A Practical Chiral Bicyclic Thioglycolate Lactam Auxiliary for Stereoselective Quaternary Carbon Formation

Abstract

[reaction: see text] Chiral bicyclic thioglycolate lactams may be prepared in three steps from inexpensive commercial materials. The resulting lactams may be alkylated three times, twice using basic enolization and once using reductive enolization, to form alpha-quaternary carboxylic acid derivatives in high yield and with high diastereoselectivity. The alkylation products may be cleaved under either acidic or reductive conditions to furnish either carboxylic acids or primary alcohols, respectively.

Stereodefined acyclic trisubstituted metal enolates towards the asymmetric formation of quaternary carbon stereocentres

“…52 These shortcomings were addressed in the following work reported by Gleason and coworkers where an improved second-generation of bicyclic lactam could be prepared on a large scale using a concise strategy that does not involve chromatographic purification of the intermediate precursors. 55 This more practical chiral thioglycolate lactam was then employed in the alkylative construction of quaternary stereocentres and in the asymmetric Mannich reactions (Scheme 23). 55,56 Scheme 18 Diastereoselective aldol addition reaction of trisubstituted acyclic (Z)-enolates derived from trisubstituted BHT-ester lithium enolates.…”

“…55 This more practical chiral thioglycolate lactam was then employed in the alkylative construction of quaternary stereocentres and in the asymmetric Mannich reactions (Scheme 23). 55,56 Scheme 18 Diastereoselective aldol addition reaction of trisubstituted acyclic (Z)-enolates derived from trisubstituted BHT-ester lithium enolates.…”

Metalated Nitriles: Internal 1,2‐Asymmetric Induction

“…Chiral lactams and lactones3 obviate selective ( E )‐ or ( Z ) ‐ enolate formation by employing small rings; they use strategically oriented substituents to impart topological differences to direct selective electrophilic attack on one face of the enolate. Asymmetric alkylations of acyclic α, α‐disubstituted enolates are more challenging because of the difficulty in selectively generating one ( E )‐ or ( Z )‐enolate and restricting conformational mobility for facial discrimination during alkylation 4…”

Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems

“…This new starting bicyclic lactam could be prepared on a large scale without chromatographic purification of the intermediates and the final adduct could be isolated directly as a crystalline solid. 66 The incorporation of the first two alkyl groups of the quaternary center could easily be achieved by sequential alkylation using LDA and alkyl halide in the presence of LiCl. Both alkylation steps proceeded in high yield and with excellent stereoselectivity.…”