Studies toward the total synthesis and structure proof of Callipeltin B: An improved method for the detection of resin -bound hydroxyl groups using the Pomonis assay
Abstract
In 1996, scientists isolated from the lithistida sponge Callipelta sp. two cyclic depsipeptides, callipeltin A (1–1 ) and callipeltin B (1–2). Callipeltin A has shown marked anti-viral, antitumor, and antifungal activities. Callipeltin B displayed potent cytotoxicity against a number of tumor cell lines. Both callipeltins A and B have a 22-membered macrolactone within the overall structure containing an unusual β-methoxy tyrosine residue with two unspecified stereocenters and two N-methylated amino acids. Additionally, extending from the macrocycle in callipeltin A are a fatty acid residue TMHEA, a homologated arginine AGDHE, and a dimethylglutamine residue. In callipeltin B, a dimethylpyroglutamic acid moiety branches from the cyclic core. Previous efforts to obtain these molecules in our research group have focused initially on the synthesis of callipeltin B on solid support. In general, the synthetic strategy features the use of the acid-labile 3XAL 4-PEG-PS resin, peptide couplings with HATU/HOAt or HBTU/HOBt, dipeptide and tripeptide intermediates, and an on-resin macrocyclization. The initial synthesis of callipeltin B resulted in low yields of two of the four diastereomers of the desired product. Consequently, current studies have evolved to: (1) construct a model of callipeltin B to explore potential improvements to the aforementioned syntheses; (2) examine methods for implementing and assessing an on-resin esterification; and (3) apply the improved synthesis to a revised structure of callipeltin B. With the data gathered from the model system as a guide, diastereomers to the originally published structures have been synthesized. Ester formation using the second threonine residue in the macrocycle was completed on the resin using an MSNT/MeIm protocol and monitored with a modified version of the Pomonis assay for the detection of free hydroxyl groups.
Degree
Ph.D.
Advisors
Lipton, Purdue University.
Subject Area
Organic chemistry
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