Morphinan-6 ones 8- substituted

Morphinan-6-ones substituted in both the 5- and 7-positions resulted from the calcium hydroxide-induced reaction of formaldehyde with 3-methoxy-N-methylmorphinan-6-one (97).<93) Scheme 3.13 illustrates the reaction sequences followed, including the products given by the reductive cleavage of the oxetane moiety (98). No interesting antinociceptive activity was found. 

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. ° ... 

Brossi s group at NIH has also investigated morphinan-6-ones lacking aromatic substitution. The availability of (-) 64 (R = H, R = OH) gave access to the desired product (-) 77 by catalytic reduction of the... 

Morphman-6-ones are, as a rule, more active than corresponding morphinans, and it would appear that C-ring geometry and substitution patterns play a role in the drug-receptor union... 

Brossi A, Atwell L, Jacobson AE, Rozwadowska MD, Schmidhammer H, Flippen-Anderson JL, Gilardi R (1982a) Structure-activity relationship of oxygenated morphinans VO 5-methyl-ated and 14-hydroxy substituted agonists and antagonists of the 4-hydroxy- and 3,4-dioxy-genated 6-morphinanone series. Helv Chim Acta 65 2394-2404 Brossi A, Hsu FL, Rice KC (1982b) A simplified synthesis of ( )-4-hydroxy-N-methylmorphinan-6-one. J Org Chem 47 5214-5216... 

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