Medicinal Drug Synthesis - Streptonigrin
A Robinson Research Group

The synthesis of the multi-substituted pyridine ring-C of Streptonigrin, with five diverse substituents, has presented quite a challenge. Construction of a pyridine ring-C (by others) with appropriate groups was best accomplished by sequential inverse electron demand aza Diels-Alder reactions. However these two steps achieved only a 28% yield of the desired pyridine due to lack of regiochemical control.

R e s e a r c h

Our approach has utilized "3+3" and "3+2+1" cyclo-condensations to form pent substituted pyridine model compounds. The free amino group of Streptonigrin ring C has to be completed secondarily so as to not interfere with the condensations. Carboxylic esters and amides gave too much steric hindrance for the precursor to be formed and the nitro was too reactive. However the small linear nitrile group proved to be very useful. Thus after the cyclocondensation, the material could be hydrolysed to the amid and rearranged to the amine. Similarly, the carboxylic acid group of Streptonigrin had to be protected. The 2-furyl group solved this problem and added aromatic stability during the cyclocondensation. 

Detailed results of these efforts with simple pyridine model components can be found in the two publications shown. Current efforts have dealt with means of synthesis for the exact precursors to similarly effect a total synthesis of Streptonigrin via this cyclo-condensation strategy. This method should allow for the versatility to synthesize many Streptonigrin analogues

Updated April 9, 2003

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