Generation of a highly enantioenriched α-phenylthio-substituted Grignard-reagent

Abstract

The α-phenylthio-substituted Grignard reagent 8 was generated in >95% ee by a sulfoxide/magnesium exchange reaction starting from the enantio- and diasteromerically pure α-phenylthio sulfoxide 6a. The α-thio-substituted Grignard reagenthas been trapped with benzaldehyde to give the syn-β-phenylthio-substituted alcohol 9b in very high diastereoselectivity and enantiomeric purity. α-Heterosubstituted alkylmetal reagents (1) are potentially useful chiral -synthons in organic synthesis On reaction with aldehydes two diastereomeric alcohols 2a and 2b are formed (Scheme 1). Simple diastereoselectivity is generally low using organolithium compounds There are indications that Grignard reagents of the type of 1 lead to higher diastereoselectivity possibly due to a change in the addition mechanism

Configurational stability of the organometallic reagents 1 is another issue. For instance, in the case of the arylthio-substituted derivatives of 1 the organolithium compounds are configurationally labile, racemizing rapidly even at -110°C–9 Substantially higher configurational stability can be expected for the corresponding Grignard reagents Thus, for both reasons Grignard reagents such as 8 would be of interest, provided they can be generated in enantiomerically pure form. Grignard reagents can be generated by a sulfoxide/magnesium exchange, a reaction studied extensively by Satoh and Takano We used this reaction previousl to generate enantiomerically pure α-chloroalkyl Grignard reagents. This led us to investigate the sulfoxide/magnesium exchange reaction of the α-arylthio alkyl sulfoxides 6.

The starting sulfoxide 6 was prepared (Scheme 2) by reacting α-phenylthio methyllithium (4) with a menthyl aryl sulfinate following precedent from the Gennari group We chose the p-chlorobenzene sulfinate 3¹⁴ instead of the more common p-toluene sulfinates in order to facilitate purification of the starting sulfoxides 6 by crystallization. Treatment of the menthyl sulfinate 3 with 4 at -78°C thus generated the (+)-(S)-α-phenylthio sulfoxide 5 as white crystals (mp 71–72°C) in 70% yield. The sulfoxide 5 was benzylated in 80% yield to furnish a 1:1 mixture of the diastereomeric sulfoxides 6a and 6b. The mixture was separated by column chromatography on silica gel to give 6a {mp 103°C, [α]_D²⁰=+17.9 (c=1.09, acetone)} and 6b {mp 75°C, [α]_D²⁰=-164.1 (c=1.56, acetone)}. The relative and absolute configuration of 6a was assigned as (S,S) by X-ray structure analysis,† cf. Fig. 1.

When the stereochemically homogeneous sulfoxide 6a was treated with ethylmagnesium bromide at -78°C in THF (Scheme 3), rapid sulfoxide/magnesium exchange ensued to give the α-phenylthio alkyl Grignard reagent 8. The latter was trapped after 10 min by addition of benzaldehyde, providing 58% of the β-hydroxy thioether 9 along with 99% of the sulfoxide 7 of 99% ee. The β-hydroxy thioether was obtained as a single diastereomer (syn:anti >98:<2).

Its relative and absolute configuration could be assigned as 9b by the following transformation. Methylation of the thioether with Meerwein's sal generated a sulfonium ion, which on treatment with base (Scheme 4) furnished the epoxide 10 (67%, cis:trans >98:<2). The enantiomeric purity of the epoxide was determined by ¹H NMR spectroscopy in the presence of Eu(hfc)₃ [hfc=3-(heptafluoropropyl hydroxymethylene)-D-camphorate] to be >95%.

Since the absolute configuration of the epoxide 10¹⁶ and the sulfoxide 7¹⁷ is known, the stereochemical course of the sulfoxide/magnesium exchange can be shown to proceed with inversion at the sulfoxide sulfur atom and with retention of configuration in the formation of the carbon magnesium bond. This corresponds to our recent results found in the sulfoxide/magnesium exchange on α-chloroalkyl sulfoxides

The present study shows that α-arylthio alkyl Grignard reagents of type 8 can be generated in enantiomerically pure form by a sulfoxide/magnesium exchange reaction, that these reagents are configurationally stable at -78°C for a sufficient period of time to be added to an aldehyde, and that this addition proceeds with very high (>98%) simple diastereoselectivity to provide the syn-diastereomer of 9. Experimental