Volume 77, Issue 7

Organic synthesis has long played a pivotal role in the chemical sciences. It is therefore unsurprising and appropriate that the International Conferences on Organic Synthesis (ICOS) continue to thrive. This series was initiated by IUPAC in 1976 and has since featured biennially as one of the core events of the Union. What is surprising is that 22 years have elapsed since an ICOS event was last hosted by Japan. On that occasion, ICOS-4 was held in 1982 at Shinjuku, Tokyo, and was acclaimed as a great success. The latest event (ICOS-15), in Nagoya, Japan on 1ñ6 August 2004, offered an opportunity to match or surpass the impact of its predecessoróa challenge that was taken up enthusiastically under the leadership of Profs. Minoru Isobe (Nagoya University) and Hisashi Yamamoto (now at the University of Chicago) as Conference co-Chairs. Almost 1000 participants converged on Nagoya from all parts of the world. A noticeably high level of participation by delegates from East Asia in relation to those from North America and Europe attested to the growing capacity of this region to contribute to research at the forefront of this area of the chemical sciences. The scientific program of the Conference embraced all aspects of modern synthetic organic chemistry, inter alia, the invention of selective synthetic methods, asymmetric synthesis, total synthesis of natural products, design and synthesis of artificial agents for pharmaceutical and agricultural uses, and molecular assembly and materials based on molecular function. This topical breadth was also captured in a poster program, which was handsomely supported by no less than 466 displays on every conceivable facet of the subject. Overall, it is evident that organic synthesis has expanded its boundaries increasingly toward biological and material sciences, in response to the new challenges arising from rapid progress in molecular biology and applied physics during recent years. A lecture program comprising 10 plenary and 20 invited presentations, in addition to the Thieme/IUPAC award lecture and two Nagoya medal lectures, contributed to a truly exciting Conference experience, and the 21 speakers who kindly agreed to contribute papers based upon their presentations have made it possible to capture some of the excitement in this issue of Pure and Applied Chemistry . The Nagoya Gold Medallist, J. F. Stoddart, used the occasion to share an absorbing and very personal perspective on molecular assembly and materials, a theme on which M. Fujita also disclosed new insights and developments. The perennial theme of total synthesis of natural products, provided scope for presentation of highly creative accomplishments by S. Ley, J. Cossy, Y. Langlois, R. Pilli, and S. Kozmin on a variety of challenging targets. Such advances in the total synthesis of biologically active natural products having extremely complex structures, often necessitate development of novel synthetic methods, and H. Overkleeft, P. Chiu, V. Nair, T.-P. Loh, S. Martin, T.-Y. Luh, E. Juaristi, and M. Catellani did justice to this theme with presentations on a variety of extremely elegant and sophisticated new developments in methodology, based upon organometallic catalysts and/or reagents. Finally, the broad theme of asymmetric synthesis using organometallic complexes with chiral ligands or chiral organocatalysts was developed in conjunction with combinatorial methodology, which is shown to be highly effective in optimizing catalytic systems. Those who contributed to the topic of asymmetric synthesis are K. Ding, A. Charette, S. H. Kang, A. Berkessel, and K. Maruoka, the recipient of the Nagoya Silver Medal. What is the future of organic synthesis? The invention of unprecedented drugs and materials has enriched and expanded the horizons of the human experience in formerly unimagined ways, and owes much to the ever increasing ingenuity of organic synthesis, and recognition and attainment of new synthetic targets. The impact of organic synthesis on cognate disciplines and on general advancement of science and technology is definitely enormous and will be further strengthened by future challenges and opportunities. Thus, it is hoped that younger generations will be inspired to participate in tapping this rich potential, in the cause of advancing science and contributing to the enrichment of future life. These aspirations may yield incalculable rewards. Such progress will certainly be reflected in the scientific program of the next Conference in the ICOS series, which will take place in Merida, Yucatan, Mexico on 11ñ15 June 2006, under the chairmanship of Dr. Eusebio Juaristi, Instituto Politecnico Nacional, Mexico. Tamejiro Hiyama Conference Editor Department of Material Chemistry Kyoto University, Kyoto, Japan *An issue of reviews and research papers based on lectures presented at the 15th International Conference on Organic Synthesis (ICOS-15), held in Nagoya, Japan, 1-6 August 2004, on the theme of organic synthesis. Other presentations are published in this issue, pp. 1087-1296.

