Anionic rearrangement natural products

In this beautiful synthesis of periplanone B, Still demonstrated a classical aspect and use of total synthesis - the unambiguous establishment of the structure of a natural product. More impressively, he demonstrated the usefulness of the anionic oxy-Cope rearrangement in the construction of ten-membered rings and the feasibility of exploiting conformational preferences of these medium-sized rings to direct the stereochemical course of chemical reactions on such templates. 

Recently, analogues of nucleosides [60], natural products Huperzine-A [61] and Hydroartemisinin [62], and inhibitors of metallo-/ -lactamases have been synthesised [63]. With acylsilane electrophiles, the initial adducts undergo Brook rearrangement which is interrupted by -Si bond fission with loss of fluoride anion (Eq. 16), leading to the formation of extremely useful difluoro-enol silanes [64]. Of the various fluoride sources employed, the tetrabutylam-monium triphenyldifluorostannate described by Gingras appears to be particularly effective. The numerous other methods for trifluoromethylation formed the subject of an exhaustive review [65]. More recently, the Olah group described a chlorodifluoromethyl trimethylsilane which is expected to have a rich chemistry [66]. 

Total synthesis has benefited from key DoM reactions. The sequence 48 —> 49 —> 50 —> 51 (Scheme 12) en route to the natural product ochratoxin A (52) takes multiple advantage of anion chemistry (53) ortho-metalation of the powerful OCONEtj group (step 1), anionic Fries rearrangement (step 2), in-between DoM and chain-extension by Li-Mg transmetalation (step 3) [12]. 

This chemistry can be very powerful, since the amide product itself offers further possibilities for functionalisation by lithiation. The synthesis of the natural product ochratoxin A (section 9.1) illustrates this point. Two successive ortholithiations of carbamate 210 are used first to introduce one amide group and then a second, by anionic ortho-Fries rearrangement. The symmetrical diamide 211 can be allylated and then cyclised in acid, with concomitant hydrolysis of the second amide and deprotection of the phenol to yield a known intermediate... 

Another natural product, (+ )-faranal (27), a trail pheromone of the Pharaoh s ant, has also been synthesized starting with 2 (see Scheme 3) [11].The crucial transformation in the sequence is a [2,3] Wittig rearrangement of 24 which, after cw-hydrogenation, gives diene 25 in > 96% ee. This intermediate, when treated with potassium hydride, undergoes an anionic oxy-Cope rearrangement to afford the erythro aldehyde 26 in 91% ee. 

A multistep conversion of 2,2-disubstituted 1,3-cyclohexadiones 191 to 3-substi-tuted 2-cyclohexenones 192 mediated by phosphonate anions was applied by Yamamoto and Furuta [69] in a formal synthesis of ( )-a-acoradiene (193) (Scheme 47). 3-Substituted 2-cyclohexenones are versatile building blocks for the synthesis of cyclic natural products such as spirocyclic and fused ring sesquiterpenes. These cyclohexenones were easily obtained in a one-pot reaction of 194 with dimethyl methanephosphonate anion in the presence of trimethylsilyl chloride. The new overall reaction is a multistep rearrangement involving... 

The third section of the chapter describes recently developed anion relay chemistry (ARC) involving threefold domino Sj -Brook rearrangement/ reactions, discovered by Tietze and extensively explored by Amos Smith 111 and his group. These reactions are also initiated by nucleophihc ring opening of epoxides, usually by silyl-substituted dithiane anions, and find useful apphcation in natural product synthesis. 

Hudlicky and coworkers also reported an elegant synthesis of the iridoid sesquiterpene (-)-specionin, by utilizing the low-temperature anion-accelerated VCP-CP rearrangement developed in their lab. The precursor siloxyvinylcyclopropane 38 was synthesized as a mixture of exo/endo isomers by the cyclopropanation of substituted cyclopentenone 36 with the lithium dienolate 37 derived from4-(dimethyl-tert-butylsilo5q )-2-bromocrotonate tScheme 11.321. Rearrangement of the diastereomeric VCP substrates was achieved by the use of TMSI/HMDS at -78 °C to afford the tricyclic ketone in high yield as a mixture of diastereomers, which was then converted to the natural product. ... 

Amongst those researchers that have studied the anionic oxy-Cope rearrangement, the achievements of Paquette are especially noteworthy. Not only has he been successful at utilizing it for complex natural product synthesis, " he and his coworkers have also provided novel insights into the subtle details which influence patterns of reactivity in these well-studied systems. Primary amongst these studies were those directed at natural (+)-taxusin - which featured the anionic oxy-Cope rearrangement/enolate... 

A common use of the Cope rearrangement is the synthesis of medium-sized rings, which are present in a variety of natural products. One example is the synthesis of the carbocyclic skeleton of the fungal diterpenoid vinigrol, a compound possessing a variety of potential medicinal uses. Sodium hydride was found to be preferential to potassium hydride in promoting the anionic oxy-Cope rearrangement of 139 to provide 140. An... 

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