The total synthesis of colombiasin A tert-butyl ether

Abstract

The thesis is concerned with the synthesis of (-)-colombiasin A, a natural product with reported anti-tubercular activity, recently isolated from the Caribbean sea whip Pseudopterogoria elisabethae. This thesis describes a new approach to (+)- and (-)- colombiasin A tert-butyl ether from (+)- and (-)-dihydrocarvone respectively.  Key features are a one-pot Shapiro reaction; an asymmetric hydroboration-oxidation reaction and an elaborate “reagent free” cascade sequence.  The latter involves sequential thermal rearrangement of a cyclobutenone to a hydroquinone, aerial oxidation to a quinone and an intramolecular Diels-Alder cycloaddition.

Since its isolation, two syntheses of (-)-colombiasin A and two further approaches have been reported, all of which are reviewed in detail in Chapter I. Model studies on the Shapiro reaction and the thermal rearrangement of the resulting cyclobutenones are described in detail in Chapter II.

Studies leading to the elaboration of a diene side-chain on (+)-dihydrocarvone are features in Chapter III.  Key reactions are an asymmetric hydroboration step, which proceeds with good diastereoselectivity and an extremely efficient Kocienski-Julia coupling which provides an appealing alternative to a Wittig reaction.

In Chapter IV, routes to (+)- and (-)-colombiasin A tert-butyl ether are described.  These sequences implement the findings of our preliminary studies together with an intramolecular Diels-Alder cycloaddition to complete the syntheses.

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