The total synthesis of (±)-petasitolone

Abstract

HSING-JANG LIU and TENG KO NGOOI. Can. J. Chem. 62, 2676Chem. 62, (1984.The total synthesis of petasitolone (I), a sesquiterpenoid of the eremophilane family, has been accomplished. The key step of this efficient synthesis is the Lewis acid catalyzed Diels-Alder addition of 2-carbomethoxy-2-cyclohexenone (3) to diene 9. The cycloaddition, which gives adduct 16 in good yield, facilitates the rapid construction of the parent ring system of the target molecule and allows an excellent control of the required stereochemistry.HSING-JANG LIu et TENG KO NGOOI. Can. J. Chem. 62, 2676Chem. 62, (1984.On a rialist la synthkse totale de la pitasitolone (I), un sesquiterpkne de la famille de 1'CrCmophilane. L'itape fondamentale de cette synthtse efficace est une addition de Diels-Alder, catalysCe par un acide de Lewis, de la carbomCthoxy-2 cyclohexkne-2 one (3) sur le dikne 9. La cycloaddition, qui conduit ? i I'adduit 16 avec un bon rendement, facilite 1'Cdification rapide du systkme cyclique parent de la molCcule recherchCe et permet un excellent contr6le de la stCrCochimie requise.[Traduit par le journal]We wish to report the first total synthesis, in racemic form, of petasitolone (I), a sesquiterpene of the eremophilane family which has been isolated from Petasites japonicus Maxim (1). The synthesis also demonstrates a new approach to eremophilane sesquiterpenes which are widely distributed in nature (2). These naturally occumng compounds have attracted a great deal of synthetic effort during the past two decades (3). IAlthough a rapid construction of the required decalin framework can conceivably be achieved by an intermolecular Diels-Alder reaction, the difficulty' in controlling the desired cis stereochemistry of the vicinal methyl groups has hampered the efficient use of such an approach to the synthesis of eremophilanes. During a recent study of the dienophilicity of 2-carbomethoxy-2-cyclohexenone (3) (5), it was observed that the Diels-Alder reactions of this enone ester with 1-substituted and 1,3-disubstituted dienes led, in each case, to the preferential formation of the adduct that arose from secondary orbital overlap between the diene and the ester moeity of 3. For example, its reaction with trans-piperylene at -78°C and under stannic chloride catalysis gave a 5 : 3 mixture of adducts 4 and 5. The major adduct 4, which has the all-cis stereochemistry for the three contiguous chiral centers, was formed by endo addition of the diene to the ester group of 3. It was also observed that addition of trans-2-methyl-l,3-pentadiene to enone ester 3 under the same conditions led to a mixture of adducts 6 and 7. In this case, an improved stereoselectivity of 13: 1 in favor of adduct 6 was obtained. The remarkable ability of the ester group to reverse the course of stereoselectivity normally observed for 2-cyclohexenones makes possible the direct control of the eremophilane stereochemistry using a Diels-Alder reaction. This is illustrated with the efficient total synthesis of petasitolone described below.Although the Die...

Transition-Metal-Mediated Exo-Selective Diels−Alder Reactions for the Preparation of Octalones with Unusual Stereochemistries. Reactions of 2-Cobaloxime-Substituted 1,3-Dienes with Cyclohexenones in Thermal and Lewis Acid-Catalyzed [4 + 2] Cycloadditions

“…The cycloaddition proceeded in high yield and was highly diastereoselective for the exo (with respect to cyclohexenone) product 19 . This stereochemical assignment was confirmed by cobalt−carbon bond cleavage to produce 20 , which had a 1 H NMR spectrum analogous to 16 . The methyl 1 H NMR doublet in 16 occurs at δ 0.83 (CDCl 3 ), whereas the same signal in 17 is at δ 1.17.…”

“…Addition of an electron-withdrawing group such as a carbalkoxy group on the 2-position of 2-cyclohexenones was known to increase their reactivity in thermal Diels-Alder reactions, but these dienophiles were still problematic. For example, ( E )-piperylene ( 4 ) is reported to react with 2-carbomethoxy-2-cyclohexen-1-one ( 15 ) (SnCl 4 , −78 °C, 6 h, 34%) to produce a 5:3 mixture of the exo (with respect to the cyclohexenone) ( 16 ) and endo (with respect to the cyclohexenone) ( 17 ) products . We first tried the analogous carboethoxy dienophile ( 18 ) 5 in a thermal cycloaddition with dienyl complex 8 .…”

Stereoselective synthesis of cis-decalins via Diels–Alder and double Michael addition of substituted Nazarov reagents

“…Ngooi also explained, in this way, the selectivity observed in the tin tetrachloride catalyzed [2+4] cycloadditions of dienes to dienophile 1 (3).…”

Lewis acid catalyzed Diels–Alder reactions of two useful dienyl phosphate esters

“…Dienyl phosphate 1 can be stored at 0°C over a long period of time without apparent decomposition. trans-2-Diethylphosphoryloxy-1,3-pentadiene (2) was obtained (30, 3 1) in a similar manner from trans-3-penten-2-one and diethyl chlorophosphate, which gave diene 2 as a stable (0°C) colorless oil in 41% yield (31). The Diels-Alder reactions of dienes 1 and 2 with a variety of dienophiles were carried out under Lewis acid catalysis.…”

“…Liu and Ngooi have used the analogue trans-2-diethylphosphoryloxy-1,3-pentadiene (2) to add to 2-carbomethoxy-2-cyclohexen-1 -one (3) with excellent stereoselectivity in the synthesis ( 3 0 , 3 1) of petasitolone (4) via adduct 5. In the same study they also found that the addition of trans-2-trimethylsilyloxy-1,3-pentadiene (6) to the dienone ester 3 gave the corresponding adduct as a mixture of degradation products, the two epimeric diketones 7, in much poorer yield (31,32). The diketones 7 apparently result from hydrolysis of the expected Diels-Alder adducts under the reaction conditions.…”