Polycyclization strategy

Rouillard, A. Deslongchamps, P. Synthesis of a pentacyclic lactone related to quinovaic acid and emmolactone using an anionic polycyclization strategy. Tetrahedron 2002, 58, 6555-6560. 

The chemistry described herein should be highly useful for the preparation of indole alkaloids and for the synthesis of a variety of complex natural products. Although unsuccessful approaches are not described in this article, they also provide quite useful information. Before closing this article, we would like to examine the 15 total syntheses with emphases on (i) the way to access optically active compounds (Scheme 17) and (ii) the polycyclization strategy (Scheme 18). 

When stereochemical complexity is embedded in topological complexity, such as in complex polycyclic structures, the stereochemical strategies which are most effective are those which are linked to both complexities. A decidedly different strategic approach is appropriate for topologically simpler systems. 

Three other modifications of the standard conditions provide synthetically useful strategies for the preparation of dihydrofurans. One method, called the interrupted Feist-Benary reaction, utilizes milder reaction conditions to stop the final dehydration step. For example, Calter combined bromide 47 with dicarbonyl 48 to produce dihydrofuran 49 as a mixture of diastereomers. He examined the scope and diastereoselectivity of this process and applied this reaction toward the synthesis of the polycyclic core of the zaragozic acids. A method principally designed to yield practical syntheses of cyclic ketodiesters also furnished a dihydrofuran via a variation of the interrupted Feist-Benary reaction. ... 

Scheme 6. Vollhardt s tandem alkyne cyclotrimerization/o-quinodimethane cycloaddition strategy for polycycle synthesis.

This lithiated epoxysulfone cyclisation strategy has been iteratively applied in the total synthesis of hemibrevitoxin B, a polycyclic ether marine toxin from the red tide organism Gymnodinium breve (Scheme 5.41) [64]. 

Closely related to the polyepoxide cascade procedure for the synthesis of polycyclic systems is Corey s biomimetic-type, nonenzymatic, oxirane-initiated (Lewis acid-promoted) cation-olefin polyannulation. By this strategy, compound 96, containing the tetracyclic core of scalarenedial, was constructed by exposure of the acyclic epoxy triene precursor 95 to MeAlCl2-promoted cyclization reaction conditions (Scheme 8.25) [45]. 

Enantiomers (M)- and (P)-helicenebisquinones [32] 93 have been synthesized by high pressure Diels-Alder reaction of homochiral (+)-(2-p-tolylsulfo-nyl)-l,4-benzoquinone (94) in excess with dienes 95 and 96 prepared from the common precursor 97 (Scheme 5.9). The approach is based on the tandem [4 + 2] cycloaddition/pyrolitic sulfoxide elimination as a general one-pot strategy to enantiomerically enriched polycyclic dihydroquinones. Whereas the formation of (M)-helicene is explained by the endo approach of the arylethene toward the less encumbered face of the quinone, the formation of its enantiomeric (P)-form can be the result of an unfavourable interaction between the OMe group of approaching arylethene and the sulfinyl oxygen of 94. 

Deslongchamps P. Transannular Diels-Alder Reaction on Macrocycles a General Strategy for the Synthesis of Polycyclic Compounds A Idrichimica Acta 199124 43-56... 

Several other twofold cyclization strategies have been developed by Smith and coworkers, ultimately to obtain access to the cyclic framework of penitrem D with the correct stereochemistry [176]. Williams group has been interested in Stemona alkaloids, which are represented by approximately 50 structurally novel, polycyclic natu-... 

Hetero Diels-Alder reactions using nitroalkenes followed by 1,3-dipolar cycloadditions provide a useful strategy for the construction of polycyclic heterocycles, which are found in natural products. Denmark has coined the term tandem [4+2]/[3+2] cycloaddition of nitroalkenes for this type of reaction. The tandem [4+2]/[3+2] cycloaddition can be classified into four families as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respectively.149 In general, electron-rich alkenes are favored as dienophiles in [4+2] cycloadditions, whereas electron-deficient alkenes are preferred as dipolarophiles in [3+2] cycloadditions. 

The classic addition of C3 tethered amine derivatives onto C2 of indolium ions has been used to access hexahydropyrrolo[2,3-fc]indole frameworks <060L4303, 060F6011>. An alternative and unique strategy for accessing similar pyrrolo[2,3-fc]indole polycyclics 137 has... 

Several ingenious syntheses of natural products have been developed by exploiting benzcyclobutene ring opening to o-quinodimethane. Particularly, the intramolecular Diels-Alder strategy employing o-quinodimethane intermediates has been very effective for the construction of polycyclic structures. Selected examples are gathered in Table 12. 

A novel approach towards the construction of the morphine skeleton is demonstrated by the total synthesis of ( )-desoxycodeine-D. One of the key steps for this synthesis is the palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic strategy for the construction of the polycyclic ring systems has provided an efficient access to the complete pentacyclic skeleton of morphine <00TL915>. 

The polycyclic structure of manzamine A 74, an alkaloid with promising antitumor activity, constitutes an ideal testing ground for probing the effciency of RCM. Although no total synthesis of 74 has yet been reported, various approaches to this complex target rely on RCM-based strategies. 

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