Stocks, Michael John (1990) Synthetic studies towards FK-506. University of Southampton, Doctoral Thesis.
Abstract
Synthetic studies towards the powerful immunosupressant FK-506 are described. The molecule was disconnected into three fragments and the syntheses of these fragments are discussed here along with studies towards the subsequent linking of these fragments. The first fragment contained an α,β-diketoamide functionality, masked as a hemiacetal, and had not previously been observed in the synthetic chemistry literature. The fundamental aspect in the synthesis of this fragment was the construction of a β-ketoamide precursor to a vicinal 1,2,3-tricarbonyl intermediate. This was achieved via the in situ generation and subsequent tapping (in the presence of an aldehyde) of an unstable lithiated diazoamide species. Treatment of the resulting α-diazo-β-hydroxy amide with rhodium (II) acetate afforded the requisite β-ketoamide. The synthesis of the first fragment was the first reported synthetic approach of this type of moiety to appear in the chemical literature. Central to the synthesis of the second fragment was the application of asymmetric Diels-Alder and aldol reactions to control absolute stereochemistry. An application of pig liver esterase hydrolysis of a meso-diester to a homochiral half-acid ester was also investigated. An application of a novel organocuprate rearrangement, between a higher order organocuprate and a lithiated dihydrofuran, was employed to construct the (E)-trisubstituted alkene contained within the third fragment of FK-506. Synthetic methodology of the preparation of various γ-lactones was also investigated. A review on all of the synthetic studies towards FK-506 is also presented.
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