Morphinans stereochemistry

The morphinan nucleus possesses three chiral centers at C-9, C-14, and C-13. As two of these, C-9 and C-13, are bridged, and thus constrained, only two diastereoisomeric pairs occur. Morphinans (49) bear a cis B/C ring fusion and in this regard are related to morphine. Where the C-14 center is inverted (i.e., trans B/C fusion), compounds are known as isomorphinans (50), and these will be discussed later (p. 136). Note that in structures 49 and 50 the stereochemistry of ring C is shown in relationship to ring B. 

The free base 3a was further converted to the mandelate salt, a white crystalline product. The cyclobutyl analog 3b was similarly prepared from 8 and converted to the crystalline mandelate salt. The (S ) A-tetrahydrofurfuryl derivative 3c was prepared from (S) tetrahydrofurfuryl (1/f) camphor-10-sulfonate (10) as previously reported (Mertz et al., 1997). The 10-keto morphinans were prepared by the oxidation (Michne and Albertson, 1972) of the morphi-nan 7 with Cr03/H2S04 followed by alkylation with cyclopropyl methyl bromide and 0-demethylation to yield 4b (Scheme 1). O-Demethylation of 11 to form 13 followed by alkylation with (S) tetrahydrofurfuryl (I R) camphor-10 sulfonate (10), led to 4a. The assignment of the stereochemistry of 4a was based on the work of Merz and Stockhaus (1979). 

One drawback of this synthesis is that it initially provides the wrong stereochemistry at C14. There are morphinanes, however, that have Ci4o stereochemistry, so this is not all bad. One such morphinane is O-methylpallidinine (125), and a strategically similar approach to this alkaloid will be the last synthesis we will consider in this chapter. 

Morphinan alkaloids are the pharmaceutically most important class of isoquinoline alkaloids. Codeine and morphine are found only in Papaver somniferwn and closely related species. Both alkaloids are derived from (R)-reticuline, the absolute stereochemistry of which corresponds with the configuration of morphinan alkaloids. Re-ticuline is therefore an important branch point in isoquinoline bio nthesis. However, either enantiomer of reticulme, when fed separately, is incorporated into morphinan alkaloids essentially to the same extent. The question therefore arises by which mechanism (R)-reticuline is formed within the plant. 

Figure 6.64 The tetracyclic structure and numbering of morphinan is shown here. The stereochemistry at the 9-, 13-, and 14-positions is always fixed unless the name of the compound specifies otherwise.

Figure 6.67 Dextromethorphan hydrobromide provides an example of a compound in which the stereochemistry of the three chiral centers of morphinan is inverted.

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