Natural product synthesis double bond migration

The Nazarov cyclization was the key step in a synthesis of ( )-trichodiene (35) by Harding and co-workers. One significant challenge in the preparation of this natural product is the presence of two adjacent quaternary stereocenters, and Harding and co-workers selected the Nazarov cyclization to tackle this problem. Although the reaction was not efficient under protic acid catalysis, the presence of an excess of boron trifluoride etherate enabled the production of 34a/b in good yield, whereby double bond migration had occurred. These specific reaction conditions were key to the success of this transformation, since under milder conditions or shorter reaction times, the expected a,p-unsaturated ketone was observed. 

Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

Serious undesired side reactions we encountered during the attempted total synthesis of multifidoside B are described here (Scheme 21). Efforts toward the total synthesis was hampered by the final-step deprotection of the partially protected natural product precursor 48, resulting in giving decomposed product 49 by P-elimination of the glycoside moiety. Use of milder conditions for the deprotection resulted in double-bond isomerization to give an /Z (2/1) mixture of multifidoside B. It has also been reported in the literature that the undesired side reactions such as acyl migration from the desired 4-(9-acylate to the undesired 6-0-acylate and overreduction, and isomerization of the p-coumaroyl moiety have been observed during... 

An intermolecular diene cycloisomerization was the key step in a synthesis of the putative structure of fistulosin 11.248, an anti-fungal compound from Welsh onion roots (Scheme 11.82)." The substrate 11.246 could be prepared by Mitsunobu alkylation of a sulfonamide 11.243, followed by migration of the double bond with a ruthenium catalyst. The cycloisomerization was achieved using a species generated from the Grubbs second-generation catalyst and the silyl enol ether of acetaldehyde. When the target structure 11.248 was finally reached, the spectroscopic data showed that the reported structure of the natural product was incorrect. 

An approach of a completely different type is the very recently pubhshed ruthenium-catalyzed reaction of allyHc chlorides with imsaturated acids, which yields an allyhc unsaturated ester via an enantioselective substitution. If the acidic component is a fS,y-unsaturated acid, an allyl fS,y-unsaturated ester is obtained, RCM of which affords an unsaturated S-lactone. The primary product is a P,y-unsaturated S-lactone (3,6-dihydropyran-2-one), but addition of isopropanol to the solvent stimulates migration of the double bond with the formation of the 5,6-dihydropyran-2-one (Scheme 2.25) [60]. The authors demonstrated the apphcability of their method to the preparation of natural products with the synthesis of (R)-massoialactone in 56% overall yield and 90% enantiomeric excess [39dj. 

Related to this methodology is another one recently developed by Kirsch et al. [61], in which (Z)-aUylic alcohols are first converted into their trichloroacetimidates, and the latter are then subjected to a catalytic Sj 2 substitution of the trichloroace-timidate by a carboxylate group under the influence of complex 132, available in both enantiomeric forms (Scheme 2.26). If a p,y-unsaturated acid is used, an allyl P,y-unsaturated ester is obtained, which, after RCM and base-catalyzed migration of the double bond, affords a 5,6-dihydro-a-pyrone. The authors demonstrated the practical applicabihty of this methodology with the synthesis of (-)-rugulactone and other natural products. 

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