Asymmetric Synthesis of an Advanced Tetracyclic Framework of (+

Publication Date (Web): October 22, 2018. Copyright © 2018 American Chemical Society. *E-mail: [email protected]. Cite this:Org. Lett. XXXX, XXX, XX...
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Letter Cite This: Org. Lett. 2018, 20, 6701−6704

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Asymmetric Synthesis of an Advanced Tetracyclic Framework of (+)-Sarain A Yu Wang,† Lingying Leng,† Ying Liu, Guiying Dai, Fanglin Xue, Zhihao Chen, Jiao Meng, Guohua Wen, Yaxin Xiao, Xiao-Yu Liu, and Yong Qin*

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Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China S Supporting Information *

ABSTRACT: An asymmetric synthetic approach to a tetracyclic framework of the marine-derived alkaloid (+)-sarain A has been developed. The key steps to constructing the congested diazatricycloundecane core include an asymmetric Diels−Alder cycloaddition, an Ireland−Claisen rearrangement, and an intramolecular aziridination/ ring-opening sequence.

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The unprecedented and intricate chemical structure of sarain A has garnered considerable interest from the synthetic community for decades. In 2006, the Overman group accomplished the first and only total synthesis of (−)-sarain A using an asymmetric Michael addition and a Mannich-type cyclization to forge the central tricycle, as well as a ring-closing metathesis and an intramolecular Stille coupling to form the two macrocycles.11 In 2015, a formal synthesis was reported by Fukuyama and co-workers employing an intramolecular nitrone [3 + 2] cycloaddition as the key step.12 Although tremendous synthetic efforts have been focused on sarain A by many other groups,13 the majority of them failed to access the challenging diazatricycloundecane framework in optically pure forms. As a continuation of our interest in the total synthesis of complex alkaloids,14 we disclose here an enantioselective approach to the advanced tetracyclic of (+)-sarain A that features a distinctive intramolecular aziridination/ring-opening strategy. Our retrosynthetic analysis is illustrated in Scheme 1. We envisioned that the 14-membered ring with the skipped triene would be formed at a late stage in the synthesis from compound 2. The 13-membered ring in 2 could be constructed via ring-closing metathesis (RCM)15 from diene 3. The latter could be traced back to compound 4 via functional group manipulations. Obviously, assembly of the diazatricycloundecane core in 4 would be critical for the whole synthesis. By in-depth analysis of the structure, we noticed that the tricyclic 4 exists as a vicinal diamine installed into a highly

arine environments provide a great number of interesting, complex, and diverse chemical compounds.1 As one such compound, sarain A (1; Figure 1) was isolated by

Figure 1. Chemcial structure of (+)-sarain A (1).

Cimino and co-workers from the marine sponge Reniera sarai in 1986.2 Subsequent spectroscopic studies3 and X-ray crystallographic analysis4 have revealed the unique chemical structure of this alkaloid. Architecturally, sarain A features a pentacyclic ring system that consists of a densely functionalized diazatricycloundecane core, a saturated 13-membered macrocycle, and a 14-membered ring bearing skipped-triene and vicinal diol functional groups. In particular, seven continuous stereogenic centers including two quaternary carbons (C3 and C3′) were embedded in its congested skeleton. A proximity interaction between the tertiary amine and the aldehyde group on the diazatricycloundecane core of sarain A was observed,5 making the molecule sensitive to the pH and solvent environment.6 Moreover, studies from different research groups have demonstrated that sarain A and its natural congeners exhibit antitumor,7 antibacterial,7,8 insecticidal,9 and antioxidation10 activities. © 2018 American Chemical Society

