-45 strophanthidol (1-6) Scheme 1-4. Yoshii's synthesis of strophanthidol.
A synthesis of strophanthidol, and its parent glycoside strophanthidin,24 was reported in 1978 by Yoshii and co-workers starting from pregnenolone acetate (Scheme 1-4). The synthesis utilized the C5-C6 olefin as a functional handle to oxidize the C19 methyl moiety,25 a historically-challenging problem in C-H oxidation. Thus, the olefin was first converted to the bromohydrin, and the resulting secondary alcohol was treated with
Suarez condition to generate a transient hypoiodite species which abstracted a hydrogen from the angular methyl group. Recombination with an iodyl radical and an intramolecular displacement generated the bridging furan ring on the B ring. Following functionalization of the D ring into the corresponding dienone, the bridging furan moiety was reductively cleaved to generate the free hydroxyl group at C19. The pendant acetyl group at C17 was elaborated into the corresponding butenolide, and the requisite C14
! 9 tertiary alcohol introduced via the formation of bromohydrin on the C14-C15 olefin.26
Lastly, oxidation of the A ring into the enone, epoxidation and reductive fragmentation generated the requisite C5 tertiary alcohol of strophanthidol.
1.2.3. Jung’s total synthesis of rhodexin
Me O O O Me Me O O Me Me Tf2NH Me 1. OsO4 Me H + Me (87%) 2. H+, H TESO OTES OMe TESO TESO OTES OMe 1-46 1-47 1-48 TESO (64% over 1-49 2 steps) 1. DMP 2. Pb(OAc)4 (32%) 3. CH2N2 4. 1,2-DCB, Me Me 180 ºC Me O O O Me Me 1. Li/NH3; Me O O allyl bromide O Me Me 2. Grubbs II, Me O O O NaBO3 PinB Me Me H Me H H (30% over Me H OTES H OTES 2 steps) OTES O O PinB O O Me 1-52 Me 1-51 1-50
(49% over KOH 2 steps) O Me Me O O O Me Me 1. H , O O 2 Me Me Pd/C HO Me O 2. L-Selectride HO Me H Me H Me H 3. Li/NH3 H OTES H OTES (41% over H OH O 3 steps) HO O 1-53 H 1-54 H Me O rhodexin A (1-55) HO HO OH Scheme 1-5. Jung's total synthesis of rhodexin A.
In 2011, Jung and co-workers reported the first total synthesis of rhodexin27 (Scheme
1-5). The route featured a key inverse-electron-demand Diels-Alder reaction to couple fragments 1-46 and 1-47 to generate the requisite BCD ring system of the cardenolides with a pendant vinyl group at C17 that would serve as a surrogate for the butenolide moiety. The extraneous acetyl group on 1-49 was removed by oxidative fragmentation
! 10 with Pb(OAc)4 and the C19 methyl group was introduced via a [3 + 2] dipolar cycloaddition with diazomethane, followed by thermal extrusion of nitrogen gas.28
Reductive allylation29 on 1-50, followed by cross-metathesis afforded vinyl boronate that was primed for Robinson annulation after oxidation of the boronate moiety. The C4-C5 olefin, C3 and C11 ketones were then reduced in a stereocontrolled fashion to complete the skeletal framework of rhodexin. Finally, the butenolide moiety was installed through condensation with Bestmann phosphoranylidene ketene.
1. O O
OTBDPS Me OTBDPS AcO PhMe Si OAc Me 2 O Me O 1-57 Cs2CO3 O
O 2. Pd(PPh3)4 H O O OH (78% over PhMe2Si O 2 steps) H O O 1-56 1-58 (61% over 1. Li(Et3CO)3AlH 2. PMBOC(NH)CCl PMP 3 steps) 3 PMP 3. KHMDS OTBDPS OTBDPS O Me O Me OTBDPS O 1. NaBH4 O OAc Me O 2. mCPBA O 5 steps PMBO H H O H (78%) H OH H OH H OH PhMe Si OH 2 PhMe2Si O O PhMe2Si O 1-61 1-60 H 1-59 1. MsCl (45% over 2. LiBH4 4 steps) 3. Ac2O 4. TBAF O OH O OTBDPS O OH Me OAc Me OAc Me AcO AcO 1. TBAF AcO PMP O PMP O PMP O H H 2. DMP H
H OH H OH 3. [(PPh3)3RhCl], H OH TMSCHN2 PhMe2Si AcO AcO OH OH (45% over OH 1-62 1-63 3 steps) 1-64
1. OsO4 2. nBu SnO O 2 nBu nBu Sn O OH O O O O O OH Me OAc Me OAc Me 1. Ph3P C C O AcO NBS AcO HO PMP O PMP O HO H H H 2. Na2CO3 (60% H OH H OH over 3 steps) H OH (58% over HO 2 steps) AcO AcO OH OH OH 1-66 1-65 ouabagenin (1) Scheme 1-6. Deslongchamps' total synthesis of ouabagenin via relay intermediate 1-63.
! 11 1.2.4. Deslongchamps’ enantioselective total synthesis of ouabagenin and ouabain
A landmark total synthesis of ouabagenin and ouabain30 was disclosed in 2008 by
Deslongchamps and co-workers starting from Hajos-Parrish ketone in 41 and 47 steps respectively (Scheme 1-6). Elaboration of Hajos-Parrish ketone into fragment 1-56 in 14 steps set the stage for the key anionic polycyclization coupling31 with cyclohexenone 1-
57 to construct the steroidal AB ring framework. Oxidation state adjustment and protection at C19 was followed by an intramolecular aldol reaction that completed the tetracycle synthesis. Subsequent oxidation state and protecting group adjustments led to enone 1-60, which was then reduced and epoxidized to furnish epoxide 1-61. Mesylation and reduction with LiBH4 effected a concomitant deoxygenation at C7 and opening of the epoxide to generate the requisite tertiary alcohol at C5. Additional concession steps and the critical Fleming-Tamao oxidation32 of the C3 phenyldimethylsilyl moiety afforded heptaol 1-63. This intermediate was intercepted via degradation of natural ouabain, and this relay intermediate was utilized to complete the synthesis. Lastly, the butenolide moiety was installed via the formation of the vinyl group at C17, dihydroxylation and condensation with Bestmann phosphoranylidene ketene. Mild methanolysis unmasked the natural product ouabagenin, which could be converted to ouabain in six additional steps.
1.2.5. Werhli’s synthesis of batrachotoxinin A and batrachotoxin
In 1972, Werhli and co-workers disclosed a groundbreaking synthesis of batrachotoxinin A (Scheme 1-7) and batrachotoxin starting from 11-oxo-progesterone (1-
67).33 The requisite oxidation state at C18 was introduced via a hypoiodite photolysis
! 12 reaction developed at Ciba AG in the early 1960s.34 After a bevy of transformations done to introduce the hemiketal moiety at C3 and a functional handle at C7, triacetate 1-69 was obtained, which was then subjected to reiterative radical bromination-elimination to generate a cyclopentadiene moiety on the D ring. A regio- and stereoselective epoxidation of the C14-C15 olefin, followed by a catalytic transfer hydrogenation revealed the tertiary alcohol at C14 with the correct stereochemical orientation.
Me O O O Me Me O AcO Me AcO O H 14 steps Me H Me H Me H H H H O O H O MeO OAc O 1-68 H 1-69 11-oxo-progesterone (1-67) 1. NBS; Li2CO3 2. NBS; Li2CO3 1. CO H AcO O 3 O HO Me AcO Me AcO Me O2N AcO AcO AcO 2. Pd on BaSO4 Me H Me H Me H
O OH O OH O MeO OAc MeO OAc MeO OAc H 1-72 H 1-71 H 1-70 DMSO, Ac2O O AcO Cl Me OAc Me Me OH O Me N 1. MeNH , N AcO 2 HO NaBH4 AcO Me H Me Me H O SMe 2. O O SMe O O O Cl O MeO OAc Cl HO H MeO OAc H H 1-73 1-74 batrachotoxinin A Scheme 1-7. Synthesis of batrachotoxinin A by Wehrli and co-workers.
Unmasking of the C18 hydroxyl group, a modified Pfitzner-Moffatt oxidation, and a reductive amination-acylation sequence installed the chloroacetamide moiety at C18 as a latent surrogate for the oxazapane ring with the concomitant protection of the C14 hydroxyl group. Installation of the oxazapane ring, acetate removal, and dehydration into
C7-C8 olefin completed the synthesis of batrachotoxinin A, which can be converted to batrachotoxin by a straightforward acylation reaction.14
! 13 1.2.6. Kishi’s total synthesis of batrachotoxinin A
A total synthesis of batrachotoxinin A beginning from Wieland-Miescher ketone was published by Kishi and co-workers35 in 1998 (Scheme 1-8). Elaboration of the Wieland-
Miescher ketone into furan 1-75 via a Garst-Spencer annulation36 was followed by an allylic oxidation, which effected an intramolecular Diels-Alder reaction to construct the steroidal framework.
HO Ac CHO N S A; NaCNBH ; TBSO S O 3 MnO2 Me Ac O S O 2 O Me S S Me S (76% overall) TBSO H TBSO OTBS TBSO H H OTBS 1-76 OTBS + NH3 1-77 1-75 TBSO - HCO2 (prepared from Wieland- A Miescher ketone)
Ac Ac TBSO Ac N O N O N O MOMO MOMO TASF; MOMO H2, PtO2 PhNTf2 Me Me OTf Me O O O (95%) O (90%) O O TBSO TBSO TBSO H H H OTBS OTBS OTBS 1-80 1-79 1-78
1. NaBH4 2. TBAF 3. DMP Ac Ac Me N O 1. DBU N O N OH MOMO 2. CSA, MOMO HO MeOH Me Me Me O O O O (85% over 5 steps) O O O MeO HO H H H O O 1-81 1-82 batrachotoxinin A Scheme 1-8. Total synthesis of batrachotoxinin A by Kishi and co-workers.
A reductive amination, followed by acylation introduced a surrogate for the oxazapane moiety. Removal of the dithiane moiety, fragmentation of the oxo-bridge, epoxidation of the tetrasubstituted olefin and oxidation of C17 carbon revealed intermediate 1-78, which was subjected to a chemoselective desilylation to close the oxazapane ring via a Michael addition reaction. The resulting enolate was trapped as the
! 14 vinyl triflate, and hydrogenated37 to obtain the correct oxidation state on the D ring.
Removal of the TBS protecting group, DMP oxidation and treatment with DBU fragmented the tetrasubstituted epoxide to afford the tertiary alcohol at C9 and the requisite C7-C8 olefin, and a simple exposure to acidic methanol furnished the hemiketal moiety at C3. Completion of the total synthesis was achieved by excision of the extraneous carbonyl moiety at C6, installation of the hydroxyethyl moiety at C17 and removal of all the protecting groups under acidic conditions.
1.2.7. Sondheimer’s synthesis of bufalin and resibufogenin
1. OH Li OEt ; O 1. NaBiO H+ CO H 3 Me O Me 2 2. H2 Me 2. K2CO3, 3. NaBH4 MeOH OH Me H Me H Me H (43% over (74%) H OH H OH H OH 3 steps) HO HO O H H 1-83 1-84 1-85 1. K, NH (95%) 3 OH OMe 2. CH2N2 OHC CO Me Me Me Me 2 1. POCl3 OMe 2. NaOH Me H Me H Me H (60%) H H H OH AcO AcO HO H 1-88 H 1-87 H 1-86
O Zn, DMF, Br 70 ºC MeO (15%) O O O O O O
Me NBS, Me Me basic Al2O3 LiAlH4 Me H Me H Me H (45%) (50%) H H O H OH AcO * AcO HO H H H 1-89 1-90 bufalin Scheme 1-9. Sondheimer's synthesis of bufalin and resibufogenin.
In 1969, the laboratory of Franz Sondheimer accomplished a synthesis of bufalin38 commencing from 14α-hydroxycortexolone, a by-product from the biotransformation process employed in the production of cortisol (Scheme 1-9). Side-chain cleavage,
! 15 followed by catalytic hydrogenation and regioselective ketone reduction furnished diol 1-
84, which was then treated with a lithium acetylide species and reduced with dissolving metal to append a methyl ester side chain at the C17 position after treatment with diazomethane. After a six-step sequence to convert the ester into the dimethyl ketal moiety, intermediate 1-87 was treated with Vilsmeier-Haack reagents to generate enol ether 1-88 which was then converted to the requisite six-membered lactone via the use of a Reformatsky-type conditions. The stereoconfiguration at C3 was then inverted, and the
C14-C15 olefin epoxidized to afford resibufogenin after removal of the acetate protecting group. Alternatively, treatment of 1-90 with LiAlH4 fragmented the epoxide and removed the acetate to furnish bufalin.
O O O O O O O OH Me O O Me O 1. Ac2O, Me Me H Li 1-92 Me H pyr Me H H H (95%) H H 2. CaCO3 H H BnO BnO (83%) OH H H BnO H 1-91 1-93 1-94
H2 (92%) O O O HO O O O O O HO Me Me Me NBS, NaOAc; SOCl2, NaBH4 pyr Me H Me H Me H (85%) H H H H OH BnO BnO BnO H 1-97 H 1-96 H 1-95
HCl (95%) OH O O O 1. O OH O O Me NHBr 1. Ag2CO3 HOAc Me 2. MsCl, Et3N Me Me
Me H 3. DBU Me H 2. Ra-Ni, Me H KOAc (64% over H H 3. H2, H OH 3 steps) Pd/C BnO BnO HO H H (49% over H 1-98 1-99 3 steps) bufalin Scheme 1-10. Wiesner's synthesis of bufalin.
! 16 1.2.8. Wiesner’s synthesis of bufalin
Using a similar approach to their synthesis of digitoxigenin (Section 1.2.1), Wiesner and Tsai were able to complete the synthesis of bufalin19 starting from testosterone
(Scheme 1-10). Thus, a 1,2-addition of lithiofuran 1-92 was followed by acetylation,
Claisen rearrangement and hydrogenation to generate intermediate 1-95, which was then treated with SOCl2 to effect dehydration to furan 1-96. Treatment with NBS effected a fragmentation of the furan moiety to the corresponding keto-aldehyde which was then reduced with NaBH4 to furnish diol 1-97. Treatment of this diol with 3 N HCl effected closure to hemiketal 1-98, which was then converted to the requisite pyrone ring system via oxidation with Ag2CO3 and dehydration of the α-hydroxyl group. Finally, formation of the bromohydrin from the C14-C15 olefin, reductive debromination and removal of the benzyl protecting group afforded bufalin.
1.2.9. Yoshii’s synthesis of bufalin and resibufogenin
Yoshii’s synthesis of bufalin39 (Scheme 1-11) employed first a homologation of the
C21 position of 5β-pregn-14-en-3β-ol-20-one (1-100) acetate to furnish vinyl ketone 1-
101. Treatment of this ketone with the Corey-Chaykovsky reagent led to the formation of epoxy cyclopropane 1-102, which rearranged to dihydropyrane 1-103 upon exposure to acidic methanol. Hydrolysis of the methyl ether and oxidation with Jones reagent generate lactone 1-104, which was converted to the bromohydrin and then to the corresponding epoxide 1-105. Dehydrogenation via an α-bromination of the lactone moiety completed the construction of the pyrone moiety to give a protected form of
! 17 resibufogenin, which can then be converted to both resibufogenin and bufalin according to Sondheimer’s procedure (Section 1.2.7).
O O O Me 1. CH(OMe)3 Me 2. HBr-pyr; Me OMe Me OMe KOtBu KH Me H Me H Me H
H H S H Me Me AcO AcO AcO H H H 1-100 1-101 1-102
(ca. 60%) O O OMe O O O
1. HCl-KCl Me 1. MeCONHBr Me 2. Jones Me 2. Al2O3 reagent Me H Me H Me H
H O H H AcO AcO AcO H H H 1-105 1-104 1-103
Br2, HOAc; DBU O O O O
Me Me LiAlH4 Me H Me H
H O H OH AcO HO H H 1-106 bufalin Scheme 1-11. Yoshii's synthesis of bufalin via Sondheimer's advanced intermediate.
1.3. Recent semisyntheses of other complex, bioactive steroidal natural products
Recently, there has been a renewed interest in the semisynthesis of complex, bioactive steroidal natural products. While still pale in comparison to the post-war period when steroid chemistry was the main drive behind medicinal research, this renaissance of sort indicated that chemists have begun to ‘re-recognize’ the importance of these molecules, especially from the medicinal and pharmacological point of views. Such renewed interest has led to the discovery of creative and novel transformations, especially in the functionalization of the steroidal framework. Selected examples of these
! 18 semisyntheses are reviewed briefly herein, with emphasis on key transformations performed to secure the final targets.
1.3.1. Baran’s synthesis of cortistatin A
In 2008, Baran and co-workers disclosed the first synthesis of cortistatin A40 (Scheme
1-12). Commencing from prednisone (1-107), expedient elaboration of the A-ring (6 steps) to intermediate 1-108 set the stage for the key double C-H activation of the C19 methyl group. Extended photolysis of 1-108 under Suarez condition41 led to the formation of the corresponding dibromide, which was then treated with DBU to effect an intramolecular cyclopropanation reaction. The resulting bromocyclopropane was then fragmented with SmI2, quenching with TBCHD to afford allylic bromide 1-109. In 3 more steps, the ketonic core of cortistatin A, dubbed cortistatinone (1-110), was secured.
Conversion to the natural product was achieved by first converting cortistatinone to the corresponding vinylic iodide,42 followed by a Stille coupling with stannane 1-111, and a chemoselective Ra-Ni reduction.
OH O 1. PIDA, hν, I ; O Me 2 19 O TMSCl; Im Me Me Br O HO Me H O 2. DBU, LiCl O OH 11 TMSO 19 9 H 9 (48%, 2 steps) Me H 10 O O O 5 H H 3. SmI ,TBCHD H H H OHCN O 2 O OHCN O O H prednisone (1-107) 1-108 H 1-109
N N N Me3Sn 1-111 Me O Me Me
Ra-Ni 1. N2H4; I2 HO HO HO O H O H (50%) O H 2.1-111, Pd(PPh3)4, HO HO HO CuCl, LiCl, (55% over Me2N Me2N cortistatin A (1-113) Me2N 1-112 2 steps) cortistatinone (1-110)
Scheme 1-12. Baran's synthesis of cortistatin A from prednisone.
! 19 1.3.2. Shair’s synthesis of cephalostatin 1
Ph O N
Me Me O NH Me O H O Me H O Me N O Me Me H OHC Me 1. PTAD OHC O hν O 2. NaOAc O Me H Me H Me H (42% over H H H 3 steps) H AcO AcO AcO H 1-114 H 1-115 H 1-116
Me O O Me O Me O H OTFA H O TBDPSO AcO Me TBDPSO AcO AcO Me 1. PCC 1. OsO4, NaIO4 2. DBU 2. NaBH(OAc)3 Me H Me H O Me H O (43%, 3. TBDPSCl H 3 steps) H (74% overall) H 4. TFA-OTf AcO AcO AcO H 1-119 H 1-118 H 1-117
Me TBDPSO Me O O HO O Me Me Me O H HO HO Me Me H N 3 O 1. Bu2SnCl2, H Me H OH H polyvinylpyridine N 2. TBAF O 1-120 H H H N TBDPSO H Me H Me TMS Me H AcO O O Me Me O O cephalostatin 1 (1-129) O O OTBS Me Me H OH N3 Me H N 1-128 H OMe
Me Me Me Br OTBDPS TMSO OTBDPS TMSO OTBDPS AcO HO O AcO HO AcO HO Me Me Me 1. PPTS CH2I2, 2. NBS Et2Zn Me H O OTBS Me H O OTBS Me H O OTBS (73%) H H H AcO AcO AcO H 1-127 H 1-126 H 1-125
(32% over 1. NaBH(OAc)3 OTBDPS 3 steps) 2. Ph3PAuCl, AgBF TBSOMe OTMS 4 1-123 TBDPSO OTBS 1. 1-123, Pd(PPh3)4, TMSO Me OH O AcO OTf CuI Me Me 2. Sharpless dihydroxylation AcO 1. Ac O, pyr Me Me H 2 Me H (89% overall) OH Me H O H H 2. PhNTf2, H H 3. (PhSeO)2O KHMDS HO AcO H H (88% over H 1-121 2 steps) 1-122 AcO H 1-124 Scheme 1-13. Shair's synthesis of cephalostatin 1 via union of fragments 1-120 and 1-128.
! 20 Shair’s synthesis43 of cephalostatin 1 (Scheme 1-13) hinged upon a key fragment union between advanced intermediates 1-120 and 1-128 via an unsymmetrical pyrazine formation. The construction of the western half of the natural product (intermediate 1-
120) commenced with a photolytic fragmentation44 of the C ring of hecogenin acetate (1-
114) to furnish lumihecogenin acetate (1-115). Submitting the latter to an ene reaction with PTAD afforded the requisite oxidation state of the C18 position. A modified Marker degradation45 excised most of the atoms belonging to the spiroketal moiety to generate intermediate 1-118, which was then taken through several steps to install the E and F rings of the western half.
The synthesis of the eastern half (1-128) began with a Schönecker oxidation46 of the
C12 position of trans-androsterone. Protection of the alcohol as the corresponding acetate was followed by vinyl triflate formation to set the stage for the key Sonogashira coupling with alkyne 1-123 that would serve as a surrogate for the E and F rings of the eastern half. Oxidation state adjustment of the D ring was followed by a Au-catalyzed 5-endo-dig cyclization47 to furnish the E ring of the eastern half. Lastly, the F ring was constructed by first cyclopropanating the enol ether moiety on the E ring, and an NBS-promoted oxidative spiroketalization that proceeded in a diastereoselective manner. The key fragment union48 was achieved by utilizing a method developed by Fuchs and co- workers. Thus, the western half was converted into the corresponding ketoazide, and the eastern half into the corresponding oxime, and these two fragments were then mixed in the presence of polyvinylpyridine and Bu2SnCl2. Finally, global deprotection afforded cephalostatin 1.
! 21 1.3.3. Giannis’ synthesis of cyclopamine
N
NH2 [Cu(MeCN) ]PF , TESO Me O N Me N 4 6 Me O O2; then NH4OH, p-TsOH HOAc Me H Me H Me H
H H (90%) H H (48%) H H BnO BnO BnO 1-130 1-131 1-132 1. Li TES (64% over 4 steps) 2. HOAc 3. Lindlar cat. 4. BAIB, TEMPO Me O Me TESO TESO H O 1. HF Me O 1. (MeS)3CLi Me O 2. Tf O 2 O 2. Ra-Ni O Me H Me H Me H (94%) (69% over H H H H 2 steps) H H BnO BnO BnO 1-135 1-134 1-133 1. LDA; (64% over TrisN 2 steps) 3 2. DIBAL OPMB O Me N3 N3 HN Me Me Me OH 1-137 Me O O H O H O O PMBO P(OMe)2 Me H Me H Me H (48%) H H H H H H BnO BnO HO 1-136 1-138 cyclopamine (1-139) Scheme 1-14. Giannis' synthesis of cyclopamine employing Schonecker oxidation.
Giannis’ synthesis of cyclopamine49 (Scheme 1-14) utilized Schönecker oxidation46 to introduce 12β-hydroxyl group on protected dehydroepiandrosterone (1-130) with complete regio- and chemoselectivity. The spirolactone moiety at the C17 position by way of acetylide addition onto the C17 carbon and oxidative cyclization. Next, conjugate addition and Ra-Ni reduction installed the requisite methyl group at C20 to generate intermediate 1-134, which was then subjected to the key Wagner-Meerwein type rearrangement to furnish the desired C-nor-D-homo steroid framework.50 An α- azidation51 was performed to install the requisite nitrogen atom into the skeleton. Lastly, reduction to azidolactol 1-136, condensation with ketophosphonate 1-137 set the stage for
! 22 the construction of the piperidine ring which was achieved via a modified Mitsunobu reaction.
1.3.4. Gademann’s synthesis of withanolide A
S O OH OMOM Me Me 1. NCS Me Me Me S 2. MOMCl, Me 1. TBSCl DIPEA O Me H Me H Me H 2. S (69% over Li 2 steps) H H S H H H H HO (82% over TBSO TBSO pregnenolone (1-140) 2 steps) 1-141 1-142 O Me 1-143, (87%) OEt LHMDS Me Me Me Me Me 1-143 MOMO MOMO Me Me MOMO Me Me 1. mCPBA Me Me Me 2. HCl Me O2, TPP O O Me O O O O Me H (74% over Me H (61%) Me H 2 steps) H H H H H H HO TBSO TBSO OH O OH 1-146 1-145 1-144 1. TPAP, NMO (77% over 2. IBX, 2 steps) MPO Me Me Me MOMO MOMO MOMO Me Me 1. N2H5Cl, Me Me Me Me H2O2, Et3N Me O Triton B Me O 2. PDC Me O O O O O Me H O Me H Me H (60%) (50% over 2 steps) H H H H H H O O OH O OH O OH O 1-147 1-148 withanolide A (1-149) Scheme 1-15. Gademann's synthesis of withanolide A.
