Asymmetric Catalytic [4 + 2] Cycloaddition via Cu–Allenylidene

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Asymmetric Catalytic [4 + 2] Cycloaddition via Cu−Allenylidene Intermediate: Stereoselective Synthesis of Tetrahydroquinolines Fused with a γ‑Lactone Moiety Hao Chen,†,§ Xuehe Lu,†,§ Xuejian Xia,† Qiongqiong Zhu,† Yanhong Song,† Jie Chen,† Weiguo Cao,*,† and Xiaoyu Wu*,†,‡ †

Center for Supramolecular Chemistry and Catalysis and Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Lu, Shanghai 200444, People’s Republic of China ‡ Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of China S Supporting Information *

ABSTRACT: A decarboxylative formal [4 + 2] cycloaddition reaction between ethynyl benzoxazinanones and 5-substituted 2silyloxyfurans catalyzed by chiral Cu−Pybox complex is described. This method allows the formation of intriguing tetrahydroquinolines fused with a butyrolactone moiety featuring three contiguous chiral centers in high yields with excellent diastereo- and enantioselectivities in most cases. The utility of this method was exemplified by the removal of the N-protecting groups and derivatization on the terminal alkyne functionality of the cyclization products.

T

he tetrahydroquinoline (THQ) scaffold is one of the privileged structural motifs found in a wide variety of biologically active natural products and pharmaceutically relevant therapeutic agents.1 Therefore, it is not surprising that intensive synthetic efforts have been invested and many catalytic asymmetric cascade reactions have been developed to access these frameworks over the past few decades.1 Despite these great achievements, new methods for the construction of THQ frameworks bearing a previously inaccessible substitution pattern are still highly desired. Recently, we and other groups have reported that, under Cucatalyzed conditions, benzoxazinanone scaffolds comprising an ethynyl function group at their C4 positions could be converted into Cu−allenylidene species tethered with a nucleophilic aryl sufamide moiety (Figure 1).2,3 Such allenylidene intermediates can be trapped with different dipolar synthons such as sulfur ylides, substituted indoles, and in situ generated ammonium enolates. These would lead to the formation of various hetero polycyclics, including THQs (Figure 1).4,5 Notably, the incorporation of 2-silyloxyfurans as assembly partners has yet to be reported. Interestingly, 2-silyloxyfurans6 have emerged as versatile nucleophiles for the rapid assembly of a variety of 5-substituted butenolides by means of vinylogous Mukaiyama aldol reaction,7 Mukaiyama Michael addition,8 and Mukaiyama Mannich reaction,9 etc. In most cases, only the nucleophilic site at C5 of 2-silyloxyfuran was involved in the design of the reactions. However, examples that take full advantage of both the nucleophilic feature and the latent electrophilic feature, i.e., the © XXXX American Chemical Society

Figure 1. Trapping of the Cu−allenylidene intermediate with dipolar synthons: previous examples and this work.

β-position of α,β-unsaturated butenolides generated from C5 addition of 2-silyoxyfurans, for the design of cascade reactions are very rarely documented.10,11 Herein, we report a highly efficient Cu-catalyzed cascade reactions of 2-silyloxyfurans with 4-ethynyl-1,4-dihydrobenzoxazinanones. By judicious selection of the copper catalysts and tertiary amine additives, both C5 and C4 of silyloxyfuran Received: January 24, 2018

A

DOI: 10.1021/acs.orglett.8b00253 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Next, we tested various base additives and found that the reactivity and enantioselectivity strongly depended on the nature of the base employed. Triethylamine led to slightly improved ee albeit with a lower yield and dr (entry 6). After a survey of several cyclic amines (entries 7−11), we found that N-alkylmorpholines significantly promoted the reactivity of the substrate and improved the enantioselectivity of the product while with a slight decrease in its dr (entries 7 and 8). In particular, when N-ethyl morpholine was employed in place of DIPEA, excellent performance (93% yield, 91:9 dr, and 95% ee) was achieved (entry 8). A brief screening of different solvents revealed that 1,2-dichloroethane (DCE) was the best in terms of yield and selectivity (entry 12, and see the Supporting Information for details). Moreover, reducing the loadings of both components of the catalyst and the amount of DCE by 50% as well to increase the concentration of the substrates and catalyst still resulted in a high yield of 3aa without deterioration of dr and ee (entry 13). With the optimized reaction conditions in hand, we set out to explore the scope of the reaction with regard to benzoxazinanones bearing different substituents on the benzoid portion (Table 2). Benzoxazinanones bearing either electron-

