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. 2022 Dec 23;24(50):9285-9289.
doi: 10.1021/acs.orglett.2c03861. Epub 2022 Dec 14.

Total Synthesis of Pargamicin A

Yassin M Elbatrawi  1 , Taylor Gerrein  1 , Avraz Anwar  1 , Kamlesh M Makwana  1 , David Degen  2 , Richard H Ebright  2 , Juan R Del Valle  1
Affiliations

Total Synthesis of Pargamicin A

Yassin M Elbatrawi et al. Org Lett. .

Abstract

We report the total synthesis and configurational assignment of pargamicin A, a highly oxidized nonribosomal peptide that potently inhibits the growth of drug-resistant bacteria. Our synthetic approach relies on late-stage piperazine ring formation and careful selection of condensation reagents to assemble the densely substituted hexapeptide backbone. This work enables the synthesis of pargamicin congeners for the development of structure-activity relationships and informs strategies for accessing other sterically congested piperazic acid-containing natural products.

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Figures

Figure 1.
Figure 1.
Structures of pargamicins A-D (PrgA-D; 1-4). Residue abbreviations for PrgA provided in blue.
Figure 2.
Figure 2.
Late-stage Piz formation approach to PrgA (1).
Figure 3.
Figure 3.
Screening of macrocyclization conditions.
Scheme 1.
Scheme 1.
Synthesis of γ-OH-d-Piz precursor 6.
Scheme 2.
Scheme 2.
Synthesis of γ-OH-d-Piz precursor 6.
Scheme 3.
Scheme 3.
Total synthesis of PrgA (1).
See this image and copyright information in PMC

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