Enantiopure 3-methyl-3,4-dihydroisocoumarins and 3-methyl-1,2,3,4-tetrahydroisoquinolines via chemoenzymatic asymmetric transformations

Abstract

PaperEnantiopure 3-methyl-3,4-dihydroisocoumarins and 3-methyl-1,2,3,4-tetrahydroisoquinolines via chemoenzymatic asymmetric transformations Juan Mangas-Sánchez, Eduardo Busto, Vicente Gotor-Fernández and Vicente Gotor Visit the Catalysis Science & Technology website for more cutting-edge research in catalysis A new divergent and asymmetric synthetic route has been developed for the production of enantiomerically pure isocoumarin and isoquinoline derivatives. Stereoselective formation of 2-(2-hydroxypropyl)benzonitriles has been identified as the key step. Rhizomucor miehei lipase has displayed from moderate to excellent selectivities in the acetylation of its (R)-enantiomers, while ADH-A from Rhodococcus ruber catalyzed the bioreduction of the corresponding ketones with excellent activities and stereopreferences. Enantiopure alcohols obtained in this manner have been used for the straightforward synthesis of a series of 3-methyl-3,4-dihydroisocoumarins and 3-methyl-1,2,3,4-tetrahydroisoquinolines with good overall yields.

Total Synthesis of (±)-Cermizine B

“…Transformation of the nitrile group of 6a to an amine by Pd-catalyzed hydrogenation was unsuccessful. Then 6a was treated with Boc 2 O/NiCl 2 /NaBH 4 followed by Dess–Martin oxidation to furnish N -Boc 10 in 74% yield over two steps. Cyclization of 10 was performed using 2 N HCl which was followed by the addition of NaBH 4 in the reaction, and the newly formed secondary amine was directly protected with p -TsCl to give the tricyclic intermediate 13 in 79% yield over two steps.…”

Development and Production of an Enantioselective Tetrahydroisoquinoline Synthesis Enabled by Continuous Cryogenic Lithium–Halogen Exchange

“…There are many known approaches to the THIQ core, but the architecture contained in 2 presented an unusual challenge because of the thermodynamically disfavored 1,3-trans relationship between the methyl group and the hydroxymethyl group. − Once the THIQ is formed, there is a driving force for the heterocycle substituents to adopt a cis conformation. The approach to the THIQ that we chose to develop is similar to that used for azasugar synthesis by Hashimoto and has been reported for 1-substituted and 3-substituted THIQs but is less precedented for 1,3-trans-disubstituted THIQs . With this approach, the two stereocenters can be forged independently, and key to the overall disconnection strategy is an intramolecular nucleophilic displacement that forms the six-membered ring (Scheme ).…”

Enantioselectivity and catalysis improvements of Pseudomonas cepacia lipase with Tyr and Asp modification

“…1,2 Biocatalysis is an economic and green approach for chiral resolution of a racemic mixture, 3 in which lipase (triacylglycerol ester hydrolases, EC 3.1.1.3) is among the most attractive targets. 1,2 Biocatalysis is an economic and green approach for chiral resolution of a racemic mixture, 3 in which lipase (triacylglycerol ester hydrolases, EC 3.1.1.3) is among the most attractive targets.…”

“…Enantiomerically pure chemicals, such as secondary alcohols, play significant roles in pharmaceuticals, agrochemicals, flavors and fragrances. 1,2 Biocatalysis is an economic and green approach for chiral resolution of a racemic mixture, 3 in which lipase (triacylglycerol ester hydrolases, EC 3.1.1.3) is among the most attractive targets. [4][5][6][7] Kazlauskas et al investigated lipase-catalyzed resolution towards 94-pair enantiomers of secondary alcohols and proposed the well-known empirical law of lipase's enantiopreference: the enzyme's stereospecific catalytic cavity contains large and small pockets, and the preferred enantiomer's large and small groups on the chiral center fit better into the corresponding pocket.…”