Polyketides are used extensively in human medicine and account for approximately 20% of the top-selling small molecule drugs. While the majority of polyketide drugs derive from soil bacteria, less than 5% of soil bacteria are amenable to culture. These data suggest that as methods for the culture of soil bacteria improve, the use of polyketides in human medicine will increase, as will the need for concise manufacturing routes to these complex structures and their functional analogues. Under the aegis of NIH support, we have developed a family of catalytic methods for the direct stereo- and site-selective conversion of lower alcohols to higher alcohols. These alcohol-mediated C-C couplings were conceived and developed exclusively in our laboratory and we remain the foremost group exploring this area of research. This technology has enabled total syntheses of diverse type I polyketides, including 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, cryptocaryol A, SCH 351448, swinholide, as well as formal syntheses of rifamycin S and scytophycin C. In all cases, our syntheses were significantly more concise than preexisting routes. These methods are finding increasingly frequent use across both academic and industrial laboratories. In the proposed funding period, two main objectives are proposed: (a) catalytic methods for type II polyketide construction will be developed and (b) simplified polyketide analogues possessing anti-cancer and anti-bacterial properties will be evaluated in ongoing collaborations. These studies advance an integrated program in which methodological innovation informs synthesis, and synthesis informs medicinal chemistry.

Public Health Relevance

Polyketides are used extensively in human medicine and account for approximately 20% of the top-selling small molecule drugs. Under the aegis of NIH support, we have pioneered a broad, new family of catalytic alcohol-mediated C-C bond formations for type I polyketide construction. In the proposed funding period, (a) catalytic methods for type II polyketide construction will be developed and (b) simplified polyketide analogues possessing anti-cancer and anti-bacterial properties will be evaluated in ongoing collaborations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM093905-09
Application #
9644663
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2011-05-01
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
Ambler, Brett R; Turnbull, Ben W H; Suravarapu, Sankar Rao et al. (2018) Enantioselective Ruthenium-Catalyzed Benzocyclobutenone-Ketol Cycloaddition: Merging C-C Bond Activation and Transfer Hydrogenative Coupling for Type II Polyketide Construction. J Am Chem Soc 140:9091-9094
Sato, Hiroki; Turnbull, Ben W H; Fukaya, Keisuke et al. (2018) Ruthenium(0)-Catalyzed Cycloaddition of 1,2-Diols, Ketols, or Diones via Alcohol-Mediated Hydrogen Transfer. Angew Chem Int Ed Engl 57:3012-3021
Roane, James; Wippich, Julian; Ramgren, Stephen D et al. (2017) Synthesis of the C(1)-C(13) Fragment of Leiodermatolide via Hydrogen-Mediated C-C Bond Formation. Org Lett 19:6634-6637
Bender, Matthias; Turnbull, Ben W H; Ambler, Brett R et al. (2017) Ruthenium-catalyzed insertion of adjacent diol carbon atoms into C-C bonds: Entry to type II polyketides. Science 357:779-781
Ketcham, John M; Volchkov, Ivan; Chen, Te-Yu et al. (2016) Evaluation of Chromane-Based Bryostatin Analogues Prepared via Hydrogen-Mediated C-C Bond Formation: Potency Does Not Confer Bryostatin-like Biology. J Am Chem Soc 138:13415-13423
Wang, Gang; Krische, Michael J (2016) Total Synthesis of (+)-SCH 351448: Efficiency via Chemoselectivity and Redox-Economy Powered by Metal Catalysis. J Am Chem Soc 138:8088-91
Perez, Felix; Waldeck, Andrew R; Krische, Michael J (2016) Total Synthesis of Cryptocaryol A by Enantioselective Iridium-Catalyzed Alcohol C-H Allylation. Angew Chem Int Ed Engl 55:5049-52
Saxena, Aakarsh; Perez, Felix; Krische, Michael J (2016) Ruthenium(0)-Catalyzed [4+2] Cycloaddition of Acetylenic Aldehydes with ?-Ketols: Convergent Construction of Angucycline Ring Systems. Angew Chem Int Ed Engl 55:1493-7
Shin, Inji; Hong, Suckchang; Krische, Michael J (2016) Total Synthesis of Swinholide A: An Exposition in Hydrogen-Mediated C-C Bond Formation. J Am Chem Soc 138:14246-14249
Feng, Jiajie; Kasun, Zachary A; Krische, Michael J (2016) Enantioselective Alcohol C-H Functionalization for Polyketide Construction: Unlocking Redox-Economy and Site-Selectivity for Ideal Chemical Synthesis. J Am Chem Soc 138:5467-78

Showing the most recent 10 out of 28 publications