In the past decade, the asymmetric synthesis of chiral nonracemic isoquinoline alkaloids, a family of natural products showing a wide range of structural diversity and biological and pharmaceutical activity, has been based either on continuation or improvement of known traditional methods or on new, recently developed, strategies. Both diastereoselective and enantioselective catalytic methods have been applied. This review describes the stereochemically modified traditional syntheses (the Pictet–Spengler, the Bischler–Napieralski, and the Pomeranz–Fritsch–Bobbitt) along with strategies based on closing of the nitrogen-containing ring B of the isoquinoline core by the formation of bonds between C1–N2, N2–C3, C1–N2/N2–C3, and C1–N2/C4–C4a atoms. Methods involving introduction of substituents at the C1 carbon of isoquinoline core along with syntheses applying various biocatalytic techniques have also been reviewed.

Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015

Tetrahydroisoquinoline alkaloids with a C1 stereo- genic center are a common unit in many natural and non- natural compounds of biological importance. Herein we describe a novel Cu I -catalyzed highly chemo- and enantiose- lective synthesis of chiral tetrahydroisoquinoline-alkaloid derivatives from readily available unsubstituted tetrahydroiso- quinolines, aldehydes, and terminal alkynes in the presence of the ligand (R,R)-N-pinap. This synthetic operation installs two substituents in the 1- and 2-positions. 1I

Enantioselective double manipulation of tetrahydroisoquinolines with terminal alkynes and aldehydes under copper(I) catalysis.

Biologically active tetrahydroisoquinolines having a chiral stereocenter at the C1-position are commonly found in nature and also in synthetic molecules, and therefore, the catalytic asymmetric synthesis of these valuable building blocks has been explored as a worthwhile research area during the past decade. In addition to asymmetric hydrogenation, catalytic asymmetric C C bond formation by nucleophilic addition to dihydroisoquinolines or isoquinolines has been given much attention in this regard. Despite these efforts, there has been only one early report, by Shibasaki and co-workers in 2001, wherein dihydroisoquinolines having two different functionalities at the C1-position (tetrasubstituted carbon center) could be successfully generated in a catalytic asymmetric manner. Although a decade has passed since their pioneering discovery, no viable alternative to achieve this goal has emerged to date. During our studies on the use of C,N-cyclic azomethine imines (e.g. 1a ; Scheme 1) in the context of catalytic asymmetric 1,3-dipolar cycloadditions, we became aware of their unique ability to act as prochiral electrophiles to dihydroisoquinolines. Namely, the copper-catalyzed reaction of 1a with phenylacetylene furnished the alkynylation product and not the [3 + 2] cycloadduct, in contrast to the reaction of N,N’-cyclic azomethine imines, reported by Fu. Although the asymmetric alkynylation of N-alkyl and N-aryl dihydroisoquinolinium salts has already been reported as a comparable method by Schreiber and Taylor, and Li and coworkers, respectively, these studies exhibited rather limited substrate scope or only modest selectivity. What is even more important is the inability of this procedure to construct an asymmetric tetrasubstituted carbon center; Schreiber and Taylor only reported a racemic product, thus clearly leaving room for further development. We report herein, the exploration of our alkynylation as a novel direct catalytic asymmetric method to provide a variety of chiral C1-alkynyl tetrahydroisoquinolines. This investigation led to the discovery of a highly enantioselective alkynylation of azomethine imines catalyzed by a Cu/Phpybox complex (pybox = 2,6-bis(2-oxazolinyl)pyridine). This reaction has a remarkably broad substrate scope in terms of the aromatic substituents of the azomethine imines and the terminal alkynes. Although we faced the difficulty of attaining high enantioselectivity when using C1-substituted azomethine imines for the challenging formation of a tetrasubstituted carbon center, this issue could be successfully overcome by the addition of an axially chiral dicarboxylic acid, originally developed in this laboratory, as a key co-catalyst. We commenced the study by screening the commercially available chiral ligands that are commonly used in coppercatalyzed asymmetric transformations, for the reaction of C,N-cyclic azomethine imine 1a and phenylacetylene (Table 1). Among the chiral bis(oxazoline) and pybox ligands that were examined at 20 mol % catalyst loading, (R,R)-Ph-pybox L5 exhibited the best results, giving 2a in 90% yield with 95% ee (Table 1, entries 2–6). The amount of the catalyst could then be decreased to 5 mol% without compromising the yield or selectivity (Table 1, entry 7). The choice of the copper source also had a significant impact on

Catalytic Asymmetric Alkynylation of C1‐Substituted C,N‐Cyclic Azomethine Imines by CuI/Chiral Brønsted Acid Co‐Catalyst

A comprehensive study of the enantioselective Pd-catalyzed α-arylation of N-Boc pyrrolidine has been carried out. The protocol involves deprotonation of N-Boc pyrrolidine using s-BuLi/(−)-sparteine in TBME or Et2O at −78 °C, transmetalation with ZnCl2 and Negishi coupling using Pd(OAc)2, t-Bu3P-HBF4 and the aryl bromide. This paper reports several new features including in situ React IR spectroscopic monitoring of the process; use of (−)-sparteine and the (+)-sparteine surrogate to access products with opposite configuration; development of a catalytic asymmetric lithiation–Negishi coupling reaction; extension to a wide range of heteroaromatic bromides; total synthesis of (R)-crispine A, (S)-nicotine and (S)-SIB-1508Y via short synthetic routes; and examples of α-vinylation of N-Boc pyrrolidine using vinyl bromides exemplified by the total synthesis of naturally occurring (+)-maackiamine (thus establishing its configuration as (R)). In this way, the full scope and limitations of the methodology are deline...

Enantioselective, palladium-catalyzed α-arylation of N-Boc pyrrolidine: in situ react IR spectroscopic monitoring, scope, and synthetic applications.

It takes three to make things go right: The first direct asymmetric three-component reaction of aldehydes, carbamates, and allyltrimethylsilane leading to enantioenriched homoallylic amines has been developed using a new chiral disulfonimide catalyst. The method employs readily available, inexpensive, and nontoxic starting materials and is applicable to both aromatic and aliphatic aldehydes.

Catalytic asymmetric three-component synthesis of homoallylic amines.

A catalytic asymmetric allylation of 3,4-dihydroisoquinoline was carried out with allyltrimethoxylsilane-Cu as the nucleophile in the presence of DTBM-SEGPHOS as the chiral ligand to afford corresponding chiral 1-allyltetrahydroisoquinoline derivatives in good yield and stereoselectivity. The allyl adduct thus obtained was applied to the synthesis of several isoquinoline alkaloids such as crispine A and homolaudanosine. The reaction was further used for the synthesis of the isoquinoline moiety of schulzeine A.

Catalytic asymmetric allylation of 3,4-dihydroisoquinolines and its application to the synthesis of isoquinoline alkaloids.

An improved method allows formation of the 1-allylated tetrahydroisoquinolines (S)- and (R)-(III) with good enantioselectivity.

Yuki Seito

Papers

Catalytic asymmetric allylation of 3,4-dihydroisoquinolines and its application to the synthesis of isoquinoline alkaloids.

Catalytic Asymmetric Allylation of 3,4‐Dihydroisoquinolines and Its Application to the Synthesis of Isoquinoline Alkaloids.