Enantioselective Catalysis by Chiral Isothioureas

Abstract

International audienceThis review covers recent developments relating to organocatalyzed transformations by chiral isothioureas (ITUs) since their original introduction by Birman in 2006. This class of nucleophilic heterocycles was first involved in anhydride activation in enantioselective acyl transfer reactions, but it was more recently shown that activation of other reagents was possible, considerably enlarging their number of catalytic enantioselective transformations. Four main modes of activation as Lewis bases can currently be listed: (1) acylisothiouronium intermediates involved in acyl transfer, (2) silylisothiouronium species involved in silyl transfer, (3) acylisothiouronium enolates involved in several concerted and formal pericyclic transformations, and (4) α,_-unsaturated acylisothiouronium species involved in domino transformations. This review is organized according to these different modes of activation of chiral isothioureas

Isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangements of N,N-diallyl allylic ammonium ylides

“…This process generates functionalized α-amino esters 6 with high diastereocontrol but in racemic form. 5 Building upon this work, we demonstrated an isothiourea-promoted 6,7 catalytic enantioselective [2,3]rearrangement of allylic ammonium ylides, leading to a range of α-amino acid derivatives 8 bearing either N,N-dimethyl or cyclic-N-alkyl substituents (Scheme 1c). 8 This process allows for the synthesis of a variety of α-amino ester derivatives and the incorporation of pharmacological relevant amine motifs such as the morpholine unit, although the preparation of free α-amino esters was not possible as suitable N-substituents amenable to facile deprotection were not incorporated.…”

“…20 Allylic Alcohols 4-nitrocinnamyl alcohol, 4-bromocinnamyl alcohol, 2-bromocinnamyl alcohol and 4-fluorocinnamyl alcohol were synthesised according to previously reported procedure. 6 Authentic racemic samples of the [2,3]-rearrangement products 22, 27-29 and 31-34 were synthesised using (±)-BTM.…”

“…Crude dr 90:10. The residue was purified by flash column chromatography on silica gel (5% EtOAc/hexanes) to give the title product (92 mg, 69%, 90:10 dr) as a yellow oil; Enantiopurity determined after derivatisation to 39 and N-Boc protection, 96% ee; [α] ୈ ଶ +54.7 (c 1, CHCl 3 ); υ max (film, cm −1 ) M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Tetrahedron 10 2980Tetrahedron 10 , 1724Tetrahedron 10 , 1518Tetrahedron 10 , 1343Tetrahedron 10 , 1155; 1 H NMR (500 MHz, CDCl 3 ) δ H 1.34 (3H, t, J 7.1, OCH 2 CH 3 ), 2.81 (2H,dd,J 14.4,8.4,NCHH),3.35 (2H,ddt,J 14.4,4.0,1.9,NCHH),3.82 (1H,d,J 11.7,C(2)H), 3.98 (1H, dd, J 11.7, 7.9, C(3)H), 4.24 (2H, dddd, J 18.0, 10.8, 7.1, 3.7, OCH 2 CH 3 ), 4.98-5.16 (6H, m, C(5)H 2 + diallyl-C(3)H 2 ), 5.36 (2H, dddd, J 16.9, 10.3, 8.3, 4.1, diallyl-C(2)H), 5.86 (1H, ddd, J 17.0, 10.3, 7.9, C(4)H), 7.33 (2H,d,J 8.8,Ar(2,6)H), 8.19 (2H,d,J 8.8,Ar(3,5) …”

“…Crude dr 94:6. The residue was purified by flash column chromatography on silica gel (5% EtOAc/hexanes) to give the title product (222 mg, 85%, 95:5 dr) as a colourless oil; HPLC analysis, Chiralpak AD-H (0.5% IPA/hexane, flow rate 1.5 mL/min, 211 nm, 40 °C) t R Major 3.3 min, Minor 4.3 min, 96% ee; [α] 2.79 (2H,dd,J 14.5,8.3,NCHH),3.34 (2H,ddt,J 14.5,4.0,1.9,NCHH),m,C(2)H + C(3)H), 4.09-4.34 (2H, m, OCH 2 CH 3 ), 4.86-5.14 (6H, m, C(5)H 2 + diallyl-C(3)H 2 ), 5.26-5.50 (2H, m, diallyl-C(2)H), 5.85 (1H, ddd, J 17.1, 10.2, 7.6, C(4)H), 6.98 (2H,t,J 8.7,Ar(3,5)H), 7.09 (2H,ddt,8.3,5.2,2.5,Ar(2,6) (−3.1 ppm).…”

Exploiting the Imidazolium Effect in Base‐free Ammonium Enolate Generation: Synthetic and Mechanistic Studies

“…[11][12] The protocol developed herein represents a new paradigm in ammonium enolate generation without the addition of external base (Scheme 1c). [13] A range of enantioselective Michael addition-cyclization processes with α,β-unsaturated enones and ketimines to form substituted dihydropyranones and dihydropyridinones have been explored. Furthermore, a detailed mechanistic investigation has revealed key differences between this new process and analogous reactions using carboxylic acids under basic conditions.…”