Asymmetric Hydrogenation of Isoquinolinium Salts Catalyzed by Chiral Iridium Complexes: Direct Synthesis for Optically Active 1,2,3,4‐Tetrahydroisoquinolines

Abstract

,4-Tetrahydroisoquinolines (THIQs), a class of highly important molecular skeletons abundant in natural alkaloids and biologically active compounds, are often used as key intermediates for the synthesis of pharmaceutical drugs and drug candidates.[1] To date, synthetic efforts have focused on introducing chirality at the C1 position with configurational integrity by employing the following synthetic methodologies:[2] 1) the formation of the six-membered ring through a Bischler-Napieralski cyclization/reduction [3] or a PictetSpengler reaction, [4] 2) the C 1 -C a connectivity approach by attaching nucleophilic or electrophilic carbon units to the C1 position of tetrahydroisoquinoline derivatives, [5] and 3) the asymmetric hydrogenation of alkylidene-1,2,3,4-tetrahydroisoquinoline derivatives.[6] However, these methods have some limitations, such as a limited substrate scope and the need for stoichiometric amounts of a chiral auxiliary. In contrast to 1-substituted THIQs, the synthesis of 3-substituted THIQs has rarely been achieved, [7] although their unique structural and diverse biologic properties have been noted.[8] Accordingly, the development of more general and straightforward synthetic methods toward 1-and 3-substituted THIQs is in high demand. Although asymmetric hydrogenation of substituted isoquinolines is considered the most attractive and straightforward synthetic protocol, isoquinoline is regarded as the most challenging substrate in asymmetric hydrogenation. An efficient catalytic system has not even been found for the reduction of isoquinolines in a nonenantioselective manner. [9] Nonetheless, the recent development of an asymmetric hydrogenation of aromatic and heteroaromatic compounds was remarkable, [10][11][12][13][14][15][16][17][18][19][20] and Zhou and co-workers reported the catalytic asymmetric hydrogenation of isoquinolines, although the substrate scope is limited and an activating reagent is sometimes required (Scheme 1). [21] As part of our continuing interest in the asymmetric hydrogenation of N-heteroaromatic compounds using halogen-bridged dinuclear iridium(III) complexes, [22] we previously reported the additive effect of aryl amine derivatives in the asymmetric hydrogenation of quinoxalines, [22d] where the addition of more-basic aliphatic amines retarded the reaction, presumably because of their tight coordination to the iridium center. These findings strongly suggested that the difficulties of catalytic hydrogenation of isoquinolines upon catalysis by iridium complexes might be due to the strong basicity of the corresponding THIQs. This hypothesis prompted us to study the asymmetric hydrogenation of isoquinolinium chlorides to give the corresponding tetrahydroisoquinolinium chlorides, thus avoiding the deactivation of the iridium catalyst and providing a direct transformation of isoquinolines to THIQs in an enantioselective manner by a simple basic workup (Scheme 1).We first examined the asymmetric hydrogenation of the 3-phenylisoquinolinium salt 2 a-HCl with H 2 (30 bar) and ...

Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights

“…1 Although the synthesis of such saturated N-heterocycles remains challenging, 2 recent advances including diastereoselective metalation/cross-coupling, 3 conjugate additions of dihydropyridinones, 4 hydrogenation of disubstituted pyridines 5 and cyclization methods 6 are bringing these once exotic building blocks into the mainstream. Unfortunately, most of the available methods for the preparation of multisubstituted N-heterocycles deliver racemic products and prospects for enantioselective approaches to many substitution patterns are limited.…”

Chloride‐Bridged Dinuclear Rhodium(III) Complexes Bearing Chiral Diphosphine Ligands: Catalyst Precursors for Asymmetric Hydrogenation of Simple Olefins

