Rearrangement reactions cyclization cascade

In the year 2010, the group of Danishefsky reported the first asymmetric total synthesis of (-)-phalarine by using a Mannich reaction/Wagner-Meerwein rearrange-ment/cyclization cascade sequence (Scheme 13.9) [10], In this reaction cascade, one carbon-nitrogen bond, one carbon-carbon bond, one carbon-oxygen bond, and two new rings were formed. 

The domino cycloaddition-iV-acyliminium ion cyclization cascade has been extensively reviewed. Tandem reactions combining Diels-Alder reactions and sigma-tropic rearrangement reactions in organic synthesis have been extensively reviewed. The tandem Diels-Alder reaction between acetylenedicarboxaldehyde and N,N -dipyrrolylmethane has been extensively studied at the RHT/3-21G and RHF/6-31G levels.The molecular mechanism of the domino Diels-Alder reaction between hexafluorobut-2-yne and A,A -dipyrrolylmethane has been studied using density functional theory. 

Saito and Hanzawa extended their cydoisomerization route, involving the amino-Claisen rearrangement-cyclization cascade reaction (Scheme 9.68), to a one-pot procedure toward the functionalized 2,3-dimethylindole derivatives 281 (Scheme 9.97) [226]. The key propargyl anilines 280 were generated in situ via the propargylation of substituted anilines 278 with the propargrl bromide 279. 

Prabhakar and colleagues used ethyl propiolate (38, R = H, R = Et) to synthesize the Amaryllidaceae alkaloid Pratosine (43) (equation 13). On heating 42 in DMSO in the presence of water, a cascade of reactions is initiated, namely a [3,3]-sigmatropic rearrangement, ester hydrolysis, decarboxylation and cyclization, to afford Pratosine (43) in one step, albeit in modest yield. 

In more sophisticated approaches, [3,3]-sigmatropic rearrangements have been incorporated in cascade reactions in which each step could be catalyzed by silver salts. Usually, the silver promoted [3,3]-sigmatropic shift is combined with a silver-catalyzed cyclization,68 as outlined in the general scheme below for alkynyl compounds (Scheme 3.44). 

Although not the best catalyst, AgSbF6 led to the rearranged product in 50% yield. This cascade reaction probably started with the well-known cyclization of the ketone to the alkyne on silver coordination, giving a cyclic oxonium intermediate that rearranged to furanone via an alkyl 1,2-migration (Scheme 3.54).82... 

Terpene synthases, also known as terpene cyclases because most of their products are cyclic, utilize a carbocationic reaction mechanism very similar to that employed by the prenyltransferases. Numerous experiments with inhibitors, substrate analogues and chemical model systems (Croteau, 1987 Cane, 1990, 1998) have revealed that the reaction usually begins with the divalent metal ion-assisted cleavage of the diphosphate moiety (Fig. 5.6). The resulting allylic carbocation may then cyclize by addition of the resonance-stabilized cationic centre to one of the other carbon-carbon double bonds in the substrate. The cyclization is followed by a series of rearrangements that may include hydride shifts, alkyl shifts, deprotonation, reprotonation and additional cyclizations, all mediated through enzyme-bound carbocationic intermed iates. The reaction cascade terminates by deprotonation of the cation to an olefin or capture by a nucleophile, such as water. Since the native substrates of terpene synthases are all configured with trans (E) double bonds, they are unable to cyclize directly to many of the carbon skeletons found in nature. In such cases, the cyclization process is preceded by isomerization of the initial carbocation to an intermediate capable of cyclization. 

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