A Modular Approach for Diversity‐Oriented Synthesis of 1,3‐trans‐Disubstituted Tetrahydroisoquinolines: Seven‐Step Asymmetric Synthesis of Michellamines B and C

Abstract

1,3-trans-Disubstituted tetrahydroisoquinoline (THIQ) is a common heterocyclic structural unit of naphthylisoquinoline alkaloids. The assembly of this structural unit is not trivial, which constitutes a substantial challenge in the total synthesis of naphthylisoquinoline alkaloids and related pharmaceuticals. Herein, we report a modular and convergent method for the rapid assembly of 1,3-trans-disubstituted THIQ frameworks through a three-component Catellani reaction and a Au I -catalyzed cyclization/reduction cascade. With widely available simple aryl iodides, aziridines and (triisopropylsilyl)acetylene as the building blocks, this method paves a practical way for the diversity-oriented synthesis of 1,3-trans-disubstituted THIQs. Based on this new method, concise syntheses of an analogue of the new drug mevidalen and four naphthylisoquinoline alkaloids have been accomplished, demonstrating the broad synthetic utility of this approach.

Benzo-Fused-Ring Toolbox Based on Palladium/Norbornene Cooperative Catalysis: Methodology Development and Applications in Natural Product Synthesis

“…As illustrated in Figure 1C, we first planned to exploit readily available epoxides and N-substituted aziridines as bifunctional alkylating reagents, which would not only enable the ortho C−H alkylation of aryl iodides but also get involved in the ipso termination or cyclization with the ipsotermination motif by the in-situ-generated nucleophilic heteroatom (via intermediate I). [1][2][3][4]18,19 Thus, a series of valuable benzo-fused heterocycles (e.g., isochromans, 1 dihydrobenzofurans (DHBF), 18a 1,3-cis-THIQs (tetrahydroisoquinolines), 2 1,3-trans-THIQs, 4 1-substituted methylene-THIQs, 19 etc. 18b ) could be constructed efficiently.…”

“…On the basis of our previous research for the rapid assembly of 1,3-cisdisubstituted THIQ, we also developed a modular and convergent method for rapid assembly of the more challenging 1,3-trans-disubstituted THIQs via a three-component Catellani reaction and an Au(I)-catalyzed cyclization/reduction cascade (Scheme 5A and 5B). 4 First, 2′-alkynylaryl-2-ethylamines 23 were quickly constructed from aryl iodides (1), 1,2-disubstituted aziridines (17), and (triisopropylsilyl)acetylene (8a) through Pd/NBE cooperative catalysis and in-situ desilylation (Scheme 5A). Then, an Au(I)-catalyzed cyclization of 23 followed by an in-situ enamine reduction by TFA/Et 3 SiH afforded a series of 1,3-trans-disubstituted THIQs (25) in moderate to high yields with excellent diastereoselectivities (Scheme 5B).…”

“…Retrosynthetically, we hypothesized that the naphthylisoquinoline unit could be introduced by a Suzuki coupling, referring to Tang's work, 54 and the 1,3-transdisubstituted THIQ core could be constructed via a Catellani reaction and an Au(I)-catalyzed cyclization/reduction cascade (Scheme 15A). 4 The synthesis began with the gram-scale preparation of 1,3-trans-disubstituted THIQ 25e from simple building blocks aryl iodide 1p, aziridine 17g, and terminal alkyne 8a in two steps (Scheme 15B). Iodination and Suzuki−Miyaura coupling gave the desired axially chiral intermediates 56a and 56b.…”

“…The diastereoisomers 56a and 56b were readily separated by preparative HPLC, which underwent a global deprotection through catalytic hydrogenation to provide korupensamines A and B in excellent yields, respectively. 4 Next, 56a and 56b were used as building blocks to assemble the more challenging dimers michellamines B and C (Scheme 16). A regioselective iodination of 56a and 56b with NIS and TFA afforded aryl iodides 58a and 58b, respectively.…”