Volume 83, Issue 3

The 18th International Conference of Organic Synthesis (ICOS-18) was held in Bergen, Norway on 1-6 August 2010, under the auspices of IUPAC and with cosponsorship of the Norwegian Chemical Society and the Research Council of Norway. The structure of the meeting was in keeping with the tradition that has developed for the ICOS series of conferences, with a scientific backbone of lectures including the Thieme-IUPAC Prize Lecture, poster sessions, and exhibitions. Due to valuable help from members of the International Advisory Board, plenary and invited lectures were delivered by chemists from 22 different countries from all around the world. The talks covered most aspects of modern organic synthesis, from new delicate methodologies based on mechanistic understanding, via greatly improved synthesis technologies and exciting total syntheses, to the application of organic synthesis to meet challenges in bioorganic chemistry and the life sciences. There were two new features at this meeting. One was a section of five parallel sessions with short talks given mainly by young chemists from 22 countries. This event was expected to be a challenge to execute because, after all, we like to talk about chemistry without paying attention to the time, but thanks to the speakers’ exemplary discipline the chairs could be lenient in a firm fashion. Collectively, the short presentations showed that a wide range of new and brave ideas are investigated by the young colleagues, which indicate that organic synthesis is heading toward a bright future. The second addition was the Thieme-IUPAC Poster Prize, five in total, to the best posters presented at the conference as judged by an international committee of outstanding synthetic chemists. The papers published in this issue of Pure and Applied Chemistry ( PAC ) give a good cross-section of topics covered at ICOS-18. I am grateful to all colleagues for their interesting contributions, which are instrumental in helping IUPAC disseminate cutting-edge research to the enormous group of organic chemists that did not come to the conference. When you read the papers you will find reviews with excellent examples of natural-product syntheses, new synthetic methodologies, applications of organic synthesis in biological research, and development of new materials with exciting functional properties. But you will also come across interesting papers that are more like traditional publications found in journals other than PAC; the reason for this being that invitations were also extended to selected younger chemists to contribute papers based upon short talks (the scope of which was of course narrower than that of invited lectures), and they responded with enthusiasm. I am sure you will find interesting material there as well. ICOS-18 certainly nourished the organic synthetic chemists’ professional development through lectures, poster presentations, and discussions dealing with the cutting-edge advances in organic synthesis. There are many that are looking forward to the next meal, to be served when ICOS-19 opens in Melbourne, Australia, on 1 July 2012 (www.icos19.com). Leiv K. Sydnes Conference Editor

The use of ring-fused gem -dihalocyclopropanes, Au(I)-catalyzed cyclization reactions, and chemoenzymatic techniques in the synthesis of natural products is described.

Synthetic studies toward the spiroimine unit of the spirolide family of shellfish biotoxins are described. Several strategies for introduction of the C7, C29, and C32 stereocenters of the A,E-ring system of the spirolides are described, such as spironitrone formation, Birch reductive alkylation, and asymmetric Diels–Alder cycloadditions.

Nature provides us with a wonderful pool of enantiopure starting materials for synthesis: amino acids, sugars, and many (but not all!) terpenes can be isolated even in large quantities in an uncompromised 100 % ee. Vicinal amino alcohols constitute a versatile group of organic structures; they are, in principle, available in enantiopure form from the chiral pool compounds or through chiral catalysis; they are potent intermediates for the synthesis of natural products and medicinally/biologically active compounds, and they provide a highly desirable scaffold for the construction of ligands for metals as well as organocatalysts. These new techniques will open up valuable new possibilities for the invention of new technologies for chemical synthesis, the desired course of chemical discoveries for the future. A robust entry to enantiopure vicinal amino alcohols from inexpensive naturally occurring amino acids has therefore become a key challenge for our endeavors in the development of methodology.

The chemistry and biology of the fumonisin family of natural products has inspired an integrated research program featuring methods development for stereoselective synthesis of homoallylic alcohols, accompanied by applications of these methods to the first synthesis of fumonisin B 1 , and to preparing a family of stereoisomeric 2-amino-3,5-diol analogs of 1-deoxysphingolipids, as a possible approach to discovering new drugs for cancer chemotherapy.

Despite the well-established methods for stereochemical assignments and synthesis of 1,3-diols, the corresponding 1,5-diols and -polyols present specific challenges which remain unsolved. This article highlights some new strategies and methodologies specifically designed for the 1,5-diol motif.

