Our laboratory has discovered a broad, new class of catalytic processes that promote C-C bond formation via direct alcohol C-H functionalization. In the prior funding period, this technology enabled total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, availing the most concise routes to any member of these respective natural products families. In the proposed funding period, these routes will be adapted to prepare functional analogues of bryostatin and trienomycin. Our bryostatin analogues will be evaluated in an ongoing collaboration with Dr. Peter M. Blumberg, who is Chief, Molecular Mechanisms of Tumor Promotion Section in the Laboratory of Cancer Biology and Genetics at the NCI. The bryostatin analogues also will be evaluated in HIV viral reactivation assays in collaboration with colleagues at GlaxoSmithKline. Trienomycin analogues will be evaluated at the Texas Institute for Drug and Diagnostics Development (TI-3D). Having utilized alcohol C-C coupling to streamline the synthesis of several type I polyketides, we will now begin to evolve a suite of methods to assemble therapeutically relevant type II polyketide natural products, such as (+)-lactonamycin, which displays potent antibacterial activity against MRSA. TYPE I Polyketides Prepared in the Prior Funding Period Me Me Me O HO OAc MeO2C Me OO Me Me OH OH O Me Me OH O OH O O Me Me O OH O Me OH Me Me O CO2Me 6-DEOXYERYTHRONOLIDE B BRYOSTATIN 7 14 Steps (LLS), 3 C-C Bonds Formed 20 Steps (LLS), 5 C-C Bonds Formed via Hydrogen Mediated C-C Coupling via Hydrogen Mediated C-C Coupling 26 Steps (Masamune), 23 Steps (Evans) 41 Steps (Masamune), 43 Steps (Yamamura) 42 Steps (Danishefsky), 23 Steps (White) 42 Steps (Evans), 30 Steps (Keck) 28 Steps (Trost), 25 Steps (Wender) Me OH OH OH OH OH Me Me OH O Me HO O Me (+)-ROXATICIN 20 Steps (LLS), 8 C-C Bonds Formed via Hydrogen Mediated C-C Coupling 45 Steps (Mori), 31 Steps (Rychnovsky) 29 Steps (Evans) HO The ideal synthesis creates a O O Me complex skeleton... in a sequence Me Me OMe NH only of successive construction MeO O O O OMe Me reactions involving no intermediary HO O refunctionalizations, and leading directly to the structure of the MeO O O O OMe O OMe target, not only its skeleton but OMe Me Me H also its correctly placed O O O N O functionality. Me R Me CYANOLIDE A TRIENOMYCINS A and F Hendrickson, J. B. 6 Steps (LLS), 2 C-C Bonds Formed 16 Steps (LLS), 3 C-C Bonds Formed J. Am. Chem. Soc. via Hydrogen Mediated C-C Coupling via Hydrogen Mediated C-C Coupling 1975, 97, 5784. 14 Steps (Hong), 17 Steps (Reddy) 30 Steps (Smith), 24 Steps (Panek) 14 Steps (She), 17 Steps (Pabbaraja) 35 Steps (Hayashi) 12 Steps (Rychnovsky), 15 Steps (Jennings) TYPE II Polyketides Inspire the Development of Convergent Methods for their Assembly; Functional Bryostatin Analogues Me Me O O OAc MeN OH O O OO O OMe O OH O HO O O Me Me OH OO O O Me OH Me OH OMe C7H15 O (+)-Lactonamycin O Potent activity against vancomycin-resistant Enterococcus (VRE) and methicillin-resistant seco-B-ring Analogue WN-1 Staphylococcus aureus (MRSA) Ki = 16.1 nM, PKC A- and C rings common to analogues that display bryostatin 1-like behavior in U937 histiocytic lymphoma cells, yet PMA-like response is observed. Inhibits the growth of multiple leukemia cell lines Made via H2-mediated C-C coupling in 17 Steps (LLS)

Public Health Relevance

Polyketides are used extensively in human medicine1,2 and account for approximately 20% of the top-selling small molecule drugs.2,3 While the majority of polyketide drugs derive from soil bacteria, less than 5% of soil bacteria are amenable to culture.4 These data clearly 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. Here, we propose to continue our investigations into 'alcohol-unsaturate C-C coupling' by demonstrating how such processes enable new synthetic strategies that significantly simplify the construction of therapeutically relevant polyketide natural products. We are the only group exploring this emergent area of research. (1) Selected reviews: (a) D. O'Hagan, The Polyketide Metabolites, Ellis Horwood, Chichester, 1991. (b) 'Polyketides Biosynthesis, Biological Activity, and Genetic Engineering,' Rimando, A. M.; Baerson, S. R. ACS Symp. Ser. 2007, 955, 282. (2) Selected reviews: (a) 'Natural Products as Sources of New Drugs over the Last 25 Years,' Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461. (b) 'Impact of Natural Products on Developing New Anti-Cancer Agents,' Newman, D. J.; Grothaus, P. G.; Cragg, G. M. Chem. Rev. 2009, 109, 3012. (3) 'A New Role for Polyketides,' Rohr, J. Angew. Chem. Int. Ed. 2000, 39, 2847. (4) 'Cultivation of Globally Distributed Soil Bacteria from Phylogenetic Lineages Previously Only Detected in Cultivation-Independent Surveys,' Sait, M.; Hugenholtz, P.; Janssen, P. H. Environ. Microbiol. 2002, 4, 654 and references cited therein.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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University of Texas Austin
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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

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