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Enantioselective Synthesis of Functionalized β‑Lactones by NHCCatalyzed Aldol Lactonization of Ketoacids Santigopal Mondal,†,§ Subrata Mukherjee,†,§ Tamal Kanti Das,†,§ Rajesh G. Gonnade,‡ and Akkattu T. Biju*,†,§,⊥ †
Organic Chemistry Division and ‡Centre for Materials Characterization, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411008, India § Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India S Supporting Information *
ABSTRACT: N-Heterocyclic carbene (NHC)-catalyzed intramolecular aldol lactonization of readily available ketoacids leading to the enantioselective synthesis of cyclopentane-fused β-lactones is presented. The reaction proceeds via the generation of NHC-bound enolate intermediates formed from the ketoacids in the presence of the peptide coupling reagent HATU and NHC generated from the chiral triazolium salt. The functionalized β-lactones are formed under mild conditions in high yields and enantioselectivities. β-Lactone derivatives (2-oxetanones) are endowed with interesting biological properties, and this moiety is frequently found in numerous pharmaceutically important molecules.1 This class of compounds exhibit selective reactivity toward the active sites of several enzymes, and hence they are important in activity-based proteome profiling.2 Among this family of compounds, the β-lactones fused to a five-membered ring are important structural elements found in various natural products. For example, the marine natural product spongiolactone (A) shows antiproliferative activity toward the leukemia (K562) cell line (Figure 1).3 Moreover, vibralactone (B) is a
straightforward method for the synthesis of β-lactone derivatives. Pioneered by the Romo group, the NCAL strategy has been applied to the synthesis of a wide variety of bicyclic βlactones with high stereoselectivity (Scheme 1, eq 1).8 The Scheme 1. NCAL of Ketoacids for the Synthesis of Bicyclic Lactones
Figure 1. Selected biologically important β-lactone-fused to fivemembered rings.
enantioselective version of NCAL proceeds with Birman’s homobenzotetramisole derivative9 or cinchona alkaloids as the organocatalyst along with the coupling reagent. 10 We envisioned that a chiral N-heterocyclic carbenes (NHCs) could be an organocatalyst for the aldol lactonization of ketoacids for the enantioselective synthesis of bicyclic βlactones.11 Although NHCs are widely utilized as organocatalysts for various transformations starting from aldehydes, the activation of carboxylic acids using NHCs has received less
pancreatic lipid inhibitor having a β-lactone fused to a cyclopentene ring,4 and salinosporamide A (C) is a potent proteasome inhibitor where the β-lactone moiety is fused to a γ- butyrolactam functionality.5 Given the importance of functionalized β-lactones in natural product synthesis and as a versatile building block in organic synthesis, development of mild, catalytic, and enantioselective routes to these target molecules are of high importance. Among other methods,6,7 the nucleophile-catalyzed aldol lactonization (NCAL) of ketoacids is considered to be a © 2017 American Chemical Society
Received: June 20, 2017 Published: August 4, 2017 9223
DOI: 10.1021/acs.joc.7b01526 J. Org. Chem. 2017, 82, 9223−9228
Note
The Journal of Organic Chemistry attention,12 and the NHC-catalyzed aldol lactonization of ketoacids is rare.13 It may be noted in this context that NHCcatalyzed routes for the synthesis of cyclopentane-fused βlactones were uncovered by the groups of Bode,14 Scheidt,15 Lupton,16 Studer,17 and us.18 Herein, we report the NHCcatalyzed aldol lactonization of ketoacids for the enantioselective synthesis of cyclopentane-fused β-lactones (eq 2).19 The reaction proceeds under mild conditions, and the products are formed in high yields and enantioselectivities. Inspired by the synthetic potential of functionalized βlactones in organic synthesis, the present study was initiated by treating the ketoacid 1a with the carbene generated from the chiral triazolium salt 320 using Cs2CO3 as base in the presence of the peptide coupling reagent 2-(7-aza-1H-benzotriazole-1yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU). To our delight, under these conditions, the cyclopentane-fused β-lactone 2a was formed in 85% yield and 98% ee (Table 1,
After optimizing the reaction conditions for the NHCcatalyzed aldol lactonization reaction, we studied the scope and limitation of this annulation reaction (Scheme 2). A series of Scheme 2. Substrate Scope of the NHC-Catalyzed Aldol Lactonization Reactiona
Table 1. Optimization of the Reaction Conditionsa
a
entry
variation of the standard conditions
1 2 3 4 5 6 7 8 9 10 11 12 13 14
none no HATU no 3 HBTU instead of HATU CDI instead of HATU Piv-Cl instead of HATU Na2CO3 instead of Cs2CO3 Et3N instead of Cs2CO3 DBU instead of Cs2CO3 KOt-Bu instead of Cs2CO3 CH2Cl2 instead of THF toluene instead of THF DME instead of THF reaction time 24 h instead of 12 h
a
yield of 2a (%) 85
