Exocyclic analog

A solid-phase combinatorial approach was used to synthesize nucleosides containing triazine-and pyrimidine-based exocyclic analogs of clitocine (194, R" = R = H), a fungal metabolite that exhibits potent cytostatic effects against leukemia cell lines through the inhibition of adenosine kinase as well as insecticidal activity (Figme 11.89). The initial library 195 of 1234 compounds was prepared by successive reaction of a 4,6-dichloro-substituted precursor attached to... 

Thompson points out that there is no evidence that adducts give other than acetates on thermolysis. The exocyclic methylene intermediate (iv) postulated by Robinson could arise by proton abstraction from a Wheland intermediate analogous to (vll) above, rather than from the adduct (in). Similarly its decomposition does not necessarily require the intermediacy of the adduct (v). The fact that i -methyl-4-nitromethylnaphthalene is the product even when the nitrating medium is nitric acid and nitromethane would then require no separate explanation. 

Two radicals in which the radical site is exocyclic should be mentioned. These are the furan (165) and thiophene (166) analogs of the benzyl radical they long ago acquired trivial names, which are recognized by lUPAC because of their widespread use. 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

The furanoid vinyl ethers described above are of interest in view of the structure of the nucleoside antibiotic angustmycin A (2) (15) which also contains an exocyclic double bond. As a first step towards the synthesis of analogs of angustmycin A (2), preparation of exocyclic vinyl ethers from hexulofuranoid derivatives was studied. Benzoylation of 2,3 4,6-di-0-isopropylidene-a-L-ryZo-hexulofuranose (44) followed by selective acid hydrolysis of the 4,6-O-isopropylidene group afforded l-0-benzoyl-2,3-0-isopropylidene-a-L-ryZohexulofuranose (45) in 72%... 

Nitration of a substituted quinoxaline usually occurs in the homocyclic ring and occasionally in an exocyclic substituent such as a phenyl group. The actual position(s) of nitration can seldom be forecast with any confidence analogy with reported nitrations is still the best guide. Accordingly, the following examples are classified, not by nitration sites but by the reagents used. 

Likewise, Sakamoto has synthesized the CC-1065/duocarmycin pharmacophore 284 via the cyclization of 282 [321]. Silver carbonate prevented unwanted isomerization of the exocyclic double bond in 283. Tietze and co-workers took full advantage of the power of these A-allyl-o-haloaniline Pd-catalyzed cyclizations in developing syntheses of the A-unit of CC-1065 and analogs [322-324]. 

In analogy with the strategy of carbocyclic construction, 1,6-enynes containing an oxygen heteroatom in the carbon atom sequence have been used for 3,4-disubstituted tetrahydrofuran synthesis. The simplest example is given by the hydrosilylation of enyne at room temperature (Reaction 7.38) [49]. Tetrahydrofurans with an exocyclic methylene functionality can also be prepared from the appropriate alkynes, such as 32, with (TMS)3SiH in refluxing benzene which afforded exclusive formation of the exomethylene in the Z conformation (Reaction 7.39) [50]. 

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