Note pubs.acs.org/joc
Organocatalytic Asymmetric Michael-Hemiacetalization Reaction Between 2‑Hydroxyacetophenones and Enals: A Route to Chiral β,γDisubstituted γ‑Butyrolactones Megha Balha, Buddhadeb Mondal, Subas Chandra Sahoo, and Subhas Chandra Pan* Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam 781039, India S Supporting Information *
ABSTRACT: The first highly enantioselective organocatalytic reaction employing 2-hydroxyacetophenones is disclosed, namely Michael-hemiacetalization reaction of 2-hydroxyacetophenones with enals. The combination of a primary amine and a secondary amine catalyst was found to be the best choice for this methodology. The products of this reaction were obtained in high enantioand diastereoselectivities and were converted to a variety of biologically important γ-butyrolactones.
C
onjunctive bivalent 1,2- and 1,3-reagents1 have played a pivotal role in asymmetric organocatalysis due to their potential to form multiple C−C and C−X bonds.2 Though aromatic hydroxy ketones (i.e., 2-hydroxyacetophenones) have been previously used in asymmetric metal catalyzed aldol and Michael reactions by Trost and Shibasaki,3 it was found to be difficult to employ in organocatalysis by secondary amine catalysts.4 Mlynarski et al. recently developed an asymmetric aldol reaction of 2-hydroxyacetopheones with tertiary amine catalysts, and moderate enantioselectivities were obtained.5 During the progress of our work, Chang and co-workers exploited the bivalent nature of 2-hydroxyacetophenone by developing dinuclear zinc catalyzed domino Michael-hemiketalization reaction with α,β-unsaturated-α-ketoesters (Scheme 1).6 Though a variety of reports on organocatalytic Michael-hemiacetalization/ketalization7 reactions has been revealed in recent years, synthesis of five membered lactols/ lactones has hardly been documented.8 Given the bivalent character of 2-hydroxyacetophenone, we envisioned whether it can be activated by primary amine catalysis and applied in organocatalytic Michael-hemiacetalization reaction (Scheme 1). The nonracemic γ-butyrolactone motif is found to be present in a variety of biologically significant natural products, including antibiotic and antitumor agents.9 Further, it serves as an important building block in synthetic organic chemistry.10 Thus, a large number of research groups are engaged in the chiral synthesis of these compounds.11,12 Despite many methods, synthesis of chiral β,γ-disubstituted γ-butyrolactone is limited11b,c and, to the best of our knowledge, no direct asymmetric approach by organocatalysis is known.13 Herein, we report highly asymmetric synthesis of β,γ-disubstituted γbutyrolactones from a Michael-hemiacetlization reaction between 2-hydroxyacetophenones and α,β-unsaturated alde© 2017 American Chemical Society
Scheme 1. 2-Hydroxyacetophenone in Asymmetric Michael Reactions and Multi-Organocatalysis Employing Primary and Secondary Amines
hydes followed by pyridinium chlorochromate (PCC) oxidation. The initial experiment involved performing the reaction between 2-hydroxyacetophenone (1a) and cinnamaldehyde Received: February 15, 2017 Published: May 19, 2017 6409
DOI: 10.1021/acs.joc.7b00363 J. Org. Chem. 2017, 82, 6409−6416
Note
The Journal of Organic Chemistry
also achieved by employing catalyst combination of I and ethylene diamine (VIII); however, poor yield was observed (entry 11). We further screened monamide (±)-IX with I, and the major product 3a was obtained in 60% yield and 90% ee with 2:1 diastereomeric ratio (entry 12). Having established the optimized condition, the substrate scope of the Michael-hemiacetalization reaction was investigated. Initially, different aryl substituted unsaturated aldehydes were studied (Table 2). Though enantioselectivity of 3a was
(2a) with Jørgensen−Hayashi catalyst I, which has been used previously for a variety of conjugate addition reactions (Table 1, entry 1).14 However, with benzoic acid as cocatalyst, only Table 1. Catalyst Optimization
Table 2. Scope of α,β-Unsaturated Aldehydes
entrya
catalyst
additive
yield (%)b
dr
eec
1 2 3 4 5 6 7 8 9 10 11 12
I II III IV V VI VII I + IV I + VII I + (±)-VII I + VIII I + (±)-IX
PhCO2H none PhCO2H PhCO2H none none PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H
