Alkylation of Chiral Glycinates

The building blocks most widely applied to the synthesis of labeled e.p. a-amino acids are the analogously labeled enantiopure 7V-(A/ -diphenylmethylideneglycyl)bomane-10,2-sultam (DPMGBS, and 7V-(iV -fcw(methylthio)methylideneglycyl)- 

Use of substituted alkyl hahdes (e.g., Br(CH2) COOR, I(CH2) C1) permits the preparation of linear and cyclic neutral, acidic and basic isotopically labeled a-amino acids of high enantiomeric purity, as demonstrated by the synthesis of e.p. (S)-[2,7- C2]-pipecolic acid, (5)-[2,6- C2]prohne and (5)-[l,2- C2]lysine in excellent yields. Alkylation of (2R)-[1,2- C2]190 with l-chloro-4-iodobutane followed by hydrolytic cleavage of the diphenyhnethylene group gave 2-amino-6-chlorohexanoyl sultam 201, which upon 

Reaction conditions 1. CH2=CHCH2Br, APr2EtN, toluene reflux 2. AIBra, toluene 50 °C 3. CH2=CHCH2Br, BU4NI, DBU, K2CO3, DMF 40 °C 4a. 

Pd(PPh3)4, A/,A/-dlmethylbarblturlc acid, CH2CI2, 35 °C, b. B0C2O, EtsN, 5a. 

fert-BuOH, DCC, DMAP, CHjCIslSa. O3, CHjClj.b. 

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In summary, the stereoselective formation of the a-azido carboximides (S)-7 by means of electrophilic azide transfer to the JV-acyloxazolidinones 5 leads to a new class of very versatile protected amino acids which can be easily tranformed into free amino acids (or peptides). This methodology, in contrast to the preparation of a-amino acids by means of alkylation of chiral glycine enolates9, also provides access to arylglycines and hindered amino acid derivatives such as tcrt-alkylglycines. 

In this segment aryl alanines have proven very effective in many cases. The meanwhile classical way to prepare aryl alanines is the diastereoselective alkylation of chiral glycine derivatives e.g. by the methods of Schollkopf [3], Evans [4], Oppolzer [5], Seebach [6] and others. (Fig.4)... 

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