Applications dihydropyrroles

Two laboratories have independently disclosed an interesting series of mechanism-based inhibitors. The dihydropyrrole 31, which appeared in a patent application [61], was reported to inhibit rat lung SSAO/VAP-1 with an IC50 = 500 nM. Recently, the Sayre team extended earlier work [74] and showed that these inhibitors, exemplified by 32, covalently bound to the enzyme with the cofactor in the reduced form [75]. Presumably, aromatization of the dihydropyrrole moiety accounts for the observed potencies. 

Both target compounds discussed in this review, kelsoene (1) and preussin (2), provide a fascinating playground for synthetic organic chemists. The construction of the cyclobutane in kelsoene limits the number of methods and invites the application of photochemical reactions as key steps. Indeed, three out of five completed syntheses are based on an intermolecular enone [2+2]-photocycloaddition and one—our own—is based on an intramolecular Cu-catalyzed [2+2]-photocycloaddition. A unique approach is based on a homo-Favorskii rearrangement as the key step. Contrary to that, the pyrrolidine core of preussin offers a plentitude of synthetic alternatives which is reflected by the large number of syntheses completed to date. The photochemical pathway to preussin has remained unique as it is the only route which does not retrosynthetically disconnect the five-membered heterocycle. The photochemical key step is employed for a stereo- and regioselective carbo-hydroxylation of a dihydropyrrole precursor. 

Another application was described by Reissig et al. with the cyclization of alkoxyallenes. The most relevant finding reported in this paper was the obtainment of aromatic pyrrole, with the absence of dihydropyrrole product [44]. 

The synthesis of 3-methyloxindole from 8-propionylphenylhydrazine demonstrates application of the Fischer method to the construction of a dihydropyrrole ring."... 

Optically pure 2,3-dihydropyrroles are important unsaturated heterocyclic compounds because of their application as chiral building blocks in the organic synthesis and the total synthesis of natural products. However, the asymmetric organocatalytic synthesis of chiral 2,3-dihydropyrroles is scarce. Highly diastereo- and enantiose-lective syntheses of 2,3-dihydropyrroles 14 by the base catalyzed asymmetric... 

The application of ligand 102 has successfully been extended to derivatiza-tions of nitrogen containing substrates. Arylation of the 2,3-dihydropyrrole 63 with phenyl triflate catalyzed by the 102-palladium complex [R=C(CH3)3] produced the single isomer 65 with 88% yield and in 85% ee [81]. 

A more recent application of a similar cyclization is during a synthesis of (+)-preussin 230 in which a key step is mercury(II)-induced cyclization of the ynone 228 to give the keto-dihydropyrrole 229 <94JOC4721>. There are a number of notable features of this reaction. Firstly, despite conjugation to the keto group, the alkyne remains sufficiently nucleophilic to interact with the electrophilic mercury, the intermediate ketone is stable to racemization and the Af-Boc group does not interfere, presumably because the 5-endo-dig mode is favoured. 

The mechanism of this interesting intermolecular indole synthesis as suggested by Feldman is depicted in Scheme 2 and presumably involves vinyl carbene 6 that cyclized to A-tosylindole [2]. The method is applicable to the synthesis of pyrroles and dihydropyrroles. 

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