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 #
5R01GM093905-02
Application #
8259146
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
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$281,765
Indirect Cost
$91,765
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
Dechert-Schmitt, Anne-Marie R; Schmitt, Daniel C; Gao, Xin et al. (2014) Polyketide construction via hydrohydroxyalkylation and related alcohol C-H functionalizations: reinventing the chemistry of carbonyl addition. Nat Prod Rep 31:504-13
Itoh, Takahiko; Montgomery, T Patrick; Recio 3rd, Antonio et al. (2014) Asymmetric alcohol C-H allylation and syn-crotylation: C9-C20 of tetrafibricin. Org Lett 16:820-3
Shin, Inji; Wang, Gang; Krische, Michael J (2014) Catalyst-directed diastereo- and site-selectivity in successive nucleophilic and electrophilic allylations of chiral 1,3-diols: protecting-group-free synthesis of substituted pyrans. Chemistry 20:13382-9
Andrews, Ian P; Ketcham, John M; Blumberg, Peter M et al. (2014) Synthesis of seco-B-ring bryostatin analogue WN-1 via C-C bond-forming hydrogenation: critical contribution of the B-ring in determining bryostatin-like and phorbol 12-myristate 13-acetate-like properties. J Am Chem Soc 136:13209-16
Dechert-Schmitt, Anne-Marie R; Schmitt, Daniel C; Krische, Michael J (2013) Protecting-group-free diastereoselective C-C coupling of 1,3-glycols and allyl acetate through site-selective primary alcohol dehydrogenation. Angew Chem Int Ed Engl 52:3195-8
Gao, Xin; Woo, Sang Kook; Krische, Michael J (2013) Total synthesis of 6-deoxyerythronolide B via C-C bond-forming transfer hydrogenation. J Am Chem Soc 135:4223-6
Del Valle, David J; Krische, Michael J (2013) Total synthesis of (+)-trienomycins A and F via C-C bond-forming hydrogenation and transfer hydrogenation. J Am Chem Soc 135:10986-9
Waldeck, Andrew R; Krische, Michael J (2013) Total synthesis of cyanolide A in the absence of protecting groups, chiral auxiliaries, or premetalated carbon nucleophiles. Angew Chem Int Ed Engl 52:4470-3
Kumpulainen, Esa T T; Kang, Byungsoo; Krische, Michael J (2011) C(21)-C(40) of tetrafibricin via metal catalysis: beyond stoichiometric chiral reagents, auxiliaries, and premetalated nucleophiles. Org Lett 13:2484-7
Gao, Xin; Han, Hoon; Krische, Michael J (2011) Direct generation of acyclic polypropionate stereopolyads via double diastereo- and enantioselective iridium-catalyzed crotylation of 1,3-diols: beyond stepwise carbonyl addition in polyketide construction. J Am Chem Soc 133:12795-800

Showing the most recent 10 out of 11 publications