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Aldrichimica Acta. Author manuscript; available in PMC 2016 January 01. Published in final edited form as: Aldrichimica Acta. 2015 ; 48(1): 15–.
Catalytic C–C Bond Formation and the Hendricksonian Ideal: Atom- and Redox-Economy, Stereo- and Site-Selectivity Inji Shin, T. Patrick Montgomery, and Michael J. Krische* Department of Chemistry, University of Texas at Austin, Austin, TX 78712, USA
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“The ideal synthesis creates a complex skeleton… in a sequence only of successive construction reactions involving no intermediary refunctionalizations, and leading directly to the structure of the target, not only its skeleton but also its correctly placed functionality.”1 The Hendricksonian view of synthetic efficiency1 tacitly recognizes the importance of merged redox-construction events (“redox-economy”);2 regio-, chemo- (site-), and stereoselectivity;3 protecting-group-free chemical synthesis;4 and the minimization of preactivation: the degree of separation between reagent and feedstock.5 Guided by these principles, it can be posited that stereo- and site-selective methods for the assembly of organic molecules that occur with the addition, acceptorless removal or redistribution of hydrogen are natural endpoints in the advancement of methods for process-relevant chemical synthesis.6,7
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Hydrogenation and hydroformylation represent two of the largest-volume applications of homogeneous metal catalysis. Merging the chemistry of hydrogenation and carbonyl addition, we have developed a broad new family of “C–C bond forming hydrogenations”— processes wherein two or more reactants are hydrogenated to form a single, more complex product in the absence of stoichiometric byproducts (Scheme 1).7a,b,8 Unlike classical carbonyl additions, such transformations bypass the use of premetallated reagents and cryogenic conditions, and are completely atom-efficient.
Author Manuscript
By folding hydrogen into the carbonyl reactant, one can exploit the native reducing ability of alcohols in the related “C–C bond forming transfer hydrogenations.” Here, redox-triggered carbonyl addition is achieved upon hydrogen exchange between alcohols and π-unsaturated reactants to generate transient aldehyde–organometal pairs that combine to form products of alcohol C–H functionalization.7c,d Remarkably, certain chiral iridium catalysts display a pronounced kinetic preference for primary alcohol dehydrogenation, enabling enantio- and site-selective C–C coupling of diols and triols (Scheme 2).9 Such site-selectivity streamlines chemical synthesis, as it precludes protecting group installation and removal, as well as discrete alcohol-to-aldehyde redox manipulations. As illustrated in the total syntheses of diverse polyketide natural products (Figure 1),7c the ability to engage polyfunctional molecules in a site-selective manner has induced a shift in retrosynthetic paradigm and a step-function change in synthetic efficiency. More broadly,
[email protected].
Shin et al.
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the hydrogen-mediated C–C couplings we have developed suggest other processes that traditionally employ premetallated reagents can now be conducted catalytically in the absence of stoichiometric metals.
Acknowledgments Acknowledgment is made to the Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM069445).
