Letter pubs.acs.org/OrgLett
A Stereocontrolled Annulation of the Taccalonolide Epoxy Lactone onto the Molecular Framework of trans-Androsterone Jakob Danielsson,‡,† Diana X. Sun,‡,† Xiao-Yang Chen,‡ April L. Risinger,§ Susan L. Mooberry,§ and Erik J. Sorensen*,‡ ‡
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States
§
S Supporting Information *
ABSTRACT: A robust and scalable route to the taccalonolide skeleton starting from trans-androsterone is presented. The synthesis features a cyclic hydroboration carbonylation reaction, which effectively establishes the trans-hydrindane DE ring junction in a remarkable annulation reaction, as well as a Claisen rearrangement and a catalytic Ullmann-type cyclization. This work is part of a larger effort to uncover new clinical candidates from the taccalonolide class of anticancer agents through advances in chemical synthesis.
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chemical synthesis. One of our approaches to this challenging objective for synthesis was guided by the following questions: Could the right-most epoxy lactone structural element of the taccalonolides be annulated onto abundant steroid architectures and would these simplified compounds, which would lack much of the oxygenation of the taccalonolide natural products, possess biological activity? Our successful effort to affix the taccalonolide-type EF ring system, including the quarternary stereogenic center at C24, to the D-ring of trans-androsterone (4) is described herein. Our effort commenced with the protection of the C-3 hydroxyl of 4 in the form of a methoxymethyl (MOM) ether and the subsequent conversion of the C-17 ketone to the corresponding enol silane (Scheme 1). A catalytic Saegusa−Ito oxidation9 of the latter functional group then afforded enone 5, which was epoxidized using sodium hypochlorite to furnish the corresponding epoxy ketone as a single diastereomer.10 A Wittig reaction with ethylidene triphenylphosphorane was then performed, which afforded the epoxy alkene 6 as the geometrical isomer shown.11 To set the stage for a pivotal, cyclative hydroboration with interpolation of a carbonyl group,12 compound 6 was allowed to undergo an anti-SN2′ epoxide opening with the organocuprate reagent derived from vinylmagnesium bromide and copper(I) cyanide;13 this reaction, which generated a new carbon−carbon bond, the desired skipped diene array, and the
he taxane diterpene paclitaxel (1) and its relatives interfere with the normal function of microtubules during cell division and are essential members of our armamentarium of cancer drugs (Figure 1).1 The clinical successes of these microtubule-stabilizing agents in the treatment of solid tumors and the emergence of taxane drug resistance has spurred an intense search for new natural products that also interfere with microtubule dynamics through the mechanism of microtubule stabilization.2 The structurally intricate polyketide cyclostreptin (2), formerly known as FR182877,3,4 and the plant-derived taccalonolides5−7 [e.g., taccalonolide AF (3)] display paclitaxellike effects in vitro and covalently bind to the same 18-unit peptide of tubulin via their electrophilic bridgehead alkene and epoxy lactone functional groups, respectively; the alkylation chemistry caused by each of these agents promotes helical structuring of the M-loop on β-tubulin, which strengthens the interactions between microtubule protofilaments.2b While cyclostreptin has not emerged as a candidate for clinical development, the taccalonolides, especially the epoxy taccalonolides, such as 3, display potent antitumor effects in animal models and overcome multiple mechanisms of drug resistance.6−8 The current view is that clinical candidates from this class could offer a therapeutic option to patients with paclitaxelresistant cancer. Despite their considerable therapeutic potential, the taccalonolides are scarce and difficult to obtain from plants of the genus Tacca.6b,8 Their intricate molecular structures, which feature 20 contiguous stereocenters and a highly oxidized steroid nucleus within the context of a larger, hexacyclic framework, also complicate efforts in medicinal chemistry and © 2017 American Chemical Society
Received: July 30, 2017 Published: August 29, 2017 4892
DOI: 10.1021/acs.orglett.7b02349 Org. Lett. 2017, 19, 4892−4895
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Organic Letters
Figure 1. Molecular structures of paclitaxel (1), cyclostreptin (2), taccalonolide AF (3), and trans-androsterone (4).
