Verbenol synthesis

Hughes P. R. (1973b) Effect of a-pinene exposure on fraras-verbenol synthesis in Dendroctonus ponderosae Hopk. Naturwissenschaften 60, 261-262. 

After identification of A9-THC as the major active compound in Cannabis and its structural elucidation by Mechoulam and Gaoni in 1964 [66], a lot of work was invested in chemical synthesis of this substance. Analogous to the biosynthesis of cannabinoids, the central step in most of the A9-THC syntheses routes is the reaction of a terpene with a resorcin derivate (e.g., olivetol). Many different compounds were employed as terpenoid compounds, for example citral [67], verbenol [68], or chrysanthenol [69]. The employment of optically pure precursors is inevitable to get the desired (-)-trans-A9-THC. 

Biotransformation of (+)- and -)-cis/trans- etheno s to (-f)-verbenone has been achieved by a cell-free system of Cannabis sativa Callus.The (—)- and (+)-verbenone (via verbenol) were the starting materials for the first synthesis of the (—)- and (+)- enantiomers of A -tetrahydrocannabinol. 

Mori K. (1976) Synthesis of optically pure (+HrDendroctonus bark beetles. Agr. Biol. Chem. 40, 415-418. 

Both a- and P-pinenes are popular starting materials for the synthesis of other monoterpene chiral synthons such as carvone, terpineol, and camphor (vide infra). Reactions leading to other monoterpenes are briefly summarized in Figure 5.1. Treatment of a-pinene with lead tetraacetate followed by rearrangement gives trans-verbenyl acetate (7), which is hydrolyzed to yield trans-verbenol (8) 8 Subsequent oxidation of 8 gives verbenone (9), which can be reduced to give cw-verbenol... 

This EPC-synthesis of dendrobine (82) is based on (+)-trani-verbenol (307) as starting material and Pauson-Khand reaction as the key step 144,166). 

The natural delta-1-THC and delta-6-THC have a (3R,4R) configuration and a negative rotation. The synthetic route, which was developed by our laboratory for delta-1-THC and delta-6-THC nearly 20 years ago (Mechoulam et al. 1967), makes possible also the synthesis of the unnatural (3S,4S) enantiomers as the starting material verbenol (28) is available in both enantiomeric forms. This sequence has been widely used for the preparation of (+) cannabinoids and apparently is the only one still practical for the synthesis of (+)-delta-l-THC. (+)-Verbenol on condensation with olivetol leads to (29), which on ring opening leads to (+)-(3S,4S)-delta-6-THC (30), which can be converted with ease into (+)-(3S,4S)-delta-l-THC (31). 

A similar example had been reported in 1976.11 (15,45,55)-a j--Verbenol (7) is a pheromone component ofIps bark beetles. Prior to Mori s work,11 some researchers had called 7 (+)- r-verbenol, while others referred to it as (—)- f-verbenol. After synthesis of 7 and measurements of its optical rotations in different solvents, it became clear that 7 was dextrorotatory in acetone or methanol but levorotatory in chloroform. It is therefore of utmost importance to use the same solvent as reported by others, when one compares the sign of the optical rotation of a new sample with the previous data. 

In the synthesis of THC with verbenol, the cis isomer is preferable to the trans since the latter decomposes at room temperature. Pinene or carvone give active THC s [JMC17,287(74)]. 

In general, synthesis of 11-hydroxy-A -THC derivatives (e.g., 17, Scheme 4) follows a strategy used for the preparation of (-)-A -THCs. Thus, verbenol (8, Scheme 1) is replaced by optically active 4-hydroxymyrtenyl pivalate (15, Scheme 4) in a Lewis-acid-catalyzed condensation with the appropriate resorcinol (15,30,40-42). 

Verbenone is an industrially important molecule as it is the principal building block in the synthesis of a sex pheromone (Silverstein et al., 1966). At a temperature of 373 K, selective saturation of the C=C bond occurs and yields verbanone (26), whereas at a higher temperature (398 K), the C=0 bond is hydrogenated and yields the alcohol, verbenol (27). 

The synthesis of the pheromon S(-)cw-verbenol in high enantiomeric excess based on a photoinduced catalytic reaction in the presence of a cyclodextrane-substituted iron(III) porphyrin complex (21) [43] may be... 

Hughes and Renwick (395) have recently conducted additional exposure experiments with I. paraconfusus males. In this species it was found that no appreciable synthesis of cw-verbenol occurred in the absence of exogenous (- )-a-pinene. Therefore, unlike D. frontalis (376), newly emerged I. paraconfusus males do not appear to have an endogenous precursor of cw-verbenol. 

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