Letter pubs.acs.org/OrgLett
Diastereoselective Synthesis of Diquinanes and Triquinanes Bearing Vicinal Quaternary Carbon Stereocenters from Acyclic Allene-based Precursors via a Cascade Reaction Shuang Li,†,§ Pengpeng Zhang,†,§ Yuanhe Li,‡ Shumin Lu,‡ Jianxian Gong,*,† and Zhen Yang*,†,‡ †
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China ‡ Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China S Supporting Information *
ABSTRACT: A cascade benzenethiol-mediated intramolecular [3 + 2] cycloaddition reaction between an allene and an α,βunsaturated aldehyde or ester is developed for the diastereoselective synthesis of [3.3.0] bicyclic system bearing two quaternary atoms at their bridgehead positions. Notably, these structurally complex systems can be found in a wide range of natural products.
P
In 1985, Curran’s group reported their pioneering syntheses of natural products hirsutene3 and capnellane4 via cascade radical cyclizations as key steps for the formation of their cyclopentanoid cores (eq 1 in Figure 2). In 2005, Krische’s group5 disclosed an intramolecular version of the Lu [3 + 2] cycloaddition6 for the formation of diquinanes7 (eq 2 in Figure 2). Herein, we report that allene8 tethered electron-deficient olefins underwent an intramolecular [3 + 2] cycloaddition upon exposure to a thiyl radical in the presence of a catalytic amount of radical initiator to
olycyclopentanoids bearing two quaternary atoms at their bridgehead positions can be found in a wide range of biologically active natural products (1−6 in Figure 1).1 However,
Figure 1. Selected naturally occurring cyclopentanoid-based natural products bearing two quaternary atoms at their bridgehead positions.
the construction of these polycyclopentanoids represents a significant challenge in natural product synthesis.2 The lack of efficient synthetic methods in this regard has limited the extent to which the biological and pharmaceutical potential of these natural products can be exploited. Despite significant progress during the last two decades toward the synthesis of the cyclopentanoids bearing the vicinal quaternary carbon centers,2b,c the development of more concise, mild and highly stereoselective processes involving readily accessible starting materials would have a pronounced impact on the field of synthetic organic chemistry. © 2017 American Chemical Society
Figure 2. Stereoselective synthesis of polycyclopentanoids. Received: June 8, 2017 Published: August 11, 2017 4416
DOI: 10.1021/acs.orglett.7b01733 Org. Lett. 2017, 19, 4416−4419
Letter
Organic Letters Table 1. Screening of the Reaction Conditionsa
form structurally diverse polycyclopentanoids (eq 3 in Figure 2). Notably, these systems had vicinal quaternary carbon stereogenic centers at their bridgehead positions. The results of several previous investigations have shown that some radicals, including Br, PhS, and RSO2 radicals, tend to attack the central carbon atoms of allene substrates and that the resulting carbon-based radicals can initiate chain reactions.9 With this in mind, we intended to design an intramolecular cascade reaction featuring a novel 5-exo/5-endo reaction pathway for the formation of [3.3.0] bicyclic systems bearing two quaternary atoms at their bridgehead positions. We envisaged that an electrophilic benzenethiol radical would add to the central spcarbon atom of allene 8 to afford the thermodynamically stabilized tertiary radical A (Figure 3).10 This radical would then
entry
solvent
PhSH (equiv)
temp (°C)
initiator
yield (%)b
1 2 3 4 5 6 7 8 9 10
PhMe PhMe PhMe PhMe CCl4 DCE CH3CN CH3CN CH3CN CH3CN
2 2 2 2 2 2 2 2 5 2
80 80 90 70 70 70 70 60 70 70
AIBN (0.1 equiv) AIBN (0.2 equiv) AIBN (0.1 equiv) A BVN (0.2 equiv) ABVN (0.2 equiv) ABVN (0.2 equiv) ABVN (0.2 equiv) ABVN (0.2 equiv) ABVN (0.2 equiv) ABVN (0.2 equiv)
36c 43 45 55c 26 33 59 40 45 70d
a
Reaction conditions: 9a (0.2 mmol), PhSH (2 equiv), initiator (0.2 equiv) in solvent (20 mL) at given temperature for 2 h. bIsolated yield. c Reaction time 3 h. dSlow addition of a premixed mixture of ABVN and PhSH by syringe pump to the solution of 9a in CH3CN.
