Masaya Ikunaka

A practical chemoenzymatic process to access (R)-quinuclidin-3-ol on scale

Abstract (±)-3-Butyryloxyquinuclidinium butyrate 6 (2 M, 571 g/L), prepared from (±)-quinuclidin-3-ol 1 and butyric anhydride, undergoes enantioselective hydrolysis by an Aspergillus melleus protease {1.0% (w/v)} in water in the presence of Ca(OH)2 to keep the reaction at pH 7 and trap butyric acid that is introduced as part of (±)-6 and generated by the enzymatic hydrolysis. After a 24 h period, extraction with n-heptane provides (R)-quinuclidin-3-yl butyrate 5a, which, on methanolysis with Na2CO3, is converted into (R)-1, a common pharmacophore of neuromodulators acting on muscarinic receptors, in 96% ee and 42% overall yield from (±)-1. The unwanted antipode (S)-1, which is extracted into n-butanol and purified via its hydrochloride salt in 89% ee and 40% overall yield from (±)-1, can be racemized by the catalysis of Raney Co at 140°C under an atmosphere of H2 (5 kg/cm2) to regenerate (±)-1 in 97% yield.

A concise synthesis of (2S, 3S)-BocAHPBA and (R)-BocDMTA, chiral building blocks for peptide-mimetic HIV protease inhibitors

Abstract Scalable syntheses of (2 S ,3 S )-3- N - tert -butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (BocAHPBA) 1 and ( R )-3- tert -butoxycarbonyl-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid (BocDMTA) 2 have been developed. Both 1 and 2 can serve as chiral building blocks in assembling JE-2147 (KNI-764) 3 , a potent HIV protease inhibitor. The synthesis of (2 S ,3 S )-BocAHPBA 1 is achieved in 41% overall yield from ( S )-2- N , N -dibenzylamino-3-phenylpropanal 4 in five steps where Tamaos reagent [Me 2 ( i -PrO)SiCH 2 MgCl] is employed for a one-carbon homologation, and Zhaos oxidation protocol (TEMPO, NaClO 2 , NaClO) is applied to convert a 1,2-glycol moiety into an α-hydroxy acid motif. ( R )-BocDMTA 2 is synthesized with 99.4% ee in 24% yield via enantioselective hydrolysis of methyl (±)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate 8b by a Klebsiella oxytoca hydrolase; the unreacted ( S )-ester 8b can be recovered and racemized with NaOMe to afford (±)- 8b in 46% yield for another round of the enzymatic processing.

A scalable chemoenzymatic preparation of (R)-tetrahydrofuran-2-carboxylic acid

Abstract To develop a practical scalable approach to (R)-tetrahydrofuran-2-carboxylic acid (THFC) 1, a chiral building block for furopenem 2, enantioselective hydrolysis of its esters is explored: When ethyl (±)-tetrahydrofuran-2-carboxylate 3d (2 M, 288 g/L) is digested by an Aspergillus melleus protease {0.2% (w/v)} in a 1.5 M potassium phosphate buffer (pH 8) for 20 h, enantioselective hydrolysis proceeds with E=60 to give (R)-THFC 1 in 94.4% ee. On separation from the left-over antipodal ester (S)-3d by partition, (R)-THFC 1 is treated with N,N-dicyclohexylamine (DCHA) in methyl ethyl ketone/methanol (5:1) to precipitate the crystalline salt 4 that contains (R)-THFC 1 of >99% ee in 22% overall yield from (±)-3d.