Humulene allylation

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 effects on coupling efficiency and regiochemical control in nonsymmetrical allyl complexes as a function of added ligand in these reactions has been determined155,156 (vide infra) and applied in the synthesis of flexibilene and humulene.157... 

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]. 

Amongst the monocyclic sesquiterpenes, the plant growth hormone (+)-abscisic acid 446 and a-humulene 451 are found which both can be synthesized by Wittig reactions. To synthesize (+)-abscisinic acid 446 D. L. Roberts et al. 239) converted a-ionone 444 into the allylic alcohol 445 by /-butyl chromate oxidation. 445 is reacted with ethoxycarbonylmethylene-triphenylphosphorane 238 and subsequently... 

Terpene cyclase enzymes catalyze the cychzation of allylic pyrophosphate substrates to form carbocyclic products via car-bocation reaction intermediates. One well-studied example is pentalenene synthase (11, 12), which catalyzes the cychzation of farnesyl pyrophosphate to give pentalenene, whose reaction mechanism is shown in Fig. 15. Cychzation of farnesyl pyrophosphate is proposed to form an 11-membered intermediate, humulene, which is followed by a five-membered ring closure to form a bicychc tertiary carbocation. 1,2-Hydride migration followed by an additional five-membered ring closure gives a tricyclic carbocation, which gives pentalenene, at elimination. 

Addition of carbenium ions to C —C double bonds and C—C triple bonds, as well as to allylic systems, is of great interest in organic chemistry. Extensive investigations due to the importance of terpenes in biosynthesis (e.g., generation of steroids, transannular reactions of humulene. etc.) led to the development of a great number of reactions employing this method of C —C bond formation. 

When treatment of humulene with mercuric nitrate is followed by addition of aqueous hydrogen bromide a mixture of two products is isolated, one of them having lost the hydroxyl group at C-10, after elimination of water, to give the allylic ether 566. The tricyclic ethers 2, 3 and 4 are precursors in pentalene, pentalenic acid and hvdroxypentalene25 - 27 syntheses, as well as in the syntheses of sterpurene67 and hirsutene68. 

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... 

Zero-valent nickel is especially effective for the cyclization of (7j5(allyl) bromides.2 4 295 Corey used this technique to cyclize 450 to 451. Subsequent photolysis in the presence of diphenyl disulfide (PhSSPh) gave humulene, 452. 94 Wender et al. reported a novel [4+4]-cycloaddition reaction in which two diene moieties are coupled with a nickel(O) catalyst to form eight-membered rings. In Wender s synthesis of asteriscanolide,... 

The intramolecular version of the allylation has been carried out by Corey. The 11-membered cyclic ketone 554 was obtained from the silyl enol ether 553 in 52% yield, and short syntheses of humulene and 5-araneosene have been achieved utilizing the reaction as a key step [203],... 

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

Humulene is a naturally occurring hydrocarbon present in the seed cone of hops and has been synthesized several times. In one of these, the retrosynthetic strategy was based on the disconnection shown. Deduce the structure, including stereochemistry, of an allylic bromide capable of yielding humulene by an intramolecular Suzuki coupling in the last step in the synthesis. Represent the boron containing unit as—B(OH)2. 

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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