"Ionic Diels-Alder reactions in the synthesis of analogues of the potent Chinese antimalarial drug Qinghaosu (Artemisinin)"
by Lam Kwok Ping
vi, 180 leaves : ill. (some col.) ; 30 cm
The Lewis acid catalysed 'ionic' Diels-Alder reaction of 2-cyclohexenones with (3E)-3,5-hexadien-1-ols in dichloromethane was reexamined with a view to optimizing yields and applying the reaction to other substrates. From 6-methyl-2-cyclohexenone and (3E)-3,5-hexadien-l-o1 in dichloromethane containing stoichiometric amount of aluminium chloride was obtained the trans-fused Diels-Alder adduct (3aRS,6aSR,-9Rs, 9aSR,9bRS)-9a-hydroxy-9-methyl- 2,3,3a,6,6a,7,8,9,9a,9b-deca-hydro-1- oxa-lH-phenalene as previously reported from this group. Configuration of the compound was secured by an X-ray crystallographic study also which indicates a β-equatorial methyl group and axial hydroxyl in the hemiacetal....[ Read more ]
The Lewis acid catalysed 'ionic' Diels-Alder reaction of 2-cyclohexenones with (3E)-3,5-hexadien-1-ols in dichloromethane was reexamined with a view to optimizing yields and applying the reaction to other substrates. From 6-methyl-2-cyclohexenone and (3E)-3,5-hexadien-l-o1 in dichloromethane containing stoichiometric amount of aluminium chloride was obtained the trans-fused Diels-Alder adduct (3aRS,6aSR,-9Rs, 9aSR,9bRS)-9a-hydroxy-9-methyl- 2,3,3a,6,6a,7,8,9,9a,9b-deca-hydro-1- oxa-lH-phenalene as previously reported from this group. Configuration of the compound was secured by an X-ray crystallographic study also which indicates a β-equatorial methyl group and axial hydroxyl in the hemiacetal.
The Bronsted acid and trifluromethanesulfonic acid were found to catalyse the reaction of 2-cyclohexenone with (3E)-3,5-hexadien- l-o1 to give the trans-fused cycloadduct (3aRS,6aSR,9aSR,9bRS)-9a-hydroxy- 2,3,3a,6,6a,7,8,9,9a,9b- decahydro-1-oxa-lH-phenalene in low yield. Based on the Noyori reaction of formation of acetals from trimethylsilyl (TMS) ethers of alcohols and ketones catalysed by trimethylsilyl triflate, it was discovered that trirnethylsilyl triflate is an efficient catalyst for the ionic Diels Alder reaction. Thus, in acetonitrile containing trimethylsilyl triflate (5 mol%) at -20 ℃ under nitrogen, 6-methyl-2-cyclohexenone reacts efficiently with 3,5-hexadien- l-o1 trimethylsilyl ether to give the trans-fused adduct (3aRS, 6aSR,9SR,9aRS,9bRS)-9a- [(3E)-3',5'-hexadienoxy]-9-methy1- 2,2,3a,6,6a,7,8,9,9a,9b-decahydro- 1-oxa-lH-phenalene (60%). In similar fashion, the corresponding adducts are obtained from 2-cyclohexenone, 2-cycloheptenone and methyl vinyl ketone. Whilst acceptable yields of adducts were also obtained in ether or toluene, in these solvents, products arising via conversion of the enone to the full acetal, and conjugate addition of the TMS ether were obtained. These products were able to be converted into the Diels-Alder adducts by treatment with trimethylsilyl triflate in acetonitrile. Similarly the ethylene acetal of 2-cyclohexenone provides the adduct, but in lower yield. Optically active acetals derived from (1R,2R)-1,2-diphenyl- 1,2-ethanediol and 2-cyclohexenone gave perfectly racemic adducts as full acetals derived from the TMS ether of hexadienol.
Acid-catalysed hydrolysis of the Diels-Alder adduct from 6-methyl-2- cyclohexenone gives (3aRS,6aSR,-9SR,9aSR,9bRS)-9a-hydroxy- 9-methyl-2,3,3a,6,6a, 7,8,9,9a,9b-decahydro- 1-oxa-lH-phenalene (85%), whose structure as revealed by X-ray crystallography contains an α-axial methyl group. The adduct is thereby differentiated from the aluminium chloride adduct, and may be converted into the latter by treatment with p-toluenesulfonic acid in dry THF or by aluminium chloride in dichloromethane.
A mechanistic rationalisation for these reactions is presented wherein it is proposed that initial addition of the TMS ether to the carbonyl group provides a hemiacetal which collapses to an oxyallylic cation; subsequent C-C bond formation takes place through C-4 of the enone and syn to the 6-methyl group. It is uncertain whether formation of the trans-fused adduct is a kinetic, that is it arises via direct C-C bond formation between C-2 of the enone and the cation, or whether it is thermodynamic, that is, arises via equilibration of an initially formed cis-adduct.
It was discovered that the TMS ether of (2R,5E)-2-methyl-3,5-heptadiene in acetonitrile containing trimethylsilyl triflate (10 mol%) at -20 ℃ reacts slowly with 6-methyl-2-cyclohexenone to give the transfused adduct (3R,3aR,6R,6aR,9R,9aR,9bS) -9a-[(R)-(5E)-2'-methyl- 3',5'-heptadienoxy]-3,6,9- trimethyl-2,3,3a,6,6a,7,8, 9,9a,9b-decahydro-1 -oxa- 1H-phenalene (24%). Acid hydrolysis provides crystalline (3R,3aR,6R,6aR,9R,9aR,9bS) -9a-hydroxy-3,6,9-trimethyl- 2,3,3a,6,6a,7,8,-9,9a,9b- decahydro-1-oxa-lH-phenalene, αD21 = -100° (c = 0.60, CHCl3) as a single enantiomer. Similarly,(2S,5E)-2- methyl-3,5-heptadienol TMS ether is converted by way of (3S,3aS,6S,6aS,9S,9aS,9bR)- 9a-[(5E)-3',5'-heptadienoxy]- 3,6,9-trimethy1-2,2,3a,6,-6a, 7,8,9,9a,9b-decahydro-1- oxa-1H-phenalene (22%) into (3S,3aS,6S,6aS,9S,9aS,9bR)- 9a-hydroxy-3,6,9-trimethyl- 2,3,3a,-6,6a,7,8,-9,9a,9b- decahydro-1-oxa-lH-phenalene, αD21 = +102° (c = 0.61, CHCl3), as a single enantiomer. The structure of the first hemiacetal was secured by X-ray crystallography. The configuration of the product indicates unambiguously that these reactions proceed via endo transition states. The origin of the remarkable enantioselectivity in these reactions has not yet been established.
(3aRS,6aSR,9SR,9aSR,9bRS)- 9a-Hydroxy-9-methyl-2,3,3a,6,6a, 7,8,9,9a,9b-decahydro- 1-oxa-lH-phenalene was converted via an efficient synthetic sequence involving hydrogenation, stereoselective reduction with lithium tri-tert-butoxy-alumino hydride to the alcohol, selective protection of the primary hydroxyl group with tert-butyldimethylsilyl chloride, dehydration of the secondary alcohol to the alkene, deprotection and oxidation of the primaryalcohol group to the carboxylic acid to provide the desmethyl artemisinic acid analogue which was converted previously into ±-6,9-desmethylartemisinin.