Chiral isoquinolines

The preparation of chiral isoquinoline derivatives continued to be investigated. Sulfanamide 59 was prepared by addition of a lateral lithiated o-toluonitrile with the corresponding sulfinimine. Treatment of 59 with MeLi followed by acidification afforded cyclic imine 60. Reduction of imine 60 with liAlHi/MejAl afforded the trans-1,3 derivative, and... 

The Ru-BINAP system has shown excellent enantioselectivity in hydrogenation of (Z)-N-acyl-1-alkyl idenetetrahydroisoquinolines 54. Thus, a series of chiral isoquinoline products 55 can be efficiently synthesized.44... 

The intramolecular addition of amines to chiral vinylic sulfoxides has been investigated by Pyne and coworkers as an approach to various chiral natural products such as ( )-(+)-carnegine (86) [60, 61] and (+) and (-)-sedamine (87) [61]. As an outline of this methodology, Pyne s approach to the chiral isoquinoline, ( )-(+)-carnegine (86), is described below. 

Sdnchez-Sancho, F., Mann, E. and Herradon, B. (2001) Efficient synthesis of chiral isoquinoline and pyrido[l,2-6]-isoquinoline derivatives via intramolecular Heck reactions. Adv. Synth. Catal., 343, 360-8. 

Maikov AV, Rami rez-Lopez P, Biedermannova L (nee Bendova), Ruh sek L, Dufkova L, Kotora M, Zhu F, Ko ovsky P. On the mechanism of asymmetric allylation of aldehydes with allyltrichlorosilanes catalyzed by QUINOX, a chiral isoquinoline A-oxide. J. Am. Chem. Soc. 2008 130 5341-5348. 

With a chiral phenylglycinol nucleophile (Scheme 8.4.17), use of the chloride Zincke salt 6 (cf. Scheme 8.4.16) gave decomposition of the salt back to isoquinoline and 2,4-dinitrochlorobenzene. The desired reaction was enabled by exchanging chloride for the weakly nucleophilic dodecyl sulfate anion. The resulting salt 49 also had improved... 

The high enantioselectivity of the exo product opens up a new and readily accessible route to an enantioselective synthesis of interesting isoquinoline alkaloids (Scheme 6.15) [35]. The tricyclic isoxazolidine exo-15b was obtained from the 1,3-dipolar cydoaddition reaction as the pure exo isomer and with 58% ee [34]. As shown in Scheme 6.15 the exo product from the 1,3-dipolar cydoaddition was converted into 17 in two steps without racemization at the chiral center. In addition to the illustrated synthesis, the 6,7-dimethoxy-derived isoxazolidine exo-15b is a very useful precursor for the synthesis of naturally occurring isoquinoline alkaloids [36-40]. 

An asymmetric synthesis of 1-aryltetrahydroisoquinolines 79 from chiral amide 78 was reported <96TL(37)4369>. Optically active cis- or rranj-1,3-disubstituted tetrahydro-isoquinolines can he prepared hy a modification of this procedure. 

The Rh-catalysed asymmetric hydrosilylation of prochiral ketones has been studied with complexes bearing monodentate or heteroatom functionalised NHC ligands. For example, complexes of the type [RhCl(l,5-cod)(NHC)] and [RhL(l,5-cod)(NHC)][SbFg ], 70, where L = isoquinoline, 3,5-lutidine and NHC are the chiral monodentate ligands 71 (Fig. 2.11). 

Catalytic properties of external chiral additives such as (2S,3/ )-4-dimethyl-amino-l,2-diphenyl-3- methyl-2-butoxide (A 16) (574, 575) and 2-magnesium-3-zinc salts of dialkyl (f ,f )-tartrate (A17) were employed in the highly stereoselective addition of organozinc reagents to derivatives of 3,4-dihydro-isoquinoline-A-oxide (Scheme 2.147) (576). 

The first successful axially chiral phosphinamine ligand in asymmetric catalysis was QUINAP 60 (Figure 8) reported by Brown in 1993 and the original synthesis has since been modified.94 The donor nitrogen atom is incorporated in an isoquinoline unit to form a six-membered chelate ring. 

Several further publications report on the (—)-sparteine-mediated addition of alkyl-or aryllithium onto imines or the C=N bond of isoquinolines . Usually, the achieved enantiomeric excesses are low and, sometimes, other chiral ligands serve better. As reported by Muller and coworkers, the nucleophilic substitution of arenecarbaldehyde dialkyl acetals by o-substituted aryllithium reagents is an alternative . 

Benzylated 1,2,3,4-tetrahydroisoquinolines possess important physiological properties and, as illustrated in Scheme 20, also serve as common intermediates for synthesis of naturally ubiquitous isoquinoline alkaloids with different skeletons. Because some natural products have the 1/ configuration while the others possess the IS configuration, the synthesis must be chirally flexible. 

---