Total synthesis of callipeltin D and towards callipeltin A
Abstract
Callipeltin A, a novel cyclic depsipeptide was shown to possess antifungal and anti-HIV acivity and cytotoxicity against selected human carcinoma cell lines, as well as powerful inhibition of the Na+/Ca2 + exchanger in guinea pig left atria. Callipeltin A contains several nonproteinogenic amino acids, including (2R,3R,4 S)-4-amino-7-guanidino-3,4-dihydroxyheptanoic acid (AGDHE) and (2 R,3R)-β-methoxytyrosine (β-MeOTyr). In efforts to complete the total synthesis of callipeltin A, the synthesis of the (2R,3S,4S) and (2 S,3R,4S) diastereomers of AGDHE, (2R,3R)-(β-MeOTyr) and callipeltin D were completed. The synthesis of the fully protected (2R,3S, 4S) and (2S,3R,4 S) diastereomers of AGDHE was carried out in eight steps, from a previously reported intermediate, and 13 and 12% overall yields, respectively. NMR comparisons of the diastereomers with callipeltin A and D lent further support to the idea that the correct stereochemical assignment of AGDHE is (2R,3R,4S). The nonproteinogenic amino acid (2R,3R)-β-Methoxytyrosine was synthesized from a readily available cinnamate ester in three steps and 62% overall yield with a greater than 28:1 er and 19:1 dr. This method provides a highly enantio- and diastereoselective synthesis of an important amino acid. The lipopeptide callipeltin D was synthesized using an Fmoc-based solid-phase strategy in seven steps and 35% overall yield. The 1H NMR of synthetic callipeltin D correlated closely with that of the natural product, confirming the configurational assignment of the novel amino acid constituent (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid. An Fmoc-based solid-phase strategy of a callipeltin A intermediate has been produced with all of the required residues except for (2R, 3R, 4S)-3-hydroxy-2,4,6-trimethylheptanoic acid (TMHEA). Key steps in the synthesis include anchoring the resin to the sidechain of the N-methylglutamine residue and an on-resin esterification.
Degree
Ph.D.
Advisors
Lipton, Purdue University.
Subject Area
Organic chemistry
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