Gymnomitrol

Gymnomitrol (579), a tricyclic sesquiterpenoid which occurs as a major metabolite of the liverwort Gyrmomitrion obtusum (Lindb.) Pears, contains a rare 4,8-methano-azulene (diquinane) carbon skeleton with five adjacent chiral centers, three of them... 

The subsequent conversion to gymnomitrol proved uneventful and the overall sequence is the most expedient yet devised. 

The last synthesis to evolve which is due to Ito and his coworkers is interesting in that it relies on a stereospecific skeletal rearrangement of a bicyclo[2.2.2]octane system which in turn was prepared by Diels-Alder methodology (Scheme XLVIII) Heating of a toluene solution of cyclopentene 1,2-dicarboxylic anhydride and 4-methylcyclohexa-l,4-dienyl methyl ether in the presence of a catalytic quantity of p-toluenesulfonic acid afforded 589. Demethylation was followed by reduction and cyclization to sulfide 590. Desulfurization set the stage for peracid oxidation and arrival at 591. Chromatography of this intermediate on alumina induced isomerization to keto alcohol 592. Jones oxidation afforded diketone 593 which had earlier been transformed into gymnomitrol. 

Another rare kind of 6-electron ionic cycloaddition is that between a pentadienyl cation and an alkene. A telling example is the key step 2.66 — 2.67 in a synthesis of gymnomitrol 2.68, where the nature of the pericyclic step is heavily disguised, but all the more remarkable for that. Ionization of the acetal gives the cationic quinone system 2.66. That this is a pentadienyl cation can be seen in the drawing of a canonical structure on the left, with the components of the pericyclic cycloaddition emphasized in bold. Intramolecular [4+2] cycloaddition takes place, with the pentadienyl cation as the 4-electron component and the cyclopentene as the 2-electron component. Th is reaction is an excellent example of how a reaction can become embedded in so much framework that its pericyclic nature is obscured. 

In recent work Coates, Mason and Shah have successfully achieved the synthesis of gymnomitrol (29Ja).280) Since intramolecular aldol condensation of the aldehyde obtained by hydrolysis of 291 (Scheme 45) was unfavorable, conversion to enol lactone 292 was effected. Dibal-H reduction of 292 resulted directly in aldoli-zation of the intermediate lactol, oxidation of which afforded 293. The latter was converted successfully to keto alcohol 294 by capitalizing on the different steric environments about the carbonyl groups. Sequential dehydration and hydride reduction of 294 gave a 45 55 mixture of exo and endocyclic isomers 295a and295 b which were separated by TLC. 

Addition of p-quinone ketals to olefins. The ketal 1 reacts with 1,2-dimethyl-cyclopentene in the presence of stannic chloride to afford, after reduction with sodium borohydride, 2 and its diastereomer 3. The major alcohol (2) was used by Biichi and Chu in a total synthesis of the sesquiterpene gymnomitrol (4). Several other syntheses of this substance have recently been reported. ... 

Aldol cyclization. Although the keto aldehyde 1 is resistant to aldol cyclization under normal, alkaline conditions, this reaction can be accomplished by a method originally developed by Raphael et Reduction of the enol lactone (2), derived from 1, with DIBAH produces a bridged ketol, which is oxidized to 3 with chromic add. This diketone was employed as an intermediate in a synthesis of the sesquiterpene gymnomitrol (4). 

Full details of two of the elegant syntheses of gymnomitrol (159)93 94 and gymnomitrene (160)94 have been published. 

Within the space of two months, no fewer than five independent syntheses of the liverwort sesquiterpenoid gymnomitrol (144) have been reported. " This must constitute some kind of record. In three of the syntheses " the key building block was the known bicyclic ketone (143) and from that point the three syntheses converged to gymnomitrol (144) (Schemes 14—16). In the... 

Under similar conditions, but with the ketone present in slightly greater amounts than the base, enolate equilibration causes the thermodynamic enolate to predominate. This procedure was used in the first step of a laboratory synthesis of gymnomitrol, a natural product isolated from liverwort. 

Gymnomitrol, 39, is another sesquiterpenoid that encompasses an embedded diquinane scaffold. This becomes readily apparent when one examines the alternate representation for the compound. Again the use of the output from the Weiss-Cook reaction was found to be a rapid entry to this system in which two groups employed 40 as their foundation for the synthesis of 39. As we have seen, 40 is easily obtained from the reaction of l(R = R" = Me)and2. 

The intramolecular Aldol reaction is a key step in recent syntheses of sey-chellene and patchouli alcohol and in two of the four syntheses of the sesquiterpene gymnomitrol (159) that have been reported in the past year." ... 

Gymnomitrol (123) and P-barbatene (=gymnomitrene) (122) have been isolated from Gymnomitrion obtusum (Jungermanniales) 108). Further study of the sesquiterpenoids from the same species revealed the presence of six new compounds (124—129) containing the same skeleton 109). These structures were established by a combination of H-NMR and Eu(FOD)3-induced spectral shifts, decoupling experiments, and extensive chemical transformations, which are summarized in Schemes 14a and b 109). 

Scheme 14b. Correlation of gymnomitrol with a-barbatene and P-barbatene...

An independent study of the essential oil of Barbilophozia species resulted in the isolation of two new sesquiterpene hydrocarbons, a-bar-batene (121) and P-barbatene (= gymnomitrene) (122) 3, 4). The LIS-induced H-NMR spectra of an allylic alcohol (149) and an enal (150) prepared from (122) were compared with those of myrtenol and myrtenal (20), thus leading to isogymnomitrene (121), an acid isomerization product of gymnomitrene (122), and to (122) as structures for a- and P-barbatene. The absolute stereochemistry assigned to gymnomitrol was further confirmed by comparing the CD spectra of the barbatenes (121,122) with those of the cedrenes (256, 257) (Scheme 15) (3, 4). 

Total syntheses of gymnomitrane-type sesquiterpenes confirm the structure of these biogenetically interesting compounds. ( )-Gymnomitrol (123) and a- and p-barbatene (121, 122) have been synthesized by five different laboratories as shown in Schemes 18 — 23 (98,107,134,176, 285, 344,345). 

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