Morphinans asymmetric synthesis

Hong, C.Y, Kado, N., Overman, L.E. (1993) Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (—)- and (-f)-Dihydrocodeinone and (—)- and (-F)-Morphine. Journal of the American Chemical Society, 115, 11028-11029. 

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. 

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. 

Hong CY, Kado N, Overman LE (1993) Asymmetric-synthesis of either enantiomer of opium-alkaloids and morphinans - total synthesis of (—)-dihydrocodeinone and (-1-)-dihydrocodeinone and (—)-morphine and (+)-morphine. J Am Chem Soc 115 11028-11029 Mulzer J, Dumer G, Trauner D (1996) Formal total synthesis of (—)-morphine by cuprate conjugate addition. Angew Chem hit Ed 35 2830-2832... 

The formation of the chiral formamidine 1658 from octahydroisoquinoline 1656 and the isocyanide 1657 derived from valinol tert-butyl ester gives an intermediate with high chirality-inducing potential, which, through further reaction steps, allows an asymmetric synthesis of (+)-morphinane with high enantiomeric purity (>98% ee in the decisive asymmetric reaction step) [1229]. The isocyanide 1657 is obtained in 85% yield by dehydration of the corresponding formamide with thionyl chloride. 

SCHEME 15.35 Enzymatic and oxidative dearomatization in the asymmetric synthesis of morphinan derivatives. 

Hong, C. Y. Overman, L. E. "Preparation of Opium Alkaioids by Paiiadium Cataiyzed Bis-Cyclizations. Formai Totai Synthesis of Morphine" Tetrahedron Lett. 1994, 35, 3453, Aiso see Hong, C. Y. Kado, N. Overman, L. E. "Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (-)- and (+)-Dihydrooodeinone and (-)- and (+)-Morphine" J. Am. Chem. Soc. 1993, 115,11028-11029. Heerdlng, E. A. Hong, C. Y. Kado, N. Look, G. C. Overman, L. E. "Simple Method for Controlling Stereoseleotion in Mannich Cyclization Reactions of Aldehydes" J. Org. Chem. 1993, 58, 6847-6948. 

Hitamura M, Hsiao Y, Noyori R, Takaya H. General asymmetric synthesis of benzomorphans and morphinans via enantioselective hydrogenation. Tetrahedron Lett. 1987 28 (41) 4829 832. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

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