Of humulene

Intramolecular allylation offers a useful synthetic method for macrocyclic compounds. An application to the synthesis of humulene (83) by the cycliza-... 

Organoboranes are reactive compounds for cross-coupling[277]. The synthesis of humulene (83) by the intramolecular cross-coupling of allylic bromide with alkenylborane is an example[278]. The reaction of vinyiborane with vinyl-oxirane (425) affords the homoallylic alcohol 426 by 1,2-addition as main products and the allylic alcohol 427 by 1,4-addition as a minor product[279]. Two phenyl groups in sodium tetraphenylborate (428) are used for the coupling with allylic acetate[280] or allyl chloride[33,28l]. 

The 11-membered ring of humulene, a major impediment to synthesis, was constructed by a novel nickel-mediated cyclization. 

Two transannular cyclizations have been reported which lead to isomers of 677. Thus, treatment of 677 or 678 with boron trifluoride etherate gives rise to capnellene (679) Also, conversion of humulene 6,7-oxide (680) to tricyclic epoxide 681 has provided the opportunity for trimethylsilyl triftate-promoted... 

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... 

Dehydration.1 Usual methods for dehydration of the hydroxy aldehyde 2 are unsatisfactory, but 1 effects the desired conversion to 3 in 90% yield. The product is a precursor to 6-protoilludene (4), a natural product considered to be an intermediate in the biosynthesis of humulenes. 

The three mono-epoxides of humulene 1 are naturally occurring, and it is believed that they are in vivo precursors of other bicyclic and tricyclic sesquiterpenes. In vitro experiments have demonstrated that the 1,2- and 4,5-epoxides undergo facile acid-catalysed rearrangement, and it has been shown recently that treatment of a chloroform solution of the 8,9-epoxide with tin(IV) chloride at -60°C for 15 minutes gives a variety of hydrocarbons and one major product (25%), the alcohol 2. 

Lewis Acid Catalysed Rearrangement of Humulene 8,9-Epoxide... 

The 11-carbon ring of the humulyl carbocation may be retained, as in the formation of humulene (Figure 5.36), or modified to give the caryophyllyl cation containing a nine-membered ring fused to a four-membered ring, as in P-caryophyllene (Figure 5.36). Humulene is found... 

Intramolecular allylation has wide application in the synthesis of macrocycles [57]. Synthesis of humulene (107) by the cyclization of allyl acetate 105 to give 106 is an early example [58]. The 14-membered ring 109 was obtained from 108 and converted to cembranolide 110 [59]. 

An investigation of the acid-catalysed cyclization of humulene (151) has provided results69 identical with those outlined in last year s Report.8 The isolation70 of... 

Complete details of the acid-catalysed rearrangement of humulene 1,2-epox-ide (249) have now been presented. With 1.8M-sulphuric acid in acetone at 0 °C for 30 min the sole product is the previously "known tricyclic diol (250). After an extended period this diol gives rise to five other identified products. 

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... 

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. 

Asymmetric Epoxidation. McKervey and co-workers have effected the asymmetric epoxidation of humulene. Complexation of humulene with (2) in a 1 2 ratio followed by peracid oxidation gave (—)-humulene 1,2-epoxide in 37% ee (eq 1). ... 

The Suzuki reaction was a key step in the synthesis of bombykol, the sex pheromone of the female silkworm moth, and humulene, a lipid isolated from hops, as shown in Figure 26.1. The synthesis of humulene illustrates that an intramolecular Suzuki reaction can form a ring. Sample Problem 26.2 shows how a conjugated diene can be prepared from an alkyne and vinyl halide using a Suzuki reaction. 

The original Shapiro reaction involves the preparation of unfiinctionalized alkenes from ketone tosyl-hydrazones by quenching of the in situ generated alkenyllithium reagents with water. Recent applications of this reaction in natural product synthesis include the synthesis of 9(0)-methanoprostacyclin (Scheme 12), the in vitro conversion of humulene to A ( -capnellene (Scheme 13), the synthesis of die basic skeleton of isoadsirene (equation S2) ° and the total synthesis of the eudesmanolides rothin A and rothin B (equation 53). ... 

Later work by Parker et a/.demonstrated that extended treatment of humulene with aqueous sulfuric acid in acetone led largely to the bicyclo[5.3.0]deca-2,10-diene (115), via initial formation of humulol... 

The three monoepoxides of humulene, i.e. (136), (150) and (162), occur in nature, and there is every reason to assume that each epoxide is involved separately in transannulation processes leading to various fused-ring systems found amongst the sesquiterpenes. All three humulene monoepoxides have been synthesized and their individual chemistry with Lewis acids has been examined in an effort to effect their biogenetic conversions to natural teipenes. 

Contemporaneous studies of the conformational behavior of humulene (72) by Shirahama et using empirical force calculations have suggested that, although the molecule can assume any of the four stable conformations (140), (141), (142) and (143), abbreviated to CT, CC, TT and TC respectively, (see Section 1.10.3), only the CT- and the CC-conformers (140) and (141) are involved in biosynthetic transannulation reactions. Thus, Shirahama et al. have suggested that the transannulation reaction leading from (136) to (139) in the presence of TMSOTf proceeds via the CT-conformer (137) of humulene-1,2-epoxide. Interestingly, when (139) was converted into the epoxide (144), treatment with TMSOTf trig-... 

Appropriate manipulations of the tricycle (152a) resulting from transannulation of humulene-4,5-epoxide permitted Roberts and Shirahama and their respective collaborators to access africanol (154) and 8-oxysenoxyn-4-en-3-one (157). Shirahama etalP have also described the in vitro conversion of africanol (154) to dactylol (158), found in the sea hare Aplsysia dactyloma, via the novel and unusual cyclopropane-sliding reaction, summarized in Scheme 19. 

A number of biomimetic syntheses have included Wagner-Meerwein rearrangements. A chemical conversion of humulene (48) to sterpurene (50) involved an interesting series of Wagner-Meerwein rearrangements (see Scheme 19).- - Humulene (48) was converted to the cyclooctenol (51) and thence to the bromide (52) via the protoilludyl cation (49). Treatment of (52) with silver acetate in acetic acid gave racemic sterpurene (50). In contrast the epimeric bromide (53) gave (54). 

The proposed intermediacy of humulene (218) in the biosynthesis of sesquiterpenoids belonging to various structural groups (caryophyllane, protoilludane, etc.)... 

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