Understanding divergent substrate stereoselectivity in the isothiourea-catalysed conjugate addition of cyclic α-substituted ß-ketoesters to α,ß-unsaturated aryl esters.
Chem Sci
; 14(48): 14146-14156, 2023 Dec 13.
Article
in En
| MEDLINE
| ID: mdl-38098722
ABSTRACT
The development of enantioselective synthetic methods capable of generating vicinal stereogenic centres, where one is tetrasubstituted (such as either an all-carbon quaternary centre or where one or more substituents are heteroatoms), is a recognised synthetic challenge. Herein, the enantioselective conjugate addition of a range of carbo- and heterocyclic α-substituted ß-ketoesters to α,ß-unsaturated aryl esters using the isothiourea HyperBTM as a Lewis base catalyst is demonstrated. Notably, divergent diastereoselectivity is observed through the use of either cyclopentanone-derived or indanone-derived substituted ß-ketoesters with both generating the desired stereodefined products with high selectivity (>95 5 dr, up to 99 1 er). The scope and limitations of these processes are demonstrated, alongside application on gram scale. The origin of the divergent substrate selectivity has been probed through the use of DFT-analysis, with preferential orientation driven by dual stabilising CHâ¯O interactions. The importance of solvation with strongly polar transition-states is highlighted and the SMD solvation model is demonstrated to capture solvation effects reliably.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Chem Sci
Year:
2023
Document type:
Article
Country of publication:
United kingdom