(entry 8) and 45% (entry 9), respectively. We then modified the procedure to include the slow addition of a mixture of ABVN and PhSH to the reaction mixture. Pleasingly, this new addition process led to an improvement in the yield of 10a to 70% yield (entry 10). The structure of 10a was confirmed by the X-ray crystallographic study of its derivative (see Supporting Information for details). To explore the effect of the substituent at the R1 position of the allene moiety on the reaction outcome, we prepared 9a−9o and investigated their annulation under the optimized conditions. The results revealed that substrates bearing a diverse range of side chains on their allene moieties reacted smoothly to afford the corresponding annulated products in similar yields (Scheme 1). Notably, substrates bearing an ethyl (9a) or cyclopentyl (9f) substituent at the R1 position performed slightly better than all of the other substrates. Substrates 9h and 9i, bearing cycloheptyl group or phenyl group as its R1 group, gave a low yield. When the α,β-unsaturated aldehyde was replaced with α,β-unsaturated ester group (9m−9o), there was no discernible difference in the yields of the corresponding annulated products 10m−10o. These results showing the effects of the substituents on the annulation outcome highlight the potential applications of this chemistry for the synthesis of structurally diverse diquinanes. Previous investigations have indicated that EDG groups, such as NH2 and OMe, can lead to a decrease in the bond dissociation energy (BDE) of PhS−H, whereas EWG groups can lead to an increase in this value.14 With this in mind, we decided to profile the reaction with benzenethiols bearing both electron-donating (EDG) and electron-withdrawing groups (EWG), and the results are shown in Scheme 2. As expected, the reactions of benzenethiols bearing an EDG (such as a methoxide or methyl group) proceeded smoothly at 70 °C in 1.5 h to give the corresponding annulated products 11a− 11e with similar yields to those reported in Table 1. However, arylthiols bearing a methyl group at the ortho- or meta-position of their phenyl ring gave low yields of the annulated products, presumably because of their unfavorable steric effects. Low yields were also observed for annulated products 11f−11i bearing an EWG at the para-position of their phenyl ring, with all of these
Figure 3. Proposed thiyl radical initiated cascade reaction.
attack the α,β-unsaturated double bond via a 5-exo-trig cyclization process11 to afford intermediate B, which would undergo a 5-endo-trig cyclization process to generate the nucleophilic carbon-centered radial C. The subsequent abstraction of a hydrogen from PhSH would afford 7 bearing two quaternary atoms at its bridgehead positions while also regenerating the electrophilic benzenthiol radical.12 To assess the feasibility of the proposed transformation, we investigated the reaction of allene 9a with PhSH using AIBN as an initiator to generate the required thiyl radicals.13 In practice, the solution of 9a (0.2 mmol) with PhSH (0.4 mmol) and AIBN (0.02 mmol) in toluene (20 mL) at 80 °C for 3 h under an argon atmosphere afforded 10a in 36% yield as a single diastereoisomer bearing three contiguous stereocenters (Table 1, entry 1). This result encouraged us to further optimize the reaction conditions, as shown in Table 1. It is noteworthy that the use of a higher concentration of AIBN (0.2 equiv) or a high temperature (90 °C) resulted in an improvement to 43% yield and 45% yield, respectively (entries 2 and 3). Furthermore, the use of ABVN as a radical initiator instead of AIBN at a reaction temperature of 70 °C led to a further improvement in the yield of 10a to 55% (entry 4). Several solvents also screened against this reaction, including CCl4, DCE, and CH3CN, and the results revealed that CH3CN gave the best result (59%, entry 7), with the other two solvents giving much lower yields (entries 5 and 6). In an attempt to improve the yield of the annulation in CH3CN, we conducted the reaction at a lower temperature of 60 °C under otherwise identical conditions or increasing the concentration of benzenethiol (5 equiv). However, these conditions led to a decrease in yields to 40% 4417
DOI: 10.1021/acs.orglett.7b01733 Org. Lett. 2017, 19, 4416−4419
Letter
Organic Letters Scheme 1. Substrate Scope for the Allene [3 + 2] Reactiona
boxylative allylation15 as a key step (see Supporting Information for details). These two substrates were then annulated with benzenethiol and ABVN, and the results are shown in Scheme 3. Accordingly, Scheme 3. Synthesis of Triquinanes
a
12 and 14 were converted to the corresponding triquinanes 13a, 13b, and 15 in good to moderate yields. It is noteworthy that 14 with an enantiomeric purity of 92% ee was converted to 15 in 30% yield and 92% ee, indicating that the chirality of the substrate was being effectively transferred to the product. In summary, we have developed an intramolecular thiyl radical-initiated [3 + 2] cycloaddition reaction involving allenetethered electron-deficient olefins. This new reaction represents a concise method for the construction of polycyclopentanoids, allowing for the diastereoselective formation of diquinanes and triquinanes bearing two contiguous quaternary all-carbon stereogenic centers at the bridgehead positions in a single manipulation. Future studies toward the application of this new method to the total synthesis of complex natural products16 are currently underway in our laboratory.
