This thesis describes the studies undertaken by our laboratory on the synthesis of the dolabelide family of marine macrolides that eventually culminated in the first published total synthesis of dolabelide D. The first chapter provides motivation for our interest in this family of molecules, framing the problem within the larger context of polyketide natural product synthesis, and describes the conceptual development of methodologies that were applied in our approach to the dolabelides. The origin of the key tandem alkyne silylformylation-crotylsilylation reaction used in our synthesis is reviewed, along with our group's related discovery of strained silacycle reagents for aldehyde allylation.
The second chapter details our initial investigations toward the total synthesis of dolabelides A and B. The isolation, structure determination, and biological activity of the dolabelides are described, followed by a discussion of our overall synthetic strategy. We then present a concise approach to the C(15)-C(30) fragment, where the C(23)-C(27) 1,5- syn -diol was established by tandem silylformylation-crotylsilylation of an alkyne bearing a chiral silane, and the C(24)-C(25) trisubstituted olefin was accessed by an intriguing Brook-like rearrangement. The C(1)-C(14) fragment was assembled by an Evans-Paterson 1,5- anti aldol coupling; the requisite aldehyde and ketone precursors were derived from chiral building blocks made available by asymmetric allylation and crotylation using our strained silacycle reagents. Difficulties with the key coupling to unite the C(1)-C(14) and C(15)-C(30) fragments prevented us from synthesizing dolabelide A or B, and exploratory studies revealed problems with our protecting group strategy.
The third chapter chronicles our pursuit of a closely related target, dolabelide D, and traces the evolution of our synthetic plan to surmount the obstacles encountered in the previous chapter. The synthesis of the modified C(15)-C(30) and C(1)-C(14) fragments is described, including our efforts to find a method for the diasteroselective reduction of the C(9) ketone. Finally, the successful fragment coupling, deprotection, and ring-closing metathesis to form the natural product is presented.
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