Asymmetric Total Synthesis of Clionastatins A and B Wei Ju,‡ Xudong Wang,‡ Hailong Tian and Jinghan Gui*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
Supporting Information Placeholder
ABSTRACT: Herein we report the first total synthesis of poly- and kiheisterone D4—are found in chlorohydrin groups, which may chlorinated steroids clionastatins A and B, which was accom- originate from the corresponding epoxides. Two notable exceptions plished asymmetrically by means of a convergent, radical fragment are the polychlorinated androstanes clionastatins A and B (1 and 2, coupling approach. Key features of the synthesis include an Ire- Figure 1),5 which were isolated by Fattorusso et al. in 2004 from land–Claisen rearrangement to introduce the C5 stereocenter the burrowing sponge Cliona nigricans. The originally proposed (which was ultimately transferred to the C10 quaternary stereocen- structures (1a and 2a), including the relative stereochemistry, were ter of the clionastatins via a traceless stereochemical relay), a regi- established by NMR spectroscopy. However, no X-ray crystal oselective acyl radical conjugate addition to join the two fragments, structures were obtained and the 13C NMR spectra were also not an intramolecular Heck reaction to install the C10 quaternary ste- registered, possibly because only approximately 1 mg of each com- reocenter, and a diastereoselective olefin dichlorination to establish pound was isolated. The complete 13C NMR assignment was de- the synthetically challenging pseudoequatorial dichlorides. This duced through inspection of the 2D NMR spectra HSQC and work also enabled us to determine that the true structures of clio- HMBC.6 Therefore, the accuracy of the reported 13C NMR data re- nastatins A and B are in fact C14 epimers of the originally proposed mains to be determined. Importantly, preliminary biological studies structures. indicated that they exhibit potent cytotoxicity against tumor cell 5 lines (IC50 = 0.8–2.0 μg/mL).
Scheme 1. Synthetic challenge and retrosynthetic analysis of Chlorinated steroid drugs, such as the corticosteroids Temovate clionastatins A and B. and Nasonex (Figure 1), are an important class of synthetic steroids
Figure 1. Structures of representative chlorinated steroid drugs and polychlorinated steroids clionastatins A and B. with a variety of therapeutic uses. For example, Nasonex, the retail sales of which reached $376 million in 2018,1 is prescribed as a treatment for nasal allergy symptoms and nasal polyps. Therefore, the development of efficient strategies to synthesize chlorinated steroids is highly desirable for exploration of their pharmaceutical applications. Interestingly, the chlorine atoms in most steroid natu- ral products—for example, physalolactone,2 blattellastanosides,3 The clionastatins are the first polyhalogenated steroids to have dichlorination has been a longstanding challenge in the synthesis of been isolated from a natural source (either marine or terrestrial). chlorinated natural products,17-24 and many elegant methods have Notably, the C1 and C2 vicinal dichlorides of these compounds are been developed.25-31 We envisioned that olefin dichlorination di- in the pseudoequatorial configurations, and thus are difficult to in- rected by the C19 hydroxyl group of homoallylic alcohol 5 could stall synthetically because dihalogenation of the C1–C2 olefin of be employed to introduce the chlorine atoms at C1 and C2 by means steroid substrates tends to deliver diaxial products.7 Moreover, alt- of a titanium-mediated selective dihalogenation method developed hough the C19 chloride could conceivably be introduced through by Burns and co-workers.29-31 Furthermore, inspired by the pio- deoxychlorination of the corresponding C19 hydroxyl group,8,9 the neering work of Overman and colleagues,32,33 we envisaged that the B-ring dienone motif tends to aromatize in the presence of the C19 cis-fused A/B-ring system of 5, including the C10 quaternary ste- hydroxyl group, as evidenced by the easy formation of estrone 4 reocenter, could