Valine bislactim ethers from

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

The disadvantage in using such symmetrical bislactim ethers is that half the chiral auxiliary ends up as part of the product molecule thus only half of the auxiliary can be recovered and reused. This drawback is avoided in the mixed bislactim ether prepared from a chiral auxiliary (L-valine) and a racemic amino acid (e.g., DL-alanine). Regiospecific deprotonation followed by diastereoselective alkylation leads to the required a-methyl amino acid ester (193) (83T2085) the de is >95%. In this method, the chiral auxiliary (L-valine) is recovered intact. (Scheme 59). 

Schdllkopf and cowoikers have pioneered the development of anions of another type of masked carboxylic acid derivative, i.e. bislactim ethers such as (159), derived from (5)-valine and glycine or alanine, for the asymmetric synthesis of amino acids. As shown in Scheme 78, compounds such as... 

A better version 47 has a larger isopropyl group, derived from valine 44, to differentiate the faces on the enolate, and no substituent at the enolate site. The starting material 46, prepared from valine 44 and glycine, is commercially available, as is its / -isomer and the derived bislactim ether 47. 

O-Alkylation of dioxopiperazines with oxonium salts yields bislactim ethers, e.g. 4, which are used as reagents for the asymmetric synthesis of amino acids (bislactimether method, Schollkopf 1979). The chiral bislactim ether 4 is converted into the 6 r-anion 5 (under kinetic control) by n-butyllithium. Alkylation proceeds with high stereoselectivity (greater than 95%). Acid hydrolysis of the alkylation product 6 leads to (unnatural) (R)-mnno acids 7 and recovery of the chiral auxiliary (5)-valine, from which the starting material dioxopiperazine 3 was derived [160]. 

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