(S)-α,α-Diphenylprolinol Trimethylsilyl Ether

Introduction

One of the most important sections of modern organic chemistry is asymmetric synthesis, and in this field particularly attractive are problems relating to asymmetric catalysis. In the recent two decades, special attention is focused on (S)-proline and its derivatives, which are known as versatile organocatalysts (‘aminocatalysts’).[1] [2] It was found that the introduction of the protecting silyl moiety into the prolinol structure results in a remarkable increase of catalytic activity, thus allowing decrease in catalyst loading and shorter reaction times without compromising the level of enantioselectivity.[ ³ ] In addition, this modification leads to significant broadening of the substrate scope. First examples of applications of the O-silyl prolinol derivatives in asymmetric synthesis were independently reported by Hayashi[ ³ ] and Jørgensen.[ ⁴ ] Since then these compounds have been used efficiently as ‘privileged catalysts’[ ^2b ] in diverse organic transformations, such as epoxidations, aldol, anti-selective Mannich, ­Friedel–Crafts and Diels–Alder reactions, etc.[5] [6] Probably, the most prominent representative of diarylprolinol derivatives containing the silyl moiety is (S)-α,α-diphenyl­prolinol trimethylsilyl ether (1).

Preparation

A straightforward synthesis of compound 1 is based on the O-protection of commercially available (S)-α,α-diphenylprolinol (2) with trimethylsilyl chloride (3) at room temperature in the presence of imidazole.[ ⁷ ]

Scheme 1

Abstracts

(A) Optically active β-hydroxy acids 5 can be prepared via enantio­selective hydroxymethylation of aldehydes 4 in the presence of catalytic amounts of 1. In this reaction, initially formed α-substituted β-hydroxy aldehydes are smoothly oxidized yielding corresponding β-hydroxy acids with excellent enantioselectivity and yields.[ 8a ] For an example of a Brønsted acid assisted regio- and enantioselective direct O-nitroso aldol reaction catalyzed by 1, see ref. 8b.
(B) Michael reaction of β-nitrostyrene (6) with acetaldehyde (7) catalyzed with 1 afforded α-substituted γ-nitro aldehyde 8 in nearly optically pure form and in high yield. The best result was obtained using 1,4-dioxane as a solvent.[ 9a ] In a recent report, significant modification of the generally accepted mechanism of the organocatalyzed Michael addition of aldehydes to nitro alkenes in the presence of 1 was postulated by D. Seebach and co-workers.[ 9b ]
(C) anti-Selective Mannich reaction can be performed using 1 as an efficient organocatalyst. Thus, reaction between ethyl N-p-methoxyphenyl-protected α-iminoglyoxylate 9 and isovaleraldehyde (10) in the presence of 1 leads to α-amino acid derivative 11. This product was formed in good yield and with high enantioselectivity and diastereoselectivity. The reaction was also observed to occur in a similar manner in water.[ 10a ] For other examples of the anti-selective Mannich reaction with fluorinated aldimines, see ref. 10b.
(D) (S)-α,α-Diphenylprolinol trimethylsilyl ether (1) is reported as a useful organocatalyst for the asymmetric epoxidation of α,β-unsaturated aldehydes. In the reaction with cinnamic aldehyde (12), hydrogen peroxide was applied as an efficient oxidizing agent. High levels of enantioselectivity were observed for reactions performed both in water or in water–alcoholic solutions in the presence of 10 mol% of 1.[ 11 ]
(E) Compound 1 can be used as an efficient organocatalyst for [4+2] cycloadditions (Diels–Alder reactions). A dieniminium derivative formed in situ from 1 and the unsaturated aldehyde 14, in the presence of o-fluorobenzoic acid (OFBA), undergoes Diels–Alder reaction with diverse dienophiles, e.g. the α,β-unsaturated ester 15, yielding expected [4+2] cycloadducts of type 16. These relatively complex molecules were formed with an excellent stereocontrol leading to ee values of >97%.[ 12 ]
(F) The asymmetric Friedel–Crafts alkylations of indole (17) with α,β-unsaturated aldehydes 18 were carried out in the presence of 1 using methyl tert-butyl ether (MTBE) as a solvent. It was observed, that these reactions occurred efficiently without addition of a traditional Lewis or protic acid. Probably, the presence of triethylamine enhances the nucleophilicity of 17 by deprotonation or by an activating hydrogen-bond interaction with the NH group present in the indole molecule.[ 13 ]

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