Enantioselective Iridium-Catalyzed Carbonyl Allylation from the Alcohol or Aldehyde Oxidation Level via Transfer Hydrogenative Coupling of Allyl Acetate: Departure from Chirally Modified Allyl Metal Reagents in Carbonyl Addition

Abstract

Under the conditions of transfer hydrogenation employing an iridium catalyst generated in situ from [Ir(cod)Cl] 2 , the chiral phosphine ligands (R)-BINAP or (R)-Cl,MeO-BIPHEP and m-nitrobenzoic acid, allyl acetate couples to allylic alcohols 1a-1c, aliphatic alcohols 1d-1l and benzylic alcohols 1m-1u to furnish products of carbonyl allylation 3a-3u with exceptional levels of asymmetric induction. The very same set of optically enriched carbonyl allylation products 3a-3u are accessible from enals 2a-2c, aliphatic aldehydes 2d-2l and aryl aldehydes 2m-2u, using iridium catalysts ligated by (-)-TMBTP or (R)-Cl,MeO-BIPHEP under identical conditions, but employing isopropanol as a hydrogen donor. As corroborated by single crystal X-ray diffraction, the active catalyst is the cyclometallated complex V, which arises upon ortho-C-H insertion of iridium onto m-nitrobenzoic acid. The results of isotopic labeling are consistent with intervention of symmetric iridium π-allylationl intermediates or rapid interconversion of σ-allyl haptomers through the agency of a symmetric π-allyl. Competition experiments demonstrate rapid and reversible hydrogenationdehydrogenation of the carbonyl partner in advance of C-C coupling. The coupling products, which are homoallylic alcohols, experience very little erosion of optical purity by way of redox equilibration under the coupling conditions, although isopropanol, a secondary alcohol, may serve as terminal reductant. A plausible catalytic mechanism accounting for these observations is proposed, along with a stereochemical model that accounts for the observed sense of absolute stereoinduction. This protocol for asymmetric carbonyl allylation transcends the barriers imposed by oxidation level and the use of preformed allyl-metal reagents.

Asymmetric Iridium-Catalyzed C–C Coupling of Chiral Diols via Site-Selective Redox-Triggered Carbonyl Addition

“…The resulting iridium alkoxide suffers β-hydride elimination to furnish an aldehyde and an iridium hydride. Competition experiments demonstrate rapid and reversible β-hydride elimination, that is, alcohol hydrogenation-dehydrogenation, in advance of carbonyl addition [50]. Deprotonation of the iridium hydride provides an anionic iridium(I) intermediate, which undergoes oxidative addition with allyl acetate to regenerate the starting π-allyliridium C,O -benzoate complex.…”

“…These processes are redox-efficient as they merge alcohol oxidation and C-C bond construction events, bypassing discrete alcohol-to-aldehyde redox reactions, as well as manipulations required for the stoichiometric formation of premetalated reagents. One of the most useful processes based on this pattern of reactivity is the enantioselective iridium catalyzed coupling of primary alcohols with allyl acetate to form secondary homoallylic alcohols (Scheme 1) [49, 50, 51, 52, 53]. Such primary alcohol C -allylations have been applied to the syntheses of diverse polyketide natural products, resulting in the most concise routes reported, to date [54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64].…”

Ti/Pd Bimetallic Systems for the Efficient Allylation of Carbonyl Compounds and Homocoupling Reactions

“…This has led to new procedures based on the use of allylic carboxylates. [3][4][5][6][7][8] However, allylic carboxylates are not substrates for the valuable Nozaki-Hiyama-Kishi (NHK) reaction. [9] Furthermore, most of these procedures are limited to aldehyde electrophiles and are unsuccessful with ketones due to the poor nucleophilicity of the allylmetals generated in situ.…”

Biotransformation of bicyclic terpenoid ketones towards compounds with olfactory properties

“…The first is chemical synthesis, which, in the most cases, is very difficult, multistep, and requires toxic reagents. [3] The second involves application of biological catalysts (enzymes or microorganisms), which work under mild, environmentally friendly conditions. [4] Biocatalysis is a useful method to obtain optically active compounds from different types of ketones.…”