Letter pubs.acs.org/OrgLett
Phosphine-Catalyzed Asymmetric (3 + 2) Annulations of δ‑Acetoxy Allenoates with β‑Carbonyl Amides: Enantioselective Synthesis of Spirocyclic β‑Keto γ-Lactams Chunjie Ni,§,† Jiangfei Chen,§,† Yuwen Zhang,† Yading Hou,† Dong Wang,† Xiaofeng Tong,*,† Shou-Fei Zhu,‡ and Qi-Lin Zhou*,‡ †
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, 1 Gehu Road, Changzhou, 213164, China ‡ State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, China S Supporting Information *
ABSTRACT: While the phosphine catalysis is a powerful tool for the construction of N-heterocycles, the phosphine-catalyzed annulations toward lactam motif are still extremely scarce. Here, we report the asymmetric (3 + 2) annulations of δ-acetoxy allenoates with β-carbonyl amides by using the (R)-SITCP catalyst. The δC and γC of allenoate respectively engage in annulation with the αC and N of the amide, forging a γ-lactam with good to excellent stereoselectivity. he chiral γ-lactam is an important structural motif and serves as a versatile building block.1 Specifically, spirocyclic β-keto γ-lactam moieties are widely found in natural and pharmaceutical compounds with a broad spectrum of biological activities (Scheme 1A).2 From a synthetic viewpoint, cyclic βketo amides 1 would be an ideal starting material for the
T
construction of such spirocycles via annulation with appropriate biselectrophiles on the basis of their inherent C,N-bisnucleophilic reactivity.3 For instance, the group of Luo reported the asymmetric (3 + 2) annulation of amide 1, wherein phenacyl bromides are used as the biselectrophile (Scheme 1B).4 However, this synthetic strategy is severely impeded by the lack of either matched 1,2-biselectrophiles or efficient asymmetric catalytic systems and, thus, attracts little attention.5 In this context, we sought to approach the construction of spirocyclic βketo lactams by using a phosphine-catalyzed asymmetric annulation of allenoate via in situ generation of a biselectrophilic intermediate with matched reactivity toward compound 1 (Scheme 1C). Since the pioneering report of Lu’s [3 + 2] annulation,6 the zwitterionic intermediates have been recognized as the cornerstone for the phosphine-catalyzed allenoate annulations.7 In general, such zwitterionic intermediates rely on the carbanion nature and serve as a nucleophile. Therefore, endeavors in this field mainly focus on the development of zwitterion variants8 with new reactivity patterns and the pursuit of novel types of C X (X = C, N) electrophiles9 as the other annulation partner. In contrast, our group has successfully developed novel cationic intermediates based on allenoates bearing an acetate group.10 These cationic intermediates intrinsically exhibit good biselectrophilic reactivity and, thus, are able to react with various bisnucleophiles.11 For instance, δ-acetoxy allenoate 2 can be converted into 2-phosphonium diene intermediate A via an addition−elimination process under phosphine catalysis (Scheme 1C), allowing for the achievement of (3 + 3)
Scheme 1. Some Related Natural Products and Construction of Spirocyclic β-Keto Lactams from Cyclic β-Keto Amides 1 under Asymmetric Catalysis
Received: June 7, 2017 Published: June 28, 2017 © 2017 American Chemical Society
3668
DOI: 10.1021/acs.orglett.7b01717 Org. Lett. 2017, 19, 3668−3671
Letter
Organic Letters
Scheme 2. Highly Stereoselective Synthesis of Spirocyclic βKeto γ-Lactams
annulations with C,O-bisnucleophiles.12 Despite these advances, the use of a C,N-bisnucleophile as the reaction partner remains underdeveloped, particularly regarding the construction of the γlactam skeleton.13 Herein, we report the phosphine-catalyzed asymmetric (3 + 2) annulations of δ-acetoxy allenoates 2 and βcarbonyl amides. Notably, spirocyclic β-keto γ-lactams can be readily constructed with good stereoselectivity by using compound 1 as a C,N-bisnucleophile (Scheme 1C). At the outset of this study, we were cognizant of some problems related to selectivity, since viable nucleophile 1 is able to trigger the competitive Michael reaction with allenoate 2 and two available electrophilic sites of intermediate A (αC and δC) would result in a regioselectivity issue. Delightedly, when the reaction of amide 1a and allenoate 2a was conducted in the presence of 20 mol % (4-MeO-C6H4)3P, spirocyclic β-keto γlactam 3aa was solely obtained while the anticipated (3 + 3) annulation product was not observed at all (eq 1). Extensive
