Synthesis of(-)-∆9-trans-Tetrahydrocannabinol:Stereocontrol via Mo-CatalyzedAsymmetric Allylic Alkylation ReactionBarry M. Trost* and Kalindi DograDepartment of Chemistry, Stanford UniVersity, Stanford, California [email protected] December 14, 2006ABSTRACT∆9-THC is synthesized in enantiomericaly pure form, where all of the stereochemistry is derived from the molybdenum-catalyzed asymmetricalkylation reaction of the extremely sterically congested bis-ortho-substituted cinnamyl carbonate in high regio- and enantioselectivity.(-)-∆9-trans-Tetrahydrocannabinol (∆9-THC, 1) isolated1from female Cannabis satiVaL. in 1964 has been identifiedas the primary psychomimetic component of marijuana. Itis also known to show antiemetic, antiglaucoma, andanalgesic properties. Currently it is administered as anantinauseant to patients undergoing chemotherapy. Discoveryof the cannabinoid receptors CB1 and CB2 and ∆9-THCanalogues2that bind selectively to them has led to a needfor the development of a flexible synthetic route that wouldyield target compounds easily in high yields and in stereo-chemically pure form.THC itself has been prepared numerous times, though mostroutes are either racemic or derive their chirality from chiralbuilding blocks.3Only Evan’s4route targets the naturalproduct enantioselectively from achiral starting materials. Theproblems associated with the synthesis of THC involve thecontrol of cis-trans stereochemistry at the cyclohexene ringand the position of the double bond, i.e., ∆9vs ∆8, the latterbeing thermodynamically more stable.Our reterosynthetic analysis of the molecule envisionedall of the stereochemistry resulting from a single Mo-catalyzed asymmetric allylic alkylation (AAA) reaction (seethe abstract). Alkylation of malonate adduct 4 with 3 should(1) Mechoulam, R.; Gaoni, Y. J. Am. Chem. Soc. 1964, 86, 1646.(2) (a) Mahadevan, A.; Siegel, C.; Martin, B. R.; Abood, M. E.;Belestskaya, I.; Razdan, R. K. J. Med. Chem. 2000, 43, 3778. (b) Drake,D. J.; Jensen, R. S.; Busch-Petersen, J.; Kawakami, J. K.; Fernandez-Garcia,M. C.; Fan, P.; Makriyannis, A.; Tius, M. A. J. Med. Chem. 1998, 41,3596. (c) Harrington, P. E.; Stergiades, I. A.; Erickson, J.; Makriyannis,A.; Tius, M. A. J. Org. Chem. 2000, 65, 6576. (d) Tius, M. A.; Makriyannis,A.; Zou, X. L.; Abadji, V. Tetrahedron 1994, 50, 2671.(3) Selected examples: (a) Mechoulam, R.; Gaoni, Y. J. Am. Chem. Soc.1965, 87, 3273. Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc.1967, 89, 4552. Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc.1972, 94, 6159. (b) Fahrenholtz, K. E.; Lurk, M.; Kierstead, R. W. J. Am.Chem. Soc. 1966, 88, 2079. Fahrenholtz, K. E.; Lurk, M.; Kierstead, R. W.J. Am. Chem. Soc. 1967, 89, 5934. (c) Chan, T. H.; Chaly, T. TetrahedronLett. 1982, 23, 2935. (d) Rickards, R. W.; Ronneberg, H. J. Org. Chem.1984, 49, 572. (e) Childers, W. E., Jr.; Pinnick, H. W. J. Org. Chem. 1984,49, 5276. (f) Malkov, A. V.; Koovsky, P. Collect. Czech. Chem. Commun.2001, 66 (8), 1257. (g) William, A. D.; Kobayashi, Y. J. Org. Chem. 2002,67, 8771. William, A. D.; Kobayashi, Y. Org. Lett. 2001, 3, 2017.(4) (a) Evans, D. A.; Shaughnessy, E. A.; Barnes, D. M. TetrahedronLett. 1997, 38, 3193. (b) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka,T.; Matt, P. V.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy,E. A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582.ORGANICLETTERSxxxxVol. 0, No. 0A-C10.1021/ol063022k CCC: $37.00 © xxxx American Chemical SocietyPAGE EST: 2.9Published on Web 02/01/2007furnish the substrate for ring-closing metathesis (RCM). TheRCM in itself results in a fixed geometry of double bondthus solving the problem of co-formation of ∆8-THC seenin many syntheses. Decarboxylation of the malonate afterRCM was planned to result in the required trans stereo-chemistry of 2. Grignard addition to ester 2 followed bydemethylation to the free phenol and cyclization yields 1.Varying the aromatic group in 5, the alkylating partner 3,orthe Grignard reagents one can potentially prepare differentanalogues of THC without fundamentally changing thechemistry involved.Allyl alcohol 9 was easily prepared in high yield fromcommercially available olivetol, 6, in 4 steps (Scheme 1).Lithiated dimethyl olvitol was quenched with dry DMF toyield the aldehyde 8 in 83% yield. Wadsworth-Horner-Emmons reaction of 8 with sodium triethylphosphonoacetateresulted in the corresponding R,β-unsaturated ethyl ester,which was subjected without further purification to DIBAL-Hreduction to yield 97% of 9. Preparation of carbonate 5proved to be a little tricky because the compound is sensitiveto both acid and base, including silica chromatography condi-tions. A preparation of 5 clean enough to take into the Mo-alkylation reaction was achieved by titrating alcohol 9 withBuLi at -78 °C in ether and quenching the resulting alkoxidewith methyl chloroformate also at -78 °C. Washing theorganic layer with ice-cold water followed by solvent re-moval gave carbonate 5 as a waxy solid, which is stable tostorage.The branched allyl alcohol 10 is prepared by condensationof acrolein with lithiated 7 in one step in 91% yield (Scheme2). We planned to use the carbonate prepared from 10 inthe Mo-AAA reaction to reduce the number of steps andincrease the efficiency of the synthesis. Unfortunately itproved impossible to prepare either the carbonate or theacetate of 10, due to their facile decomposition aided by thehighly electron rich aromatic ring.We did, however, take advantage of this to isomerize thebranched alcohol 10 into the linear alcohol 9.5Treatment ofthe lithium alkoxide of 10 with dry CO2gas gives thecorresponding carbonate, which rearranges in the presenceof PdCl2(CH3CN)2to yield the more stable linear carbonatethat decomposes to the alcohol 9 on workup (Figure 1). A74% yield of 9 was observed with 6% recovered 10.Tothebest of our knowledge this reaction has not been previouslyreported. This alternate strategy using this novel isomeriza-tion should prove to be a more efficient, atom economicalapproach to cinnamyl alcohols then the more traditionalprotocol based upon olefination.With the carbonate in hand we began examining the allylicalkylation reaction. Although molybdenum is known forgiving the product resulting from attack at the more sub-stituted carbon, we were concerned that the two o-methoxygroups on the aryl ring would make this reaction stericallyunfavorable. Nevertheless, the reaction of carbonate 5
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