An Enantioselective Ketene−Imine Cycloaddition Method for Synthesis of Substituted Ring-Fused 2-Pyridinones

Abstract

Previously, a method for the stereoselective synthesis of beta-lactams, starting from 2H-Delta(2)-thiazolines and Meldrum's acid derivatives, has been reported from our laboratory. We now report a new method for the synthesis of optically active, highly substituted ring-fused 2-pyridinones. This was discovered when 2-alkyl-Delta(2)-thiazolines and Meldrum's acid derivatives were treated with HCl(g) in benzene at 5 --> 78 degrees C. Further refinement of the synthetic protocol revealed that use of 1,2-dichloroethane as solvent at 0 --> 64 degrees C led to the desired 2-pyridinones in good yields and with excellent enantioselectivity. Use of these conditions allowed preparation of 2-pyridinones from several different Delta(2)-thiazolines and Meldrum's acid derivatives and may be a general route to 2-pyridinones.

Design and Parallel Solid-Phase Synthesis of Ring-Fused 2-Pyridinones That Target Pilus Biogenesis in Pathogenic Bacteria

“…53 Second, both in the formation of the ∆ 2 -thiazoline and in the synthesis of the 2-pyridinone in solution, some epimerization had previously been observed. 34 Since we knew that the enantiomeric ratio (er) for the methyl esters of the 2-pyridinones could be established by a chiral-phase HPLC ((S,S) Whelk-O 1 column), 34 we prepared the corresponding methyl esters of four of the 2-pyridinones 13{10,1}, 13{8,1}, 13{5,5}, and 13{4,5} by treating them with TMS-diazomethane. 55 These 2-pyridinones were chosen to represent different substitution patterns, thus giving representative information of the limitations of the method for providing enantiomerically enriched material.…”

“…34 The key intermediates in this reaction are substituted ∆ 2 -thiazolines 2 and Meldrum's acid derivatives 3. ∆ 2 -Thiazolines are easily synthesized from imino ethers 1 and (R)-cysteine methyl ester hydrochloride, and Meldrum's acid derivatives are prepared from Meldrum's acid and activated carboxylic acids.…”

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

“…The R8͞K112 cleft region of the chaperone was originally targeted (20,21), followed by compounds 1a and 1b with two substituents (R 1 and R 2 , Fig. 1) (22)(23)(24) that bound to PapD and FimC, the P and type 1 pili chaperones, respectively (21,22,25). However, the poor water solubility limited their utility.…”

Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure–activity study

“…20 In general, the acyl-ketene imine cyclocondensation produced the desired compounds in good yields (66–93%). However, the polar C-7 substituent in building block 1g proved problematic and resulted in lower yields (15–50%).…”

“…18 The pilicide core structure ( 5 ) is based on a dihydrothiazolo ring-fused 2-pyridone that can be synthesized via an acyl-ketene imine cyclocondensation of acyl-Meldrum’s acid derivatives ( 3 ) and thiazolines ( 4 ). 19,20 The acyl-Meldrum’s acid derivatives ( 3 ) and thiazolines ( 4 ) are generally obtained from commercially available carboxylic acids ( 1 ) and nitriles ( 2 ), respectively. This synthetic procedure introduces substituent diversity in position C-7 and C-8 already in the scaffold formation by the choice of carboxylic acids ( 1 ) and nitriles ( 2 ).…”