An improved gram-scale synthesis of Bn 5 CpRu(CO) 2 Cl is reported based on heating of pentabenzylcyclopentadiene with Ru 3 (CO) 12 at 160 °C under argon atmosphere in mesitylene followed by addition of chloroform, continued heating, and evaporation of the solvents. Subsequent washing of unreacted ligand precursor with hexane provided pure title compound in 77 % yield. In combination with Candida antarctica lipase B (CAL-B) (Novozym 435), this complex forms a highly active racemization catalyst for metallo-enzymatic dynamic kinetic resolution (DKR) of secondary alcohols as demonstrated in the present work by converting 100 g of racemic 1-phenylethanol to ( R )-1-phenylethanol in >99 % ee and 93 % overall yield over two steps using 0.05 mol % loading of the metal catalyst and 1 mass % loading of immobilized enzyme. In addition, the synthesis and crystallographic characterization of the palladium congener Bn 5 CpPd(PPh 3 )Cl are briefly discussed.

Four 2,5-disubstituted pyrrole and two 2-disubstituted thiophene analogs of the natural products mycalazol 5 and mycalazal 2 have been prepared using the Stille coupling reaction. All four analogs displayed potent antiproliferating activity against several human cancer cell lines with IC 50 values in the nanomolar range.

We present a compilation of methodologies developed in our laboratories to assemble polycyclic structures containing small- and medium-sized cycles, relying on the use of transition-metal-catalyzed (TMC) cycloadditions. First, we discuss the use of alkylidenecyclopropanes (ACPs) as 3C-atom partners, in particular in their Pd-catalyzed (3 + 2) cycloadditions with alkynes, alkenes, and allenes, reactions that lead to cyclopentane-containing polycyclic products in excellent yields. Then, we present the expansion of this chemistry to a (4 + 3) annulation with conjugated dienes, and to inter- and intramolecular (3 + 2 + 2) cycloadditions using external alkenes as additional 2C-π-systems. These reactions allow the preparation of different types of polycyclic structures containing cycloheptene rings, the topology of the products depending on the use of Pd or Ni catalysts. Finally, we include our more recent discoveries on the development of (4 + 3) and (4 + 2) intramolecular cyclo-additions of allenes and dienes, promoted by Pt and Au catalysts, and discuss mechanistic insights supported by experimental and density functional theory (DFT) calculations. An enantioselective version of the (4 + 2) cycloaddition with phosphoramidite Au(I) catalysts is also presented.

Samarium diiodide (SmI 2 ) smoothly promotes the cyclizations of suitably substituted carbonyl compounds with styrene subunits leading to benzannulated cyclooctenes. The intramolecular samarium ketyl addition to arene or hetarene moieties enables a new, efficient, and highly stereoselective entry to dearomatized products such as hexahydronaphthalenes, steroid-like tetra- or pentacyclic compounds, or dihydroindole derivatives. The usefulness of the developed SmI 2 -induced cyclization method was demonstrated by the shortest formal total synthesis of the alkaloid strychnine.

The degenerative radical addition-transfer of xanthates onto alkenes allows the rapid assembly of richly functionalized structures. Various families of open-chain, cyclic, and polycyclic compounds can thus be readily accessed. Furthermore, the process can be extended to the synthesis or modification of aromatic and heteroaromatic derivatives by exploiting the possibility of using peroxides both as initiators and stoichiometric oxidants. The modification of existing polymers and the controlled synthesis of block polymers by what is now known as the RAFT/MADIX (reversible addition–fragmentation transfer/macromolecular design by interchange of xanthate) process is described briefly.

Olefin metathesis as a catalytic process constantly gains interest among organic chemists. Over the last decade, it became an efficient tool to accomplish the synthesis of many complex molecules. The development of new well-defined catalysts and continuous examination of novel ligands led to the establishment of metathesis methodology in a group of widespread chemical transformations. Not only does the selection of the catalyst seem to be of crucial importance, but modifying the reaction conditions, such as choice of the solvent and temperature, also allows one to make olefin metathesis a practical industrial process. This contribution, based on examples from our research, is devoted to answering the question “What may have a greater impact on the performance of metathesis reaction: a sophisticated catalyst design or unique reaction conditions?” Based on the data reported in the paper, we discuss two complementary strategies concerning the tuning of the olefin metathesis process.

The halodiazoacetates are a group of synthetically useful halogenated diazo compounds that can be used in Rh(II)-catalyzed carbenoid reactions. In the reactions between the halodiazoacetates and electron-rich, sterically unhindered alkenes, halocyclopropanes are formed in good to excellent yields. The halodiazoacetates also react well in C–H and Si–H insertion reactions, broadening the synthetic utility of these reactions. The products of the reactions are synthetically useful α-halocarbonyl compounds. Density functional theory (DFT) calculations have given insight into the mechanism of the cyclopropanation and C–H insertion reactions of the halodiazoacetates, and have also shown that the halodiazoacetates have a particularly high kinetic activity.