be established by an intramolecular Heck reaction from dienone 3 even under mild conditions (Scheme 1A). On top of enol triflate 6, which could in turn be assembled through a radi- of that, the clionastatins feature a unique 3,5,8(9)-16-tetraen-7,15- cal fragment coupling reaction between acyl telluride34,35 7 and dione core, which distinguishes them from any other known steroid. known enone 8.36 Although there are three possible sites for acyl The complicated polychlorination pattern and the highly unsatu- radical37 conjugate addition to 8, we anticipated that the desired C8 rated androstane framework, as well as the structural ambiguity position would be the most reactive on the basis of steric and elec- make clionastatins a formidable synthetic challenge, and no com- tronic factors. Acyl telluride 7 would be readily accessed from acid pleted synthesis of clionastatins has previously been reported.10 9, which could be prepared from 10 by means of the Ireland– Herein we report the first total synthesis of clionastatins, which was Claisen rearrangement.38 We expected to install the C1 stereogenic accomplished asymmetrically via a convergent approach11,12 in- center of 10 via the Corey–Bakshi–Shibata reduction39 of known volving radical fragment coupling.13-16 Moreover, our synthetic compound 11.40 Notably, the stereochemical information at C1 of studies resulted in revision of the originally proposed structures of 10 would be transferred to C5 of 9 by the Claisen–Ireland rear- these natural products. rangement, which would ultimately relay its stereochemical infor- As outlined in Scheme 1B, we anticipated that 2a could be ac- mation to the C10 quaternary stereocenter of 5 by the intramolecu- cessed from 1a through regioselective chlorination at C16. We lar Heck reaction. Thus, the C10 quaternary stereocenter of the two planned to introduce the C3 C5 diene of 1a at a late stage to avoid clionastatins would be derived from C1 of 10 via a traceless stere- – 41,42 undesired aromatization of the B ring. Stereoselective olefin ochemical relay strategy.
Scheme 2. Asymmetric total synthesis of clionastatins A and B.
aAbbreviations: MOM, methoxymethyl; CBS, Corey-Bakshi-Shibata reagent; Ac, acetyl; KHMDS, potassium bis(trimethylsilyl)amide; TMS, trimethylsilyl; NMM, N-methylmorpholine; DIBAL-H, diisobutylaluminum hydride; Tf, trifluoromethanesulfonyl; dppp, 1,3-bis(di- phenylphosphino)propane; PMP, 1,2,2,6,6-pentamethylpiperidine; DMP, Dess-Martin periodinane; DMF, N,N-dimethylformamide; DMAP, N,N-4-dimethylaminopyridine; m-IBX, meta-iodoxybenzoic acid.
Our synthesis commenced with the Corey–Bakshi–Shibata re- duction of 11 (Scheme 2),43 which provided allylic acetate 10 in 93% yield with a 85% enantiomeric excess after in situ protection of the resulting hydroxyl group as an acetate. Ireland–Claisen rearrange- ment of 10 with potassium bis(trimethylsilyl)amide and trime- thylsilyl chloride afforded carboxylic acid 9,43,44 which was then converted to acyl telluride 7.45,46 Pleasingly, treatment of 7 with 46-48 Et3B in air smoothly generated the corresponding acyl radical, which underwent conjugate addition to enone 8 exclusively at C8. Addition of MeOH to the reaction mixture was necessary to facili- tate tautomerization of the resulting 1,3-diketone to the requisite C9 enol constitutional isomer (not shown), which was transformed to enol triflate 12 in 50% yield over two steps. Notably, the use of an acyl telluride as the acyl radical precursor proved uniquely ef- fective;34,35 other alternatives, such as an acyl selenide,49 failed to yield any conjugate addition products upon reaction with 8. With 12 in hand, we turned our attention to the crucial intramo- lecular Heck reaction to install the C10 quaternary stereocenter. Unfortunately, the C7 and C15 carbonyl groups of 12 were found to be incompatible with various Heck cyclization conditions,43,50,51 which gave mainly enone 13 through elimination of the trifluoro- methanesulfonyl group. To address this issue, we reduced 12 with NaBH4 and CeCl3 to give a mixture