screening of reaction parameters disclosed that the combination of 1.1 equiv of K2CO3 as the base additive and CH2Cl2 as the solvent was the best choice, affording 3aa in 76% yield and with 8.3:1 diastereoselectivity.14 After verification of the phosphine-catalyzed (3 + 2) annulation of 1a and 2a, we focused on the development of the asymmetric version. To achieve this goal, we utilized SITCP developed by our group (Scheme 2),15 which has become a privileged chiral phosphine catalyst for several asymmetric annulations.16 Indeed, (R)-SITCP was found to be an efficient catalyst for the (3 + 2) annulation of allenoate 2a and amide 1a even with reduced catalyst loading (10 mol %), delivering 3aa in 64% yield and with 92% ee and 6.2:1 dr (Scheme 2). The structure as well as absolute configuration of (3 + 2) annulation products was unambiguously established by single-crystal X-ray analysis of 3jb (Figure 1). Having identified the optimal reaction conditions, we then turned our attention to exploring the generality of the (R)SITCP-catalyzed (3 + 2) annulations of allenoates 2 with cyclic β-keto amides 1, and the results are summarized in Scheme 2. The effect of a nitrogen protecting group was first examined. Compared with the PMB-protected amide 1a, the reaction of Nbenzyl amide 1b and 2a was less efficient, affording product 3ba only in 46% yield albeit with improved diastereoselectivity (12.5:1). Either the Ph- or PMP-protecting group is deleterious to the reaction performances, giving the corresponding products 3ca and 3da in relatively lower yields and enantioselectivity. Then, various cyclic N-PMB amides were further tested. Cyclohexanone amide 1e shows better reactivity, and its reaction with allenoate 2b produces product 3eb as a single isomer with as high as 97% ee. The reaction of cycloheptanone amide 1f with 2b gives similar results while the diastereoselectivity of cyclooctanone amide 1g significantly drops to 3.7:1. These results clearly indicated that the ring size of cyclic amide would play an important role on stereoselectivity. Benzocyclic amides, on the other hand, are found to be more reactive. For instance, the reaction of benzocyclopentanone amide 1h with allenaote 2b gives product 3hb in 88% yield and with improved
Figure 1. X-ray crystal structure of 3jb (CCDC 1548943).
diastereoselectivity (16.6:1). Benzocyclohexanone amides 1i and 1j also react well with various allenoates, and the corresponding products 3ib and 3ja−3jc are obtained in good yields and with excellent stereoselectivity. Moreover, heteroarylfused amides, such as cyclohexa[b]furan-4-one amide 1k and cyclohexa[b]thiophen-4-one 1l, are also suitable substrates, affording products 3kb and 3lb in somewhat lower yields and still with excellent stereoselectivity. Interestingly, the reaction can be applicable to cyclohexenone amide 1m. Within the broad substrate scope and the mild reaction conditions, we applied the present method to late-stage modification of estrone derivative 1n. As expected, spirocyclic lactam 3nb is still obtained as a single 3669
DOI: 10.1021/acs.orglett.7b01717 Org. Lett. 2017, 19, 3668−3671
Letter
Organic Letters isomer in a synthetically useful yield without being affected by the complex steroid structure. To further explore the synthetic utility of the present asymmetric (3 + 2) annulation, acyclic β-carbonyl amide 4 was investigated as the three-atom component (Scheme 3). 3-
Scheme 4. Mechanistic Studies (E = CO2Et)
Scheme 3. Highly Stereoselective Synthesis of γ-Lactams
the reaction of 4c and 2a was conducted in the presence of additional D2O under the otherwise identical conditions, 5ca-d2 was isolated with incorporation of 63% D and 67% D into αC and βC, respectively, and without observation of deuterium at the γC position (Scheme 4). On the basis of the above observations and our previous work, a proposal mechanism is depicted in Scheme 5. The reaction Scheme 5. Proposed Mechanism and Rationale for Stereochemical Outcome
Oxobutanamides 4a and 4b exhibit similar reactivity as that of cyclic amide 1a, affording the corresponding lactams 5aa and 5cb with an asymmetric all-carbon quaternary center. Moreover, 2carbamoylmalonates 4c−4g with different N-protecting groups, including benzyl, aryl, and allyl, are also able to participate in the (3 + 2) annulations with 2a to deliver lactams 5c−5g in excellent yields. Among these amides, only Ph-protected amide 4e shows unique activity to furnish the (3 + 2) annulations with allenoates 2d−2f bearing an aryl group at the δC position, affording lactams 5ed−5ef in good yields and excellent ee. Finally, the activity of 4c is examined by reacting with a wide range of allenoates 2. Various substituents at the δC position of allenoate, such as a bulky alkyl group (5cg and 5ch), protected hydroxyl (5ci and 5cj), and alkene (5ck), are tolerated, and these reactions exhibit excellent enantioselectivity. Intriguingly, the dicarbamoyl group of products 5 can be removed easily, thus enabling compound 4c to serve as an acetamide surrogate (eq 2).