Received: August 30, 2018 Published: October 22, 2018 6701

DOI: 10.1021/acs.orglett.8b02779 Org. Lett. 2018, 20, 6701−6704

Letter

Organic Letters

by hydrolysis of the known ester 12.20 Coupling of acid 13 with the camphorsulfonic acid derived chiral auxiliary 14 in the presence of EDC/DMAP afforded dienophile 9 in 61% yield over two steps. Next, we investigated the Diels−Alder cycloaddition between diene 8 and dienophile 9. Our initial attempts to promote this cycloaddition with various Lewis acids (e.g., Et2AlCl, AlCl3, and Sc(OTf)3) were unfruitful, which might be due to the acid sensitivity of enoxysilane in diene 8. In contrast, by heating a mixture of 8 and 9 in toluene, we were delighted to obtain the desired cycloadduct 15 in 68% yield and with 12:1 dr at C3′.21 Subjection of 15 to LiAlH4 in THF led to removal of both the chiral auxiliary and the TBS protecting group, which was followed by selective TBS protection of the primary hydroxyl group to furnish allylic alcohol 16. Mitsunobu inversion22 of the hydroxyl group in 16 with acid 17 was carried out to provide the rearrangement precursor 7. After examining various bases (e.g, LHMDS, LDA, NaHMDS, nBuLi, and KHMDS), we found that the Ireland− Claisen rearrangement of 7 proceeded efficiently in the presence of KHMDS/TMSCl/Et3N, giving carboxylic acid 18 as a pair of diastereomers at C2 (3:2 dr) in 91% combined yield. According to Barton’s protocol,23 decarboxylation of 18 occurred through a one-pot procedure to afford functionalized cyclohexene 20. The aforementioned synthetic route could easily produce decagrams of compound 20 with the key C3 quaternary center. With cyclohexene 20 in hand, we turned our attention to the aziridination/ring-opening sequence to establish the diazatricycloundecane core of sarain A (Scheme 3). The removal of

Scheme 1. Retrosynthetic Analysis of (+)-Sarain A

substituted cyclohexane moiety. Thus, an intramolecular aziridination/ring-opening sequence was envisaged to access 4 from diazide 6 via aziridine intermediate 5.16 The quaternary stereogenic center at C3 in 6 would be generated via an Ireland−Claisen rearrangement of 7.17 In turn, the contiguous stereogenic centers in 7 would be derived from diene 8 and dienophile 9 via a chiral-auxiliary-induced asymmetric Diels− Alder reaction.18 Our synthesis began with the preparation of a functionalized cyclohexene moiety with the key C3 quaternary center (Scheme 2). First, we synthesized diene 8 in two steps from the known allylic alcohol 10.19 Specifically, MnO2 oxidation of 10, followed by treating the resulting aldehyde 11 with TBSOTf/Et3N, delivered diene 8 as a 3:2 mixture of alkene isomers. On the other hand, carboxylic acid 13 was obtained

Scheme 3. Synthesis of the Diazatricycloundecane Core 4

Scheme 2. Synthesis of the Functionalized Cyclohexene 20 Bearing the C3 Quaternary Center

the TBS protecting group in 20 with TBAF yielded a primary alcohol intermediate, which was then converted to cyanide 21 upon mesylation and cyanide replacement. Subjecting 21 to sequential reduction using DIBAL-H and NaBH4 gave alcohol 22 in 90% yield over two steps. The removal of the MOM group in 22 with PPTS, followed by TBS protection of the resulting diol, furnished alkene 23. A cyanide group was then installed at the C3′ position of 23 via a sequence of steps that involved epoxidation, regioselective epoxide opening with Me2AlCN, and dehydration mediated by Martin sulfurane,24 delivering acrylonitrile 24 smoothly. Both the TBS groups in 6702

DOI: 10.1021/acs.orglett.8b02779 Org. Lett. 2018, 20, 6701−6704

Letter

Organic Letters

In summary, we have developed an asymmetric synthetic approach to the advanced tetracyclic framework of (+)-sarain A. The features of this synthesis include the following: (1) a chiral-auxiliary-induced asymmetric Diels−Alder cycloaddition to establish the molecular chirality, (2) an Ireland−Claisen rearrangement to form the C3 all-carbon quaternary center, (3) an aziridination/ring-opening sequence to forge the rigid diazatricycloundecane core, and (4) a ring-closing metathesis to construct the 13-membered macrocycle. Notably, the current study provides a new entry to an advanced intermediate of the complex marine alkaloid sarain A, containing most of the stereogenic centers as well as suitable functional groups for the total synthesis of the target molecule.

