diethyl ;(9-15) 3,4-dipropyl;(11) 3-ethyl-4-methyl;(16) 3-methyl-4-ethyl;(16) 3-methyl-4-propyl.f The predominant product (65-75 per cent yields and arbitrarily designated a) obtained in the acid cyclization of (33) has been shown (vide infra) to conform to the structure and stereochemistry represented by (34). In all instances but one (cyclization of (33.6)f) a small yield (5-8 per cent) of an isomeric product was isolated. The latter (designated /?) proved to be diastereoisomeric (at C-9) with the a-isomers by degradation of two representatives (35.1 and 35.2) to 1,2-dimethyl- and l,2-diethyl-7-methoxy-naphthalenes (36.1 and 36.2) respectively(14,16), identical with those obtained from the corresponding (34.1) and (34.2).

That the stereochemistry of the predominant (a) products and the lesser diastereomers (/?) is accurately represented by (34) and (35) respectively, in addition to having been predicted by theory0 3), has been demonstrated by methiodide reaction-rate data°7). Qualernization of the a-compounds with methyl iodide occurred from five to ten times as rapidly as the /S-counter-parts. This could only mean that in the a compounds the 9-alkyl substituent is oriented away from the nitrogen (axial for the hydroaromatic ring) of the iminoethano system (34) geometrically constrained to a m(diaxial)-fusion as in morphine (1) and the morphinans (2). The slower-reacting ¡3 compounds must therefore be assigned structure (35) in which the 9-alkyl substituent, equatorially oriented for the hydroaromatic ring, is close enough to the nitrogen to cause steric hindrance. It was noted in the rate studies0 7) that, as the size of R^ increased in the ¡3 series, reaction with methyl iodide became slower. This, then, related the a compounds (34) with their m-juxtaposed (for the hydroaromatic ring) 5,9-dialkyl groups, to morphine and the morphinans whose m-fusion of rings B and C is a certainty (see Part IIa).

Further confirmation of these configurational assignments was observed in nuclear magnetic resonance spectra of the 5,9-dimethyl compounds (34.1 and 35.1)°7). Thus the 9-methyl frequencies (doublet) of the a-isomer are at higher field (about 25 c/s) than those of the /3-isomer attributable to aromatic ring current elfects. This is possible in structure (34.1), not (35.1).

As will be shown in the pharmacological discussion, the scarce /î-isomers are from five to seventy times more potent as analgesic agents than their a counterparts. The ¡3 bases are also lower melting and more soluble in acetone than the a bases. In three of the five pairs of diastereoisomers isolated, there were distinct infrared spectral differences, particularly in the 6-6-5 ¡jl region. A comparison of some of these properties which were most helpful in separation procedures is given in Table XVIII.


The substitution of a hydroxyl group at position 14 of morphine-like structures generally has an enhancing effect on analgesic activity. For example, 14-hydroxydihydrocodeinone (oxycodone) (37.1) and 14-hydroxy-dihydromorphinone, (oxymorphone) (37.2) are from two to four times as potent as dihydrocodeinone (hydrocodone) (38.1) and dihydromorphinone

Table XVIII. Comparison of melting point and infrared spectral data of a- and /?-5,9-dialkyl-2'-hydroxy-2-methyl-6,7-benzomorphans


Melting point




1. <x-5,9-Dimethyl

0 0

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