Origin of Stereocontrol in Guanidine-Bisurea Bifunctional Organocatalyst That Promotes α-Hydroxylation of Tetralone-Derived β-Ketoesters: Asymmetric Synthesis of β- and γ-Substituted Tetralone Derivatives via Organocatalytic Oxidative Kinetic Resolution

Abstract

The mechanism of asymmetric α-hydroxylation of tetralone-derived β-ketoesters with guanidine-bisurea bifunctional organocatalyst in the presence of cumene hydroperoxide (CHP) was examined by means of DFT calculations to understand the origin of the stereocontrol in the reaction. The identified transition-state model was utilized to design an enantioselective synthesis of β- or γ-substituted tetralones by catalytic oxidative kinetic resolution reaction of tetralone-derived β-ketoesters. This kinetic resolution reaction proceeded with high selectivity, and selectivity factors (s value) of up to 99 were obtained. The potential utility of this oxidative kinetic resolution method for synthesis of natural products was confirmed by applying it to achieve an enantioselective synthesis of (+)-linoxepin (13) from β-substituted tetralone rac-7 in only six steps.

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…The biological relevance of chiralalcohols hasdriven the development of many methods for their kinetic resolution (KR), which have been subjected to numerous experimental and theoretical studies. [1][2][3][4][5][6][7][8][9][10][11][12][13] Amonga vailables trategies for the KR of alcohols, chiral 4-dimethylaminopyridine (DMAP) catalyzed KRs are particularly appealingd ue to their operational simplicity,h igh turnover,a nd environmental friendliness. [14][15][16][17][18][19] Studying such reactions computationally not only enriches our understanding of thesep rocesses but also creates opportunities to improvetheir efficiency.…”

Total Synthesis of Rishirilide B by Organocatalytic Oxidative Kinetic Resolution: Revision of Absolute Configuration of (+)‐Rishirilide B

“…Construction of the oxabenzonorbornadiene moiety corresponding to the Cring could be achieved by aD iels-Alder reaction of the AB ring with furan. Under the previously developed reaction conditions, [10] kinetic resolution took place smoothly,a nd (À)-13 was obtained in 48 %yield with 90 % ee,together with (+ +)-14 in 50 %y ield with 86 % ee (s = 53). Asymmetric synthesis of (À)-13 was planned by organocatalytic oxidative kinetic resolution of the b-keto ester rac-14.…”

“…Although these approaches are efficient, construction of the consecutive stereogenic centers in the Aring is still achallenge.W erecently developed an oxidative kinetic resolution reaction to obtain chiral b-substituted 1tetralones, [10,11] and we planned to use this in an alternative strategy for the synthesis of (2R,3R,4R)-2 as depicted in Scheme 2. Although these approaches are efficient, construction of the consecutive stereogenic centers in the Aring is still achallenge.W erecently developed an oxidative kinetic resolution reaction to obtain chiral b-substituted 1tetralones, [10,11] and we planned to use this in an alternative strategy for the synthesis of (2R,3R,4R)-2 as depicted in Scheme 2.…”

“…Although these approaches are efficient, construction of the consecutive stereogenic centers in the Aring is still achallenge.W erecently developed an oxidative kinetic resolution reaction to obtain chiral b-substituted 1tetralones, [10,11] and we planned to use this in an alternative strategy for the synthesis of (2R,3R,4R)-2 as depicted in Scheme 2. [10] Our synthesis commenced with an asymmetric synthesis of (À)-13 from rac-14,w hich was synthesized from commercially available 4-hydroxybenzaldehydei nt en steps (Scheme 3). Construction of the oxabenzonorbornadiene moiety corresponding to the Cring could be achieved by aD iels-Alder reaction of the AB ring with furan.…”

“…Both groups used similar strategies for constructing the Bring in 2 by connecting ahighly functionalized Aring to the Cring (Scheme 1). Although these approaches are efficient, construction of the consecutive stereogenic centers in the Aring is still achallenge.W erecently developed an oxidative kinetic resolution reaction to obtain chiral b-substituted 1tetralones, [10,11] and we planned to use this in an alternative strategy for the synthesis of (2R,3R,4R)-2 as depicted in Scheme 2. We envisioned that (2R,3R,4R)-2 could be synthesized from the oxabenzonorbornadiene 11 by regioselective isomerization.…”