An alkaloid-mediated desymmetrization of meso-anhydrides via a nucleophilic ring opening with benzyl alcohol and its application in the synthesis of highly enantiomerically enriched β-amino acids

Integrated Synthetic, Pharmacological, and Computational Investigation of cis‐2‐(3,5‐Dichlorophenylcarbamoyl)cyclohexanecarboxylic Acid Enantiomers As Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 4

“…The quinine-mediated opening afforded (1S,2R)-2-(benzyloxycarbonyl)cyclohexanecarboxylic acid, whereas the use of quinidine as the chiral auxiliary afforded (1R,2S)-2-(benzyloxycarbonyl)cyclohexanecarboxylic acid. The spectroscopic data are in accordance with those described by Bolm et al [18] (1R, 95); [18] 96 % ee, conditions: Daicel Chiralpak IA, eluent: hexane (0.1 % TFA)/iPrOH (0.1 % TFA) (1:1), flow rate 0.5 mL min À1 , detection l = 254 nm; t R = 9.6 min (minor enantiomer using quinidine) and 11.2 min (major enantiomer using quinidine). [18] 86 % ee, conditions: Daicel Chiralpak IA, eluent: hexane (0.1 % TFA)/iPrOH (0.1 % TFA) (1:1), flow rate 0.5 mL min À1 , detection l = 254 nm; t R = 9.6 min (major enantiomer using quinine) and 11.2 min (minor enantiomer using quinine).…”

“…It is reported that this alkaloid gives the carboxylic acid enantiomeric to that obtained with quinidine. [18] In our hands, this reaction gave hemiester (1S,2R)-4 in 40 % yield and 86 % ee. With this compound in hand, the synthetic sequence was similar to that followed for the synthesis of the other enantiomer.…”

“…Enantioselective opening of cis-cyclohexane-1,2-dicarboxylic anhydride: The opening of the cis anhydride was accomplished by following the procedure described by Bolm et al [18] Two alkaloids were used to obtain both enantiomers. The quinine-mediated opening afforded (1S,2R)-2-(benzyloxycarbonyl)cyclohexanecarboxylic acid, whereas the use of quinidine as the chiral auxiliary afforded (1R,2S)-2-(benzyloxycarbonyl)cyclohexanecarboxylic acid.…”

“…Both enantiomers were obtained from achiral cis-cyclohexane-1,2-dicarboxylic anhydride by an alkaloid-mediated desymmetrization following the procedure described by Bolm et al [18] Our first idea was to obtain both enantiomers of the desired compound from the carboxylic acid intermediate (1R,2S)-4 (Scheme 1), which could be obtained by the Bolm desymmetrization reaction of the anhydride with benzyl alcohol in the presence of quinidine. The reaction of (1R,2S)-4 with 3,5-dichloroaniline followed by hydrogenolysis of the benzyl protecting group should give (1S,2R)-2.…”

Synthesis and Alcoholysis of α-Alkylated Cyclopentane and Cyclohexane Fused Succinic Racemic Anhydrides in the Presence of Chiral Bases

“…Derived β-and γ-amino acids are either already biologically active compounds (Cispentacin, [2] Pregabalin, [3] Baclofen [4] ) or potential building blocks in the synthesis of more complex molecules (Biotin, [5] Brefeldin [6] ). Whereas desymmetrization of mesoanhydrides has been extensively studied, there are only few trials to perform the same reaction on racemic anhydrides.…”