Current Organic Chemistry - Volume 11, Issue 15, 2007

Since the discovery that indium could affect a Barbier-type allylation of carbonyls in water over a decade ago, interest in the utility of indium metal and its salts to influence organic transformations has increased exponentially. Control of chemo-, regio-, and especially stereoselectivity in indium-mediated reactions has proven to be a challenge, however, examples of such discerning processes are now beginning to appear on a regular basis. Indium has been found to be effective in the allylation of carbonyls, carbometallation of some alkenes and alkynes. It has also been shown to be a reducing agent for a variety of organic functional groups, mediators for a variety of coupling reactions, and more recently indium reagents have been utilized as initiators for radical transformations. This review presents an overview of the development of stereoselective indium-mediated organometallic reactions.

The various approaches to the synthesis of hydroporphyrins are summarized. Transformations of synthetic porphyrins have been extensively studied in the last decade due to their easy availability. Many two and three step reaction sequences have been developed, which have allowed access to a broad variety of structures including not only chlorins but also benzochlorins, secochlorins etc. The fact that porphyrins can act as dienophiles or dipolarophiles has been broadly investigated and utilized. On the other hand ‘total syntheses’ of chlorins from pyrrole and other simple starting materials have been pursued by only a few research groups. Generally a [2+2] approach has been investigated and usually chlorins possessing two geminal methyl groups on the reduced pyrrole ring (‘locked’ chlorins) were the targets of the studies. The synthesis of tetrahydrodipyrrin derivatives as popular building blocks was the subject of intense investigation. Overall, a few interesting and ingenious approaches toward ‘total synthesis’ of chlorins were proposed, reaching total yields on the level of 1-5%. Some derivatives with auxochromic groups were prepared, which allowed the study of the relationship between structure and spectroscopic properties. Bacteriochlorin synthesis, probably due to their limited stability, has been studied less extensively.

Synthesis of macrocyclic compounds including natural products with varying complexities by ring closing metathesis is described. Twelve to very large rings that have been synthesized in moderate to good yields and the synthesis of larger rings as a part of bi- or poly-cyclic systems are also described in this review. The effectiveness of the Grubbs’ catalyst towards the RCM in presence of free alcohols, epoxides as well as with various silyl ethers is also presented. In addition to these, the application of RCM towards the syntheses of various naturally occurring macrolides, lactams and unnatural cyclic poly ethers, catenanes etc. are described.

Imidoyl radicals (R1N=C.R2) are very attractive intermediates that can be readily produced by several methods, i.e. hydrogen atom abstraction from aldimines, homolytic fragmentation of certain imidoylic precursors, and addition of both carbon- and heteroatom-centered radicals to isonitriles and isothiocyanates. As far as their synthetic potential is concerned, they have been shown to perform smooth intra- and intermolecular additions to double and triple carbon-carbon bonds, as well as cyclizations onto aromatic rings, sulfur atoms, and cyano groups. They have been therefore efficiently employed in cyclizations, annulations, and cascade reactions leading to the construction of various nitrogen-containing heterocyclic compounds, e.g. indoles, phenanthridines, pyrrolidines, quinolines, quinoxalines, and fused polycyclic derivatives. They have been also used as key intermediates in the synthesis of carbonyl compounds, amides, and nitriles and as precursors of alkyl radicals in tin-free reactions. In this review we discuss thoroughly the generation methods, the structural features, and, above all, the reactivity of imidoyl radicals, with particular attention devoted to their synthetic applications.

Oxcarbazepine (OXC), the active ingredient of Trileptal® (Novartis Pharma), has become the most widely prescribed drug for the treatment of epilepsy and other CNS diseases, due to its improved side-effect profile and relevant anticonvulsant activity compared to the parent drug, carbamazepine (CBZ). Given its importance and well-established therapeutic applications, much effort has been devoted to the improvement of its original synthetic protocol, searching for shorter, milder and more efficient routes, employing not only classical transformations but also modern synthetic tools, such as palladium-catalysed arylation reactions. In this article it is intended to resume the applications and features of OXC as an anticonvulsant drug, as well as to compile for the first time all the reported routes to OXC, from the originally-developed protocol to the latest methodology, which allowed for the synthesis of a family of structural analogues. Such synthetic sequences will be discussed and comprehensively classified according to whether the approach to OXC is based on either modifications on the iminodibenzyl ring or coupling reactions.