Enantioselective Synthesis of 2-Substituted Alcohols Using (+)-(1S,2S)-Pseudoephedrine as Chiral Auxiliary

Abstract

An improved method for the selective synthesis of enantiopure 2-substituted alcohols is described. Highly diastereoselective alkylation of pseudoephedrine-derived amides and subsequent oxidation of the hydroxyl group in the amide side chain, leads to oxoamides. These oxoamides can be purified by crystallization or preparative HPLC to obtain diastereomeric ratios of >99:1. The following reductive cleavage of the modified auxiliary allows the epimerization-free formation of enantiopure 2-substituted alcohols with up to 99.9% ee.

alcohols - auxiliary - asymmetric synthesis - reduction - alkylation

References

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5

The desired S-configuration for alcohol 5a originates in the alkylation reaction. According to Myers,^4b the newly introduced alkyl chain is attached from the side which comprises the methyl substituent of the pseudoephedrine side chain. We measured the optical rotation for (S)-5a to be [α]_D ²⁰ -11.8 (c 1.00, CHCl₃). In the literature the value for the enantiomer (R)-5a was published as [α]_D ²⁴ +9.04 (c 1.2, CHCl₃).¹⁵ The opposite signs illustrate that these compounds are enantiomers and the higher value for our compound is due to its higher optical purity. Additionally, the absolute configuration of the oxoamide precursor (-)-(2S),1′S)-6a, which was converted into alcohol (S)-5a, was determined by X-ray diffraction.¹¹

6

For determination of ee values by chiral capillary GC or chiral HPLC, racemic mixtures of the alcohols were used as standards. These were synthesized by alkylation of isovaleric acid enolates and reduction of the resulting
2-substituted carboxylic acids by LiAlH₄.

7

The oxoamide 6a was recrystallized from EtOH-H₂O. Daicel Chiralpak^® IA columns (n-hexane-2-propanol, 99:1) were used for the analytical and semi-preparative HPLC separation.

8

HPLC experiments were performed on Jasco Kromasil^® RP-18 (MeCN-H₂O and MeOH-H₂O) and Daicel Chiralpak^® IA and IB (n-hexane-2-propanol and n-hexane-CH₂Cl₂) columns. Epimeric mixtures of the hydroxyamides were used as standards; they were synthesized from racemic 2-substituted carboxylic acids, activated as acid chlorides, and reacted with (+)-(1S,2S)-pseudoephedrine.

9

Yields for the alkylation correspond to those published in the experimental section. The yields for the reduction of hydroxyamides 4a-f directly to the alcohols originate in unpublished results (L. F. Tietze, C. Raith).

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11

(11) X-ray christallograhpy: Data were collected on a Stoe IPDS II-aray detector system instrument with graphite-monochromated Mo-K_α radiation (λ = 0.71073 Å). The structure was solved by direct methods using SHELXS-97¹² and refined against P ²¹ on all data by full-matrix least-squares with SHELXS-97.¹³ All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included in the model. CCDC-664393 [(-)-(2S,1′S)-6a] contains the supplementary crystallographic data for this article. These data can be obtained free of charge from The Cambridge Cyrstallographic Data Centre via www.ccdc.ac.uk/data_request/cif.

12

Sheldrick, G. M., SHELXS-97, Programm for Crystal Structure Solution, Göttingen (Germany), 1997.

13

Sheldrick, G. M., SHELXS-97, Programm for Crystal Structure Refinement, Göttingen (Germany), 1997.

14

Mixtures of n-hexane-2-propanol and n-hexane-CH₂Cl₂ in different compositions were tried. Epimeric mixtures of the oxoamides were used as standards for HPLC separation. These mixtures were obtained from oxidation of the epimeric mixtures of the corresponding hydroxyamides.

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