Asymmetric Synthesis of Hexahydropyrrolo‐isoquinolines by an Organocatalytic Three‐Component Reaction

Abstract

The pyrrolo-isoquinoline moiety [1] is present in alkaloid families such as erythrines, [2] lamellarins, [3] and pyrroloA C H T U N G T R E N N U N G [2,1-a]isoquinoline derivatives, [4, 5] all of which exhibit biological activities. The importance of this heterocyclic system is further enhanced by its utility as an intermediate for the synthesis of alkaloids.[1] Consequently, the interest in new synthetic methodologies for this moiety has increased.[6] Three strategies have been developed for the asymmetric construction of polyhydropyrroloA C H T U N G T R E N N U N G [2,1-a]isoquinoline derivatives: a) N-acyliminium cyclization, [7] b) Mitsunobu reaction of optically pure 3-(tetrahydroisoquinolin-1-yl)propan-1-oles, [4a, 8] and c) asymmetric hydrogenation of prochiral iminium salts with a chiral metal complex. [4b, 9] A diastereoselective route to this moiety involving a [3+2]-cycloaddition of 3,4-dihydroisoquinolinium ylides to chiral dipolarophiles was recently presented. [10] One strategy to optically active polysubstituted pyrrolidines is the metal- [11] or organocatalyzed [11c, 12] [3+2]-cycloaddition of alkenes with azomethines. However, these reactions focus on a-iminoesters as azomethine ylide precursors and only recently has an organocatalytic [3+2]-cycloaddition of azomethine ylides to a,b-unsaturated aldehydes been presented.[13]Herein we present a new multicomponent [14] concept for the construction of hexahydropyrroloA C H T U N G T R E N N U N G [2,1-a]isoquinoline derivatives. The concept is based on a [3+2]-cycloaddition reaction of in situ generated dihydroisoquinolinium ylides, from the corresponding imines and a-bromoesters or ketone, [15] to a,b-unsaturated aldehydes, and is catalyzed by a chiral pyrrolidine in the presence of a base (Scheme 1). This multicomponent approach allows the formation of two new CÀC bonds, a CÀN bond, and four stereocenters in one-step.The three-component reaction between 6,7-dimethoxy-3,4-dihydroisoquinoline HCl (1 a), methyl 2-bromopropanoate (2 a), and cinnamic aldehyde (3 a) was the model system for optimization of the experimental parameters. [16] (S)-2-(Diphenyl(trimethylsilyloxy)methyl)pyrrolidine (4 a),[17] Na 2 CO 3 , CH 2 Cl 2 , and room temperature were the best conditions for the [3+2]-cycloaddition and gave the optically active product, as the conjugated ester 5 a, in high yields, good diastereoselectivity and an excellent enantioselectivity of 95 % ee.The scope of the three-component [3+2]-cycloaddition using different a,b-unsaturated aldehydes is given in Table 1.

Recent advances in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides

“…82 The reaction catalyzed by diphenyl-prolinol 32 proceeded with high enantioselectivity for a variety of aldehydes, imines and a-bromo derivatives. The resulting adducts were directly transformed into a,b-unsaturated esters by standard Wittig olefination (Scheme 33).…”

Stereoselective Organocatalytic Addition of Nucleophiles to Isoquinolinium and 3,4-dihydroisoquinolinium Ions: A Simple Approach for the Synthesis of Isoquinoline Alkaloids

“…The pyrrolo-isoquinoline moiety, that is present in the alkaloid families of erythrines [84] and lamellarins [85], is one of the structures that can be accessed through a multicomponent reaction. In 2012 Jørgensen reported [86] a three-component organocatalytic asymmetric reaction of imines, a-bromoesters or a-bromoketones with a,b-unsaturated aldehydes to give optically active pyrrolo-isoquinolines 64, with excellent enantioselectivity for a large number of substituents showing broad scope for this reaction (Scheme 21). Computational studies shed light on the reaction pathway that proceeded in a stepwise manner.…”

Formal [3 + 2] cycloaddition of azomethine ylides generated in situ with unactivated cyclic imines: A facile approach to tricyclic imidazolines derivatives

“…In 2014, the first enantioselective inverse electron demand imino Diels‐Alder reaction is described by Waldmann and co‐workers between electron‐poor chromone dienes and cyclic imine . In 2012, Jørgensen and co‐workers developed a three‐component organocatalytic asymmetric reaction of cyclic imines, α‐bromoesters, or ketone with α,β‐unsaturated aldehydes to give optically active pyrrolo‐isoquinolines . The other examples of cyclic imines as a substrate, such as directly coupled with carboxylic acids or nitro‐mannich/lactamization cascades or condensation reaction had been developed.…”