The Stereoselective Total Synthesis of Axially Chiral Naphthylisoquinoline Alkaloids

Abstract

Metrics & MoreArticle Recommendations * sı Supporting Information CONSPECTUS: The naphthylisoquinoline (NIQ) alkaloids are a thrilling class of natural biaryls�structurally, biosynthetically, and pharmacologically. A common feature of these metabolites is the biaryl bond between their naphthalene and isoquinoline moieties, which in most cases is rotationally hindered, leading to the phenomenon of axial chirality. Depending on their individual structures, including the respective axial configurations, NIQs show promising bioactivities. Their total synthesis is a challenging but rewarding goal, with the stereocontrolled construction of the biaryl linkage as the key step.The position of the biaryl axis and its configuration determine the overall molecular shape and thus the choice of the best possible method for efficient asymmetric aryl−aryl bond formation. The axis in NIQs can cover a broad range of steric hindrance, from freely rotating to configurationally stable. For dioncophylline B (1) and dioncophylline F (2a/b), with only two ortho-substituents next to the axis, the synthesis is easy to accomplish by direct coupling of the intact naphthalene moiety with the isoquinoline unit, and no atropo-selectivity is required.Naphthylisoquinolines with a configurationally stable biaryl axis are the focus of the present Account. They are more difficult to synthesize because, in addition to the problem of decreased chemical yields with increasing steric hindrance at the axis, the synthesis needs to proceed stereoselectively. Within this class of NIQs, 5,8′-coupled representatives, such as korupensamine A (3a), have received considerable synthetic attention because the rotational barrier is high enough for the existence of atropisomerism without being too excessive, and they show potent bioactivities. Their synthesis, as systematically presented herein, thus occupies a central role in this report. For their aryl−aryl bond formation, both intra-and intermolecular approaches can be successfully applied. Axial stereoinformation is introduced by internal asymmetric induction from stereogenic elements already present in the isoquinoline or its precursors, from chiral auxiliary elements artificially introduced, or by external asymmetric induction using chiral catalysts.To overcome even higher steric hindrance, as in ancistrocladine (4a), innovative approaches were developed. A most successful strategy is the "lactone concept" developed by the Bringmann group, which allows the directed synthesis of any desired atropisomer in high chemical and optical yields, thus permitting the atropo-divergent preparation of the two isomers from a single joint precursor. In this approach, the two formal tasks of stereoselective biaryl synthesis, which are usually done simultaneously�the C−C linkage and the asymmetric induction�are achieved consecutively. The coupling step is performed intramolecularly after prefixation of the coupling partners by an ester bridge. The resulting biaryl lactone already possesses the biaryl axis but is still configu...

Rh(III)-Catalyzed Enaminone-Directed C–H Coupling with Diazodicarbonyls for Skeleton-Divergent Synthesis of Isocoumarins and Naphthalenes

“… Our C carbonyl –C β bond is less polarized and contrasts with these conventional bonding systems. Naphthalenes are also critical molecular components in many academic and industrial applications . Our previous Rh­(III) catalysis protocol using enaminones and diazoketoesters features the exclusive generation of a naphthalene skeleton, and no isocoumarin scaffold has been identified…”

Korupensamine A, but not its atropisomer, korupensamine B, inhibits SARS-CoV-2 in vitro by targeting its main protease (Mpro)

“…Due to the existence of more or less bulky ortho -substituents, most of these alkaloids show the phenomenon of hindered rotation about that central biaryl axis, which – in most cases - leads to rotationally stable atropisomers [ [30] , [31] , [32] , [33] ]. Atropisomerism as an important structural feature of these alkaloids constitutes a synthetic challenge for their directed, stereoselective production that has been addressed in numerous elegant total syntheses [ 34 , 35 ]. One motivation for these synthetic efforts is the fact that, depending on their individual structures, naphthylisoquinoline alkaloids exhibit pronounced anti-malarial [ 32 , [36] , [37] , [38] , [39] ], anti-trypanosomal [ 30 , 32 , 40 ], anti-leishmanial [ 31 , 32 , [40] , [41] , [42] , [43] ], anti-bacterial [ 32 , 44 ], anti-fungal [ 32 ], larvicidal [ 45 ], molluscicidal [ 46 , 47 ], insecticidal [ 48 , 49 ], antibabesial [ 50 ], or cytotoxic activities against leukemia [ 51 ] and various cancer cell lines [ [52] , [53] , [54] , [55] ].…”

Advances in Atroposelectively De Novo Synthesis of Axially Chiral Heterobiaryl Scaffolds

“…Although Christie and Kenner resolved the stable isomers of 6,6′-dinitro-2,2′-diphenic acid as early as 1922 [ 4 ], the importance of atropisomerism was only realized after the pioneering work of Noyori and Takaya in 1980, in which atropisomeric chiral BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) was successfully applied as a ligand for rhodium-catalyzed asymmetric hydrogenation of α-(acylamino) acrylic acids [ 4 , 5 ]. Since then, atropisomerically chiral catalysis has received remarkable attention, and axially chiral heterobiaryl frameworks have, thus, been recognized as a privileged structure in many natural products, pharmaceutically active molecules, and chiral ligands ( Figure 1 ) [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. For example, natural products with the heterobiaryl skeleton, such as Ancistrocladinium A , Rivularin D 3 , Murrastifoline F , and Marinopyrrole A , were isolated from marine blue-green alga Rivularia firma , Murraya koenigii , and actinomycete strain CNQ-418, and some of these products exhibit excellent activities in antimicrobial bioassays ( Figure 1 A) [ 14 , 15 , 16 ].…”