Germacrane

One interesting facet of the germacrane-type sesquiterpenoids is the conformation of the ten-membered ring. This aspect has previously been discussed in terms of transannular electronic effects (anomalous u.v. spectra) and transannular chemical reactions (Cope rearrangement and cyclisations to eudesmane and/or guaiane types). Recently, the power of two spectroscopic techniques has been brought to bear on this problem. The first of these is the use of the Nuclear Overhauser Effect (NOE) and the second is the A -ray analysis of a suitable derivative. 

Hikino.C. Konno.T.Takemoto, K.Tori, M. Ohtsuru, and I. Horibe, Chem. Comm. 1969, 662. 

From a study of the temperature-dependent n.m.r. and c.d. spectra of neo-linderalactone, Tori et have concluded that this compound exists in the two conformers (201) and (202) in the ratio of 8 2 at room temperature. The barrier to inversion, AE, is calculated to be about lOkcal mole from n.m.r. data, while variable temperature c.d. observations lead to a value of 0.6 + 0.2 kcal mole for AG between (201) and (202). Yet another example of conforma- 

Horibe, K. Kuriyama, and K. Takeda, Chem. Comm., 1970, 957. 

The X-ray analysis of the silver nitrate adduct of costunolide clearly shows that the molecule exists as the conformer (204) with the methyl groups in a syn relationship and the double bonds mutually perpendicular. The same features have also been found by the A -ray analyses of the pregeijerene (205)-silver nitrate complex and heavy-atom derivatives of elephantol (206) and shiromodiol (207).  

Molecular mechanics calculations have been carried out on germacrene B with the result that theoretical heats of formation have been ascribed to the four conformers (305)—(308) of 4.08,4.31, 5.35, and 5.14 kcal moP respectively. Further calculations on the germacrene B supersurface indicates that the estimated barrier to inversion of the CT conformer (305) to its mirror image is 

Bellesia, U. M. Pagnoni, A. Pinetti, and R. Trave, Gazz. Chim. Ital., 1978,108, 39. 

In order to explain the stereospecificity of the thermally induced cyclization of preisocalamendiol (315) to give dehydroisocalamendiol (316), Terada and Yamamura have carried out molecular mechanics calculations on the ground-state conformers and probable transition states of (315). The computed values of the steric energies of the possible transition states are in good agreement with the observed experimental facts. Other studies related to the conformational aspects of germacrane sesquiterpenoids include an examination of the NOE effects in the isofuranodiene (317), which shows the 1,5-diene system to be in a crossed 

159 rp YqjJjJjJjj Muraki, K. Takahashi, T. Kato, C. Kabuto, T. Suzuki, T. Uyehara, and T. Ohnuma, J. Chem. Soc., Chem. Commun., 1979, 512. 

Reagents i, LDA ii, MeCH=CHCHO iii, AC2O iv, MejSnLi-MejSiCl v, MeaCuLi  

The diverse biological activity (allergenic, antitumour, fungitoxic, phytotoxic, cytotoxic, etc.) of germacranolides (226a and b) and other sesquiterpenoids containing cx/S-unsaturated y-butyrolactone units has been reviewed. During the period of 

Holub and Z. Samek, Coll. Czech. Chem. Comm., 1977, 42, 1053. 

Reagents i, TsNHNHz ii, LiNPr j-THF iii, Oj-CHjCla-MeOH iv, NaBH4 v, ArSeCN-PBuj-THF-py vi, H2O2-THF vii, LiNPr 2-PhSeSePh-HMPA-THF viii. A, 200 C, g.I.c. 

Reagents i, Me2CHC(Li)=CH2 ii, KH-THF-18-crown-6 iii, LiNPr j-THF-HMPA-HOAc iv, Mc3SnLi v, Me3SiCl vi, Mn02 

Takahashi, S. Muraki, and T. Yoshida, Agric. Biol. Chem., 1981, 45, 129. 

On the other hand, reaction of (438) with methyl-lithium gives predominantly (442) and (443) via the diradical (444), whereas similar treatment of (439) gives largely (445). 

In an effort to mimic the proposed cyclization of the germaci tdienyl cation (450) to the cadinane skeleton, Ito et a/.215 have examined the fate of the four hedycaryol phenyl sulphides (451)—(454) on reaction with methyl iodide (cf. Vol. 10, p. 51). In all four cases the products derived (455)—(462) were eudesmane derivatives and this finding has been explained in terms of Hi-induced cycliz-ations, the HI being generated from the initially formed sulphonium salts. De- 

Four products (473)—(476) resulted from this reaction, three of which are of the eudesmane class while the fourth has the cadinane skeleton. 

