Theoretical Study of Diastereoselective NHC-Catalyzed Cross-Benzoin Reactions between Furfural and N‑Boc-Protected α‑Amino Aldehydes

• Published in: Journal of organic chemistry Vol. 84; no. 21; pp. 13565 - 13571
• Main Authors: Duan, Abing, Fell, Jason S, Yu, Peiyuan, Lam, Colin Yu-hong, Gravel, Michel, Houk, K. N
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.11.2019
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.9b01821

The mechanism and origins of syn and anti selectivity of cross-benzoin reactions between furfural and α-amino aldehydes, catalyzed by a triazolium-based NHC, were investigated using density functional theory calculations. N-Boc-α-amino aldehydes were found to react with anti selectivity, while N-Bn-N-Boc-α-amino aldehydes react with syn selectivity. We find that the anti product is more thermodynamically favored than the syn product for reactions with N-Boc-α-amino aldehydes, and that the formation of the syn product for reactions involving N-Bn-N-Boc-α-amino aldehydes is kinetically favored. The switch in selectivity is a result of an intramolecular hydrogen bond in the N-Boc-α-amino aldehyde, whereas switching to N-Bn-N-Boc-α-amine removes the hydrogen bond. The steric and electronic interactions in the transition state are rationalized by a Felkin–Anh model.