Scheme 1. Synthesis of Allylic Alcohol 11 from trans-Androsterone (4)a
a
MOM = CH2OCH3; LDA = lithium diisopropylamide; TMS = trimethylsilyl; DMSO = dimethyl sulfoxide; TES = triethylsilyl; DCME = dichloromethyl methyl ether.
methyl cyclohexenone with Br2 and Et3N produced αbromoenone 10. A subsequent Luche reduction18 then afforded bromo allylic alcohol 11 as the major component of a 4:1 mixture of epimers; we suspect that torsional effects from the bromo substituent influence the stereochemical outcome of this reduction because a Luche reduction of the analogous enone lacking the bromine substituent displayed the opposite diastereoface selectivity. Allylic alcohol 11 was then converted to lactate ester 12 by a condensation with the p-methoxybenzyl ether of lactic acid under the conditions shown in Scheme 2. While compound 12 will undergo Cα-deprotonations on exposure to strong bases, these reactions usually regenerated alcohol 11 through decomposition of the ester enolate and also, to a smaller extent, eliminated the ester functionality altogether. In addition, the silylations of the metal enolates derived from 12 were plagued by preferential C-silylation, as opposed to O-silylation, and only trace amounts of the desired Ireland−Claisen rearrangement products were isolated in all attempts; moreover, these products were produced with low diastereoisomer ratios (e.g., 55:45). Propionate ester 14 was similarly unsuitable as a precursor to the Ireland−Claisen rearrangement products (e.g., 15) due to unexpected difficulties we encountered in attempts to produce the required silyl ketene acetals. In an effort to surmount these experimental barriers, we retreated to the less functionalized substrate for a traditional vinyl ether Claisen rearrangement. This instinct was well founded, as alcohol 11 efficiently reacted with phenyl vinyl sulfoxide to furnish a heteroconjugate addition adduct that underwent a sequential sulfoxide elimination/Claisen rear-
taccalonolide-type secondary methyl group at C-21, was followed by an efficient triethylsilylation of the resulting secondary hydroxyl group to give compound 7. After considerable experimentation, we identified the conditions outlined in Scheme 1 for transforming 7 into transhydrindanone 8. Treatment of diene 7 with 2 equiv of 9borabicyclo[3.3.1]nonane (9-BBN) causes hydroboration of the trisubstituted cyclic double bond to the bottom face, thereby establishing the stereochemistry of the eventual transhydrindane ring in product 8. A subsequent “stitching” of the intermediate diborane with BH3·SMe2 produces a putative, sixmembered boracycle,14 and a subsequent quenching with CH3OH results in the formation of the corresponding, cyclic borinic ester. Treatment of the intermediate borinic ester with dichloromethyl methyl ether and LiOt-Bu then triggers two boron → carbon bond migrations. To our delight, upon oxidation with hydrogen peroxide, a single isomer of ketone 8 was the outcome of these regio- and diastereoselective reactions. With a scalable and efficient route to ketone 8 in hand, we investigated several ways to transform this material into substrates for stereospecific Claisen rearrangements. After some experimentation, we settled on a reaction sequence involving a Saegusa−Ito oxidation9 of ketone 8 to the corresponding enone, a cerium-induced carbonyl addition to afford allylic alcohol 9,15 and an oxidative transposition of the tertiary allylic alcohol with PCC.16 Alternative oxidants known to promote analogous transpositions (e.g., TEMPO and IBX) failed to furnish the desired enone.17 In the wake of the successful oxidative transposition, a simple exposure of the β4893
DOI: 10.1021/acs.orglett.7b02349 Org. Lett. 2017, 19, 4892−4895
Letter
Organic Letters Scheme 2. Synthesis of Epoxylactone 18 from Allylic Alcohol 11b
b PMB = para-methoxybenzyl; EDC = 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide; NaHMDS = NaN(SiMe3); TMS = trimethylsilyl; TMEDA = N,N,N′,N′-tetramethylethylenediamine; TBAF = tetrabutylammonium fluoride; DMDO = 2,2-dimethyldioxirane; DMS = dimethylsulfide.
