Isoquinolines asymmetric hydrogenation

Asymmetric hydrogenation of Scheme 1.101 provides a general route to isoquinoline alkaloids (see Section 1.3.1.1). An imine substrate is hydrogenated with the chiral titanocene (/ )-34 to give the S product with 98% ee [346a,b,352], A neutral BCPM-Ir complex with phthalimide in toluene also shows high enantioselection [358]. The choice of a weakly polar... 

The optically active isoquinoline derivative 30 was prepared by asymmetric hydrogenation of the l-benzylidene-l,2,3,4-tetrahydroisoquinoline 29 catalysed by 27, and optically pure tetrahydropapaverine (31) is synthesized by this method [28]. 

Table 6.6 Asymmetric hydrogenations of 1 substituted isoquinolines in the presence of chloroformates and lithium salts [134].

Asymmetric hydrogenation of isoquinolines activated by chloroformates also... 

Asymmetric Hydrogenation of Isoquinolines 321 Table 10.8 Asymmetric reduction of 2 substitued quinolines by Du. 

Two ruthenium complexes, binap 3.43-Ru(OCOR)2(R = Me,CF3) [892] and binap 3.43-RuX2 (X = Cl, Br, I) [893, 894], are quite useful. The acetate and trifluoroacetate complexes of 3.43 induce selective asymmetric hydrogenations of classes of prochiral olefins that are poorly selective with rhodium complexes. These classes include a,(3- or fcy-unsaturated acids and esters, ally alcohols, j3-acylaminoacrylates and enamide precursors of isoquinoline alkaloids [752, 853, 859, 881, 883, 895]. 

Several approaches have been followed for the generation of optically active heteroarenes by homogeneous asymmetric hydrogenation. One approach involves direct asymmetric hydrogenation of the unactivated heteroarene. This approach has been most successful for heteroarenes that are polycyclic, like quinolines, isoquinolines, or quinoxa-lines (benzopyrazines). Less success has been achieved on the direct asymmetric hydrogenation of pyridines. To address this limitation, the hydrogenation of modified pyridines has been conducted. In one set of examples, pyridines and related benzo-fused heteroarenes were modified at tfie nitrogen by acylation or the installation of another auxiliary to make the pyridine more electron poor and to dock the catalyst. In a second set of examples, a chiral auxiliary was placed on the pyridine, and the product was formed diastereoselectively by an achiral catalyst. 

Somewhat more effective catalysts are obtained by replacing BINAP with TolBINAP, which is 2,2 -bis(di-p-tolylphosphino)-l,l -binaphthyl.4 The presently preferred catalysts are complexes of Ru(OCOCF3)2 with (R)- or (S)-TolBINAP, obtained by treatment of Ru(OAc)2TolBINAP with 2 equiv. of trifluoroacetic acid. Such catalysts promote hydrogenation of typical enamides in 98% ee and 98% yield. This reaction can be used to provide asymmetric synthesis of isoquinoline alkaloids as well as of morphinans used as substitutes for morphine. 

Isoquinoline Synthesis. Olefins that contain certain neutral donor functionalities are also effectively hydrogenated. Investigation of the enan-tioselective hydrogenation of enamide substrates has resulted in a general procedure for the asymmetric synthesis of isoquinoline alkaloids. 

Enantioselective hydrogenation of certain a- and 3-(acylamino)acrylic acids or esters in alcohols under 1-4 atm H2 affords the protected a- and 3-amino acids, respectively (eqs eq 3 and eq 4). Reaction of N-acylated 1-alkylidene-1,2,3,4-tetrahydroisoquinolines provides the IR- or 15-alkylated products. This method allows a general asymmetric synthesis of isoquinoline alkaloids (eq 5). ... 

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