The use of N-urethane-protected N-carboxyanhydrides (UNCAs) in amino acid and peptide synthesis

N-Urethane-protected N-carboxyanhydrides (UNCAs) are very reactives. They have been successfully used in peptide synthesis, in both solution and solid phase. We have demonstrated that UNCAs are interesting starting materials for the synthesis of various amino acid derivatives. Chemoselective reduction of UNCAs with sodium borohydride led the corresponding N-protected β amino alcohols. Reaction of UNCAs with Meldrum's acid, followed by cyclisation, yielded enantiomerially pure tetramic acid derivatives. Diastereoselective reduction of tetramic acid derivatives produced (4S,5S)-N-alkoxycarbonyl-4-hydroxy-5-alkylpyrrolidin-2-ones derived from amino acids, which after hydrolysis yielded statine and statine analogues. Tetramic acid derivatives could also be obtained by reaction of UNCAs with benzyl ethyl followed by hydrogenolytic deprotection and decarboxylation. UNCAs also reacted with phosphoranes to produce the ketophosphorane in excellent yields. Subsequent oxidation with oxone or with [bis(acetoxy)-iodol]-benzene produced vicinal tricarbonyl derivatives. These reactions usually proceeded smoothly and with high yields.     

Reactivity of UNCAs with Grignard reagents

The reactivity of Grignard reagents with UNCAs (UrethaneN-protected Carboxyanhydrides of Amino acids)is described. We observed that, depending on the method ofaddition of the organometallic compounds, the reactionproceeded differently:(i) when the UNCA was added to the Grignard reagent, weobtained a mixture of five different products whichwere all identified; and (ii) when the organometallic reagent was added to theUNCA, we also obtained a mixture of the same productsbut in different proportions, with the major componentcorresponding to the urethane N-protected N-acyl aminoacid derivative.     

Synthesis of chiral N-protected amino acid esters by the use of UNCAs

Summary An easy synthesis of N-protected amino acid esters, including tert-butyl esters, is described by the use of urethane N-protected carboxyanhydrides (UNCAs). Treating UNCAs with tert-butanol in the presence of potassium bicarbonate at 45°C yielded the corresponding N-protected amino acid tert-butyl esters in a very simple way. Benzyloxycarbonyl and tert-butyloxycarbonyl N-protected amino acid tert-butyl esters have been obtained by this procedure. Once more, this reaction showed the great reactivity of UNCAs.     

Reactivity of UNCAs with Grignard reagents

Summary The reactivity of Grignard reagents with UNCAs (Urethane N-protected Carboxyanhydrides of Amino acids) is described. We observed that, depending on the method of addition of the organometallic compounds, the reaction proceeded differently: (i) when the UNCA was added to the Grignard reagent, we obtained a mixture of five different products which were all identified; and (ii) when the organometallic reagent was added to the UNCA, we also obtained a mixture of the same products but in different proportions, with the major component corresponding to the urethane N-protectedN-acyl amino acid derivative.