For the ultimate purpose of preparing analogues of the Chinese antimalarial qinghaosu (artemisinin), the scope and application of the cationic Diels-Alder reactions between substituted 3,5-dienol trimethylsilyl ethers and cyclic enones have been evaluated.
(2E,4E)-2,4-Hexadienoic acid was converted into the methyl ester, and deconjugated with LDA, and reduced to the alcohol (3E)-3,5-hexadienol. Each of (2R,3E,5E)- and (2S,3E,5E)-2-methyl-3,5-heptadien-1-ol were prepared from the respective enantiomers of 3-bromo-2-methylpropan-1-ol via conversion into the corresponding phosphonium salts, and reaction with (E)-2-butenal (crotonaldehyde); the alcohols were obtained as an inseparable 4:1mixture of E and Z isomers. Each of (2R,3E,5Z)- and (2R,3Z,5Z)-2-methyl-3,5-heptadien-1-ol were prepared from 2-butyn-1-ol via reduction and then conversion to (Z)-1-brormobut-2-ene and conversion of the latter into crystalline (Z)-(but-2-enyl)diphenylphosphine oxide which was crystallized to geometric purity. Reaction of the phosphine oxide with (2S)-3-[(tert-butyldimethylsilyl)oxy]-2-methylpropionaldehyde and hydrolysis of the product gave (2R,5Z)-2-methyl-3,5-heptadien-1-ol as a 14:1mixture of 3E and 3Z isomers. (2R,3E)-and (2R,3Z)-2-methyl-3,5-hexadien-1-ol were prepared as a 4:1mixture from [(2S)-3-hydroxy-2-methylpropyl] triphenylphosphonium bromide and acrolein with a Wittig reaction. The Wittig-Horner reaction was also used to prepare this diene from allyl diphenylphosphine oxide and (S)-3-[(tert-butyldimethylsilyl)oxy]-2-methylpropanal. The alcohols were each converted into their trimethylsilyl ethers.
6-Methyl-2-cyclohexenone was prepared from methylcyclohexanone by bromination of the kinetic silyl enol ether, and dehydrobromination of the resulting 2-bromo-6-methylcyclohexanone. 2-Methyl-2-cyclohexenone was prepared from methylcyclohexanone by chlorination with sulfuryl chloride, and dehydrochlorination with magnesium oxide.
The above dienes and enones were submitted in the Diels-Alder reaction by reacting in acetonitrile and in the presence of the catalyst trimethylsilyl trifluoromethanesulfonate. Thereby preparing a series of adducts as full acetals in varying yields, depending upon the substitution pattern of the diene. In general, yields were higher if the alkenes did not bear a terminal substituent. Structures of the adducts were established by hydrolysis to hemiacetals, as careful analysis by NMR spectroscopy, and in some cases, by X-ray crystallography. It was not possible to obtain unambiguous structural information from the adducts obtained from 2-methycyclohex-2-enone and 2-methylcyclopent-2-enone, as these products, or the hemiacetals obtained from them by hydrolysis, were unable to be crystallized.
Whilst the outcome of the Diels-Alder reactions of 6-methylcyclohexenone with each of (2R,3E,5E)- and (2S,3E,5E)-2-methyl-3,5-heptadien-1-ol TMS ethers were highly stereoselective, the reactions of the corresponding terminally-unsubstituted dienes were not so selective, and the stereochemistry of the adducts obtained indicates that the dienes react with the enone from both the Si- and Re-faces via an endo transition state.
The use of the Diels-Alder reaction is illustrated in the preparation of (4a'RS,8'SR,8a'RS)-2-(2'-methyl-3',4',4a',5',6',7',8',8a'-octahydronaphthalen-8'-yl)-acetic acid from 1SR,2SR,4aSR,8RS,8aRS)-8-(1'-hydroxyethan-2'-yl)-2-methyl-1,2,3,4,4a,5,8,8a-octahydro-1-naphthol. The former compound has been converted previously into an artemisinin analogue.
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