Isoquinolines alkaloids, asymmetric synthesis

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). ... 

Scheme 25. General asymmetric synthesis of isoquinoline alkaloids.

The enormous number of naturally occurring isoquinoline alkaloids, and their importance biologically, has stimulated a great deal of effort in their synthesis. The asymmetric alkylation of the 1-position of the tetrahydroisoquinoline nucleus affords an extremely valuable method for the construction of... 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

The efficient synthesis of racemic triphyophilline (60) paved the way for the first asymmetric total synthesis of the 5,1-linked napthylisoquinoline alkaloid (-)-ancistrocladine (1) (ref. 47). The approach once again relied on the successful intramolecular strategy used previously and required the development of asymmetric synthesis of the tetrahydroisoquinoline portion of 1. The route to isoquinoline segment 79 began with the synthesis of homochiral amphetamine derivative 83 via a reductive methylation protocol (Scheme 10) (ref. 54, 55) Thus, condensation of ketone 80 with (S)-... 

Scheme 27. Asymmetric synthesis of optically active isoquinoline moieties of Ancistrocladus alkaloids (70).

Chrzanowska M, Rozwadowska MD (2004) Asymmetric Synthesis of Isoquinoline Alkaloids. Chem Rev 104 3341... 

Noyori R, Ohta M, Hsiao Y, Kitamura M, Ohta T, Takaya H (1986) Asymmetric synthesis of isoquinoline alkaloids by homogeneous catalysis. I Am Chem Soc 108 7117-7119... 

Chrzanowska M, Rozwadowska MD. Asymmetric synthesis of isoquinoline alkaloids. Chem. Rev. 2004 104 3341-3370. 

The asymmetric synthesis of isoquinoline alkaloids, such as 19, provided an example of a class of substrates for which unsatisfactory enantioselectivity was obtained with Rh catalysts (Scheme 10.2, top). The corresponding BINAP-Ru(II) dicarboxylate complex proved superior (Scheme 10.2, bottom)... 

The asymmetric total synthesis of rauwolfia alkaloids (-)-yohimbane and (-)-alloyohimbane was carried out by S.C. Bergmeier et al. by utilizing a novei aziridine-allylsilane cyclization and the Bischler-Napieralski isoquinoline synthesis as key steps.These alkaloids have a characteristic pentacyclic ring framework and exhibit a wide range of interesting biological activities such as antihypertensive and antipsychotic properties. 

Asymmetric total synthesis of (—)-octahydro-l f-benzofuro[3,2- ]isoquinoline 149, a partial structure of morphine, a potent analgesic alkaloid, was accomplished using the ATH protocol (Scheme 30.28). The ketone 147... 

---