Humulene macrocyclization

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

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]. 

With the increased chain length and additional double bond, the number of possible ways that cyclization can occur is also increased, and there exists a wide variety of cyclic sesquiterpenes, for example, abscisic acid, fumagillin, germacrene, dendrolasin, and trans-y-monocyclo famesol. In addition to common six-membered ring systems such as in zingiberene, a constituent of the oil from ginger, cyclization of one end of the chain to the other end can lead to macrocyclic rings such as humulene. 

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). ... 

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. 

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