Synthesis of Humulene

Allylic acetates become electrophilic on forming complexes with palladium (0) and will therefore alkylate stabilised enolates. Kitagawa et al.7 20 used this to good effect in the synthesis of (7.187) from (7.186) en route to humulene (7.139). Similarly, Corey and Hamanka7 21 used nickel carbonyl to intramolecularly couple the two allylic bromide functions of (7.188). The -double bond in the substrate (7.188) was 

The characteristic scent of violet flowers is due to carotenoid degradation products 

Chemical compounds isolated from nature may be the products of degradation of other materials. 

Complex products are sometimes produced most economically from available natural feedstocks. 

The reader will no doubt be familiar with amber, the fossilised form of rosin, which is a sought after material for use in jewellery. The main source of amber is the coastline of the Baltic where it is often found washed up on beaches. Since amber is derived from rosin, we can consider it to be terpenoid in nature. There is another terpenoid material which resembles amber to some extent and is also found on beaches, but which is much less known. This second product is called ambergris, from the French ambregris - grey amber. This name was coined to distinguish 

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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]. 

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... 

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]. 

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. 

Miyaura, N., and Suginome, H., New stereo- and regiospecific synthesis of humulene by means of the palladium catalyzed cyclization of haloalkenylboranes, Tetrahedron Lett., 25, 761, 1984. 

Nickel carbonyl cyclization was the key step in a total synthesis of humulene (18) by Corey and Hamanaka.18 When a solution of the dibromide (16) in N-methyl-... 

Neighboring group effects can compete with steric effects, as illustrated by treatment of oxetane 142 with diethylaluminum-At-methylaniline. This elimination reaction gave a 99% yield of (E)-alkene 143 in a synthesis of humulene. The aluminum coordinated to the oxetane oxygen on the less hindered p face in 144 and 145, the two key rotamers. Rotamer 144 is lower in energy due to the severe nonbonded interaction... 

Japanese chemists have reported a stereoselective synthesis of humulene (9), an 11-membered cyclic sesquiterpene, by intramolecular a-alkylation of a keto group by a jr-allylpalladium complex. The starting material (7) was derived from geranyl acetate. In this case, the efficiency of the cyclization was markedly improved by addition of a diphosphine ligand such as l,3-bis(diphenylphosphino)-... 

Another noteworthy earlier example is the synthesis of humulene, albeit in 32% yield, via Pd-catalyzed intramolecular alkenyl-allyl coupling shown in Scheme... 

In a biogenetic-type synthesis of humulene the 7r-allylpalladium complex (164), derived from the acetate (163), has been observed to cyclize intramolecularly in a highly stereoselective fashion, producing the cycloundecadienone (165)/° No detectable amounts of the positional isomer (nine-membered ring) or stereoisomers about the double bonds were observed. 

The use of the Suzuki-Miyaura reaction in the synthesis of natural products has been wide spread over the years and is well reviewed. The intramolecular Suzuki-Miyaura reaction macrocyclisation to form macrocyclic natural products has been well reviewed by Fairlamb. Interestingly the first report employing this type of approaeh for maeroeyelic formation came from the group of Miyaura and Suzuki in their synthesis of humulene (Scheme 13.23). ... 

This procedure has been applied to the synthesis of humulene (CXII), the overall yield being 10% (Corey and Hamanaka, 1967). t/,/-Elemol (CXIII)... 

Kitagawa Y, Itoh A, Hashimoto S, Yamamoto H, Nozaki H (1977) Total synthesis of humulene. A stereoselective approach. J Am Chem Soc 99 3864... 

Intramolecular allylation has proved extremely useful in the synthesis of macrocyclic compounds. In 1977, Nozaski and co-workers reported the first example in the synthesis of humulene 31. Intramolecular Tsuji-Trost allylation provided key intermediate 30 in moderate yield. 

The formation of cycloolefins from allylic dihalides (i) and nickel carbonyl has previously been shown to provide an unusually efficient route for the formation of large rings, and is exemplified in the synthesis of humulene (11-membered ring formation) by E. J. Corey and E. Hamanaka, J. Amer. Chem. Soc., 89, 2758 (1967). However, in the case of 1,10-dibromo-2,8-decadiene (i, n = 4), the predominant course of cyclization was formation of the 6-membered ring structure (ii) by 3,8 coupling rather than the expected 1,5-cyclodecadiene (iii), E. J. Corey and E. K. W. Watt, J. Amer. Chem. Soc., 89, 2757 (1967). 

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