features the involvement of 2-phosphonium diene A via the addition−elimination process between allenoate 2 and SITCP. Since the si-face of δC is shielded by the phenyl group from (R)SITCP, the nucleophile attacks from the re-face via 1,6-addition to form intermediate B. After a proton transfer, the resultant intermediate C undergoes intramolecular aza-Michael addition via pseudochair conformation, leading to intermediate D. Finally, another proton transfer and subsequent 1,2-elimination of the phosphine catalyst yield product 3 (Scheme 5). No observation of deuterium at the γC position might imply that the carbanion of intermediate B would rapidly undergo proton transfer rather than delocalization. In summary, we have developed the (R)-SITCP-catalyzed asymmetric (3 + 2) annulations of δ-acetoxy allenoates and βcarbonyl amides, in which the δC and γC positions of allenoate serve as two electrophilic sites engaging in the annulation with the αC and N of the amide, respectively. The present protocol features a wide substrate scope with respect to both allenoate and β-carbonyl amide, providing a robust method for synthesis of various γ-lactams and spirocyclic β-keto lactams with high stereoselectivity in most cases (up to 97% ee and >20:1 dr). The potential reactivity of the 2-phosphonium diene intermediate
Attempts to capture 2-phosphonium diene intermediate A via NMR experiments were unfruitful. However, enyne 7 was isolated in 73% yield upon treatment with tBuOK in the absence of amide 1, which arises from the 1,2-elimination of phosphine on the cationic intermediate A (Scheme 4).17 Moreover, when 3670
DOI: 10.1021/acs.orglett.7b01717 Org. Lett. 2017, 19, 3668−3671
Letter
Organic Letters
Basle, O.; Isambert, N.; Gaudel-Siri, A.; Genisson, Y.; Plaquevent, J.-C.; Rodriguez, J.; Constantieux, T. Org. Lett. 2011, 13, 3296. (6) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (7) For selected reviews, see: (a) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. (b) Fan, Y. C.; Kwon, O. Chem. Commun. 2013, 49, 11588. (c) Xie, P.; Huang, Y. Eur. J. Org. Chem. 2013, 2013, 6213. (d) Gomez, C.; Betzer, J.-F.; Voituriez, A.; Marinetti, A. ChemCatChem 2013, 5, 1055. (e) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102. (f) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520. (g) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (h) Xiao, Y.; Sun, Z.; Guo, H.; Kwon, O. Beilstein J. Org. Chem. 2014, 10, 2089. (i) Wang, T.; Han, X.; Zhong, F.; Yao, W.; Lu, Y. Acc. Chem. Res. 2016, 49, 1369. (8) For selected examples, see: (a) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Chem. Sci. 2012, 3, 1231. (b) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632. (c) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. (d) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716. (e) Li, E.; Huang, Y.; Liang, L.; Xie, P. Org. Lett. 2013, 15, 3138. (f) Gicquel, M.; Gomez, C.; Retailleau, P.; Voituriez, A.; Marinetti, A. Org. Lett. 2013, 15, 4002. (g) Jung, C.-K.; Wang, J.-C.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4118. (h) Sampath, M.; Lee, P.