Gademann’s synthesis of withanolide A52 (Scheme 1-15) commenced with protection of the C3 hydroxyl group, followed by a Corey-Seebach dithiane addition53 onto the C20 ketone to generate compound 1-141. Oxidative cleavage of the dithiane unit, followed by protection of the tertiary alcohol at C20 provided aldehyde 1-142, which underwent a stereoselective vinylogous aldol reaction54 to furnish lactone 1-144 in excellent yield and stereoselectivity. A singlet oxygen ene reaction55 afforded allylic alcohol 1-145, which was treated with mCPBA to effect a directed epoxidation reaction to generate 1-146 after deprotection. The A-ring was then converted to the corresponding enone via sequential
! 23 Ley oxidation and dehydrogenation with IBX.56 Lastly, epoxidation of the C1-C2 olefin, followed by a Wharton rearrangement57 transposed the enone moiety to provide the final target, withanolide A (1-149).
1.4. Other polyoxygenated steroids
Me Me HO Me HO Me H Me Me Me O O HO O OH H O HO Me Me H OH H H OH HO H OH OH HO OH withangulatin G (1-150) herbasterol (1-151)
MeHN O Me Me AcO Me O Me Me Me Me H O OH Me Me OH H H OSO2NHMe H OH NaO3SO OSO3Na H HO HO OH stephanthraniline A (1-152) haplosamate B (1-153) Figure 1-2. Other examples of bioactive polyoxygenated steroids.
Despite the remarkable progress that organic chemistry has made in the total synthesis and semisynthesis of steroidal natural products, challenges still remain. In particular, efficient and scalable access to polyoxygenated steroids such as those shown in figure 1-2 remains an unmet challenge in the realm of steroid synthesis. Several of these targets are highly bioactive molecules, for example, stephanthraniline A,58 isolated from the stems of Stephanotis mucronata, was reported to inhibit the prolieferation and activation of T cells both in vitro and in vivo and has been touted as a potential candidate for anti-inflammatory treatment. Withangulatin B,59 a close relative to withanolide A, was shown to possess potent cytotoxic activity against a panel of human cancer cell lines
(EC50 ranging from 0.2 to 1.6 µg/mL). In addition, they possess hydroxylation patterns
! 24 rarely seen in steroidal framework (for example, at C8 in stephanthraniline, and at C15 in withangulatin B). Rest assured, in addressing these challenges, the practicing chemist will have more than ample opportunities to develop creative and innovative solutions to the problem of selective functionalizations of steroids and terpenes and ultimately expand the frontiers of organic synthesis.
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! 29
Chapter 2
A Scalable Synthesis of Ouabagenin
! 30 2.1. Synthesis planning part 1: taking into consideration lessons from literature
In addition to the landmark total synthesis of ouabagenin and ouabain by
Deslongchamps and coworkers,1 synthetic studies by various research groups as well as analytical studies conducted on the characterization of endogenous ouabain have aided greatly in our synthesis planning. Of particular note are the efficient construction of the tetracyclic ring system of ouabagenin possessing the requisite stereoconfiguration at both the A/B and C/D ring juncture by Overman and coworkers,2 and the synthesis of fully elaborated A/B ring system by Jung and coworkers.3
1. Et2NLi,
I O Me OH 1. NaBH4 OTMS 2. Me2NNH2 Me O 3. TMS-imid 2-4 O
(85%) N 2. AcOH, NaOAc O NMe2 2-3 (90%) 2-5 path O (a)
PhO2S Li
O Me CN O Me CN PhO S O CN O 2 SmI2; HMDS, Me 5 steps Me then TBAF MeO2C 2-7 O OH O path (70%) O (60%) O (b) O O 2-2 2-6 O 2-8 2-9 O
1. KHMDS, PhNTf2 (72% over 2. Pd(dppb), 2 steps) KOAc O
O Me CN Me CN AcO 1. (CF3CO)2O, OH Me H AcOH O HO H HO H OH 2. SeO2 3. DMP O OH O H OH OH (50% over HO 2-11 3 steps) 2-10 OH ouabagenin (2-1) Scheme 2-1. Overman's Heck annulation strategy towards ouabagenin.
! 31 In 1998, Overman disclosed a novel annulation strategy for the construction of ouabagenin tetracyclic ring system commencing from the Hajos-Parrish ketone (Scheme
2-1). The first generation route involved alkylation of hydrazone 2-3 with iodide 2-4 to generate the annulation precursor 2-5. An improved preparation of 2-9 was later disclosed,4 which–in a strategy reminiscent of Deslongchamps’ total synthesis of ouabagenin–featured the cleavage of the enone moiety of 2-2 to generate ketoester 2-6.
This ketoester was submitted to a sulfone-variant of Claisen condensation to afford 2-8.
5 Treatment of 2-8 with SmI2 effected a Reformatsky reaction that set the stage for the key
Heck annulation strategy. Conversion of 2-9 to the corresponding vinyl triflate, followed by treatment with Pd(dppb) furnished pentacycle 2-10, which was elaborated further to introduce the ketone moiety at C3, and the C1-C2 olefin. In addition, Overman also published degradation studies6 of natural ouabain that imparted valuable lessons for future synthetic studies. Of particular note are the observations that the various hydroxyl moieties exhibit differential reactivities towards silyl protection, as well as the possibility of generating different epimers of C11-alcohol through judicious choice of reduction protocols of the corresponding ketone.
1. H+, OH O OEt HO HO EtO C 2 KOtBu HO + O H O Me O O 2. LiAlH4; O H2SO4 O O 2-12 2-13 2-14 (37% overall) 2-15 2-16 Scheme 2-2. Jung's synthesis of the fully elaborated A/B ring system of ouabagenin.
Jung’s model study (Scheme 2-2) for the synthesis of the A/B ring system of ouabagenin3 utilized a Robinson annulation7 for the construction of decalin 2-14, which was then converted to hydroxyenone 2-15. This compound could then be converted to the corresponding protected tetraol in an efficient manner, a result that would later become
! 32 valuable in our synthesis planning. Further insights that would contribute to our synthesis planning could be obtained from the synthesis of various isomers of ouabain by Corey and coworkers.8 In particular, the authors commented, “sodium borohydride reduction of this pentaacetoxy ketone was very slow and led to a complex mixture of very stable borate complexes from concurrent deacetylation and complexation.” This statement echoed the observation of facile formation of ouabain-borate complex (Figure 2-1) by
Nakanishi and coworkers.9 Indeed, the lopsided oxidation pattern of ouabain and ouabagenin (most of the hydroxyl groups are on the β-face) renders these molecules able ligands for inorganic species, including borosilicate glassware. Thus, any synthesis efforts towards ouabagenin will likely involve strategic protection of the various hydroxyl groups of the molecule.
HO O O B O Me HO O Me O O O B O HO OH O OH HO O
O O Me O HO Me O HO HO OH HO OH Figure 2-1. Facile formation of ouabain-borate complex.
2.2. Synthesis planning part 2: cyclase-oxidase approach
In 2009, our laboratory (Baran) formulated a “two-phase” synthetic strategy towards terpenes and terpenoids which strives to mimic the biosynthesis of these natural products.10 The first phase of this strategy, the “cyclase phase” involves efficient and rapid construction of the basic carbon skeleton of the target molecule, and the second
! 33 phase, the “oxidase phase” deals with the introduction of the requisite oxidations at the appropriate positions on the framework (Scheme 2-3).
A highest [O]-state
"retrosynthesis pyramid" Me Me OH level 4 OH HO HO Me
Me Me Me Me Me level 3 Me HO HO Me HO HO HO
Me Me Me Me "oxidase- OH phase" level 2 Me Me HO HO Me HO Me both accessible Me Me Me Me Me Me OH level 1 Me Me HO Me HO Me Me (most logical SM) Me
O Me "cyclase-phase" + MgBr + Me Me2CuLi + O Me lowest [O]-state
B Me Me Me Me Me Me
Me Me HO HO HO HO Me Simple 4-epi-ajanol dihydroxyeudesmane Me Me commercially- "cyclase "oxidase [reassigned structure] available phase" phase" building blocks Me Me Me HO Me Me Me OH dihydrojunenol OH Me HO HO HO HO HO Me pygmol eudesmantetraol Scheme 2-3. Utilization of the "two-phase" approach in the total synthesis of the eudesmane family of natural products.
This strategy has resulted in the total synthesis of the members of the eudesmane family of natural product, and has formed the basis of many other synthetic approaches in our laboratory. In addition, loose application of this strategy could also be observed in the synthesis of cortistatin A11 in our laboratory starting from prednisone. Inspired by these
! 34 achievements, and the success of the development of commercial semisynthetic steroid medicines such as finasteride and dexamethasone, we realized that a semisynthetic approach would be a more viable option for achieving a scalable synthesis of ouabagenin.
In addition to the aforementioned lessons gained from synthetic studies conducted on ouabain and ouabagenin, it is also well-established in the steroid literature12 that the A ring exhibits higher reactivity than the rest of tetracyclic framework. Thus, we posited that it is imperative that the A ring be fully elaborated first before the rest of the molecule in our approach towards ouabagenin.
O Me [1,4] O O O H Me O HO Me H
H H a O O
O Me O O Me O HO HO HO C14 O Me H b (direct oxidation?) [O] HO HO HO OH HO HO H H O O HO HO
O c Me O O [1,6] Me Me H O H O H H HO H C19-hydroxylation Figure 2-2. Initial strategic considerations towards accessing C19 methyl oxidation.
Several different scenarios exist for the elaboration of the A ring, and these permutations of oxidation sequence are depicted in figure 2-2. From the outset of the project, we were cognizant that the C11 hydroxyl group could be obtained with the correct stereochemical orientation by a judicious choice of reduction condition on the corresponding ketone and these significantly narrowed the list of potential steroidal starting materials to choose from as many commercially available steroids are devoid of oxidation at C11. Given the multitude of hydroxyl groups to be introduced, a ‘pre-built’ oxidation state (or functional handle) within the A ring, for example in the form of an
! 35 enone or a dienone (which can be readily obtained from either prednisone or cortisone), would be highly beneficial. In pathway a, it is envisioned that either the C1 or the C5 hydroxyl group could be introduced via a conjugate addition onto the dienone moiety.
However, introduction of the hydroxyl group at C19 would become problematic as the
C19 position exists in a 1,4-relationship13 to either C1 or C5. The same problem would also be encountered if one were to try to use a hydroxyl group at C3 to direct oxidation onto the C19 position, as they exist in a 1,6-relationship. Thus, it is apparent that the oxidation at the C19 carbon is unlikely to be accessed via the use of other functionalities on the A ring as directing groups and would have to be attained via other means, and preferably early in the synthesis (vide infra).
2.3. C19 methyl oxidation literature
A brief literature search for C19 methyl functionalization of steroids revealed an intriguing report of a completely catalyst-controlled, direct functionalization of the steroidal C19 position.14 It was reported that a modified iron-porphyrin catalyst system could effect a highly regioselective oxidation of the C19 carbon in a reasonable yield
(Scheme 2-4). Interestingly, only HPLC yields were reported and the products were characterized only by their HPLC retention time. In our hands, this result could not be reproduced, as neither our dienone substrate 2-23 nor the substrate reported by the authors showed any propensity towards oxidation at all. Disappointingly, switching to the more active perfluorinated porphyrin catalyst15 afforded only epoxidation of the enone moiety.
! 36 III A O 0.01 eq. Cl8TPPFe Cl, O O O Me 0.1 eq CumOOH, Me Me Me N-methylimidazole HO O Me H H H H
H H CH2Cl2, rt. H H H H H H O O O HO 2-17 2-18 (31.3%) 2-19 (15.7%) 2-20 (32.1%)
B 0.01 eq. Cl TPPFeIIICl, Me O 8 Ar 0.1 eq CumOOH, N-methylimidazole Me H No Reaction N Cl N H H CH2Cl2, rt. Ar Fe Ar O N N 2-17 III 0.01 eq. Cl8TPPFe Cl, MeO 0.1 eq CumOOH, MeO O O O N-methylimidazole HO O Ar Me H H Cl
H H CH2Cl2, rt. H H III O O 2-21; Cl8TPPFe Cl: Ar= 2-23 O Me O Cl Me III 0.1 eq. F20TPPFe Cl, F F PhIO Me H Me H 2-22; F TPPFeIIICl: Ar= F H H 20 H H CH2Cl2, rt. O O O F F 2-17 2-24 Scheme 2-4. Attempted direct C19 functionalization with iron porphyrin catalysis.
In 1987, Rindone and co-workers reported the formation of a dichloromethane adduct
(Scheme 2-5) of estrone in the presence of CoII(salen) catalyst and molecular oxygen.16
A Me O Me O Me O II Cl Co (salen), O2 Cl H H + OH H CH2Cl2 H H rt H H H H HO O O 2-20 2-25 (Reported) 2-26
B O MeO Me MeO II O Co (salen), O2 O O H H + OH H CH2Cl2 H H rt H H H H HO O O O 2-27 Me 2-29 O H
H H O O 2-28 (Actual)
Scheme 2-5. Attempted alkylative dearomatization of estrone.
! 37 This result was viewed as yet another potential solution for the construction of the A ring of ouabagenin. This reaction was found to be reproducible with the formation of two products with identical NMRs to the ones reported by the authors. Control experiments, however, gave peculiar result: it was found that the two products could still be formed in the absence of dichloromethane! This led us to reconsider the identity of 2-25, and it was eventually determined by X-ray analysis that the supposed dichloromethyl adduct was in fact an oxidized dimer of estrone. In addition, several other conditions were attempted to effect a para-functionalization of estrone, but none gave encouraging result (Scheme 2-
6). The preference for ortho-functionalization could be rationalized by the high thermodynamic penalty of breaking the aromaticity of the A ring associated with the para-functionalization pathway.
Me O Me O X H H HO H H H H MeO MeO 2-30 2-31 HO X Lewis acids, Me O O R = Me, tBu H X H NC TBHP, O O O H H Me Me PIFA, S OH MeO TMSCN O NaO 2-33 H H O Me R = Me R = H H H H H H RO MeO 2-27 2-32 H H LDA, R = H MeO S S [O] CN 2-34
No reaction Scheme 2-6. Attempted oxidative dearomatization of estrone derivatives.
! 38 These failures led us to retool our synthesis plan and consider the possibility of introducing the hydroxyl group at C19 via the use of an appropriate functionality embedded at C11, resulting in the final retrosynthesis for ouabagenin as depicted in figure 2-3.
HO Me O HO HO OH HO 2-35 HO Redox-Relay [C17 C14] O O AcO HO Me O 17 O HO OH HO Me HO 14 Me Stereochemical 2-36 HO Relay HO H H [C C ; O OH 19 1 H HO C19 C5] Me H HO O Me H HO 19 O OH 1 cortisone HO O 5 2-37 Redox-Relay O acetate (2-39) ouabagenin (2-1) [C11 C19] (US$1.2/gram) O Me 19Me O 11
O 2-38 Quasi-Biomimetic Oxidation Figure 2-3. Final retrosynthesis of ouabagenin.
It was envisioned that the butenolide moiety would be appended late in the synthesis, revealing the ouabagenin ketonic core, so called ouabageninone (2-35) in a retrosynthetic sense. From here on, we would rely on the interplay of two relay elements: (i) redox relay, defined as rapid transfer of redox information from one site to another within a framework, and (ii) oxidative stereochemical relay, defined as transfer of stereochemical information during an oxidative process. The first could be found in the installation of the tertiary alcohol at pentaol 2-36 through relay of redox information coded in the C17 ketone. The second element, oxidative stereochemical relay, would leverage the primary alcohol at C19 to correctly install the requisite oxidation state at the C1 and C5 positions,
! 39 and this could be viewed as another advantage of introducing the C19 oxidation early in the synthesis. Last, disconnection of the hydroxyl group at C19 inspired the invention of another redox relay from the C11 ketone functionality of 2-38.
2.4. Norrish photochemistry
It was long-established that a Suarez-type photochemistry would lead to nonselective functionalization of both the C19 and C18 positions.17 On the other hand, a Norrish type
II photochemistry could selectively functionalize the C19 methyl group without affecting the C18 position at all. Jaeger and co-workers were able to introduce hydroxyl moiety at
C19 (Scheme 2-7) by first effecting a Norrish type II photochemistry to generate cyclobutanol 2-41 in modest yield, and then performing an oxidative fragmentation with
18 Pb(OAc)4.
O O O O O O Me Me Me Me Me Me O h HO Pb(OAc)4 O ν HO Me H H H 16% 77% O H H O H H O H H
O H O H O H 2-40 2-41 2-42 Scheme 2-7. Norrish type II photochemistry for the functionalization of C19 carbon.
In attempting to emulate this approach, we first had to synthesize the appropriate photochemistry substrate. Preliminary investigations suggested that the presence of ketone moiety at C3 led to formation of complex mixture of products, presumably via its competitive photoexcitation. Thus, we opted for diketal substrate 2-43, which could be obtained in two steps19 from commercially available, inexpensive steroid starting material cortisone acetate. Initial experimentation revealed that although desired cyclobutanol 2-
! 40 44 could be obtained by conventional solution photochemistry, the reaction proceeded in only modest yield and plagued by competitive formation of side products, most notably from Norrish type I cleavage of the C9-C11 bond of the steroidal framework to yield ester 2-45 (Scheme 2-8(A), path (a)). Varying reaction solvents and light filter led only marginal change in the outcome of the reaction.
A O EtO O Me 11 O HO Me hν O Vycor filter H O + Me H (a) EtOH O H H O H O O Me 2-44 (43%) O 2-45 (38%) O 11 O 19 Me H
O H H O O 11 Me hν HO O O (Vycor filter) 2-43 (b) O O H SDS solution + Me Me Solid-State O H H Norrish Type II O H H OH O 2-44 (68%) O 2-46 (5%)
B O O Me Me HO O O Pb(OAc)4 AcO O H H (Complex mixture of products was obtained) O H H O H H
O 2-44 O 2-47
Scheme 2-8. A) Application of Norrish Type II photochemistry on 2-43; B) Attempted oxidative fragmentation with Pb(OAc)4.
In 2004, a total synthesis of herbertenolide20 was accomplished by Garcia-Garibay and co-workers and featured for the first time the application of a solid-state Norrish type
I photoreaction in total synthesis. Remarkably, the authors reported a highly chemoselective formation of cyclopentane 2-49, which stood in stark contrast to the non- selective outcome obtained with solution photochemistry. In addition, Scheffer and co- workers also reported a highly differential outcome of a Norrish type II photoreaction when conducted in solution and in solid-state.21 They observed significant improvement in the formation of cyclobutanols 2-51 and 2-52 when solid-state photochemistry was used in place of solution photochemistry (Scheme 2-9).
! 41 A Me Me O O hν OMe Me Me Me Me CO2Me OMe OMe 2-49
2-48 solution photochemistry: 0% solid-state photochemistry: 76%
B O OH OH H H n-1 n+2 hν H (CH2) (CH2) Me (CH ) (CH ) (CH ) (CH ) (CH2)n (CH2)n 2 n-2 2 n 2 n-2 2 n O O
O O O 2-53 2-50 2-51 2-52
solution photochemistry solid-state photochemistry diketone (n) 2-51 (%) 2-52 (%) 2-53 (%) 2-51 (%) 2-52 (%) 2-53 (%)
2-50a (3) 84 0 16 99 0 1 2-50b (4) 65 25 10 58 29 13 2-50c (5) 22 35 43 89 10 1 Scheme 2-9. Selected precedents for solid-state photochemistry.
Gratifyingly, the use of this solid-state photochemistry on our substrate led to improvement of the yield for the cyclobutanol formation while suppressing side products formation (Scheme 2-8(A), path (b)). This improvement in chemoselectivity does come with a trade-off in the rate of the reaction (3 to 5 days to ~90% conversion, 2.5 g scale), presumably due to the limited exposure of solid surface area in a typical photoreaction vessel. The use of a flow reactior should improve the reaction efficiency and allow this reaction to be conducted on an even larger scale because continuous operation will allow more uniform exposure of solid surface area and closer positioning to the light source.22
Oxidative fragmentation protocol described by Jaeger was attempted on 2-44
(Scheme 2-8(B)) but a complex mixture of products was observed, none of which corresponded to our desired C19 functionalized product. It was hypothesized that the C5-
C6 olefin of 2-44 is incompatible with the strong oxidant employed, leading to the formation of various undesired products.
! 42 2.5. Cyclobutanol fragmentation and diepoxide synthesis
No Reaction
O Inorganic Oxidants Me AcO Me O O (eg. FeCl3, Mn(OAc)3, O O I Cu(OAc)2, NH4VO3), O H IBX, DMP hν, IPy BF O H H 2 4 O H H
O 94% PhI(OAc)2, O 2-59 80 ºC O 2-54 Me HO O H
O H H Me O O hν, I2, O Pd(OAc) , AcO O PhI(OAc) 2-44 2 2 PhI(OAc)2, H 80 ºC O Me O O H H O Selectfluor I O 2-55 2-54 : 2-55 : 2-56 = ca. 3 : 1 : 1 O H H 2-58 O O O HO Me Me AcO O O H H
O H H O H H HO O O F 2-57 2-56 Scheme 2-10. Attempts at oxidative fragmentation of cyclobutanol 2-44.
Following precedents by Snider, Phillips and several other research groups,23 a range of inorganic oxidants was also screened to effect the oxidative fragmentation of the C11-
C19 bond of cyclobutanol 2-44 to no avail (Scheme 2-10).
OAc AcO O I OAc O O O Me O Me HO O O I AcO O O OAc Me O H AcO O H O O H H AcO O H H
O O H O 2-44 O Scheme 2-11. Mechanistic reasoning for the proposed oxidative fragmentation of cyclobutanol 2-44 with hypervalent iodine reagent.
A proposition based on the general reactivity of hypervalent iodine reagent was then put forth. It was reasoned that an arbitrary iodine(III) or iodine(V) species (illustrated in
Scheme 2-11 with DMP) could undergo a ligand exchange reaction with our cyclobutanol substrate and the resulting adduct could then undergo an oxidative fragmentation that would result in incorporation of hydroxyl or acetate group at C19. Unfortunately, no
! 43 reaction was observed with both IBX and DMP, and undesired fragmentation of the C9-
C11 bond to hemiketal 2-54 was observed when PIDA was employed.
AcO O II O Me Pd AcO Me Me O HO O II O O Pd(OAc) Pd O H 2 O H H
O H H O H H O H H O O 2-44 O [O]
Me O AcO Me O O IV O K2CO3 AcO O R.E. L Pd O H L H
O H H O H H
O O 2-55 2-55' Scheme 2-12. Mechanistic proposal for the formation of acetate 2-55.
Building on precedents set by Uemura and co-workers,24 we envisaged a palladium- mediated fragmentation reaction (Scheme 2-12). It was shown that cyclobutanols can be engaged in β-carbon elimination from the initial palladium(II) alcoholate adduct.
Similarly, if this metallo ketone intermediate could be intercepted by an oxidant to generate a PdIV species,25 one could envisage a reductive elimination event to regenerate a PdII species along with acetate 2-55.
Thus, cyclobutanol 2-44 was mixed with Pd(OAc)2 and PIDA, with Ac2O as solvent and heated to 80 ºC. The desired C19 functionalized compound was indeed formed, albeit in minor amount, validating our hypothesis. The major product from this reaction turned out to be hemiketal 2-54, indicating significant background reaction of the cyclobutanol substrate with the oxidant itself. Despite extensive experimentations, this relative distribution of products could not be altered/overturned. During the course of this optimization, we also observed an entirely different product, 2-57, when Selectfluor was
! 44 used as oxidant. This A-ring fragmentation product was also observed in the absence of any palladium species.
O O Me Me HO a O I O O NIS, Li CO 19 H b 2 3 19 H (85%) H H H H O [gram scale] O O O 2-44 bond a = 1.567 Å, bond b = 1.538 Å 2-59
(71% overall) TiCl4; AgOAc [gram scale]
O O O Me H2O2 Me Me O O 1. H2O2 O HO O (50% over HO O 2. SeO2 HO O O 1 H 3 steps) H 19 H 2 [C19 directed [C19 directed 5 H H epoxidation] 5 H H epoxidation] H H O [gram scale] O [gram scale] O O O 2-62 2-61 2-60 [single diastereomer] [single diastereomer]
HCl
2-62' Scheme 2-13. Oxidative fragmentation of 2-44 with NIS and synthesis of diepoxide 2-62.
