Synthesis of α-Amino Acids via a Carbolithiation Reaction on Acyclic Ene-Carbamates and an Internal N→C Alkyloxycarbonyl Migration

Abstract

A novel and efficient synthesis of precursors of a-amino acids is described. The key step involves a carbolithiation reaction on acyclic ene-carbamates generated from the corresponding vinylphosphates via a palladium cross-coupling reaction followed by a spontaneous internal N→C alkyloxycarbonyl migration.The development of new synthetic approaches to nonnatural amino acids is a blossoming field of research since such compounds find applications in the synthesis of pharmacologically useful molecules, analogues of bioactive peptides mimetics. 1 Our goal was to devise a new route to a-amino acids based on a vinyl carbolithiation performed on acyclic ene-carbamates as the original key synthetic step. Carbolithiation has seen increasing use as a powerful method for complex ring synthesis. 2 However, very few teams have reported the intermolecular nucleophilic addition of organolithium reagents to an alkene, an addition generally difficult to control since it may lead to polymerization of the olefin. 3 To obtain synthetically useful carbolithiation reactions, the final organometallic adduct must be stabilized 4 or must differ markedly from the starting one. 5 In a previous work, we reported a successful carbolithiation approach on seven-membered ring enecarbamates. 6 In this paper, we want to explore the scope of our method and to this purpose, study carbolithiation on acyclic ene-carbamates in order to develop a process that would give easy access to a-amino acids bearing a quaternary carbon next to the nitrogen (cf. Scheme 1). The first part of this work concerns the preparation of acyclic enecarbamates from the corresponding vinylphosphates via a palladium cross-coupling reaction. Carbolithiation on the latter will be investigated in a second stage. Scheme 1 Access to a-amino acidsIn connection with our efforts to develop synthetic routes to nitrogen-containing derivatives, we have undertaken a research program directed towards expanding the range of lactam-derived vinyl phosphates available to the organist chemist. 6,7 Taking advantage of our previous results, a synthesis of the original acyclic amide-derived vinylphosphates 3 was envisaged. Starting from aromatic primary amines 1, after protection of the nitrogen, the amide 2 was treated with LDA (1.2 equiv) at -78°C in THF providing the desired lithium enolate that was quenched with diphenylchlorophosphate (1.2 equiv, cf. Table 1). After workup and purification by silica gel chromatography, the required acyclic amide-derived vinylphosphates 3a-c were isolated in good yields. A Pd-catalyzed Suzuki-Miyaura coupling reaction was then investigated. By using classical conditions, a range of acyclic ene-carbamates 4a-f, substituted a to nitrogen by different aryl or heteroaryl groups, was isolated in fair to good yields (cf. Table 2). 8Carbolithiation was then considered, and acyclic ene-carbamates 4a-f were submitted to reaction with a small range of commercially available organolithium reagents. Treatment of 4a-f in THF at -78°C with an excess of RLi followed by war...

Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates

“…Similar reactivity is observed with related O -carbamoyl enols [10–12]. The organolithium resulting from the enamine carbolithiation is nucleophilic at the atom α to nitrogen, and such carbolithiations have been used to generate hindered organolithiums as intermediates for further rearrangement reactions [13], for example intramolecular acylation [6], arylation [3–4] or vinylation [4]. In this paper, we now report our studies on the scope of the carbolithiation–protonation of styrenes carrying α-acylamino substituents, namely N -alkenyl ureas and N -alkenyl carbamates.…”

“…However, we reasoned that the related tert -butyloxycarbonyl-substituted carbamates would give more readily manipulated carbamate products bearing a standard Boc protecting group, providing they too could be carbolithiated and trapped without rearrangement. Related carbamates are reactive towards carbolithiation–rearrangement reactions [6]. Thus, Boc-protected carbamates 9 – 11 were synthesised by acylation of the imines 7 and 8 with di- tert -butyl dicarbonate or with (−)-menthylchloroformate (Scheme 4).…”