Special topics have come to represent a familiar albeit irregular feature of Pure and Applied Chemistry (PAC) in recent years, and were originally conceived as a way of promoting occasional and sometimes extraordinary IUPAC projects. The concept has served to publicize new initiatives, and promote the role of chemistry in multidisciplinary activities and collaboration. For example, the proceedings of two successive Workshops on Advanced Materials featured prominently as special topic issues, and the series has now been assimilated into the program of established IUPAC events, whilst projects arising from close collaboration with fellow international bodies have enjoyed similar coverage, with special topic issues on "Natural and Anthropogenic Environmental Estrogens" and "Implications of Endocrine Active Substances for Humans and Wildlife". Publication policy has also been evolving to ensure that the Journal continues to occupy a unique and indispensable niche in the primary chemistry literature, and recent changes have been influenced by the distinctive features of special topic projects. Most notably, a prerequisite for publication coverage of IUPAC-sponsored events is prior editorial agreement on the desirability and scope of Journal coverage, as is acceptance of centrally coordinated peer review of all manuscripts. The policy recognizes that the core business of the Journal is to promote representative coverage of the established series of IUPAC-sponsored international conferences, for the good reason that they serve the topical mainstream of the subject with distinction. It is therefore logical to seek out and promote certain events in these established series as "special topics", and thus offer readers more in-depth coverage of the scientific proceedings. The recent history of special topics drawn from established series has vindicated this approach, and early citation statistics reveal an encouraging trend toward high recognition of such coverage. Conversely, above-average citation statistics provide valuable clues to established events that merit coverage as special topics. Organic synthesis is one such topic ó the series has a 30-year history of immensely popular and well-supported international conferences that have witnessed some of the epochal disclosures of the discipline. Although earlier proceedings were sometimes published as monographs, PAC now enjoys the privilege of featuring proceedings from this series regularly, thanks to the enthusiastic support of conference organizers and presenters alike. It is a pleasure to introduce this issue, devoted to a fine selection of works arising from the scientific proceedings of the 15th International Conference on Organic Synthesis, held in Nagoya, Japan on 1ñ6 August 2004. The papers capture the vitality and ongoing promise of organic synthesis, and offer readers an opportunity to participate vicariously in another milestone in its advancement. Special topic issues will feature more regularly in the future, as a deliberate initiative to showcase some of the most prominent and enduring disciplinary themes on offer in the calendar of established IUPAC-sponsored conferences. James R. Bull Scientific Editor *An issue of reviews and research papers based on lectures presented at the 15th International Conference on Organic Synthesis (ICOS-15), held in Nagoya, Japan, 1-6 August 2004, on the theme of organic synthesis. Other presentations are published in this issue, pp. 1087-1296.

The hurly-burly life of a scientific nomad is traced through thick and thin from the Athens of the North to the City of Angels with brief and not so brief interludes on the edge of the Canadian Shield, in the Socialist Republic of South Yorkshire, on the Plains of Cheshire beside the Wirral, and in the Midlands in the heartland of Albion.

Cavity-directed chemical transformations represent one of the most important features in 3-D host chemistry, yet they are unexplored as synthetic receptors. We are developing such functions with the large cavity of self-assembled cages, particularly an M 6 L 4 -type cage. The photodimerization of olefins within this cage shows remarkable rate enhancement, perfect regio- and stereoselection, and high pairwise selection (when two different olefins are used) giving only the cross [2+2] adduct. Another intriguing property of the cavity is the stabilization of labile molecules by encapsulation. We succeeded in trapping labile molecules by in situ preparation from small components coming through small portals of the cage. For example, hydrolysis and condensation of PhSi(OMe) 3 , which ordinarily provides a sophisticated Si-O 3-D network (so-called sol-gel condensation), selectively gave a cyclic trimer, [PhSi(OH)O] 3 , in a "ship-in-a-bottle" fashion. Cavity-sensitized photochemical oxidation of alkanes within the cage is also discussed.

Our synthesis work on the insect antifeedant azadirachtin is described. Particular emphasis is placed on the key coupling of a left-hand decalin fragment with a right-hand hydroxydihydrofuran acetal unit via a Claisen rearrangement reaction of an intermediate propargylic enol ether. New chemistry has been developed leading to control of an endo -selective intramolecular Diels–Alder reaction using silicon, which was essential for the construction of the appropriately functionalized decalin fragment. In order to install the five-ring hemiacetal of azadirachtin, we also developed a new ring contraction protocol via an intermediate six-ring cyano ester.

