Unprecedented Direct Asymmetric Total Syntheses of 5,8’‐Naphthylisoquinoline Alkaloids from their Fully Substituted Precursors Employing a Novel Nickel/N,N‐ligand‐Catalyzed Atroposelective Cross‐Coupling Reaction

Abstract

A general and concise synthetic pathway for the preparation of four different 5,8’‐coupled naphthylisoquinoline alkaloids, employing a specially developed nickel/N,N‐ligand‐catalyzed atroposelective Negishi coupling is reported. In the first reported direct atroposelective coupling of the fully substituted precursors, the naturally occurring cross‐coupled products were generally obtained directly in reasonable yields and high optical purities. For the synthesis of the cross‐coupling precursors, we employed a modification of Bringmann’s known approach to the dihydroisoquinoline compounds and a newly developed route for the naphthalene building blocks. For the latter 1,8‐dioxynaphthalene precursors, our strategy utilized Hartwig’s borylation/methylation approach and included the efficient installation of orthogonal protecting groups.

Atroposelective NiII‐Catalyzed Cross‐Coupling Reactions Enable a Deeper Understanding of Negishi Couplings: Isolation and Application of Solid Aryl Higher‐Order Zincates

“…Our first indication on the special role of salts present in the Negishi cross-coupling reaction was due to our observations during the optimization of an atroposelective, [9] Ni II /N,N-ligand-catalyzed cross-coupling reactions employing Lassaletta's ligand [10] reaction towards the synthesis of the two naphthylisoquinoline enantiomers Ancistrolikokine J 3 (1) and Ancistrobreveine D (ent-1). [11] To our surprise, the outcome of the synthesis of either of these two enantiomeric natural products was dependent on the method applied for the synthesis of the zinc reagent and its accompanying salt additives, rather than the added salt additives alone. As it is depicted in Table 1, we only obtained the desired natural products 1 or ent-1, respectively, if the zinc reagent was prepared via the transmetallation of an previously generated organolithium or Grignard reagent (Table 1, entry 6 and 7).…”

“…[15] Noteworthy, its stoichiometric composition corresponded to the transmetallating higher-order ate-species postulated by Böhrer and Organ (Scheme 2b). [5] Applying this procedure for different aryl zinc reagents several other higher-order zincates (11)(12)(13)(14)(15)(16)(17)(18)(19) have been isolated as solids in general high yields (Scheme 2c). [16.17] In our experience, it was reasonably simple to store these higher-order zincate reagents in a glove-box under inert conditions, however, we were also interested in evaluating their stabilities under air, as we handled them usually during reaction set-up.…”

“…[c] Zinc reagent was prepared from 1-iodonaphthalene (10) via insertion of Zn dust in DMF. [d] Zn reagent was prepared from 1-bromonaphthalene(11) via BrÀ Li-exchange and subsequent transmetallation to ZnBr 2 . [e] Zn reagent was prepared from 1-bromonaphthalene(11) via Grignard reaction and subsequent transmetallation to ZnBr 2 .…”

“…[d] Zn reagent was prepared from 1-bromonaphthalene(11) via BrÀ Li-exchange and subsequent transmetallation to ZnBr 2 . [e] Zn reagent was prepared from 1-bromonaphthalene(11) via Grignard reaction and subsequent transmetallation to ZnBr 2 . [f] Enantiomeric excesses were determined by chiral HPLC analysis.…”

C–H borylation: a tool for molecular diversification

“…These compounds have axial chirality and exhibit different biological properties as well as being active against the pancreatic cancer cell line. 105 Recently, Otterlo et al reported 106 the total synthesis of ancistrolikokine J 3 where a C–H borylation followed by methylation is an important step. They borylated ( 154 ) under iridium-catalyzed conditions to achieve ( 155 ), which was then employed for methylation utilizing Hartwig's methylation protocols 107 to obtain ( 156 ).…”