Organocatalytic Asymmetric Conjugate Additions of Oxindoles and Benzofuranones to Cyclic Enones

Abstract

The asymmetric catalytic synthesis of densely functionalized molecules that contain vicinal quaternary and tertiary stereocenters is a challenge for modern chemical methodology. Here we show that a chiral primary amine, derived from natural molecules, efficiently catalyzes the stereoselective conjugate addition of oxindoles to cyclic enones, leading directly to valuable chiral scaffolds. Proof-of-concept for extending the method to benzofuranone derivatives is also provided.

Key words

asymmetric catalysis - ketones - Michael addition - quaternary carbon - organocatalysis

References and Notes

• 1a Nicolaou KC. Snyder SA. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  11929 
• 1b Shenvi RA. O’Malley DP. Baran PS. Acc. Chem. Res.  2009,  42:  530 
• 2a Mohr JT. Krout MR. Stoltz BM. Nature (London)  2008,  455:  323 
• 2b Grondal C. Jeanty M. Enders D. Nature Chem.  2010,  2:  167 
• 2c Woodward RB. Bader FE. Bickel H. Frey AJ. Kierstead RW. J. Am. Chem. Soc.  1956,  78:  2023 
• 2d Corey EJ. Angew. Chem. Int. Ed.  2002,  41:  1650 
• 2e Dounay AB. Overman LE. Chem. Rev.  2003,  103:  2945 
• 3a Newman DJ. Cragg GM. J. Nat. Prod.  2007,  70:  461 
• 3b Stereochemical Aspects of Drug Action and Disposition   Eichelbaum M. Testa B. Somogyi A. Springer; Berlin: 2003. 
• 3c Kumar K. Waldmann H. Angew. Chem. Int. Ed.  2009,  48:  3224 
• 4a Quaternary Stereocenters. Challenges and Solutions in Organic Synthesis   Christoffers J. Baro A. Wiley-VCH; Weinheim: 2006. 
• 4b Douglas CJ. Overman LE. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5363 
• 4c Trost BM. Chunhui J. Synthesis  2006,  369 
• 4d Bella M. Gasperi T. Synthesis  2009,  1583 
• 5a Lin H. Danishefsky SJ. Angew. Chem. Int. Ed.  2003,  42:  36 
• 5b Marti C. Carreira EM. Eur. J. Org. Chem.  2003,  2209 
• 5c Galliford CV. Scheidt KA. Angew. Chem. Int. Ed.  2007,  46:  8748 
• 6a Venkatesan H. Davis MC. Altas Y. Snyder D. Liotta C. J. Org. Chem.  2001,  66:  3653 
• 6b Lo MM.-C. Neumann CS. Nagayama S. Perlstein EO. Schreiber SL. J. Am. Chem. Soc.  2004,  126:  16077 
• 6c Kotha S. Deb AC. Lahiri K. Manivannan E. Synthesis  2009,  165 ; and references cited therein
• 6d Lik K.-C, So S.-S, Zhang J, and Zhang Z. inventors; WO  2006/136606. 
• 6e Liu J.-J, and Zhang Z. inventors; WO  2008/055812. 
• Selected examples:
• 7a Madin A. O’Donnell CJ. Oh T. Old DW. Overman LE. Sharp MJ. J. Am. Chem. Soc.  2005,  127:  18054 
• 7b Trost BM. Zhang Y. J. Am. Chem. Soc.  2007,  129:  14548 
• 7c Kündig EP. Seidel TM. Jia Y. Bernardinelli G. Angew. Chem. Int. Ed.  2007,  46:  8484 
• 7d Ma S. Han X. Krishnan S. Virgil SC. Stoltz BM. Angew. Chem. Int. Ed.  2009,  48:  8037 
• Selected examples:
• 8a Lee TBK. Wong GSK. J. Org. Chem.  1991,  56:  872 
• 8b Hills ID. Fu G. Angew. Chem. Int. Ed.  2003,  42:  3921 
• 8c Ogawa S. Shibata N. Inagaki J. Nakamura S. Toru T. Shiro M. Angew. Chem. Int. Ed.  2007,  46:  8666 