24 were converted to diazide 6 via three steps including desilylation, mesylation, and azide replacement in a high overall efficiency. Having established a route to diazide 6, the stage was set to conduct the aziridination/ring-opening sequence to assemble the diazatricycloundecane ring system. A [3 + 2] cycloaddition between an azide and the olefin double bond, followed by extrusion of one molecule of N2, would deliver the desired aziridine.25 The challenge with our substrate (6) was how to differentiate the regioselectivity between two azides, as well as the chemoselectivity between the olefin and the cyano functionalities. We investigated the reaction conditions by subjecting compound 6 to thermal conditions in various solvents (e.g., DMF, DMSO, HMPA, odichlorobenzene, and ethylene glycol) with or without additives (e.g., DBU, AlCl3, and ZnI2). As a result, we found that when 6 was heated in o-dichlorobenzene (o-DCB) at 180 °C, the desired aziridine 25 was isolated with an optimal 36% yield along with the tricyclic tetrazole 26 (41%).26 Although the two azide groups in the precursor 6 were well differentiated, the cycloaddition onto the olefin and the cyano functionalities was nonselective. Subsequently, reduction of the remaining azide group in 25 with PPh3, followed by ring opening of the aziridine by the resulting primary amine, gave the desired diazatricycloundecane core 4 in 67% yield over two steps. Having the key tricycle 4 in hand, our next task was to construct the 13-membered macrocycle. As shown in Scheme 4, monoprotection of the two secondary amines with tosyl

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02779. Detailed experimental procedures, spectral data, and Xray crystallography (PDF) Accession Codes

CCDC 1853187 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Scheme 4. Synthesis of the Advanced Tetracyclic Intermediate 2

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yong Qin: 0000-0003-3434-5747 Author Contributions †

Y.W. and L.L. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support was provided by the National Natural Science Foundation of China (21372158 and 21732005).

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groups yielded 27a (44%) and 27b (41%). While the latter could be recycled by converting back to 4 using Li/ naphthalene, the desired 27a underwent catalytic hydrogenation smoothly to remove the benzyl group and afford alcohol 28 (81% yield). A reductive amination of 28 with aldehyde 29 installed a linear chain at the piperidine nitrogen atom, leading to alcohol 30 in 89% yield. Subsequently, DessMartin oxidation of the primary hydroxyl group in 30 furnished aldehyde 31, the structure of which was unambiguously determined by an X-ray crystallography analysis.27 After transformation of the aldehyde into a terminal alkene via Wittig methylenation (31 to 3, 86%), the resulting diene 3 was treated with Grubbs’ first generation catalyst followed by hydrogenation to successfully assemble the 13membered macrocycle.

REFERENCES

(1) Blunt, J. W.; Carroll, A. R.; Copp, B. R.; Davis, R. A.; Keyzers, R. A.; Prinsep, M. R. Nat. Prod. Rep. 2018, 35, 8−53. (2) Cimino, G.; De Stefano, S.; Sodano, G.; Trivellone, E. Bull. Soc. Chim. Belg. 1986, 95, 783−800. (3) (a) Cimino, G.; Scognamiglio, G.; Spinella, A.; Trivellone, E. J. Nat. Prod. 1990, 53, 1519−1525. (b) Guo, Y.; Madaio, A.; Trivellone, E.; Scognamiglio, G.; Cimino, G. Tetrahedron 1996, 52, 8341−8348. (4) Cimino, G.; Mattia, C. A.; Mazzarella, L.; Puliti, R.; Scognamiglio, G.; Spinella, A.; Trivellone, E. Tetrahedron 1989, 45, 3863−3872. (5) Leonard, N. J.; Oki, M.; Chiavarelli, S. J. Am. Chem. Soc. 1955, 77, 6234−6237. (6) (a) Guo, Y.; Trivellone, E.; Scognamiglio, G.; Cimino, G. Tetrahedron 1998, 54, 541−550. (b) Douglas, C. J.; Hiebert, S.; Overman, L. E. Org. Lett. 2005, 7, 933−936.

