Stereospecific Rhodium-Catalyzed Allylic Substitution with Alkenyl Cyanohydrin Pronucleophiles: Construction of Acyclic Quaternary Substituted α,β-Unsaturated Ketones

Abstract

A highly regio- and stereospecific rhodium-catalyzed allylic alkylation of tertiary allylic carbonates with alkenyl cyanohydrin pronucleophiles is described. This protocol offers a fundamentally novel approach toward the synthesis of acyclic quaternary-substituted α,β-unsaturated ketones and thereby provides a new cross-coupling strategy for target directed synthesis. A particularly attractive feature with this process is the ability to directly couple di-, tri- and tetrasubstituted alkenyl cyanohydrin pronucleophiles to prepare the corresponding α,β-unsaturated ketone derivatives in a highly selective manner. Additionally, the chemoselective 1,4-reduction of the enone products provides rapid access to acyclic enantiomerically enriched α,α'-dialkyl-substituted ketones, which are challenging motifs to prepare using conventional enolate alkylation.

Regio- and stereospecific rhodium-catalyzed allylic alkylation with an acyl anion equivalent: an approach to acyclic α-ternary β,γ-unsaturated aryl ketones

“…In accord with our previous studies using enantiomerically enriched tertiary carbonates, 12 the electron-poor tris(2,2,2-trifluoroethyl)-phosphite ligand proved optimal, furnishing the acyclic ketone ( R )- 3d with excellent regiocontrol ( b / l ≥19 : 1) and conservation of enantiomeric excess (95% cee ) on gram scale (Scheme 2A). 18 Stereoselective reduction of the resulting aryl ketone ( R )- 3d with the Corey–Bakshi–Shibata reagent 19 afforded the secondary alcohol 7 with excellent diastereocontrol, which was subsequently protected as the benzyl ether 8a and methyl ether 8b under standard reaction conditions to provide the intermediates required to functionalize the dimethylamino group and establish the absolute configuration in the allylic alkylation.…”

“…12 For instance, tert -butyldimethylsilyl-protected cyanohydrins derived from the corresponding aryl and alkenyl aldehydes, 13 function as acyl anion equivalents that can be unmasked in situ to afford the requisite ketone. Hence, we envisioned that the application of this strategy to acyclic chiral nonracemic secondary allylic carbonates should provide a direct one-pot approach to enantiomerically enriched α-ternary ketones, provided the isomerization of the olefin could be suppressed.…”

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

“…For instance, heteroatom‐stabilized allylic anions constitute useful homoenolate synthons for the construction of β‐substituted carbonyl compounds . Nevertheless, the utility of these masked homoenolate equivalents is complicated by their ambident nature, which often leads to the formation of regioisomeric products (Scheme A) . Notwithstanding this limitation, the asymmetric functionalization of allylic amines, carbamates and α‐amino nitriles has been described, albeit these approaches employ either a chiral auxiliary or require a stoichiometric chiral base to promote the formation of a chiral nonracemic lithium carbanion (Scheme B) .…”

Intramolecular vinylation of carbanions using N-acyl benzomorpholines as masked vinylureas and vinylcarbamates

“…Spectroscopic data for 33 match those reported in the literature. [38] (±)-3-(2-Hydroxyphenyl)-1,5-dimethyl-5-vinylimidazolid-ine-2,4-dione (35); In a dried Schlenk flask under a N2 atmosphere, urea 34 (600 mg, 2.45 mmol, 1.0 eq.) was dissolved in anhydrous THF (25 mL, 0.1 M) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (2.4 mL, 19.57 mmol, 8.0 eq.)…”