The principal goals for the 24-27 years update since July 2005 will now include: (A) development of an enantioselective total synthesis of the potent insecticidal agent (+)-nodulisporic acid A, (B) completion of the total synthesis of the challenging macrolide antibiotic (+)-sorangicin A; and (C) development of a viable enantioselective total synthesis of the architecturally complex marine antitumor macrolide spirastrellolide A. As in the past, each of these targets will require the development of as yet unforeseen new synthetic methodology to overcome unforeseen obstacles. This is indeed the excitement and frustration of target oriented total synthesis. In the area of new synthetic methods, we will: (D) develop the new modular indole synthesis comprising a sequential Stille and Buchwald-Hartwig cross-coupling union/cyclization tactic, devised in conjunction with the nodulisporic acid A synthetic venture; (E) expand and showcase the new concept of Anion Relay Chemistry (ARC), a powerful synthetic tactic introduced at the time of our previous renewal application, albeit without """"""""proof of concept"""""""". Towards the latter end,we will explore a wide variety of nucleophiles, silyl linchpins possessing various anion stabilizing groups (ASG), and electrophiles to demonstrate the feasibility and rapid assembly of diverse, stereochemically complex oxygen and nitrogen substituted products in a single flask. Beyond these specific synthetic objectives, a general, long-range goal of this program is the identification of the molecular architecture responsible for biological activity. Thus, as we develop an approach to each target, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships. Our experience with discodermolide gives us great confidence in this area.
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