Treatment of the fraw.Mrart.s-germacranolide, epitulipanolide (477) and two of its derivatives with selenium dioxide and t-butyl hydroperoxide gives the melampolide-type alcohol (478).218 A mechanism for this allylic oxidation with inversion of configuration at the A1-10 double bond is proposed. It should be noted, however, that this is not the first report of such a process (cf. Vol. 11, p. 55). 

A photochemical study of f.f-germacrene (335) has been carried out. Direct irradiation leads to the formation of the photoproducts (336)—(340), whereas sensitized irradiation produces mainly the isomerized Z,Z-derivative (341) together with small amounts of (336), (337), and (339). Direct irradiation of 

Iguchi, and S. Yamamura, Chem. Pharm. Bull., 1980, 28, 997. 

OOH vi, MsCl-EtjN vii, LiBr viii, HjO ix, NaOMe -TiCl4  

These results indicate that this organism is capable of three different types of biotransformation, including reduction of the a,jS-unsaturated-y-lactone, epoxi-dation, and cyclization. In another biogenetically motivated experiment it has been demonstrated that selenium dioxide oxidation of costunolide (354) proceeds with isomerization of the double bond to produce the melampolide-type compounds (364) and (365). 

New germacrane sesquiterpenoids include the furan (366), (367), bacchascandone (368), cyclachaenin (369), and /8-germacrene C (370). The three furanogermacrenes (371)—(373) have been identified in the essential oil of myrrh. 

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The first report on the Pd(II)-promoted Cope rearrangement is the conversion of fw./ra/w-l,5-cyclodecadiene (44) into c/5-l,2-divinylcyclohexane-PdCl2 complex (45) with a stoichiometric amount of PdCl2(PhCN)2 at room temperature. The complex formation is the driving force of this unusual rearrangement [38,39]. A similar transformation of germacrane (l,5-dimethyl-8-isopropyli-dene-/rfflu,/ra j-l,5-cyclodecadiene) takes place[40j. 

Synthesis of germacrane sesquiterpenoid lactones and related compounds 99T2115. 

P, 5-epoxy-5,10-dihydroxy -6a-angeloyloxy -9(5-isobutyloxy -germacran -8a, 12-olid... 

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... 

Photocycloaddition of allene to cyclohexenone (341) gave the (3,y-enone (342), which reacted with vinyl magnesium bromide to produce the tertiary alcohol (343) in 79% yield. When the compound (343) was treated with KH and 18-crown-6 in THF at room temperature for two hours and quenched with aq. NH4C1, the cyclobutene (344) was obtained. The thermal ring opening of the cyclobutene (344) proceeded in toluene in a sealed-tube at 180 °C for twelve hours to give a readily separable 5 1 mixture of the civ-olefin (345), and the trans-olefin (346) respectively in 95 % yield. Moreover, (345) could be converted to a mixture of (346) and (345) in the ratio of 10 1 by irradiation. The compounds (345) and (346) possess the skeleton of the germacranes (347), (348) and (349) 122). 

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. 

Vieira, L. et al., Germacranes and flavonoids from Achillea ageratum. Phytochemistry, 45, 111, 1997. 

Brown algae of the family Dictyotaceae yielded diterpenes of the dolabellane, xenicane, crenulide as well as extended germacrane and hydroazulenoid types. Some of these compounds were identified as capable of demonstrating appreciable selectivity as antimalarial agents... 

Recently, germacrene-A (III) has been identified as the alarm pheromone of the sweet clover aphid Therioaphis trifolii (38). This alarm releaser, which has often been proposed as the progenitor of cyclic sesquiterpenes, constitutes the second compound with a germacrane-type skeleton to be identified as an insect pheromone. 

SqSO Atractylon Germacrane Atractylodes japonica TPA, Skin-1 [156]... 

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

The names periplanone-A and periplanone-B were first coined by Ritter and Persoons in 1974 at the International Congress of Pesticide Chemistry in Helsinki, in a general paper on pheromone research in the Netherlands. In this paper the isolation of a number of pheromones were described, including the two peripla-nones, both sex pheromones, present in the excreta of the female American cockroach, Periplaneta americana. The elementary formulae of these two sesquiterpenoids, C15H20O2 and C15H20O3, were given and the carbon skeleton of periplanone-B, a germacrane derivative, was revealed. Unfortunately, we were informed, one year after the... 

The formation from farnesol of the picrotoxane skeleton of dendrobine (40) has been assumed to involve a 1,3 shift of the l-pro-R hydrogen in the germacrane intermediate (41), although no direct proof of this had been presented. The finding75... 

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