Enantioselective Catalytic Aldehyde α‐Alkylation/Semipinacol Rearrangement: Construction of α‐Quaternary‐δ‐Carbonyl Cycloketones and Total Synthesis of (+)‐Cerapicol

Abstract

An enantioselective aldehyde α‐alkylation/semipinacol rearrangement was achieved through organo‐SOMO catalysis. The catalytically generated enamine radical cation serves as a carbon radical electrophile that can stereoselectively add to the alkene of an allylic alcohol and initiate ensuing ring‐expansion of cyclopropanol or cyclobutanol. This tandem reaction enables the production of a wide range of nonracemic functionalizable α‐quaternary‐δ‐carbonyl cycloketones in high yields and excellent enantioselectivity from simple aldehydes and allylic alcohols. As a key step, the intramolecular reaction was also successfully applied in the asymmetric total synthesis of (+)‐cerapicol.

Recent development and applications of semipinacol rearrangement reactions

“…Recently, Zhang and Tu developed an enantioselective aldehyde α-alkylation/semipinacol rearrangement taking advantage of organo-SOMO catalysis. 61 As depicted in Scheme 14 , oxidation of the enamine generated from aldehyde 65 and secondary amine catalyst cat. 9 (ref.…”

Enantioselective Organocatalytic Syntheses and Ring‐Expansions of Cyclobutane Derivatives

“…[37] In this case, strained allylic cyclobutanols were appropriate SOMO-nucleophiles affording a new carbocation intermediate amenable to the rearrangement (Scheme 18). [38] According to this strategy, a large panel of 1,5-dicarbonyl compounds bearing a quaternary stereogenic carbon atom have been obtained with satisfactory results in terms of yield and stereoselectivity. Some intramolecular versions of this reaction afforded the corresponding bicyclic products, which are valuable synthetic platforms as illustrated with an elegant enantioselective total synthesis of (+)-cerapicol.…”

Enantioselective Catalytic Aldehyde α‐Alkylation/Semipinacol Rearrangement: Construction of α‐Quaternary‐δ‐Carbonyl Cycloketones and Total Synthesis of (+)‐Cerapicol

“…After unmasking the aldehyde functionality, the devised epimerization/aldol process was realized by treatment of the crude product with NaOMe in MeOH, affording tricyclic compound 12 as a major diastereoisomer with excellent diastereoselectivity (dr > 20:1), the relative configuration of which was unambiguously confirmed by the X-ray crystal structure of its methanesulfonate derivative 14. [20] The excellent stereocontrol of this reaction can be rationalized by conformational analysis of the cyclization event. As shown in Scheme 5, in the presence of a base, equilibration of enol A and B occurs.…”

“…The absolute and relative configuration of 3 a was also unambiguously assigned by Xray analysis of its homologated p-toluenesulfonylhydrazone derivative (see the Supporting Information). [14] Having established the optimal conditions, the substrate scope was then explored. As shown in Table 2, a broad range of aldehydes 2 were found to be viable substrates.…”

“…The absolute and relative configurations of these cyclic products were assigned by X-ray analysis of a single crystal of the ptoluenesulfonylhydrazone derivative 6 b. [15] The establishment of such a tandem reaction enables us to assemble the enantioenriched a-quaternary cyclopentanones with a functionalizable scaffold that could be further elaborated and used in natural product synthesis (Scheme 3). An application of this method was demonstrated through a catalytic enantioselective total synthesis of (+)-cerapicol, a fungal metabolite with a tricyclic sesquiterpene skeleton.…”