Stereoselective total synthesis of (−)-nupharamine utilizing an α-chlorosulfide and a sulfinimine for C–C bond formation

Abstract

An efficient stereoselective synthesis of the nuphar alkaloid, (-)-nupharamine, is reported. The key features include the Lewis acid catalyzed reaction of an α-chlorosulfide with a silyl ketene acetal for C-C bond formation, creation of the stereocenter at C2 by a diastereoselective reaction of allyl indium with a sulfinimine and reductive amination for the introduction of the C6 stereocenter of the piperidine ring.

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

“…In unrelated work, (À)-nupharamine (32), a piperidine Nuphar alkaloid, was synthesised from alcohol (S)-31, which was prepared by acylative kinetic resolution of the racemate, again using lipase PS (Scheme 4b). 46 The enantioselectivity of the biotransformation was excellent in this case (E $50), resulting in 45% yield and 99% ee of (S)-31, while the corresponding (R)-acetate was not isolated. The optically pure alcohol was elaborated into the target alkaloid in nine steps with an overall yield of 12%.…”

Scalable Regioselective and Stereoselective Synthesis of Functionalized (E)-4-Iodobut-3-en-1-ols: Gram-Scale Total Synthesis of Fungal Decanolides and Derivatives

“…To a stirred solution of CuBr 2 (12.2 g, 54.5 mmol) in EtOAc (100 mL) was added a solution of 3-acetylfuran (synthesized from aldehyde 10j by known procedure 38 ) (3.00 g, 27.2 mmol) in CHCl 3 (100 mL). The reaction was brought to reflux for 3 hours then was cooled to room temperature, filtered through a short plug of silica, and concentrated.…”

Convergent Synthesis of the Dihydropyran Core Containing the C1–C15 Subunit of Sorangicin A Employing Gold(I)-Catalyzed Cyclization of an Allenic Alcohol

“…The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using 20% EtOAc/Hexane (v/v) as the eluent to afford compound 9 (1.68 g, 3.96 mmol) in 90% yield as a colorless liquid: TLC R f 0.4 (20% EtOAc/hexane); [α] 20 D = +49.24 (c 1.0, CHCl 3 ); IR (neat) 3070, 2932, 2858, 1964, 1734, 1427, 1108, 704 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.52 (d, J = 1.3 Hz, 1H), 7.68− 7.63 (m, 4H), 7.45−7.35 (m, 6H), 5.41 (qd, J = 7.1, 1.9 Hz, 1H), 5.10−5.03 (m 1H), 4.76 (d, J = 6.7 Hz, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.46 (dt, J = 7.2, 1.7 Hz, 1H), 3.73 (td, J = 6.6, 1.6 Hz, 2H), 3.37 (s, 3H), 2.31 (qd, J = 6.6, 2.7 Hz, 2H), 1.05 (s, 9H); 13 ( 8 S , 1 0 S , 1 1 R , 1 4 R , E ) -1 0 -( M e t h o x y m e t h o x y ) -2,2,12,14,21,21,22,22-octamethyl-3,3-diphenyl-4,20-dioxa-3 , 2 1 -d i s i l a t r i c o s a -7 , 8 , 1 2 -t r i e n -1 1 -o l ( 2 9 ) a n d ( 8 S , 1 0 S , 1 1 S , 1 4 R , E ) -1 0 -( M e t h o x y m e t h o x y ) -2,2,12,14,21,21,22,22-octamethyl-3,3-diphenyl-4,20-dioxa-3,21-disilatricosa-7,8,12-trien-11-ol (7). n-BuLi (2.5 M in hexane, 0.96 mL, 2.4 mmol) was added dropwise to a stirred solution of vinyl iodide 8 (990 mg, 2.5 mmol) in Et 2 O (17 mL) cooled at −78 °C.…”

“…The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using 5−8% EtOAc/Hexane (v/v) as the eluent to afford compound VII (243 mg, 0.35 mmol) in 88% yield as light yellow liquid: TLC R f 0.15 (5% EtOAc/hexane); [α] 20 D = +109.76 (c 0.33, CHCl 3 ); IR (neat) 2930,2858,1964,1680,1466,1105,1033,704; 1 H NMR (500 MHz, CDCl 3 ) δ 7.68−7.63 (m, 4H), 7.45−7.35 (m, 6H), 6.43 (dq, J = 9.7, 1.2 Hz, 1H), 5.32−5.23 (m, 2H), 5.19− 5.13 (m, 1H), 4.76 (d, J = 6.8 Hz, 1H), 4.58 (d, J = 6.8 Hz, 1H), 3.72 (td, J = 6.6, 0.6 Hz, 2H), 3.58 (t, J = 6.5 Hz, 2H), 3.33 (s, 3H), 2.59− 2.52 (m, 1H), 2.30 (qd, J = 6.7, 2.6 Hz, 2H), 1.79 (d, J = 1.2 Hz, 3H), 1.52−1.45 (m, 2H), 1.43−1.34 (m, 1H), 1.34−1.21 (m, 5H), 1.04 (s, 9H), 1.00 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H); 13 ( 8 S , 1 0 S , 1 1 S , 1 4 R , E ) -1 0 -( M e t h o x y m e t h o x y ) -2,2,12,14,21,21,22,22-octamethyl-3,3-diphenyl-4,20-dioxa-3,21-disilatricosa-7,8,12-trien-11-ol (7). To a solution of ketone VII (235 mg, 0.34 mmol) in 1:1 mixture of dichloromethane/water (1.8 mL) were added sodium formate (231 mg, 3.4 mmol) and n-Bu 4 NBr (32.8 mg, 0.102 mmol).…”