Synthesis of enantiomerically pure N-(2,3-dihydroxypropyl)arylamides via oxidative esterification

Summary A highly efficient synthesis of enantiomerically pure (S) and (R)-isomers of N-(2,3-dihydroxypropyl)arylamides has been developed with good overall yields in a two step process. The key step involves the ring opening of the chiral epoxide with a nitrogen heterocyclic carbene (NHC) and further rearrangement to chiral N-(2,3-dihydroxypropyl)arylamides in high yields and enantioselectivity. During the reaction, no erosion in chiral purity was observed.


Introduction
Chiral structures with three carbons are an integral part of many biologically active compounds including alkaloids, pharmaceuticals and research probes. The development of synthetic routes to these structures is often challenging. Chiral building blocks with three carbon atoms such as glycidol, 1-bromo-2,3-dihydroxypropane and 3-amino-1,2-dihydroxypropane (1) are considered powerful tools by synthetic chemists in organic synthesis [1][2][3][4].
In the recent past, synthesis of these chiral building blocks has gained significant interest leading to the publication of many reports. The most common methods include (i) reacting a chiral 1,2-propanediol with a leaving group such as a halide or a tosylate ester in the 3-position with base [5,6] or (ii) catalytic oxidations with peroxides and chiral transition metal complexes [7][8][9]. The oxidative esterification of aldehydes involving oxidation followed by a C-O or C-N bond formation has received Scheme 1: Retro synthetic approach for the construction of N- (2,3-dihydroxypropyl)arylamides.
The opening of the epoxide ring 4a was attempted with benzaldehyde in the presence of various nitrogen heterocyclic carbenes, such as 9a to 9k, with different bases (triethylamine, DBU, and DABCO) and with or without an additive to optimize the reaction conditions (Table 1). When the NHC was used in 0.25 equivalents in THF or THF/butanol (10:1) the major product isolated in the reaction was benzoin, and the desired product (S)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl benzoate (5a) was isolated in only 20% yield. However, when the reaction was performed in NMP at elevated temperatures by using 0.25 equivalent of NHC, the yield of 5a was significantly improved to 68% along with 10% of benzoin. We did not observe any racemization under these optimized conditions. Higher dilutions of NMP resulted in longer reaction times and lower yields.
A plausible mechanism for the ring opening of epoxide with a nitrogen heterocyclic carbene is presented in Scheme 3. Yadav and co-workers reported the ring opening of epoxide by the Breslow intermediate 11 to provide the corresponding Aldol products [36]. Studer et al. reported the preparation of acids by an oxidation of Breslow intermediates with molecular oxygen [37][38][39]. The highly activated Breslow intermediate 11 formed by the addition of the NHC to the aldehydes, reacts with dioxygen to form the peroxy-species, which afforded the corresponding hydroxypropyl benzoate. A similar kind of mechanism was also proposed by Ding et al. [40]. To study the mechanism,  we conducted a reaction with benzoic acid as a substrate under optimized conditions with or without NHC. Surprisingly, in both cases the formation of the desired product was observed in 40% yield.
The representative examples and the reaction conditions are given in Table 2. All the starting epoxides required for this transformation were prepared by using the reported procedures.

Conclusion
A highly enantioselective synthesis of (S) and (R)-isomers of N- (2,3-dihydroxypropyl)arylamides was developed with high overall yields. We report the nitrogen heterocyclic carbene catalyzed enantioselective ring opening of chiral epoxide with an aryl or heteroaryl aldehyde by oxidative esterification. This method may prove significant from the perspective of green chemistry. The application of this methodology for the synthesis of several bicyclic frameworks and natural products is under progress, and will be reported in due course.

Experimental
General procedure for the synthesis of 5a-h Phthalimide epoxide 4a (10 g, 0.049 mol), NMP (30 mL, 3 equiv), benzaldehyde (5.2 g, 0.049 mol), NHC (3.15 g, 0.0123 mol) and DBU (2.99 g, 0.0197 mol) were mixed in a round bottom flask at 25-30 °C. The reaction mixture was heated to 85-90 °C for 4-5 h. The reaction mixture was then quenched with cold water (300 mL, 10 volume with respect to NMP) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (2 × 50 mL) and brine solution and dried over sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure. The crude product was purified by column chromatography with 20% ethyl acetate in hexane, and the pure product was isolated as pale yellow solid in 68% yield.

Supporting Information
Supporting Information File 1 Analytical data and NMR, MS and IR spectra.