-Y. B.; Loh, T.P. Chem. Sci. 2011, 2, 1988. (i) Sampath, M.; Loh, T.-P. Chem. Commun. 2009, 1568. (9) For selected examples, see: (a) Sankar, M. G.; Garcia-Castro, M.; Golz, C.; Strohmann, C.; Kumar, K. Angew. Chem., Int. Ed. 2016, 55, 9709. (b) Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318. (c) Jia, Z.-J.; Daniliuc, C. G.; Antonchick, A. P.; Waldmann, H. Chem. Commun. 2015, 51, 1054. (d) Li, E.; Jin, H.; Jia, P.; Dong, X.; Huang, Y. Angew. Chem., Int. Ed. 2016, 55, 11591. (e) Li, E.; Huang, Y. Chem. - Eur. J. 2014, 20, 3520. (f) Kumari, A. L. S.; Swamy, K. C. K. J. Org. Chem. 2015, 80, 4084. (g) Steurer, M.; Jensen, K. L.; Worgull, D.; Jørgensen, K. A. Chem. - Eur. J. 2012, 18, 76. (h) Yao, W.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2015, 137, 54. (i) Jones, R. A.; Krische, M. J. Org. Lett. 2009, 11, 1849. (j) Wang, D.; Lei, Y.; Wei, Y.; Shi, M. Chem. - Eur. J. 2014, 20, 15325. (k) Wang, T.; Ye, S. Org. Lett. 2010, 12, 4168. (l) Xu, S.; Zhou, L.; Ma, R.; Song, H.; He, Z. Chem. - Eur. J. 2009, 15, 8698. (m) Lee, S. Y.; Fujiwara, Y.; Nishiguchi, A.; Kalek, M.; Fu, G. C. J. Am. Chem. Soc. 2015, 137, 4587. (10) (a) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc. 2010, 132, 2550. (b) Gu, Y.; Hu, P.; Ni, C.; Tong, X. J. Am. Chem. Soc. 2015, 137, 6400. (11) (a) Ziegler, D. T.; Riesgo, L.; Ikeda, T.; Fujiwara, Y.; Fu, G. C. Angew. Chem., Int. Ed. 2014, 53, 13183. (b) Han, X.; Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.; Kwiatkowski, J.; Lu, Y. Angew. Chem., Int. Ed. 2014, 53, 5643. (c) Kramer, S.; Fu, G. C. J. Am. Chem. Soc. 2015, 137, 3803. (12) Hu, J.; Dong, W.; Wu, X.-Y.; Tong, X. Org. Lett. 2012, 14, 5530. (13) At the point that we prepared this manuscript, we were not aware of any progress by others toward C,N-bisnucleophiles: Xing, J.; Lei, Y.; Gao, Y.-N.; Shi, M. Org. Lett. 2017, 19, 2382 (online on 26th April). In Shi’s work, only allenoate 2l was used as the 2-atom component. Although they have tested a wide range of chiral phosphine catalysts, the highest ee value obtained is 71%, demonstrating the challenge for asymmetric version.. (14) For the detailed discussion, see the Supporting Information. (15) Zhu, S.-F.; Yang, Y.; Wang, L.-X.; Liu, B.; Zhou, Q.-L. Org. Lett. 2005, 7, 2333. (16) (a) Takizawa, S.; Arteaga, F. A.; Yoshida, Y.; Suzuki, M.; Sasai, H. Asian J. Org. Chem. 2014, 3, 412. (b) Kalek, M.; Fu, G. C. J. Am. Chem. Soc. 2015, 137, 9438. (c) Wang, D.; Wang, G.-P.; Sun, Y.-L.; Zhu, S.-F.; Wei, Y.; Zhou, Q.-L.; Shi, M. Chem. Sci. 2015, 6, 7319. (d) Liu, H.; Liu, Y.; Yuan, C.; Wang, G.-P.; Zhu, S.-F.; Wu, Y.; Wang, B.; Sun, Z.; Xiao, Y.; Zhou, Q.-L.; Guo, H. Org. Lett. 2016, 18, 1302. (e) Takizawa, S.; Kishi, K.; Yoshida, Y.; Mader, S.; Arteaga, F. A.; Lee, S.; Hoshino, M.; Rueping, M.; Fujita, M.; Sasai, H. Angew. Chem., Int. Ed. 2015, 54, 15511. (f) Chung, Y. K.; Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 2225. (17) (a) Choe, Y.; Lee, P. H. Org. Lett. 2009, 11, 1445. (b) Deng, Y.; Jin, X.; Fu, C.; Ma, S. Org. Lett. 2009, 11, 2169.
