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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Zou, Yike; Smith 3rd, Amos B (2018) Total synthesis of architecturally complex indole terpenoids: strategic and tactical evolution. J Antibiot (Tokyo) 71:185-204
Zou, Yike; Li, Xiangqin; Yang, Yun et al. (2018) Total Synthesis of (-)-Nodulisporic Acids D, C, and B: Evolution of a Unified Synthetic Strategy. J Am Chem Soc 140:9502-9511
Han, Heeoon; Smith 3rd, Amos B (2017) Anion Relay Chemistry: Development of an Effective Diastereoselective [3+2] Annulation Tactic Exploiting an Aldol/Brook Rearrangement/Cyclization Cascade. Angew Chem Int Ed Engl 56:14102-14106
Deng, Yifan; Liu, Qi; Smith 3rd, Amos B (2017) Oxidative [1,2]-Brook Rearrangements Exploiting Single-Electron Transfer: Photoredox-Catalyzed Alkylations and Arylations. J Am Chem Soc 139:9487-9490
Liu, Qi; Deng, Yifan; Smith 3rd, Amos B (2017) Total Synthesis of (-)-Nahuoic Acid Ci (Bii). J Am Chem Soc 139:13668-13671
Nguyen, Minh H; O'Brien, Kevin T; Smith 3rd, Amos B (2017) Design, Synthesis, and Application of Polymer-Supported Silicon-Transfer Agents for Cross-Coupling Reactions with Organolithium Reagents. J Org Chem 82:11056-11071
Liu, Qi; Chen, Yu; Zhang, Xiao et al. (2017) Type II Anion Relay Chemistry: Conformational Constraints To Achieve Effective [1,5]-Vinyl Brook Rearrangements. J Am Chem Soc 139:8710-8717
Nguyen, Minh H; Imanishi, Masashi; Kurogi, Taichi et al. (2016) Total Synthesis of (-)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol. J Am Chem Soc 138:3675-8
Farrell, Mark; Melillo, Bruno; Smith 3rd, Amos B (2016) Type?II Anion Relay Chemistry: Exploiting Bifunctional Weinreb Amide Linchpins for the One-Pot Synthesis of Differentiated 1,3-Diketones, Pyrans, and Spiroketals. Angew Chem Int Ed Engl 55:232-5
Martinez-Solorio, Dionicio; Melillo, Bruno; Sanchez, Luis et al. (2016) Design, Synthesis, and Validation of an Effective, Reusable Silicon-Based Transfer Agent for Room-Temperature Pd-Catalyzed Cross-Coupling Reactions of Aryl and Heteroaryl Chlorides with Readily Available Aryl Lithium Reagents. J Am Chem Soc 138:1836-9

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