Date of Award:

5-1983

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Chemistry and Biochemistry

Advisor/Chair:

Richard K. Olsen

Abstract

Studies have been carried out towards the synthesis of bicyclic octadidepsipeptide lanthionine 4, an analog of des-N-tetramethyl triostin A. Starting with a symmetrical lanthionine unit 5 (R1, R3 = Me; R2, R4 = t-butyloxycarbonyl), synthesized from the corresponding cystine by contraction with hexaethylphosphorus triamide, linear octadidepsipeptides 29 and 32 were synthesized.

Attempted cyclizations of 29 and 32 to the bicyclic octapeptide were unsuccessful.

The failure of the symmetrical approach to 4 prompted the synthesis of an unsymmetrical lanthionine unit with appropriate compatible protecting groups. Attempts to synthesize unsymmetrical lanthionines by nucleophilic displacement on N-benzyloxycarbonyl-B-chloro-L-alanine and appropriate O-activated serine derivatives with the thiol function of L-cysteine were unsuccessful. L-valine as the C-terminal amino acid of the O-activated serine was found to sterically hinder the nucleophilic displacement with the thiol, since the displacement could be effected when glycine was present in lieu of valine.

The reaction of thiolsulfinate with cysteine led to an unsymmetrical cystine which was then contracted with hexaethylphosphorus triamide to yield the corresponding lanthionines. The synthesis of unsymmetrical lanthionines cystine which was then contracted with hexaethylphosphorus triamide to yield the corresponding lanthionines. The synthesis of unsymmetrical lanthionines 76 (R1 = t-butyl, R2 = t-butyloxycarbonyl, R3 = ethyl, R4 = benzyloxycarbonyl) and 80 (R1 = t-butyl, R2 2,2,2-trichloroethyloxycarbonyl, ethyl, benzyloxycarbonyl) has been accomplished. Lanthionines 76 and 80 each have four different protectings on the amino and carboxyl functions. These can be selectively removed in the right sequence for a proposed synthesis of 4. further studies towards the synthesis of 4, as proposed, were not pursued.

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