with other bisnucleophiles in an asymmetric fashion is currently being investigated in our laboratory.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01717. Detailed experimental procedures, spectral data for all compounds, NMR and HPLC spectra (PDF) X-ray data of compounds 3jb (CIF)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xiaofeng Tong: 0000-0002-6789-1691 Shou-Fei Zhu: 0000-0002-6055-3139 Qi-Lin Zhou: 0000-0002-4700-3765 Author Contributions §
C.N. and J.C. contributed equally.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work is supported by the National Natural Science Foundation of China (No. 21472042), the Jiangsu Province Funds for Distinguished Young Scientists (BK20160005), and Qing-Lan Project. We are also grateful to Advanced Catalysis and Green Manufacturing Collaborative Innovation Center, Changzhou University for financial support.
■
REFERENCES
(1) (a) Royer, J. Asymmetric Synthesis of Nitrogen Heterocycles; WileyVCH: Weinheim, 2009. (b) Martelli, G.; Orena, M.; Rinaldi, S. Curr. Org. Chem. 2014, 18, 1373. (c) Ye, L.-W.; Shu, C.; Gagosz, F. Org. Biomol. Chem. 2014, 12, 1833. (d) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571. (e) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355. (f) Kwan, C.-Y.; Harrison, P. H. M.; Kwan, T. K. Vasc. Pharmacol. 2003, 40, 35. (g) Newhouse, B.; Allen, S.; Fauber, B.; Anderson, A. S.; Eary, C. T.; Hansen, J. D.; Schiro, J.; Gaudino, J. J.; Laird, E.; Chantry, D.; Eberhardt, C.; Burgess, L. E. Bioorg. Med. Chem. Lett. 2004, 14, 5537. (h) Pilli, R. A.; Rosso, G. B.; de Oliveira, M. C. F. Nat. Prod. Rep. 2010, 27, 1908. (i) Tan, S. W. B.; Chai, C. L. L.; Moloney, M. G.; Thompson, A. L. J. Org. Chem. 2015, 80, 2661. (2) (a) Jang, J.-H.; Asami, Y.; Jang, J.-P.; Kim, S.-O.; Moon, D.-O.; Shin, K.-S.; Hashizume, D.; Muroi, M.; Saito, T.; Oh, H.; Kim, B. Y.; Osada, H.; Ahn, J. S. J. Am. Chem. Soc. 2011, 133, 6865. (b) Zhang, Y.; Wang, T.; Pei, Y.; Hua, H.; Feng, B. J. Antibiot. 2002, 55, 693. (c) Tomikawa, T.; Shin-Ya, K.; Kinoshita, T.; Miyajima, A.; Seto, H.; Hayakawa, Y. J. Antibiot. 2001, 54, 379. (d) Sarma, K. D.; Zhang, J.; Huang, Y.; Davidson, J. G. Eur. J. Org. Chem. 2006, 2006, 3730. (e) For a review, see: Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617. (3) (a) Sternativo, S.; Battistelli, B.; Bagnoli, L.; Santi, C.; Testaferri, L.; Marini, F. Tetrahedron Lett. 2013, 54, 6755. (b) Habib-Zahmani, H.; Viala, J.; Hacini, S.; Rodriguez, J. Synlett 2007, 2007, 1037. (c) Hanessian, S.; Johnstone, S. J. Org. Chem. 1999, 64, 5896. (4) Zhu, Y.; Zhang, L.; Luo, S. J. Am. Chem. Soc. 2014, 136, 14642. (5) (a) Goudedranche, S.; Bugaut, X.; Constantieux, T.; Bonne, D.; Rodriguez, J. Chem. - Eur. J. 2014, 20, 410. (b) Sanchez Duque, M. M.; 3671
DOI: 10.1021/acs.orglett.7b01717 Org. Lett. 2017, 19, 3668−3671
