Optical activity Grignard reagents

As mentioned in Section 10.6.2, synthesis of 1-hydroxyethylene peptides can be initiated by adding a ferf-butoxycarbonyl N-protected a-amino aldehyde to an optically active Grignard reagent (Scheme 7)J11-13 This reaction affords a diastereomeric mixture of the C4 epimers of the hydroxy ether in good yields. In most cases the mixture is enriched in the 45-epimer and the epimers are readily separable. The yields and the ratios of the resulting 45- and 4R-epimers obtained from several examples of this reaction are summarized in Table 1. When this reaction was attempted with the aldehyde prepared from Aa,Ae-bis-tert-butoxycarbonyl-protected Lys, the desired product was not obtained. The anion of the Lys Ne-tert-butoxy-carbonylamino group probably reacts with the aldehyde to form a cyclic aminol that does not... 

An optically active Grignard reagent has the ability to differentiate between the two enantiofaces of a carbonyl compound such as 45 [64], In the example shown, the (S)-enantiomer of the product alcohol, 46, is obtained with a high degree of optical purity (= specific rotation of mixture- - specific rotation of one pure enantiomer X 100 for definitions of other terms used in this work, see [65]). 

In 1961 it was reported that the reaction of chiral l-bromo-l-methyl-2,2-diphenylcyclopropane (51) with magnesium metal produced a partially optically active Grignard reagent . It was suggested that the racemization observed occurred in the Grignard formation step. In 1964 it was also established that the racemization occurred... 

A. Intermediacy of Radicals and Pathways Leading to Radicals and to Grignard Reagent Optically Active Grignard Reagent... 

The first successful formation of an optically active Grignard reagent in which the magnesium is directly attached to the chiral center was reported in a short communication in 1961 [43], followed by a full paper in 1964 [44]. Previous attempts to prepare optically active Grignard reagents from acyclic halides such as (— )-2-iodobutane [45], ( —)-2-bromooctane [46, 47] and optically active 1-phenylethyl bromide [48], as well as a cyclic halide (— )-3,3-dimethylcyclohexyl chloride [48], all had given rise to racemic products. 

To establish the stereochemistry of the reaction, optically pure (SH + )-l-bromo-methylspiro[25]octane 19 was treated with Rieke magnesium at room temperature in both ether and THF, and the reaction mixture was carbonated [22] (Scheme 50). The results are shown in Table 23. The reaction in ether resulted in a 25% yield of optically active acid 22, the result of optically active Grignard reagent, and 42% of racemic hydrocarbon 154. Reaction in THF afforded a much higher yield of the optically active Grignard reagent (58 /o) and only 20% of racemic hydrocarbon 154. As predicted by the surface nature of... 

The reduction process has not been of great synthetic importance, although its potential for asymmetric reductions of ketones has been recognized and investigated." For example, the reduction of isopropyl phenyl ketone to the corresponding alcohol occurs in 82% optical yield with the optically active Grignard reagent 1 ... 

Nickel catalysts with optically active ligands, e.g. (49), couple optically active Grignard reagents with vinyl halides in up to 32.9% enantiomeric excess.A Pd/neomenthyldiphenyl phosphine catalyst achieves only a modest 12% e.e. in the allylation of PhZnCl with allylic acetates.Chelating asymmetric... 

Grignard reagents - - have been used extensively to prepare alkylzinc halides (1 see equatirxi 5) and to s< ne extent to prepare dialkylzinc reagents not available by oxidative addition reactions, such as di-r-butylzinc or divinylzinc (see Scheme 4). Although moderate yields are often obtained, some optically active dialkylzinc reagents have been prepared in 49-81% yield. 

Especially in the early steps of the synthesis of a complex molecule, there are plenty of examples in which epoxides are allowed to react with organometallic reagents. In particular, treatment of enantiomerically pure terminal epoxides with alkyl-, alkenyl-, or aryl-Grignard reagents in the presence of catalytic amounts of a copper salt, corresponding cuprates, or metal acetylides via alanate chemistry, provides a general route to optically active substituted alcohols useful as valuable building blocks in complex syntheses. 

Preparation of the appropriate optically active sulfmate ester is initially required for reaction with a Grignard or other organometallic reagent. If the method is to produce homochiral sulfoxides, the precursor sulfmate ester must be optically pure. An exception to this statement occurs if the reaction yields a partially racemic sulfoxide which can be recrystallized to complete optical purity. 

Further utility of the Andersen sulphoxides synthesis is demonstrated by the preparation of optically active unsaturated sulphoxides which were first prepared by Stirling and coworkers359 from sulphinate 276 and the appropriate vinylic Grignard reagents. Later on, Posner and Tang360 prepared in a similar way a series of ( )-l-alkenyl p-tolyl sulphoxides. Posner s group accomplished also the synthesis of (+)-(S)-2-(p-tolylsulphinyl)-2-cyclopentenone 287, which is a key compound in the chiral synthesis of various natural products361 (equation 159). 

Treatment of (—)-(S)-276 with allyl Grignard reagents gives optically active allylic sulphoxides 288. This reaction, however, involves an allylic rearrangement via transition state 289 as evidenced by Mislow and his collaborators362 (equation 160). 

C. Reactions of Phosphoric and Phosphinic Acid Derivatives.—The optically active phosphinate ester (90) has been shown to react with benzyl Grignard reagents or lithium anilide with inversion of configuration. Oxidation of... 

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