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

Seock Yong Kang; Jinho Baek; Yi Kyung Ko; Chan Im; Yong Sun Park

doi:10.1055/s-0032-1318301

Synlett, Table of Contents

Synlett 2013; 24(5): 630-634
DOI: 10.1055/s-0032-1318301

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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

Seock Yong Kang

Department of Chemistry and KFnSC, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea Fax: +82(2)34365382 Email: parkyong@konkuk.ac.kr

,

Jinho Baek

Department of Chemistry and KFnSC, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea Fax: +82(2)34365382 Email: parkyong@konkuk.ac.kr

,

Yi Kyung Ko

Department of Chemistry and KFnSC, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea Fax: +82(2)34365382 Email: parkyong@konkuk.ac.kr

,

Chan Im

Department of Chemistry and KFnSC, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea Fax: +82(2)34365382 Email: parkyong@konkuk.ac.kr

,

Yong Sun Park*

Department of Chemistry and KFnSC, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea Fax: +82(2)34365382 Email: parkyong@konkuk.ac.kr

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Abstract

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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

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References

References and Notes

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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)

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For reviews on kinetic resolution of racemic aldehydes in oxidation and Horner–Wadsworth–Emmons reactions, see:

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The absolute configuration of 5a was assigned by comparison of CSP-HPLC retention time with the reported value in the following references:

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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.
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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.

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