Humulene derivatives

In another attempt to mimic the in vivo cyclization of humulene, Mlotkiewicz et have shown that treatment of humulene 4,5-epoxide (272) with boron trifluoride etherate leads to the formation of the two tricyclic alcohols (273) and (274) in 70% yield. The carbon skeleton of these two compounds is exactly that found in africanol (276) and the more recently isolated keto-angelate (275). Further elaboration of the alcohol (273) has in fact resulted in a biomimetic synthesis of the keto-alcohol corresponding to (275). This work constitutes the first example of the direct conversion of a humulene derivative into a naturally occurring compound. 

Studies of the precursor-product relationship in various biogenetically related humulene-derived metabolites have led to a unified scheme (equation 5) in which intramolecular cyclization of trans,trans-farnesyl pyrophosphate (73) generates humulene (74) by the attack at C(ll) of the distal double bond and loss of a proton from C(9) reprotonation at C( 10) of the key intermediate initiates further cyclization to a cyclobutyl-containing protoilludyl cation (75). Subsequent bond migration accompanied by contraction of the cyclobutane ring to the cyclopropane as shown, would then yield illudins. In accordance with the postulated pathway of illudin formation, C(l), C(14) and one of the... 

Humulenes (167) and (168), which were detected in various oils, presumably do not play an essential role in hop oil [odor threshold in water solution 120 ppb (71)]. Oxygen-containing humulene derivatives, among which epoxides (169) and (170) (77), humulol (174) (428) and ketones (176) and (177) (429) were identified, might contribute much to the hop character imparted to hop beverages (71). All these substances (167) to (173) as well as zerumbone (175) were first isolated from the essential oil of wild ginger (99, 100, 101). 

Hiickel linear combination of atomic orbitals pyridines and benzo derivatives, 2, 102 Hiickel molecular orbital method colour and constitution, 1, 342 Hugerschoff bases synthesis, 6, 475-477, 493 Humulene... 

The similarity between humulene and caryophyllene had not escaped Chapman s notice at the time that he isolated humulene, but as he was nnable to prepare a hydrate, which is one of the easiest of the caryophyllene derivatives to obtain in a pure state, he concluded that the sesquiterpene was not identical with caryophyllene. Eecent work by fiemmler does not tend to establish the identity of the two sesquiterpenes, and unless and until further evidence to the contrary is forthcoming, humvdene may be regarded as a definite chemical individual. 

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. 

The fermentation broth of various Streptomyces species can be separated into an acidic fraction shown to contain pentalenic acid 776) The somewhat less oxidized pentalenolactone precursor has been independently prepared from humulene from which is is probably derived biogenetically Thus, treatment of humulene with mercuric nitrate followed by aqueous potassium bromide solution gave two bromo-mercury derivatives which were oxygenated in the presence of sodium borohydride. The resulting pair of diols (770 and 771) were separately converted to exo methylene... 

A new elegant stereoselective synthesis of humulene (192) has been achieved by a route (Scheme 22) in which the 11-membered-ring framework [cf. (191)] is produced by cyclization of the 11-allylpalladium complex derived from intermediate (190). Buddledin-A (193), -B (194), and -C (195) are new piscicidal sesquiterpenoids which have recently been isolated from the root bark of Buddleja davidiC The caryophyliane framework of these compounds has been established by spectroscopic data and X-ray analysis of the mono-bromohydrin (196) derived from buddledin A (193). An extension of previous studies on the cyclization of the epoxy-ketone (197) derived from caryophyllene has shown that the base-catalysed cyclization of the isomeric epoxy-ketones (198) and (199) provides compounds... 

In recent years humulene has been viewed as a focal biogenetic precursor of an ever-increasing number of tricyclic sesquiterpenoids. To date, however, there has been little real success in the in vitro conversion of humulene or its derivatives into... 

