Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 136, Issue 5, Pages 1960-1967Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja4109616
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Funding
- National Science Foundation of China [21133002, 2123201, 21302006]
- MOST of China [2013CB911501]
- Shenzhen Peacock Program [KQTD201103]
- U.S. National Science Foundation [NSF CHE 1058075]
- Swedish Research Council [2010-4856]
- National Institutes of Health [NIGMS RO1 GM063540]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1058075] Funding Source: National Science Foundation
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The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of beta-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict Delta Delta G(double dagger) of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C-O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.
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