Starting from the early 1990’s, the chemistry of polyvalent iodine organic compounds has experienced an explosive development. This surging interest in iodine compounds is mainly due to the very useful oxidizing properties of polyvalent organic iodine reagents, combined with their benign environmental character and commercial availability. Iodine(III) and iodine(V) derivatives are now routinely used in organic synthesis as reagents for various selective oxidative transformations of complex organic molecules. Several areas of hypervalent organoiodine chemistry have recently attracted especially active interest and research activity. These areas, in particular, include the synthetic applications of 2-iodoxybenzoic acid (IBX) and similar oxidizing reagents based on the iodine(V) derivatives, the development and synthetic use of polymer-supported and recyclable polyvalent iodine reagents, the catalytic applications of organoiodine compounds, and structural studies of complexes and supramolecular assemblies of polyvalent iodine compounds.

The chemistry of polyvalent iodine has previously been covered in four books1–4 and several comprehensive review papers.5–17 Numerous reviews on specific classes of polyvalent iodine compounds and their synthetic applications have recently been published.18–61 Most notable are the specialized reviews on [hydroxy(tosyloxy)iodo]benzene,41 the chemistry and synthetic applications of iodonium salts,29,36,38,42,43,46,47,54,55 the chemistry of iodonium ylides,56–58 the chemistry of iminoiodanes,28 hypervalent iodine fluorides,27 electrophilic perfluoroalkylations,44 perfluoroorgano hypervalent iodine compounds,61 the chemistry of benziodoxoles,24,45 polymer-supported hypervalent iodine reagents,30 hypervalent iodine-mediated ring contraction reactions,21 application of hypervalent iodine in the synthesis of heterocycles,25,40 application of hypervalent iodine in the oxidation of phenolic compounds,32,34,50–53,60 oxidation of carbonyl compounds with organohypervalent iodine reagents,37 application of hypervalent iodine in (hetero)biaryl coupling reactions,31 phosphorolytic reactivity of o-iodosylcarboxylates,33 coordination of hypervalent iodine,19 transition metal catalyzed reactions of hypervalent iodine compounds,18 radical reactions of hypervalent iodine,35,39 stereoselective reactions of hypervalent iodine electrophiles,48 catalytic applications of organoiodine compounds,20,49 and synthetic applications of pentavalent iodine reagents.22,23,26,59

The main purpose of the present review is to summarize the data that appeared in the literature following publication of our previous reviews in 1996 and 2002. In addition, a brief introductory discussion of the most important earlier works is provided in each section. The review is organized according to the classes of organic polyvalent iodine compounds with emphasis on their synthetic application. Literature coverage is through July 2008.

Chemistry of Polyvalent Iodine

Organic chemists have always been fascinated by the cyclopropane subunit.1 The smallest cycloalkane is found as a basic structural element in a wide range of naturally occurring compounds.2 Moreover, many cyclopropane-containing unnatural products have been prepared to test the bonding features of this class of highly strained cycloalkanes3 and to study enzyme mechanism or inhibition.4 Cyclopropanes have also been used as versatile synthetic intermediates in the synthesis of more functionalized cycloalkanes5,6 and acyclic compounds.7 In recent years, most of the synthetic efforts have focused on the enantioselective synthesis of cyclopropanes.8 This has remained a challenge ever since it was found that the members of the pyrethroid class of compounds were effective insecticides.9 New and more efficient methods for the preparation of these entities in enantiomerically pure form are still evolving, and this review will focus mainly on the new methods that have appeared in the literature since 1989. It will elaborate on only three types of stereoselective cyclopropanation reactions from olefins: the halomethylmetal-mediated cyclopropanation reactions (eq 1), the transition metal-catalyzed decomposition of diazo compounds (eq 2), and the nucleophilic addition-ring closure sequence (eqs 3 and 4). These three processes will be examined in the context of diastereoand enantiocontrol. In the last section of the review, other methods commonly used to make chiral, nonracemic cyclopropanes will be briefly outlined.

Stereoselective Cyclopropanation Reactions

Using continuous flow techniques for multi-step synthesis enables multiple reaction steps to be combined into a single continuous operation. In this mini-review we discuss the current state of the art in this field and highlight recent progress and current challenges facing this emerging area.

/pdf/continuous-flow-multi-step-organic-synthesis-2p7n5fghtp.pdf

Continuous flow multi-step organic synthesis

Ten key issues in modern flow chemistry.

Laboratory scaled flow-through processes have seen an explosive development over the past decade and have become an enabling technology for improving synthetic efficiency through automation and process optimization. Practically, flow devices are a crucial link between bench chemists and process engineers. The present review focuses on two unique aspects of modern flow chemistry where substantial advantages over the corresponding batch processes have become evident. Flow chemistry being one out of several enabling technologies can ideally be combined with other enabling technologies such as energy input. This may be achieved in form of heat to create supercritical conditions. Here, indirect methods such as microwave irradiation and inductive heating have seen widespread applications. Also radiation can efficiently be used to carry out photochemical reactions in a highly practical and scalable manner. A second unique aspect of flow chemistry compared to batch chemistry is associated with the option to carry out multistep synthesis by designing a flow set-up composed of several flow reactors. Besides their role as chemical reactors these can act as elements for purification or solvent switch.

Flow Chemistry – A Key Enabling Technology for (Multistep) Organic Synthesis

The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3−12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki−Hiyama−Kishi coupling to form the C15−C16 carbon−carbon bond, an aldol reaction to construct the C6−C7 carbon−carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC50 = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure−activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemi...

Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues.

http://www.cornellpharmacology.org/faculty/labs/giannakakou/documents/BueyRMetal.ChemBiol.2004.pdf

Interaction of Epothilone Analogs with the Paclitaxel Binding Site: Relationship between Binding Affinity, Microtubule Stabilization, and Cytotoxicity

A multistep continuous-flow system for rapid on-demand synthesis of receptor ligands.

With some members in clinical trials, the epothilones command attention as potential anticancer agents of considerable promise In addition to several naturally occurring substances, an impressive array of epothilone analogues has been constructed and biologically evaluated 2] We have previously reported the apartialo construction of two 12,13-cyclopropyl epothilone A analogues Their structures recently came under closer scrutiny by us and by a Bristol ± Myers Squibb (BMS) group, whose independent synthesis of one of these compounds led to a revision of its structure Here we wish to report i) an unambiguous chemical synthesis of cis-(12S,13S)-cyclopropyl epothilone A (2) and its 15R epimer 3 ; ii) the correct structure of the previously synthesized cyclopropyl epothilones and a mechanistic rationale for their unexpected formation; iii) the chemical synthesis of cis-(12S,13S)-cyclobutyl epothilone A (4) and its 15R epimer 5 ; and iv) the molecular modeling and biological evaluation of the newly synthesized compounds Remarkably, compounds 2 and 4 exhibit potencies comparable

http://cornellpharmacology.org/faculty/labs/giannakakou/documents/nicolaoukcetal.chembiochem.2001.pdf

Andreas Ritzén

Papers

Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues.

Interaction of Epothilone Analogs with the Paclitaxel Binding Site: Relationship between Binding Affinity, Microtubule Stabilization, and Cytotoxicity

A multistep continuous-flow system for rapid on-demand synthesis of receptor ligands.

Synthesis and Biological Evaluation of 12,13-Cyclopropyl and 12,13-Cyclobutyl Epothilones