participate in the [4 + 2] cycloaddition process. We believe this work is synthetically useful for accessing structurally diverse butyrolactone-fused THQ scaffolds featuring three consecutive chiral centers by employing silyloxyfurans with sterically hindered substituents at C5 position. The amine additives appear to be crucial for improving the performance of this type of reaction. Initially, we examined the reaction between 4-ethynylbenzoxazinanone 1a and 5-methyl-2-trimethylsilyloxyfuran 2a promoted by a copper complex in situ generated from Cu(CH3CN)4BF4 (10 mol %) and (S)-methyl-Pybox (L1, 12 mol %) at −10 °C using DCM as solvent and DIPEA as base (Table 1, entry 1). The reaction proceeded to afford the desired Table 1. Optimization of Reaction Conditionsa

Table 2. Scope of Ethynyl Benzoxazinanones for [4 + 2] Cycloadditiona

entry

2

base

yieldb (%)

drc

eec (%)

1 2 3 4 5 6 7 8 9 10 11 12d 13d,e

2a 2a 2b 2c 2d 2d 2d 2d 2d 2d 2d 2d 2d

DIPEA DIPEA DIPEA DIPEA DIPEA TEA B1 B2 B3 B4 B5 B2 B2

51 75 60 65 73 53 92 93 45 65 91 87 89

90:10 95:5 96:4 87:13 95:5 89:11 87:13 91:9 51:49 91:9 90:10 97:3 97:3

59 68 78 80 80 84 91 95 12 90 95 95 95

a

General conditions: 1a (0.1 mmol), 2 (0.2 mmol), Cu(CH3CN)4BF4 (10 mol %), ligand (L1 for entry 1, L2 for entries 2−13, 12 mol %), and base (2.5 equiv) in DCM (2 mL) at −10 °C; the reaction was followed by TLC until the complete consumption of 1a (4−24 h). b Yield referred to isolated pure 3aa. cDiastereomeric ratio and enantiomeric excess of 3aa were determined by chiral HPLC analysis. d 1,2-Dichloroethane (DCE) was employed as solvent. eReaction performed with 5 mol % of Cu(CH3CN)4BF4, 6 mol % of L2, and 2.0 equiv of 2d in DCE (1 mL).

entry

1

R1, R2

3

yieldb (%)

drc

eec (%)

1 2 3 4 5d 6 7 8 9 10 11 12

1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1n

6-Me, Ts 6-MeO, Ts 6-F, Ts 6-Br, Ts 7-Me, Ts 7-Cl, Ts 7-Br, Ts 7-CF3, Ts 8-F, Ts 8-Me, Ts H, PhSO2 H, 4-nosyl

3ba 3ca 3da 3ea 3fa 3ga 3ha 3ia 3ja 3ka 3la 3ma

87 70 79 75 90 91 77 73 83 71 92 68

97:3 95:5 99:1 99:1 98:2 91:9 91:9 96:4 96:4 97:3 99:1 99:1

91 93 91 88 93 94 94 93 87 85 94 92

a

General conditions: 1a (0.1 mmol), 2 (0.2 mmol), Cu(CH3CN)4BF4 (5 mol %), L2 (6 mol %), and B2 (2.5 equiv) in DCE (1 mL) at −10 °C for 4−24 h. bYield referred to isolated pure 3. cDiastereomeric ratio and enantiomeric excess of 3 were determined by chiral HPLC analysis. dIn HPLC analysis of 3fa baseline resolution of different stereoisomers was not achieved.

donating or -withdrawing substituents at the C6, C7, or C8 positions all performed well to deliver the annulated products in good to excellent yields (71−91% yield) with excellent diastereoselectivities (90:10 to 99:1) and enantioselectivities (85−94% ee) (entries 1−10). Next, we briefly evaluated the effect of the substituents at the sulfamide moiety on the performance of the annulation reaction. Substrate 1l bearing a phenylsulfonyl group instead of a tosyl group afforded 3la with comparable yield, dr and ee to those of 3aa (entry 11). However, 1m with an N-(4-nitrophenyl)sulfonyl group gave the corresponding annulation products in markedly lower yield albeit with excellent stereoselectiviy (entry 12). Attempts to

product 3aa in 51% yield with high diastereoselectivity (90:10, dr) and moderate enantioselectivity (59% ee). To identify the optimal ligand for the cascade reaction between 1a and 2a, we tested a wide array of functionalized Pybox ligands (see the Supporting Information for details). To our delight, promising results, 75% yield, 95:5 dr, and 68% ee, could be obtained when L2 was employed (entry 2). An investigation of the effect of the silyl group in silyloxyfuran on the outcome of the reaction revealed that 2d bearing a triisopropylsilyl group was the best choice (entries 3−5). B

