BF₃-Mediated cis-Selective Cycloaddition of O-Silyloxime with Alkenes

Abstract

A C-amide-substituted O-silylated oxime, (E)-(tert-butyldimethylsiloxyimino)acetic acid N,N-dimethylamide (8b), on treatment with 2.2 equiv of BF3·OEt2, in situ generated boracyclic nitrone-type intermediate BF3·14, which underwent cycloaddition with alkenes to give 3,5-cis-isoxazolidines as the major products. The mechanism was strongly supported by isolation of the reaction intermediate 14 that was characterized by X-ray diffraction and its further reaction. This cycloaddition was successfully applied to the synthesis of syn-HPA-12 known as an inhibitor of CERT that mediates the transport of ceramide.

Chemistry and Biology of HPAs: A Family of Ceramide Trafficking Inhibitors

“…Synthesis of racemic syn-HPA-12 by Ta mura: [29] a) i) BF 3 ·Et 2 O, 1,2dichloroethane,608C; ii)Boc 2 O, CH 2 Cl 2 ,r t, 99 %( d.r.3 .4:1);b)CF 3 COOH, CH 2 Cl 2 ,rt, then C 11 H 23 COCl, NaHCO 3, CH 2 Cl 2 ,rt, 55 %. Synthesis of racemic syn-HPA-12 by Ta mura: [29] a) i) BF 3 ·Et 2 O, 1,2dichloroethane,608C; ii)Boc 2 O, CH 2 Cl 2 ,r t, 99 %( d.r.3 .4:1);b)CF 3 COOH, CH 2 Cl 2 ,rt, then C 11 H 23 COCl, NaHCO 3, CH 2 Cl 2 ,rt, 55 %.…”

“…Scheme17. Synthesis of racemic syn-HPA-12 by Ta mura: [29] a) i) BF 3 ·Et 2 O, 1,2dichloroethane,608C; ii)Boc 2 O, CH 2 Cl 2 ,r t, 99 %( d.r.3 .4:1);b)CF 3 COOH, CH 2 Cl 2 ,rt, then C 11 H 23 COCl, NaHCO 3, CH 2 Cl 2 ,rt, 55 %. ;c)Mo(CO) 6, CH 3 CN/H 2 O (10:1), reflux, 27 %i na mino alcohol and 70 %i nl actone;d )toluene, reflux, 48 %; e) NaBH 4 ,M eOH, 0 8C, 86 %.…”

“…Chemler and co‐workers described in 2012 an approach to (1 S ,3 R )‐ syn 1,3‐amino alcohol 53 as a potential precursor of (1 S ,3 R )‐HPA‐12 based on a stereoselective isoxazolidine synthesis (Scheme ). Tamura and co‐workers published in 2015 a synthesis of racemic syn ‐(1 R* ,3 S* )‐HPA‐12 relying on a BF 3 ‐mediated cis ‐selective cycloaddition of O ‐silyloxime with alkenes (Scheme ). According to a similar strategy, Tamura's group also described in 2008 a synthesis of racemic anti ‐1,3‐amino alcohol …”

“… Synthesis of racemic syn ‐HPA‐12 by Tamura: a) i) BF 3 ⋅ Et 2 O, 1,2‐dichloroethane, 60 °C; ii) Boc 2 O, CH 2 Cl 2 , rt, 99 % (d.r. 3.4:1); b) CF 3 COOH, CH 2 Cl 2 , rt, then C 11 H 23 COCl, NaHCO 3, CH 2 Cl 2 , rt, 55 %.…”

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

“…1) using a Zn-catalyzed asymmetric Mannich-type reaction in water, and unambiguously ascertained the revised configuration by X-ray crystallography [14]. The other syntheses of (1 R ,3 S )-HPA-12 ( 2 ) used the chiral pool approach [15–16], crystallization-induced asymmetric transformation [17], diastereoselective reduction of γ-aryl-γ-oxo-β-amino alcohol [18], cycloaddition of oxime with alkenes [19], enantioselective carbonyl reduction followed by an organocatalyzed α-amination reaction [20], tandem approach from ( S )-Wynberg lactone [21], chiral ruthenium-catalyzed N -demethylative rearrangement of 1,2-isoxazolidines [22], gold(I)-catalyzed cyclization of a propargylic N -hydroxylamine [23], from β-sulfinamido ketones derived from chiral sulfinimines [24], and a Kornblum–DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines followed by diastereoselective reduction [25]. Most of these methods employ starting materials or catalysts, which are not commercially available, and also require operationally demanding reaction conditions.…”