The aim of this proposal is to develop facile synthetic entries into various classes of biologically active molecules. We are examining the question of whether tailor-made transition metal complexes may serve as templates to control selectivity in a way reminiscent of enzymes. The first section deals with the development and understanding of metal catalyzed cyclizations at high substrate concentration and with high control stereochemistry to form medium and large ring carbo- and heterocycles whose biological functions include antibiotic and antifungal activity. Some example are: 1) a 9-membered carbocyclic ring such as pachyaldehyde, a representative of a family of antimicrobial marine natural products, 2) a 10- membered macrolide such as the antibiotic cephalosporilide C, 3) an 11-membered carbocyclic ring such as the antibiotic aspochalasin B, 4) a 12-membered metal bridged aryl cyclic ether such as the PG synthetase inhibitor arnebinol, 5) the 14 - membered macrolide portion of the cytochalasin antibiotics, 6) The 17-membered para bridged antibiotic lankacidin C, and 7) The 36-membered ring system of amphotericin B, a clinically important antifungal compound. Cyclopentanes are a structural type of exploding biological significance. Delicate selectivity in cyclizations will be explored in the case of the antifungal terpene chokol C, the antimicrobials udoteatrial and petiodial, the antibiotics enterocine and merulidial, the pharmacologically important picrotaxane neurotoxins, the anticonvulsant anisatin, the antibiotics punctatin A and mellodonal, and retigeranic acid. Mimicking enzymes with transition metal templates is examined to improve selectivity in cycloadditions to five-membered rings. Enzymes use substrate structural features remote from the reaction center to control conformation and thus selectivity; the specific introduction of such remote binding sites will be developed for controlling cycloadditions. Especially relevant is use of gamma -alkoxy -alpha, beta -unsaturated sulfones for 1) asymmetric cyclopentenone annulation, 2) carbacyclin and prostaglandin synthesis, and 3) a synthesis of ginkgolide A, a PAF inhibitor. The third section encompasses steroids and related terpenes using related methodology. A short asymmetric synthesis of the A ring and a totally new metal catalyzed reaction for forming the CD rings of the clinically important Vitamin D metabolites will examined. Closely related chemistry offers a simple strategy to the novel and clinically important antifungal sicannin. The fourth section extends these new synthetic concepts to the beta-lactam antibiotics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Stanford University
Schools of Arts and Sciences
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Trost, Barry M; Yang, Hanbiao; Dong, Guangbin (2011) Total syntheses of bryostatins: synthesis of two ring-expanded bryostatin analogues and the development of a new-generation strategy to access the C7-C27 fragment. Chemistry 17:9789-805
Trost, Barry M; Silverman, Steven M; Stambuli, James P (2011) Development of an asymmetric trimethylenemethane cycloaddition reaction: application in the enantioselective synthesis of highly substituted carbocycles. J Am Chem Soc 133:19483-97
Trost, Barry M; Gutierrez, Alicia C; Ferreira, Eric M (2010) Differential reactivities of enyne substrates in ruthenium- and palladium-catalyzed cycloisomerizations. J Am Chem Soc 132:9206-18
Trost, Barry M; O'Boyle, Brendan M; Hund, Daniel (2010) Investigation of a domino Heck reaction for the rapid synthesis of bicyclic natural products. Chemistry 16:9772-6
Trost, Barry M; Brindle, Cheyenne S (2010) The direct catalytic asymmetric aldol reaction. Chem Soc Rev 39:1600-32
Trost, Barry M; Dong, Guangbin (2010) Total synthesis of bryostatin 16 using a Pd-catalyzed diyne coupling as macrocyclization method and synthesis of C20-epi-bryostatin 7 as a potent anticancer agent. J Am Chem Soc 132:16403-16
Trost, Barry M; Hitce, Julien (2009) Direct asymmetric Michael addition to nitroalkenes: vinylogous nucleophilicity under dinuclear zinc catalysis. J Am Chem Soc 131:4572-3
Trost, Barry M; Gutierrez, Alicia C; Livingston, Robert C (2009) Tandem ruthenium-catalyzed redox isomerization--O-conjugate addition: an atom-economic synthesis of cyclic ethers. Org Lett 11:2539-42
Trost, Barry M; Xu, Jiayi; Schmidt, Thomas (2009) Palladium-catalyzed decarboxylative asymmetric allylic alkylation of enol carbonates. J Am Chem Soc 131:18343-57
Trost, Barry M; Bertogg, Andreas (2009) Si-based benzylic 1,4-rearrangement/cyclization reaction. Org Lett 11:511-3

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