Iridium-Catalyzed Asymmetric Cascade Allylation/Pictet–Spengler Cyclization Reaction for the Enantioselective Synthesis of 1,3,4-Trisubstituted Tetrahydroisoquinolines

Abstract

An iridium-catalyzed trifluoroacetic acid-promoted asymmetric cascade allylation/Pictet–Spengler cyclization reaction of azomethine ylides with aromatic allylic alcohols is reported. This protocol provides a facile and scalable method for the construction of 1,3,4-trisubstituted tetrahydroisoquinolines containing two stereogenic centers in good yields (up to 96%) with generally excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). Furthermore, a series of aromatic heterocycle-fused piperidines were also obtained with excellent enantiocontrol by this methodology.

Stereoselective Synthesis of Azacycles Induced by Group 8–11 Late Transition Metals

“…The Deng group used this catalyst system with enantiomeric (S)-11 ligand and found excellent results in the synthesis of 1,3,4-trisubstituted tetrahydroisoquinolines at room temperature (Scheme 16). [23] The 1-cyclohexyl derivative was highly unreactive (a yield of 20 %) and gave similar low selectivity values (45 % ee, 8 : 1 d.r.). Formation of the highly substituted products with multiple stereogenic centers was accounted for by an asymmetric cascade allylation/Pictet-Sprengler cyclization.…”

Recent Developments in Enantioselective Domino Reactions. Part A: Noble Metal Catalysts

“…The same year, chiral cyclic phosphoramidite ligand 333 was employed by Deng and Yang at 8 mol% of catalyst loading in combination with only 2 mol% of [Ir(cod)Cl] 2 as precatalyst to promote enantioselective domino allylation/Pictet−Spengler cyclization reaction of imino esters 335 with aromatic allylic alcohols 334 [95] . The reaction performed at room temperature in chloroform as solvent in the presence of one equivalent of CF 3 CO 2 H as superstoichiometric additive resulted in the formation of chiral 1,3,4‐trisubstituted tetrahydroisoquinolines 336 exhibiting two stereocenters in good yields (55–96%) with moderate to high diastereoselectivities (34–88% de ) and uniformly excellent enantioselectivities (94–>99% ee ), as illustrated in Scheme 85.…”

“…[94] The process was catalyzed by a combination of 4 mol% of [Ir(cod)Cl] The same year, chiral cyclic phosphoramidite ligand 333 was employed by Deng and Yang at 8 mol% of catalyst loading in combination with only 2 mol% of [Ir(cod)Cl] 2 as precatalyst to promote enantioselective domino allylation/PictetÀ Spengler cyclization reaction of imino esters 335 with aromatic allylic alcohols 334. [95] The reaction performed at room temperature in chloroform as solvent in the presence of one equivalent of CF 3 CO 2 H as superstoichiometric additive resulted in the formation of chiral 1,3,4-trisubstituted tetrahydroisoquinolines 336 exhibiting two stereocenters in good yields (55-96%) with moderate to high diastereoselectivities (34-88% de) and uniformly excellent enantioselectivities (94-> 99% ee), as illustrated in Scheme 85. The scope of the methodology was extended to heteroaromatic allylic alcohols 337 and 339, delivering the corresponding chiral heterocyclefused piperidines 338 and 340 in high yields (70-91%), moderate to excellent diastereoselectivities (34-> 90% de) and excellent enantioselectivities (97-> 99% ee), as shown in Scheme 85.…”

Recent advances in iridium-catalyzed enantioselective allylic substitution using phosphoramidite-alkene ligands

“…Yang and Deng reported an asymmetric cascade allylation/Pictet–Spengler cyclization to give 1,3,4-trisubstituted tetrahydroisoquinolines (Scheme 22). 67 Alcohol 40 reacted with imino ester 41 to give the cyclization product 42 in excellent diastereo- and enantioselectivity. Azomethine ylide is generated in situ by protonation of imino ester 41 .…”