Volume 80, Issue 4

This issue of Pure and Applied Chemistry comprises 12 papers from some of the speakers at the 21st International Congress for Heterocyclic Chemistry, which was held at the University of New South Wales, Sydney, Australia from 15-20 July 2007. The topics of these papers cover some of the major themes of the conference, including natural products synthesis (as highlighted by the presentation of K. C. Nicolaou during his ISHC Senior Award in Heterocyclic Chemistry lecture on the synthesis of complex natural products and further demonstrated by contributions by Profs. Banwell, Bates, Sodeoka, Naito, Vogel, and Pyne); new methods for the synthesis of heterocycles based on metal-catalyzed reactions (Profs. Ma and Mase); and new catalysts for asymmetric synthesis based on chiral heterocyclic ligands (Prof. Nishiyama). Papers on the synthesis of heterocyclic compounds using the borono-Mannich reaction (Prof. Hutton) and green chemistry methods (Prof. Varma) are also included. I would like to thank all contributors for their timely efforts and the editorial staff for their help. Stephen Pyne Conference Editor

This article describes the utility of certain readily accessible, ring-fused gem -dihalogenocyclopropanes as building blocks for the synthesis of heterocyclic and biologically active compounds.

Hydroxylamines can be cyclized under various conditions according to the nature of the unsaturation in the N -substituent. Both isoxazolidines and tetrahydrooxazines can be formed with good synthetic control. The choice of the appropriate cyclization reaction leads to syntheses of the natural products sedamine and monomorine. The related N , O -acetals are shown to undergo efficient ring-opening under Sakurai conditions.

Several chiral amines were investigated for the stereoselective preparation of homophenylalanine derivatives using the Petasis reaction. Chiral secondary amines such as N ,α-dimethylbenzylamine and N- benzylphenylglycinol gave the best results in terms of both yield and diastereoselectivity. The use of N- benzylphenylglycinol leads directly to 3-alkenyl-4-benzyl-5-phenyloxazin-2-one products. Intriguing variation was observed in the stereoselectivity of reactions employing para- substituted styrenylboronic acid substrates, where presumably only electronic factors are involved.

Alkylidenecyclopropyl, cyclopropenyl, or azacyclocyclopropenyl ketones or carboxylates have been demonstrated to be versatile starting materials for the synthesis of oxygen- and/or nitrogen-containing heterocycles. The reactivities and regioselectivities may be nicely controlled by subtle choice of the catalysts and reaction condition parameters.

The carbon-sulfur bond formation of aryl bromides and triflates catalyzed by a new catalyst system, Pd 2 (dba) 3 /xantphos, has been demonstrated. Based on this finding, a novel and practical synthesis of benzothiazoles has been developed. This new methodology allows for the assembly of a wide range of benzothiazoles.

A novel synthetic method for the preparation of nitrogen-containing heterocycles via the route involving domino-type radical addition/cyclization reaction of oxime ethers is described. Alkyl radical addition/cyclization of oxime ethers carrying an appropriate leaving group proceeded smoothly to form the alkylated nitrogen-containing heterocyclic compounds. Additionally, tin-mediated radical addition/cyclization/elimination (RACE) reaction of oxime ethers is newly found and successfully applied to an asymmetric total synthesis of (-)-martinellic acid.

Total synthesis campaigns toward complex heterocyclic natural products are a prime source of inspiration for the design and execution of complex cascade sequences, powerful reactions, and efficient synthetic strategies. We highlight selected examples of such innovations in the course of our total syntheses of diazonamide A, azaspiracid-1, thiostrepton, 2,2'- epi -cytoskyrin A and rugulosin, abyssomycin C, platensimycin, and uncialamycin.

A new class of phenyl-bis(oxazoline) auxiliaries was readily prepared from isophthaloyl chloride and appropriate β-amino alcohols, and the derived rhodium complexes underwent new cyclization reactions at the metal center and exhibited high catalytic efficiency for asymmetric conjugate reduction of α,β-unsaturated carbonyl compounds and reductive aldol reactions of aldehydes and ketones.

