Polycyclic compounds domino cyclization

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

Clive and coworkers have developed a new domino radical cyclization, by making use of a silicon radical as an intermediate to prepare silicon-containing bicyclic or polycyclic compounds such as 3-271 and 3-272 (Scheme 3.69) [109], After formation of the first radical 3-267 from 3-266, a 5-exo-dig cyclization takes place followed by an intramolecular 1,5-transfer of hydrogen from silicon to carbon, providing a silicon-centered radical 3-269 via 3-268. Once formed, this has the option to undergo another cyclization to afford the radical 3-270, which can yield a stable product either by a reductive interception with the present organotin hydride species to obtain compounds of type 3-271. On the other hand, when the terminal alkyne carries a trimethylstannyl group, expulsion of a trimethylstannyl radical takes place to afford vinyl silanes such as 3-272. 

The cyclic ylide intermediate 366, as a 1,3-dipole, is generated by intramolecular reaction of Rh-carbene with the ketone in 365, and undergoes cycloaddition with n-bonds to give the adduct 367 [121]. When a-diazocarbonyls have additional unsaturation, domino cyclizations occur to produce polycyclic compounds. The Rh-carbene method offers a powerful tool for the construction of complex polycyclic molecules in short steps, and has been applied to elegant syntheses of a number of complex natural products. 

One very fascinating domino reaction is the fivefold anionic/pericyclic sequence developed by Heathcock and coworkers for the total synthesis of alkaloids ofthe Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero-Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cyclized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

Domino cyclizations of various types of polyenynes offer powerful synthetic tools for efficient syntheses of polycyclic compounds. Among many possibilities, several representative patterns are cited here. A fully intramolecular version of a three-step domino reaction of 2-bromododeca-l,l l-dien-6-yne 184 and 2-bromotrideca-l,12-dien-7-yne 189 offers a useful synthetic method of the tricycles 188 and 191 with a central cyclohexa-1,3-diene moiety. In these compounds 184 and 189, an alkenyl bromide starter, an alkynyl relay, and an alkenyl terminator are all tethered as summarized by 184 in Scheme 3.14. The final step is facile 6- 7r-electrocyclization of 187 and 190 to give rise to 188 and 191 [61]. 

General Procedure for Synthesis of (Aminomethyl)isoquino-line-Fused Polycyclic Compounds by Domino Mannich-Type Reaction and Cascade Cyclization Synthesis o/6-/(N,N-Diisopropylamino)methyl]-3,4-dihydro-2H-pyrimido[2,l-SL] isoquinoline (12a) (Table 1, Entry 10)... 

ABSTRACT In the synthesis of relevant organic compounds such as natural products and analogues, the proportion of the number of steps coupled with the increase of complexity is now a universal paradigm to ascertain the quality and efficiency of a process. Alongwith providing accessibility to a multitude of diversified classes of natural products such as alkaloids, terpenoids, steroids and others, these criteria have been addressed by us via the application of domino processes. The acid-catalyzed intermolecular cyclization has been used as a viable synthetic tool for the stereospecific formation of different classes of polycyclic natural products. 

Treatment of this intermediate with BFa-OEta then induced a domino fragmentation and cyclization cascade The cleavage of the oxabicyclic ring produced the intermediate A -acyl iminium ion 114, which was trapped by the pendant t-butyl ester carbonyl, followed by the loss of isobutene, to give the advanced intermediate 116 in 94% yield (Scheme 29). This compound, which contains the complete polycyclic framework of aspidophytine (117), was then further elaborated to produce the natural product in subsequent steps. 

The first step of the domino process again was the laccase-catalyzed oxidation of catechol 25 to o-quinone 26, which reacted through Michael addition with N,N-dimethyl barbituric add 31 to yield the intermediate 32. This compound underwent a further oxidation followed by cyclization through two Michael additions. Finally, laccase-catalyzed oxidation provided polycyclic dispiropyrimidinone 35 in excellent yield of 90% (Scheme 9.7). Recently, the same authors reported the synthesis of... 

Radical domino strategies have been scarcely described in the construction of polycyclic cyclopropanic structures. Indeed, radicals formed by 3-exo-trig cyclization are being rapidly reopened, and this property is notably used in radical clocks experiments. In order to suppress this unwanted event, Malacria and Fensterbank have devised a (dichloromethyl)dimethylsilyl ether able to play both roles of the initiation and termination sites of the radical process [108]. By designing an appropriate acyclic structure 98, the expected cyclopropanic compounds 99 have been obtained in good yields and diastereoselectivities after addition of MeLi to the silyloxycyclopentene intermediate (Scheme 5.35). 

Conventional multistep synthesis of natural products reduces the overall yield of the target molecules. In contrast, biomimetic enantioselective domino reactions, promoted by small-molecule artificial enzymes, are more useful for the practical synthesis of natural products and related compounds. The stereoselective formation of polycyclic isoprenoids by the cyclase-induced cyclization of polypren-oids is one of the most remarkable steps in biosynthesis because this reaction results in the formation of several new quaternary and tertiary stereocenters and new rings in a single step. The use of biomimetic polycyclization with artificial cyclase is the most ideal chemical method for the synthesis of these polycyclic terpenoids. In this chapter, biosynthesis of polycyclic terpenoids, biomimetic stereoselective polyene cyclization induced by artificial cyclases, and total synthesis of bioactive natural products using stereoselective polyene cyclization as a key step will be discussed. 

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