Unfunctionalized, α-epimerizable nonracemic ketones and aldehydes can be accessed by crystallization-induced dynamic resolution of imines

Journal of the American Chemical Society

Volumn 125, Issue 11, 2003, Pages 3208-3209

  Košmrlj, Janez ^b   Weigel, Leland O ^a   Evans, David A ^c   Downey, C Wade ^c   Wu, Jimmy ^c  

^a ELI LILLY AND COMPANY   (United States)

^b UNIVERSITY OF LJUBLJANA   (Slovenia)

^c HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALDEHYDE; IMINE; KETONE;

ALKYLATION; CONFERENCE PAPER; CRYSTAL STRUCTURE; CRYSTALLIZATION; EPIMERIZATION; HYDROLYSIS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; STEREOCHEMISTRY; SYNTHESIS; X RAY DIFFRACTION;

EID: 0344609024     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja029715n     Document Type: Conference Paper

References (16)

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5. This protocol describes host-guest complexation but the method is limited to 2-alkylcylcohexanones with n or π electrons in the α-substituent, requires molar excesses of the chiral host (TADDOL), and requires chromatographic separations (13 examples approximately 60% ee with two examples exceeding 90% ee). (a) Kaku, H.; Ozako, S.; Kawamura, S. Takatus, S.; Ishii, M.; Tsunoda, T. Heterocycles 2001, 55, 847-850. (b) Tsunoda, T.; Kaku, H.; Nagaku, M.; Okuyama, E. Tetrahedron Lett. 1997, 38, 7759-7760. (c) Kaku, H., Takaoka, S., Tsunoda, T. Tetrahedron 2002, 58, 3401-3407.
6. This protocol describes host-guest complexation but the method is limited to 2-alkylcylcohexanones with n or π electrons in the α-substituent, requires molar excesses of the chiral host (TADDOL), and requires chromatographic separations (13 examples approximately 60% ee with two examples exceeding 90% ee). (a) Kaku, H.; Ozako, S.; Kawamura, S. Takatus, S.; Ishii, M.; Tsunoda, T. Heterocycles 2001, 55, 847-850. (b) Tsunoda, T.; Kaku, H.; Nagaku, M.; Okuyama, E. Tetrahedron Lett. 1997, 38, 7759-7760. (c) Kaku, H., Takaoka, S., Tsunoda, T. Tetrahedron 2002, 58, 3401-3407.
7. This protocol describes host-guest complexation but the method is limited to 2-alkylcylcohexanones with n or π electrons in the α-substituent, requires molar excesses of the chiral host (TADDOL), and requires chromatographic separations (13 examples approximately 60% ee with two examples exceeding 90% ee). (a) Kaku, H.; Ozako, S.; Kawamura, S. Takatus, S.; Ishii, M.; Tsunoda, T. Heterocycles 2001, 55, 847-850. (b) Tsunoda, T.; Kaku, H.; Nagaku, M.; Okuyama, E. Tetrahedron Lett. 1997, 38, 7759-7760. (c) Kaku, H., Takaoka, S., Tsunoda, T. Tetrahedron 2002, 58, 3401-3407.
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9. (b) THF, methanol, ethanol, IPA, diglyme, hexane, triethyl orthoformate, ether, acetonitrile.
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11. Example synthesis of (R)-1b (all operations at 23 °C): A mixture of rac-1b (7.05 g, 96% purity, 53 mmol) and (R,R)-2 (50 mmol) in THF (0.15 L) was stirred for 30 min. The volatile compounds were evaporated in a stream of nitrogen (5 mL/h) to give 3b (dr 3:1). The enriched 3b was stirred in methanol (0.1 L, 6 h) and evaporated (nitrogen stream) to afford 3b (dr 96:4). Repeating the above sequence twice (70 mL and 50 mL of MeOH) resulted in 3b (dr 99:1), 100% yield based on (R,R)-2). The aldimine 3b (20 mmol) was allowed to stir with hexane (0.24 L), diethyl ether (0.1 L), and sodium acetate/acetic acid buffer (pH 3.8, 0.14 L; under nitrogen, 1 h). The layers were separated and the aqueous layer was extracted with hexane (3 × 50 mL). The standardized solution was analyzed by quantitative GLC (98% yield (R)-1b based on input (R,R)-2; reaction with 2,4-dinitrophenylhydrazine (2,4-DNP) yielded 93% of the hydrazone), and by chiral GLC (90% ee (R)-1b).
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