References
Author Manuscript
1. Hendrickson JB. J. Am. Chem. Soc. 1975; 97:5784. 2. Burns NZ, Baran PS, Hoffmann RW. Angew. Chem. Int. Ed. 2009; 48:2854. 3. (a) Trost BM. Science. 1983; 219:245. [PubMed: 17798254] (b) Trost BM. Science. 1991; 254:1471. [PubMed: 1962206] 4. (a) Hoffmann RW. Synthesis. 2006:3531.(b) Young IS, Baran PS. Nature Chem. 2009; 1:193. [PubMed: 21378848] (c) Roulland E. Angew. Chem. Int. Ed. 2011; 50:1226. 5. Han SB, Kim IS, Krische MJ. Chem. Commun. 2009:7278. 6. Dunn PJ. Chem. Soc. Rev. 2012; 41:1452. [PubMed: 21562677] 7. (a) Ngai M-Y, Kong J-R, Krische MJ. J. Org. Chem. 2007; 72:1063. [PubMed: 17288361] (b) Hassan A, Krische MJ. Org. Process Res. Dev. 2011; 15:1236. [PubMed: 22125398] (c) DechertSchmitt A-MR, Schmitt DC, Gao X, Itoh T, Krische MJ. Nat. Prod. Rep. 2014; 31:504. [PubMed: 24514754] (d) Ketcham JM, Shin I, Montgomery TP, Krische MJ. Angew. Chem. Int. Ed. 2014; 53:9142. 8. (a) Bee C, Han SB, Hassan A, Iida H, Krische MJ. J. Am. Chem. Soc. 2008; 130:2746. [PubMed: 18266373] (b) Ngai M-Y, Barchuk A, Krische MJ. J. Am. Chem. Soc. 2007; 129:12644. [PubMed: 17914825] 9. (a) Dechert-Schmitt A-MR, Schmitt DC, Krische MJ. Angew. Chem. Int. Ed. 2013; 52:3195.(b) Feng J, Garza VJ, Krische MJ. J. Am. Chem. Soc. 2014; 136:8911. [PubMed: 24915473]
Author Manuscript Author Manuscript Aldrichimica Acta. Author manuscript; available in PMC 2016 January 01.
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Figure 1.
Polyketide Natural Products Prepared via Direct Alcohol C–H Functionalization. (Ref. 7c)
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Shin et al.
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Scheme 1.
Byproduct-Free Carbonyl and Imine Addition via C–C Bond-Forming Hydrogenation. (Ref. 8)
Author Manuscript Author Manuscript Aldrichimica Acta. Author manuscript; available in PMC 2016 January 01.
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Author Manuscript Author Manuscript Scheme 2.
Catalyst-Directed Diastereo- and Site-Selectivity Ir-Catalyzed Alcohol C–H Functionalization. (Ref. 9)
Author Manuscript Author Manuscript Aldrichimica Acta. Author manuscript; available in PMC 2016 January 01.
Aldrichimica Acta. Author manuscript; available in PMC 2016 January 01. Published in final edited form as: Aldrichimica Acta. 2015 ; 48(1): 15–.
Catalytic C–C Bond Formation and the Hendricksonian Ideal: Atom- and Redox-Economy, Stereo- and Site-Selectivity Inji Shin, T. Patrick Montgomery, and Michael J. Krische* Department of Chemistry, University of Texas at Austin, Austin, TX 78712, USA
Author Manuscript
“The ideal synthesis creates a complex skeleton… in a sequence only of successive construction reactions involving no intermediary refunctionalizations, and leading directly to the structure of the target, not only its skeleton but also its correctly placed functionality.”1 The Hendricksonian view of synthetic efficiency1 tacitly recognizes the importance of merged redox-construction events (“redox-economy”);2 regio-, chemo- (site-), and stereoselectivity;3 protecting-group-free chemical synthesis;4 and the minimization of preactivation: the degree of separation between reagent and feedstock.5 Guided by these principles, it can be posited that stereo- and site-selective methods for the assembly of organic molecules that occur with the addition, acceptorless removal or redistribution of hydrogen are natural endpoints in the advancement of methods for process-relevant chemical synthesis.6,7
Author Manuscript
Hydrogenation and hydroformylation represent two of the largest-volume applications of homogeneous metal catalysis. Merging the chemistry of hydrogenation and carbonyl addition, we have developed a broad new family of “C–C bond forming hydrogenations”— processes wherein two or more reactants are hydrogenated to form a single, more complex product in the absence of stoichiometric byproducts (Scheme 1).7a,b,8 Unlike classical carbonyl additions, such transformations bypass the use of premetallated reagents and cryogenic conditions, and are completely atom-efficient.
