Rationale on the Abnormal Effect of Temperature on the Enantioselectivity in the Asymmetric Borane Reduction of Ketones Catalyzed by L‐Prolinol

Abstract

The effect of temperature on the enantioselectivity of the oxazaborolidine-catalyzed asymmetric borane reduction of ketones was investigated in the presence of (5S)-3-oxa-1-aza-2-borabicyclo[3.3.0]octane ( (3aS)-tetrahydro-1H,3H-pyrolo[1,2-c][1,3,2]oxazaborole; 1a) and its 2-methoxy derivative (1b) as catalysts, which were synthesized from l-prolinol with borane and trimethyl borate, respectively. The results indicate that the two catalysts induce a different temperature-dependent enantioselectivity. The enantioselectivity of the Bunsubstituted (5S)-3-oxa-1-aza-borabicyclo[3.3.0]octane (1a) increases with increasing temperature, while its B-methoxy-substituted derivative 1b shows the highest enantioselectivity at ca. 508. (5S)-3-Oxa-1-aza-2-borabicyclo[3.3.0]octane (1a) is more likely to dimerize than its 2-methoxy derivative 1b. The conversion rates of l-proline to l-prolinol in the presence of different amounts of borane were also determined in this study.1. Introduction. ± Enantioselective 1,3,2-oxazaborolidine-catalyzed borane reduction of prochiral ketones to chiral secondary alcohols is one of the most-often applied reactions in asymmetric syntheses and has been widely used in the preparation of various secondary alcohols during the past two decades (for recent reviews, see [4c], the additive [6], the electronic effect [7], etc. Although a few papers have reported the effects of temperature on enantioselectivity, different 1,3,2-oxazaborolidines seem to show obviously different effects on the enantioselectivity, and the effect of B-unsubstituted 1,3,2-oxazaborolidine has not been investigated in detail. Herein, we wish to report our observations and rationale on the effects of prolinolderived, B-unsubstituted and B-methoxy-substituted 1,3,2-oxazaborolidine catalysts in the asymmetric borane reduction of acetophenone.

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“…[12] l-Prolinol-derived 1,3,2-oxazaborolidine catalysts prepared from l-proline and giving the reduction product with moderate enantiomeric excess (ee) values were also studied. [13] Taking note of these reports we selected amino acids l-Leu (4 a), l-Phe (4 b), and l-Val (4 c) with a primary amino functionality as starting compounds for realization of the proposed one-pot reaction sequence.…”

“…It was expected that B À OMe derivatives might perform better than the B-unsubstituted oxazaborolidines. [13,15] Notably, preliminary studies (see Table S3 in the Supporting Information) demonstrated that the use of 0.6 equiv of B-A C H T U N G T R E N N U N G (OMe) 3 (relative to the in situ generated amino alcohols 5 a-c, taking into consideration their theoretically possible yield from Table 1) was crucial to obtain good yield and enantioselectivity in the reduction of acetophenone. Therefore, B À OMe-derived oxazaborolidines 6 a-c were prepared in situ by addition of BA C H T U N G T R E N N U N G (OMe) 3 (0.6 equiv) to 5 a-c and stirring for 1 h at the desired temperature (RT or 60 8C).…”

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“…1) die meisten Veränderungen der geminalen Substituenten einen ungünstigen Einfluss auf die Enantioselektivität nehmen. 13 und 14) [31] nicht bestätigt werden. 2), aber auch für ortho-substituierte Aryl-(Nr.…”

“…Dies gilt für den a-Naphthylrest (Nr. [31] Jedenfalls sind die von Prolinol abgeleiteten Oxazaborolidine, die Phenylethanol mit 20-60 % ee liefern, den Oxazaborolidinen auf der Basis von Diphenylprolinol bezüglich der Enantioselektivität definitiv unterlegen und weniger effizient als diese. 3 und 4) und 2-Thienylgruppen (Nr.…”

“…12) [30] und Xu (Nr. 13 und 14) [31] nicht bestätigt werden. Eine detaillierte Studie ergab, dass die Enantioselektivität mit zunehmender Temperatur ansteigt, ein Effekt, der durch das Postulat eines Gleichgewichts zwischen monomeren und dimeren Oxazaborolidinen erklärt wurde.…”