Angewandte Chemie International Edition

Biological activity at the molecular level involves the binding of a small-molecule ligand to a macromolecular receptor, usually a protein, in aqueous solution (see scheme). Enthalpic and entropic contributions arising from inter- and intramolecular effects determine the affinity of both binding partners towards each other. Affinity as a key element in life sciences—how well is this quantity understood today?

Total synthesis programs directed toward complex molecules may take the form of unrelentless campaigns in which the synthetic chemist is faced with unprecedented challenges and unforeseen obstacles, but which often lead to invaluable fundamental knowledge and powerful new technologies. Here the authors describe one of the most arduous and rewarding endeavors in total synthesis of modern times—the synthesis of the CP molecules (see scheme)—and compare it to the Greek mythology's Labyrinth and the conquest of the Minotaur by Theseus.

Transgenic goats to spin webs! The silk of spider nets (see picture) possesses unique mechanical properties. By using suitable microbiological methods, a structurally similar fiber protein has recently been prepared that, after spinning, exhibits comparable strength and elasticity to natural spider silk. The American firm Nexia Biotechnology plans to use transgenic goats to express this silk protein in their milk.

The P₅rings of the first inorganic metallocene, [Ti(η⁵-P₅)₂]²⁻ (see picture) are generated from white phosphorus in a selective reaction. The steric and electronic properties of these rings provide the remarkable stability of this unprecedented sandwich complex.

At least four different polymorphic forms are possible for the previously uncharacterized compound Rb₂Te. One form is a metastable phase at room temperature and two are high-temperature phases; in one of the latter, the Te atoms are coordinated in the form of an Edshammar polyhedron (see picture). Rb₂Te is therefore unique within the di(alkali metal) monotellurides.

In hydrophobic nanometer clefts in membranes, ridge molecules, such as cellobiose, can be anchored for months. They do not diffuse into the neighboring bulk water and electrolytes from the bulk water do not penetrate the immobilized layer. In the presence of dimethyl viologen, cycling of the Au electrode potential causes the viologen molecules to stir the anchored molecules out of the cleft and into the bulk water (see picture: the bulk water phase does not penetrate the hydrate layer but the viologen molecules can).

Carbohydrate coupling at any desired peptide carboxylate moiety is possible with a highly selective biocatalytic route for the synthesis of carbohydrate–peptide conjugates (see picture).

A useful tool for the investigation of synthetically important tributyltin-mediated radical chain reactions is electrospray ionization mass spectrometry (ESIMS). A microreaction system is coupled online to the ESI source. Transient radicals were detected unambiguously by using MS/MS methods (see picture).

Elements of a carbene and a nitrene are linked by a common delocalized π electron in the molecule described here (see picture). The organic high-spin molecule with a quartet ground state could be photochemically generated and spectroscopically characterized in an argon matrix at 3 K.

Rapid and regioselective CF bond activation of hexafluoropropene occurs on reaction with 1. Treatment of the resulting complex 2 with hydrogen yields the rhodium fluoro complex 3 and 1,1,1-trifluoropropane (4).

By using a new “titration” technique, the activation barrier for the strictly unimolecular 1,3-hydrogen migration 1^.+→2^.+ has been determined (0.74±0.06 eV; see reaction profile). With this technique the internal energy of 1^.+ is controlled by variable photoionization of acetamide and the chemistry of the resulting enol ion 2^.+ is then probed by structure-specific ion–molecule reactions.

New stereogenic centers are generated in the [TiCl₂(OiPr)₂]-catalyzed reaction of [(S)R]-[(p-tolylsulfinyl)methyl]-p-quinamines 1 with α,β-unsaturated ketones 2 to give hydroindole-substituted systems 3 in a domino process. Up to four stereogenic centers are formed in the reaction of cycloalkenones and up to five when acyclic enones (2 equiv) are used.

The tetracyclic skeleton of C4-oxygenated angucyclinone-type antibiotics rubiginones A₂ ((+)-3) and C₂ ((−)-4) is constructed by Diels–Alder reaction of a racemic sulfinyl-substituted methyl juglone and the enantiopure vinyl cyclohexene 2, which is prepared in nine steps and in 26 % overall yield from sulfinyl-substituted p-quinol 1. TBDMS=tert-butyldimethylsilyl.

Stereoselective alkenylated compounds are formed from the reaction of organozinc halides and aldehydes (see scheme; FG=functional group). Under mild conditions, and in the presence of a silylating agent, the Ni-catalyzed procedure gives E-alkenes and E-stilbenes in excellent yield.

A [3×3] Ag⁺₉metallogrid self-assembles by a highly complex mechanism involving several intermediates, which may be generated at different metal/ligand stoichiometries. Extensive NMR spectroscopic studies have allowed the unraveling of the structure of these species and have revealed that the final grid entity presents high structural robustness and that the last assembly step (see scheme) occurs with strong cooperativity.

