Studies in ring D fragmentation of estrone

Master Thesis


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University of Cape Town

Studies have been conducted in synthesising 14-allyl 19-norsteroids. The eventual aim is to convert the 14-allyl derivatives into bridge-functionalised 19-norsteroids. Two approaches were investigated, with the immediate aim of generating fragmentation intermediates suitable for 14-allylation. The approaches were based on cleavage of the 16,17-bond via oxidative cleavage or fragmentation methodology. The oxidative cleavage routes involved the preparation of 3-methoxy-17 –methylestra-1,3,5(10), 16-tetraen-15-one, which was shown not to undergo regioselective 14-methylation. In an alternative approach 3-methoxy-17a-methylestra-1,3,5(10),14tetraene- 16β, 17β-diol was synthesised. However, the lability of the primary cleaved product prompted synthesis of 3-methoxy-16,17-seco-17a-homoestra-1,3,5(10)-triene16,17a- dione. Chemodifferentiation of the carbonyl groups of the seco derivative provided access to 16-acetoxy-3-methoxy-16, 17-seco-17a-homoestra-1,3,5(10)-trien-17a-one, in an overall yield of 60% from estrone 3-methyl ether. The fragmentation approaches involved conjugate stannylation and silylation of 3-methoxyestra-1,3,5,(10), 15-tetraen-17 -one to give the 15β-trimethylstannyl and 15β-trimethylsilyl 17 -ketones respectively. The stannyl ketone was converted to the 3-methoxy-17a-methyl-15β-trimethylstannylestra-1,3,5,(10)-trien-l7β-ol. Generation of the derived alkoxy radical resulted in formation of 3-methoxy-16, 17-seco-17a-homoestra1,3,5( 10),15-tetraen-17a-one, in low yield, The silyl ketone was converted to the 17acetoxyimino- 3 -methoxy-15β-trimethylsilylestra-l,3,5( 10)-trien, Fragmentation with the borontrifluoride diethyl ether complex resulted in formation of the undesired 3-methoxy13,17-secoestra-l ,3,5(1 0),l4-tetraen-17-nitrile. Since the 15β-trimethylsilyl group did not direct the fragmentation, the 17-acetoxyimino-3-methoxy-16β-trimethylsilylmethylestra-1,3,5(10)-triene was synthesised in the hope that it would be more amenable to silicon directed fragmentation, However, fragmentation with the boron trifluoride diethyl ether complex resulted In formation of the undesired 17-acetoxy-3-methoxy 16β-trimethylsilylmethyl-17a-aza-17a-homoestra-1,3,5(10), 17-tetraene.

Includes bibliographical references.