Lastly, a range of electrophilic halogen reagents was screened to effect the desired oxidative fragmentation. Undesired fragmentation of the C9-C11 bond was again observed when a Suarez-type condition (PhI(OAc)2/I2) was employed. Eventually, iodide
2-59 could be obtained in excellent yield by the use of Barluenga’s reagent,26 but the cost of the reagent proved to be a substantial drawback for large-scale operations. A more economical alternative was finally realized (Scheme 2-13) by using N-iodosuccinimide as oxidant.27 This transformation is likely to proceed via the intermediacy of a transient
I HO Me O Me H O Me I H O NIS O H O O O O O H H O O H H O H H O 2-44 O 2-59 Scheme 2-14. Proposed mechanism for NIS-assisted oxidative fragmentation.
! 45 hypoiodite species, which undergoes a chemoselective homolysis of the C11-C19 bond, followed by recombination with an iodine radical (Scheme 2-14).!
Selective deketalization of C3 and hydrolysis of the C19 iodide moiety furnished enone alcohol 2-60 (Scheme 2-13), which was primed for the next series of relay events, where the C19 hydroxyl moiety would serve to facilitate the introduction of additional hydroxyl moieties on C1 and C5. In addition, we surmised that the angular disposition of the C19 hydroxyl moiety would also translate to a diastereoselective stereochemical relay to the β face of the A ring. Success was eventually realized by epoxidation of the enone moiety that–in contrast to epoxidation literature on simpler C19 methyl substrates28– proceeded with complete facial selectivity, likely through the formation of a hydrogen- bonding network under the protic conditions of the reaction. Dehydrogenation of the C1-
29 C2 bond necessitated the use of selenium dioxide, as the use of IBX or HIO3 led to formation of over-oxidized products (Scheme 2-15). Lastly, another iteration of a directed epoxidation event provided diepoxide 2-62 in good yield. Facial selectivity of the two epoxidation events was confirmed by X-ray analysis after deketalization.
O O O Me Me Me O IBX O O HO O O O O O H or HIO3 H H + H H H H H H O O O O O O 2-63 2-64 2-65 Scheme 2-15. Attempted dehydrogenation of 2-63 with IBX or HIO3.
2.6. Diepoxide fragmentation and synthesis of protected ouabageninone
Reductive opening of diepoxide 2-62 proved to be the most difficult transformation to secure. A gamut of conditions30 was surveyed (Table 2-1), only to give a mixture of A
! 46 Me O Me O Me O Me O HO O HO O HO O HO O O reagent O O O O H HO H H HO H
H H H H H H H H O O O O O OH OH 2-62 2-66 2-67 2-68 Table 2-1. Reagent screening for diepoxide fragmentation.
Reagent Product(s)
PhSeNa 2-67 + 2-68 NaTeH 2-67 + 2-68 NaI/NaOAc/HOAc (no reaction) Zn/MeOH 2-67 + 2-68
SmI2 2-67 + 2-68 Li/naphthalene 2-67 + 2-68 Mg/MeOH (no reaction)
N2H4 (no reaction) Cr(OAc)2 (decomposition) ring enones as products. Hydrogenation condition (Scheme 2-16), despite multiple precedents by Porco,31 led to only reduction of the C3 ketone while leaving the two epoxides intact. The free hydroxyl group was protected as the acetate, in the hope of altering the outcome of the reaction. Subjecting acetate 2-71 to hydrogenation conditions, however, led to little improvement in the outcome of the reaction.
Me O Me O Me O O H2, O O HO O Pt/C HO O HO O O H O H O H + H H EtOAc H H H H O HO HO O 2-62 O 2-69 (40%) O 2-70 (48%)
Ac O, 2 quant. pyr
O O Me Me Me O O O AcO H2, AcO AcO O O Pt/C O O O H O H HO H
H H H H H H O HO O O 2-71 O OH 2-72 2-73, not observed Scheme 2-16. Attempted hydrogenation of diepoxide 2-62 and its acetate derivative, 2-71.
Gratifyingly, triol 2-66 was accessible via treatment of 2-62 with in situ generated aluminum amalgam. Preliminary trials of the use of this reagent in a mixture of organic solvent and water (Table 2-2) were beset by unsatisfactory conversion and observation of
! 47 partial reduction of the epoxides (only one epoxide was cleaved, and the other remained intact, compound 2-74). After extensive optimization, we found that the use of ‘on-water’ conditions32 was critical to obtaining satisfactory yield of triol 2-66. Specifically, a saturated NaHCO3 solution was found to be the optimal medium for this transformation.
In addition, we observed formation of over-reduced product 2-75, suggesting that this aqueous medium provided a higher reduction potential for the reagent than conventional organic solvents.
O O O O Me Al-Hg, Me Me Me O solvent, O O O HO O HO O HO O HO O O H 0 ºC HO H O H HO H
H H H H H H H H O O O HO O OH OH OH 2-62 2-66 2-74 2-75 Table 2-2. Solvent screen for diepoxide fragmentation (Al-Hg added in one portion).
Solvent 2-66 yield (%)
THF:EtOH:sat. NaHCO3 (2:1:0.15) 15 THF:EtOH (2:1) 0
EtOH:sat. NaHCO3 (1:0.15) <5 sat. NaHCO3 51
sat. K2CO3 0 sat. NH4Cl 19 pH 7.4 buffer 41 sat. LiCl 0 sat. NaCl <10
Reduction of the C3 ketone of 2-66 in the presence of three free hydroxyl groups was attempted despite precedents8,9 of the ligating ability of the A ring of ouabain.
A Me O Me O HO O HO O PPTS, O LiBEt H O HC(OMe) HO H 3 HO H 3
H H THF, –78 ºC H H O OH O O 2-66 B 2-76 (+ other boronate isomers, NMR broadening) Et 2-76'
B OMe Me O Me O O O O O Me Me Me H O PPTS, O PPTS, O O O HO O Me O O HC(OMe) Me CO O O O H 3 HO H 2 O H O + H H H H H H O O O O 2-78 (not observed) OH OH OH 2-66 2-79 2-77 (+ other orthoesters isomers) Scheme 2-17. A) Attempted reduction of free triol 2-66; B) Outcome of attempted protection of triol 2-66.
! 48 Unsurprisingly, reduction with both NaBH4 and LiBEt3H afforded a mixture of compounds (presumably an intercoverting mixture of borate complexes, Scheme 2-17) that exhibit broadened NMR spectra. Nevertheless, we were able to use the isomeric mixtures from the LiBEt3H reduction to obtain the structural confirmation of the diepoxide fragmentation product and the facial selectivity of the C3 ketone reduction by recrystallization of the orthoester derivative 2-76’. This result led us to consider the introduction of an appropriate protecting group on the A ring. Attempt of tying the three hydroxyl groups as the orthoformate afforded only a mixture of incompletely protected compounds 2-77 and isomers as judged by LCMS. Gratifyingly, a clean acetonide formation could be performed on 2-66 in acidic acetone. The ketone moiety at C3 was then reduced with LiBEt3H, which effected a concomitant formation of the ethyl boronic ester33 of the two hydroxyl moieties on C1 and C5, thereby bypassing the need for an additional protection step. The desired α-configuration of the hydroxyl group at C11 could be accessed by employing a thermodynamic reduction (Li/NH3). Last, mild deketalization of C17 set the stage for the final redox-relay event (Scheme 2-18).
Me O Me O 1. Li, NH Me O Me Me Me Me 3 Me OH Me 11 11 2. PPTS, O O O O O 17 O LiBEt3H O Me CO 11 O H O H 2 O H (69% over H H 3 5 H H 5 H H 2 steps) 3 [gram scale] O 1. TMSOTf; PdII OH O O O O B 2-79 B 2. SiO2, DIPEA Et Et (55% over 2 steps) 2-80 2-81
Me Me Me OH Me O Me OH Me O O O O2, Co(acac)2 O H 14 O H 14 15 H OH [stereocontrolled H hydration] O O (86%) O O B B Et Et 2-84 (protected 2-83 ouabageninone) Scheme 2-18. Completion of the synthesis of ouabagenin ketonic core.
! 49 The C17 ketone moiety so revealed rendered the C15-C16 methylene subunits amenable to dehydrogenation to furnish the conjugated enone. Initial attempts at olefin isomerization on this enone,34 however were hampered by low conversion and significant epimerization of the C14 stereocenter, which represented a dead end because this epimer could not be converted to 2-83. In a case of fortuitous happenstance, we found that the use of fluorinated solvents, in particular perfluorotoluene, aided the conversion to 2-83, while suppressing the epimerization of the C14 center (Table 2-3). Formation of π-π complexes has been suggested35 in the observed catalyst activity enhancement of olefin metathesis in fluorinated aromatic solvents, and this phenomenon between perfluorotoluene and our enone system could also play a role in the rate enhancement of our isomerization reaction, although other effects–such as dielectric constant and silicon- fluorine interactions–cannot be ruled out.
Me Me Me Me OH Me O Me OH Me O Me OH Me O 17 17 O 11 SiO , DIPEA O O 11 O H 2 O H O H 14 15 H H H H H
O O O O O O B B B Et Et Et 2-82 2-83 2-85 Table 2-3. Solvent screen for olefin isomerization of 2-82.
Solvent 2-82 2-83 2-85
EtOAc 1 1.1 0.1 PhF 1 6 1.4
PhCF3 1 7.5 2
C7F8 1 8.7 0.6
Mukaiyama hydration of the resulting olefin,35 although straightforward, necessitated the use of dioxane as solvent to obtain a satisfactory diastereomeric ratio of hydration products (dr = 8:1, in favor of 2-84). Success of this transformation marked the
! 50 completion of strategically protected ouabageninone, the ketonic core of the target molecule that would enable not only the synthesis of ouabagenin but also the versatile access to analogs varied at C17, as well as the related bufadienolide family of natural products. As a testament to the scalability of this 15-step sequence (full sequence is provided as Scheme 2-19), >500 mg of this moelecule has been synthesized to date.
+ O O O A H , Me Me Me OH HO a O O 11 HO I O O NIS, Li CO (81%) 19 H C 2 3 19 H 19Me H b B hν (85%) H H H H H H (68%+ O [gram scale] O 12% O recovered sm) O O adrenosterone (2-38) [solid state] 2-44 bond a = 1.567 Å, bond b = 1.538 Å 2-59 [gram scale] PhI(OAc)2 = bond "b" cleavage; NIS = bond "a" cleavage (71% overall) [reagent controlled chemo- and regioselective C-C fragmentation] D TiCl4; AgOAc [gram scale]
O O O O Me Me G H2O2 Me Me O O O E H O O HO O HO O (50% over HO O 2 2 HO O H Al-Hg, H2O F SeO HO 1 H O 1 H 3 steps) H 2 19 H (56%) 2 [C19 directed [C19 directed H H H H H H H H 5 ["on-water"] 5 epoxidation] 5 epoxidation] O [gram scale] O [gram scale] O [gram scale] O OH O O 2-66 2-62 2-61 2-60 [single diastereomer] [single diastereomer] I PPTS, (63% over Me2CO 2 steps) J LiBEt3H [gram scale] P HCl 2-62' Me O K Li, NH Me O Me O Me O Me Me 3 Me OH Me M TMSOTf; PdII Me OH Me Me OH Me O 11 L PPTS, 17 O O O 11 O O O , Co(acac) O Me2CO N SiO2, DIPEA 2 2 O H O H O H O H 14 F F 14 (69% over 15 H H H H H [stereocontrolled H OH 5 2 steps) F3C F 3 hydration] [gram scale] (PFT) O O O O F F O O (86%) O O B B essential additive B [15 steps overall] B (55% over 2 steps) Et Et Et [8 column purifications] Et 2-80 2-81 [gram scale] 2-83 [600 mg of 16 prepared] 2-84 (protected ouabageninone) Scheme 2-19. Final route for the synthesis of protected ouabageninone (2-84).
2.7. Model study development for butenolide attachment
With a scalable route to ouabageninone secured, attention turned to the introduction of the butenolide moiety in the right stereochemical orientation. To that end, a model study employing estrone as starting material was conducted. Using a similar route to
Scheme 2-19, the tertiary hydroxyl group at C14 was introduced (Scheme 2-20). It was first envisioned that the butenolide moiety would be appended via a palladium cross- coupling with the appropriate coupling partner, followed by a chemo- and
! 51 diastereoselective reduction of the C14-C15 olefin. Thus, ketone 2-86 was first converted to the corresponding vinyl iodide using Barton’s protocol.36 A gamut of conditions was tried for the butenolide attachment, but initial results were discouraging as our desired product could only be obtained in a very poor yield (Table 2-4). In fact, a lot of the protocols screened gave only decomposition of the starting materials. Eventually it was found that the use of Furstner’s modification37 of the Stille coupling led to the formation of dienoate 2-89 in a synthetically-useful yield.
Me O Me O Me O Me I 1. TMSOTf; O2, PhSiH3, N2H4; Pd(OAc) 2 Co(acac)2 I2, Et3N H H H H
2. SiO2, H H DIPEA H H OH H OH MeO MeO MeO MeO 2-31 2-85 2-86 2-87
O
Stille coupling O (See table 2-4) Table 2-4. Optimization of Pd coupling reaction. X
2-88; X = SnBu3 Condition X Result 2-88'; X = H
1. Pd(PPh3)4, LiCl, CuCl SnBu3 Decomposition O O 2. Pd dba , PFur , 50 ºC SnBu Decomposition 2 3 3 3 O O º H Dimerization 3. Pd(OAc)2, KOAc, 80 C SnBu Decomposition Me Me 4. PdCl2(MeCN)2, DMF, heat 3 Ra-Ni, SnBu Decomposition THF 5. PdCl2(PPh3)4, toluene, heat 3 H H
6. CuTC, NMP SnBu3 ca. 5% desired product H OH H OH 7. Pd(PPh3)4, CuTC, Ph2P(O)ONBu4 SnBu3 55% desired product MeO MeO 2-90 2-89 Scheme 2-20. Synthesis of estrone model system using Stille coupling and its dienoate reduction.
With sufficient quantities of 2-89 in hand, chemoselective reduction of the C16-C17 olefin was attempted. No reaction was observed when palladium on carbon was used as catalyst for hydrogenation. Turning to the more active platinum catalyst, however, led to a nonselective hydrogenation of the two olefins. A chemoselective hydrogenation could eventually be effected by using Ra-Ni,38 but this led to the wrong stereochemical outcome of the reaction (Scheme 2-20). This result stood in stark contrast to hydrogenation conducted on steroids possessing a more conventional trans C/D ring juncture, where reduction from the a face is typically observed. Clearly, the cis
! 52 configuration of 2-89 rendered its convex face more accessible for hydrogenation.
Alternatively, a directing effect of the C14 hydroxyl group could also be invoked to explain the stereochemical outcome. A radical-based method39 employing iodide 2-91 and lactones 2-88, 2-92 and 2-93 was also attempted but only deiodination of 2-91 was observed as the outcome of the reaction (Scheme 2-21).
O O O
Me I I O O , N H , Me Me 2 2 4 X EtCO2H H H H
H OH H OH 2-88; X = SnBu3 H OH MeO 2-92; X = SPh MeO 2-93; X = Br MeO 2-87 2-91 2-94 Scheme 2-21. Preparation of alkyl iodide 2-91 and attempted radical and nickel cross-coupling reactions.
It was then posited that this stereochemical outcome could be rectified if one were to use a butenolide anion equivalent to effect a nucleophilic addition onto the C17 carbon from the more accessible β-face. A hydrazone-boronic acid coupling protocol disclosed by Barluenga40 in 2009 was viewed as a highly attractive option owing to the minimal number of concession steps that would need to be performed either before or after the coupling, and thus, the potential brevity of the overall sequence. A C2-substituted furanboronic acid 2-97 was identified as a suitable butenolide equivalent (Scheme 2-22) and this compound could be accessed by first protecting the free boronic acid as the pinacol ester, followed by an iridium-catalyzed C-H silylation41 employing a procedure developed by Falck and co-workers. Lastly, treatment with NaIO4 removed the pinacol ester to unmask the free boronic acid.42 Gratifyingly, coupling of this boronic acid and the tosyl-hydrazone 2-98 proceeded with the right diastereoselectivity, albeit in modest yield. Conversion of the substituted furan moiety to butenolide could be readily achieved by treatment with basic AcOOH solution.43 It is worth noting that in the absence of the
! 53 hydroxyl group at C14, a 1,2-shift of the C18 methyl group was observed as the sole product of the reaction and no coupled product could be detected (vide infra).
[Ir(OMe)(cod)]2, PhMe SiH, Bpin 2 Bpin NaIO4, B(OH) norbornene, dtbpy HCl 2 PhMe2Si O (43%) PhMe Si PhMe Si O 2 O 2 O O O 2-95 2-96 2-97 K2CO3, Δ AcOOH, Me KOAc Me O NHTs Me Me N (ca. 20%) TsNHNH2 H (ca. 70%) H H H H OH H OH (64%) MeO H OH H OH MeO MeO MeO 2-99 2-94 2-86 2-98 Scheme 2-22. Preparation of furan derivative 2-97 via C-H activation, its use in hydrazone-boronic acid cross-coupling and competion of estrone model system.
2.8. Back to the real system
With methodology for accessing the β-oriented butenolide moiety secured, efforts were devoted to its application to the real system (Scheme 2-23). The first hurdle was encountered in the preparation of the corresponding tosylhydrazone from ouabageninone: concomitant deprotection of all the protecting groups was observed (on LCMS) upon conversion to hydrazone 2-100. This problem was rectified by the use of TrisNHNH2 which could effect the hydrazone formation at ambient temperature (Scheme 2-23B).
Submitting this hydrazone to the Barluenga coupling condition with boronic acid 2-97, however, led to formation of complex mixture of products, none of which could be identified as the desired coupled product. Positing that the two free hydroxyl groups were incompatible with the transient diazo species generated, their global protection to the corresponding TMS ether was undertaken. Subjection of this TMS-protected hydrazone to the coupling reaction condition led to the formation of a major product which possessed both the steroidal core and the furan moiety as judged by NMR spectroscopy.
! 54 However, comparison of this NMR data with that of the model system revealed some peculiar details: the C18 methyl group, which showed up at 0.74 ppm in the model system (upfield shifted due to the shielding effect of the furan ring), showed at 1.71 ppm in the real system. In addition, the benzylic triplet at 2.52 ppm assigned to the C17 methine proton in the model system was notably absent in this coupled product. Tentative structure 2-103 was proposed for this coupled product.
A Me O Me OH Me NHTs O OH Me N O H HO TsNHNH2 HO H H OH dioxane, 80 ºC H OH O O HO B OH Et 2-84 2-100 (LCMS) SiMe2Ph B
Me Me NHTris O Me OH Me O Me OH Me N O O (HO)2B O H O H TrisNHNH K2CO3 2 complex mixture H OH H OH of products CH2Cl2, dioxane, rt 110 ºC O O O O B B 2-101 2-84 (80%) Et Et TMSOTf, Et3N SiMe2Ph PhMe2Si PhMe2Si Me NHTris O singlet, O Me TMSO Me N O 0.74 ppm O Me (HO)2B OH OH Me O H Me K2CO3 O Me triplet, O H H H OTMS 2.52 ppm dioxane, 110 ºC H OTMS H OH O O B 2-99 2-102 (ca. 50% MeO over 2 steps) O O Et B 2-103 singlet, 1.71 ppm no allylic triplet Et
C PhMe2Si Me Me O Me OH Me O Me OR Me O O O Me O H O H Me OR Me O H OH H OH O H
O O O O H OH B B 2-104a, R = Ac O O Et 2-84 Et 2-104b, R = MOM B 2-105 Et Scheme 2-23. Attempts at effecting hydrazone-boronic acid coupling on protected ouabageninone.
A plausible mechanism for the formation of 2-103 is outlined in Scheme 2-24.
Exploring other options for protecting group of the hydroxyl moieties, the C11 hydroxyl group was converted to its corresponding acetate 2-104a (Scheme 2-23C), and MOM
! 55 PhMe2Si PhMe2Si Me O O Me TMSO Me N2 O Me Me O H Me TMSO Me Me TMSO Me OH O O B(OH)2 B O H O H OH H OTMS X
O O H OTMS H OTMS B O O O O Et B B Et Et
PhMe2Si PhMe2Si O H O H O Me Me Me OH OH Me TMSO Me O Me O O O H O H X B after OH H OTMS TMS H OTMS hydrolysis O O O O B 2-103 B Et Et Scheme 2-24. Proposed mechanism for the formation of 2-103. ether 2-104b respectively. Subjection of both compounds to the Barluenga coupling condition led again to formation of complex mixture of products and none could be identified as the desired coupled product. Several additives, notably fluoride salts, were tried, but led to no improvement.44
O
O Me Me Me OH Me O Me OH Me O 17 O 17 O H O H 16 A N2H4; I2, Et3N H OH H OH B 17, CuTC, Pd(PPh ) O O 3 4 O O B (42% over B 2-84 2-106 Et 2 steps) Et
via O C [Co2B] D Me2N O O NtBu Me N Me 2 O (70% over 2 steps) Bu3Sn 2-88 O O OH 2-107 O O Me Me OH Me OH Me E HCl O 17 HO O H HO H (90%) H OH H OH HO O O OH B ouabagenin (2-1) Et 2-108 Scheme 2-25. Completion of the synthesis of ouabagenin (2-1).
! 56 2.9. Reinventing your exit
O O O O
O O O O Me Me Me Me Me OH Me Me OH Me Me OH Me Me OH Me O O O O O H O H O H O H
H OH H OH H OH H OH
O O O O O O O O B B B B Et 2-106 Et 2-109 Et 2-110 Et 2-107 Table 2-5. Screening of reduction condition on dienoate 2-106. Conditions Product(s) Conditions Product(s) NiCl2-NaBH4 2-107 + 2-110 Crabtree 2-110 Mg/MeOH (decomposition) Wilkinson's 2-110 CoCl2-NaBH4 2-107 N2H2 (no reaction) Zn, NiCl2 (no reaction) SmI2/H2O 2-109 + 2-110 Na/HMPA (decomposition)
O O O
O O O Me Me OH Me Me Me OH Me Me Me OH Me O base O O O H O H O H
H OH H OH H OH
O O O O O O B B B 2-107 2-108 2-110 Et Et Et
Table 2-6. Screening of bases for olefin isomerization of 2-107. Conditions 2-108 : 2-110 Conditions 2-108 : 2-110 BTMG, PhCF3 1:1.7 DBU, C6D6 1:4 Verkade's base (decomposition) AcOH, CDCl3 (no reaction) Proton Sponge, C6H6 (no reaction) BEMP, C6D6 1:11 TMG, C6H6 0:1 BTMG, C6D6 1:1.3 BTMG, MeCN 0:1 Schwesinger P1, C6D6 1:4.2 BTMG, C6H6, 80 ºC 2.5:1 TBD, C6D6 1:3.8 BTMG, C H , 100 ºC 3:1 6 6
Eventually, we decided to reinvestigate the Stille coupling/chemoselective reduction route (Scheme 2-25). Thus, ketone 2-84 was converted to the corresponding vinyl iodide using Barton’s protocol and then subjected to the Still cross-coupling conditions described in Section 2.7 to deliver dienoate 2-106. As observed previously in the model
! 57 system, direct reduction of the C16-C17 olefin of 2-106 turned out to be formidable because many conditions tried led to undesired outcomes (Table 2-5).
This problem was circumvented by first treating dienoate 2-106 with in situ generated
45 Co2B to afford exclusively tetrasubstituted olefin 2-107 (no reduction of C16-C17 or butenolide moiety was observed). A myriad of bases were tried to isomerize this olefin
(Table 2-6), only to produce the wrong stereochemistry of the newly generated chiral center at C17. While stirring 2-107 in the presence of Barton’s base46 gave predominantly the undesired epimer, it was found (serendipitously, yet again) that at elevated temperature, enoate 2-108 could be accessed with a predominantly correct disposition of the butenolide moiety (dr = 3:1). Lastly, unmasking of all the hydroxyl groups under acidic condition delivered synthetic ouabagenin (2-1).
