Volume 79, Issue 2

Organic synthesis continues to grow and develop impressively in response to new research challenges at the boundaries of structural complexity, while playing a central role in the industrial activities and applications of the chemical sciences. The International Conferences on Organic Synthesis (ICOS), which have been organized biennially around the world since 1976 under IUPAC sponsorship, faithfully reflect this growth and development. The 16th event in this series (ICOS-16) was held in Mérida, México, from 11 to 15 June 2006. The scientific program included 22 plenary and invited speakers, as well as 36 experts who participated in symposia on medicinal chemistry, organocatalysis, enantioselective synthesis of β-amino acids, organolithium compounds in organic synthesis, organic selenium and tellurium compounds in organic synthesis, and applications of microwaves in organic synthesis. In addition, almost 300 posters covering all aspects of modern organic synthesis were displayed by scientists and research scholars. The strong Latin American participation in this feature of the program, followed by those of European, North American, and Asian delegates, attested to the growing contribution of this region to chemical research in organic synthesis. Overall, the scientific program offered comprehensive and fruitful coverage of organic synthesis from a variety of different perspectives. The Mexican Academy of Sciences and the Mexican Chemical Society (celebrating its 50th Anniversary) featured as cosponsors of ICOS-16 together with IUPAC. This was the second occasion that an IUPAC-sponsored conference has been held in Mexico, the first being the 6th International Symposium on Natural Products Chemistry in Mexico City, in 1969. ICOS-16 attracted almost 500 delegates from 40 countries, mainly those of Latin America, a gratifyingly high proportion of whom were younger scientists. This issue of Pure and Applied Chemistry contains a representative selection of papers based upon lectures delivered at ICOS-16. The theme of synthesis of natural products was covered by M. Brimble (New Zealand), L. C. Dias (Brazil), and C. Gennari (Italy). Different aspects on methodology and control of chemical reactivity were presented by J. Tamariz (Mexico), S. F. Martin (USA), S. Ma (China), and Ph. Renaud (Switzerland). Organic synthesis using phosphorous was covered by R. Réau (France) and C. Nájera (Spain). The broad topic of catalysis was presented by S. Kobayashi (Japan) and C. Crudden (USA). New insights on synthesis using epoxides and aziridines were disclosed by D. Hodgson (UK) and F. McDonald (USA). Organic synthesis is a fascinating field of chemistry that has often been compared with art. The control of regio-, stereo-, and site selectivity demands deep insight into chemical reactivity as well as knowledge of new and old methodology and catalysis, and the ability to combine these creatively in sustainable processes in order to achieve specific objectives. Despite remarkable progress during recent years, efficient synthesis of specific organic compounds with tailored activities and properties will continue to challenge future generations of chemists. Further progress of organic synthesis will be covered during the next conference in this series (ICOS-17), which will take place in Korea during 2008. Thanks are due to members of the ICOS-16 Committees, to all participants, and to authors contributing to this issue. Guillermo Delgado Conference Editor

The synthesis of the ABC spiroacetal-containing fragment of the marine biotoxins, the pectenotoxins (PTXs), is described. The synthetic strategy involves appendage of the highly substituted tetrahydofuran C ring to the AB spiroacetal unit via stereocontrolled cyclization of a γ-hydroxyepoxide. The bis-spiroacetal moiety of the spirolide family of shellfish toxins is also described, making use of an iterative radical oxidative cyclization strategy.

This paper describes the convergent and stereocontrolled asymmetric total synthesis of (+)-crocacins C and D, potent inhibitors of animal cell cultures and several yeasts and fungi, and (-)-callystatin A, a potent antitumor polyketide.

Eleutherobin and dictyostatin are antimitotic compounds which exert their cytotoxic activity by a taxol-like mode of action, i.e., hypernucleating tubulin assembly and interfering with the dynamic instability of the cytoskeleton during mitosis. A formal total synthesis of eleutherobin was accomplished by accessing a key intermediate reported by Danishefsky and coworkers in their 1998 synthesis of the natural product. The key step of our strategy, used for obtaining the [8.4.0] fused bicyclic ring system, is a ring-closing metathesis (RCM) reaction of a densely functionalized diene under forcing conditions, using Grubbs' second-generation catalyst. Synthetic approaches to dictyostatin are also described, and in particular the preparation of the C15-C23 fragment of the macrolide, containing 5 of its 11 stereocenters.

The synthetic application of 4,5-bis-alkylidene-1,3-oxazolidin-2-ones led to the efficient and regioselective synthesis of 2-(3 H )-benzoxazolones and diarylamines with a short methodology. They were also valuable synthons in a total synthesis of naturally occurring carbazoles. New enantiopure 4-oxazoline-2-one and 4-methylene-2-oxazolidinone were prepared via a one-pot microwave (MW)-promoted condensation of α-ketols and an enantiopure isocyanate. These enamides were efficient nucleophiles when added to Michael acceptors to give a series of compounds with quaternary stereocenters in fairly good stereoisomeric ratios. The novel approach for the synthesis of benzofurans and indoles by intramolecular cyclization of enaminones has been applied in the preparation of furobenzofurans starting from benzo-bis-enaminones.

