Biosynthesis
Strychnine is a terpene indole alkaloid belonging to the Strychnos family of Corynanthe alkaloids, and it is derived from tryptamine and secologanin. The enzyme, strictosidine synthase, catalyzes the condensation of tryptamine and secologanin, followed by a Pictet-Spengler reaction to form strictosidine. While the enzymes that catalyze the following steps have not been identified, the steps have been inferred by isolation of intermediates from Strychnos nux vomica. The next step is hydrolysis of the acetal, which opens the ring by elimination of glucose (O-Glu) and provides a reactive aldehyde. The nascent aldehyde is then attacked by a secondary amine to afford geissoschizine, a common intermediate of many related compounds in the Strychnos family.
A reverse Pictet-Spengler reaction cleaves the C2-C3 bond, while a subsequent Mannich reaction forms the C3-C7 bond, and a Michael addition forms the C2-C16 bond to provide dehydropreakuammicine. Hydrolysis of the methyl ester and decarboxylation leads to norfluorocurarine. Stereospecific reduction of the endocyclic double bond by NADPH and hydroxylation provides the Wieland-Gumlich aldehyde, which was first isolated by Heimberger and Scott in 1973, although previously synthesized by Wieland and Gumlich in 1932. To elongate the appendage by 2 carbons, acetyl-CoA is added to the aldehyde in an aldol reaction to afford prestrychnine. Stychnine is then formed by a facile addition of the amine with the carboxylic acid or its activated CoA thioester, followed by ring-closure via displacement of an activated alcohol.
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