rangement19 in 94% overall yield upon heating in 1,2dichlorobenzene in the presence of an excess of sodium bicarbonate. The resulting aldehyde was then converted to vinyl bromo carboxylic acid 16 via oxidation under Pinnick− Lindgren−Kraus conditions.20 We were drawn to the catalytic method of Li and co-workers and the idea that compound 16 could undergo a direct, Cu(I)catalyzed, intramolecular O-vinylation of the carboxyl group.21 By the action of CuI (1.0 equiv), tetramethylethylenediamine (TMEDA) (2.0 equiv), and potassium carbonate (2.0 equiv) on vinyl bromo acid 16 in refluxing 1,4-dioxane, the desired enol lactone 17 was, in fact, produced in an excellent yield of 95%. A fluoride-induced cleavage of the triethylsilyl ether and a subsequent, highly efficient epoxidation of the ene lactone with dimethyldioxirane (DMDO) resulted in the formation of polycyclic epoxy lactone 18. By analogy to the DMDO epoxidations of naturally occurring taccalonolide ene lactones by Mooberry and co-workers,5c,d,6c we also isolated a single epoxy lactone stereoisomer with a cis-locked EF system in the ene lactone epoxidation of the C-15 alcohol derived from compound 17.5d In the wake of the desilylation of 17, we also efficiently formed 19 by a Lewis acid mediated cleavage of the MOM ether. The possibility that taccalonolide-like epoxy lactones in simplified steroidal contexts might display promising cytotoxic activity was a strong stimulus for this research effort. However, neither compound 18 nor its ene lactone precursor exhibited
microtubule-stabilizing or antiproliferative activity in HeLa cells.22 While compound 18 possesses the epoxy lactone structural element that is critical for the potent antitumor effects of the naturally occurring epoxy-taccalonolides, it lacks oxygenated functionality that apparently mediates binding interactions with cellular microtubules, as well as the natural configuration at position 15 of the steroid nucleus. In summary, we achieved a stereocontrolled synthesis of the hexacyclic skeleton of the taccalonolide family of natural products from a commercially available steroid. The enol-γlactone motif was constructed by a copper catalyzed Ovinylation reaction, and the quarternary carbon center at C-24 was established by a stereospecific Claisen rearrangement. We also employed a variant of Brown’s cyclic hydroboration/ carbonylation method to effectively construct the challenging D−E trans-hydrindane stereochemistry. On the foundation of the strategy for semisynthesis and the structural transformations described herein, our future efforts will target new compounds that more closely approximate the full structures of these promising natural products. The ultimate goal of these efforts is to uncover new clinical candidates from the taccalonolide class through advances in chemical synthesis. 4894
DOI: 10.1021/acs.orglett.7b02349 Org. Lett. 2017, 19, 4892−4895
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(7) Risinger, A. L.; Jackson, E. M.; Polin, L. A.; Helms, G. L.; LeBoeuf, D. A.; Joe, P. A.; Hopper-Borge, E.; Ludueña, R. F.; Kruh, G. D.; Mooberry, S. L. Cancer Res. 2008, 68, 8881−8888. (8) Risinger, A. L.; Mooberry, S. L. Cancer Lett. 2010, 291, 14−19. (9) (a) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett. 1995, 36, 2423−2426. (b) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011−1013. (10) The stereochemical outcome observed in this transformation is presumably dictated by torsional effects. (11) Konno, K.; Ojima, K.; Hayashi, T.; Takayama, H. Chem. Pharm. Bull. 1992, 40, 1120−1124. (12) (a) Carlson, B. A.; Brown, H. C. J. Am. Chem. Soc. 1973, 95, 6876−6877. (b) Soderquist, J. A.; Hassner, A. J. Org. Chem. 1983, 48, 1801−1810. (c) Soderquist, J. A.; Shiau, F.; Lemesh, R. A. J. Org. Chem. 1984, 49, 2565−2569. (d) Dhokte, U. P.; Pathare, M. P.; Mahindroo, V. K.; Brown, H. C. J. Org. Chem. 1998, 63, 8276−8283. (13) Marino, J. P.; Abe, H. J. Am. Chem. Soc. 1981, 103, 2907−2909. (14) (a) Burke, P. L.; Negishi, E.; Brown, H. C. J. Am. Chem. Soc. 1973, 95, 3654−3662. (b) Brown, H. C.; Pai, G. G. J. Organomet. Chem. 1983, 250, 13−22. (15) (a) Imamoto, T.; Kusumoto, T.; Yokoyama, M. J. Chem. Soc., Chem. Commun. 1982, 1042−1044. (b) Imamoto, T.; Sugiura, Y. J. Phys. Org. Chem. 1989, 2, 93−102. (16) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682− 685. (17) Luzzio, F. A. Tetrahedron 2012, 68, 5323−5339. (18) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226−2227. (19) Mandai, T.; Ueda, M.; Hasegawa, S.-i.; Kawada, M.; Tsuji, J.; Saito, S. Tetrahedron Lett. 1990, 31, 4041−4044. (20) (a) Lindgren, B.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888− 890. (b) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091−2096. (b1) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175−1176. (21) Sun, C.; Fang, Y.; Li, S.; Zhang, Y.; Zhao, Q.; Zhu, S.; Li, C. Org. Lett. 2009, 11, 4084−4087. (22) These assays were performed by Drs. April Risinger and Susan Mooberry, University of Texas, San Antonio.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02349. Experimental procedures, characterization data, and spectral data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xiao-Yang Chen: 0000-0003-3449-4136 Erik J. Sorensen: 0000-0002-9967-6347 Author Contributions †
J.D. and D.X.S. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge The Swedish Chemical Society and The Swedish Pharmaceutical Society for postdoctoral fellowships to J.D. and the National Institute of General Medical Sciences grant GM065483 for financial support. We thank Drs. Susan L. Mooberry and April L. Risinger of the School of Medicine, University of Texas, San Antonio for the bioactivity assays on compounds 17 and 18. We also thank Dr. István Pelczer of Princeton University for assisting our structural and stereochemical characterizations by the methods of NMR spectroscopy.
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DOI: 10.1021/acs.orglett.7b02349 Org. Lett. 2017, 19, 4892−4895
