Towards the total syntheses of the Papuamides, Callipeltin A and analogues

Gurusankar Ramamoorthy, Purdue University

Abstract

Papuamides A and B, a novel 22-membered cyclic depsipeptides, were shown to possess anti-HIV activity and antitumor activities against a variety of human cancer cell lines. The papuamides contain several non-proteinogenic amino acid residues such as (2R,3R)-β-methoxytyrosine (β-MeOTyr), (2S,3S,4R)-3,4-dimethylglutamine (DiMeGln) and a previously undescribed 2,3-dihydroxy-2,6,8-trimethyldeca-(4 Z,6E)-dienoic acid (Dhtda) moiety. Towards the total synthesis of Papuamides A and B, all four diastereomers of 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid were synthesized from the commercially available isomers of diethyl tartrate in 10-11 steps with 10% overall yield. A crucial, highly Z-selective Wittig reaction approach was developed to couple two fragments of Dhtda. To assign the relative stereochemistry of the Dhtda moiety, NMR spectra of the diastereomers of synthetic Dhtda were recorded in various solvents and correlated with those of natural Dhtda, resulting in a conclusion that the likely configuration of Dhtda is either (2R,3S,8S) or its enantiomer (2S,3R,8R). Callipeltin A, a novel 22-membered cyclic depsipeptide was shown to exhibit anti-HIV activity, antitumor activity against a variety of human cancer cell lines and antifungal activity. Callipeltin A also showed a powerful inhibition of the Na+/Ca2+ exchanger in guinea pigs. Callipeltin A contains several proteinogenic and nonproteinogenic amino acids, including (2R,3R,4S)-4-amino-7-guanidino-3,4-dihydroxyheptanoic acid (AGDHE), (2R,3R)-β-methoxytyrosine (β-MeOTyr), (2S,3S,4R)-3,4-dimethylglutamine (DiMeGln) and (2R,3R,4S)-3-hydroxy-2,4,6-trimethyl heptanoic acid (TMHEA). In pursuit of the total synthesis of callipeltin A, all the necessary and appropriately protected non-proteinogenic amino acid building blocks were synthesized in an enantio- and diastereoselective fashion. In our efforts to scale up, some of the crucial steps were re-optimized to obtain the required amino acid residues in high yields and multigram quantities. To expedite the total synthesis of callipeltin A and analogues, an Fmoc-based solid phase approach has been developed. The TG Sieber amide resin anchored to the side chain of the N-methylglutamine residue was chosen for the relatively low amounts of TFA needed for cleavage of the peptide from the solid support. In efforts to the synthesis of callipeltin A, a reliable on-resin esterification method was developed in high yield and purity. One pot on-resin macrolactamization of the linear peptide was successfully achieved that also effectively reduced the number of steps of the synthesis. The coupling of Arg residue was accomplished with both the resin-bound Gln and DiMeGln during the efforts to study the difficult AGDHE coupling that still needs a careful examination.

Degree

Ph.D.

Advisors

LIPTON, Purdue University.

Subject Area

Organic chemistry

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