Diastereo- and Enantioselective Synthesis of Hexasubstituted Cyclohexanes via a Metal–Organocatalytic Quadruple Cascade Sequence

Abstract

A quadruple cascade reaction, comprising iminium, enamine–copper, iminium, and enamine catalysis, was investigated. This reaction afforded highly optically active hexasubstituted cyclohexanes from α,β-unsaturated aldehydes, nitromethane, and 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO). To enhance the stereoselectivity of the organocatalytic cyclization, TEMPO was incorporated into the cyclohexane skeleton using copper catalysts.

Key words

asymmetric catalysis - domino reaction - radicals - copper - cyclization

• References and Notes


For review articles of multi-catalytic reactions using transition-metal catalysts, biocatalysts, and organocatalysts:
• 1a Shao Z, Zhang H. Chem. Soc. Rev. 2009; 38: 2745
• 1b Zhou J. Chem. Asian J. 2010; 5: 422
• 1c Zhong C, Shi X. Eur. J. Org. Chem. 2010; 2999

For reviews on organocatalytic domino reactions, see ref. 1b and:
• 2a List B. Chem. Commun. 2006; 819
• 2b Enders D, Grondal C, Hüttl MR. M. Angew. Chem. Int. Ed. 2007; 46: 1570
• 2c Tsogoeva SB. Eur. J. Org. Chem. 2007; 1701
• 2d Yu X, Wang W. Org. Biomol. Chem. 2008; 6: 2037
• 2e Dondoni A, Massi A. Angew. Chem. Int. Ed. 2008; 47: 4638
• 2f Westermann B, Ayaz M, van Berkel SS. Angew. Chem. Int. Ed. 2010; 49: 846
• 2g Pellissier H. Adv. Synth. Catal. 2012; 354: 237
• 2h Wende RC, Schreiner PR. Green Chem. 2012; 14: 1821

For selected recent reviews and articles of tandem organocatalytic reactions using transition-metal complexes, see refs. 1a,c and:
• 3a Poe SL, Kobašlija M, McQuade DT. J. Am. Chem. Soc. 2006; 128: 15586
• 3b Poe SL, Kobašlija M, McQuade DT. J. Am. Chem. Soc. 2007; 129: 9216
• 3c Simmons B, Walji AM, MacMillan DW. C. Angew. Chem. Int. Ed. 2009; 48: 4349
• 3d Chercheja S, Nadakudity SK, Eilbracht P. Adv. Synth. Catal. 2010; 352: 637
• 3e Quintard A, Alexakis A. Adv. Synth. Catal. 2010; 352: 1856
• 3f Lin S, Zhao G.-L, Deiana L, Sun J, Zhang Q, Leijonmarck H, Córdova A. Chem. Eur. J. 2010; 16: 13930
• 3g Quintard A, Alexakis A, Mazet C. Angew. Chem. Int. Ed. 2011; 50: 2354
• 3h Rueping M, Sundén H, Hubener L, Sugiono E. Chem. Commun. 2012; 48: 2201
• 3i Du Z, Shao Z. Chem. Soc. Rev. 2013; 42: 1337

For selected recent articles of transition-metal-catalyzed activation of allyl and alkyne groups for the reaction with enamines, see:
• 4a Ibrahem I, Córdova A. Angew. Chem. Int. Ed. 2006; 45: 1952
• 4b Bihelovic F, Matovic R, Vulovic B, Saicic RN. Org. Lett. 2007; 9: 5063
• 4c Ding Q, Wu J. Org. Lett. 2007; 9: 4959
• 4d Binder JT, Crone B, Haug TT, Menz H, Kirsch SF. Org. Lett. 2008; 10: 1025
• 4e Yang T, Ferrali A, Campbell L, Dixon DJ. Chem. Commun. 2008; 2923
• 4f Vulovic B, Bihelovic F, Matovic R, Saicic RN. Tetrahedron 2009; 65: 10485
• 4g Ikeda M, Miyake Y, Nishibayshi Y. Angew. Chem. Int. Ed. 2010; 49: 7289
• 4h Zweifel T, Hollmann D, Prüger B, Nielsen M, Jørgensen KA. Tetrahedron: Asymmetry 2010; 21: 1624
• 5 For selected articles regarding sequential metal/organocatalysis, see refs. 3a–e,g.

