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. 2017 Nov 10;359(21):3713-3719.
doi: 10.1002/adsc.201701015. Epub 2017 Aug 14.

A Cooperative Ternary Catalysis System for Asymmetric Lactonizations of α-Ketoesters

Kathleen J R Murauski  1 , Daniel M Walden  2 , Paul Ha-Yeon Cheong  2 , Karl A Scheidt  1
Affiliations

A Cooperative Ternary Catalysis System for Asymmetric Lactonizations of α-Ketoesters

Kathleen J R Murauski et al. Adv Synth Catal. .

Abstract

A general and enantioselective N-heterocyclic carbene (NHC)-catalyzed lactonization of simple enals and α-ketoesters has been discovered using a new ternary cooperative catalytic system. The highly selective annulation was achieved by using a combination of a chiral NHC, a hydrogen-bond donor, and a metal salt, facilitating self-assembly of the reactive partners. A proposed model for this new mode of NHC chiral relay catalysis is supported by experimental and computational mechanistic studies.

Keywords: N-heterocyclic carbene; NHC; Umpolung; cooperative catalysis; homoenolate; lactone; ternary catalysis.

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Figures

Figure 1
Figure 1
NHC-catalyzed lactonizations.
Figure 2
Figure 2. NMR Studies of the Lactonization
(A) 1H NMR spectra (CDCl3) of solutions of (1) catalyst D, (2) α-ketoester 2c, (3) 2c + D + Ca(OMe)2, (4) enal 1l, and (5) 1l + D + Ca(OMe)2. (B) NOESY 1D spectra of solutions of (2) α-ketoester 2c + D and (3) 2c + D + Ca(OMe)2.
Figure 3
Figure 3
(A) Mechanistic studies through modifications of the HBD catalyst. (B) Computed stereodetermining TSs with catalyst B, HBD D, and Ca(OMe)2 (Table 1, Entry 9). adr was determined by unpurified 1H NMR spectroscopy, and %ee was determined by HPLC analysis. NHC catalyst highlighted in green. Light green lines indicate electrostatic interactions and dashed lines show coordination to the Ca2+ ion. Distances are in Å and energies (ΔΔG‡) in kcal/mol.
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