Atroposelective Total Synthesis of the Fourfold ortho‐Substituted Naphthyltetrahydroisoquinoline Biaryl O,N‐Dimethylhamatine

Abstract

As tereoselective total synthesis of O,N-dimethylhamatine, an analogueo fa na xially chiral naphthylisoquinoline natural biaryl product from tropical Ancistrocladus lianas, is reported. The route featuresalate-stage atropo-diastereoselective biarylb ond formation. Generationo ft his especially challenging, sterically hinderedt etra-ortho-substituted array was achieved by using Nolan's (IPr*NHC)PdCinCl pre-catalyst undermild Negishicoupling conditions. Discussion is offered regarding the selectivity obtained experimentally and predictedf rom DFT calculations on the keyb iaryl coupling step that leads to the desired M-diastereomer. Figure 1. Structures of tetra-ortho-substituted biarylt etrahydroisoquinolines.[a] Dr.

N2Phos – an easily made, highly effective ligand designed for ppm level Pd-catalyzed Suzuki–Miyaura cross couplings in water

“…The enhanced proximity of the two phenyl rings could translate into an increased rate of reductive elimination for the N 2 Phoscontaining intermediate compared with that with EvanPhos in this complex. 41 The explanation can be attributed to the N,Ndibenzyl moieties of the naphthyl ring, such that the -NBn 2 residues signicantly crowd the available space around palladium, thereby forcing the two phenyl rings into closer proximity and increasing their rate of reductive elimination. No such phenomenon is in play with EvanPhos.…”

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

“…However, the subsequent attempts to transform 13 a into the corresponding arylboron species for Suzuki–Miyaura coupling were unsuccessful, mainly due to the competing deiodination side reaction. Nevertheless, an efficient iodine‐magnesium exchange was delightfully achieved upon treatment of 13 a with the Turbo Grignard reagent ( i PrMgCl⋅LiCl), [33] which further led to arylzinc reagent 14 through transmetalation [9g, 34] . Gratifyingly, promoted by the catalyst Pd(PPh 3 ) 4 , the late‐stage Negishi coupling [9g, 34] between 13 b and the in situ formed organozinc reagent 14 proceeded smoothly to furnish the key heterodimer intermediate 15 in 63 % yield.…”

“…Nevertheless, an efficient iodine‐magnesium exchange was delightfully achieved upon treatment of 13 a with the Turbo Grignard reagent ( i PrMgCl⋅LiCl), [33] which further led to arylzinc reagent 14 through transmetalation [9g, 34] . Gratifyingly, promoted by the catalyst Pd(PPh 3 ) 4 , the late‐stage Negishi coupling [9g, 34] between 13 b and the in situ formed organozinc reagent 14 proceeded smoothly to furnish the key heterodimer intermediate 15 in 63 % yield. Ultimately, a Pd/C‐catalyzed hydrogenolysis of 15 removed all the protecting groups (six benzyl groups and two Cbz groups) efficiently to complete the total synthesis.…”

Design, synthesis, and evaluation of cytotoxic activities of arylnaphthalene lignans and aza‐analogs

“…Here too, the most significant obstacle in this scheme was the regioselective aromatic bromination as it has been strongly affected by the solvents and brominating agents used together with the substituents on the naphthalene core. [48][49][50][51][52][53][54][55][56][57][58][59][60][61] So, several parameters were examined and trials have been carried out to control the regioselectivity. The best conditions found were, on the one hand, reaction of 1 with pyridinium tribromide at 0°C in tetrahydrofuran (THF), [50] which gave the 3-bromo compound 15 in excellent yield without producing the 1-regioisomer (Scheme 6).…”