DOI: 10.1021/acs.orglett.8b00253 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

To demonstrate the usefulness of this method, the cyclization between 1a and 2d was performed on a 1 mmol scale (1a, 0.325 g) under optimal conditions, and the cyclization product 3aa was obtained in a yield of 91% with 97:3 dr and 95% ee (Figure 3). The N-Ts bond was readily

prepare benzoxazinanone substrates bearing other protecting groups, such as Cbz and Boc, on nitrogen atom were unsuccessful. To further demonstrate the generality of this cascade protocol, we investigated the substrate scope with respect to C5-substituted silyloxyfurans (Table 3). To our delight, Table 3. Scope of Silyloxyfurans for [4 + 2] Cycloadditiona

entry

2

R

3

yield (%)

dr

ee (%)

1 2 3 4 5 6b 7b 8 9 10 11

2e 2f 2g 2h 2i 2j 2k 2l 2m 2n 2o

Et n-Bu i-Bu i-Pr allyl homoallyl 4-Cl-butyl 4-Br-butyl 3-oxobutyl Bn H

3ae 3af 3ag 3ah 3ai 3aj 3ak 3al 3am 3an 3ao

81 76 71 70 73 75 67 65 78 69 72

99:1 97:3 97:3 96:4 99:1 98:2 97:3 99:1 99:1 87:13 96:4

96 97 92 88 95 98 91 91 98 92 92

a

See footnotes in Table 2. bSubstrates 2j and 2k containing minor impurities were employed in these two entries.

silyloxyfurans with a wide range of substituents including linear alkyl, branched alkyl, allyl, homoallyl, halogenated alkyl, 3oxobutyl, and benzyl groups could be employed as reaction components, and the annulation products were obtained in 60−81% yields in most cases with excellent diastereo- and enantioselectivities, except for benzyl-substituted 2n, which gave a modest dr of 87:13. The absolute configuration of annulation products 3ea was unambiguously determined by single-crystal X-ray diffraction analysis (see the SI for details). The absolute configuration of other annulation products could be assigned by analogy. The sense of stereoselectivity observed can be rationalized by a transition state involving the copper allenylidene complex as shown in Figure 2.2−5 The Si face of C5 of silyoxyfuran 2d

Figure 3. Preparation of 3aa on 1 mmol scale and further derivatization of cyclization products.

cleaved upon treating with soldium/naphthalene in THF at −78 °C, affording THQ 4 in moderate yield without deterioration of optical purity. Derivatizations on terminal alkyne moiety of 3aa were demonstrated by a click reaction with tosyl azide, a Sonogashira reaction with phenyl iodide, bromination with NBS catalyzed by AgNO3, or hydrogenation over Pd/C. No loss of diastereomeric purity was observed in all of these derivatization reactions. Furthermore, intramolecular cyclization (RCM) of 3ai and 3aj catalyzed by Grubbs (II) catalyst led to polycyclic 9 and 10 respectively in high yields with slight deterioration of optical purity. In summary, we have developed a formal [4 + 2] cycloaddition reaction between ethynyl benzoxazinanones and silyloxyfurans catalyzed by a chiral copper−Pybox complex. A series of THQs bearing three contiguous chiral centers and one terminal alkyne function were obtained in high yields with excellent dr’s and ee’s in most cases. The base additive of Nethylmorpholine was found to be beneficial to both the yield and stereoselectivity of the reaction. The utility of this method was demonstrated by a little larger scale synthesis of 3aa, removal of the tosyl group of 3aa, and derivatization on the terminal alkyne functionality of the cyclization products. Further work is currently underway to better understand the specific role of the tertiary amine additive in this copper-based catalytic system and will be reported in due course.

