Grignard reagent stereoselective

Direct substitution reaction of 125 <1995EJM697> with organozinc reagents derived from allyl, benzyl, phenyl, vinyl, and -butyl Grignard reagents stereoselectively produced C-lO-substituted deoxoartemisinins 142 in good to moderate yields (Scheme 17 Table 12) <2002TL2891>. 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

Addition of Grignard reagents to ketones and aldehydes was one of the reactions which led to the formulation of Cram s rule. Many ketones and aldehydes have subsequently been examined to determine the degree of stereoselectivity. Cram s rule is obeyed when no special complexing functional groups are present near the reaction site. One series of studies is summarized in Table 8.2. 

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

Reaction of estrone methyl ether with methyl Grignard reagent followed by Birch reduction and hydrolysis of the intermediate enol ether affords the prototype orally active androgen in the 19-nor series, normethandrolone (69). ° (Note that here again the addition of the methyl group proceeded stereoselectively by approach from the least hindered side.) The preparation of the ethyl homolog starts by catalytic reduction of mestranol treatment of the intermediate, 70, under the conditions of the Birch reduction and subsequent hydrolysis of the intermediate enol ether yields norethandrolone (71). ... 

The fact that only Grignard reagents add with high diastereoselectivity to the phenylmenthyl ester of glyoxylic acid, whereas methyllithium reacts nonstereoselectively, may be the result of a different aggregation of the reagents. This is supported by the tremendous improvement of the stereoselectivity when the addition of methyllithium is undertaken in the presence of lithium perchlorate13. 

The enantioselective addition of organometallic reagents to, V-(trimethylsilyl)benzaldehyde imine (1) in the presence of enantiomerically pure modifiers has been investigated. The best result is obtained with butyllithium (the corresponding Grignard reagent affords both lower yield and selectivity, 1 fails to react with diethylzinc) and two equivalents of the enantiomerically pure diol 2 in diethyl ether. It should be noted that the choice of the solvent is crucial for the stereoselectivity of the reaction1 2 3 5 7 8 9. 

The reversal of the stereoselectivity is attributed to the ability of chlorotrimethylsilane to trap the initially formed cuprate-enone complex, thereby suppressing equilibration of the diastereomeric complexes. The copper-catalyzed 1,4-addition of Grignard reagents to 5-substituted 2-cyclo-hexenone also proceeded with very high trans diastereoselectivity22. 

Of greater potential practical significance, however, are the note193 and full papers194,195 in which Fabre, Julia and Verpeaux describe a new stereoselective synthesis of trisubstituted alkenes in which vinyl sulphones are attacked by Grignard reagents in the presence of iron or nickel catalysts (equations 82-84). 

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