Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 May 20;81(10):4393-8.
doi: 10.1021/acs.joc.6b00589. Epub 2016 May 6.

A Scalable Synthesis of the Difluoromethyl-allo-threonyl Hydroxamate-Based LpxC Inhibitor LPC-058

Xiaofei Liang  1 , Ramesh Gopalaswamy  1 , Frank Navas 3rd  1 , Eric J Toone  1   2 , Pei Zhou  1   2
Affiliations

A Scalable Synthesis of the Difluoromethyl-allo-threonyl Hydroxamate-Based LpxC Inhibitor LPC-058

Xiaofei Liang et al. J Org Chem. .

Abstract

The difluoromethyl-allo-threonyl hydroxamate-based compound LPC-058 is a potent inhibitor of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) in Gram-negative bacteria. A scalable synthesis of this compound is described. The key step in the synthetic sequence is a transition metal/base-catalyzed aldol reaction of methyl isocyanoacetate and difluoroacetone, giving rise to 4-(methoxycarbonyl)-5,5-disubstituted 2-oxazoline. A simple NMR-based determination of enantiomeric purity is also described.

PubMed Disclaimer

Conflict of interest statement

Notes The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A and D) Racemic hydrochloride salt 20a in CD3OD. (B and E) Racemic hydrochloride salt 20a in the presence of a 10-fold excess of (+)-tartaric acid in CD3OD. (C and F) Recrystallized optically pure sample of 21 in the presence of a 10-fold excess of (+)-tartaric acid in CD3OD. (A–C) 1H spectra and (D–F) 19F spectra.
Figure 2
Figure 2
X-ray crystallographic structures of 11 and 21. The compounds are colored in the following atom colors: carbon, gray; nitrogen, blue; oxygen, red; sulfur, yellow; fluorine, green; chlorine, deep green.
Scheme 1
Scheme 1
Initial Route to LPC-058
Scheme 2
Scheme 2
Synthesis of Diyne Carboxylic Acid 4
Scheme 3
Scheme 3
Synthesis of Amine
Scheme 4
Scheme 4
Amide Coupling
See this image and copyright information in PMC

References

    1. Vergidis PI, Falagas ME. Curr Opin Invest Drugs. 2008;9:176. - PubMed
    1. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett Clin Infect Dis. 2009;48:1. - PubMed
    1. Cooper MA, Shlaes D. Nature. 2011;472:32. - PubMed
    1. Lee CJ, Liang XF, Wu QL, Najeeb J, Zhao J, Gopalaswamy R, Titecat M, Sebbane F, Lemaitre N, Toone EJ, Zhou P. Nat Commun. 2016;7:10638. - PMC - PubMed
    1. Glaser C. Ber Dtsch Chem Ges. 1869;2:422.

Publication types

MeSH terms