Asymmetric Preparation of New N,N-Dialkyl-2-amino-1,1,2-triphenylethanol Catalysts and a Kinetic Resolution in the Addition of Diethylzinc to Flavene-3-carbaldehydes

Abstract

Enantiopure N,N-dialkyl-(S)-2-amino-1,1,2-triphenyl­ethanols were prepared using a new synthetic methodology and tested for their ability to catalyze the enantioselective addition of diethylzinc to aldehydes. The structural modification of N-substituents of the catalysts led us to identify N-methyl-N-(S)-1-phenyl­ethyl-substituted 4d as an effective catalyst for the addition. Also disclosed is a kinetic resolution of racemic flavene-3-carbaldehydes with the chiral catalyst.

Key words

addition - asymmetric catalysis - chirality - enantioselectivity - kinetic resolution

• References and Notes

• 1a Hatano M, Miyamoto T, Ishihara K. Curr. Org. Chem. 2007; 11: 127
• 1b Pu L, Yu H.-B. Chem. Rev. 2001; 101: 757
• 2a Liu C, Guo Z, Weng J, Lu G, Chan AS. C. Chirality 2010; 22: 159
• 2b Wang Q, Zhang B, Hu G, Chen C, Zhao Q, Wang R. Org. Biomol. Chem. 2007; 5: 1161
• 2c Bastero A, Font D, Pericàs MA. J. Org. Chem. 2007; 72: 2460
• 2d Rodríguez-Escrich S, Reddy KS, Jimeno C, Colet G, Rodríguez-Escrich C, Solà L, Vidal-Ferran A, Pericàs MA. J. Org. Chem. 2008; 73: 5340
• 2e García-Delgado N, Reddy KS, Solà L, Riera A, Pericàs MA, Verdaguer X. J. Org. Chem. 2005; 70: 7426
• 2f García-Delgado N, Fontes M, Pericàs MA, Riera A, Verdaguer X. Tetrahedron: Asymmetry 2004; 15: 2085
• 2g Blay G, Fernández I, Marco-Aleixandre A, Pedro JR. Tetrahedron: Asymmetry 2005; 16: 1207
• 2h Dai W.-M, Zhu H.-J, Hao X.-J. Tetrahedron: Asymmetry 2000; 11: 2315
• 2i Ohga T, Umeda S, Kawanami Y. Tetrahedron 2001; 57: 4825
• 2j Soai K, Ookawa A, Kaba T, Ogawa K. J. Am. Chem. Soc. 1987; 109: 7111
• 3 Park YS. Tetrahedron: Asymmetry 2009; 20: 2421
• 4a Kim HJ, Shin E.-k, Chang J.-y, Kim Y, Park YS. Tetrahedron Lett. 2005; 46: 4115
• 4b Kim HJ, Kim Y, Choi ET, Lee MH, No ES, Park YS. Tetrahedron 2006; 62: 6303
• 4c Kim Y, Lee MH, Choi ET, No ES, Park YS. Heterocycles 2007; 71: 5
• 5a Koh K, Durst T. J. Org. Chem. 1994; 59: 4683
• 5b Koh K, Ben RN, Durst T. Tetrahedron Lett. 1994; 35: 375
• 5c O’Meara JA, Gardee N, Jung M, Ben RN, Durst T. J. Org. Chem. 1998; 63: 3117
• 5d Ben RN, Durst T. J. Org. Chem. 1999; 64: 7700
• 5e Jang JI, Kang SY, Kang KH, Park YS. Tetrahedron 2011; 67: 6221
• 6 Preparation of Chiral Catalyst 4d To a solution of 1:1 diastereomeric mixture of 2-bromo-2-phenylacetic acid (R)-pantolactone ester 2 in dry CH₂Cl₂ (0.1 M) at r.t. was added (S)-1-phenylethylamine (1.2 equiv), TBAI (1.0 equiv), and DIPEA (1.0 equiv). After the resulting reaction mixture was stirred at r.t. for 12 h, the solvent was evaporated, and the crude material was purified by column chromatography on silica gel to give 3d in 71% yield with 99:1 dr. To a solution of 3d in DMF at r.t., MeI (2.0 equiv) and DIPEA (1.2 equiv) were added slowly. The resulting reaction mixture was stirred at r.t. for 24 h. After the mixture was concentrated, the crude product was dissolved in anhyd THF. To the solution of the product was added a solution of PhMgBr (4.0 equiv). The reaction was then allowed to proceed at r.t. for 24 h. The reaction was quenched by the addition of 1 M aq HCl and extracted with EtOAc. The combined organic extracts were dried with anhyd MgSO₄, filtered, and concentrated in vacuo. Chromatographic separation on silica gel afforded the chiral catalyst 4d with 41% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.25–6.87 (m, 20 H), 5.68 (s, 1 H), 4.98 (s, 1 H), 3.49 (q, J = 6.8 Hz, 1 H), 1.88 (s, 3 H), 1.15 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.7, 146.1, 142.6, 138.4, 131.0, 128.2, 128.1, 127.9, 127.5, 127.3, 127.0, 126.8, 126.4, 126.3, 125.4, 125.3, 79.1, 74.0, 59.8, 35.3, 15.5. HRMS: m/z calcd for C₂₉H₃₀NO [M⁺ + 1]: 408.2327; found: 408.2329.
• 7 General Procedure for the Addition of Diethylzinc to Aldehydes Diethylzinc (1.0 M in toluene, 2.0 equiv) was added to a solution of chiral catalyst (0.05 equiv) and aldehyde (1.0 equiv) in t-BuOMe at 0 °C. The homogeneous solution was stirred at r.t. for 5 h (3 h for kinetic resolution). The reaction was quenched by addition of 1 M aq HCl and extracted with CHCl₃. The combined organic extracts were dried with anhyd MgSO₄, filtered, and concentrated in vacuo. Chromatographic separation on silica gel (eluent hexane–EtOAc) afforded the enantioenriched ethanols, and the enantioselectivity of the products was measured by HPLC with chiral columns using racemic material as a standard (eluent: i-PrOH in hexane; 0.5 mL/min, 217 nm UV detector)
• 8a Goldfuss B, Steigelmann M, Khan SI, Houk KN. J. Org. Chem. 2000; 65: 77
• 8b Yamakawa M, Noyori R. Organometallics 1999; 18: 128
• 8c Yamakawa M, Noyori R. J. Am. Chem. Soc. 1995; 117: 6327

