Daniel B. Werz

A New Golden Age for Donor–Acceptor Cyclopropanes

The effective use of ring strain has been applied to considerable advantage for the construction of complex systems. The focus here is directed towards cyclopropanes as building blocks for organic synthesis. Although thermodynamics should take the side of synthetic chemists, only a specific substitution pattern at the cyclopropane ring allows for particularly mild, efficient, and selective transformations. The required decrease in the activation barrier is achieved by the combined effects of vicinal electron-donating and electron-accepting moieties. This Review highlights the appropriate tools for successfully employing donor-acceptor cyclopropanes in ring-opening reactions, cycloadditions, and rearrangements.

Automated synthesis of oligosaccharides as a basis for drug discovery

Carbohydrates present both potential and problems — their biological relevance has been recognized, but problems in procuring sugars rendered them a difficult class of compounds to handle in drug discovery efforts. The development of the first automated solid-phase oligosaccharide synthesizer and other methods to assemble defined oligosaccharides rapidly has fundamentally altered this situation. This review describes how quick access to oligosaccharides has not only contributed to biological, biochemical and biophysical investigations, but also to drug discovery. Particular focus will be placed on the development of carbohydrate-based vaccines, defined heparin oligosaccharides and aminoglycosides that have recently begun to affect drug discovery.

anti-Oligoannelated THF Moieties: Synthesis via Push−Pull-Substituted Cyclopropanes‡

The first synthesis of anti-fused oligoannelated THF moieties is reported. The key transformation of the synthetic sequence, consisting of cyclopropanation, reduction and oxidation, is the expansion of a push-pull-substituted three-membered ring into a five-membered enol ether system. A repetition of the sequence allows the creation of oligoacetals up to a nonacyclic system.

Synthesis of [n,5]-Spiroketals by Ring Enlargement of Donor-Acceptor-Substituted Cyclopropane Derivatives

Exocyclic enol ethers served as starting materials for the synthesis of [n,5]-spiroketals (n = 5, 6). A metal-mediated cyclopropanation using ethyl diazoacetate afforded spiroannelated cyclopropane derivatives bearing an ester group. A reduction of the corresponding ester by LiAlH(4), followed by subsequent oxidation using hypervalent iodine reagents, produced [n,5]-spiroketals in moderate to good yields. The key step within this three-step sequence is the ring enlargement of the three-membered ring with an oxygen donor and a carbonyl acceptor group into the five-membered enol ether system. Catalytic amounts of the Lewis acid Yb(OTf)(3) facilitate the ring enlargement and increase the yield of the corresponding spiroketal in many cases. When Yb(OTf)(3) was used, our experiments revealed an open transition state rather than a concerted mechanism because the stereochemistry of the spirocenter was not conserved during the ring enlargement. As a result, the thermodynamically more favored anomeric [n,5]-spiroketal was observed as the major product. All the structures were established unambiguously by NOESY experiments.

Ring-enlargement reactions of donor-acceptor-substituted cyclopropanes: which combinations are most efficient?

A detailed theoretical study of ring-enlargement reactions of 72 differently substituted donor-acceptor-substituted cyclopropanes is presented. Transition states, activation barriers, and, for representative examples, the behavior in solution were additionally determined using the B3LYP/6-311G(d) level of theory.

[3 + 3]-Cycloaddition of Donor–Acceptor Cyclopropanes with Nitrile Imines Generated in Situ: Access to Tetrahydropyridazines

Donor-acceptor cyclopropanes are reacted under the influence of a Lewis acid with hydrazonyl chlorides to afford tetrahydropyridazines. Formally, this transformation can be regarded as a [3 + 3]-cycloaddition of three-membered rings and nitrile imines generated in situ. This efficient method provides fast access to a variety of structurally diverse pyridazine derivatives. The structure of a typical product was confirmed by X-ray crystallography.

Dinitrogen Splitting and Functionalization in the Coordination Sphere of Rhenium

[ReCl3(PPh3)2(NCMe)] reacts with pincer ligand HN(CH2CH2PtBu2)2 (HPNP) to five coordinate rhenium(III) complex [ReCl2(PNP)]. This compound cleaves N2 upon reduction to give rhenium(V) nitride [Re(N)Cl(PNP)], as the first example in the coordination sphere of Re. Functionalization of the nitride ligand derived from N2 is demonstrated by selective C-N bond formation with MeOTf.

Domino reactions of donor-acceptor-substituted cyclopropanes for the synthesis of 3,3'-linked oligopyrroles and pyrrolo[3,2-e]indoles.

Multiple displacement of oxygen: Electron-rich oligopyrroles and pyrrolo[3,2-e]indoles are generated by a domino process induced by donor-acceptor-substituted cyclopropanes. Up to seven molecules of water are eliminated, thus allowing the introduction of nitrogen and aromaticity.

From furan to molecular stairs: syntheses, structural properties, and theoretical investigations of oligocyclic oligoacetals.

The synthesis of oligocyclic oligoacetals using five-membered rings as repetitive unit is described. Furan was used as the starting material, which is converted by a three-step procedure consisting of twofold cyclopropanation, reduction, and oxidative ring enlargement into a tricyclic bis(enol ether). A repetition of this synthetic procedure leads to the formation of extended oligoacetal systems. Insights into the structures were gained by X-ray crystallographic investigations and revealed helical arrangements of the subunits in the solid-state. DFT (B3LYP) calculations have been carried out to elucidate the transition state of the ring enlargement and the flexibility of the annelated oligocyclic systems. Strain energies and topologies of potential cyclically condensed oligoacetals are predicted.

Alkynes Between Main Group Elements: From Dumbbells via Rods to Squares and Tubes

Since its first reported synthesis from calcium carbide in 1862 by Friedrich Wöhler,1 acetylene and its alkylor aryl derivatives have developed as key reagents in organic chemistry. The CtC triple bond proved to be reactive toward electrophiles, nucleophiles, hydrogenation reagents, various catalysts, light, and heat. This high reactivity makes the CtC triple bond an ideal reagent for the formation of new C-C bonds. It is therefore of high interest in industry and research laboratories. In the latter places very often main group elements play a pivotal role as reaction partner of the CtC triple bond. In Scheme 1, we list four examples for this role. In most protocols for alkylation of acetylene or monosubstituted triple bonds such as 1 alkali or alkali earth metal salts of an acetylide anion, usually generated in situ, are used as starting materials2 (eq 1 in Scheme 1). Alkynyl 9-BBN derivatives (e.g., 4) are utilized to prepare enynones by reacting them with alkyl ethers of -ketoaldehydes3 (eq 2 in Scheme 1). Trialkylor triarylsilyl groups are frequently used to protect one end of a triple bond when the other will be functionalized. These bulky groups play also an important role to synthesize and stabilize (oligo)alkynes. To couple two different alkyne units together to a diyne, it is effective to use a cross-coupling protocol suggested by Cadiot and Chodkiewicz with a monobrominated alkyne 8 as one component4 (eq 3 in Scheme 1). Most recently, a nitrogensubstituted alkyne 10 was used to construct an aldol product 12 with a quaternary all-carbon stereocenter in a sequential one-pot procedure5 (eq 4 in Scheme 1).