For selected recent articles of organocatalyzed domino reactions for chiral cyclohexane derivatives, see:
• 6a Enders D, Hüttl MR. M, Grondal C, Raabe G. Nature (London) 2006; 441: 861
• 6b Marigo M, Bertelsen S, Landa A, Jørgensen KA. J. Am. Chem. Soc. 2006; 128: 5475
• 6c Carlone A, Marigo M, North C, Landa A, Jørgensen KA. Chem. Commun. 2006; 4928
• 6d Enders D, Hüttl MR. M, Runsink J, Raabe G, Wendt B. Angew. Chem. Int. Ed. 2007; 46: 467
• 6e Carlone A, Cabrera S, Marigo M, Jørgensen KA. Angew. Chem. Int. Ed. 2007; 46: 1101
• 6f Hayashi Y, Okano T, Aratake S, Hazelard D. Angew. Chem. Int. Ed. 2007; 46: 4922
• 6g Reyes E, Jiang H, Milelli A, Elsner P, Hazell RG, Jørgensen KA. Angew. Chem. Int. Ed. 2007; 46: 9202
• 6h Ramachary DB, Reddy YV, Prakash BV. Org. Biomol. Chem. 2008; 6: 719
• 6i Enders D, Jeanty M, Bats JW. Synlett 2009; 3175
• 6j Wang Y, Han R.-G, Zhao Y.-L, Yang S, Xu P.-F, Dixon DJ. Angew. Chem. Int. Ed. 2009; 48: 9834
• 6k Hong B.-C, Nimje RY, Lin C.-W, Liao J.-H. Org. Lett. 2011; 13: 1278
• 6l Ishikawa H, Sawano S, Yasui Y, Shibata Y, Hayashi Y. Angew. Chem. Int. Ed. 2011; 50: 3774
• 6m Mao Z, Jia Y, Xu Z, Wang R. Adv. Synth. Catal. 2012; 354: 1401
• 6n Ma C, Jia Z.-J, Liu J.-X, Zhou Q.-Q, Dong L, Chen Y.-C. Angew. Chem. Int. Ed. 2013; 52: 948
• 6o Zeng X, Ni Q, Raabe G, Enders D. Angew. Chem. Int. Ed. 2013; 52: 2977
• 7a Yoon H.-S, Ho X.-H, Jang J, Lee H.-J, Kim S.-J, Jang H.-Y. Org. Lett. 2012; 14: 3272
• 7b Ho X.-H, Oh H.-J, Jang H.-Y. Eur. J. Org. Chem. 2012; 5655
• 7c Kim J.-H, Park E.-J, Lee H.-J, Ho X.-H, Yoon H.-S, Kim P, Yun H, Jang H.-Y. Eur. J. Org. Chem. 2013; 4337
• 8 CCDC-977839 contains the crystallographic data for 2a; C₂₈H₃₆N₂O₅, M_r  = 480.59, orthorhombic, space group P2₁2₁2₁, a = 8.7335(4) Å, b = 15.6355(5) Å, c = 19.6968(6) Å, V = 2689.67(16) ų, Z = 4, T = 290(1) K, μ(MoKα) = 0.081 mm^–1. Of 26365 reflections collected in the θ range 3.0°–27.50° using ω scans on a Rigaku R-axis Rapid S diffractometer, 6162 were unique reflections (R _int = 0.0255, completeness = 99.7%). The structure was solved and refined against F ² using SHELX97, 460 variables, wR ₂ = 0.0899, R ₁ = 0.0309 [Fo ² > 2σ(Fo ²)], GOF = 1.107, and max/min residual electron density 0.129/–0.169 e Å^–3. Bond lengths and angles are included in the Supporting Information.