• 8d Tian X. Jiang K. Peng J. Du W. Chen Y.-C. Org.Lett.  2008,  10:  3583 
• 8e Chen X.-H. Wei Q. Luo S.-W. Xiao H. Gong L.-Z. J. Am. Chem. Soc.  2009,  131:  13819 
• 8f Bencivenni G. Wu L.-Y. Mazzanti A. Giannichi B. Pesciaioli F. Song M.-P. Bartoli G. Melchiorre P. Angew. Chem. Int. Ed.  2009,  48:  7200 
• For selected examples on the catalytic construction of adjacent quaternary and tertiary chiral centers, see:
• 9a Austin JF. Kim S.-G. Sinz CJ. Xiao W.-J. MacMillan DWC. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5482 
• 9b Li H. Wang Y. Tang L. Wu F. Liu X. Guo C. Foxman BM. Deng L. Angew. Chem. Int. Ed.  2005,  44:  105 
• 9c Lalonde MP. Chen Y. Jacobsen EN. Angew. Chem. Int. Ed.  2006,  45:  6366 
• 9d Bartoli G. Bosco M. Carlone A. Cavalli A. Locatelli M. Mazzanti A. Ricci P. Sambri L. Melchiorre P. Angew. Chem. Int. Ed.  2006,  45:  4966 
• 9e Streuff J. White DE. Virgil SC. Stoltz BM. Nature Chem.  2010,  2:  192 
• 10a Galzerano P. Bencivenni G. Pesciaioli F. Mazzanti A. Giannichi B. Sambri L. Bartoli G. Melchiorre P. Chem. Eur. J.  2009,  15:  7846 
• 10b Bui T. Syed S. Barbas CF. J. Am. Chem. Soc.  2009,  131:  8758 
• 10c Kato Y. Furutachi M. Chen Z. Mitsunuma H. Matsunaga S. Shibasaki M. J. Am. Chem. Soc.  2009,  131:  9168 
• 10d He R. Shirakawa S. Maruoka K. J. Am. Chem. Soc.  2009,  131:  16620 
• For recent examples on the catalytic, asymmetric addition of oxindoles to vinyl sulfones and vinyl ketones, generating a single, quaternary stereocenter:
• 11a He R. Ding C. Maruoka K. Angew. Chem. Int. Ed.  2009,  48:  4559 
• 11b Li X. Xi Z.-G. Luo S. Cheng J.-P. Org. Biomol. Chem.  2010,  8:  77 
• 12a Bartoli G. Melchiorre P. Synlett  2008,  1759 
• 12b Chen Y.-C. Synlett  2008,  1919 
• For the first use of primary amines in iminium catalysis with enones, see:
• 12c Martin NJA. List B. J. Am. Chem. Soc.  2006,  128:  13368 
• For the first demonstration that catalysts A or B can be used in iminium-enamine cascades of enones, see:
• 12d Wang X. Reisinger CM. List B. J. Am. Chem. Soc.  2008,  130:  6070 
• Selected examples:
• 13a Xie J.-W. Chen W. Li R. Zeng M. Du W. Yue L. Chen Y.-C. Wu Y. Zhu J. Deng J.-G. Angew. Chem. Int. Ed.  2007,  46:  389 
• 13b Bartoli G. Bosco M. Carlone A. Pesciaioli F. Sambri L. Melchiorre P. Org. Lett.  2007,  9:  1403 
• 13c Chen W. Du W. Duan Y. Wu Y. Yang S.-Y. Chen Y.-C. Angew. Chem. Int. Ed.  2007,  46:  7667 
• 13d Zhang E. Fan C.-A. Tu Y.-Q. Zhang F.-M. Song Y.-L. J. Am. Chem. Soc.  2009,  131:  14626 
• 13e Wu L.-Y. Bencivenni G. Mancinelli M. Mazzanti A. Bartoli G. Melchiorre P. Angew. Chem. Int. Ed.  2009,  48:  7196 
• 13f Galzerano P. Pesciaioli F. Mazzanti A. Bartoli G. Melchiorre P. Angew. Chem. Int. Ed.  2009,  48:  7892 
• 14 Bordwell FG. Fried HE. J. Org. Chem.  1991,  56:  4218 
• 16 For an example of catalytic and enantioselective O-to-C rearrangements of O-acylated benzofuranone derivatives, see ref. 8b. For an early example, see: Black TH. Arrivo SM. Schumm JS. Knobeloch JM. J. Chem. Soc., Chem. Commun.  1986,  1524 