of diastereomeric 7,15-diols (not shown), which underwent the desired intramolecular Heck re- action and subsequent in situ oxidation with Dess–Martin perio- dinane to afford 14 in 46% yield over two steps. Removal of the methoxymethyl protecting group of 14 delivered homoallylic alco- hol 15, which set the stage for the pivotal diastereoselective olefin dichlorination to install the C1 and C2 pseudoequatorial dichlorides. Our initial plan was to accomplish the olefin dichlorination through titanium-mediated selective dihalogenation of 15 by means of Burns’s protocol.29-31 However, dichlorination of 15 with i t ClTi(O Pr)3 and BuOCl furnished desired dichloride 22 only as a minor product, along with undesired diastereomer 23 and oxetane 24 as major products (Scheme 3). Despite extensive experimenta- tion (see Supporting Information for details), we were unable to minimize the formation of 23, and therefore searched for an alter- native approach. We surmised that through careful tuning of the steric environment around the C1-C2 olefin, the synthetically chal- To this end, olefin 16 was oxidized with SeO2 to furnish allylic 58 lenging pseudoequatorial dichlorides might be installed preferen- alcohol 17 as a single diastereomer (Scheme 2). Dichlorination of tially via substrate control. Eventually, in an attempt to accomplish 17 with 3.3 equiv of Et4NCl3 produced a 62% yield of dichloride 18, the structure of which was unambiguously established by X-ray deoxychlorination of 15 with SOCl2, we unexpectedly found that the reaction afforded sultine52 16 as a single diastereomer rather crystallographic analysis. Alternatively, adding 17 to a solution of than the desired C19 chloride product. Encouragingly, 16 under- 8.0 equiv of Et4NCl3 in dichloromethane (reverse addition method) went substrate-controlled diastereoselective dichlorination with delivered trichloride 19 and dichloride 18 in 61% and 19% yields, 53 respectively. Notably, the successful chlorination at C16 to afford Et4NCl3 (Mioskowski reagent) to generate desired dichloride 27 in 61% yield, together with undesired diastereomer 26 in 20% yield. 19 was an encouraging result in that it suggested that conversion of 2 We rationalized the observed diastereoselectivity by surmising that clionastatin A to clionastatin B via direct C(sp )–H chlorination the presence of the sultine moiety made the β-face of the C1–C2 might be possible. Moreover, 19 could also be utilized for the syn- olefin of 16 less sterically hindered than the α-face. Therefore, the thesis of clionastatin B by means of the sequence used for the syn- chlorine cation approached the C1–C2 olefin from the β-face, and thesis of clionastatin A from 18. the resulting β-chloronium ion was attacked by chloride at the less To complete the synthesis, we protected the C3 hydroxyl group hindered C2 position from the α-face to deliver 27 as the main prod- of 18 as an acetate and then desulfinated the protected compound uct. Desulfination of 27 could be achieved under acidic and basic to generate 20. Deoxychlorination of 20 and subsequent desatura- hydrolysis conditions, and heating a solution of 27 in DMF with tion (m-iodoxybenzoic acid, Ph2Se2) delivered trichloride 21 TiCl4 and LiCl was found to be optimal, affording 22 in 79% yield. smoothly, after in situ hydrolysis of the C3 acetate. Finally, dehy- 54 59 Deoxychlorination of the C19 hydroxyl group of 22 (PPh3, CCl4) dration of 21 with Martin sulfurane to introduce the C3–C4 olefin then furnished trichloride 28. Although we were able to introduce completed the synthesis of clionastatin A (1). Pleasingly, regiose- 55 the C5–C6 olefin by using m-iodoxybenzoic acid and Ph2Se2 to lective chlorination of 1 at C16 with Et4NCl3 using the reverse ad- give 29, attempts to desaturate 29 to access 1 failed under various dition method for the synthesis of 19 delivered clionastatin B (2) in conditions.56,57 Accordingly, we sought to install a hydroxyl group 42% yield, along with a 45% yield of recovered 1. The 1H NMR at C3 to facilitate late-stage introduction of the C3–C4 olefin. data for our synthetic 1 and 2 were in good agreement with those reported for the natural isolates (see Supporting Information for a Scheme 3. Investigation of the olefin dichlorination reaction discussion of some discrepancies in the 13C NMR data). 