“…[4] Such high enantioselectivity was considered ac onsequence of the chelating coordination of substrates.Atypically proposed intermediate in asymmetric hydrogenation of olefinic substrates bearing acoordinating amide group involves,1 )both the C = Cd ouble bond and the coordinating functional group,2 )a dihydride rhodium(III) species generated in situ by the reaction of ar hodium(I) precursor with H 2 . [10] Asymmetric hydrogenation of heteroaromatics,such as quinolinium salts, [11] quinoxalines, [12] isoquinolinium salts, [13] pyridinium salts, [14] and quinazolinium salts, [15] was accomplished with the latter.A ccordingly,w e envisioned that rhodium analogues could serve as efficient new catalyst precursors,t hat could provide monohydride rhodium(III) species capable of catalyzing the asymmetric hydrogenation of simple olefins.W efound that chiral chloride-bridged dinuclear rhodium(III) complexes proficiently catalyzed the asymmetric hydrogenation of simple olefins,a sw ell as allylic alcohols,a lkenylboranes,a nd unsaturated cyclic sulfones.We initially synthesized chloride-bridged dinuclear rhodium(III) complex (S)-1a,b earing (S)-BINAP,b ya dding 5equiv of HCl in diethyl ether to am ixture of [RhCl(cod)] 2 and 2.05 equiv of (S)-BINAP in toluene at room temperature (Scheme 1). [2b, 4, 7, 8] Aiming to develop arhodium(III) catalytic system, we focused our attention on monohydride rhodium(III) complexes.O ur research was based on the reported reactivity of ethene inserted into aR h À Hb ond of monohydride rhodium(III) complexes bearing dicyclohexyl(2-methoxyethyl)phosphine.…”

“…[5] Thus,h ydrogenation of simple olefins with high enantioselectivity by chiral rhodium systems has remained challenging, [6] despite the tremendous advances in iridium-catalyzed asymmetric hydrogenation of unfunctionalized olefins.I nt his pioneering work, Pfaltz demonstrated the high catalytic performance of P, N-ligated iridium complexes. [10] Asymmetric hydrogenation of heteroaromatics,such as quinolinium salts, [11] quinoxalines, [12] isoquinolinium salts, [13] pyridinium salts, [14] and quinazolinium salts, [15] was accomplished with the latter.A ccordingly,w e envisioned that rhodium analogues could serve as efficient new catalyst precursors,t hat could provide monohydride rhodium(III) species capable of catalyzing the asymmetric hydrogenation of simple olefins.W efound that chiral chloride-bridged dinuclear rhodium(III) complexes proficiently catalyzed the asymmetric hydrogenation of simple olefins,a sw ell as allylic alcohols,a lkenylboranes,a nd unsaturated cyclic sulfones. [9] Previously,wedeveloped chloride-bridged dinuclear iridium complexes that dissociated into the corresponding mononuclear monohydride iridium(III) complexes.…”

“…[2b, 4, 7, 8] Aiming to develop arhodium(III) catalytic system, we focused our attention on monohydride rhodium(III) complexes.O ur research was based on the reported reactivity of ethene inserted into aR h À Hb ond of monohydride rhodium(III) complexes bearing dicyclohexyl(2-methoxyethyl)phosphine. [10] Asymmetric hydrogenation of heteroaromatics,such as quinolinium salts, [11] quinoxalines, [12] isoquinolinium salts, [13] pyridinium salts, [14] and quinazolinium salts, [15] was accomplished with the latter.A ccordingly,w e envisioned that rhodium analogues could serve as efficient new catalyst precursors,t hat could provide monohydride rhodium(III) species capable of catalyzing the asymmetric hydrogenation of simple olefins.W efound that chiral chloride-bridged dinuclear rhodium(III) complexes proficiently catalyzed the asymmetric hydrogenation of simple olefins,a sw ell as allylic alcohols,a lkenylboranes,a nd unsaturated cyclic sulfones. [10] Asymmetric hydrogenation of heteroaromatics,such as quinolinium salts, [11] quinoxalines, [12] isoquinolinium salts, [13] pyridinium salts, [14] and quinazolinium salts, [15] was accomplished with the latter.A ccordingly,w e envisioned that rhodium analogues could serve as efficient new catalyst precursors,t hat could provide monohydride rhodium(III) species capable of catalyzing the asymmetric hydrogenation of simple olefins.W efound that chiral chloride-bridged dinuclear rhodium(III) complexes proficiently catalyzed the asymmetric hydrogenation of simple olefins,a sw ell as allylic alcohols,a lkenylboranes,a nd unsaturated cyclic sulfones.…”

Iridium-catalyzed Asymmetric Hydrogenation of Pyridinium Salts for Constructing Multiple Stereogenic Centers on Piperidines

“…9 In the course of our investigation, we found that salt formation of the substrate facilitated the asymmetric hydrogenation of isoquinolines with high enantioselectivity. 10 We achieved asymmetric hydrogenation of 1,3-disubstituted isoquinolinium salts to construct two stereocenters on a cyclic amine skeleton. Encouraged by this result, we examined the asymmetric hydrogenation of multisubstituted pyridine derivatives in which multiple stereogenic centers can be introduced to the piperidine skeleton in a single operation.…”