Pyrrolidinones derived from (S)-pyroglutamic acid: penmacric acid and analogues

Abstract

Alkylation reactions using alpha-halolactams or lactam enolates derived from bicyclic lactam templates can proceed with high endo- or exo- diastereoselectivity respectively. In the latter case, stereochemical correction by means of enolate generation and hindered phenol quench is possible with moderate efficiency. This protocol has been applied to the synthesis of protected penmacric acid and its analogues.

Synthesis of 3-acyltetramates by side chain manipulation and their antibacterial activity

“…Condensation of the anion of phosphonate 12, generated by treatment with t-butoxide, with a series of aldehydes (Scheme 3), gave excellent yields of the enone products 10a-h, a process which was significantly more efficient than those involving direct condensation and shown in Scheme 2. Attempted deprotection of these systems, however, via Corey-Reichard protocol 24 proved to be problematic; for example, reaction of 10c under conditions which we have previously found to be universally successful in related substrates, [25][26][27] gave a low and irreproducible yield of the expected tetramate 13 (Scheme 4). In addition, use of other acidic conditions such as THF-H 2 O-formic acid (3 : 1 : 1) 28 or BiBr 3 -MeCN with catalytic H 2 O 29 resulted in no conversion of the oxazolidine.…”

Stereoselective synthesis of conformationally constrained ω-amino acid analogues from pyroglutamic acid

“…However, modified lysine chimeras derived from pyroglutamic acid 23 or proline, 21,24, 25 and conformationally restricted lysine, 26 ornithine, 27,28 arginine 29-31 and glutamine, 32 have all recently been reported. The synthesis of cyano-33 or indole-substituted 34 glutamate analogues, and of penmacric acid, 35 have also recently been described, although their biological activity has not been investigated. 36 Scheme 1 (i) LDA, THF, −78 • C then BrCH 2 CN (55%) for 2a or BrCH 2 CO 2 t-Bu (53%) for 2b; (ii) NaBH 4 , CoCl 2 , EtOH (76%); (iii) CBZCl, Et 3 N (64%) or AcCl, Et 3 N, THF, 0 • C (75%); (iv) TFA, DCM, RT (80%); (v) RuO 2 , NaIO 4 then CH 2 N 2 (34%).…”

Functionalised Nitrogen Heterocycles and the Search for New Antibacterials and Bioactives

“…More recently, the understanding of the basis for, and ability to control, diastereoselectivity in lactam alkylations has been very considerably enhanced. 35,37 We used these alkylations to access protected penmacric acid 8 38 and novel spirocycles 9, 39 an approach which was also exploited by others. 40 Of great interest was that selenylation and elimination gave enelactam 10 very efficiently, and this…”