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A Synthesis of the ABC The Supporting Information is available free of charge on the Tricyclic Core of the Clionastatins Serves To Corroborate Their Proposed ACS Publications website. Structures. Org. Lett. 2014, 16, 1458-1461. Experimental procedures and characterization data for all new (11) For selected reviews on the convergent synthesis, see refs 11 and 12: compounds (PDF) Urabe, D.; Asaba, T.; Inoue, M. Convergent Strategies in Total Syntheses X-ray crystallographic data for 1 (CIF) (CCDC 2092061) of Complex Terpenoids. Chem. Rev. 2015, 115, 9207-9231. (12) Gao, Y.; Ma, D. In Pursuit of Synthetic Efficiency: Convergent Ap- X-ray crystallographic data for 18 (CIF) (CCDC 2092062) proaches. Acc. Chem. Res. 2021, 54, 569-582. X-ray crystallographic data for 24 (CIF) (CCDC 2092063) (13) For selected reviews on the fragment coupling, see refs 13 and 14: X-ray crystallographic data for 25 (CIF) (CCDC 2092064) Jamison, C. R.; Overman, L. E. Fragment Coupling with Tertiary Radicals X-ray crystallographic data for 29 (CIF) (CCDC 2092065) Generated by Visible-Light Photocatalysis. Acc. Chem. Res. 2016, 49, 1578-1586. AUTHOR INFORMATION (14) Tomanik, M.; Hsu, I. T.; Herzon, S. B. Fragment Coupling Reac- tions in Total Synthesis That Form Carbon–Carbon Bonds via Carbanionic Corresponding Author or Free Radical Intermediates. Angew. Chem. Int. Ed. 2021, 60, 1116-1150. (15) For selected recent examples of natural product synthesis using the *[email protected] fragment coupling, see refs 15 and 16: Han, A.; Tao, Y.; Reisman, S. E. A Author Contributions 16-step synthesis of the isoryanodane diterpene (+)-perseanol. Nature 2019, 573, 563-567. ‡These authors contributed equally. (16) Turlik, A.; Chen, Y.; Scruse, A. C.; Newhouse, T. R. Convergent Total Synthesis of Principinol D, a Rearranged Kaurane Diterpenoid. J. Am. Notes Chem. Soc. 2019, 141, 8088-8092. The authors declare no competing financial interests. (17) For selected reviews, see refs 17-20: Bedke, D. K.; Vanderwal, C. D. Chlorosulfolipids: Structure, synthesis, and biological relevance. Nat. Prod. Rep. 2011, 28, 15-25. ACKNOWLEDGMENT (18) Nilewski, C.; Carreira, E. M. Recent Advances in the Total Synthe- Financial support was provided by the National Natural Science sis of Chlorosulfolipids. Eur. J. Org. Chem. 2012, 2012, 1685-1698. Foundation of China (Grant No. 21871289), the Science and Tech- (19) Chung, W.-J.; Vanderwal, C. D. Approaches to the Chemical Syn- thesis of the Chlorosulfolipids. Acc. Chem. Res. 2014, 47, 718-728. nology Commission of Shanghai Municipality (Grant No. (20) Umezawa, T.; Matsuda, F. Recent progress toward synthesis of 21ZR1476400), the Shanghai Sailing Program (Grant No. chlorosulfolipids: total synthesis and methodology. Tetrahedron Lett. 2014, 21YF1456400), the Strategic Priority Research Program of the Chi- 55, 3003-3012. nese Academy of Sciences (Grant No. XDB20000000), CAS Key (21) For selected examples, see refs 21-24: Bedke, D. K.; Shibuya, G. Laboratory of Synthetic Chemistry of Natural Substances, and M.; Pereira, A. R.; Gerwick, W. H.; Vanderwal, C. D. A Concise Enanti- Shanghai Institute of Organic Chemistry. We thank Dr. Jian Wu oselective Synthesis of the Chlorosulfolipid Malhamensilipin A. J. Am. (SIOC) for assistance with NMR spectroscopy, and Prof. Orazio Chem. Soc. 2010, 132, 2542-2543. Taglialatela-Scafati (University of Naples Federico II) for provid- (22) Bucher, C.; Deans, R. M.; Burns, N. Z. Highly Selective Synthesis 1 of Halomon, Plocamenone, and Isoplocamenone. J. Am. Chem. Soc. 2015, ing the H NMR spectrum of natural clionastatin B and helpful dis- 137, 12784-12787. cussions. (23) Nilewski, C.; Geisser, R. W.; Carreira, E. M. 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