For reviews on kinetic resolution of racemic aldehydes in oxidation and Horner–Wadsworth–Emmons reactions, see:
• 9a Minato D, Nagasue Y, Demizu Y, Onomura O. Angew. Chem. Int. Ed. 2008; 47: 9458
• 9b Pedersen TM, Jensen JF, Humble RE, Rein T, Tanner D, Bodmann K, Reiser O. Org. Lett. 2000; 2: 535
• 10a Magar DR, Chen K. Tetrahedron 2012; 68: 5810
• 10b Das BC, Mohapatra S, Campbell PD, Nayak S, Mahalingam SM, Evans T. Tetrahedron Lett. 2010; 51: 2567
• 10c Lee MH, Choi ET, Kim D, Lee YM, Park YS. Eur. J. Org. Chem. 2008; 5630
• 10d Konoike T, Matsumura K.-i, Yorifuji T, Shinomoto S, Ide Y, Ohya T. J. Org. Chem. 2002; 67: 7741
• 10e Hardouin C, Burgaud L, Valleix A, Doris E. Tetrahedron Lett. 2003; 44: 435

The absolute configuration of 5a was assigned by comparison of CSP-HPLC retention time with the reported value in the following references:
• 11a Sundén H, Ibrahem I, Zhao G.-L, Eriksson L, Córdova A. Chem. Eur. J. 2007; 13: 574
• 11b Li H, Wang J, E-Nunu T, Zu L, Jiang W, Wei S, Wang W. Chem. Commun. 2007; 507
• 11c Govender T, Hojabri L, Moghaddam FM, Arvidsson PI. Tetrahedron: Asymmetry 2006; 17: 1763
• 12 The selectivity factor (s) was estimated using the equation, s = k_S/k_R = ln[(1 – C)(1 – ee)]/ln[(1 – C)(1 + ee)], where ee is the enantiomeric excess of unconverted aldehyde 5 and the conversion (C) determined by ¹H NMR of reaction mixture.
• 13 The absolute configuration at the 2-position of major enantiomers of 6a and 7a was confirmed by the reaction of highly enantioenriched (R)-5a with diethylzinc.
• 14 Vedejs E, Jure M. Angew. Chem. Int. Ed. 2005; 44: 3974
• 15 The use of commercially available (S)-2-piperidino-1,1,2-triphenylethanol for the kinetic resolution of flavenes 5e–h gave selectivity values ranging from 4 to 6.