Cycloheptanoids

Over the past several years, Mascarenas and co-workers (150-153) utilized the oxidopyrylium ion with variously hetero-substituted olefin tethers. Mascarenas has used this methodology in tandem with a Diels-Alder reaction to prepare tricyclic cycloheptanoid substrates. Further, Mascarenas and co-workers (154—156) achieved the synthesis of optically active oxabicyclic[3.2.1]octane derivatives through the addition of a homochiral p-tolylsulfinyl group substituted at the olefin tether. The Mascarenas group has also used this methodology to prepare the THF portion of ( )-nemorensic acid via oxidative cleavage of the substituted a-hydroxyketone moiety (157) (Scheme 4.78). 

Intermolecular meta cycloadditions provide yet another option for the facile [SC -i- 2C] construction of seven-membered rings, as illustrated in Srinivasan s pioneering studies (Scheme 24). The availability of simple arenes and alkenes and of numerous methods as discussed above for the modification of meta cycloadducts makes this a particularly effective stategy for cycloheptanoid synthesis. 

Naturally occurring or commercially available cycloheptanoid starting materials are not at all common and have rarely been used in S3mthesis, with the possible exception of cycloheptatrienone. The chemistry of all carbon atom seven-membered rings is different from the immediate neighbors, as well... 

The cross-coupling reactions developed over the past 50 years have now been recognized by Nobel prizes to Heck, Suzuki, and Negishi. The relevance of these reactions in synthesis is obvious by the enormous number of publications dealing with the applications for the formation of sp carbon to sp carbon bond formation. Perhaps for this reason, only a few examples will be presented here, as the cycloheptanoid skeleton is basically made up of sp carbon atoms. Certainly, the inherent creativity of the synthetic organic chemist will change this situation very soon. 

In this second section, the cycloaddition approach to the cycloheptanoid skeleton in natural products will be discussed, and both the (4 + 3) and (5 + 2) options have undergone tremendous developments. The (4 + 3) cycloaddition has been reviewed [27] and also studied by Houk and colleagues as to the mechanism [64]. In a similar fashion, the (5 + 2) cycloaddition has been reviewed [28] and also studied theoretically by the Tantillo group [65]. 

The Molander group has used the (4 + 3) cycloaddition to form the cycloheptanoid system, as an entry to the 10-membered ring of the very important exmicellin diterpenes of renowned anticancer activity (Scheme 30) [67]. 

In 1968, Tobey and Law reported on the intriguing reaction of furan, substituted furans, and cyclopentadiene with both tetrachloro- and tetrabromocyclo-propene (TBCP). The two unsaturated systems reacted smoothly to directly produce cycloheptanoid systems, the products of a formal [4-i- 3]-cycloaddition reaction. The authors proposed in their early manuscripts that the tetrahalocy-clopropenes underwent an initial thermal Diels-Alder cycloaddition to produce the cyclopropyl norbornene derivatives la and lb (Figure 2). However, these workers were unable to isolate or characterize the primary cycloadducts and instead observed a product which had spontaneously rearranged by way of a halogen atom migration to yield the bicyclo[3.2.1]octadiene nucleus 2a and 2b. 

This chemistry has been applied to the synthesis of intermediates to muconic esters [38], hydrazulene derivatives [39], and a number of other cyclopentanoid or cycloheptanoid compounds [40]. The chemoselectivlty of the reaction could be improved by the presence of a phenylsulfanyl substituent at the double bond in 33 [41], and the diastereoselectivity has been investigated in the context... 

Wender and coworkers had established a methodology for the synthesis of a family of simple tigliane-daphnane analogues, based on the zirconocene-me-diated enyne carbocyclization, demonstrating both the extension of the car-bocyclization methodology to cycloheptanoid synthesis and the control of stereochemistry from a pre-existing ring system with the zirconocene-medi-ated carbocyclization reaction (Eq. 45) [47]. 

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