Chiral isoquinolines synthesis

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

New modifications of the traditional approach to isoquinoline synthesis via carbocation intermediates continue to be reported. Abnormal products of the Bischler-Napieralski reaction were observed <97JCS(P1)2217>. A stereoselective introduction of a quaternary carbon center in the A-acyliminium cyclization (Scheme 14) of the chiral enamide 46 affords an asymmetric synthesis of tetrahydroisoquinolines <97T2449,3045>. An asymmetric Pictet-Spengler reaction has been developed mediated by the chiral urethane 47 <97T16327>. A Pummerer reaction of A-acyl-A-(aryl)methyl-2-(phenylsulfinyl)ethylamine allows cyclization to the 4-phenylthio-... 

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. 

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 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. 

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. 

The catalytic and chiral efficiency of (S,S)-le was also appreciated in the asymmetric synthesis of isoquinoline derivatives, which are important conformationally constrained a-amino acids. Treatment of 2 with a,a -dibromo-o-xylene under liquid-liquid phase-transfer conditions in the presence of (S,S)-le showed complete consumption ofthe starting Schiffbase. Imine hydrolysis and subsequent treatment with an excess amount of NaHCOs facilitated intramolecular ring closure to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butyl ester 38 in 82% yield with 98% ee. A variety of l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives possessing different aromatic substituents, such as 39 and 40, can be conveniently prepared in a similar manner, with excellent enantioselectivity (Scheme 5.20) [25]. 

Nickel(O) complexes catalyse [2+2+2] cycloaddition. Catalytic asymmetric synthesis of isoquinoline derivative 134 is possible based on enantiotopic group-selective formation of the nickelacyclopentadiene 133 from 132 using the Ni(0) complex coordinated by a chiral ligand under acetylene atmosphere [56]. 

The asymmetric syntheses of tetrahydroisoquinoline derivatives were also reported. Optically pure 3,4-disubstituted tetrahydroisoquinolines such as 78 were prepared by Friedel-Crafts cyclization of amino alcohols 77 <02TL1885>. Enantioselective syntheses of dihydropyrrolo[2,l-a]isoquinolines via a highly diastereoselective, chiral auxiliary assisted N-acyliminium cyclization was disclosed <02SL593>. The enantioselective synthesis (-)-tejedine, a seco-bisbenzyltetrahydroisoquinoline was also reported. One key step in this synthesis involved a chiral auxiliary-assisted diastereoselective Bischler-Napieralski cyclization <02OL2675>. Additionally, an asymmetric Bischler-Napieralski was reported for the preparation of 1,3,4-trisubstituted 1,2,3,4-tetrahydroisoquinolines <02JCS(P1)116>. 

Chiral phosphoramides, particularly C2-symmetric examples, are widely used in asymmetric synthesis (see section 3.2). One example is the asymmetric catalysis of Aldol reactions, where the phosphoramide catalyst is used in combination with a Lewis base. A solid state and solution study of the structure of chiral phosphoramide-tin complexes used in such reactions has now been reported. A number of chiral, non-racemic cyclic phosphoramide receptors (387) have been synthesised and their interactions with homochiral amines studied using electrospray ionisation MS. Although (387) bind the amines strongly, no evidence of chiral selectivity was found. Evidence from a combination of its X-ray structure, NMR, and ab initio calculations suggests that the cyclen phosphorus oxide (388) has an N-P transannular interaction in the solid state. A series of isomers of l,3,2-oxazaphosphorino[4,3-a]isoquinolines(389), containing a novel ring-system, have been prepared and their stereochemistry and conformation studied by H, C, and P NMR spectroscopy and X-ray crystallography... 

Bringman et al. have described a synthesis of the unusual isoquinoline alkaloid ancistrocladine (82) starting from the chiral tetrahydroisoquinoline (79). Conversion of (79) to the ester (80), followed by a palladium catalysed coupling reaction led to the helicene-type lactone (81) which was then easily converted to (82). In a new route to the morphine ring system, Ludwig and Schafer have developed the intramolecular Lewis acid catalysed coupling of the tetrahydroisoquinoline (83) to (84) as a key step.26 The tetracycle... 

For a preparation of alkaloids 35 configurated beyond all doubt, synthetic pathways from the ehiral pool were also elaborated (71). The C3N unit destined to represent the crucial chiral center at C-3 turned out to be the amino acid alanine, in its natural L-form 118, which should easily be incorporated into the isoquinoline framework by reductive amination with the acetophenone 119 and subsequent intramolecular acylation, as outlined in Scheme 29. The practical realization of such a non-biomimetic synthesis (see Scheme 30), however, differs from this very simple concept in three ways ... 

Scheme 30. Synthesis of the isoquinoline moiety 116 of <3-methylancistrocladine (5) from the chiral pool (71).

An enantioselective synthesis of chiral QUINAP 234 was reported by Knochel et al. (07SL2655). The organolithium species obtained from l-(2-bromo-l-naphthyl)isoquinoline by treatment with f-BuLi reacted with (—)-menthyl (S)-p-toluene-sulfinate at-78 °C. The resulting diastereomers were separated via column chromatography. One pot sulfoxide lithium exchange at low temperature, Ph2PCl reaction, sulfur protection with Ss and a Raney-Ni desulfurization step afforded optically pure QUINAP (99% ee) in 60% yield. The s)mthetic route avoided the use of Pd complexes for the resolution. The ees were determined after resulfurization on Chiralcel OD-H. 

Selected recent advances in the stereoselective synthesis of isoquinoline and p-carboline derivatives with the use of chiral auxiliaries of natural origin 05COS301. 

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