Favorskii rearrangement, natural product

Cyclopropanone cleavage with elimination 72 can also lead to ring contraction as in the synthesis of the trans acid 74 from natural pulegone13 70. Bromination gives the unstable dibromide 71 that is immediately treated with ethoxide to initiate the Favorskii rearrangement. The product is a mixture of cis and trans isomers of the ester 73 but hydrolysis under vigorous conditions (reflux in aqueous ethanol) epimerises the ester centre and gives exclusively the trans acid 74. 

Aliphatic c a -dibromo ketones, such as 2,4-dibromopentan-3-one (262), react with primary amines RNH2 (R = Me, Et, Pr, /-Pr or t-Bu) to give mixtures of imines 263 and lesser amounts of diimines 264. l,3-Dibromo-l-phenylpropan-2-one yields only the amide 265, the product of a Favorskii rearrangement. The nature of the products from aliphatic amines and cyclic a,a -dibromo ketones depends on ring size the cyclohexanone derivative 266 gave Favorskii amides 267 (R = Pr, /-Pr or t-Bu), while trans-2,5-dibromocyclopentanone afforded the enamines 268 (R = /-Pr or t-Bu) (equation 95)296. 

In the presence of base, a-haloketones rearrange to give acid derivatives depending upon the reaction conditions (equation 180). This very versatile reaction, the Favorskii rearrangement, has been the subject of several reviews966-968. The reaction was used in the synthesis of natural products, particularly steroids969-971, and the reader is referred to the reference sources for in-depth information. 

White and coworkers used a Favorskii rearranjgement in their synthesis of the natural product ( )-byssochlamic acid 17. 4-Ethylcyclohexanone 18 synthesized by Jones oxidation of the corresponding alcohol, was carboxylated to 19 and then dibrominated to 20. The Favorskii rearrangement was carried out with NaOMe to form the unsaturated diester... 

The purpose of the present chapter is not to present an extensive report concerning all the studies related to the Favorskii rearrangement. It is limited to cyclohexane and constrained polycyclic molecules. However, as an introduction, we will survey rapidly the various processes which have been considered for this reaction. We will then present a general discussion of these mechanisms. The behavior of linear aliphatic a-haloketones will be compared with those of cyclic ones when submitted to basic conditions. We will emphasize the influence of the structure upon the nature of the reaction mechanism involved, as well as on the product distribution. It will be shown that the strain in polycyclic a-haloketones has a decisive influence on the rearrangement mechanism involved. 

Harmata et al. have applied their [4+3] cycloaddition/quasi-Favorskii rearrangement to several different classes of natural products. One of these are the sterpuranes, which are sesquiterpenes represented by sterpurene 103 (Scheme 19.27) [57]. Treatment of diene 97 with a shght stoichiometric excess of 2,5-dibromocyclopentanone 98 and triethylamine using tri-fluoroethanol and benzene as the solvent resulted in the formation of cycloadduct 99. This is a relatively rare example of an intermolecular [4+3] cycloaddition in which the diene is used stoichiometrically. Typically, the diene is used in excess relative to the ally lie cation precursor. Reduction of the ketone 99 with lithium aluminum hydride, followed by treatment with potassium hydride to effect the quasi-Favorskii rearrangement, gave aldehyde 101, presumably through intermediate 100. Reduction of aldehyde 101 gave alcohol 102 in 91% yield from ketone 99. Alcohol 102 was subsequently converted into sterpurene 103. 

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