Figure 2. Transition-state model for chiral induction.

attacks the relatively less sterically hindered Re face of the Cu− allenylidene complex at the γ carbon atom (TS) to create two chiral centers at once. The newly generated chiral centers would induce the intramolecular addition of tosyl amide nitrogen from the α face of α,β-unsaturated butenolide moiety to create the third chiral center. C

DOI: 10.1021/acs.orglett.8b00253 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

■

Tang, H.; Yang, K.-R.; Wan, L.-Q.; Zhang, X.; Liu, J.; Fu, Z.; Niu, D.W. Angew. Chem., Int. Ed. 2017, 56, 7213. (k) Xu, H.; Laraia, L.; Schneider, L.; Louven, K.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Angew. Chem., Int. Ed. 2017, 56, 11232. (l) Zhang, K.; Lu, L.-Q.; Yao, S.; Chen, J.-R.; Shi, D.-Q.; Xiao, W.-J. J. Am. Chem. Soc. 2017, 139, 12847. (4) (a) Wang, Q.; Li, T.-R.; Lu, L.-Q.; Li, M.-M.; Zhang, K.; Xiao, W.-J. J. Am. Chem. Soc. 2016, 138, 8360. (b) Li, T.-R.; Cheng, B.-Y.; Wang, Y.-N.; Zhang, M.-M.; Lu, L.-Q.; Xiao, W.-J. Angew. Chem., Int. Ed. 2016, 55, 12422. (c) Li, T.-R.; Lu, L.-Q.; Wang, Y.-N.; Wang, B.C.; Xiao, W.-J. Org. Lett. 2017, 19, 4098. (5) (a) Song, J.; Zhang, Z.-J.; Gong, L.-Z. Angew. Chem., Int. Ed. 2017, 56, 5212. (b) Lu, X.; Ge, L.; Cheng, C.; Chen, J.; Cao, W. G.; Wu, X. Y. Chem. - Eur. J. 2017, 23, 7689. (c) Shao, W.; You, S.-L. Chem. - Eur. J. 2017, 23, 12489. (6) For reviews, see: (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929. (b) Martin, S. F. Acc. Chem. Res. 2002, 35, 895. (c) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (d) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076. (e) Jusseau, X.; Chabaud, L.; Guillou, C. Tetrahedron 2014, 70, 2595. (f) Mao, B.; Fañanás-Mastral, M.; Feringa, B. L. Chem. Rev. 2017, 117, 10502. (7) For enantioselective vinylogous Mukaiyama−aldol reactions of 2silyloxyfurans, see: (a) Ube, H.; Shimada, N.; Terada, M. Angew. Chem., Int. Ed. 2010, 49, 1858. (b) Singh, R. P.; Foxman, B. M.; Deng, L. J. J. Am. Chem. Soc. 2010, 132, 9558. (c) Szlosek, M.; Figadère, B. Angew. Chem., Int. Ed. 2000, 39, 1799. (d) Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2007, 36, 8. (e) Sedelmeier, J.; Hammerer, T.; Bolm, C. Org. Lett. 2008, 10, 917. (8) For enantioselective vinylogous Mukaiyama−Michael reactions of 2-silyloxyfurans, see: (a) Desimoni, G.; Faita, G.; Guala, M.; Laurenti, A.; Mella, M. Chem. - Eur. J. 2005, 11, 3816. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (c) Robichaud, J.; Tremblay, F. Org. Lett. 2006, 8, 597. (d) Takahashi, A.; Yanai, H.; Taguchi, T. Chem. Commun. 2008, 2385. (e) Takahashi, A.; Yanai, H.; Taguchi, T. Chem. Commun. 2008, 2385. (f) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc. 2008, 130, 7202. (g) Zhang, Q.; Xiao, X.; Lin, L.; Liu, X.; Feng, X. Org. Biomol. Chem. 2011, 9, 5748. (9) For enantioselective vinylogous Mukaiyama−Mannich reactions of 2-silyloxyfurans, see: (a) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2006, 45, 7230. (b) Akiyama, T.; Honma, Y.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2008, 350, 399. (c) Akiyama, T.; Honma, Y.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2008, 350, 399. (d) Deng, H.-P.; Wei, Y.; Shi, M. Adv. Synth. Catal. 2009, 351, 2897. (e) Wieland, L. C.; Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 570. (f) Ruan, S.-T.; Luo, J.-M.; Du, Y.; Huang, P.-Q. Org. Lett. 2011, 13, 4938. (g) Ranieri, B.; Curti, C.; Battistini, L.; Sartori, A.; Pinna, L.; Casiraghi, G.; Zanardi, F. J. Org. Chem. 2011, 76, 10291. (10) (a) Li, J.; Huang, R.; Xing, Y.-K.; Qiu, G.; Tao, H.-Y.; Wang, C.J. J. Am. Chem. Soc. 2015, 137, 10124. (b) Liu, K.; Chang, X.; Wang, C.-J. Org. Lett. 2016, 18, 6288. (c) Huang, R.; Chang, X.; Li, J.; Wang, C.-J. J. Am. Chem. Soc. 2016, 138, 3998. (11) For examples using β,γ-unsaturated butenolides as reaction components for cascade reaction design, see: (a) Wu, B.; Yu, Z. Y.; Gao, X.; Lan, Y.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2017, 56, 4006. (b) Cui, H.-L.; Huang, J. R.; Lei, J.; Wang, Z.-F.; Chen, S.; Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12, 720. (c) Li, C.; Jiang, K.; Chen, Y.-C. Molecules 2015, 20, 13642. (d) Li, X.; Lu, M.; Dong, Y.; Wu, W.-B.; Qian, Q.-Q.; Ye, J.-X.; Dixon, D. J. Nat. Commun. 2014, 5, 4479.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00253. Experimental details and analytical data (PDF) Accession Codes