Isolated yield.
Scheme 2. Electronic Effects of Arylthiols on the Annulationsa
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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.7b01733. Experimental procedures and spectra copies (PDF) Crystallographic data of 10a (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Zhen Yang: 0000-0001-8036-934X a
Author Contributions
Isolated yield.
§
These authors contributed equally to this work.
Notes
reactions requiring a higher temperature and longer reaction time. Inspired by the success of this cascade reaction for the construction of diquinanes bearing two-vicinal quaternary carbon stereocenters at their bridgehead positions, we wondered if this type of reaction could be applied to the construction of angularly fused triquinanes bearing the same structural features. To this end, 12 and 14 were prepared, the latter of which was prepared using Stoltz’s Pd-catalyzed enantio-convergent decar-
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Science Foundation of China (Grant Nos. 21632002, 21572009, and 21402002), Guangdong Natural Science Foundation (Grant Nos. 2014A030312004 and 2016A030306011), and the Scientific and Technological Innovation Project financially supported by Qingdao National 4418
DOI: 10.1021/acs.orglett.7b01733 Org. Lett. 2017, 19, 4416−4419
Letter
Organic Letters
Henriet-Bernard, C. D.; Grimaldi, J.; Hatem, J. M. J. Org. Chem. 1997, 62, 1202. (11) (a) Schwartz, C. E.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 9272. (b) Kim, K.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 67. (c) Petit, M.; Lapierre, A. J. B.; Curran, D. P. J. Am. Chem. Soc. 2005, 127, 14994. (d) Zhou, K.; Xia, H.; Wu, J. Org. Chem. Front. 2016, 3, 865. (12) For the definition of the above-mentioned electrophilic and nucleophilic properties, see: (a) Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25. (b) De Vleeschouwer, F.; Van Speybroeck, V.; Waroquier, M.; Geerlings, P.; De Proft, F. Org. Lett. 2007, 9, 2721. (13) Dénès, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114, 2587. (14) (a) Pratt, D. A.; DiLabio, G. A.; Mulder, P.; Ingold, K. U. Acc. Chem. Res. 2004, 37, 334. (b) Nau, W. M. J. Org. Chem. 1996, 61, 8312. (c) Bordwell, F. G.; Zhang, X.-M.; Satish, A. V.; Cheng, J.-P. J. Am. Chem. Soc. 1994, 116, 6605. (15) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. (b) Enquist, J. A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228. (c) Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2010, 2, 192. (16) Lee, H.; Kang, T.; Lee, H.-Y. Angew. Chem., Int. Ed. 2017, 56, 8254.
Laboratory for Marine Science and Technology (No. 2015ASKJ02).
