Total synthesis of the spirans of Cannabis: cannabispiradienone, cannabispirenone-A and -B, cannabispirone, α- and β-cannabispiranols and the dihydrophenanthrene cannithrene-1

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Abstract
O-Methylcannabispirenone has been synthesised (57% overall from 3,5-dimethoxycinnamic acid)via 5,7-dimethoxyindanone, p-tolylsulphonylmethyl isocyanide conversion into the 1-nitrite, alkylation with 1-iodo-3,3-ethylenedioxybutane, deacetalisation, and spirocyclisation. 5,7-Dimethoxyindanone is 7-deprotected by boron trichloride with high selectivity, and re-protected as the methoxyethoxymethyl ether: following the above route, finally deprotecting by boron trichloride, gives cannabispirenone-A (2) in 21% overall yield. O-Methylcannabispirenone can be demethylated to give (2) by lithium 1,1-dimethylethanethiolate: demethylation with boron tribromide gives cannabispirenone-B (3). Hydrogenation of synthetic cannabispirenone-A gives cannabispirone (4), reduced by borohydride to the epimeric α-(6) and β-(5) cannabispiranols, separated by h.p.l.c. Dehydrogenation of O-methylcannabispirenone with dichlorodicyanobenzoquinone, followed by lithium 1,1-dimethylethanethiolate demethylation, gives cannabispiradienone (1). Under acidic conditions, the latter undergoes dienone–phenol rearrangement to give cannithrene-1 (8), thus completing the total synthesis of the spiro-cannabinoid group of natural products discussed in the preceding paper. The unsubstituted cannabispirenone parent has also been synthesised.