CCDC 1580778 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 data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xiaoyu Wu: 0000-0001-7179-4280 Author Contributions §

H.C. and X.L. contributed equally.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Nos. 21272150 and 21672137). Dr. Hanwei Hu at Shanghai Kylin Science is also gratefully acknowledged for helpful discussions.

■

REFERENCES

(1) For selected reviews on the synthesis of tetrahydroquinolines, see: (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031. (b) Nammalwar, B.; Bunce, R. A. Molecules 2014, 19, 204. (c) Fochi, M.; Caruana, L.; Bernardi, L. Synthesis 2014, 46, 135. (d) Masson, G.; Lalli, C.; Benohoud, M.; Dagousset, G. Chem. Soc. Rev. 2013, 42, 902. (e) Jiang, X.; Wang, R. Chem. Rev. 2013, 113, 5515. (2) For reviews on catalyzed propargylic substitution, see: (a) Ljungdahl, N.; Kann, N. Angew. Chem., Int. Ed. 2009, 48, 642. (b) Detz, R. J.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2009, 2009, 6263. (c) Miyake, Y.; Uemura, S.; Nishibayashi, Y. ChemCatChem 2009, 1, 342. (d) Ding, C.-H.; Hou, X.-L. Chem. Rev. 2011, 111, 1914. (e) Nishibayashi, Y. Synthesis 2012, 2012, 489. (f) Bauer, E. Synthesis 2012, 44, 1131. (g) Hu, X.-H.; Liu, Z.-T.; Shao, H.; Hu, X.-P. Synthesis 2015, 47, 913. (h) Zhang, D.-Y.; Hu, X.-P. Tetrahedron Lett. 2015, 56, 283. (3) For selected examples on asymmetric catalyzed propargylic substitution, see: (a) Detz, R. J.; Delville, M. M. E.; Hiemstra, H.; van Maarseveen, J. H. Angew. Chem., Int. Ed. 2008, 47, 3777. (b) Hattori, G.; Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2008, 47, 3781. (c) Hattori, G.; Sakata, K.; Matsuzawa, H.; Tanabe, Y.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc. 2010, 132, 10592. (d) Zhang, C.; Hu, X.-H.; Wang, Y.-H.; Zheng, Z.; Xu, J.; Hu, X.-P. J. Am. Chem. Soc. 2012, 134, 9585. (e) Zhu, F.-L.; Zou, Y.; Zhang, D.-Y.; Wang, Y.-H.; Hu, X.-H.; Chen, S.; Xu, J.; Hu, X.-P. Angew. Chem., Int. Ed. 2014, 53, 1410. (f) Zhu, F.-L.; Wang, Y.- H.; Zhang, D.-Y.; Xu, J.; Hu, X.-P. Angew. Chem., Int. Ed. 2014, 53, 10223. (g) Nakajima, K.; Shibata, M.; Nishibayashi, Y. J. Am. Chem. Soc. 2015, 137, 2472. (h) Shao, W.; Li, H.; Liu, C.; Liu, C.-J.; You, S.-L. Angew. Chem., Int. Ed. 2015, 54, 7684. (i) Tsuchida, K.; Senda, Y.; Nakajima, K.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2016, 55, 9728. (j) Li, R.-Z.; D

DOI: 10.1021/acs.orglett.8b00253 Org. Lett. XXXX, XXX, XXX−XXX