Rhodium-catalyzed enantioselective hydroacylation reactions allow rapid access to chiral substituted ketones. However, due to the low reactivity of disubstituted alkenes in intermolecular versions of this process, only a small number of asymmetric intermolecular reactions have been described. Strategies employed to avoid reactivity issues include the use of norbornadienes, linear dienes, acrylamides, and allenes as the alkene components. In addition, our laboratory has recently reported the rhodium-catalyzed enantioselective inter-molecular alkyne hydroacylation reaction, leading to the formation of enone products via a kinetic resolution procedure.

A variety of α,β-unsaturated acetylenic ketones, prepared in good yields from 3,3,4,4-tetraethoxybut-1-yne (TEB), have been reacted with selected mono- and bis-nucleophilic reagents. The mononucleophiles react in a Michael fashion and give in most cases the corresponding α,β-unsaturated alkenones in good yield. Many of the alkenes are formed as single stereoisomers, but the configuration depends on the nature of the nucleophile. If hydrogen bonds can be formed, the Z geometry is preferred, otherwise the E geometry is completely predominant. Experiments have also uncovered that α,β-unsaturated acetylenic ketones with a gem -diethoxy moiety in the α' position decompose when reacted with sodium hydroxide in aqueous tetrahydrofuran (THF); the carbonyl group is attacked and a carboxylic acid and a terminal alkyne are formed. If the nucleophiles contain two nucleophilic centers or if the α,β-unsaturated acetylenic ketones contain an additional reactive group, such as a hydroxyl group or an acyloxy moiety, useful secondary reactions may occur. By taking advantage of such secondary transformations, two completely regioselective syntheses of furans have so far been developed.

Two types of enantioselective [2 + 2 + 2] cycloadditions of triynes using chiral rhodium catalysts are disclosed. The intramolecular reaction of ortho -aminophenol-tethered triynes provides chiral tripodal compounds. Consecutive inter- and intramolecular reactions of ortho -phenylene-tethered triynes provide chiral tetraphenylenes.

Formation of the nitrile was the outcome of the investigation of biochemically significant oxidative decarboxylation of amino acids using o -iodoxybenzoic acid (IBX) in aqueous ammonia system.

A convergent synthetic method for new types of carotenoid compounds containing phenyl substituents at C(13) and C(13') has been developed by the coupling of allylic sulfone and 2,7-diphenyloct-4-enedials, followed by the double elimination strategy. These carotenoid compounds are fairly stable and legitimate candidates for nanosized molecular wires, which show diverse conductance values according to the electronic nature of the substituent group in the phenyl ring.

The one-pot, three-component synthesis of 2,3-di- and 2,2,3-trisubstituted-3-methoxycarbonyl-γ-butyrolactones starting from aryl bromides, dimethyl itaconate, and aldehydes or ketones is described. The cobalt-catalyzed domino process formally involves the in situ metallation of an aromatic bromide, a conjugate addition onto dimethyl itaconate, an aldolization reaction with a carbonyl compound, and a final cyclization into a five-membered ring lactone. This procedure is applied to the concise synthesis of a range of polyfunctionalized γ-butyrolactones displaying a paraconic acid methyl ester subunit.

Transition-metal (TM) complexes of new phosphines, readily prepared by a straight-forward three-step modular synthesis, were successfully employed in difficult cross-coupling reactions conducted under mild conditions (water, “open-flask”, low temperature) that aspire to meet green chemistry criteria. High yielding catalyzed by bismuth or rhodium complexes oxidative arylation of naphthoquinone gave the key 2-arylnaphthoquinone intermediates for facile bismuth triflate-catalyzed Michael addition of secondary phosphine oxides. Subsequent O - methylation and reductions of the resulting products gave access to the target air-stable phosphine ligands in good overall yields (up to 60 %).

2-Substituted N -methoxy-9-methyl-9 H -purin-6-amines were synthesized either from their corresponding 6-chloro-9-methyl-9 H -purines or 2-chloro- N -methoxy-9-methyl-9 H -purin-6-amine. Great diversity in the amino/imino tautomeric ratios was observed and calculated based on 1 H NMR. The tautomers were identified by 1D and 2D 1 H, 13 C, and 15 N NMR techniques, and showed significant variation both in 13 C and 15 N shift values. Comparison of the tautomeric ratios with Hammett F values revealed that as the field/inductive withdrawing abilities of the 2-substituent increased, the ratio of amino:imino tautomers was shifted toward the amino tautomer. Computational chemistry exposed the significance of hydrogen bonding between solvent and the compound in question to reach accurate predictions for tautomeric ratios. B3LYP/def2-TZVP density functional theory (DFT) calculations resulted in quantitatively more accurate predictions than when employing the less expensive BP86 functional. N-7-Alkylation of the 2-substituted N -methoxy-9-methyl-9 H -purin-6-amines showed that when the field/inductive withdrawing ability of the 2-substituent reached a certain point the reactivity drastically dropped. This correlated with the atomic charges on N-7 calculated using a natural bond orbital (NBO) analysis. Biological screening of the final 2-substituted agelasine analogs indicated that the introduction of a methyl group in the 2-position is advantageous for antimycobacterial and antiprotozoal activity, and that an amino function may improve activity against several cancer cell lines.