A total synthesis of the naturally occurring ionophore zincophorin has been realized. The key steps are an intramolecular oxymercuration of a cyclopropanemethanol for the elaboration of the tetrahydropyran ring and a Carroll–Claisen rearrangement to control the configuration of the double bond at C20–C21 as well as the stereogenic center at C21.

Syntheses of fumagillol, a precursor of antiangiogenic sesquiterpene fumagillin, and of cytotoxic marine alkaloid bengacarboline are described.

Synthetic studies that established the relative configuration of (–)-delactonmycin, a polyketide with inhibitory activity against HIV-1 Rev protein, and our efforts toward the structural elucidation of the alkaloids (+)-plumerinine, isolated from P. rubra , and (–)-parvistemoamide, isolated from S. parviflora , are discussed.

This paper describes a convergent and stereocontrolled synthesis of leucascandrolide A, a marine natural product that exhibits potent growth inhibition of mammalian and yeast cells. The approach features a substrate-directed relay of the stereochemical information via a series of highly diastereoselective transformations. Spontaneous macrolactolization discovered during this synthetic exercise has provided an unprecedented access to this marine macrolide and demonstrates a new tactic for assembling large-ring systems based on the thermodynamic preference of hemiacetalization.

This paper presents our recent results concerning the use of carbohydrates as cheap, chiral, and enantiopure starting materials in the construction of a variety of densely functionalized molecules. The compatibility of ring-closing metathesis with standard carbohydrate chemistry is demonstrated in the synthesis of new stereoisomers of deoxystreptamine and neamine–important building blocks for the generation of synthetic aminoglycosides with potential antibacterial activity. Ring-closing metathesis is also a key step in the rapid synthesis of new indolizidines and quinolizidines, and in a new solid-phase assisted carbohydrate-based combinatorial scaffold strategy. Further, some of our latest results in the conformational analysis of sugar amino acid-based peptide mimetics and in the development of a novel Ugi-type three-component reaction of sugar-derived azido-aldehydes are discussed.

The title reaction is a key transformation that has been applied to the synthetic studies of the antitumor and antifungal compounds, the pseudolaric acids.

Zwitterionic intermediates generated from the addition of nonprotic nucleophiles to activated acetylenes are intercepted with various third components constituting novel multicomponent organic transformations. Catalytic amounts of an organic base like pyridine were found to trigger reactions between an electrophilic acetylene and a variety of electrophiles. The reactions proceed through dipolar intermediates and show high stereoselectivity.

We have demonstrated that metal-mediated allylation of aldehydes can afford γ-homoallylic alcohols or α-linear homoallylic alcohols by judicious choice of the solvents. A new mechanism has been proposed to account for this new α-selective metal-mediated allylation reaction. On the other hand, the metal-mediated prenylation under the same conditions to obtain α-prenyl alcohols was unsuccessful. Detailed mechanistic studies have resulted in the discovery of a new method to obtain compounds with diverse structures via an oxonium-ene cyclization. Suppressing the oxonium-ene reaction during the reaction has resulted in the formation of α-prenyl alcohols. A highly enantioselective process to obtain α-prenyl product in high optical purity has also been accomplished.

Ring-closing metathesis has been found to be a highly effective reaction for the synthesis of functionalized, bridged nitrogen heterocycles. The utility of the process has been established in several case studies, including a facile synthesis of the tropane ring system and efficient, enantioselective syntheses of the natural products (–)-peduncularine and (+)-anatoxin-a.

Reaction of propargylic dithioacetals with BuLi followed by treatment with dialdehydes yields the corresponding allenyl carbinols which can be cyclized to give the 2,3,5-trisubstituted furans. The use of this strategy for the synthesis of a range of alternating benzene-furan oligoaryls is described.

The inter- and intramolecular Diels–Alder reactions of masked o -benzoquinones generated in situ from the oxidation of easily accessible 2-methoxyphenols with diacetoxyiodobenzene or bis(trifluoroacetoxy)iodobenzene provided cycloadducts in excellent regio- and stereoselectivity and good yields. A general approach to the synthesis of highly substituted cis -decalins and triquinanes with complete stereocontrol from the cycloadducts has been developed. The applicability of our methodology is demonstrated by the total syntheses of several natural products.

