Memory of chirality trapping of low inversion barrier 1,4-benzodiazepin-2-one enolates

We have previously demonstrated that chiral, enantiopure 3-substituted 1,4-benzodiazepin-2-ones undergo retentive deprotonation/trapping at −78 °C, if the N1-substituent is sufficiently large (e.g., i-Pr). Stereocontrol in this reaction is attributed to the formation of an enantiopure, conformationally chiral enolate; at −78 °C a large N1 substituent (e.g., i-Pr) is needed to impart a sufficient barrier to enolate racemization. Herein, we report strategies to achieve high enantiomeric excess in deprotonation/alkylation of low inversion barrier 1,4-benzodiazepin-2-ones featuring small N1 substituents.

Highly enantioselective deprotonation/trapping of 1,4-benzodiazepin-2-ones bearing small N1 substituents is demonstrated for the first time.Figure optionsDownload as PowerPoint slide

(S)-(+)-7-Chloro-3-deutero-1,3-dihydro-1,3-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneC17H14ClDN2OEe = 97% (HPLC)[α]D23 = +196 (c 3.82, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (3S)

(S)-(+)-3-Benzyl-7-chloro-3-deutero-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneC23H18ClDN2OEe = 97% (HPLC)[α]D23 = +89.7 (c 1.06, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (3S)

(S)-(+)-7-Chloro-1,3-dihydro-3-isobutyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneC20H21ClN2OEe = 100% (HPLC)[α]D23 = +180 (c 1.11, CHCl3)Source of chirality: (S)-Leu-OHAbsolute configuration (3S)

(S)-(+)-7-Chloro-3-deutero-1,3-dihydro-3-isobutyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneC20H20ClDN2OEe = 95% (HPLC)[α]D23 = +187 (c 0.35, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (3S)

(S)-(+)-7-Chloro-1,3-dihydro-1-methyl-5-phenyl-3-(2-thiomethylethyl)-2H-1,4-benzodiazepin-2-oneC19H19ClN2OSEe = 100% (HPLC)[α]D23 = +170 (c 0.29, CHCl3)Source of chirality: (S)-Met-OHAbsolute configuration (3S)

(S)-(+)-7-Chloro-3-deutero-1,3-dihydro-1-methyl-5-phenyl-3-(2-thiomethylethyl)-2H-1,4-benzodiazepin-2-oneC19H18ClDN2OEe = 98% (HPLC)[α]D23 = +142 (c 0.88, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (3S)

(S)-(+)-7-Chloro-1,3-dihydro-1-(4-methoxybenzyl)-3-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneC24H21N2O2ClEe = 100% (HPLC)[α]D23 = +129 (c 0.99, CHCl3)Source of chirality: (S)-Ala-OHAbsolute configuration (3S)

(R)-(+)-3-Benzyl-7-chloro-1,3-dihydro-1-(4-methoxybenzyl)-3-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneC31H27N2O2ClEe = 97% (HPLC)[α]D23 = +11.5 (c 1.17, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (3R)

(R)-(+)-3-Allyl-7-chloro-1,3-dihydro-1-(4-methoxybenzyl)-3-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneC27H25N2O2ClEe = 89% (HPLC)[α]D23 = +9.5 (c 0.78, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (3R)

(S)-(+)-1-Benzyl-7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneC23H19N2OClEe = 100% (HPLC)[α]D23 = +158.4 (c 0.94, CHCl3)Source of chirality: (S)-AlaAbsolute configuration (3S)

(R)-(+)-7-Chloro-1,3-dihydro-1-(4-methoxybenzyl)-3-methyl-5-phenyl-3-(2-phenylbenzyl)-2H-1,4-benzodiazepin-2-oneC37H31N2O2ClEe = 97% (HPLC)[α]D23 = +126 (c 1.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (3R)

(R)-(+)-7-Chloro-1,3-dihydro-1-(4-methoxybenzyl)-3-methyl-3-(4-methylbenzyl)-5-phenyl-2H-1,4-benzodiazepin-2-oneC32H29N2O2ClEe = 93% (HPLC)[α]D23 = +16.0 (c 1.11, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (3R)