Current Organic Chemistry - Volume 12, Issue 17, 2008

The isolation and structural determination of Martinella alkaloids were first reported in 1995, and since that time these heterocycles have elicited considerable interest from the synthetic community. Although in many respects, these molecules appear to be relatively simple targets, possessing only three stereocenters, an impressive collection of strategies towards the synthesis of these molecules has emerged. This review is a comprehensive overview of both the synthetic approaches to the pyrrolo[3,2-c]quinoline core found in these molecules, as well as a description of the racemic and enantioselective total syntheses reported to date.

Alkaloid lipids comprise a class of natural compounds with significant biological activities of medicinal interest. Their structural framework consists of a 2,6-disubstituted-3-piperidinol moiety (polar head group) and a lipid tail. Representative examples of alkaloid lipids are (+)-Cassine, (-)-Prosophylline, (-)-Prosopinine, (-)-Spectalline. Many synthetic strategies have been developed for the efficient stereoselective synthesis of various natural alkaloid lipids and their synthetic analogues. This mini-review focuses on the most successful approaches published during the new millennium. The synthetic strategies are grouped in two main sections, depending on whether the lipophilic side chain is introduced before (“early”) or after (“late”) piperidine ring formation. These sections are further organised based on the key ring forming reaction/strategy employed. For the strategies that opt to introduce the lipophilic side chain early on the synthetic sequence, the intramolecular reductive amination, either with or without isolation of the intermediate imine/enamine, constitutes one of the most popular methods for constructing the piperidine ring followed closely by approaches based on the intramolecular alkylation of suitable amine derivatives. Olefin ring closing metathesis and intramolecular hetero-Diels-Alder reactions have also been exploited to secure the azaheterocycle. The intramolecular alkylation of an amine or the, retrosynthetically related, intramolecular amine addition to an olefin have also been employed as key ring-forming reactions by syntheses that adopt the more convergent approach of introducing the side chain on a preformed heterocycle. In this regard the introduction of the side chain via alkylation of pyridinium salts, alkylation of a lactam (2-piperidone) or glutarimide derivatives have been investigated. Several groups have also exploited the oxidative cyclization of α-furylamines to prepare 2-dihydropyridones as a convenient scaffold for the late introduction of the lipid tail. In some cases, carbohydrates and aminoacids were used (either as starting materials or as chiral auxiliaries) for the enantioselective synthesis of alkaloid lipids. Enzymatic or chemical (Jacobsen's epoxide hydrolysis protocol) resolutions of racemic starting materials and Sharpless asymmetric epoxidation, dihydroxylation or aminohydroxylation of olefins have also been utilized. Finally, it is noteworthy that in several cases, apart from the Witting reaction and the use of Grignard reagents, olefin cross-metathesis has also been successfully employed for the introduction of the lipid side chain.

N-heterocyclic carbenes (NHCs) found numerous applications as ligands for transition metal complexes during the last two decades. Only recently, however, increasing attention is turning to high oxidation state organometallics with NHC ligands. A surprising number of stable complexes of that type have been described mainly during the last five years and several of them have potential for application in both homogeneous and heterogeneous catalysis of organic reactions. This article describes the preparation and characteristics of these high oxidation state organometallic complexes with NHC ligands and gives an outlook on their possible applications.

The review covers various metalation reactions of aromatics, which cannot be regarded purely as common ortho- directed metalations (DoM). In the past decade there has been an increased interest and, accordingly, there has been a number of reports about long range electronic effects as they frequently increase the rate of ortho-metalation. Sometimes they are even able to redirect an appropriate metalating agent to a remote position irrespective of an existing ortho activation. Such “remote-substituent-directed” metalations can be rationalized in terms of “through-bond” electronic activation, which typically act in conjunction with specific steric (buttressing) effects. A different class of “remote-substituentdirected” reactions constitute “through-space” induced metalations where the lithiation site is located close to the directing group. We hope that our review will stimulate further research in this relatively still (with respect to the DoM-based transformations) unexplored area, which is, however, of a great synthetic potential and importance.

A large number of cyclic peptides, which exhibit a range of biological activities, have been found in nature. The reason of cyclic peptides that attracted world wide attention and made them extensively studied, is their enhanced metabolic stabilities, biological specificities, bioavailability, and conformational constrained structural feature, which make them important leads for drug discovery, and as actual drugs. Many cyclic peptides show very promising biological activities, including anticancer, antibacterial, antiviral, antifungal, anti-inflammatory, and anti-clotting or anti-atherogenic properties. Peptide cyclization becomes an effective and commonly employed strategy for peptide modifications. During the past several decades, great efforts have been made to develop more efficient methods for the synthesis of cyclic peptides and peptidomimetics. This review will be focused on the major progress of the novel recently developed peptide cyclization approaches and the profitable applications since 2002.