15

Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, accession number CCDC 771490(4), and are available free of charge via www.ccdc.cam.ac.uk/data_request/cif.

17

General Procedure All the reactions were carried out with no precautions to exclude moisture in undistilled toluene. In an ordinary vial equipped with a magnetic stir bar, amine A or B (0.02 mmol, 6.5 mg, 10 mol%) and benzoic acid (0.04 mmol, 4.9 mg, 20 mol%) were dissolved in toluene (1 mL). After stirring at r.t. for 10 min, the cyclic enones 2 (0.2 mmol) was added, followed by the addition of oxindole 1 or benzofuranone 5 (0.24 mmol, 1.2 equiv). The vial was sealed, and the mixture stirred for 1 d at r.t. The crude mixture was diluted with CH₂Cl₂ and flushed through a short plug of silica, using CH₂Cl₂-EtOAc (1:1) as the eluent. Solvent was removed in vacuo, and the Michael adduct 3 or 6 was purified by flash column chromatography (silica gel, hexane-EtOAc). All new compounds gave satisfactory spectroscopic and analytical data. As a typical example, the data of the compound 3a are given. ( R )- tert -Butyl 3-Benzyl-2-oxo-3-[( S )-3-oxocyclohexyl]-indoline-1-carboxylate (3a, Entry 1, Table 2)
Isolated as a mixture of diastereomers (5.2:1 dr) by column chromatography (hexane-acetone = 90:10) in 80% yield. The ee (96% ee) was determined by HPLC on a chiral stationary phase [Chiralpak AD-H; hexane-i-PrOH (98:2); 0.50 mL/min; λ = 214, 254 nm; t _R = 34.1 min(major), 41.7 min (minor, based on the racemic mixture)]; [α]_D ^rt -17.37 (c 0.98, CHCl₃, dr = 5.2:1, 96% ee). ^¹H NMR (400 MHz, CDCl₃): δ = 1.47-1.64 (m, 2 H), 1.55 (s, 9 H), 1.70-1.81 (m, 1 H), 1.97-2.12 (m, 1 H), 2.15-2.32 (m, 1 H), 2.32-2.50 (m, 2 H), 2.55-2.61 (m, 2 H), [CH₂ A-B type spectrum (3.04, d, 1 H, J _gem = -12.8 Hz), (3.30, d, 1 H, J _gem = -12.8 Hz)], 6.72-6.77 (m, 2 H), 6.93-7.06 (m, 3 H), 7.13-7.31 (m, 3 H), 7.52-7.57 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 25.1 (CH₂), 26.4 (CH₂), 28.3 (3× CH₃), 41.4 (CH₂), 42.2 (CH₂), 43.0 (CH₂), 46.2 (CH), 57.4 (C), 84.3 (C), 115.0 (CH), 123.6 (CH), 124.4 (CH), 126.9 (CH), 127.9 (CH), 128.6 (CH), 129.3 (C), 130.0 (CH), 135.1 (C), 140.3 (C), 148.8 (C), 177.2 (C), 210.6 (C). HRMS (EI): m/z calcd for C₂₆H₂₉NO₄: 419.2096; found: 419.2092.