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Letter

Organic Letters (7) Caprioll, V.; Cimino, G.; De Giulio, A.; Madaio, A.; Scognamiglio, G.; Trivellone, E. Comp. Biochem. Physiol. B 1992, 103, 293−296. (8) Defant, A.; Mancini, I.; Raspor, L.; Guella, G.; Turk, T.; Sepčić, K. Eur. J. Org. Chem. 2011, 2011, 3761−3767. (9) Blihoghe, D.; Manzo, E.; Villela, A.; Cutignano, A.; Picariello, G.; Faimali, M.; Fontana, A. Biofouling 2011, 27, 99−109. (10) Alvariño, R.; Alonso, E.; Tribalat, M.-A.; Gegunde, S.; Thomas, O. P.; Botana, L. M. Neurotoxic. Res. 2017, 32, 368−380. (11) (a) Garg, N. K.; Hiebert, S.; Overman, L. E. Angew. Chem., Int. Ed. 2006, 45, 2912−2915. (b) Becker, M. H.; Chua, P.; Downham, R.; Douglas, C. J.; Garg, N. K.; Hiebert, S.; Jaroch, S.; Matsuoka, R. T.; Middleton, J. A.; Ng, F. W.; Overman, L. E. J. Am. Chem. Soc. 2007, 129, 11987−12002. (12) Higo, T.; Ukegawa, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2015, 54, 7367−7370. (13) (a) Sisko, J.; Weinreb, S. M. J. Org. Chem. 1991, 56, 3210− 3211. (b) Sisko, J.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4945−4951. (c) Hong, S.; Yang, J.; Weinreb, S. M. J. Org. Chem. 2006, 71, 2078−2089. (d) Griffith, D. A.; Heathcock, C. H. Tetrahedron Lett. 1995, 36, 2381−2384. (e) Heathcock, C. H.; Clasby, M.; Griffith, D. A.; Henke, B. R.; Sharp, M. J. Synlett 1995, 1995, 467−474. (f) Denhart, D. J.; Griffith, D. A.; Heathcock, C. H. J. Org. Chem. 1998, 63, 9616−9617. (g) Sung, M. J.; Lee, H. I.; Chong, Y.; Cha, J. K. Org. Lett. 1999, 1, 2017−2019. (h) Sung, M. J.; Lee, H. I.; Lee, H. B.; Cha, J. K. J. Org. Chem. 2003, 68, 2205−2208. (i) Lee, H. I.; Sung, M. J.; Lee, H. B.; Cha, J. K. Heterocycles 2004, 62, 407− 422. (j) Hourcade, S.; Ferdenzi, A.; Retailleau, P.; Mons, S.; Marazano, C. Eur. J. Org. Chem. 2005, 2005, 1302−1310. (k) Ge, C. S.; Hourcade, S.; Ferdenzi, A.; Chiaroni, A.; Mons, S.; Delpech, B.; Marazano, C. Eur. J. Org. Chem. 2006, 2006, 4106−4114. (l) Peixoto, S.; Martin, M.-T.; Crich, D.; Delpech, B.; Marazano, C. Chem. - Eur. J. 2011, 17, 9907−9910. (m) Price Mortimer, A. J.; Pang, P. S.; Aliev, A. E.; Tocher, D. A.; Porter, M. J. Org. Biomol. Chem. 2008, 6, 2941− 2951. (n) Yang, R.-F.; Huang, P.-Q. Chem. - Eur. J. 2010, 16, 10319− 10322. (o) Franklin, A. I.; Bensa, D.; Adams, H.; Coldham, I. Org. Biomol. Chem. 2011, 9, 1901−1907. (14) For recent reports from our group, see: (a) Jin, S.; Gong, J.; Qin, Y. Angew. Chem., Int. Ed. 2015, 54, 2228−2231. (b) Li, X.-H.; Zhu, M.; Wang, Z.-X.; Liu, X.-Y.; Song, H.; Zhang, D.; Wang, F.-P.; Qin, Y. Angew. Chem., Int. Ed. 2016, 55, 15667−15671. (c) Leng, L.; Zhou, X.; Liao, Q.; Wang, F.; Song, H.; Zhang, D.; Liu, X.-Y.; Qin, Y. Angew. Chem., Int. Ed. 2017, 56, 3703−3707. (d) Wang, X.; Xia, D.; Qin, W.; Zhou, R.; Zhou, X.; Zhou, Q.; Liu, W.; Dai, X.; Wang, H.; Wang, S.; Tan, L.; Zhang, D.; Song, H.; Liu, X.-Y.; Qin, Y. Chem 2017, 2, 803−816. (15) A recent review on RCM reactions in natural product synthesis: Lecourt, C.; Dhambri, S.; Allievi, L.; Sanogo, Y.; Zeghbib, N.; Ben Othman, R.; Lannou, M.-I.; Sorin, G.; Ardisson, J. Nat. Prod. Rep. 2018, 35, 105−124. (16) For selected examples of using the aziridination/ring-opening strategy for the preparation of diamine moieties, see: (a) Blackham, E. E.; Knowles, J. P.; Burgess, J.; Booker-Milburn, K. I. Chem. Sci. 2016, 7, 2302−2307. (b) Koteva, K.; King, A. M.; Capretta, A.; Wright, G. D. Angew. Chem., Int. Ed. 2016, 55, 2210−2212. (c) Zhang, J.; Wang, S.; Bai, Y.; Guo, Q.; Zhou, J.; Lei, X. J. Org. Chem. 2017, 82, 13643− 13648. (17) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868−2877. (b) Ireland, R. E.; Wipf, P.; Xiang, J. N. J. Org. Chem. 1991, 56, 3572−3582. (c) Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991, 56, 650−657. For a review, see: (d) Martín Castro, A. M. Chem. Rev. 2004, 104, 2939−3002. (18) (a) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta 1984, 67, 1397−1401. (b) Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T. M.; Bernardinelli, G. Tetrahedron Lett. 1988, 29, 5885− 5888. (c) Hirama, M.; Kato, Y.; Seki, C.; Nakano, H.; Takeshita, M.; Oshikiri, N.; Iyoda, M.; Matsuyama, H. Tetrahedron 2010, 66, 7618− 7624.

