Humulene synthesis

Elegant applications of this method to the syntheses of large ring (12,14, and 18) compounds and natural products have been reported by Corey and Wat 129>. The last step of the humulene synthesis by Corey and Hamanaka is the following coupling reaction of ally lie dibromide via jr-allylnickel complex formation 13°). 

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]. 

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

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. 

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... 

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]. 

Other applications of this method include, e.g. the synthesis of the antibiotic A26771B (5i) [118] and the marine cembranolide isolobophytolide [119], Trost and Warner [120] reported that a-sulfonyl sulfones can also serve as the substrates of ir-allylpalladium complexes for macrocyclization. Furthermore, an a-hydroxy-carbonyl ketone was alkylated intramolecularly by a a-allylpalladium complex in the total synthesis of the macrocyclic sesquiterpene humulene [121]. 

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. 

The Suzuki reaction in the synthesis of bombykol, the sex pheromone of the female silkworm moth, and humulene, a lipid isolated from hops (Section 26.2B)... 

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). ... 

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