We report a broad, new class of metal-catalyzed C-C bond formations - the direct C-C coupling of alcohols and ?-unsaturated compounds. These processes enable carbonyl addition from the alcohol oxidation level and provide access to chiral building blocks that are typically prepared using stoichiometric quantities of pre-metallated nucleophiles (e.g. allylmetal reagents). However, unlike classical approaches, the alcohol C-C coupling processes we report circumvent discrete redox manipulations required for generation of aldehyde electrophiles, and they avoid the generation of molar quantities of metallic byproducts. Here, we propose the first systematic investigations into """"""""alcohol-unsaturated C-C coupling"""""""" and demonstrate how such processes dramatically simplify the synthesis of polyketide natural products, which are an important class of FDA-approved therapeutic agents. Established Catalytic Enantioselective Processes OH [Ir (cod) Cl] 2 (2.5 mol%) OH AcO (R)-Cl,MeO-BIPHEP (5 mol%) R R m-NO2BzOH (10 mol%) Cs2CO3 (20 mol%) 100 mol% 10 equiv. THF (0.2 M), 100 oC 51-83% Yield or 200 mol% 86-95% ee Proposed Catalytic Enantioselective Processes OH MLn (cat.) Diverse R2 R1 Unsaturates R1 Chiral Ligand Me or Modifier From Olefins R2 OH [Ir(cod)Cl]2 (2.5 mol%) OH AcO (S)-SEGPHOS (5 mol%) R R Me 4-CN-3-NO2BzOH (10 mol%) Me Cs2CO3 (20 mol%) 100 mol% 200 mol% THF (1.0 M), 90 oC 61-73% Yield 86-97% ee 5:1-8:1dr OH R2 OH OH OH R2 R1 R1 R1 R2 R1 Me R2 R3 R3 Me From Dienes From Allenes From Alkynes From Enynes R2 R2 R2 R2 R3 R3

Public Health Relevance

Over 60% of the 974 small molecules introduced as drugs worldwide from 1981-2006 were inspired by """"""""Natural Products"""""""".1 Among naturally occurring compounds, polyketides rank among 20% of the top-selling FDA-approved small molecule drugs.2 Accordingly, over 50% of the world's top-selling drugs are single enantiomers, and it is estimated that 80% of all drugs currently entering development are chiral and will be marketed as single-enantiomer entities.4 Here, we propose the first systematic investigations into """"""""alcohol- unsaturated C-C coupling"""""""" and demonstrate how such processes dramatically simplify the synthesis of polyketide natural products, which are an important class of FDA-approved therapeutic agents. (1) """"""""Natural Products as Sources of New Drugs over the Last 25 Years,"""""""" Newman, D. J.;Cragg, G. M. J. Nat. Prod. 2007, 70, 461. (2) (a) """"""""Natural Products in Drug Discovery and Development,"""""""" Cragg, G. M.;Newman, D. J.;Snader, K. M. J. Nat. Prod. 1997, 60, 52-60. (b) """"""""Recent Natural Products Based Drug Discovery: A Pharmaceutical Industry Prospective,"""""""" Shu, Y.-Z. J. Nat. Prod. 1998, 61, 1053. (3) """"""""Chiral Drugs,"""""""" Stinson, S. C. Chem. Eng. News 1998, 76 (Sept. 21), 83. (4) """"""""The Impact of Chiral Technology on the Pharmaceutical Industry,"""""""" Richards, A.; McCague, R. Chem. Ind. 1997, June 2, 422.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM093905-03
Application #
8452719
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2011-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$277,574
Indirect Cost
$90,214
Name
University of Texas Austin
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
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
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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
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
Shin, Inji; Krische, Michael J (2016) Asymmetric Iridium-Catalyzed C-C Coupling of Chiral Diols via Site-Selective Redox-Triggered Carbonyl Addition. Top Curr Chem 372:85-101
Kasun, Zachary A; Gao, Xin; Lipinski, Radoslaw M et al. (2015) Direct Generation of Triketide Stereopolyads via Merged Redox-Construction Events: Total Synthesis of (+)-Zincophorin Methyl Ester. J Am Chem Soc 137:8900-3
Shin, Inji; Krische, Michael J (2015) Formal Synthesis of Premisakinolide A and C(19)-C(32) of Swinholide A via Site-Selective C-H Allylation and Crotylation of Unprotected Diols. Org Lett 17:4686-9

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