Merging Chemo- and Biocatalysis to Facilitate the Syntheses of Complex Natural Products: Enantioselective Construction of an N-Bridged [3.3.1] Ring System in Indole Terpenoids

Abstract

Although the molecular structural motif of indole-fused azabicyclo[3.3.1]nonane is common in biologically significant natural products, its catalytic asymmetric synthesis remains underexplored. Herein, we report a catalytic approach for the formal synthesis of more than 20 types of sarpagine/macroline alkaloids. Two key steps are the amide insertion reaction using a metalcarbene species based on cheap copper and biocatalytic asymmetric desymmetrization, producing the desired chiral N-bridged [3.3.1] scaffold. The enzymatic step proceeds highly enantioselectively when using lipase from Candida rugosa, which turned out to be the best for breaking the symmetry. Late-stage introduction of an indole unit with functionalities then established a diversityoriented synthetic pathway toward indole terpenoid variants.

Enantioselective Formal Synthesis of (–)-Catharanthine through Enzyme-Catalyzed Desymmetrization of a meso-Azabicyclo [2.2.2]octane

“…We next evaluated various enzyme catalysts for the enantioselective desymmetrization of the prochiral diacetate 5 (Table 2 ). Based on the previous biocatalytic screening results, 9 we first selected a commercially available lipase from Candida rugosa as the catalyst (Table 2 , entry 1). Although the desired 6 , possessing a 1,2-amino alcohol functionality as a subunit within a sterically complex three-dimensional structure, was produced, the observed enantioselectivity from 5 was only 35% ee.…”

“…The widely used and commercially available Rh 2 (OAc) 4 complex was not practical for amide insertion (entry 2). With reference to a method for synthesizing an N-bridged [3.3.1] ring system, 9 we tested a Cu(II) catalyst with acetylacetonate or its variant as the supporting ligand under heating conditions (entries 3 and 4), but the reaction outcome was unsatisfactory. After examining the metal catalyst, product 13 was converted into the meso-diacetate 5 for subsequent asymmetric deacylation; 5 was obtained in 68% yield (Scheme 3).…”

“…Enzyme catalysts 8 are produced under sustainable conditions and they catalyze chemical reactions under mild conditions, allowing environmentally friendly organic syntheses. In 2022, we reported a method for synthesizing the N-bridged [3.3.1] ring system found in indole terpenoids 9 based on an amide-insertion reaction 10 of metal carbene species 11 using a copper catalyst (Scheme 1 ). For the subsequent symmetry-breaking process, asymmetric acylation of the meso -1,3-diol 12 2 using a chiral acid catalyst did not proceed because the bridging nitrogen inactivated the catalyst.…”

Systematic Studies of Functional Group Tolerance and Chemoselectivity in Carbene-Mediated Intramolecular Cyclopropanation and Intermolecular C–H Functionalization

“…[17][18][19][20][21][22] As part of our ongoing research program to synthesize biologically important molecules, 23) we focused on developing carbene chemistry using metal catalysis. 24) Metal carbenes 25,26) are reactive transient species that enable insertion reactions into C-H bonds, cyclopropanation reactions of olefins, and so on. [27][28][29] Transition metals, mainly in group 8-11 elements, are commonly used as catalytic core elements to generate carbene species from the corresponding diazo compounds or their chemical equivalents.…”

Short, Scalable Access to Pyrrovobasine

“…The obtained 5 - Z with Boc group was deprotected to achieve a simple formal synthesis of koumidine with antitumor activity (Scheme ). , However, 5 - E was converted to 16 by the Wittig reaction. The resulting 16 was hydrolyzed to the aldehyde with trifluoroacetic acid, and the thermodynamically stable stereochemistry of methyl ester 17 was obtained using iodine, KOH, and MeOH, followed by Boc protection.…”