Author Manuscript
By folding hydrogen into the carbonyl reactant, one can exploit the native reducing ability of alcohols in the related “C–C bond forming transfer hydrogenations.” Here, redox-triggered carbonyl addition is achieved upon hydrogen exchange between alcohols and π-unsaturated reactants to generate transient aldehyde–organometal pairs that combine to form products of alcohol C–H functionalization.7c,d Remarkably, certain chiral iridium catalysts display a pronounced kinetic preference for primary alcohol dehydrogenation, enabling enantio- and site-selective C–C coupling of diols and triols (Scheme 2).9 Such site-selectivity streamlines chemical synthesis, as it precludes protecting group installation and removal, as well as discrete alcohol-to-aldehyde redox manipulations. As illustrated in the total syntheses of diverse polyketide natural products (Figure 1),7c the ability to engage polyfunctional molecules in a site-selective manner has induced a shift in retrosynthetic paradigm and a step-function change in synthetic efficiency. More broadly,
[email protected].
Shin et al.
Page 2
Author Manuscript
the hydrogen-mediated C–C couplings we have developed suggest other processes that traditionally employ premetallated reagents can now be conducted catalytically in the absence of stoichiometric metals.
Acknowledgments Acknowledgment is made to the Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM069445).
References
Author Manuscript
1. Hendrickson JB. J. Am. Chem. Soc. 1975; 97:5784. 2. Burns NZ, Baran PS, Hoffmann RW. Angew. Chem. Int. Ed. 2009; 48:2854. 3. (a) Trost BM. Science. 1983; 219:245. [PubMed: 17798254] (b) Trost BM. Science. 1991; 254:1471. [PubMed: 1962206] 4. (a) Hoffmann RW. Synthesis. 2006:3531.(b) Young IS, Baran PS. Nature Chem. 2009; 1:193. [PubMed: 21378848] (c) Roulland E. Angew. Chem. Int. Ed. 2011; 50:1226. 5. Han SB, Kim IS, Krische MJ. Chem. Commun. 2009:7278. 6. Dunn PJ. Chem. Soc. Rev. 2012; 41:1452. [PubMed: 21562677] 7. (a) Ngai M-Y, Kong J-R, Krische MJ. J. Org. Chem. 2007; 72:1063. [PubMed: 17288361] (b) Hassan A, Krische MJ. Org. Process Res. Dev. 2011; 15:1236. [PubMed: 22125398] (c) DechertSchmitt A-MR, Schmitt DC, Gao X, Itoh T, Krische MJ. Nat. Prod. Rep. 2014; 31:504. [PubMed: 24514754] (d) Ketcham JM, Shin I, Montgomery TP, Krische MJ. Angew. Chem. Int. Ed. 2014; 53:9142. 8. (a) Bee C, Han SB, Hassan A, Iida H, Krische MJ. J. Am. Chem. Soc. 2008; 130:2746. [PubMed: 18266373] (b) Ngai M-Y, Barchuk A, Krische MJ. J. Am. Chem. Soc. 2007; 129:12644. [PubMed: 17914825] 9. (a) Dechert-Schmitt A-MR, Schmitt DC, Krische MJ. Angew. Chem. Int. Ed. 2013; 52:3195.(b) Feng J, Garza VJ, Krische MJ. J. Am. Chem. Soc. 2014; 136:8911. [PubMed: 24915473]
Author Manuscript Author Manuscript Aldrichimica Acta. Author manuscript; available in PMC 2016 January 01.
Shin et al.
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Figure 1.
Polyketide Natural Products Prepared via Direct Alcohol C–H Functionalization. (Ref. 7c)
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Shin et al.
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Scheme 1.
Byproduct-Free Carbonyl and Imine Addition via C–C Bond-Forming Hydrogenation. (Ref. 8)
Author Manuscript Author Manuscript Aldrichimica Acta. Author manuscript; available in PMC 2016 January 01.
Shin et al.
Page 5
Author Manuscript Author Manuscript Scheme 2.
Catalyst-Directed Diastereo- and Site-Selectivity Ir-Catalyzed Alcohol C–H Functionalization. (Ref. 9)
Author Manuscript Author Manuscript Aldrichimica Acta. Author manuscript; available in PMC 2016 January 01.