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REFERENCES
(1) (a) Wang, X.-J.; Zhang, G.-J.; Zhang, Y.; Yu, S.-S.; Bao, X.-Q.; Zhang, D.; Yuan, Y.-H.; Chen, N.-H.; Ma, S.-G.; Qu, J.; Li, Y. Org. Lett. 2012, 14, 2614. (b) Groweiss, A.; Fenical, W.; Cun-heng, H.; Clardy, J.; Zhongde, W.; Zhongnian, Y.; Kanghou, L. Tetrahedron Lett. 1985, 26, 2379. (c) Anke, T.; Heim, J.; Knoch, F.; Mocek, U.; Steffan, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1985, 24, 709. (d) Clarke, D. B.; Hinkley, S. F. R.; Weavers, R. T. Tetrahedron Lett. 1997, 38, 4297. (e) Kaneda, M.; Takahashi, R.; Iitaka, Y.; Shibata, S. Tetrahedron Lett. 1972, 13, 4609. (f) Hanssen, H.-P.; Abraham, W.-R. Tetrahedron 1988, 44, 2175. (2) (a) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11943. (b) Long, R.; Huang, J.; Gong, J.; Yang, Z. Nat. Prod. Rep. 2015, 32, 1584. (c) Büschleb, M.; Dorich, S.; Hanessian, S.; Tao, D.; Schenthal, K. B.; Overman, L. E. Angew. Chem., Int. Ed. 2016, 55, 4156. (3) Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448. (4) Curran, D. P.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991. (5) (a) Wang, J.-C.; Ng, S.-S.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 3682. (b) Wang, J.-C.; Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 5855. (6) Kwon’s group and Fu’s group have established the intramolecular version of the Lu [3 + 2] annulation, see: (a) Henry, C. E.; Kwon, O. Org. Lett. 2007, 9, 3069. (b) Lee, S. Y.; Fujiwara, Y.; Nishiguchi, A.; Kalek, M.; Fu, G. C. J. Am. Chem. Soc. 2015, 137, 4587. (7) (a) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (b) For a review, see: Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (c) For an enantioselective variant of this catalytic cycloaddition, see: Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. (8) For allenes as three-carbon units in [3 + 2] cycloaddition reactions, see: (a) Ma, S. Chem. Rev. 2005, 105, 2829. (b) Brasholz, M.; Reissig, H.U.; Zimmer, R. Acc. Chem. Res. 2009, 42, 45. (c) Lee, H.-Y. Acc. Chem. Res. 2015, 48, 2308. For Lewis acid-promoted [3 + 2] cycloaddition of allenylsilane, see: (d) Danheiser, R. L.; Carini, D. J.; Basak, A. J. Am. Chem. Soc. 1981, 103, 1604. (e) Danheiser, R. L.; Kwasigroch, C. A.; Tsai, Y.-M. J. Am. Chem. Soc. 1985, 107, 7233. (f) Daidouji, K.; Fuchibe, K.; Akiyama, T. Org. Lett. 2005, 7, 1051. (g) Brawn, R. A.; Panek, J. S. Org. Lett. 2009, 11, 473. and references therein. For a review, see: (h) Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293. For phosphinetriggered reaction of the 2,3-butadienoate of allene derivative with electron-deficient alkene and aziridine, see: (i) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (j) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (k) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. (l) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (m) Du, Y.-H.; Lu, X.-Y. J. Org. Chem. 2003, 68, 6463. (n) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426. (o) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470. (p) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988. (q) Voituriez, A.; Panossian, A.; Fleury-Brégeot, N.; Retailleau, P.; Marinetti, A. J. Am. Chem. Soc. 2008, 130, 14030. (r) García Ruano, J. L.; Nunez, A., Jr.; Martin, M. R.; Fraile, A. J. Org. Chem. 2008, 73, 9366. Imines (s) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660. (t) Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318. (u) Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398. (v) Zhang, G.; Catalano, V. J.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 11358. (w) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614. (x) Mauleón, P.; Zeldin, R. M.; González, A. Z.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 6348. (y) Kusama, H.; Ebisawa, M.; Funami, H.; Iwasawa, N. J. Am. Chem. Soc. 2009, 131, 16352. (z) Zhang, D.-Y.; Shao, L.; Xu, J.; Hu, X.-P. ACS Catal. 2015, 5, 5026. (9) Pan, F.; Fu, C.; Ma, S. Chin. J. Org. Chem. 2004, 24, 1168. (10) (a) Hartung, J.; Thomas Kopf, T. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.: Wiley-VCH Verlag GmbH & Co., 2004; p 701. (b) Pasto, D. J.; Warren, S. E.; Morrison, M. A. J. Org. Chem. 1981, 46, 2837. (c) Pasto, D. J.; L’Hermine, G. J. Org. Chem. 1990, 55, 685. (d) Marco-Contelles, J.; Balme, G.; Bouyssi, D.; Destabel, C.; 4419
DOI: 10.1021/acs.orglett.7b01733 Org. Lett. 2017, 19, 4416−4419