The cyclization of various β-amino acids with PhP(O)Cl 2 affords cyclo-β-dipeptides, whose boat conformation is probably responsible for the high diastereoselectivity observed in the alkylation reactions of their lithium enolate derivatives.

Joint palladium and norbornene catalysis for selective aromatic functionalization via palladacycles is reported. Both alkylation and arylation of aromatics are considered after a brief outlook on the mechanism. These are multistep reactions that proceed in ordered sequences and are chemio-, regio-, and stereoselective. The study of the single steps with isolation of the organometallic species involved has allowed us to detect subtle steric and electronic effects which have been exploited to achieve catalytic reactions. Recent developments of aromatic alkylation and arylation are reported, in particular, condensed heterocyclic ring formation involving dialkylated arylpalladium complexes or both symmetrically and unsymmetrically substituted biphenylylpalladium complexes.

The powerfulness of a combinatorial approach in the discovery of novel chiral catalyst systems, particularly for the development of highly efficient, enantioselective, and practical catalysts for asymmetric reactions, was demonstrated by screening modular chiral catalyst libraries created by the strategy of two-component ligand modification of metal ions on the basis of molecular recognition and assembly.

The copper-catalyzed diorganozinc addition to N -diphenylphosphinoylimines was shown to proceed with a very high degree of enantiocontrol if the reaction was run in the presence of Me-DuPHOS monoxide ligand (BozPHOS). The scope of the reaction is described as well as our efforts to identify the nature of the enantioactive metal complex responsible for the high asymmetric induction.

Asymmetric iodocyclization and mercuriocyclization of γ-hydroxy- cis -alkenes have been established. The iodocyclization has been attained with 1.2 equiv of iodine in the presence of the catalyst system prepared from 0.3 equiv of ( R , R )-salen−Co(II) complex and 0.75 equiv of NCS to produce 2-substituted tetrahydrofurans with up to 90% ee. The mercuriocyclization has been achieved using 1.2 equiv of Hg(II) complexed with 4-(2-naphthyl)bisoxazoline (1:1 complex) in the presence of 5 equiv of K 2 CO 3 and 10 equiv of MeOH to procure 2-substituted tetrahydrofurans with up to 95 % ee.

The lecture summarized our recent work in the fields of (i) catalytic asymmetric epoxidation and cyclopropanation, (ii) C–C coupling reactions, and (iii) dynamic kinetic resolution (DKR). The first section describes the use of chiral Ru-porphyrins as catalysts for the asymmetric epoxidation and cyclopropanation of nonfunctionalized olefins, and of peptides and alkaloid-based phase-transfer catalysts for the asymmetric epoxidation of enones. The second section highlights the application of the DIANANE-salen ligands (DIANANE: endo,endo -2,5-diamino-norbornane) to the asymmetric Nozaki–Hiyama–Kishi coupling of aldehydes with allylic and vinylic electrophiles, and of N -tosyl proline amides for asymmetric aldol additions. In the final section, bifunctional urea-based organocatalysts for the DKR of azlactones to provide enantiomerically enriched amino acid esters are presented.

A series of C 2 -symmetric, spiro-type chiral quaternary ammonium bromides have been designed as new, purely synthetic chiral phase-transfer catalysts, and readily prepared from commercially available optically pure ( R )- or ( S )-1,1'-bi-2-naphthol as a basic chiral unit. The structures of the assembled N -spiro chiral quaternary ammonium bromides were unequivocally determined by single-crystal X-ray diffraction analysis. The reactivity and selectivity of these chiral ammonium bromides as chiral phase-transfer catalysts have been evaluated in the asymmetric alkylation of N -(diphenylmethylene)glycine tert -butyl ester under mild liquid–liquid phase-transfer conditions, and the optimization of the reaction variables (solvent, base, and temperature) has also been conducted. Furthermore, the scope and limitations of other asymmetric transformations have been thoroughly investigated with a variety of substrates, in which the advantage of the unique N -spiro structure of our chiral phase-transfer catalysts and dramatic effect of the steric as well as the electronic properties of the aromatic substituents on the 3,3'-position of one binaphthyl moiety have been particularly emphasized.