It is generally assumed that preorganizing a flexible ligand in the three-dimensional shape it adopts when bound to a macromolecular receptor will provide a derivative having an increased binding affinity, primarily because the rigidified molecule is expected to benefit from a lesser entropic penalty during complexation. We now provide the first experimental evidence that demonstrates this common belief is not universally true. Indeed, we find that ligand preorganization may be accompanied by an unfavorable entropy of binding, even when the constrained ligand exhibits a higher binding affinity than its flexible control. Thus, the effects that ligand preorganization have upon energetics and structure in protein-ligand interactions must be reevaluated.

The synthesis and properties of linear π-conjugated systems incorporating phosphole rings are described. Their supramolecular organization in the solid state can be controlled either by chemical modifications or coordination to transition metals of the phosphorus atom. Furthermore, chemical transformations of the phosphole ring allow organizing these P-chromophores in 3D assemblies exhibiting σ-π conjugation or in organometallic ferrocene-like derivatives. Phosphole-pyridine-containing π-conjugated chromophores act as P,N-chelates toward transition-metal ions, giving rise to mono- and di-nuclear complexes. The specific properties of these complexes make them valuable materials for organic light-emitting diodes (OLEDs) and interesting building blocks for the tailoring of π-conjugated systems.

Aluminum complexes of the chiral ( R )- or ( S )-3,3'-bis(diethylaminomethyl)-1,1'-bi-2,2'-naphthol (BINOLAM) ligand behave as efficient catalysts for the enantioselective cyanation- O -functionalization of aldehydes, thereby leading to enantiomerically enriched O -silyl, O -methoxycarbonyl, or O -phosphate derivatives of cyanohydrins. The enantioenriched cyanohydrin- O -phosphates are useful for the synthesis of several enantioenriched compounds such as α-hydroxy esters, β-amino alcohols, and γ-substituted α,β-unsaturated nitriles. Natural products such as (-)-aegeline and (-)-tembamide have been prepared in this manner.

Boron derivatives are becoming key reagents in radical chemistry. Here, we describe reactions where an organoboron derivative is used as a radical initiator, a chain-transfer reagent, and a radical precursor. For instance, B -alkylcatecholboranes, easily prepared by hydroboration of alkenes, represent a very efficient source of primary, secondary, and tertiary alkyl radicals. Their very high sensitivity toward oxygen- and heteroatom-centered radicals makes them particularly attractive for the development of radical chain processes such as conjugate addition, allylation, alkenylation, and alkynylation. Boron derivatives have also been used to develop an attractive new procedure for the reduction of radicals with alcohols and water. The selected examples presented here demonstrate that boron-containing reagents can efficiently replace tin derivatives in a wide range of radical reactions.

Lewis acid catalysis has attracted much attention in organic synthesis because of unique reactivity and selectivity attained under mild conditions. Although various kinds of Lewis acids have been developed and applied in industry, these Lewis acids must be generally used under strictly anhydrous conditions. The presence of even a small amount of water handles the reactions owing to preferential reactions of the Lewis acids with water rather than the substrates. In contrast, rare earth and other metal complexes have been found to be water-compatible. Several catalytic asymmetric reactions in aqueous media, including hydroxymethylation of silicon enolates with an aqueous solution of formaldehyde in the presence of Sc(OTf) 3 -chiral bipyridine ligand or Bi(OTf) 3 -chiral bipyridine ligand, Sc- or Bi-catalyzed asymmetric meso -epoxide ring-opening reactions with amines, and asymmetric Mannich-type reactions of silicon enolates with N -acylhydrazones in the presence of a chiral Zn catalyst have been developed. Water plays key roles in these asymmetric reactions.

The use of mesoporous molecular sieves (MMSs) modified by mercaptopropyl trimethoxysilane (MPTMS) to scavenge Pd is described. The ordered mesoporous material displays excellent ability to remove Pd from organic and aqueous solutions. After only one treatment, a 500-ppm solution of PdCl 2 in water can be reduced to 1 ppb. In addition, the resulting material is an effective, leach-proof catalyst for the Suzuki-Miyaura and Mizoroki-Heck reactions. Thus, the Suzuki-Miyaura reaction can be conducted in water at 80 °C with as little as 3 ppb Pd leaching. Hot filtrations and three-phase tests confirm that the catalyst acts without leaching Pd from the surface.

The halohydroxylation reaction of 1,2-allenyl sulfoxides exhibits E -selectivity while those of analogous sulfides and selenides show Z -selectivity. Rationales for the stereoselectivities are proposed. The reaction of 2,3-allenols with X + affords 3-halo-2,5-dihydrofurans or 3-halo-3-enals depending on the nature of the alcohols.

Deprotonation of terminal epoxides and aziridines with organolithium/diamine combinations or lithium amides allows the regio- and stereoselective formation of α-lithiated species. Judicious choice of reaction conditions allows these species to operate as nucleophiles, enolate equivalents, vinyl cation equivalents, or carbenes.

The biomimetic synthesis of trans,syn,trans -fused polycyclic ether natural products involving a cascade of stereospecific and regioselective oxacyclizations of polyepoxide substrates is described as applied to the synthesis of polyoxepane and polypyran structures. In addition, an extension of biomimetic polyene cyclizations to terpenoid natural products is outlined.