[2+2] Cycloaddition Reactions of Imines with Cyclic Ketenes: Synthesis of 1,3‐Thiazolidine Derived Spiro‐β‐lactams and Their Transformations

Abstract

On the occasion of the 85th birthday of Professor Rolf Huisgen Unsymmetric cyclic ketenes were generated from N-acyl-1,3-thiazolidine-2-carboxylic acids 1a ± c by means of Mukaiyamas reagent, and then reacted with imines 2a ± c to the new, isomeric spiro-b-lactams 3 and 4 via [2 2] cycloaddition (Staudinger ketene ± imine reaction; Scheme 1). The reactions were stereoselective ( Table 1) , make them potentially useful compounds for drug development. They can also act as bturn mimetics [10] and, particularly the 4-spiro-b-lactams, are synthetic precursors for cyclic a,a-disubstituted b-amino acids and peptide derivatives [11]. The synthesis of conformationally constrained amino acids is of special interest because the peptides derived from these modified amino acids may have valuable biological properties. As a consequence, the synthesis of 4-spiro-b-lactams has recently received particular attention [12].Further to our previous studies on the synthesis [13] and reactivity [14] of spiro-blactams, we now report the Staudinger ketene ± imine reaction between unsymmetrical cyclic ketenes generated from N-acyl-1,3-thiazolidine-2-carboxylic acids 1 and imines 2 for the synthesis of the new 1,3-thiazolidine derived 4-spiro-b-lactams 3 and 4 (Scheme 1). Our interest in these compounds is based on the spiro-fused thiazolidine ring, which could be opened to obtain a-keto-b-lactams.In our early work on cycloaddition reactions between mesoionic compounds (generated from cyclic N-acyl-a-amino acids via

The diverse chemistry of oxazol-5-(4H)-ones

“…b-Lactams have also been prepared by Cremonesi and coworkers utilizing bicyclic mu ¨nchnones with imines under basic conditions (Scheme 18). 28 The authors illustrated good control of diastereoselectivity through manipulation of the imine N-substituent. The reaction provided mainly the cisproduct (with respect to the sulfur and phenyl groups) when performed with imines containing electron withdrawing moieties.…”

“…Conversely, high yields of trans-b-lactams could be selectively formed when imines contained electron donating groups. 28 Both products are proposed to arise from initial attack of the imine to the least-hindered side of the ketene, as shown in Scheme 19. When R 1 is an electron donating group the initial iminium intermediate is stabilized and the reaction undergoes a [2 + 2] cycloaddition to afford the trans-products.…”

“…However, the iminium intermediate is destabilized when R 1 is an electron withdrawing group, causing double bond isomerization, which gives rise to the thermodynamically favored cis-products. 28…”

HPLC determination of enantiomeric thiazolidine-2-carboxylic acid on chiral stationary phase with pre-column derivatization

“…Pushpan et al [3] used it for synthesis of a series compounds which are useful as antibacterial agents in the treatment of conditions such as nosocomial pneumonia, community acquired pneumonia, and infections. Moreover, thiazolidine-2-carboxylic acid can be used to synthesize asymmetric cyclic ketenes [4], naphthoxazepine inhibitors of HIV-1 integrase [5], thiazolothiazepine [6,7], and non-hydroxamate histone deacetylase inhibitors [8].…”

“…The preparation of tricyclic [1,4] benzothiazepine derivative started from one enantiomer of thiazolidine-2-carboxylic acid [9]. Therefore, the resolution of this racemic thiazolidine-2-carboxylic acid is an important problem in the determination of its enantiomeric purity.…”