Germacrane synthesis

Synthesis of germacrane sesquiterpenoid lactones and related compounds 99T2115. 

In one of the earliest applications of this type of process to complex molecule synthesis, Corey and Hortmann, in their synthesis of dihydrocostunolide 38, found that photolysis of 36 afforded a photostationary state of 36 and 37 (Scheme 9)19. Hydrogenation of this mixture then gave 38. A recent modification of this synthesis, which avoids the photostationary equilibrium between eudesmane (36) and germacrane (37) forms, was realized using a modified substrate, 3920. Irradiation of 39 provided a 77% yield of a mixture of diastereomeric ketones 41 these are produced via tautomerization of the intially produced trienol 40. Dienone 41 was then easily converted to 38 via a series of conventional steps (Scheme 9). 

The trans-cis isomerization process observed in the eudesmane/germacrane ring system has been utilized for the synthesis of the c/s-fused sesquiterpene occidentalol, 48a, and its 7-epi isomer, 48b (Scheme ll)22. Photolysis of the traws-fused diene 45 at —78°C afforded triene 46, which upon warming underwent disrotatory electrocyclization to give 47a and 47b as a 1 2 mixture of diastereomers. Apparently, the carboalkoxy group imparts... 

A quite detailed review of transannular cyclizations was published201 wherein their important role in biomimetic syntheses of sesquiterpenes as well as explanation of the biogenetic formation of the polycyclic natural compounds from their monocyclic precursors is discussed. The great significance of these transformations for the synthesis of natural products is also emphasized in a series of reviews which describe the cyclizations to form terpene derivatives, e.g., of the germacrane and humulene systems202-206. 

Raucher et al. used a tandem Cope-Claisen rearrangement during total synthesis of the germacrane sesquiterpene (+)-dihydrocostunolide (3)2 (Scheme 1.4c). 

Dauben et al. [153] successfully applied this procedure to the total synthesis of the cembranoid crassin acetate methyl ether (258). As shown in Scheme 86, the keto aldehyde 256 was treated with TiClj/Zn-Cu in refluxing DME to give the cyclic olefin 257 in 65% yield (E Z = 4 3). The germacrane sesquiterpenes have also been synthesized using this method [154],... 

A new synthetic approach to the synthesis of germacrane sesquiterpenoids involving cyclization of 10,ll-epoxy-rran5,trans-farnesyl phenyl sulphide (306) provides a mixture of hedycaryol (307) and the isomeric alcohols (308) and (309). Studies on the biosynthesis of germacrane sesquiterpenoids have appeared recently. 

Reduction of the photo-adduct (446) derived from (+)-isopiperitone and cyclobutene-1-carboxylic acid with NaCNBH3 gives the lactone (447). Thermolysis of this compound affords the 6a-epimer of isoaristolactone (448) and the elemanolide (449).213 A novel approach to the synthesis of germacranes involves the thermal opening of a bridgehead cyclobutene which, in turn, is derived by an oxy-Cope rearrangement (Scheme 57).214... 

This reductive alkylation was used in a synthesis of 8, which contains the 10-membered ring system of germacrane sesquiterpenes. Thus the tetralonc 5 was converted by way of 6 into the tosylate 7. On treatment with LDA in THF at 24°, 7 underwent a Grob-type fragmentation to give 8. 

Oxy-Cope rearrangement (7, 302). The Evans modification of the oxy-Cope rearrangement has been used in recent syntheses. It is an important step in a new synthesis by StilE of germacrane-type sesquiterpenes shown in equation (I). 

Two notable germacrane syntheses have been completed. The first one (Scheme 42) involves the synthesis of isolinderalactone (452) and epi-isolin-deralactone (453), each of which undergoes a thermal Cope rearrangement to yield linderalactone (454) and neolinderalactone (455) respectively. The second synthetic achievement in this area is that of isabelin (457) in which the key step is the thermally induced opening of photoisabelin (456) to produce isabelin and its cw-A -isomei (Scheme 43). ... 

Periplanone B is the most active sex pheromone found in the alimentary tract and excreta of the American cockroach Periplaneta americana. An elegant total synthesis of this germacrane sesquiterpene was achieved by SCHREIBER and SANTINI Cyclodecatrienone 1 is an obvious precursor. One of the oxirane rings arises from epoxidation of the enone CC double bond, the other from [2-1-1]-cycloaddition of a carbene to the carbonyl bond of the enone. Oxidation of the methylene group introduces the additional carbonyl double bond. The CC double bond of the enone results from an elimination of HX in the a-X-substituted cyclodecadienone 2, which, on its part, is feasible by substitution of cyclodecadienone 3. An electrocyclic opening of the cyclobutene ring in 4 provides the 1,3-diene substructure in 3. 

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