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Molecules 2018, 23(7), 1762; https://doi.org/10.3390/molecules23071762

Preparation and Use of a General Solid-Phase Intermediate to Biomimetic Scaffolds and Peptide Condensations

1
Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, 402 N. Blackford St., Indianapolis, IN 46202, USA
2
Melinta Therapeutics, Inc., 300 George Street, S 301, New Haven, CT 06511, USA
*
Author to whom correspondence should be addressed.
Received: 23 June 2018 / Revised: 11 July 2018 / Accepted: 14 July 2018 / Published: 18 July 2018
(This article belongs to the Special Issue Solid Phase Synthesis)
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Abstract

The Distributed Drug Discovery (D3) program develops simple, powerful, and reproducible procedures to enable the distributed synthesis of large numbers of potential drugs for neglected diseases. The synthetic protocols are solid-phase based and inspired by published work. One promising article reported that many biomimetic molecules based on diverse scaffolds with three or more sites of variable substitution can be synthesized in one or two steps from a common key aldehyde intermediate. This intermediate was prepared by the ozonolysis of a precursor functionalized at two variable sites, restricting their presence in the subsequently formed scaffolds to ozone compatible functional groups. To broaden the scope of the groups available at one of these variable sites, we developed a synthetic route to an alternative, orthogonally protected key intermediate that allows the incorporation of ozone sensitive groups after the ozonolysis step. The utility of this orthogonally protected intermediate is demonstrated in the synthesis of several representative biomimetic scaffolds containing ozonolytically labile functional groups. It is compatible with traditional Fmoc peptide chemistry, permitting it to incorporate peptide fragments for use in fragment condensations with peptides containing cysteine at the N-terminus. Overall yields for its synthesis and utilization (as many as 13 steps) indicate good conversions at each step. View Full-Text
Keywords: distributed drug discovery; peptide fragment condensation; biomimetic scaffolds; bicyclic thiazolidine lactams; cyclitive cleavage; homoserine lactones; diastereomers; acetal; orthogonal protection; nuclear Overhauser enhancement distributed drug discovery; peptide fragment condensation; biomimetic scaffolds; bicyclic thiazolidine lactams; cyclitive cleavage; homoserine lactones; diastereomers; acetal; orthogonal protection; nuclear Overhauser enhancement
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Samaritoni, J.G.; Martynow, J.G.; O’Donnell, M.J.; Scott, W.L. Preparation and Use of a General Solid-Phase Intermediate to Biomimetic Scaffolds and Peptide Condensations. Molecules 2018, 23, 1762.

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