Pergamon Tetrahedron Letters, Vol. 37, No. 47, pp. 848%8492, 1996 Copyright © 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved PII: S0040-4039(96)01973-9 0040-4039/96 $15.00 + 0.00 Synthesis of N-protected ~,-amino-13-keto-esters from Urethane N-carboxyanhydi'ides (UNCAs) Marielle Paris 1, Jean-Alain Fehrentzl, Annie Heitz 2, Albert Loffet 3 and Jean Martinez 1 ILAPP, ass0d6 au (3~RS-Univet~i~ M0eq~ef I & IL Fam~ de Paatme~15 av. C FL~dt,34060 MmtI~ff, F~ 2Urit~ Mira Ct~&Fw~ ~ gmma~ Mmttxai~, Frame. 3 ~ 91710 V~t k P~L Frame, Abstract: N-protected?-amino-~-keto-esters were synthesized fromthe corresponding N-protectedN- carboxyanhydride(UNCAs)by reaction with the lithiumenolate of ethyl acetate in good yields. TheseCOmlxmnds are precursors of statine derivatives. Copyright© 1996ElsevierScienceLtd Our laboratory is involved in the study of the reactivity of urethane N-protected carboxyanhydrides (UNCAs) in peptide synthesis and in several reactions leading to aminoacid derivatives. UNCAs are very reactive aminoacid derivatives. They were used with success in solid phase peptide synthesis (SPPS) 1 and we have shown their usefulness in the synthesis of peptides in solution. 2 We have also shown that UNCAs can be considered as starting material for the synthesis of various aminoacid derivatives such as I~-amino alcohols3, statine derivatives 4, ct-amino-aldehydes 5 and vicinal tricarbonyl compounds 6 in good yields. Recendy we showed that UNCAs are reactive enough to yield to the corresponding tert-butyl esters when tert-butanol is used as solvenL in the presence of potassium bicarbonate at 45°C.7 However, the use of UNCAs in the presence of tertiary amines has to be controlled, since 1,8-diazabicyclo[5.4.0.]undec-7-ene (DBU) or triethylamine (TEA) in dimethylformamide solutions can lead to the formation of pyrrolidine-2,4-dione derivatives 8 that should be avoided in the synthesis of peptides. N-methylmorpholine is highly recommended when UNCAs are used in peptide synthesis. All the reactions involving UNCAs are characterized by their simplicity, efficiency and mild conditions and can be performed from readily available commercially materials.9 Statine derivatives have been widely used for the synthesis of aspartyl protease inhibitors such as renin or more recently HIV proteases. These ?-amino-~-hydroxy acids are recognized to mimic the transition state analog of the substrate when interacting with the enzyme. Many stereoselective or non stereoselective syntheses of syn and anti-statine derivatives have been reported, including acylation of ester enolates with amino aldehyde derivatives 10,11 or diastereoselective reduction of the corresponding [~-oxoesters. 12 These ~-oxo esters can also be useful intermediates for the synthesis of amino-acid and pyrrazole derivatives. We report herein a simple and efficient preparation of N-protected "t-amino-13-keto-esters from the corresponding UNCAs. These N-protected "t-amino-l~-keto-esters are precursors of N-protected "t-amino-l~-hydroxy-estersor stadnes derivatives which can be obtained as a mixture of diastereoisomers by reduction with non chiral reducing agents or as pure diastereoisomers by chiral reduction of the corresponding ketones as described by Nishi et al. 13 in the presence of Wilkinson catalyst. However, they can be used as chiral building blocks in combinatorial chemistry. 8489