Date of Award:

5-1978

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Chemistry and Biochemistry

Advisor/Chair:

Richard K. Olsen

Abstract

A convenient, economical, large scale synthesis of N-acetyldehydro-alanine (a-acetamidoacrylic acid) and its methyl ester was developed via a sequence of N-chlorination-dehydrochlorination. The method was extended to the synthesis of the corresponding N-benzoyl, N-phenylacetyl and N-benzyloxycarbonyl derivatives.

The conversion of a-methoxy-N-acetyl alanine derivatives to the corresponding a-mercapto alanine derivatives, using zinc chloride and an appropriate mercaptan, was investigated. Methyl a-methoxy-N-acetyl-D, L-alaninate was successfully converted to the a-acetylthio derivative, in 24% yield; however, a 90% yield could be obtained by treatment of the dehydroalanine derivative with hydrogen chloride gas in neat thiolacetic acid.

A facile conversion of the a-acetylthio derivative to the a-methoxy derivative, using sodium methoxide in methanol, was observed to occur.

The normally facile conversion of an acetylthio group to a mercapto group, using sodium borohydride, gave mixtures of the a-mercapto derivative and alanine derivative.

The reactions at the a position of a-hetero-N-acetyl-D,L-alanines and a,B-disubstituted N-acetyl-D,L-alanine derivatives seemed consistent with the formation of an acylimine intermediate under basic conditions and a carbonium ion intermediate under acidic conditions.

From these studies, a facile, clean synthesis of a-halo-a-mercapto-and a-alkoxy-N-acetyl-D,L-alanine derivatives was accomplished.

All attempts to synthesize a,B-dimercapto derivatives failed because the B-halogen could not be replaced with a mercapto group when the a position was a mercapto or methoxy derivative. Attempts to generate a B-mercapto-a-halo derivative also failed.

A facile synthesis of the E and Z isomers of methyl B-chloro-N-acetyldehydroalaninate was developed. The ratio of Z to E isomers was found to vary with the base used for the elimination.

The E and Z isomers of methyl B-chloro-N-acetyldehydroalaninate were converted to the B-mercapto derivatives by reaction with mercaptan. The reaction proceeded with retention of stereochemistry.

The formation of B-substituted N-acetyldehydroalanine derivatives seemed consistent with an acylimine intermediate followed by a sequence of Michael-type addition and dehydrochlorination.

A study of the conversion of the B-mercapto-N-acetyldehydroalanine derivatives to mixed dithioacetals, which would be useful in the synthesis of natural antibiotics, was undertaken. This approach to the synthesis of mixed dithioacetals was unsuccessful because an exchange of mercapto groups was observed, the addition of a second, different mercaptan failed or the yield was too low to be synthetically useful.

A synthesis of B,B-dimercapto-N-aeetyldehydroalanine (mixed, unsaturated dithioacetals) derivatives was accomplished. However, because of low yields, a reduction to B,B- dimercapto-N- acetyl-D,L-alanine derivatives (mixed dithloacetals) was not investigated.

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