We have demonstrated that the borono-Mannich reaction is a versatile and efficient reaction for the diastereoselective preparation of chiral 1,2-amino alcohols. These Mannich products are valuable starting materials as shown in this report by the synthesis of bioactive polyhydroxylated pyrrolizidine and indolizidine alkaloids. Initial studies, directed at the more complex Stemona alkaloids and using the borono-Mannich reaction on cyclic N -acyliminium ions, are encouraging, as demonstrated by the synthesis of the pyrido[1,2- a ]azepine core structure of stemocurtisinol.

Highly enantioselective Pd(II)-catalyzed Michael addition, Mannich-type reaction, aldol reaction, fluorination, conjugate addition of amine, and conjugate reduction have been developed. Asymmetric synthesis of biologically interesting heterocyclic compounds, calycotomine, BMS-204352, torcetrapib, and warfarin, was achieved by using these Pd-catalyzed asymmetric reactions as a key step.

The utilization of green chemistry techniques is dramatically reducing chemical waste and reaction times as has recently been proven in several organic syntheses and chemical transformations. To illustrate these advantages in the synthesis of bioactive heterocycles, we have studied various environmentally benign protocols that involve greener alternatives. Microwave (MW) irradiation of neat reactants catalyzed by the surfaces of recyclable mineral supports, such as alumina, silica, clay, or their "doped" versions, enables the rapid one-pot assembly of heterocyclic compounds, such as flavonoids, related benzopyrans, and quinolone derivatives. The strategy to assemble oxygen and nitrogen heterocycles from in situ generated reactive intermediates via enamines or using hypervalent iodine reagents is described. Examples of multicomponent reactions that can be adapted for rapid parallel synthesis include solventless synthesis of dihydropyrimidine-2(1 H )-ones (Biginelli reaction), imidazo[1,2- a ]annulated pyridines, pyrazines, and pyrimidines (Ugi reaction). The relative advantages of greener pathways, which use MW irradiation and eco-friendly aqueous reaction medium, for the synthesis of various heterocycles, such as N -aryl azacycloalkanes, isoindoles, 1,3-dioxane, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyrazole, and diazepines, are also summarized.

At low temperature and in the presence of an acid catalyst, SO 2 adds to 1,3-dienes equilibrating with the corresponding 3,6-dihydro-1,2-oxathiin-2-oxides (sultines). These compounds are unstable above -60 °C and equilibrate with the more stable 2,5-dihydrothiophene 1,1-dioxides (sulfolenes). The hetero-Diels-Alder additions of SO 2 are suprafacial and follow the Alder endo rule. The sultines derived from 1-oxy-substituted and 1,3-dioxy-disubstituted 1,3-dienes cannot be observed at -100 °C but are believed to be formed faster than the corresponding sulfolenes. In the presence of acid catalysts, the 6-oxy-substituted sultines equilibrate with zwitterionic species that react with electron-rich alkenes such as enoxysilanes and allylsilanes, generating β,γ-unsaturated silyl sulfinates that can be desilylated and desulfinylated to generate polypropionate fragments containing up to three contiguous stereogenic centers and an ( E )-alkene unit. Alternatively, the silyl sulfinates can be reacted with electrophiles to generate polyfunctional sulfones (one-pot, four-component synthesis of sulfones), or oxidized into sulfonyl chlorides and reacted with amines, then realizing a one-pot, four-component synthesis of polyfunctional sulfonamides. Using enantiomerically enriched dienes such as 1-[( R )- or 1-( S )-phenylethyloxy]-2-methyl-( E , E )-penta-1,3-dien-3-yl isobutyrate, derived from inexpensive ( R )- or ( S )-1-phenylethanol, enantiomerically enriched stereotriads are obtained in one-pot operations. The latter are ready for further chain elongation. This has permitted the development of expeditious total asymmetric syntheses of important natural products of biological interest such as the baconipyrones, rifamycin S, and apoptolidin A.