(19) Micali, E.; Chehade, K. A. H.; Isaacs, R. J.; Andres, D. A.; Spielmann, H. P. Biochemistry 2001, 40, 12254−12265. (20) Kobayashi, S.; Ando, A.; Kuroda, H.; Ejima, S.; Masuyama, A.; Ryu, I. Tetrahedron 2011, 67, 9087−9092. (21) Both diastereomers could be converted to the rearrangement precursor 7; see the Supporting Information for details. (22) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380−2382. (b) Mitsunobu, O. Synthesis 1981, 1981, 1−28. A recent review: (c) Fletcher, S. Org. Chem. Front. 2015, 2, 739−752. (23) (a) Barton, D. H.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939−941. For a review of the use of Barton ester in organic synthesis, see: (b) Saraiva, M. F.; Couri, M. R. C.; Le Hyaric, M.; de Almeida, M. V. Tetrahedron 2009, 65, 3563−3572. (24) (a) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003−5010. (b) Pooppanal, S. S. Synlett 2009, 2009, 850−851. (25) For selected examples, see: (a) Banwell, M. G.; Lupton, D. W. Org. Biomol. Chem. 2005, 3, 213−215. (b) Zhou, Y.; Murphy, P. V. Org. Lett. 2008, 10, 3777−3780. (c) Rambla, M.; Duroure, L.; Chabaud, L.; Guillou, C. Eur. J. Org. Chem. 2014, 2014, 7716−7720. (26) (a) Carpenter, W. R. J. Org. Chem. 1962, 27, 2085−2088. (b) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2004, 69, 2896−2898. (c) Shie, J.-J.; Fang, J.-M. J. Org. Chem. 2003, 68, 1158−1160. (d) Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2110−2113. (27) The crystal of 31 was obtained in its hemiacetal form by recrystallization from MeOH/CH2Cl2 (3:1).

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