An efficient enantioselective approach to multifunctionalized γ-butyrolactone: concise synthesis of (+)-nephrosteranic acid

A short, efficient and novel approach for multifunctionalized γ-butyrolactone paraconic acids and its application to the total synthesis of (+)-nephrosteranic acid from readily available PMB (R)-glycidyl ether as a starting material are described. Key transformations include asymmetric Michael addition catalyzed by chiral diphenylprolinol silyl ether and stereoselective α-methylation.


General methods
All reactions were carried out under argon or nitrogen in oven-dried glassware using standard glass syringes and septa. The solvents and chemicals were purchased from Merck and Sigma Aldrich chemical company. Solvents and reagents were purified and dried by standard methods prior to use. Progress of the reactions was monitored by TLC using precoated aluminium plates of Merck kieselgel 60 F254. Column chromatography was performed on silica gel (60-120 and 100-200 mesh) using a mixture of n-hexane and ethyl acetate. Optical rotations were measured on automatic polarimeter AA-65. IR spectra were recorded on Agilent resolution Pro 600 FT-IR spectrometer, fitted with a beam condensing ATR accessory. 1 H and 13 C NMR spectra were recorded in CDCl3 (unless otherwise mentioned) on JEOL ECS operating at 400 and 100 MHz, respectively.
Chemical shifts are reported in δ (ppm), referenced to TMS.

S3 ethyl (R,E)-4-((tert-butyldiphenylsilyl)oxy)pentadec-2-enoate, 20
To a stirred solution of oxalyl chloride (628 mg, 0.427 mL, 4.95 mmol) in dry CH2Cl2 (2 mL) at -78 o C was added DMSO (798 mg, 0.725 mL, 10.24 mmol) in dry CH2Cl2 (2 mL) dropwise and stirred the reaction mixture for 30 min and then a solution of silyl protected alcohol derivative 19 (1.50 g, 1.52 mmol) in dry CH2Cl2 (10 mL) was added dropwise over 15 min at the same temperature. The reaction mixture was stirred for 30 min at -78 °C and 1 hours at -60 °C and then Et3N (1.46 g, 2.02 mL, 14.54 mmol) was added dropwise at the same temperature and stirred for an additional 1 hour. The reaction mixture was allowed to warm to room temperature and diluted with water and CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 x 15 mL) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude aldehyde, which was used in the next step after filter column purification.
To a solution of the above aldehyde in THF (10 mL) was added to a solution of

S4
To a stirred solution of α, β-unsaturated ester derivative 20 (1.0 g, 1.92 mmol) in dry CH2Cl2 (15 mL) was added DIBAL-H (2.30 mL, 2.30 mmol, 1 M in hexane) under inert atmosphere at -78 °C. After stirring the reaction mixture for 1 hour at same temperature the reaction was quenched with saturated aqueous solution of sodium potassium tartrate and stirred for additional 30 min. The two phases were separated and aqueous phase was extracted with CH2Cl2 (3 x 15 mL). The combined organic layers extract was dried over anhydrous Na2SO4 and concentrated in vacuo to give α, β-unsaturated aldehyde which was used as such for the next step after filtration column using Celite.
To the above α, β-unsaturated aldehyde intermediate in dry methanol was added nitromethane (0.31 mL, 5.76 mmol), (S)-diphenyltrimethylsiloxymethylpyrrolidine (62 mg, 0.19 mmol) and benzoic acid (23 mg, 0.19 mmol) sequentially at room temperature. The reaction mixture was stirred for 16 h at room temperature. After completion of reaction as monitored by TLC the reaction was quenched with saturated aqueous NaHCO3 solution. The organic layer was extracted with EtOAc (3 x 10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to furnish nitroaldehyde intermediate which was used directly for the next step without further purification.