2013
DOI: 10.1002/anie.201207748
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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… Show more

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Cited by 144 publications
(41 citation statements)
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“…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.…”
Section: Introductionmentioning
confidence: 99%
“…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.…”
Section: Introductionmentioning
confidence: 99%
“…[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.…”
mentioning
confidence: 99%
“…[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.…”
mentioning
confidence: 99%
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“…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.…”
mentioning
confidence: 99%