Formolysis of (264) produces the formate ester of (259) and (265) in 66% and 20% yield respectively the latter hydrocarbon is related to the pentalane class of sesquiterpenoids (see below). A study of this rearrangement, again using a deuteriated substrate, provided evidence for the pathway outlined in Scheme 38. Matsumoto et have also studied the mechanism of formation of the two tricyclic ethers (257) and (260) [with Hg(OAc)2] and the three tricyclic ethers [with Hg(N03)2] derived from humulene after NaBD4 work-up. Under these conditions the five deuteriated products are (266)—(270) respectively. The... 

X-Ray analyses of two heavy-atom derivatives of illudol (203) and marasmic acid (204) have confirmed the ds-fused hydrindane skeletons in each and this fact is in accord with the stereochemistry of the hypothetical precursor (205) derivable from humulene. Matsumoto and co-workers have now completed... 

Composition Eugenol (65-85%), methyl eugenol, 1,8-cineole and numerous mono-and sesquiterpene hydrocarbons, e.g. myrcene, p-caryophyllene and humulene [230], The commercially available oils also derive from the leaves and possess a similar composition, whereas the content of methyl eugenol in most cases is higher in the berry oil [231, 232[. For further research results see [233[. 

Reaction of the 4,5-monoepoxide of humulene 8 with boron trifluoride-diethylether complex or trimethylsilyl triflate yielded two isomeric alcohols 6,6,9-trimethyltricyclo[6.3.0.0 ]un-dec-9-en-5-ol 9 and 6,6,9-trimethyltricyclo[6.3.0.0 ]undec-8-en-5-ol 10, in a 1 1 proportion with yields of 70 and 80%, respectively. The isomeric alcohols have the structure of the naturally occurring sesquiterpenes africene and africanol and of some of their derivatives. 

When the C1-C2 double bond is deactivated, for instance by oxidation of the methyl group to an aldehyde group as in 11, opening of the oxirane ring by trimethylsilyl triflate provided a homoallyl carbenium ion which then underwent transannular Ti-cyclization but with participation of the C8-C9 double bond leading to a mixture of secoprotoilludane derivatives 12 and 13. In this case the rearrangement took place from a different C-C conformation, where in an intermediate step an additional Z/ isomerization of the C1-C2 double bond occurred. Reaction of the 8,9-epoxide of humulene with tin(IV) chloride led initially to formation of a cationic center at C9, but internal 7r-cyclization yielded an alcohol with a hydroazulene structure. ... 

We prefer the IUPAC numbering (see Editor s note in ref. 172) although we recognise the preference of Professor Matsumoto and others for humulene numbering based on its derivation from famesyl pyrophosphate. 

C-l and/or C-2 have been converted to sp3 geometry. One possible explanation for this apparent anomaly is to invoke a A1-2 trans- cis isomerization in humulene prior to cyclization. This permits a more favourable interaction between a developing cationic centre at C-4 and the A8-9 double bond. Thus the conformer (375) of isohumulene could serve as a precursor for the protoilludyl-derived metabolites while its enantiomer could proceed to the hirsutane sesquiterpenoids. 

Both the pioneers in understanding chirality, van t Hoff and Le Bel, pointed out that cpl might be used to induce asymmetry in chemical reactions [17,18]. In the following decades there were many vain efforts to realize this idea [19,20-22,24-27]. The failure, most probably, was due to the small effects caused by the small differences in Ae. The first successful asymmetric photoreactions were found by W. Kuhn, who published a series of papers in 1929 and 1930 [3,28-28] on the photolysis of racemic a-azido propionic dimethylamide 2 and a-bromopropionic ethyl ester 3 derivatives. Mitchell [33] reported in 1930 on humulene nitrosite (probably 4 ) and Tsuchida et al in 1935 on [Co(ox)3] Ca-malogue to 5) [98]. 

Scheme 5.7 Biosynthetic relationships amongst the sesquiterpene skeleta derived from humulene.

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