Internal Lewis Acid Coordination as a Powerful Tool To Promote Highly Stereoselective Alkylation ofα-Alkyl-β-Hydroxy Ketones with Grignard Reagents

Abstract

An efficient and highly diastereoselective protocol is described for the alkylation of b-hydroxy ketones that contain an a-stereocenter. This method is based on the preliminary transformation of the b-hydroxy group into a titanium alcoholate by means of the facile transmetalation of the corresponding b-silyloxy derivative with TiCl 4 (Method A) or by reaction of the lithium alcoholate with TiCl 4 (Method B).On account of the strong internal coordinating action of the Lewis acid, this intermediate assumes a rigid half-chair conformation with the a-alkyl substituent in a pseudoaxial position. This geometrical arrangement facilitates the attack of the entering carbanion on the carbonylic function opposite to the asubstituent. The method uses simple Grignard reagents as the alkylating agents and allows the addition of a wide variety of carbon frameworks to the carbonyl function, including primary and secondary alkyl chains, arylic, alkynylic, vinylic, and benzylic moieties, with high efficiency and stereoselectivity.

The Role of theα-Stereogenic Center in the Control of Stereoselection in the Reduction ofα-Alkyl-β-hydroxy Ketones: A Highly Diastereoselective Protocol for the Synthesis of 1,2-syn-2-Alkyl-1,3-diols

“…In addition, we found that the reaction carried out with BH 3´T HF alone does not work at low temperature. Finally, the stereochemical picture shown in the reduction is quite similar to that observed for the alkylation process, [7] in which experimental evidence proved that the attack of the carbanion on the carbonyl group occurs before any interaction with titanium.…”

“…[7] In particular, a solution of the hydride ion source in THF was added at À 78 8C to a b-hydroxy ketone titanium alcoholate prepared in THF by transmetallation of the corresponding lithium alcoholate with TiCl 4 . When the reduction was complete, the mixture was quenched with dilute HCl (1m).…”

Copper‐Catalyzed Borylacylation of Activated Alkenes with Acid Chlorides

“…After oxidation of the Bpin unit of 9 to an alcohol, highly diastereoselective addition of a methyl Grignard generated 46 . [24] Likewise, diastereoselective reduction of the oxidized product derived from 43 provided 47 , which could also be cyclized under copper catalysis to provide chromane derivative 48 . [25] …”

Copper‐Catalyzed Borylacylation of Activated Alkenes with Acid Chlorides

“…Owing to the ring strain of bicyclic alkene 37 , ring‐opening cross‐metathesis with ethylene allowed for the formation of 45 . After oxidation of the Bpin unit of 9 to an alcohol, highly diastereoselective addition of a methyl Grignard generated 46 . Likewise, diastereoselective reduction of the oxidized product derived from 43 provided 47 , which could also be cyclized under copper catalysis to provide chromane derivative 48…”