2.10. Conclusion and future direction
Salient features of the current route include: (i) the application of a solid-state Norrish type II photochemistry in natural product synthesis; (ii) chemoselective cyclobutanol fragmentation using an inexpensive reagent, N-iodosuccinimide; (iii) implementation of an ‘on-water’ epoxide fragmentation; (iv) a remarkably selective olefin isomerization promoted by fluorous media; (v) a highly-diastereoselective Mukaiyama hydration to furnish the requisite cis C/D ring junction; (vi) a chemoselective dienoate reduction with
Co2B; and (vii) robustness and scalability of the route in an academic setting (20 steps from adrenosterone, 0.56% overall yield, 77% average yield per step). Despite being a semisynthetic approach, this route is amenable to scaffold diversification: preliminary
! 58 A Me Me Me OH Me O Me OH Me O O Fe2(ox)3, O O H Selectfluor, O H NaBH4 H H F 51% O O O O B B Et 2-83 Et 2-111 O B O via O OH Me Me Me 19 Me H 14 Me H
H OH H H H OH HO O H •15 steps; • 7-step digitoxigenin installation testosterone of C14-OH (indirect Me functionalization) Me O N OH via O Me AcO Me Me HO O Me Me H O
O H H HO Br O H batrachotoxinin A • >40 steps; • 6-step 11-oxo-progesterone installation O of C14-OH (indirect functionalization) O via O Me Me Me HO O H Me H AcO Br H OH H H • 24 steps; • 8-step HO installation of C14 AcO OH strophanthidol and C19-OH (indirect pregnenolone acetate O functionalization)
O
via O OH Me O Me Me O 11 HO 17 HO H 19 Me H 14 H OH H H HO • 20 steps; O OH • 3-step installation adrenosterone (2-38) ouabagenin (2-1) of C14-OH; = redox "donor" [concise synthesis achieved • 2-step installation through redox-relay] of C19-OH = redox "acceptor" Figure 2-4. A) Radical fluorination of 2-83; B) Comparison with previous semisynthesis efforts. studies suggest that opposite stereochemistry of both the C3 and C11 centers is readily accessible in a controlled fashion; the isolated olefin on 2-83 affords a platform for versatile functionalizations, including the introduction of heteroatoms, such as fluorine, via radical-based methods47 (showcased in Fig. 2-4); lastly, the late-stage Stille coupling
! 59 represents yet another potential point of diversification by way of attachment of different heterocyclic domains at C17.
The synthesis of the highly oxidized natural product ouabagenin represented a proof of concept for the development of a retrosynthetic strategy centered solely upon the synergistic union of redox and stereochemical relays. As illustrated in figure 2-4, previous approaches to the semisynthesis of cardenolides48 and related steroids
(batrachotoxin49) used indirect means to install crucial oxidized functionality at C19 and
C14. In all three cases, this resulted in lengthy routes, compromising both the brevity and scalability of the syntheses. In contrast, by using a transform-based approach to “look ahead”,50 the C11 and C17 ketones were viewed as “redox donors” for the requisite oxidations at C19 and C14, respectively. This logic enabled a dramatic increase of complexity to be imparted on a minimally oxidized, readily available steroid. In a similar vein to synthesis designs predicated on minimizing protecting group chemistry51 or maximizing aspects of synthesis economy,52 the primary purpose of this work was to generate opportunities to innovate. Although the ouabagenin case study reported here is only a singular example, we anticipate that syntheses that incorporate such a strategic interplay will result in more efficient routes and inspire the invention of new methods.
As an extension of this work, we are currently applying some of the methodologies developed in this campaign for the preparation of C19-hydroxylated analogs of corticosteroid drugs (Figure 2-5).53 Interest in these analogs stemmed from the prevalent use of the corticosteroid drugs for the treatment of various skin disorders and the desire to explore the pharmacological effect of substituents present at the C19 carbon. The outcome of this on-going investigation will be reported in due course.
! 60 R5 Cl HO HO O O O O O R3 Me O O Pr 4 Me Me Me HO R HO HO HO O OH O Me H Me H Me H Me Me H Cl H F H H H R1 R2 O O O novel corticosteroid analog mometasone furoate betamethasone budesonide Et O O Cl AcO Cl O O O O O Me O Me Me Me Me O Me Me O Me HO Et HO Et HO HO O O O O Me H Me H Me H Me H Me Me H H Cl H H H F H F H O O O O F beclometasone dipropionate clobetasol propionate fluocinonide halcinonide Figure 2-5. Selected examples of semisynthetic corticosteroids.
Position Effect(s)
OH C11 Converting ketone to β-OH provided topical activity unknown O pharmacophore 21 C9 Fluorine increased potency but also increased sodium retention Me O 11 (mineralocorticoid activity) 17 OH 1 Me H 9 16 C6 Fluorine increased potency 2 H H C16, C17 Acetonide moiety provided increased penetrability and enhanced percutaneous absorption. C16-methyl increased anti-inflammatory O 6 activity while eliminating sodium retention effect of C9-F H C1,2 Presence of double bond increased activity
C21 Esterification resulted in increased resistance to metabolic breakdown Table 2-7. Effects of functional groups (by functional groups in approximate chronological sequence of development).
2.11. Distribution of credit
The synthesis plan as outlined in figures 2-2 and 2-3 was designed by Phil and I in
2009. I was solely responsible for the initial exploratory work on the porphyrin-catalyzed oxidation of steroid skeletons while the estrone functionalization efforts were conducted together with Dr. Georg Manolikakes (Georg) and Dr. Hiroki Shigehisa (Hiro) as part of their exploratory work for an improved synthesis of cortistatin A. The key crystal structure for compound 2-28 was obtained by Hiro. I developed the final route as outlined
! 61 in Scheme 2-19, and was responsible for most of the inventions as described in the first paragraph of section 2.9. Dr. Qianghui Zhou (Qianghui) joined the project towards the end of 2011 and was responsible for some of the reoptimization work for the chemistry described in Scheme 2-13 as well as optimization work on the hydrazone-boronic acid coupling step for the estrone model system. Lastly, Qianghui and Rohan Merchant were responsible for the development of novel corticosteroid analogs.
2.12. References
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! 66 2.13. Supplementary Information
General procedures. All reactions were carried out under a nitrogen atmosphere with dry solvents using anhydrous conditions unless otherwise stated. Dry diethyl ether
(Et2O), dichloromethane (CH2Cl2), acetonitrile (CH3CN), toluene (PhMe), N,N- dimethylformamide (DMF), tetrahydrofuran (THF), methanol (MeOH) and triethylamine
(Et3N) were obtained by passing these previously degassed solvents through activated alumina columns. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials, unless otherwise stated.
Reactions were monitored by thin layer chromatography (TLC) carried out on 0.25 mm
E. Merck silica gel plates (60F-254) using UV light as the visualizing agent and an acidic mixture of anisaldehyde, phosphomolybdic acid, or ceric ammonium molybdate, or basic aqueous potassium permangante (KMnO4), and heat as developing agents. E. Merck silica gel (60, particle size 0.043–0.063 mm) was used for flash column chromatography.
Preparative thin layer chromatography (PTLC) separations were carried out on 0.25 or
0.5 mm E. Merck silica gel plates (60F-254). NMR spectra were recorded on Bruker
DRX-600, DRX-500, and AMX-400 instruments and calibrated using residual
1 undeuterated solvent as an internal reference (CHCl3 @ 7.26 ppm H NMR, 77.16 ppm
13C NMR). The following abbreviations (or combinations thereof) were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad. High-resolution mass spectra (HRMS) were recorded on Agilent LC/MSD TOF time-of-flight mass spectrometer by electrospray ionization time of flight reflectron experiments. IR spectra were recorded on a Perkin Elmer Spectrum BX FTIR
! 67 spectrometer. Melting points were recorded on a Fisher-Johns 12-144 melting point apparatus and are uncorrected.
Experimental Procedures
Adrenosterone Preparation: To a solution of cortisone acetate (20.0 g, 49.7 mmol) in
1:1 DCM:EtOH (320 mL) at 0 ºC was added NaBH4 (564 mg, 14.91 mmol, 0.3 eq). After
45 min, additional portion of NaBH4 (282 mg) was added. After another 45 min, one final portion of NaBH4 (282 mg) was added. A mixture of acetone:water (1:1, 160 mL) was added after another 45 min and the mixture was warmed to ambient temperature, followed by addition of NaIO4 (53.2 g, 248.5 mmol, 5 eq) over 5 mins. The resulting white slurry was stirred overnight and then filtered through Celite and evaporated until the majority of DCM, EtOH and acetone had been removed to provide suspension of off- white solid in water. Water (ca. 400 mL) was added to this mixture. Following vacuum filtration and washing with Et2O (300 mL), an off-white solid (12.8 g, 86%) was collected that was sufficiently pure for the next step.
Ketalization Procedure: To a solution of adrenosterone (12.8 g, 42.6 mmol) in toluene
(530 mL) was added ethylene glycol (70 mL) and p-TsOH.H2O (0.81 g, 4.26 mmol, 0.1 equiv). The reaction vessel was incorporated into a standard Dean-Stark setup and immersed in an oil bath preheated to 140 ºC and stirred vigorously. After 6 hours, the reaction was lifted out of the oil bath and allowed to cool. The layers were allowed to settle and the ethylene glycol was separated from the organic layer; the latter was neutralized with sat. aq. NaHCO3 (100 mL) and the aqueous portion was extracted with
EtOAc (3 x 100 mL). The organic portions were combined, washed with sat. aq. NaCl
! 68 (150 mL), dried over MgSO4 and concentrated. Recrystallization of the crude product by boiling in 10:1 Et2O:EtOAc (ca. 450 mL), followed by cooling at 4 ºC furnished the known ketal compound 2-43 (13.4 g, 81%) after three cycles.
Cyclobutanol 2-44:
A. Photolysis in Ethanol
Diketal 2-43 (5.00 g, 12.87 mmol) was dissolved in dry ethanol (1.0 L), transferred to a photoreactor [ACE glass, 1 L jacketed reaction vessel (#7841) with quartz immersion well (#7854)] and purged with argon for 15 minutes, followed by irradiation using a
450W mercury Hanovia lamp through a vycor filter for 60 h. The solution was then poured into a roundbottom flask and concentrated in vacuo. The resulting oil was purified by column chromatography (1:4 to 3:2 EtOAc:hexanes) to give 2-45 (1.90 g,
38% yield) as a clear oil and 2-44 (2.15 g, 43% yield) as a white solid.
B. Solid-State Photolysis of Crystal Suspension
Crystals of diketal 2-43 (2.00 g, 5.15 mmol, grown as described in the ketalization procedure) and sodium dodecyl sulfate (SDS) (1.0 g) were transferred to a photoreactor with quartz immersion well. Degassed water (1.0 L, purged with argon) was then added followed by irradiation using a 450W mercury Hanovia lamp through a vycor filter for
120 h. The mixture was poured into a separatory funnel and extracted with EtOAc (3 x
150 mL). The combined organic layer was then washed with brine (250 mL), dried over
MgSO4, filtered through a pad of silica to remove any remaining SDS and concentrated
! 69 in vacuo. The resulting yellow oil was purified as described above to give recovered 2-43
(0.24 g, 12%) and 2-44 (1.36 g, 68%) as a white solid.
Physical state: white solid; (m.p. 190 ºC);
Rf = 0.34 (silica gel, 3:2 EtOAc:hexanes);
[α]D = +14.8º (c = 1.0, CH2Cl2);
+ HRMS (m/z): calcd for C23H32O5, [M+H] , 389.2322; found, 389.2303;
IR (film) λmax = 3466, 2967, 2937, 2880, 1734, 1709, 1172, 1121, 1075, 978, 949;
1 H NMR (400 MHz, CDCl3): δ 5.61 (d, J = 6.8 Hz, 1 H), 4.02–3.71 (m, 8 H), 2.84 (dt, J
= 13.4, 3.5 Hz, 1 H), 2.47 (d, J = 11.6 Hz, 1 H), 2.21–2.09 (m, 3 H), 2.04 (dd, J = 11.7,
4.9 Hz, 1 H), 1.94 (ddd, J = 14.6, 11.5, 3.3 Hz, 1 H), 1.87–1.77 (m, 2 H), 1.76–1.65 (m, 4
H), 1.61 (d, J = 14.0 Hz, 1 H), 1.58–1.25 (m, 5 H), 0.97 (s, 3 H).
13 C NMR(CDCl3, 101 MHz): δ141.3, 125.9, 119.0, 109.6, 77.0, 65.1, 64.7, 64.5, 64.4,
57.3, 49.6, 45.0, 44.3, 42.6, 42.4, 41.8, 38.7, 34.7, 34.6, 32.1, 27.1, 20.8, 17.1.
Spectroscopic data for 2-45:
Physical state: colorless oil;
Rf = (silica gel, 3:2 EtOAc:hexanes);
[α]D = -8.4º (c = 1.5, CH2Cl2);
+ HRMS (m/z): calcd for C25H38O6, [M+H] , 435.2471; found, 435.2748;
IR (film) λmax = 2945, 2882, 1728, 1464, 1365, 1342, 1318, 1152, 1095, 1034;
1 H NMR (400 MHz, CDCl3): δ 5.29 (m, 1 H), 4.02 (m, 2 H), 3.94–3.74 (m, 8 H), 2.41
(d, J = 13.8 Hz, 1 H), 2.31 (d, J = 13.8 Hz, 1 H), 2.12–2.02 (m, 2 H), 2.02–1.92 (m, 2 H),
! 70 1.82–1.58 (m, 8 H), 1.48–1.33 (m, 4 H), 1.20 (t, J = 7.2 Hz, 3 H), 1.07 (s, 3 H), 1.04 (s, 3
H).
13 C NMR(CDCl3, 101 MHz): δ 172.4, 139.2, 122.0, 119.4, 109.7, 65.0, 64.4, 64.3, 63.7,
59.7, 48.8, 47.7, 44.7, 41.3, 40.6, 38.7, 34.8, 32.4, 31.5, 31.1, 31.0, 23.8, 17.2, 14.4.
Iodide 2-59: Cyclobutanol 2-44 (3.60 g, 9.26 mmol) was dissolved in toluene (180 mL,
0.05 M), followed by sequential addition of MeOH (6 mL), Li2CO3 (2.39 g, 32.41 mmol,
3.5 equiv) and NIS (6.25 g, 27.78 mmol) under Ar. The resulting suspension was irradiated with sunlamp (90 W, 6 inches from the walls of the flask) for 15 minutes.
Irradiation was then halted and the crude mixture was washed with saturated aqueous
Na2S2O3 (75 mL) until colorless. The aqueous layer was back-extracted twice with
EtOAc (2 x 125 mL) and the combined organic layer washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow oil was used for the next step without further purification. This yellow oil could also be purified by silica gel chromatography (1:4 EtOAc:hexanes) to give pure 2-59 (4.77 g, 85%) as a white soild.
Physical state: white solid (decomp. 110–115°C);
Rf = 0.42 (silica gel, 2:3 EtOAc:hexanes);
+ HRMS (m/z): calcd for C23H31IO5, [M+H] , 515.1289; found, 515.1298;
[α]D = -23.6º (c = 0.5, CH2Cl2);
IR (film) λmax = 2945, 2877, 1698, 1446, 1372, 1313, 1280, 1245, 1215, 1174, 1100,
1056;
1 H NMR (400 MHz, CDCl3): δ 5.74–5.33 (m, 1 H), 4.35 (d, J = 11.1 Hz, 1 H), 4.00–3.76
(m, 8 H), 3.62 (dd, J = 11.0, 1.4 Hz, 1 H), 2.83 (qd, J = 10.8, 5.2 Hz, 1 H), 2.62 (dd, J =
! 71 13.9, 4.5, 2.8 Hz, 1 H), 2.61 (dd, J = 13.6, 1.2 Hz, 1 H), 2.41 (dq, J = 14.1, 2.8 Hz, 1 H),
2.25 (td, J = 5.4, 2.7 Hz, 1 H), 2.16 (dd, J = 13.9, 2.4 Hz, 2 H), 2.09–2.00 (m, 2 H), 1.96–
1.75 (m, 5 H), 1.62 (ddt, J = 14.3, 4.3, 2.8 Hz, 1 H), 1.47–1.32 (m, 2 H), 0.95 (s, 3 H).
13 C NMR(CDCl3, 101 MHz): δ 211.4, 137.9, 124.0, 118.0, 108.5, 65.5, 64.7, 64.6, 64.5,
60.8, 50.2, 50.0, 48.8, 41.6, 39.6, 35.6, 34.4, 33.7, 31.4, 31.1, 22.5, 15.9, 10.0.
Enone 2-60: Crude iodide 2-59 was dissolved in CH2Cl2 (180 mL). After cooling to –10
ºC, a solution of 1 M TiCl4 in CH2Cl2 (9.26 mL, 9.26 mmol) was added dropwise, at which point, the solution turned dark red. After 20 minutes, the reaction was quenched with sat. aq. NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (2 x 75 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo.
The resulting oil was dissolved in THF (180 mL), followed by sequential addition of H2O
(9 mL) and AgOAc ( 2.32 g, 13.89 mmol, 1.5 eq). The resulting mixture was heated to 50
ºC for 2 h. The reaction was cooled to room temperature, diluted with EtOAc (75 mL), filtered through a pad of celite and concentrated in vacuo. The yellow oil was purified by silica gel chromatography (3:7 to 3:2 EtOAc:hexanes) to give enone 2-60 (2.00 g, 60% over 3 steps) as a white solid.
Physical state: white solid (m.p. 155–157°C);
Rf = 0.25 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C21H28O5, [M+H] , 361.2009; found, 361.2000;
[α]D = +106º (c = 1.0, CH2Cl2);
IR (film) λmax: 3346, 2974, 2935, 2894, 1698, 1664, 1617, 1169, 1157, 1047, 1041;
! 72 1 H NMR (400 MHz, CDCl3): δ 5.79 (s, 1 H), 4.17 (dd, J = 11.7, 2.3 Hz, 1 H), 4.03 –
3.77 (m, 4 H), 3.74 (dd, J = 11.7, 8.7 Hz, 1 H), 2.84 – 2.71 (m, 2 H), 2.84 – 2.71 (m, 2H),
2.38 – 2.20 (m, 4 H), 2.14 (d, J = 11.8 Hz, 1 H), 2.10 – 1.88 (m, 5 H), 1.86 – 1.77 (m, 1
H), 1.58 (td, J = 13.9, 4.4 Hz, 1 H), 1.38 (tt, J = 12.1, 5.9 Hz, 1 H), 1.31 – 1.15 (m, 1H),
0.84 (s, 3 H).
13 C NMR(CDCl3, 101 MHz): δ 214.0, 199.7, 165.5, 125.6, 117.4, 65.6, 64.7, 64.3, 64.3,
50.1, 49.9, 49.5, 43.4, 38.4, 34.4, 34.4, 32.9, 31.7, 31.4, 22.1, 14.9.
Enone 2-61: Enone alcohol 2-60 (2.00 g, 5.55 mmol) was dissolved in MeOH (56 mL,
0.1 M) and cooled to 0 ºC. 10% NaOH solution (2.0 mL, 1 equiv) was added, followed by 35% H2O2 (2.84 mL, 6 equiv, added in 3 portions in 25 min intervals). The reaction was diluted with EtOAc (75 mL) and quenched with sat. Na2S2O3 (75 mL) at 0 ºC. After warming to room temperature, H2O was added to dissolve the white precipitate that was formed upon quenching. The aqueous layer was extracted with EtOAc (2 x 125 mL) and the combined organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The resulting off-white foam was used for the next step without further purification.
Physical state: foam;
Rf = 0.38 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C21H28O6, [M+H] , 377.1959; found, 377.1971;
[α]D = +102º (c = 1.0, CH2Cl2);
IR (film) λmax: 3465, 2946, 2879, 1701, 1166, 1100, 1052, 1038;
! 73 1 H NMR (400 MHz, CDCl3): δ 4.22 (dd, J = 11.4, 2.5 Hz, 1 H), 4.07 – 3.66 (m, 4 H),
3.41 (dd, J = 8.9, 3.0 Hz, 1 H), 2.92 (s, 1 H), 2.72 (dt, J = 11.6, 1.1 Hz, 1 H), 2.41 (dt, J =
18.8, 3.7 Hz, 1 H), 2.35 (d, J = 10.3 Hz, 1 H), 2.21 – 1.88 (m, 10 H), 1.85 – 1.72 (m, 1
H), 1.43 – 1.20 (m, 2 H), 1.14 (ddd, J = 13.4, 4.2, 2.5 Hz, 1 H), 0.83 (s, 3 H).
13 C NMR(CDCl3, 101 MHz): δ 213.1, 205.7, 117.3, 68.9, 65.6, 64.8, 64.7, 61.7, 57.7,
50.4, 49.7, 49.5, 41.0, 37.6, 34.3, 32.5, 30.3, 29.5, 22.1, 21.1, 15.0.
The above epoxide (epoxidation yield assumed to be quantitative) was dissolved in PhCl
(56 mL), followed by the addition of SeO2 (678 mg, 6.11 mmol, 1.1 eq) and heating to 90
ºC for 12 h. The reaction was cooled to room temperature and neutralized with solid
NaHCO3 (1.90 g), followed by MgSO4 (2.40 g). The dark brown suspension thus obtained was filtered through a pad of celite and concentrated in vacuo. The resulting brown oil (2-61) was used for the next step without further purification. This brown oil could be purified by silica gel chromatography (2:3 to 1:1 EtOAc:hexanes) to give a pale yellow foam for characterization purposes.
Physical state: foam;
Rf = 0.38 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C21H26O6, [M+H] , 375.1802; found, 375.1799;
IR (film) λmax: 3470, 2946, 2880, 1703, 1680, 1167, 1099, 1057, 1039, 915, 833, 732;
1 H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 10.8 Hz, 1 H), 5.94 (dd, J = 10.8, 2.0 Hz, 1
H), 4.43 (dd, J = 11.2, 6.3 Hz, 1 H), 4.17 (dd, J = 11.2, 5.8 Hz, 1 H), 3.96–3.76 (m, 4 H),
3.16 (d, J = 2.0 Hz, 1 H), 2.63 (td, J = 12.4, 1.1 Hz, 1 H), 2.60 (t, J = 6.2 Hz, 1 H), 2.35
(td, J = 14.6, 4.1 Hz, 1 H), 2.22–1.74 (m, 8 H), 1.42–1.23 (m, 3 H), 0.84 (s, 3 H).
! 74 13 C NMR(CDCl3, 151 MHz): δ 210.4, 194.8, 151.7, 125.2, 117.3, 65.6, 65.4, 64.8, 64.7,
63.2, 59.9, 49.6, 49.3, 49.1, 46.2, 37.8, 34.2, 30.1, 29.7, 22.1, 15.1.
Diepoxide 2-62: Enone 2-61 from the aforementioned reaction (assumed to be 5.55 mmol) was dissolved in MeOH (56 mL, 0.1 M) and cooled to 0 ºC. 10% NaOH solution
(2.0 mL, 1 equiv) was added, followed by 35% H2O2 (2.84 mL, 6 equiv, added in 3 portions in 25 min intervals). The reaction was diluted with EtOAc (75 mL) and quenched with sat. aq. Na2S2O3 (75 mL) at 0 ºC. After warming to room temperature,
H2O was added to dissolve the white precipitate that was formed upon quenching. The aqueous layer was extracted with EtOAc (2 x 125 mL) and the combined organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. After a short silica plug (washing with EtOAc), the resulting off-white foam (1.08 g, 50% over 3 steps) was obtained which was pure enough to be used for the next step.
Physical state: foam;
Rf = 0.28 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C21H26O7, [M+H] , 391.1751; found, 391.1769;
[α]D = +62.9º (c = 1.0, CH2Cl2);
IR (film) λmax: 3461, 2946, 2879, 1700, 1165, 1101, 1056, 915, 735;
1 H NMR (400 MHz, CDCl3): δ 4.56 (dd, J = 11.7, 3.4 Hz, 1 H), 4.30 (dd, J = 11.7, 9.2
Hz, 1 H), 4.07 (d, J = 4.0 Hz, 1 H), 3.99 – 3.77 (m, 4 H), 3.29 (dd, J = 4.0, 2.5 Hz, 1 H),
3.16 (dd, J = 9.2, 3.4 Hz, 1 H), 3.09 (d, J = 2.5 Hz, 1 H), 2.76 (d, J = 11.9 Hz, 1H), 2.24
(d, J = 1.1 Hz, 1 H), 2.24 – 2.16 (m, 1 H), 2.18 (d, J = 11.9 Hz, 1 H), 2.11 – 1.90 (m, 4
! 75 H), 1.86 – 1.74 (m, 1 H), 1.45 – 1.21 (m, 2 H), 1.07 (dt, J = 13.9, 3.3 Hz, 1 H), 0.86 (s, 3
H).
13 C NMR(CDCl3, 101 MHz): δ 211.7, 200.5, 117.2, 72.7, 65.6, 64.7, 63.2, 63.2, 61.2,
59.2, 54.8, 50.1, 49.8, 49.4, 42.1, 37.6, 34.3, 31.7, 29.9, 22.0, 15.0.
