The principal goals for the 16-19 years are: (A) to complete the total synthesis of the indole-diterpene tremorgen penitrem D (36), the premier synthetic target in their laboratory; (B) to exploit the penitrem D """"""""eastern hemisphere"""""""" lactone (37) as a common advanced intermediate for the total syntheses of other indole-diterpene tremorgens [e.g., the sulpinines (38 and 39), lolitrems B and C (40 and 41) and janthitrems E, F, and G (42 - 44)]; (C) to construct the unusually complex cytotoxic macrolides, tedanolide and 13-deoxytedanolide (34 and 35), further demonstrating the s-bond olefin construction and dithiane coupling tactics developed in their FK506, rapamycin and discodermolide synthetic ventures: (D) to define the chemo-, regio-, and stereoselectivity of stannylcupration and free-radical and palladium-catalyzed hydrostannylations of diynes, generating a wide variety of enynes and dienes found in bioactive natural products; and (E) to further explore and develop the multicomponent linchpin coupling of 2-lithio-2-trialkylsilyl-1,3-dithiane (45) with electrophiles via controlled Brook rearrangement. A central theme of these efforts and other synthetic programs underway in their laboratory is the development of strategies that are not single-target oriented, but instead will permit construction of entire classes of natural and unnatural products. This philosophy of """"""""unified synthetic strategies"""""""" will be further developed in this proposal.
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