The mechanism of our previously reported DDQ-mediated oxidative C–C bond-forming reaction is investigated. We are able to trap and characterize an iminium ion intermediate with X-ray crystallography, elemental analysis, and solid-state NMR spectroscopy; to our knowledge this is the first time this putative intermediate ion has been directly observed in such cross-dehydrogenative couplings (CDCs). The intermediate can be reacted with a range of nucleo-philes, including a malonate that is not amenable to a one-pot reaction protocol.

After a short introduction to place our work in a proper context, this account summarizes our theoretical and synthetic results in the field of frustrated Lewis pair (FLP) chemistry.

Electron paramagnetic resonance (EPR) spectroscopy has increasingly been applied for the study of nucleic acid structure and dynamics. Such studies require incorporation of free radicals (spin labels) into the biopolymer. The labels can be incorporated during chemical synthesis of the oligomer (phosphoramidite approach) or postsynthetically, by reaction of a spin-labeling reagent with a reactive functional group on the oligonucleotide. Incorporation of the rigid nitroxide spin label Ç is an example of the phosphoramidite method, and reaction of a spin-labeled azide with an alkyne-modified oligomer to yield a triazole-derived, spin-labeled nucleotide illustrates the postsynthetic spin-labeling strategy. Characterization and application of these labels to study structural features of DNA by EPR spectroscopy is discussed. Finally, a new spin-labeling strategy is described for nucleic acids that relies on noncovalent interactions between a spin-labeled nucleobase and an abasic site in duplex DNA.

Chemical genetics, which relies on selecting small molecules for their ability to induce a biological phenotype or to interact with a particular gene product, is a new powerful tool for lead generation in drug discovery. Accordingly, diversity-oriented synthesis (DOS) of small-molecule peptidomimetics gives access to collections of new chemotypes bearing high structural diversity. Biological evaluation using cell growth as a phenotypic screening on Saccharomyces cerevisiae deletant strains is a powerful tool to identify new chemotypes as hit compounds in the discovery of new antifungal and anticancer agents, and also in the dissection of their mode of action. Our contribution in this field focused on the screening of morpholine-based peptidomimetic collections toward yeast deletant strains, which provided the identification of new chemotypes involved in mitochondria metabolism and respiration.

The highly tumor inhibitory cephalostatins (e.g., cephalostatin 1), a marine natural product isolated from Cephalodiscus gilcristi , have attracted us to synthesize biologically active analogues. The goal of this study is to shed more light on selective desymmetrization of a symmetrical starting analogue through the F-ring opening route applied to certain analogues using different borane complexes. Previously, we have reported a selective opening of the spiroketal in the northern part of an analogue using catechol-borane and D-( N -tosyl) valine-borane complexes. We demonstrate here the possibility of opening the southern part of the same analogue using salicylic acid-borane complex by which extra flexibility is harvested. In contrast, a different reaction type took place when another analogue was treated with 3,4-diaminobenzonitrile-borane complex, which give after H 2 O 2 oxidation, products arising from ∆ 14 bond hydration. This led us to conclude that the geometry of both borane complex and substrate govern the regioselectivity of the products. However, the electronic nature of both substrate and borane-complex govern the chemoselectivity.

The green synthesis of a new series of polycyclic procyanidin derivatives has been achieved in good yields by tandem dinucleophilic addition of indolin-2-thiones to flavylium salts. The procedure is efficient and simple, and the substrates are easily available.

A series of novel 5-(2-hydroxypropyl)amino-1,2,3-thiadiazole and 5-(2-hydroxy-propyl)sulfanyl-1,2,3-triazole derivatives were designed and synthesized as candidate fungicides. The new compounds were identified by NMR and IR spectroscopy, mass spectrometry, and elemental analysis. Their antifungal activities were evaluated.

A small library of pyridine-based rhodanine analogues of BH3I-1 were synthesized and screened against B-cell lymphoma-extra large (Bcl-XL) and myeloid cell leukemia sequence 1 (Mcl-1) for the ability to displace 5-carboxyfluorescein-labeled Bak peptide (Flu-Bak). Differences in selectivity toward Bcl-XL and Mcl-1 were observed, and the binding modes of selected compounds were studied further. The results may be useful in designing potent small-molecule inhibitors of Bcl-XL and Mcl-1 as well as selective Mcl-1 inhibitors.