Triol 2-66: Diepoxide 2-62 (1.18 g, 2.56 mmol) was suspended in saturated NaHCO3
(350 mL) and cooled to –5 ºC. Then aluminum foil (11.0 g) was cut into small strips and immersed in 2% aqueous HgCl2 solution (540 mL) for 30 s. The aluminum strips were collected by vacuum filtration and sequentially washed with EtOH (150 mL) and Et2O
(150 mL). The strips were then added piecewise to the heterogeneous reaction mixture over 1 h period, followed by addition of THF (10 mL). After another 10 min period, the mixture was diluted with EtOAc and filtered through celite washing with EtOAc (200 mL). The aqueous layer was washed with EtOAc (2 x 75 mL) and the combined organic layer was washed with brine (100 mL) and dried over NaSO4. After filtration and concentration in vacuo, the crude product was purified by silica gel chromatography (1:1 to 1:0 EtOAc:hexanes) to give 2-66 (664 mg, 56%) as a white solid, 95 mg of recovered
2-62, and 137 mg (13%) of tetraol 2-75.
Spectroscopic data for triol 2-66:
Physical state: white solid (decomp. 120–130 °C);
Rf = 0.20 (silica gel, 4:1 EtOAc:hexanes);
+ HRMS (m/z): calcd for C21H30O7, [M+H] , 395.2064; found, 395.2065;
[α]D = +8.2º (c = 0.8, CH2Cl2);
IR (film) λmax: 3409, 2943, 2875, 1705, 1424, 1166, 1038, 908;
! 76 1 H NMR (400 MHz, CDCl3): δ 5.09 (s, 1 H), 4.87 (q, J = 3.9 Hz, 1 H), 4.58 (dd, J =
11.7, 2.9 Hz, 1 H), 4.41 (td, J = 12.1, 1.3 Hz, 1 H), 4.32 (dd, J = 3.9, 2.0 Hz, 1 H), 4.13
(dd, J = 12.5, 2.9 Hz, 1 H), 4.01–3.80 (m, 4 H), 2.92 (d, J = 15.2 Hz, 1 H), 2.81 (dt, J =
11.7, 1.0 Hz, 1 H), 2.65 (ddd, J = 15.4, 3.8, 2.4 Hz, 1 H), 2.58 (d, J = 11.0 Hz, 1 H), 2.49
(ddd, J = 15.4, 4.3, 2.0 Hz, 1 H), 2.31 (dd, J = 15.2, 2.4 Hz, 1 H), 2.19 (d, J = 11.7 Hz, 1
H), 2.16–2.09 (m, 1 H), 2.07 (dt, J = 11.6, 3.3 Hz, 1 H), 1.98 (ddd, J = 14.5, 9.6, 6.3 Hz,
1 H), 1.91–1.78 (m, 3 H), 1.57 (td, J = 14.0, 4.0 Hz, 1 H), 1.46 (ddd, J = 15.2, 5.1, 3.2
Hz, 1 H), 1.39 (dd, J = 12.2, 6.5 Hz, 1 H), 1.35–1.20 (m, 1 H), 0.87 (s, 3H).
13 C NMR(CDCl3, 101 MHz): δ 214.9, 207.8, 117.2, 78.8, 73.8, 65.6, 64.7, 61.7, 58.1,
50.7, 50.0, 49.9, 49.8, 45.7, 44.4, 38.1, 34.4, 34.0, 27.6, 22.0, 15.1.
Spectroscopic data for tetraol 2-75:
Physical state: white solid;
Rf = 0.13 (silica gel, EtOAc);
+ HRMS (m/z): calcd for C21H32O7, [M+H] , 397.2226; found, 397.2232;
IR (film) λmax: 3417, 2932, 2875, 1690, 1458, 1386, 1260, 1168, 1100, 1089;
1 H NMR (400 MHz, CDCl3): δ 4.92 (s, 1 H), 4.78 (dd, J = 12.1, 2.5 Hz, 1 H), 4.59 (t, J
= 3.3 Hz, 1 H), 4.44–4.39 (m, 1 H), 4.35 (t, J = 12.3 Hz, 1 H), 4.23 (dd, J = 3.7, 1.9 Hz, 1
H), 4.01–3.78 (m, 5 H), 2.74 (d, J = 11.4 Hz, 1 H), 2.61 (d, J = 11.0 Hz, 1 H), 2.19–2.15
(m, 1 H), 2.13–2.08 (m, 1 H), 2.10 (d, J = 11.4 Hz, 1 H), 2.08–2.01 (m, 1H), 1.96 (td, J =
9.1, 8.5, 4.8 Hz, 1 H), 1.91 (t, J = 11.8 Hz, 1 H), 1.81–1.66 (m, 4 H), 1.47–1.38 (m, 3 H),
1.32 (ddt, J = 15.5, 10.6, 4.6 Hz, 2 H), 0.82 (s, 3 H).
! 77 13 C NMR(CDCl3, 101 MHz): δ 216.0, 117.3, 75.8, 71.6, 65.6, 64.8, 63.5, 61.4, 57.3,
50.9, 50.0, 49.9, 45.0, 42.2, 38.4, 36.3, 34.5, 34.1, 27.0, 21.9, 15.0.
Acetonide 2-79: Triol 2-66 (1.06 g, 2.69 mmol) was dissolved in acetone (106 mL) and stirred at room temperature with PPTS (135 mg, 0.54 mmol, 0.2 equiv) and anhydrous
CaSO4 (916 mg, 6.73 mmol, 2.5 equiv). After 24 h, the reaction was neutralized with
K2CO3, filtered through a pad of celite and concentrated in vacuo. Silica gel chromatography purification (1:3 to 1:1 EtOAc:hexanes) afforded pure 2-79 (807 mg,
69%) as a white solid.
Physical state: white solid (m.p. 175–176°C);
Rf = 0.50 (silica gel, 4:1 EtOAc:hexanes);
+ HRMS (m/z): calcd for C24H34O7, [M+Na] , 457.2197; found, 457.2188;
[α]D = +9.2º (c = 0.5, CH2Cl2);
IR (film) λmax: 3490, 2940, 2875, 1702, 1384, 1202, 1168, 1097, 1052;
1 H NMR (400 MHz, CDCl3): δ 5.42 (dd, J = 4.8, 2.6 Hz, 1 H), 4.64 (d, J = 12.1 Hz, 1
H), 4.59 (s, 1 H), 4.17 (d, J = 12.0 Hz, 1 H), 3.95–3.74 (m, 4 H), 2.84 (d, J = 14.5 Hz, 1
H), 2.66 (d, J = 12.1 Hz, 1 H), 2.46 (dd, J = 15.4, 4.7 Hz, 1 H), 2.40–2.30 (m, 2 H), 2.22
(dd, J = 14.5, 2.6 Hz, 1 H), 2.10 (d, J = 12.0 Hz, 1 H), 2.04–1.75 (m, 5 H), 1.69 (s, 3 H),
1.65–1.50 (m, 2 H), 1.38–1.14 (m, 2 H), 1.32 (s, 3 H), 0.78 (s, 3 H).
13 C NMR(CDCl3, 101 MHz): δ 210.3, 207.3, 117.3, 99.7, 79.8, 71.3, 65.5, 64.6, 60.7,
54.4, 50.4, 49.9, 49.7, 49.6, 43.3, 39.4, 36.5, 35.5, 34.1, 28.8, 28.6, 22.2, 20.2, 14.9.
! 78 Boronate 2-80: Acetonide 2-79 (1.02 g, 2.35 mmol) was dissolved in THF (47 mL, 0.05
M) under Ar. After cooling to –78 ºC, 1 M solution of LiBEt3H in THF (2.6 mL, 1.1 equiv) was added dropwise. After 30 minutes, acetone (5 mL) was added at –78 ºC to quench any remaining active hydride species. Ethyl acetate (30 mL) and sat. aq. NH4Cl
(50 mL) was added and the mixture was warmed to room temperature, after which 1 M
NaOH solution (25 mL) was added to dissolve white precipitate formed. The aqueous layer was extracted with EtOAc (2 x 100 mL) and the combined organic layer was washed with brine (75 mL), dried over NaSO4 and concentrated in vacuo. The resulting amorphous solid was passed through a short pad of silica gel, washing with 1:1
EtOAc:hexanes and concentrated to afford 2-80 (1.02 g, 92%) as an amorphous solid that was sufficiently pure for the next step.
Physical state: amorphous solid;
Rf = 0.54 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C26H39BO7, [M+H] , 475.2861; found, 475.2872;
[α]D = +24.2º (c = 0.5, CH2Cl2);
IR (film) λmax: 2938, 2878, 1707, 1332, 1201, 1165, 1099, 909;
1 H NMR (400 MHz, CDCl3): δ 4.78 (d, J = 2.8 Hz, 1 H), 4.26 (d, J = 11.9 Hz, 1 H), 4.20
(s, 1H), 3.95 (d, J = 12.0 Hz, 1 H), 3.95–3.74 (m, 4 H), 2.59 (d, J = 11.8 Hz, 1 H), 2.20
(d, J = 11.5 Hz, 1 H), 2.19 (dd, J = 14.1, 2.2 Hz, 1 H), 2.11 (dq, J = 16.4, 2.6 Hz, 1 H),
2.07 (d, J = 11.9 Hz, 1 H), 2.02–1.58 (m, 8 H), 1.55–1.46 (m, 1 H), 1.50 (s, 3H), 1.40–
1.15 (m, 3 H), 1.32 (s, 3 H), 0.87 (t, J = 7.7 Hz, 3 H), 0.80 (s, 3 H), 0.68 (q, J = 7.7 Hz, 2
H).
! 79 13 C NMR(CDCl3, 101 MHz): δ 209.4, 117.5, 99.7, 72.5, 66.2, 65.5, 65.0, 64.7, 60.2,
55.4, 50.4, 50.0, 49.7, 43.6, 36.5, 35.4, 35.3, 34.3, 33.5, 27.1, 25.7, 23.1, 22.2, 15.1, 7.9.
Alcohol 2-81: In a flask equipped with dry-ice condenser containing ammonia (ca. 200 mL) at –78 ºC was added lithium wire (1224 mg, 60 equiv). After 15 minutes, acetonide
2-80 (1400 mg, 2.95 mmol) in THF (98 mL) was introduced to the blue ammonia solution at –78 ºC. The reaction was allowed to stir for 30 mins and then quenched with dropwise addition of 10:1 THF:tBuOH (30 mL), followed by sat. aq. NH4Cl (75 mL).
After warming to room temperature, the aqueous layer was extracted with EtOAc (2 x
150 mL) and the combined organic layer was washed with brine (100 mL), dried over
MgSO4 and concentrated in vacuo. The resulting colorless oil was purified by column chromatography (3:1 to 3:2 EtOAc:hexanes) to give the corresponding alcohol (980 mg,
70%) as an amorphous solid.
Physical state: amorphous solid;
Rf = 0.44 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C26H41BO7, [M+H] , 477.3018; found, 477.3014;
[α]D = -5.0º (c = 0.5, CH2Cl2);
IR (film) λmax: 3466, 2934, 2876, 1379, 1333, 1226, 1203, 1092;
1 H NMR (400 MHz, CDCl3): δ 5.23 (dd, J = 5.2, 2.0 Hz, 1 H), 4.35 (d, J = 12.0 Hz, 1
H), 4.26–4.19 (m, 1 H), 4.15 (ddd, J = 10.8, 8.7, 5.0 Hz, 1 H), 3.96 – 3.79 (m, 4H), 3.72
(d, J = 12.0 Hz, 1H), 2.17–2.09 (m, 2 H), 1.98 (ddd, J = 14.6, 11.6, 3.0 Hz, 1 H), 1.91–
1.83 (m, 1 H), 1.83–1.75 (m, 1 H), 1.72 (dd, J = 11.9, 4.9 Hz, 1 H), 1.66–1.57 (m, 2 H),
1.50 (ddt, J = 15.1, 10.3, 3.8 Hz, 4 H), 1.39–1.33 (m, 1 H), 1.31 (s, 3 H), 1.28 (s, 3 H),
! 80 1.26–1.18 (m, 3 H), 1.08–0.96 (m, 1 H), 0.89 (s, 3 H), 0.88 (t, J = 7.7 Hz, 3 H), 0.66 (q, J
= 7.6 Hz, 2 H).
13 C NMR(CDCl3, 101 MHz): δ 118.6, 101.5, 72.4, 69.9, 67.1, 65.4, 65.2, 64.7, 60.5,
51.2, 49.3, 49.0, 46.4, 42.0, 37.1, 35.2, 34.9, 34.3, 33.2, 25.7, 24.2, 23.2, 22.6, 15.8, 7.9.
To the above alcohol (1020 mg, 2.14 mmol) in acetone (42 mL) at room temperature was added PPTS (807 mg, 3.21 mmol, 1.5 equiv). The solution was then heated to 70 ºC and stirred for 16 hours. Upon completion of the reaction, the solution was concentrated in vacuo and redissolved in EtOAc before being filtered through a short pad of silica gel, washing with EtOAc. Concentration in vacuo afforded 2-81 (907 mg, 98%) as an amorphous solid. Note that the Rf of the product is the same as that of the starting material in EtOAc:hexanes solvent system, thus the reaction was monitored by NMR spectra of its aliquot.
Physical state: amorphous solid;
Rf = 0.44 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C24H37BO6, [M+H] , 433.2756; found, 433.2759;
[α]D = +51.5º (c = 0.5, CH2Cl2);
IR (film) λmax: 3456, 2933, 2870, 1737, 1403, 1378, 1333, 1223, 1206, 1092;
1 H NMR (400 MHz, CDCl3): δ 5.27 (dd, J = 5.1, 2.0 Hz, 1 H), 4.37 (dd, J = 12.0, 1.3
Hz, 1 H), 4.29– 4.17 (m, 2 H), 3.70 (d, J = 12.1 Hz, 1 H), 2.46 (dd, J = 19.5, 8.4 Hz, 1
H), 2.22 –2.05 (m, 5 H), 1.97–1.84 (m, 2 H), 1.67–1.58 (m, 1 H), 1.57–1.48 (m, 3 H),
1.46–1.36 (m, 3 H), 1.31 (s, 3 H), 1.27 (s, 3 H), 1.27–1.22 (m, 1 H), 1.17–1.01 (m, 1 H),
0.90 (s, 3 H), 0.87 (t, J = 7.7 Hz, 3 H), 0.67 (q, J = 7.7 Hz, 2 H).
! 81 13 C NMR(CDCl3, 101 MHz): δ 218.8, 101.5, 72.4, 68.9, 67.0, 65.3, 60.7, 51.5, 49.9,
49.3, 48.1, 42.6, 37.1, 35.9, 35.3, 34.4, 33.2, 25.4, 24.3, 23.2, 21.9, 15.0, 7.9.
Enone 2-82: Ketone 2-81 (1140 mg, 2.634 mmol) was dissolved in CH2Cl2 (54 mL).
After cooling to 0 ºC, Et3N (1.47 mL, 10.56 mmol, 4 equiv) was added to the solution, followed by TMSOTf (1.44 mL, 7.92 mmol, 3 equiv) dropwise. After 20 minutes, the solution was warmed to room temperature, stirred for another 20 minute period before being poured into ice-cold sat. aq. NaHCO3 solution. The aqueous layer was then extracted with hexanes (3 x 75 mL) and the combined organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The resulting oil was used for the next step without further purification.
The aforementioned oil was dissolved in MeCN (54 mL), followed by the addition of
Pd(OAc)2 (711 mg, 3.18 mmol, 1.2 equiv). After 3 hour of stirring, the dark brown solution was cooled to 0 ºC and FeCl3 (750 mg, 2.778 mmol, 1.05 equiv) was added in one portion. After 10 minutes, the mixture was neutralized with the addition of K2CO3
(1092 mg, 7.92 mmol, 3 equiv). Following filtration through a short pad of silica gel, the crude mixture was concentrated and then purified by column chromatography to provide pure 2-82 (750 mg, 66%) as a white soild.
Physical state: white soild (m.p. 210–211 ºC);
Rf = 0.44 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C24H35BO6, [M+H] , 431.2599; found, 431.2595;
[α]D = -22.7º (c = 0.5, CH2Cl2);
IR (film) λmax: 3448, 2932, 2873, 1708, 2459, 1403, 1378, 1334, 1287, 1226, 1205;
! 82 1 H NMR (400 MHz, CDCl3): δ 7.48 (dd, J = 5.9, 1.7 Hz, 1 H), 6.07 (dd, J = 5.9, 3.1 Hz,
1 H), 5.19 (dd, J = 4.8, 2.1 Hz, 1 H), 4.48 (td, J = 9.5, 6.2 Hz, 1 H), 4.39 (dd, J = 12.1,
1.4 Hz, 1 H), 4.28–4.16 (m, 1 H), 3.73 (d, J = 12.1 Hz, 1 H), 2.40 (dt, J = 11.7, 2.2 Hz, 1
H), 2.34 (dd, J = 12.3, 6.2 Hz, 1 H), 2.27 (dd, J = 13.8, 2.1 Hz, 1 H), 2.16–2.09 (m, 1 H),
1.95 (ddd, J = 15.3, 5.0, 2.8 Hz, 1 H), 1.84 (dq, J = 12.9, 3.6 Hz, 1 H), 1.73 (ddd, J =
22.5, 11.6, 3.3 Hz, 1 H), 1.62 (td, J = 13.7, 4.0 Hz, 1 H), 1.58–1.45 (m, 3 H), 1.40–1.33
(m, 1 H), 1.31 (s, 3 H), 1.29 (s, 3 H), 1.25–1.16 (m, 1 H), 1.08 (s, 3 H), 0.89 (t, J = 7.8
Hz, 3 H), 0.68 (q, J = 7.8 Hz, 2 H).
13 C NMR (CDCl3, 101 MHz): δ 211.3, 157.4, 132.6, 101.3, 72.5, 67.7, 67.1, 65.5, 61.4,
54.9, 53.4, 50.6, 49.4, 40.9, 37.2, 35.4, 33.1, 32.9, 25.7, 24.3, 23.2, 21.8, 7.9.
Enone 2-83: SiO2 (3500 mg) was added to 2-82 (500 mg, 1.16 mmol), followed by C7F8
(30 mL) and DIPEA (11.4 mL, 63.8 mmol, 55 equiv). The mixture was then stirred at room temperature and monitored by TLC until satisfactory conversion was observed
(typically 45 minutes to 1 hour). The mixture was filtered through a Celite pad and concentrated in vacuo. The resulting yellow oil was purified by column chromatography to provide 2-83 (420 mg, 84%) as a white foam and recovered 2-82 (26 mg, 5%).
Physical state: white foam;
Rf = 0.62 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C24H35BO6, [M+H] , 431.2599; found, 431.2596;
[α]D = +63.4º (c = 1.0, CH2Cl2);
IR (film) λmax: 3455, 2933, 2875, 1743, 1403, 1377, 1333, 1286, 1225, 1203, 1051;
! 83 1 H NMR (400 MHz, CDCl3): δ 5.56 (d, J = 2.1 Hz, 1 H), 5.09 (dd, J = 5.3, 1.9 Hz, 1 H),
4.41 (dd, J = 12.1, 1.3 Hz, 1 H), 4.20 (tq, J = 8.8, 3.4 Hz, 2 H), 3.82 (d, J = 12.1 Hz, 1 H),
3.63 (d, J = 4.1 Hz, 1 H), 3.03 (ddd, J = 23.0, 3.7, 1.8 Hz, 1 H), 2.82 (dt, J = 22.9, 2.2 Hz,
1 H), 2.10 (td, J = 14.4, 13.6, 2.2 Hz, 2 H), 1.99 (dd, J = 12.7, 3.7 Hz, 2 H), 1.83 (ddd, J
= 15.4, 5.3, 2.7 Hz, 1 H), 1.76–1.65 (m, 1 H), 1.6–1.49 (m, 3 H), 1.44 (dd, J = 9.3, 2.9
Hz, 1 H), 1.36 (t, J = 12.0 Hz, 1 H), 1.33 (s, 3 H), 1.28 (s, 3 H), 1.23–1.17 (m, 1 H), 1.17
(s, 3 H), 0.87 (t, J = 7.7 Hz, 3 H), 0.67 (q, J = 7.7 Hz, 2 H).
13 C NMR (CDCl3, 101 MHz): δ 151.1, 114.9, 102.1, 71.8, 70.5, 67.3, 64.8, 59.7, 50.8,
50.7, 49.0, 41.9, 41.5, 36.2, 35.1, 34.6, 33.3, 24.0, 23.3, 22.9, 21.8, 20.6, 7.8.
Alcohol 2-84: A solution of 2-83 (600 mg, 1.39 mmol) in dioxane (30 mL) was saturated with O2 by bubbling O2 through the stirred solution for 15 min. To this solution was added Co(acac)2 (72 mg, 0.278 mmol, 0.2 equiv). A solution of PhSiH3 (0.516 mL, 4.18 mmol, 3 equiv) in dioxane (3 mL) was added over 60 minutes via syringe pump. The stirring was continued under an O2 atmosphere (no bubbling) at ambient temperature for approximately 3 h. The reaction was quenched with sat. Na2S2O3 (40 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layer was washed sequentially with sat. aq. NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The green oil obtained was purified by silica gel chromatography
(2:3 to 3:2 EtOAc:hexanes) to provide 2-84 (538 mg, 86%, isolated as inseparable mixture of diastereomers in the ratio of 8:1 in favor of the desired one) as a white solid.
Physical state: white solid;
Rf = 0.36 (silica gel, 3:2 EtOAc:hexanes);
! 84 + HRMS (m/z): calcd for C24H37BO7, [M+H] , 449.2705; found, 449.2710;
[α]D = +19.4º (c = 1.0, CH2Cl2);
IR (film) λmax: 3418, 2935, 2875, 1730, 1644, 1402, 1378, 1334, 1281, 1223, 1205,
1056;
1 H NMR (400 MHz, CDCl3): (major diastereomer) δ 5.12 (dd, J = 5.5, 2.0 Hz, 1 H),
4.40 (d, J = 12.1 Hz, 1 H), 4.33–4.21 (m, 1 H), 4.06 (tt, J = 8.2, 4.1 Hz, 1 H), 3.76 (d, J =
12.2 Hz, 1 H), 3.22 (d, J = 4.4 Hz, 1 H), 2.52–2.40 (m, 2 H), 2.23–2.14 (m, 2 H), 2.09
(dd, J = 13.8, 2.0 Hz, 1 H), 1.94–1.84 (m, 3 H), 1.65 –1.44 (m, 6 H), 1.34 (s, 3 H), 1.31–
1.23 (m, 1 H), 1.29 (s, 3 H), 1.15 (s, 3 H), 0.90 (t, J = 7.7 Hz, 3 H), 0.70 (q, J = 7.7 Hz, 2
H).
13 C NMR (CDCl3, 151 MHz): δ 219.2, 102.0, 81.6, 71.6, 69.2, 67.2, 64.7, 59.7, 53.8,
48.8, 45.9, 41.5, 41.1, 36.6, 35.1, 33.4, 33.1, 27.7, 24.0, 23.2, 20.5, 14.5, 7.9.
Dienoate 2-106: To a solution of 2-84 (30 mg, 66.7 µmol) in 4:1 mixture of
CH2Cl2/EtOH (1.2 mL) was added anhydrous N2H4 (21 µL, 667 µmol, 10 equiv) and
Et3N (93 µL, 667 µmol, 10 equiv). The mixture was heated at 50 ºC for 5 hours, after which the reaction was allowed to cool and concentrated in vacuo. The residue so obtained was dissolved in degassed THF (1.4 mL) and Et3N (38 µL, 268 µmol, 4 equiv) was added. A stock solution of I2 (52 mg, 202 µmol, 3 equiv) in THF (0.4 mL) was prepared and added dropwise to the reaction mixture. After the solution stayed brown for more than 30 sec, addition was halted and stirring was continued for 10 min. The reaction was then diluted with EtOAc (5 mL) and washed with sat. aq. Na2S2O3 (5 mL). The aqueous layer was extracted with EtOAc (3 x 5 mL) and the combined organic portions
! 85 were washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was passed through a short pad of silica gel, washing with
1:1 hexanes:EtOAc. Concentration in vacuo afforded vinyl iodide which was used for the next step without further purification.
The above iodide and stannane 2-88 (100 mg, 268 µmol, 4 equiv) were dissolved in DMF
(1.1 mL) and the resulting solution was degassed by bubbling argon through for 15 min.
To this solution was sequentially added [Ph2PO2][NBu4] (123 mg, 268 µmol, 4 equiv),
Pd(PPh3)4 (11 mg, 10 µmol, 0.15 equiv) and CuTC (38 mg, 200 µmol, 3 equiv). The reaction mixture was then stirred for 2 hours and then quenched with water (2.5 mL). The suspension was passed through a pad of Celite, washing with EtOAc (10 mL). The aqueous phase was extracted with EtOAc (3 x 5 mL) and the combined organic layers were successively washed with sat. aq. NaHCO3 (10 mL), H2O (2 x 5 mL) and sat. aq.
NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (1:1 to 4:1 EtOAc:hexanes) afforded dienoate 2-106 (15 mg,
42% over 2 steps) as a white solid.
Physical state: white solid (m.p. 234–235 ºC);
Rf = 0.37 (silica gel, EtOAc);
+ HRMS (m/z): calcd for C28H39BO8, [M+H] , 515.2811; found, 515.2828;
[α]D = +20.0º (c = 0.4, CH2Cl2);
IR (film) λmax: 3451, 2956, 2929, 2875, 2247, 1783, 1739, 1622, 1460, 1404, 1378, 1335,
1287, 1224;
1 H NMR (600 MHz, CDCl3): δ 6.11 (s, 1 H), 6.00 (s, 1 H), 5.01 (m, 1 H), 4.98 (dd, J =
16.4, 1.8 Hz, 1 H), 4.92 (dd, J = 16.4, 1.8 Hz, 1 H), 4.43 (d, J = 12.1 Hz, 1 H), 4.27 (t, J =
! 86 2.9 Hz, 1 H), 4.02 (ddd, J = 11.8, 9.0, 3.2 Hz, 1 H), 3.80 (d, J = 12.2 Hz, 1 H), 2.73 (d, J
= 18.7 Hz, 1 H), 2.43 (dd, J = 18.7, 3.4 Hz, 1 H), 2.18 (td, J = 13.7, 2.9 Hz, 2 H), 2.06
(dd, J = 13.7, 1.8 Hz, 1 H), 2.01 (dt, J = 12.0, 3.9 Hz, 1 H), 1.88 (ddd, J = 15.3, 5.4, 2.8
Hz, 1 H), 1.61–1.49 (m, 4 H) 1.47–1.40 (m, 2 H), 1.37 (s, 3 H), 1.36 (s, 3 H) 1.31 (s, 3
H), 1.19 (qd, J = 13.6, 3.7 Hz, 1 H), 0.87 (t, J = 7.7 Hz, 3 H), 0.67 (q, J = 7.7 Hz, 2 H).
13 C NMR (CDCl3, 151 MHz): δ 174.1, 157.8, 143.3, 131.8, 113.3, 102.2, 84.7, 71.7,
71.5, 68.9, 67.4, 64.6, 59.8, 52.7, 48.5, 47.4, 46.1, 41.1, 40.4, 36.4, 35.1, 33.5, 29.9, 23.9,
23.2, 21.8, 18.5, 7.9.
Enoate 2-108: To a solution of dienoate 2-106 (10 mg, 19.4 µmol) in EtOH (200 µL) was added CoCl2.6H2O (11.5 mg, 48.5 µmol, 2.5 equiv). The blue solution was cooled to 0 ºC and solid NaBH4 (3.7 mg, 97 µmol, 5 equiv) was added. After evolution of gas had ceased and the mixture turned black (typically within 5 minutes), the mixture was warmed to rt. After further stirring for 20 mins, the mixture was filtered through a pad of
Celite, washing with EtOAc (10 mL). Concentration in vacuo afforded enoate 2-107 (10 mg, 100%) as a mixture of olefin isomers which was used for the next step without further purification.
A solution of enoate 2-107 (10 mg, 19.4 µmol) in C6H6 (200 µL) was pre-heated to 100
ºC before a stock solution of Barton’s base in C6H6 (0.6 M, 50 µmol, ca. 1.5 equiv) was added. After 10 mins, the solution was cooled to rt and then concentrated in vacuo. NMR analysis of the crude reaction mixture revealed a 3:1 β:α butenolide ratio at C17. These diastereomers can be separated by preparative TLC (2:1 MTBE:Et2O) to afford enoate 2-
108 (7 mg) as a white solid and the C17 epimer 2-110 (2.3 mg). The former (2-108) was
! 87 found to match spectroscopically (see spectra comparison) with ouabagenin derivative prepared from commercial ouabain using the following procedure:
Ouabain octahydrate was converted to ouabagenin-11,19-acetonide following the procedure described by Mannich in reference 6 in section 1.5. A suspension of this acetonie (15 mg, 31.3 µmol) in THF (1 mL) was cooled to –78 ºC and then treated with 1
M solution of LiBEt3H in THF (38 µL, 38 µmol, ca. 1.2 equiv). After 30 min, the reaction was quenched by the addition of sat. aq. NH4Cl (10 mL), warmed to rt and stirred for 1 h.
The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo.
Purification by silica gel chromatography (3:1 EtOAc:hexanes to EtOAc) afforded 2-108
(8 mg, 49%) as a white solid.
Physical state: white solid (m.p. 235 ºC);
Rf = 0.36 (silica gel, EtOAc);
+ HRMS (m/z): calcd for C28H41BO8, [M+H] , 517.2967; found, 517.2987;
[α]D = +22.4º (c = 0.4, CH2Cl2);
IR (film) λmax: 3455, 2956, 2932, 2875, 1737, 1623, 1403, 1378, 1341, 1289, 1225,
1205;
1 H NMR (600 MHz, CDCl3): δ 5.91 (s, 1 H), 5.04 (dd, J = 5.3, 1.8 Hz, 1 H), 4.93 (dd, J
= 18.0, 1.7 Hz, 1 H), 4.80 (dd, J = 17.9, 1.7 Hz, 1 H), 4.38 (d, J = 12.1 Hz, 1 H), 4.27 (s,
1 H), 4.11 (td, J = 7.9, 4.0 Hz, 1 H), 3.74 (d, J = 12.1 Hz, 1 H), 3.10 (d, J = 4.2 Hz, 1 H),
2.89 (dd, J = 9.0, 6.2 Hz, 1 H), 2.22–2.15 (m, 2 H) 2.11 (dt, J = 13.7, 9.7 Hz, 1 H), 2.06
(dd, J = 13.7, 1.9 Hz, 1 H), 1.95–1.82 (m, 3 H), 1.80–1.70 (m, 2 H), 1.61 (dt, J = 13.9,
! 88 2.8 Hz, 1 H), 1.55 (dt, J = 13.9, 2.8 Hz, 1 H), 1.53–1.39 (m, 3 H), 1.34 (s, 3 H), 1.29 (s, 3
H), 1.19 (m, 1 H), 0.97 (s, 3 H), 0.90 (t, J = 7.7 Hz, 3 H), 0.69 (q, J = 7.7 Hz, 2 H).
13 C NMR (CDCl3, 151 MHz): δ 174.3, 173.3, 118.2, 101.9, 84.7, 73.6, 71.7, 69.3, 67.2,
64.8, 59.9, 50.2, 49.7, 48.9, 48.7, 45.8, 41.2, 36.6, 35.0, 33.8, 33.3, 29.8, 27.2, 24.1, 23.2,
22.0, 17.8, 7.9.
Spectroscopic data for C17-epimer 2-110:
Rf = 0.36 (silica gel, EtOAc);
+ HRMS (m/z): calcd for C28H41BO8, [M+H] , 517.2967; found, 517.2987;
IR (film) λmax: 3400, 2956, 2932, 2875, 1746, 1624, 1403, 1378, 1333, 1226, 1205;
1 H NMR (600 MHz, CDCl3): δ 5.91 (d, J = 1.9 Hz, 1 H), 5.10 (d, J = 5.0 Hz, 1 H), 4.82
(dd, J = 17.6, 1.8 Hz, 1 H), 4.77–4.70 (m, 1 H), 4.40 (d, J = 12.1 Hz, 1 H), 4.27 (s, 1 H),
4.00 (tt, J = 9.6, 4.5 Hz, 1 H), 3.76 (d, J = 12.1 Hz, 1 H), 3.33 (d, J = 4.1 Hz, 1 H), 3.14
(dd, J = 11.1, 8.5 Hz, 1 H), 2.21–2.16 (m, 1 H), 2.12 (ddt, J = 15.1, 11.4, 5.0 Hz, 2 H),
2.07–2.03 (m, 1 H), 1.93–1.82 (m, 3 H), 1.70–1.63 (m, 1 H), 1.62–1.53 (m, 3 H), 1.51–
1.37 (m, 3 H), 1.34 (s, 3 H), 1.29 (s, 3 H), 1.19 (m, 1 H), 1.14 (s, 3 H), 0.90 (t, J = 7.8 Hz,
3 H), 0.69 (q, J = 7.9 Hz, 2 H).
13 C NMR (CDCl3, 151 MHz): δ 176.8, 117.4, 102.0, 85.2, 73.7, 71.6, 69.4, 67.2, 64.7,
59.8, 49.4, 48.8, 48.6, 46.2, 41.3, 41.2, 36.6, 35.1, 33.4, 32.2, 24.7, 24.0, 23.2, 21.6, 19.9,
7.9.
Fluoride 2-111: Iron(III) oxalate hexahydrate (68 mg, 0.14 mmol, 4 equiv) was stirred in
H2O (2.8 mL) until it completely dissolved (approximately 2 h). The clear yellow
! 89 solution was degassed by bubbling argon through for 10 min and then cooled to 0 ºC.
Selectfluor (50 mg, 0.14 mmol, 4 equiv) was added to the reaction mixture, followed by
MeCN (4.2 mL). A solution of 2-83 (15 mg, 0.035 mmol, 1 equiv) in THF (1.4 mL) was added to the mixture at 0 ºC, followed by NaBH4 (8.4 mg, 0.224 mmol, 6.4 equiv). After
5 min, the mixture was treated with additional portion of NaBH4 (8.4 mg). The mixture was stirred for 15 more min before being quenched by addition of 30% aqueous NH4OH
(2 mL). The mixture was extracted with CH2Cl2 (3 x 5 mL) and the combined organic layer was dried with Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography (1:4 to 2:3 EtOAc:hexanes) afforded 2-111 (8 mg, 51%) as a white solid.
Physical state: white solid (m.p. 98–100 ºC);
Rf = 0.40 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C24H36BFO6, [M+H] , 451.2662; found, 451.2673;
[α]D = +12.0º (c = 0.5, CH2Cl2);
IR (film) λmax: 3441, 2936, 2875, 1742, 1403, 1379, 1334, 1291, 1224, 1207, 1057;
1 H NMR (600 MHz, CDCl3): δ 5.04 (m, 1 H), 4.42 (d, J = 12.2 Hz, 1 H), 4.28 (t, J = 3.0
Hz, 1 H), 4.12 (ddd, J = 14.8, 8.4, 3.7 Hz, 1 H), 3.77 (d, J = 12.2 Hz, 1 H), 2.56 –2.40 (m,
2 H), 2.27–2.13 (m, 3 H), 2.11–2.01 (m, 1 H), 1.93–1.78 (m, 3 H), 1.68 (dt, J = 13.7, 4.1
Hz, 1 H), 1.62–1.40 (m, 9 H), 1.35 (s, 3 H), 1.29 (s, 3 H), 0.90 (t, J = 7.7 Hz, 3 H), 0.70
(q, J = 7.7 Hz, 2 H).
13 C NMR (CDCl3, 151 MHz): δ 218.0, 105.0 (d, J = 181.2 Hz), 102.0, 71.5, 68.8, 67.0,
64.7, 52.8 (d, J = 21.4 Hz), 48.8, 45.9 (d, J = 8.0 Hz), 41.0 (d, J = 6.7 Hz), 38.9 (d, J =
! 90 22.0 Hz), 36.2, 35.1, 33.3 (d, J = 9.1 Hz), 26.1 (d, J = 25.7 Hz), 24.0, 23.2, 20.2 (d, J =
3.0 Hz), 14.5 (d, J = 9.0 Hz), 7.8.
19F NMR (CDCl3, 376 MHz): δ -156.8
Ouabagenin (2-1). To a solution of 2-108 (10 mg, 19.4 µmol) in MeOH (200 µL) was added a stock solution of conc. HCl in MeOH (0.8 M, 50 µL, 2 equiv) at rt. After 30 min, the mixture was neutralized with solid Na2CO3, filtered through Celite pad and concentrated in vacuo and then purified by silica gel chromatography (1:10 to 1:4
MeOH:CH2Cl2) to afford ouabagenin (7.6 mg, 90%) as a white solid. This synthetic ouabagenin was found to match spectroscopically with authentic ouabagenin obtained from degradation of ouabain.
[α]D = -11.1º (c = 0.5, 2:1 (CD3)2SO:CDCl3);
[α]D (from degradation) = -8.8º (c = 0.5, 2:1 (CD3)2SO:CDCl3) [lit [α]D = +11.32º (c =
1.27, H2O)];
1 H NMR (600 MHz, 2:1 (CD3)2SO:CDCl3): δ 5.84 (s, 1 H), 4.92 (d, J = 18.4 Hz, 1 H),
4.81 (dd, J = 18.4, 1.8 Hz, 1 H), 4.41 (s, 1 H), 4.21 (d, J = 10.4 Hz, 1 H), 4.20–4.10 (m, 1
H), 3.98 (d, J = 10.4 Hz, 1 H), 2.83 (t, J = 7.1 Hz, 1 H), 2.03–1.93 (m, 3 H), 1.92–1.85
(m, 1 H), 1.82–1.72 (m, 2 H), 1.61 (dd, J = 11.4, 8.6 Hz, 1 H), 1.56 (dd, J = 13.5, 4.5 Hz,
1H), 1.49–1.40 (m, 1 H), 1.37–1.28 (m, 2 H), 1.22 (s, 1 H), 1.11 (s, 1 H), 0.81 (s, 3 H).
13 C NMR (2:1 (CD3)2SO:CDCl3, 151 MHz): 175.0, 173.5, 116.3, 83.5, 75.1, 72.9, 66.2,
65.4, 60.6, 49.7, 49.0, 48.6, 48.4, 47.2, 40.1, 32.3, 26.0, 22.7, 16.9.
! 91 Ketal 2-54: To a solution of 2-44 (10 mg, 0.0258 mmol) in Ac2O (0.25 mL) was added
PhI(OAc)2 (12.8 mg, 0.0386 mmol, 1.5 equiv). The solution was then heated at 80 ºC for
2 h, upon which TLC analysis showed that all starting material has been consumed. The reaction mixture was concentrated in vacuo, azeotroping with toluene to remove trace acetic acid, and then purified by silica gel chromatography (3:7 EtOAc : hexanes) to afford ketal 2-54 (8 mg, 69%) as a white solid.
Physical state: white solid;
Rf = 0.13 (silica gel, 1:4 EtOAc:hexanes);
+ HRMS (m/z): calcd for C25H34O7, [M+H] , 447.2383; found, 447.2386;
IR (film) λmax: 2974, 2944, 2882, 1733, 1442, 1369, 1255, 1112, 1099, 1079, 1011, 960;
1 H NMR (600 MHz, CDCl3): δ 5.71–5.53 (m, 1 H), 4.03–3.74 (m, 8 H), 3.44 (d, J = 8.3
Hz, 1 H), 2.63 (dt, J = 12.1, 7.7 Hz, 1 H), 2.55 (d, J = 14.6 Hz, 1 H), 2.35 (d, J = 14.6 Hz,
1H), 2.30 (dd, J = 13.8, 2.8 Hz, 1 H), 2.22 (dd, J = 13.7, 2.5 Hz, 1 H), 2.17 (d, J = 13.6
Hz, 1 H), 2.13 (d, J = 13.6 Hz, 1 H), 2.05 (s, 3H), 2.00 (dt, J = 13.2, 3.3 Hz, 1 H), 1.96–
1.87 (m, 3 H), 1.85 (dd, J = 9.2, 6.3 Hz, 2 H), 1.74 (dd, J = 13.2, 3.1 Hz, 1 H), 1.67–1.39
(m, 5 H), 1.04 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 169.8, 139.2, 127.9, 118.7, 113.7, 109.3, 86.9, 65.1,
64.7, 64.6, 64.4, 51.0, 50.9, 46.8, 43.4, 40.6, 39.0, 38.8, 33.7, 33.4, 31.4, 29.0, 22.3, 20.0,
18.8.
Acetates 2-55 and 2-56: To a solution of 2-44 (20 mg, 0.0514 mmol) in Ac2O (1 mL) was added Pd(OAc)2 (2.3 mg, 0.0103 mmol, 0.2 equiv) and PhI(OAc)2 (24.8 mg, 0.0771 mmol, 1.5 equiv). The solution was then heated at 80 ºC for 3 h, upon which TLC
! 92 analysis showed that all starting material has been consumed. The reaction mixture was concentrated in vacuo, azeotroping with toluene to remove trace acetic acid, and then purified by preparative TLC (1:9 EtOAc: CH2Cl2) to afford acetate 2-55 (2.1 mg, 9.5%), hemiketal 2-54 (7.5 mg, 33%), and acetate 2-56 (2.3 mg, 10%).
Spectroscopic data for 2-55:
Physical state: white foam;
Rf = 0.11 (silica gel, 1:4 EtOAc:hexanes);
+ HRMS (m/z): calcd for C25H34O7, [M+H] , 447.2383; found, 447.2387;
1 H NMR (600 MHz, CDCl3): δ 5.58 (d, J = 5.4 Hz, 1 H), 4.78 (d, J = 11.5 Hz, 1 H), 4.60
(d, J = 11.4 Hz, 1 H), 4.01–3.81 (m, 8 H), 2.69–2.64 (m, 1 H), 2.62 (d, J = 13.5 Hz, 1 H),
2.57 (dt, J = 13.9, 3.8 Hz, 1 H), 2.26 (qd, J = 10.9, 5.1 Hz, 1 H), 2.18–2.13 (m, 1 H), 2.17
(d, J = 11.7 Hz, 1 H), 2.12–2.01 (m, 2 H), 1.98 (s, 3 H), 1.96–1.80 (m, 5 H), 1.77 (td, J =
14.3, 4.3 Hz, 1 H), 1.40–1.26 (m, 2 H), 0.88 (s, 3 H).
Spectroscopic data for 2-56:
Physical state: white foam;
Rf = 0.23 (silica gel, 1:4 EtOAc:hexanes);
+ HRMS (m/z): calcd for C25H34O6, [M-OAc] , 371.2222; found, 371.2211;
IR (film) λmax: 2951, 2880, 1729, 1434, 1368, 1296, 1247, 1170, 1122, 1077, 1041,
1014;
1 H NMR (600 MHz, CDCl3): δ 5.66 (d, J = 6.7 Hz, 1 H), 4.00–3.73 (m, 8 H), 2.64 (d, J
= 13.0 Hz, 1 H), 2.51 (dd, J = 13.0, 4.2 Hz, 1 H), 2.30 (dt, J = 13.3, 3.4 Hz, 1 H), 2.22–
! 93 2.15 (m, 2 H), 2.03 (s, 3 H), 1.95 (ddd, J = 14.7, 11.6, 3.3 Hz, 1 H), 1.91–1.57 (m, 10 H),
1.42–1.32 (m, 1 H), 1.02 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 170.5, 140.8, 126.4, 118.7, 109.4, 98.2, 85.8, 65.2, 64.7,
64.6, 64.5, 54.8, 49.5, 44.0, 43.6, 42.4, 41.8, 38.3, 37.8, 34.7, 34.7, 32.1, 26.9, 22.8, 20.8,
17.6.
Fluoride 2-57: To a solution of 2-44 (30 mg, 0.0772 mmol) in MeCN (1 mL) was added
Selectfluor (41 mg, 0.116 mmol) at room temperature. The mixture was stirred for 15 min, upon which it became almost homogeneous and TLC analysis showed full consumption of starting material. The crude mixture was filtered through Celite and concentrated in vacuo. Purification by silica gel chromatography (1:1 EtOAc:hexanes to
6:1 EtOAc:hexanes) afforded allyl fluoride 2-57 (21 mg, 64%) as a white solid.
Physical state: white solid;
Rf = 0.33 (silica gel, EtOAc);
1 H NMR (600 MHz, CDCl3): δ 5.30–5.22 (m, 1 H), 5.22–5.08 (m, 1 H), 4.95–4.69 (m, 1
H), 4.25 (dddd, J = 17.7, 12.0, 6.2, 3.9 Hz, 1 H), 4.14 (dddt, J = 20.3, 11.8, 5.8, 3.1 Hz, 1
H), 3.95–3.76 (m, 6 H), 2.81 (ddt, J = 107.6, 14.6, 7.6 Hz, 1 H), 2.48 (dd, J = 22.2, 12.5
Hz, 1 H), 2.44–2.33 (m, 2 H), 2.28–2.15 (m, 2 H), 2.16–2.03 (m, 1 H), 1.95 (ttd, J = 13.8,
10.0, 8.7, 5.0 Hz, 2 H), 1.90–1.77 (m, 2 H), 1.73–1.39 (m, 8 H), 1.36–1.22 (m, 1 H), 0.96
(d, J = 9.2 Hz, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 174.50 (d, J = 46.9 Hz), 151.21 (dd, J = 228.7, 14.7 Hz),
118.65 (d, J = 2.5 Hz), 117.43 (d, J = 10.7 Hz), 108.36 (d, J = 11.6 Hz), 96.56 (d, J =
168.4 Hz), 89.78 (d, J = 185.7 Hz), 75.97, 66.29 (d, J = 4.5 Hz), 65.28, 64.72 (d, J = 5.9
! 94 Hz), 61.21 (d, J = 3.1 Hz), 56.41, 55.91, 49.03 (d, J = 24.7 Hz), 45.80, 45.16, 44.30,
43.62, 43.47 (d, J = 4.2 Hz), 42.06 (d, J = 15.5 Hz), 35.61 (d, J = 21.9 Hz), 35.17 (d, J =
4.3 Hz), 34.87 (d, J = 25.9 Hz), 34.45, 34.15, 32.45, 31.30, 30.74 (d, J = 4.8 Hz), 20.78
(d, J = 2.0 Hz), 16.71.
Iodide 2-58: To a solution of 2-44 (10 mg, 0.0257 mmol) in CH2Cl2 (0.5 mL) was added sequentially PhI(OAc)2 (16.8 mg, 0.0515 mmol, 2 equiv) and I2 (9.8 mg, 0.0386 mmol,
1.5 equiv) at room temperature. The resulting suspension was irradiated with sunlamp (90
W, 6 inches from the walls of the flask) for 20 minutes. Irradiation was then halted and the crude mixture was washed with saturated aqueous Na2S2O3 (2.5 mL) until colorless.
The aqueous layer was back-extracted twice with EtOAc (2 x 2.5 mL) and the combined organic layer washed with brine (5 mL), dried over MgSO4 and concentrated in vacuo.
The resulting yellow oil was purified by silica gel chromatography (1:4 EtOAc:hexanes) to give pure 2-58 (8.0 mg, 61%) as a white soild.
Physical state: white solid;
Rf = 0.42 (silica gel, 2:3 EtOAc:hexanes);
1 H NMR (600 MHz, CDCl3): δ 5.76–5.65 (m, 1 H), 4.91 (s, 1 H), 4.07–3.79 (m, 8 H),
3.15 (d, J = 12.5 Hz, 1 H), 2.86 (d, J = 11.8 Hz, 1 H), 2.49 (dt, J = 14.5, 2.7 Hz, 1 H),
2.44–2.40 (m, 1H), 2.37 (d, J = 12.5 Hz, 1 H), 2.27 (dd, J = 14.6, 2.5 Hz, 1 H), 2.18–2.08
(m, 2 H), 2.07–1.87 (m, 4 H), 1.67–1.59 (m, 3 H), 1.49–1.35 (m, 2 H), 0.93 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 210.0, 136.7, 128.6, 117.1, 108.6, 65.5, 64.8, 64.6, 64.3,
59.9, 57.2, 56.8, 50.7, 49.7, 47.5, 43.7, 41.9, 41.3, 36.1, 33.0, 31.3, 20.4, 14.9.
! 95 Aldehydes 2-64 and 2-65: A stock solution of 1 M of HIO3 in DMSO was heated at 80
ºC for 1 h. After cooling to 60 ºC, 40 µL of this stock solution (1.5 equiv) was transferred to a vial that has been pre-heated at 60 ºC. A solution of 2-63 (10 mg, 0.0266 mmol) in
4:1 DMSO:cyclohexene (125 µL) was then added and the resulting mixture heated at 60
ºC overnight. After cooling, sat. aq. NaHCO3 (2.5 mL) was added to the reaction mixture.
The aqueous phase was extracted with EtOAc (3 x 2.5 mL), and the combined organic portions were washed sequentially with H2O (2.5 mL) and brine (2.5 mL), and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (1:9 to 7:3 EtOAc:hexanes) to afford aldehydes 2-64 and 2-65.
