Chemical Synthesis

Gleason Chiral Auxiliary

The stereocontrolled synthesis of all-carbon quaternary centers is a formidable challenge in asymmetric synthesis. Alkylation of an enolate is a fundamental reaction which may be used towards this task. While progress has been made using catalytic asymmetric methods in allylation and arylation, the majority of direct alkylation methods continue to require the use of chiral auxiliaries. Professor James Gleason of McGill University has developed an elegant method of preparing quaternary carbons using a chiral thioglycolate lactam auxiliary.1 The lactam can be alkylated three times; twice using basic enolization and once using reductive enolization, to give alpha quaternary carboxylic acid derivatives (Scheme 1). Each alkylation step occurs in excellent yield and with a high degree of diastereoselectivity. Cleavage of the auxiliary via acidic or reductive conditions furnishes the corresponding carboxylic acid or primary alcohol, respectively.

Scheme 1

Furthermore, from a single chiral auxiliary, access to both antipodes can be achieved simply by altering the order of enolate alkylation. For instance, both enantiomers of 2-ethyl-2-methylpentanoic acid were synthesized in good overall yield and in excellent optical purity (Scheme 2). Importantly, this example illustrates that the third reductive alkylation step proceeds diastereoselectively for both (Z)- or (E)-disubstituted enolates. Gleason and co-workers have demonstrated that synthetically useful groups such as: allyl, functionalized alkyl, and benzyl groups can be introduced at the quaternary center while maintaining good yields and stereocontrol (Figure 1). Sigma-Aldrich is pleased to offer this versatile auxiliary for your research purposes.

Scheme 2

Figure 1

Product Information

Prod. No.  Product Name Product Structure Add to Cart
667587 (7R,10S)-(+)-1-Aza-10-isopropyl-8-oxa-4-thiabicyclo(5,3,0)-2-decanone, 97%


  1. Arpin, A.; Manthorpe, J. M.; Gleason, J. L. Org. Lett. 2006, 8, 1359.