Versatile synthesis of pathogen specific bacterial cell wall building blocks

Abstract

A modular three coupling strategy involving a versatile solid phase peptide synthesis enables access to pathogen specific lipid analogs in high yield, revealing high spectroscopic resolution of these key bacterial cell wall building blocks.

Strategies and tactics for the synthesis of lipid I and II and shortened analogues: functional building blocks of bacterial cell wall biosynthesis

“…The synthesis of the required tetrapeptide 11 was obtained by a peptide supplier (New England Peptide, Fitchburg, MA), and no experimental details were given. The corresponding free phosphate of 25 (not shown) was then obtained by hydrogenolysis, activated with CDI and coupled to undecaprenyl phosphate (10). Two multiple deprotection reactions to remove the peptidyl silyl and the hydroxyl acetate groups rendered lipid II (6) in 14% yield over the last four steps and in an overall yield of 0.7% starting from carbohydrate 22.…”

“…Their retrosynthetic analysis (not shown) is very similar to the one reported by Schwartz 18 (Scheme 4) and analogous to their previous synthesis of lipid I, which was published in May 2001. 24 In detail, the same building block for side chain (10) as reported by Schwartz 18 (see Schemes 4 and 5) and a slightly altered disaccharide 34 containing a different protecting group on the L-alanine residue was used, and a slightly modied peptide fragment 30 with different protective groups was utilized. Although side chain compound 10 was commercially acquired, carbohydrate building block 34 allowed the selective unmasking of the functional groups for coupling with either tetrapeptide 30 or undecaprenyl chain 10, ensuring triple orthogonality.…”

“…Overall, the desired suitably protected pentapeptide 64 was prepared in 59% over 11 steps compared to 15% over 11 steps starting from commercially available 49, as reported by Walker et al 22 Subsequently, the generality of this sequence was shown by the preparation of peptide analogues that are characteristic of S. aureus 72 (Scheme 15) and E. faecalis 73 (Scheme 15). 10 As shown in Scheme 15, the application of the sequence for the synthesis of 72 required a modication of the protecting group strategy to allow for a selective deprotection of the 3-amino group of the Llysine residue without the liberation of the a-amino group. Thus, instead of L-lysine bearing, a Fmoc-protected a-amino group and a Teoc-protected 3-amino group 58 HO-L-Lys(N-Fmoc)-Alloc (65) were used.…”

“…In these analogues, the disadvantageous authentic bactoprenol terpene residue has been shortened, leading to truncated derivatives, such as farnesyl derivative 8 (Scheme 3) of even further simplified side chains, such as 13 (Scheme 3). 10 Importantly, it has become increasingly apparent that these shortened analogues are fully functional for cell wall biosynthesis. 11 This has led to a renewed interest in developing synthetic ventures, around 20 years after the first total synthesis of lipid II has been reported, especially as these shortened analogues may be prepared with unprecedented purity by scalable routes that may also be adaptable to interpeptidic analogues.…”

“…11 This has led to a renewed interest in developing synthetic ventures, around 20 years after the first total synthesis of lipid II has been reported, especially as these shortened analogues may be prepared with unprecedented purity by scalable routes that may also be adaptable to interpeptidic analogues. 10,12,13 In general, despite impressive synthetic advancements, the preparation of these peptidoglycan structures continues to present challenges, especially in increasing the overall yield, broadening the applicability, improving the purity of the final product and eventually resolving the critical supply issue of these scarce metabolites to enable significantly detailed structural studies. In recent years, several novel approaches or important modifications of the original routes have been developed.…”