Spectroscopic data for 2-64:
1 H NMR (600 MHz, CDCl3): δ 9.86 (d, J = 1.6 Hz, 1 H), 4.05–3.71 (m, 4 H), 2.97 (s, 1
H), 2.67–2.59 (m, 1 H), 2.65 (d, J = 11.4 Hz, 1 H), 2.59–2.55 (m, 1 H), 2.38 (qd, J =
11.3, 3.5 Hz, 1 H), 2.31 (d, J = 11.3 Hz, 1 H), 2.27–2.19 (m, 2 H), 2.13 (d, J = 12.3 Hz, 1
H), 2.10–1.98 (m, 5 H), 1.95 (ddd, J = 14.4, 9.7, 6.2 Hz, 1 H), 1.80 (dddd, J = 13.0, 9.6,
7.4, 3.5 Hz, 1 H), 1.42 (qd, J = 12.2, 6.2 Hz, 1 H), 1.30–1.21 (m, 2 H), 0.91 (d, J = 0.9
Hz, 3 H).
Enones 2-67 and 2-68: To a solution of (PhSe)2 (62.4 mg, 0.2 mmol) in EtOH (1 mL) was added NaBH4 (15 mg, 0.397 mmol, ca. 2 equiv relative to (PhSe)2) upon which vigorous bubbling was observed. After the solution turned colorless, 400 µL of this stock solution (ca. 3 equiv relative to 2-62) was added to a solution of 2-62 (10 mg, 0.0256 mmol) in EtOH (125 µL) at room temperature. After 15 min, H2O (3 mL) was added to the reaction, followed by EtOAc (3 mL). The aqueous phase was extracted with EtOAc
! 96 (2 x 2.5 mL) and the combined organic portions were washed with brine (3 mL), dried over Na2SO4, and concentrated in vacuo. The crude mixture was purified by preparative
TLC (3:1 EtOAc:hexanes) to afford enones 2-67 (1.1 mg, 11%) and 2-68 (5.4 mg, 56%).
Spectroscopic data for 2-68:
1 H NMR (600 MHz, CDCl3): δ 5.98 (d, J = 1.4 Hz, 1 H), 4.64 (d, J = 3.1 Hz, 1 H), 4.41
(dd, J = 11.8, 3.2 Hz, 1 H), 4.34–4.27 (m, 1 H), 3.97–3.79 (m, 5 H), 2.77 (d, J = 12.1 Hz,
1 H), 2.68 (dd, J = 16.2, 8.1 Hz, 1 H), 2.58 (dd, J = 16.1, 4.5 Hz, 1 H), 2.46 ? 2.39 (td, J =
13.4, 4.4 Hz, 1H), 2.38 (dt, J = 3.1, 1.7 Hz, 1 H), 2.35 (d, J = 10.6 Hz, 1 H), 2.20 (d, J =
12.0 Hz, 1 H), 2.14–1.91 (m, 5 H), 1.81 (dddd, J = 13.1, 10.1, 6.9, 3.4 Hz, 1 H), 1.39
(dtd, J = 24.1, 12.4, 6.1 Hz, 1 H), 1.32–1.22 (m, 1 H), 0.86 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 215.2, 197.3, 163.0, 126.1, 117.2, 71.5, 65.6, 64.7, 62.9,
62.7, 50.00, 49.9, 49.5, 48.6, 43.0, 38.6, 34.3, 33.4, 32.8, 22.1, 15.1.
Note: Occasionally, aromatization of the A ring to the phenol could also be observed in some of the screenings we attempted. Spectroscopic data for this product:
1 H NMR (600 MHz, CDCl3): δ 7.19 (d, J = 8.5 Hz, 1 H), 6.66 (dd, J = 8.6, 2.7 Hz, 1 H),
6.56 (d, J = 2.8 Hz, 1 H), 4.07–3.79 (m, 4 H), 3.51 (d, J = 11.5 Hz, 1 H), 2.87 (d, J = 11.4
Hz, 1 H), 2.84–2.71 (m, 2 H), 2.31 (td, J = 11.8, 7.4 Hz, 1 H), 2.22 (d, J = 11.4 Hz, 1 H),
2.09 (tt, J = 15.6, 12.9 Hz, 1 H), 1.97 (tdd, J = 15.6, 7.6, 4.5 Hz, 2 H), 1.86 (dddd, J =
12.8, 9.8, 7.3, 3.3 Hz, 1 H), 1.78 (qd, J = 11.6, 2.4 Hz, 1 H), 1.48 (dqd, J = 47.3, 12.3, 5.9
Hz, 2 H), 0.87 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 210.4, 153.9, 139.0, 131.6, 123.9, 117.7, 115.2, 113.0,
65.6, 64.8, 55.8, 51.2, 49.5, 49.2, 40.4, 34.7, 29.9, 27.3, 21.7, 15.1.
! 97 Diols 2-69 and 2-70: To a vial containing diepoxide 2-62 (25 mg, 0.064 mmol) was added 10% Pt/C (3 mg) and EtOAc (0.5 mL). This vial was placed inside a bomb reactor, which was then charged with H2 gas (30 bar). After 24 h, the reactor was vented, and the reaction mixture was filtered through a pad of Celite, washing with EtOAc. The resulting colorless solution was concentrated in vacuo and the crude mixture was purified by preparative TLC (EtOAc) to afford diols 2-69 (12 mg, 48%) and 2-70 (10 mg, 40%) as white solids.
Spectroscopic data for 2-69:
Rf = 0.09 (silica gel, EtOAc);
+ HRMS (m/z): calcd for C21H28O7, [M+H] , 393.1913; found, 393.1916;
IR (film) λmax: 3445, 2942, 2880, 1702, 1459, 1311, 1170, 1101, 1046, 916;
1 H NMR (600 MHz, CDCl3): δ 4.40 (d, J = 11.6 Hz, 1 H), 4.15 (t, J = 3.0 Hz, 1 H), 4.12
(d, J = 11.6 Hz, 1 H), 3.91–3.72 (m, 4 H), 3.69 (d, J = 4.0 Hz, 1 H), 3.14 (dt, J = 4.1, 2.6
Hz, 1 H), 2.93 (t, J = 2.7 Hz, 1 H), 2.69 (d, J = 11.8 Hz, 1 H), 2.16 (d, J = 11.2 Hz, 1 H),
2.10 (d, J = 11.7 Hz, 1 H), 2.06 (td, J = 13.9 4.0 Hz, 1 H), 2.02–1.95 (m, 2 H), 1.93–1.82
(m, 3 H), 1.77–1.70 (m, 1 H), 1.31 (qd, J = 12.1, 6.2 Hz, 1 H), 1.20–1.10 (m, 2 H), 1.00
(dt, J = 13.8, 3.3 Hz, 1 H), 0.78 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 211.8, 117.4, 67.5, 65.6, 64.8, 64.8, 63.2, 60.7, 59.7,
59.4, 53.2, 50.2, 50.0, 49.8, 40.1, 37.9, 34.4, 31.7, 30.2, 22.1, 15.0.
Spectroscopic data for 2-70:
Rf = 0.15 (silica gel, EtOAc);
+ HRMS (m/z): calcd for C21H28O7, [M+H] , 393.1913; found, 393.1915;
! 98 IR (film) λmax: 3452, 2944, 2881, 1702, 1459, 1311, 1173, 1101, 1054, 937, 917;
1 H NMR (600 MHz, CDCl3): δ 4.63 (s, 1 H), 4.46 (d, J = 11.5 Hz, 1 H), 4.17 (d, J =
11.5 Hz, 1 H), 4.00–3.78 (m, 4 H), 3.60 (d, J = 3.6 Hz, 1 H), 3.05 (s, 1 H), 2.82 (s, 1 H),
2.80 (d, J = 11.8 Hz, 1 H), 2.54 (d, J = 11.3 Hz, 1 H), 2.16 (d, J = 11.7 Hz, 1 H), 2.14–
2.03 (m, 3H), 1.99–1.88 (m, 3 H), 1.81 (dddd, J = 12.9, 10.2, 7.3, 3.4 Hz, 1 H), 1.38 (tt, J
= 12.2, 6.0 Hz, 1 H), 1.35–1.22 (m, 1 H), 1.04 (dt, J = 13.7, 3.4 Hz, 1 H), 0.85 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 212.5, 117.5, 65.6, 64.8, 63.4, 62.5, 62.1, 59.7, 59.4,
54.6, 52.1, 50.2, 50.0, 49.5, 40.5, 37.9, 34.4, 31.6, 30.1, 22.1, 15.0.
Ketone 2-86: The procedure outlined for the synthesis of 2-84 from 2-81 was employed for the preparation of 2-86 from 2-31.
Physical state: white foam;
Rf = 0.11 (silica gel, 1:4 EtOAc:hexanes);
+ HRMS (m/z): calcd for C19H24O3, [M-OH] , 283.1698; found, 283.1691;
IR (film) λmax: 3489, 2932, 2863, 2837, 1726, 1609, 1499, 1465, 1269, 1253, 1236, 1052,
1039;
1 H NMR (600 MHz, CDCl3): δ 7.20 (d, J = 8.7 Hz, 1 H), 6.74 (dd, J = 8.7, 2.9 Hz, 1 H),
6.66 (d, J = 2.8 Hz, 1 H), 3.78 (s, 3 H), 2.99–2.84 (m, 2 H), 2.63–2.57 (m, 1 H), 2.51–
2.45 (m, 2 H), 2.33 (dq, J = 13.3, 3.6 Hz, 1 H), 2.25–2.20 (m, 2 H), 1.88 (ddd, J = 13.8,
6.8, 4.3 Hz, 1 H), 1.65–1.47 (m, 4 H), 1.45–1.36 (m, 2 H), 1.09 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 221.2, 157.8, 137.7, 131.4, 126.9, 113.9, 112.1, 82.0,
55.4, 53.6, 45.1, 40.1, 33.4, 32.3, 30.5, 26.9, 25.8, 22.2, 13.1.
! 99 Dienoate 2-89: To a solution of 2-86 (20 mg, 66.6 µmol) in EtOH (1.2 mL) was added anhydrous N2H4 (21 µL, 666 µmol, 10 equiv) and Et3N (93 µL, 666 µmol, 10 equiv). The mixture was heated at 50 ºC for 5 hours, after which the reaction was allowed to cool and concentrated in vacuo. The residue so obtained was dissolved in degassed THF (1.4 mL) and Et3N (37 µL, 266 µmol, 4 equiv) was added. A stock solution of I2 (51 mg, 200
µmol, 3 equiv) in THF (0.4 mL) was prepared and added dropwise to the reaction mixture. After the solution stayed brown for more than 30 sec, addition was halted and stirring was continued for 10 min. The reaction was then diluted with EtOAc (5 mL) and washed with sat. aq. Na2S2O3 (5 mL). The aqueous layer was extracted with EtOAc (3 x
5 mL) and the combined organic portions were washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was passed through a short pad of silica gel, washing with 1:1 hexanes:EtOAc. Concentration in vacuo afforded vinyl iodide 2-87 which was used for the next step without further purification.
Iodide 2-87 and stannane 2-88 (75 mg, 201 µmol, 3 equiv) were dissolved in DMF (1 mL) and the resulting solution was degassed by bubbling argon through for 15 min. To this solution was sequentially added [Ph2PO2][NBu4] (91 mg, 200 µmol, 3 equiv),
Pd(PPh3)4 (11.6 mg, 10 µmol, 0.15 equiv) and CuTC (32 mg, 167 µmol, 2.5 equiv). The reaction mixture was then stirred for 2 hours and then quenched with water (2.5 mL). The suspension was passed through a pad of Celite, washing with EtOAc (10 mL). The aqueous phase was extracted with EtOAc (3 x 5 mL) and the combined organic layers were successively washed with sat. aq. NaHCO3 (10 mL), H2O (2 x 5 mL) and sat. aq.
NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by
! 100 silica gel chromatography (3:1 to 1:1 EtOAc:hexanes) afforded dienoate 2-89 (13.4 mg,
55% over 2 steps) as a white solid.
Rf = 0.59 (silica gel, 3:2 EtOAc:hexanes);
+ HRMS (m/z): calcd for C23H26O4, [M+H] , 367.1909; found, 367.1918;
1 H NMR (600 MHz, CDCl3): δ 7.24 (d, J = 8.8 Hz, 1 H), 6.74 (dd, J = 8.7, 2.8 Hz, 1 H),
6.66 (d, J = 2.6 Hz, 1 H), 6.16 (s, 1 H), 6.01 (s, 1 H), 5.03 (d, J = 16.3 Hz, 1 H), 4.97 (d, J
= 16.3 Hz, 1 H), 2.96–2.87 (m, 2 H), 2.76 (d, J = 18.6 Hz, 1 H), 2.49 (t, J = 11.7 Hz, 1
H), 2.42 (dd, J = 17.9, 2.7 Hz, 1 H), 2.32–2.22 (m, 2 H), 2.17 (d, J = 13.8 Hz, 1 H), 1.67
(t, J = 11.6 Hz, 1 H), 1.50–1.31 (m, 3 H), 1.33 (s, 3H).
13 C NMR (CDCl3, 151 MHz): δ 174.5, 158.4, 157.8, 143.9, 137.9, 132.6, 131.1, 127.3,
113.9, 112.7, 112.1, 84.9, 71.8, 55.4, 52.5, 44.5, 40.4, 40.0, 38.7, 30.6, 25.9, 23.6, 16.8.
Enoate 2-90: For this procedure, Raney nickel (1.0 g) was washed with H2O (3 x 5 mL), sat. aq. Rochelle’s salt (3 x 5 mL), H2O (5 x 5 mL), MeOH (3 x 5 mL), and H2O (3 x 5 mL) after which it was stored under H2O (10 mL). To dienoate 2-89 (4 mg, 0.011 mmol) in THF (0.4 mL) was added the washed Raney nickel (40 mg, 10 wt. equiv, which includes water). The heterogeneous mixture was stirred at room temperature for 14 h, at which point NMR analysis showed that all starting material has been completely consumed. The mixture was filtered through a pad of Celite, washing with EtOAc and concentrated in vacuo. The crude reaction mixture was purified by preparative TLC (1:1
EtOAc:hexanes) to afford enoate 2-90 (3.6 mg, 90%) as a white solid.
Physical state: white solid;
Rf = 0.59 (silica gel, 3:2 EtOAc:hexanes);
! 101 IR (film) λmax: 3465, 2927, 2863, 1781, 1737, 1621, 1499, 1258, 1234, 1036, 905;
1 H NMR (600 MHz, CDCl3): δ 7.19 (d, J = 8.6 Hz, 1 H), 6.73 (dd, J = 8.7, 2.8 Hz, 1 H),
6.64 (d, J = 2.8 Hz, 1 H), 5.93 (d, J = 1.7 Hz, 1 H), 4.86 (dd, J = 17.6, 1.8 Hz, 1 H), 4.77
(dd, J = 17.6, 1.8 Hz, 1 H), 3.78 (s, 3 H), 3.24 (t, J = 9.7 Hz, 1 H), 2.92–2.86 (m, 2 H),
2.54–2.44 (m, 1 H), 2.31–2.24 (m, 1 H), 2.23–2.12 (m, 3 H), 1.91–1.81 (m, 1 H), 1.67
(ddd, J = 15.7, 10.3, 4.6 Hz, 1 H), 1.49–1.29 (m, 4 H), 1.08 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 174.1, 171.2, 157.7, 137.7, 131.5, 126.9, 117.0, 113.8,
112.0, 85.5, 73.9, 55.37, 49.1, 48.3, 45.2, 40.00, 31.2, 30.7, 30.6, 26.1, 24.8, 23.3, 18.5.
Iodide 2-91: To a solution of vinyl iodide 2-87 (10 mg, 0.0243 mmol), N2H4 (25 µL), and
EtCO2H (20 µL) in EtOH (0.5 mL) was saturated with O2 gas via bubbling over a period of 15 min. The resulting solution was refluxed for 2.5 h. After cooling, the crude mixture was concentrated in vacuo, redissolved in CH2Cl2 (7.5 mL), and washed with H2O (2.5 mL) and then brine (2.5 mL). The organic layer was dried over MgSO4, concentrated in vacuo to afford 2-91 as white foam. This material was used for the next step without further purification.
Physical state: white foam;
Rf = 0.59 (silica gel, 3:2 EtOAc:hexanes);
1 H NMR (600 MHz, CDCl3): δ 7.22 (d, J = 8.6 Hz, 1 H), 6.74 (dd, J = 8.7, 2.8 Hz, 1 H),
6.64 (d, J = 2.8 Hz, 1 H), 4.46 (t, J = 9.6 Hz, 1 H), 3.78 (s, 3 H), 2.95–2.81 (m, 2 H), 2.50
(dtd, J = 14.3, 9.6, 4.9 Hz, 1 H), 2.43 (dt, J = 10.9, 5.5 Hz, 1 H), 2.30–2.17 (m, 3 H),
2.07 (ddd, J = 14.4, 12.3, 5.0 Hz, 1 H), 1.65 (dd, J = 10.6, 3.3 Hz, 1 H), 1.60 (ddd, J =
! 102 14.5, 9.9, 4.7 Hz, 1 H), 1.50 (td, J = 11.5, 2.1 Hz, 1 H), 1.45–1.37 (m, 1 H), 1.34 (td, J =
7.0, 3.9 Hz, 1 H), 0.99 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 157.8, 137.8, 131.8, 126.9, 113.8, 112.0, 80.6, 55.4,
48.5, 45.9, 42.5, 40.3, 35.0, 32.7, 32.2, 30.7, 26.7, 23.0, 16.6.
Furan 2-95: To a solution of 2-furanboronic acid (1.00 g, 8.94 mmol) in benzene (30 mL) was added pinacol (1.27 g, 10.73 mmol, 1.2 equiv). The reaction vessel was incorporated into a standard Dean-Stark setup and immersed in an oil bath preheated to
110 ºC and stirred vigorously. After 12 hours, the reaction was lifted out of the oil bath and allowed to cool. The crude mixture was concentrated in vacuo, and purified by silica gel chromatography (20:1 to 10:1 EtOAc:hexanes) to afford 2-95 (1.61 g, 93%) as a white solid.
Physical state: white solid;
Rf = 0.41 (silica gel, 10:1 EtOAc:hexanes);
IR (film) λmax: 2979, 2933, 1570, 1504, 1373, 1347, 1306, 1141, 1066;
1 H NMR (400 MHz, CDCl3): δ 7.78 (dd, J = 1.4, 0.8 Hz, 1 H), 7.46 (t, J = 1.6 Hz, 1 H),
6.59 (dd, J = 1.8, 0.8 Hz, 1 H), 1.31 (s, 12 H).
13 C NMR (CDCl3, 100 MHz): δ 151.3, 143.0, 113.2, 83.6, 24.9.
Silylfuran 2-96: A flame-dried pressure vessel was charged with furan 2-95 (70 mg,
0.361 mmol), [Ir(OMe)(cod)]2 (12 mg, 0.018 mmol, 0.05 equiv), and dtbpy (10 mg, 0.036 mmol, 0.1 equiv), and then evacuated and flushed with argon three times. Under a positive flow of argon, 2-norbornene (51 mg, 0.541 mmol, 1.5 equiv) and degassed THF
! 103 (1.8 mL) were added. After stirring for 5 min, PhMe2SiH (86 µL, 0.541 mmol, 1.5 equiv) was added dropwise and the reaction mixture was heated at 80 ºC for 8 h. The mixture was concentrated in vacuo, and the crude product was purified by silica gel chromatography (1:40 Et2O:hexanes) to afford furan 2-96 (51 mg, 43%) as a white solid.
Physical state: white solid;
Rf = 0.18 (silica gel, 40:1 Et2O:hexanes);
IR (film) λmax: 2978, 2932, 1573, 1479, 1372, 1325, 1193, 1143, 1105, 969;
1 H NMR (600 MHz, CDCl3): δ 8.02 (s, 1 H), 7.60–7.51 (m, 2 H), 7.43–7.32 (m, 3 H),
6.91 (s, 1 H), 1.33 (d, J = 8.3 Hz, 12 H), 0.55 (s, 6 H).
13 C NMR (CDCl3, 151 MHz): δ 158.9, 155.8, 134.0, 129.5, 128.0, 125.1, 83.6, 24.9, -
2.8.
Estrone-furan adduct 2-99: The pinacol protecting group on furan 2-96 was removed according to the procedure described in reference 42 in Section 2.12 to provide boronic acid 2-97. Hydrazone 2-98 was prepared by heating ketone 2-86 (10 mg, 0.0333 mmol) and TsNHNH2 (9.4 mg, 0.050 mmol, 1.5 equiv) in dioxane (0.4 mL) at 110 ºC. After 5 h, the reaction was allowed to cool, and concentrated in vacuo. The crude product was purified by silica gel chromatography (1:1 EtOAc:hexanes) to afford hydrazone 2-98 (10 mg, 64%) as a white solid.
A mixture of hydrazone 2-98 (10 mg, 0.0213 mmol), boronic acid 2-97 (10.5 mg, 0.0426 mmol, 2 equiv), and K2CO3 (6.5 mg, 0.0469 mmol, 2.2 equiv) in dioxane (0.3 mL) was heated at 110 ºC for 5 h. The reaction mixture was allowed to cool, filtered through a pad
! 104 of Celite, and concentrated in vacuo. Purification by preparative TLC (4:1
EtOAc:hexanes) afforded adduct 2-99 (2.1 mg, ca. 20%).
Butenolide 2-94: To a solution of 2-99 (2.1 mg, 0.0043 mmol) in CH2Cl2 (0.3 mL) was added solid NaOAc (1.7 mg, 0.0205 mmol, ca. 5 equiv) and a 32% wt. solution of
AcOOH (5 µL). The resulting solution was stirred at room temperature for 24 h and then quenched with sat. aq. Na2S2O3 (2.5 mL). The aqueous phase was extracted with EtOAc
(3 x 2.5 mL) and the combined organic portions were dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (1:1 EtOAc:hexanes) afforded butenolide 2-94 (1.1 mg, ca. 70%) as a white solid.
Rf = 0.59 (silica gel, 3:2 EtOAc:hexanes);
1 H NMR (600 MHz, CDCl3): δ 7.19 (d, J = 8.6 Hz, 1 H), 6.73 (dd, J = 8.7, 2.8 Hz, 1 H),
6.64 (d, J = 2.7 Hz, 1 H), 5.92 (d, J = 1.9 Hz, 1 H), 5.00 (dd, J = 18.0, 1.8 Hz, 1 H), 4.84
(dd, J = 17.9, 1.9 Hz, 1 H), 3.78 (s, 3 H), 2.96–2.81 (m, 3 H), 2.55 (t, J = 11.6 Hz, 1 H),
1.94 (ddt, J = 18.4, 8.8, 4.5 Hz, 1 H), 1.75–1.67 (m, 2 H), 1.63 (td, J = 13.7, 4.0 Hz, 1 H),
1.51–1.41 (m, 3 H), 1.26–1.22 (m, 2 H), 0.92 (s, 3 H).
13 C NMR (CDCl3, 151 MHz): δ 174.5, 174.4, 157.8, 137.6, 131.7, 126.9, 118.0, 113.8,
112.1, 85.0, 73.6, 55.4, 50.8, 49.9, 45.5, 40.3, 39.9, 32.7, 30.7, 27.4, 27.3, 23.8, 16.1.
Hydrazone 2-101: To a solution of 2-84 (10 mg, 0.0224 mmol) in CH2Cl2 (0.25 mL) was added TrisNHNH2 (10 mg, 0.0336 mmol, 1.5 equiv). The resulting solution was stirred at room temperature under Ar for 10 h. The crude mixture was concentrated in vacuo, and purified by flash chromatography (gradient) to afford hydrazine 2-101 (13 mg, 80%) as a white solid.
! 105 Physical state: white solid;
1 H NMR (600 MHz, CDCl3): δ 7.18 (s, 1 H), 7.14 (s, 2 H), 5.08 (dd, J = 5.4, 1.9 Hz, 1
H), 4.36 (d, J = 12.1 Hz, 1 H), 4.24 (dd, J = 3.8, 2.1 Hz, 1 H), 4.18 (p, J = 6.7 Hz, 2 H),
3.97 (td, J = 8.8, 4.5 Hz, 1 H), 3.72 (d, J = 12.0 Hz, 1 H), 3.15 (d, J = 4.2 Hz, 1 H), 2.90
(p, J = 6.9 Hz, 1 H), 2.43–2.28 (m, 2 H), 2.19–2.11 (m, 1 H), 2.11–2.01 (m, 2 H), 1.92–
1.77 (m, 3 H), 1.53 (dd, J = 13.7, 3.7 Hz, 2 H), 1.48–1.35 (m, 5 H), 1.27–1.21 (m, 20 H),
1.08 (s, 3 H), 0.88 (t, J = 7.8 Hz, 3 H), 0.67 (q, J = 7.8 Hz, 2 H).
13 C NMR (CDCl3, 151 MHz): δ 167.8, 153.4, 151.4, 131.2, 123.8, 101.9, 82.9, 71.6,
69.4, 67.2, 64.7, 59.8, 50.6, 48.8, 45.9, 44.7, 40.7, 36.7, 35.1, 34.3, 33.3, 30.0, 29.4, 25.0,
24.9, 24.0, 23.7, 23.7, 23.7, 23.2, 21.2, 16.5, 7.8.
