54
S. M. Wilkinson et al. / Tetrahedron Letters 54 (2013) 52–54
OH
OH
allowing further development of cannabinoids possessing interest-
ing biological activity.
(i)
C5H11
7
12
Acknowledgements
Scheme 3. Synthesis of m-pentylphenol. Reagents and conditions: (i) n-BuLi, t-
BuOK, TMEDA, hexane, À50 to À20 °C, 3 h then n-BuBr, THF, À60 °C to rt, 20 h, 70%
The X-ray crystal structure was solved by Jason Price of the
crystal structure analysis facility at the University of Sydney,
NSW, Australia. NMR analysis was aided by Dr. Ian Luck of the
NMR facility at the School of Chemistry, the University of Sydney,
NSW, Australia. Mass spectrometry results were acquired by
Dr. Nick Proschogo and Chris Phippin of the Mass Spectrometry
laboratory at the University of Sydney, NSW, Australia. Elemental
analysis was performed by Dr. Christopher McRae of the Chemical
Analysis Facility at Macquarie University, NSW, Australia.
hypothesized to go via a Friedel–Crafts alkylation of 7 with the
cyclohexene 6 to first form desoxy CBD 4, with the boron Lewis
acid then catalysing an intramolecular cyclization/etherification
between the phenol and the isopropenyl tail to yield desoxy THC
3. Unlike the acetal-promoted coupling step (Scheme 1), this Lewis
acid mediated coupling is reported to be reversible via a retro-
Friedel–Crafts reaction so the formation of certain by-products
(such as the ether generated in the acetal-mediated coupling or
regioisomers) can be recycled back into the reaction to contribute
towards the yield of the desired product.26 Given that desoxy CBD
4 is generated as an intermediate in this reaction, boron trifluor-
ide–diethyl etherate was deactivated with basic alumina28 in the
hope of trapping desoxy CBD 4, but only the cyclized desoxy THC
3 and starting material were isolated. However, after systematic
exploration of reagent concentrations, reducing the boron trifluor-
ide–diethyl etherate concentration to 0.1% successfully slowed fur-
ther reaction, allowing the isolation of desoxy CBD 4 in 42% yield
(Scheme 2). In addition to improved yields of desoxy THC 3 and
desoxy CBD 4 from a common route by judicious selection of
reagent concentration, the desired products were prepared more
expediently (<2 h) than the acetal-mediated coupling (63 h).
Deoxygenation of desoxy CBD 4 was achieved by phosphoryla-
tion of the phenol group followed by a Birch reduction (Scheme
2).11,13 The didesoxy CBD 5 was obtained in 82% over two steps.
NMR spectra of all three desoxy analogues 3–5 were identical to
those previously reported in the literature.11
Supplementary data
Supplementary data (synthesis procedures, spectral data and
crystal structure data) associated with this article can be found,
References and notes
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In summary, an alternative procedure that improves the syn-
thetic accessibility of desoxy THC 3, desoxy CBD 4 and didesoxy
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etherate to the coupling of key precursory fragments 6 and 7
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OH
OH
(i)
+
O
C5H11
C5H11
23. Laus, G. J. Chem. Soc., Perkin Trans. 2 2001, 864.
24. Johnson, C. K., ORTEPII. Report ORNL-5138, Oak Ridge National Library, Oak
Ridge, Tennessee.
25. Bates, R. B.; Siahaan, T. J. J. Org. Chem. 1986, 51, 1432.
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desoxy THC
3
6
7
(ii)
28. Baek, S.-H.; Srebnik, M.; Mechoulam, R. Tetrahedron Lett. 1985, 1083, 26.
OH
(iii), (iv)
C5H11
C5H11
desoxy CBD
4
didesoxy CBD
5
Scheme 4. Synthesis of desoxy THC and CBD analogues. Reagents and conditions:
(i) 1% BF3ÁOEt2, MgSO4, CH2Cl2, À10 °C, 39%; (ii) 0.1% BF3ÁOEt2, MgSO4, CH2Cl2, À78
to À10 °C, 42%; (iii) NaH, (EtO)2P(O)Cl, THF, 0 °C, 1 h, quant.; (iv) Li(s), NH3(l), THF,
À78 °C, 2 h, 82%.