I. Stereoselective synthesis of four stereoisomers of beta-methoxytyrosine, a component of callipeltin A. II. Efforts toward the total synthesis of cyclomarin A.

摘要

The synthesis of unnatural amino acids contained within peptide based natural products remains a significant challenge in total synthesis. Cyclomarin A and callipeltin A are two representative natural products that contain a variety of noncoded amino acids. Common to both natural products is the occurrence of beta-hydroxy derived amino acids. Many methods exist for the construction of beta-hydroxy amino acids but all suffer from such drawbacks as low stereocontrol, narrow scope, and low yields. The use of Lajoie's chiral serine aldehyde provides a general route toward the synthesis of beta-hydroxy derived amino acids. With this method we were able to successfully construct all four stereoisomers of beta-methoxytyrosine an amino acid contained within callipeltin A. The method was further applied toward the synthesis of cyclomarin A, for the construction of beta-methoxyphenylalanine and N-(1,1-dimethyl-2,3-epoxypropyl)-beta-hydroxytryptophan. In order to finish the total synthesis of cyclomarin A the construction of two additional unnatural amino acids was necessary. The proposed synthesis of delta-hydroxyleucine as its methyl ester and 2-amino-3,5-dimethylhex-4-enoic acid were based on a combination of an asymmetric alkylation and Davis's asymmetric Strecker reaction. The synthesis of delta-hydroxyleucine methyl ester was achieved using the prescribed methods, but the synthesis of 2-amino-3,5-dimethylhex-4-enoic acid failed because of the forcing conditions required to hydrolyze the amino nitrile product of the Strecker reaction. In an effort to circumvent this problem the addition of dithianes into chiral sulfinimines was examined. While the method has yet to yield the desired amino acid the addition of dithianes has been successful and with further optimization this method would be a powerful addition to the asymmetric synthesis of unnatural amino acids. The synthesis of several noncoded amino acids contained within callipeltin A and cyclomarin A have been successfully synthesized using a combination of Lajoie's chiral serine aldehyde and Davis's asymmetric Strecker reaction.