Acetate 2-104a: To a solution of 2-84 (10 mg, 0.0224 mmol) in DMF (0.25 mL) was added Ac2O (6.4 µL, 0.067 mmol, 3 equiv), pyridine (12.6 µL, 0.156 mmol), and DMAP
(2.7 mg, 0.0224 mmol, 1 equiv). The resulting solution was stirred at 40 ºC for 20 h. The reaction was quenched by addition of H2O (2.5 mL), and the aqueous phase was extracted with EtOAc (3 x 2.5 mL). The combined organic portions were washed with H2O (2.5 mL) and brine (2 x 2.5 mL), dried over Na2SO4, and concentrated in vacuo. The crude mixture was purified by preparative TLC (3:2 EtOAc:hexanes) to afford acetate 2-104a
(7.2 mg, 66%) as white foam.
Physical state: white foam;
Rf = 0.38 (silica gel, 3:2 EtOAc:hexanes);
IR (film) λmax: 3496, 2933, 2876, 1740, 1459, 1378, 1334, 1228, 1207, 1057;
! 106 1 H NMR (600 MHz, CDCl3): δ 5.32 (td, J = 9.0, 4.5 Hz, 1 H), 4.46 (dd, J = 5.1, 2.0 Hz,
1 H), 4.33 (d, J = 12.4 Hz, 1 H), 4.29 (d, J = 3.2 Hz, 1 H), 3.74 (d, J = 12.3 Hz, 1 H),
2.54–2.37 (m, 2 H), 2.26–2.15 (m, 3 H), 1.99 (s, 3 H), 2.00–1.96 (m, 1 H), 1.91–1.85 (m,
2 H), 1.83–1.72 (m, 2 H), 1.64 (td, J = 12.5, 3.7 Hz, 1 H), 1.56–1.44 (m, 3 H), 1.31 (s, 3
H), 1.19 (s, 3 H), 1.13 (s, 3 H), 0.89 (t, J = 7.8 Hz, 3 H), 0.68 (q, J = 8.0 Hz, 2 H).
13 C NMR (CDCl3, 151 MHz): δ 218.7, 169.0, 101.5, 80.7, 712.0, 69.4, 66.4, 65.0, 59.8,
52.7, 49.0, 44.1, 41.0, 37.3, 36.8, 345.0, 33.4, 32.9, 27.9, 24.2, 23.0, 21.7, 20.9, 14.8, 7.8.
MOM ether 2-104b: To a solution of 2-84 (10 mg, 0.0224 mmol) in CH2Cl2 (0.25 mL) at 0 ºC was added Hunig’s base (14 µL, 0.0804 mmol, ca. 3.5 equiv), MOMCl (4 µL,
0.0527 mmol, ca. 2.4 equiv) and DMAP. The reaction was warmed from 0 ºC to room temperature, and stirred for 24 h. MeOH (50 µL) was added, and the reaction mixture was concentrated in vacuo, before being purified by preparative TLC (3:2
EtOAc:hexanes) to afford 2-104b (6.8 mg, 62%) as white foam.
Physical state: white foam;
Rf = 0.45 (silica gel, 3:2 EtOAc:hexanes);
IR (film) λmax: 3485, 2930, 1738, 1459, 1378, 1334, 1280, 1226, 1206, 1148, 1098, 1057,
1031;
1 H NMR (600 MHz, CDCl3): δ 4.81 (dd, J = 4.8, 2.2 Hz, 1 H), 4.62 (s, 2H), 4.33 (dd, J
= 12.2, 1.4 Hz, 1 H), 4.28 (t, J = 3.0 Hz, 1 H), 4.04 (td, J = 7.9, 4.1 Hz, 1 H), 3.68 (d, J =
12.2 Hz, 1 H), 3.29 (s, 3 H), 2.53–2.36 (m, 2 H), 2.32–2.12 (m, 3 H), 1.98–1.87 (m, 2 H),
1.86–1.77 (m, 2 H), 1.74–1.62 (m, 2 H), 1.61–1.46 (m, 2 H), 1.32 (s, 3 H), 1.26 (s, 3 H),
1.08 (s, 3 H), 0.90 (t, J = 7.8 Hz, 3 H), 0.69 (q, J = 8.2 Hz, 2 H).
! 107 13 C NMR (CDCl3, 151 MHz): δ 219.8, 101.5, 96.9, 80.8, 74.2, 72.2, 66.5, 65.2, 60.0,
56.1, 52.6, 48.9, 45.7, 41.0, 38.3, 36.9, 35.1, 33.6, 33.1, 28.2, 24.4, 23.2, 20.9, 15.8, 7.9.
! 108
Appendix 1
Spectra
! 109 ! !! ! O O H Me H 2-44 H HO O O
! ! !
! 110 ! ! ! O O H Me H 2-44 H HO O O
! !
! 111 ! ! ! O O H Me H 2-59 H O I O O
! ! ! !
! 112 ! ! ! O O H Me H 2-59 H O I O O ! ! ! !
! 113 ! ! ! O O H Me H 2-60 H O HO O
! ! !
! 114 ! ! ! O O H Me H 2-60 H O HO O
! ! !
! 115 ! O O H Me H 2-61 H 5 O O HO O
! ! ! ! !
! 116 O O H Me H 2-61 H 5 O O HO O ! ! ! ! ! !
! 117 ! ! ! O O H Me H H 2-62 O O HO O O ! ! !
! 118 ! ! ! O O H Me H H 2-62 O O HO O O
! ! !
! 119 O O H Me H 2-66 H O OH HO HO O
! ! ! ! ! ! !
! 120 O O H Me H 2-66 H O OH HO HO O ! ! ! ! ! !
! 121 ! ! ! O O H Me H 2-79 H O OH O O Me O Me
! ! !
! 122 ! ! ! O O H Me H 2-79 H O OH O O Me O Me
! ! !
! 123 ! ! ! O O H Me H H 2-80 O O O Et B Me O O Me
! ! !
! 124 ! ! ! O O H Me H H 2-80 O O O Et B Me O O Me
! ! !
! 125 ! ! O O H Me H H OH O O Et B Me O O Me
! ! ! !
! 126 ! ! O O H Me H H OH O O Et B Me O O Me
! ! ! !
! 127 ! ! ! O H Me H H OH 2-81 O O Et B Me O O Me
! ! !
! 128 ! ! ! O H Me H H OH 2-81 O O Et B Me O O Me
! ! !
! 129 ! ! O H Me H H OH 2-82 O O Et B Me O O Me
! ! ! !
! 130 ! ! O H Me H H OH 2-82 O O Et B Me O O Me
! ! ! !
! 131 ! ! O Me H H OH 2-83 O O Et B Me O O Me
! ! ! !
! 132 ! ! O Me H H OH 2-83 O O Et B Me O O Me
! ! ! !
! 133 ! ! ! O OH Me H H OH (protected O O Et B 2-84 ouabageninone) Me O O Me
! ! !
! 134 ! ! ! O OH Me H H OH (protected O O Et B 2-84 ouabageninone) Me O O Me ! ! !
! 135 ! ! ! O O H Me O 2-54 H AcO O O
! ! !
! 136 ! ! ! O O H Me O 2-54 H AcO O O ! ! !
! 137 ! ! ! O O H Me H 2-55 H O AcO O O
! ! !
! 138 ! ! ! O O H Me H 2-56 H AcO O O
! ! !
! 139 ! ! ! O O H Me H 2-56 H AcO O O ! ! !
! 140 ! ! ! O O H Me 2-57 H F H HO O O HO
! ! !
! 141 ! ! ! O O H Me 2-57 H F H HO O O HO ! ! !
! 142 ! ! ! O 2-58 O H Me I H O O O
! ! !
! 143 ! ! ! O 2-58 O H Me I H O O O
! ! !
! 144 ! ! ! O O H Me H 2-68 H O HO HO O
! ! !
! 145 ! ! O O H Me H 2-68 H O HO HO O
! ! ! !
! 146 ! ! ! O O H Me H H O HO
! ! !
! 147 ! ! O O H Me H H O HO
! ! !
! 148 ! ! ! O O H Me H 2-70 H O O HO O HO
! ! !
! 149 ! ! O O H Me H 2-70 H O O HO O HO
! ! ! !
! 150 ! ! O O H Me H 2-69 H O O HO O HO ! ! ! !
! 151 ! ! O O H Me H 2-69 H O O HO O HO
! ! ! !
! 152 ! ! O O H Me H 2-75 H O OH HO HO HO
! ! ! !
! 153 ! ! O O H Me H 2-75 H O OH HO HO HO ! ! ! !
! 154 ! ! O OH Me H 2-86 H MeO
! ! ! !
! 155 ! ! O OH Me H 2-86 H MeO ! ! ! !
! 156 ! ! ! O O OH Me H 2-89 H MeO
! ! ! !
! 157 ! ! O O OH Me H 2-89 H MeO
! ! !
! 158 ! ! ! O O OH Me H 2-90 H MeO ! ! !
! 159 ! ! ! O O OH Me H 2-90 H MeO ! ! !
! 160 ! ! I OH Me H 2-91 H MeO
! ! ! !
! 161 ! ! I OH Me H 2-91 H MeO ! ! ! !
! 162 ! ! Bpin O 2-95
! ! ! !
! 163 ! ! Bpin O 2-95
! ! !
! 164 ! ! ! Bpin O 2-96 Si 2 PhMe
! ! !
! 165 ! ! Bpin O 2-96 Si 2 PhMe
! ! !
! 166 ! ! ! O O OH Me H 2-94 H MeO
! ! !
! 167 ! ! ! O O OH Me H 2-94 H MeO ! ! !
! 168 ! ! NHTris N OH Me H 2-101 H OH O O Et B O O Me Me ! ! ! !
! 169 ! ! ! NHTris N OH Me H 2-101 H OH O O Et B O O Me Me
! ! ! !
! 170 ! ! ! O Me Si 2 OH OTMS H PhMe 2-103 H OH O O Et B O O Me Me
! ! !
! 171 ! ! O Me Si 2 OH OTMS H PhMe 2-103 H OH O O Et B O O Me Me
! ! ! !
! 172 ! ! ! O OH Me H H OAc 2-104a O O Et B O O Me Me ! ! ! !
! 173 ! ! O OH Me H H OAc 2-104a O O Et B O O Me Me
! ! ! !
! 174 ! ! ! O OH Me H H 2-104b O O MOMO Et B O O Me Me
! ! !
! 175 ! ! O OH Me H H 2-104b O O MOMO Et B O O Me Me
! ! ! !
! 176 ! ! ! O O OH Me H 2-110 H OH O O Et B Me O O Me
! ! !
! 177 ! ! O O OH Me H 2-110 H OH O O Et B Me O O Me
! ! ! !
! 178 ! ! ! O O OH Me H 2-106 H OH O O Et B Me O O Me
! ! ! !
! 179 ! ! ! O O OH Me H 2-106 H OH O O Et B Me O O Me ! ! !
! 180 ! ! ! O O OH Me H 2-107 H OH O O Et B Me O O Me
! ! ! !
! 181 ! ! O O OH Me H 2-107 H OH O O Et B Me O O Me
! ! ! !
! 182 ! ! O O OH Me (synthetic) H H OH 2-108 O O Et B Me O O Me
! ! ! !
! 183 ! ! O O OH Me (synthetic) H H OH 2-108 O O Et B Me O O Me
! ! ! !
! 184 ! ! ! O O O ouabain O OH Me OH Me (synthetic) (from H H H OH 2-108 H OH degradation) 2-108 O O O Et B O Et B Me O O Me O O Me Me
! ! !
! 185 ! ! ! O O O ouabain O OH Me OH Me (synthetic) (from H H H OH 2-108 H OH degradation) 2-108 O O O Et B O Et B Me Me O O O O Me Me ! ! !
! 186 ! ! ! O F Me H H OH 2-111 O O Et B Me O O Me
! ! !
! 187 ! ! ! O F Me H H OH 2-111 O O Et B Me O O Me ! ! !
! 188 ! ! ! O O OH Me H H OH synthetic) OH , ouabagenin 2-1 ( HO HO HO
! ! ! !
! 189 ! ! ! O O OH Me H H OH synthetic) OH , ouabagenin 2-1 ( HO HO HO ! ! !
! 190 ! ! ! O O O O OH OH Me Me H H H H OH OH degradation) synthetic) OH OH , ouabagenin ouabagenin from 2-1 ( , HO HO 2-1 ( HO HO HO HO
! ! !
! 191 ! ! O O O O OH OH Me Me H H H H OH OH degradation) synthetic) OH OH , ouabagenin ouabagenin from 2-1 ( , HO HO 2-1 ( HO HO HO HO ! ! ! !
! 192 Table S3. 1H NMR data comparison between synthetic 2-108 and that obtained from ouabain degradation
2-108 from degradation (CDCl3, Synthetic 2-108 (CDCl3, 600 MHz) 600 MHz) 5.91 (s, 1 H) 5.91 (s, 1 H) 5.04 (dd, J = 5.3, 1.8 Hz, 1 H) 5.04 (dd, J = 5.2, 1.8 Hz, 1 H) 4.93 (dd, J = 18, 1.7 Hz, 1 H) 4.93 (dd, J = 18.0, 1.8 Hz, 1 H) 4.80 (dd, J = 17.9, 1.7 Hz, 1 H) 4.80 (dd, J = 17.9, 1.8 Hz, 1 H) 4.38 (d, J = 12.1 Hz, 1 H) 4.39 (d, J = 12.0 Hz, 1 H) 4.27 (s, 1 H) 4.27 (s, 1 H) 4.11 (td, J = 7.9, 4.0 Hz, 1 H) 4.11 (td, J = 8.1, 3.9 Hz, 1 H) 3.74 (d, J = 12.1 Hz, 1 H) 3.74 (d, J = 12.2 Hz, 1 H) 3.10 (d, J = 4.2 Hz, 1 H) 2.89 (dd, J = 9.2, 6.3 Hz, 1 H) 2.89 (dd, J = 9.0, 6.2 Hz, 1 H) 2.89 (dd, J = 9.2, 6.3 Hz, 1 H) 2.22–2.15 (m, 2 H) 2.22–2.15 (m, 2 H) 2.11 (dt, 13.7, 9.7 Hz, 1 H) 2.11 (dt, J = 13.5, 9.6 Hz, 1 H) 2.06 (dd, 13.7, 1.9 Hz, 1 H) 2.06 (dd, J = 13.7, 1.9 Hz, 1 H) 1.95–1.82 (m, 3 H) 1.95–1.82 (m, 3 H) 1.80–1.70 (m, 2 H) 1.80–1.71 (m, 2 H) 1.61 (dt, J = 13.9, 2.8 Hz, 1 H) 1.62–1.58 (m, 1 H) 1.55 (dt, J = 13.9, 2.8 Hz, 1 H) 1.56 (dt, J = 13.8, 3.0 Hz, 1 H) 1.53–1.39 (m, 3 H) 1.53–1.39 (m, 3 H) 1.34 (s, 3 H) 1.34 (s, 3 H) 1.29 (s, 3 H) 1.30 (s, 3 H) 1.20 (ddd, J = 16.0, 11.6, 5.4 Hz, 1 1.19 (m, 1 H) H) 0.97 (s, 3 H) 0.97 (s, 3 H) 0.90 (t, J = 7.7 Hz, 3 H) 0.90 (t, J = 7.8 Hz, 2 H) 0.69 (q, J = 7.7 Hz, 2 H) 0.69 (q, J = 7.8 Hz, 3 H) !
Table S4.13C NMR data comparison between synthetic 2-108 and that obtained from ouabain degradation
2-108 from degradation (CDCl3, Synthetic 2-108 (CDCl3, 600 MHz) 600 MHz) 174.3 174.3 173.3 173.2 118.2 118.2
! 193 101.9 101.9 84.7 84.7 73.6 73.5 71.7 71.7 69.3 69.4 67.2 67.2 64.8 64.8 59.9 59.9 50.2 50.2 49.7 49.7 48.9 48.9 48.7 48.7 45.8 45.8 41.2 41.2 36.6 36.6 35.0 35.0 33.8 33.8 33.3 33.3 29.8 29.9 27.2 27.2 24.1 24.1 23.2 23.2 22.0 22.0 17.8 17.8 7.9 7.9 !
Table S5. 1H NMR data comparison between synthetic ouabagenin (2-1) and that from degradation
Synthetic 2-1 (2:1 (CD3)2SO:CDCl3, From degradation (2:1 (CD3)2SO:CDCl3, 151 MHz) 151 MHz) 5.84 (s, 1 H) 5.84 (s, 1 H) 4.92 (d, J = 18.4 Hz, 1 H) 4.92 (d, J = 18.3 Hz, 1 H) 4.81 (dd, J = 18.4, 1.8 Hz, 1 H) 4.81 (dd, J = 18.3, 1.8 Hz, 1 H) 4.41 (s, 1 H) 4.41 (d, J = 4.8 Hz, 1 H) 4.21 (d, J = 10.4 Hz, 1 H) 4.20 (d, J = 10.3 Hz, 1 H) 4.20–4.10 (m, 1 H) 4.20–4.10 (m, 1 H) 3.98 (d, J = 10.4 Hz, 1 H) 3.99 (d, J = 10.3 Hz, 1 H) 2.83 (t, J = 7.1 Hz, 1 H) 2.83 (t, J = 7.2 Hz, 1 H)
! 194 2.03–1.93 (m, 3 H) 2.03–1.93 (m, 3 H) 1.92–1.85 (m, 1 H) 1.92–1.85 (m, 1 H) 1.82–1.72 (m, 2 H) 1.81–1.70 (m, 2 H) 1.61 (dd, J = 11.4, 8.6 Hz, 1 H) 1.61 (dd, J = 11.4, 8.6 Hz, 1 H) 1.56 (dd, J = 13.5, 4.5 Hz, 1 H) 1.56 (dd, J = 13.5, 4.5 Hz, 1 H) 1.49–1.40 (m, 1 H) 1.44 (p, J = 7.9, 5.9 Hz, 1 H) 1.37–1.28 (m, 2 H) 1.37–1.28 (m, 2 H) 1.22 (s, 1 H) 1.11 (s, 1 H) 1.11 (s, 1 H) 0.81 (s, 3 H) 0.81 (s, 3 H) !
Table S6. 13C NMR data comparison between synthetic ouabagenin (2-1) and that from degradation
Synthetic 2-1 (2:1 (CD3)2SO:CDCl3, From degradation (2:1 (CD3)2SO:CDCl3, 151 MHz) 151 MHz) 175.0 175.0 173.5 173.6 116.3 116.3 83.5 83.5 75.1 74.9 72.9 72.9 66.2 66.3 65.4 65.4 60.6 60.6 49.7 49.7 49.0 49.0 48.6 48.6 48.4 48.4 47.2 47.2 40.1 40.0 32.3 32.3 26.0 26.0 22.7 22.6 16.9 16.9 ! ! !
! 195
Appendix 2
X-ray crystal structures
! 196 ! ! ! O ! Me ! O ! H ! ! H H ! O ! Me O ! O ! H ! ! H H ! ! O ! O ! 2-28
! 197 !
! ! ! ! ! ! Me O ! HO ! O ! H ! ! O H H ! ! O ! 2-44 ! ! ! ! ! ! ! ! ! ! ! !
! 198 ! ! ! ! ! ! ! O ! ! O ! O ! Me Me ! ! O H H OH ! ! O ! 2-46 ! ! ! ! ! ! ! ! ! ! ! ! ! ! !
! 199 ! ! ! ! ! ! ! ! ! ! ! ! ! AcO Me O ! O ! O ! ! ! O H H ! ! O ! 2-54 ! ! ! ! ! ! ! !
! 200 ! ! ! ! O O Me HO Me O K CO , AcO O 2 3 O O H MeOH H
O H H O H H
O O 2-55 2-55' ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !
! 201 ! ! ! ! ! ! !
! ! ! ! O ! HO Me ! O ! H ! ! O H H ! HO ! O F ! 2-57 ! ! ! ! ! ! !
! 202 ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! O O ! Me Me ! HO O O O PIDA, I O ! H 2 O ! ! H H H H ! O O ! O O ! 2-63 !
! 203 ! ! ! ! ! ! ! ! ! O ! Me O ! HO ! O H ! ! H H ! O ! O ! 2-62' ! ! ! ! ! ! ! ! !
! 204 ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! O Me ! O ! HO O ! O H ! ! H H ! HO ! O 2-70 !
! 205 ! ! ! ! ! ! ! ! ! Me O ! O ! HO O ! HO H ! ! H H ! HO ! OH 2-75 ! ! ! ! ! ! ! ! ! ! ! ! ! ! !
! 206 ! ! ! ! ! Me O O HO Me O PPTS, O HO H OMe HC(OMe)3 O H H O H O O H O O O B 2-76 (+ other boronate isomers) Et ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !
! 207 ! ! ! ! ! ! ! !
! ! ! ! ! NHTs Me Me N K2CO3, Δ H H
H H H H TBSO TBSO ! ! ! ! ! ! ! ! ! ! !
! 208 ! ! ! ! ! ! ! ! ! !
! ! ! ! ! ! ! Me O ! ! H ! ! H OH ! ! MeO ! 2-86 ! ! ! ! ! !
! 209 ! ! ! ! ! !
! ! ! ! ! ! O ! ! O ! ! Me ! ! H ! ! H OH ! MeO ! 2-90 ! ! ! ! !
! 210 ! ! ! ! ! !
! ! ! ! ! ! ! O Me ! O ! HO O ! H ! ! F H H ! ! F O ! ! ! ! !
! 211 ! ! ! ! ! !
! ! ! ! ! ! ! ! OMe ! OH H ! ! H ! ! Me ! Me ! H ! ! H OH ! MeO ! ! ! ! ! ! ! ! ! ! ! !
! 212 ! ! ! !
! ! ! ! ! ! MeTMS ! Me O Me O ! O ! O H ! ! H OH ! ! O O ! B ! Et ! ! ! ! !
! 213
Appendix 3
Curriculum Vitae
! 214 Hans Renata Curriculum Vitae
Department of Chemistry The Scripps Research Institute Tel: (858) 784-7372 10550 North Torrey Pines Road email: [email protected] BCC 169 La Jolla, CA 92037
Education
2008 – 2013 Ph.D. candidate in Organic Chemistry TSRI Dean’s Fellowship Advisor: Professor Phil S. Baran The Scripps Research Institute, La Jolla, California
2004 – 2008 B.A. in Chemistry (Summa Cum Laude) Columbia College Global Scholar Advisor: Professor Tristan H. Lambert Columbia University, New York, New York
2002 – 2003 Raffles Junior College (High School) Singapore
Awards
• Bristol-Myers Squibb Graduate Fellowship, 2011–2012 • TSRI Dean’s Fellowship, 2008 • Phi Beta Kappa, 2007 • Pfizer Summer Undergraduate Research Fellowship, 2007 • Mazur Summer Undergraduate Research Fellowship, 2007 • GlaxoSmithKline- Singapore EDB Junior College Book Prize, 2003 • Gold Medal, Singapore Chemistry Olympiad, 2002
Research Presentations
• Poster Presentation, TSRI Graduate Student Retreat, 2012 • Speaker, TSRI Graduate Student Retreat, 2011 • Poster Presentation, Pfizer Summer Undergraduate Research Fellowship, 2007 • Speaker, Columbia Summer REU Symposium, 2007 • Poster Presentation, Singapore Ministry of Education Science Research Programme, 2003
! 215 Research Experience
• Graduate Student Research Assistant, Baran Lab, The Scripps Research Institute, 2008-present. Syntheses of cardiac glycoside, ouabagenin and ouabain; synthesis efforts towards ryanodol; development of hydroxylated analogs of clobetasol propionate • Undergraduate Student Research Assistant, Lambert Lab, Columbia University, 2006-2007. Model study towards the total synthesis of cortistatin A • Undergraduate Student Research Assistant, Breslow Lab, Columbia University, 2004-2005. Synthesis of a chiral PAMAM dendrimer as vitamin B6 mimic • High School Student Research Assistant, Leong Lab, National University of Singapore, 2002. Synthesis of triosmium cluster containing amino acid ligand
Teaching Experience
• Teaching Assistant, Heterocyclic Chemistry, The Scripps Research Institute, 2011 • Teaching Assistant, Columbia University, Department of Chemistry Help Room, 2007 • Teaching Assistant, Chem 3543X, Organic Chemistry Laboratory, Columbia University, 2006 • Chemistry Tutor, Columbia University Academic Success Program, 2005
Publications
1. Renata, H., Zhou, Q., Baran, P. S. “Strategic Redox-Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide” Science, 2013, 339, 59– 63.
! 216