STUDIES DIRECTED TOWARD THE TOTAL SYNTHESIS OF MORPHINE
Abstract
The results of research on the application of vinyl sulfones to the synthesis of Morphine is detailed. The approach involves an intramolecular conjugate-addition/intramolecular alkylation reaction of a vinyl sulfone. Model systems performed as desired; however, compounds with the functionality required for the synthesis of Morphine failed to react analogously. The initial approach called for conjugate-addition of a nucleophile to a beta-substituted vinyl sulfone. Beta-phenyl vinyl sulfones were made by the conjugate-addition of a phenyl anion followed by trapping of the resultant alpha-sulfonyl anion with a bromine source to yield an alpha-bromo sulfone. Elimination of HBr with tetra-n-butylammonium fluoride produced the desired olefin regioisomer. Enolate and acetylide anions were shown to add in reasonable to excellent yield to simple vinyl sulfones, but the introduction of a beta-aryl moiety prevented the desired reaction. Application of these reactions in an attempt to make a beta-alkyl vinyl sulfone yielded only the undesired regioisomer. The intramolecular conjugate-addition reaction of gamma-(o-bromophenoxy)-cyclohexenyl sulfones was shown to be possible even in the presence of a beta-phenyl or a beta-vinyl substituent. When the aryl group was further substituted with a 2'-bromo-1'-methoxyethyl group a subsequent intramolecular alkylation of the sulfone anion partially took place. One diastereomer yielded the desired 1,9-ethanodibenzofuran, but the other diastereomer yielded only the tricyclic dibenzofuran. This necessitated the use of a simpler 2'-bromoethylaryl moiety. Application of the above methodology to a system containing the functionality necessary for Morphine failed due to intramolecular deconjugation of the vinyl sulfone by the aryl anion. This side reaction was avoided by synthesizing a dienyl sulfone devoid of the acidic gamma-proton. Transmetalation of this material led to formation of the desired benzofuran when the simple o-bromophenoxy group was used. The reaction of an analogous substrate bearing the required bromoethyl side chain also led to formation of the benzofuran, but the second cyclization failed to take place.
Degree
Ph.D.
Subject Area
Organic chemistry
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