Suppressing the charge-transfer quenching with an externally applied electrochemical bias results in a fluorescence enhancement of a fluorophore (pyrene) on a gold nanoparticle surface (see scheme). At positive bias the fluorophore is totally quenched on the gold surface while at negative bias (less than −0.5 V) it becomes highly fluorescent.

Chains change: Novel valence-ordering structures of the ground states of MMX chain compounds, [Pt₂(RCS₂)₄I]_∞ (1: R=nBu, 2: R=Et), are determined by low-temperature crystal-structure analyses to be -Pt²⁺-Pt³⁺-I⁻-Pt³⁺-Pt²⁺-I⁻-. Magnetic susceptibility measurements of 1 (see graph) revealed an abrupt drop in magnitude from a 1D antiferromagnetic spin system to a spin-singlet state accompanying a first-order phase-transition around 210 K. This result is in contrast to the spin degree of freedom of 2 that survived down to 2 K.

Continuous separation of organic compounds is possible by selective transport through a supported liquid membrane, which contains the room-temperature ionic liquid 1-n-butyl-3-methylimidazolium hexafluorophosphate immobilized in the porous structure of a hydrophilic polyvinylidene fluoride membrane. A mixture (1:1 molar ratio) of the isomeric amines diisopropylamine (S¹) and triethylamine (S²) was continuously fractionated over 14 days without any observable decrease in selectivity (see scheme).

The selective generation of 1,2- and 1,4-addition products (3 and 4, respectively) in the addition of Ti^IV enolates 1 to α,β-unsaturated carbonyl compounds 2 can be almost completely controlled by the choice of Lewis acid. The high selectivity for 1,4 addition when the enones are activated by TiCl₄ or SnCl₄ is probably a result of the bridging chlorine atoms.

Despite the weakness of SH⋅⋅⋅S interactions and the fact that they have rarely been reported in transition-metal compounds, variable-temperature NMR data and theoretical calculations provide evidence for fast intramolecular proton exchange between the bridging sulfur atoms in the complexes [Pt₂{Ph₂P(CH₂)_nPPh₂}₂(μ-S)(μ-SH)]ClO₄ (n=2, 3; see scheme).

A significant increase in yield is observed when DMAD is added to the reaction of 1-methylimidazole (1) with aldehydes 2 and diethylmethylsilane in the presence of a catalytic amount of [Ir₄(CO)₁₂] to produce 2-(1-diethylmethylsiloxyalkyl)imidazoles 3. DMAD=dimethyl acetylenedicarboxylate.

Efficient carbonyl insertion into CO and CN bonds using [Lewis acid]⁺[Co(CO)₄]⁻ complexes 1 and 2 gives regio- and stereoselective carbonylation of a variety of epoxides and aziridines to yield β-lactones and β-lactams, respectively. Both transformations are proposed to occur by the same mechanism, yielding products with inversion of configuration at the site of CO insertion.

A four-component reaction: A nickel catalyst promotes the conjugate addition of Me₂Zn and a carbonyl compound to 1,ω-dienynes 1 at the terminal positions of the alkyne and the diene moieties, respectively; the through-space interactions of the alkyne and diene groups ensure CC coupling at the internal positions. The products 2 are obtained in good yields and with excellent 1,5-diastereoselectivity and stereoselectivity about the exocyclic double bond.

Only through total synthesis could the absolute configuration of the 3″R,4″R ring junction of the polyenoltetramic acid polycephalin C (1) be unambiguously established. Key features of the synthesis include a double Swern oxidation, double Stille coupling, and a double Takai olefination.

Treble clefts: The dendritic porphyrin receptor 1 has three fullerene-binding clefts, each of which consists of two face-to-face-oriented porphyrins. [60]Fullerene guests bind to each subunit, successively suppressing the rotational freedom (“domino” effect) and the guest-binding proceeds according to positive homotropic allosterism. As expected, the binding constant achieved in this system is large.

Nitrogen splits: The reaction of the linked aryloxide–niobium complex 1 with a hydride reagent under 1 atm of N₂ gave the nitride-bridging dimer 2. The origin of the nitride ligands has been confirmed to be N₂ by repeating the experiment under an atmosphere of ¹⁵N₂.

An effective sequence: Palladium-catalyzed asymmetric allylic alkylation, Heck cyclization, and diastereoselective allylic oxidation were used in the total synthesis of (−)-galanthamine (3) in 14.8 % overall yield (from 1 and 2, Troc=2,2,2-trichloroethoxycarbonyl) and with 96 % ee. This improved procedure provides the shortest and most efficient nonbiomimetic synthesis of the acetylcholinesterase inhibitor.

HYSCORE with a vanadium core: Examples of monomeric metal compounds containing the cis-[M(O)(OH)]ⁿ⁺ unit, namely the V^IVO²⁺ complexes [V^IVO(OH)(bipy)₂]BF₄ (1; see picture) and [V^IVO(OH)(phen)₂]BF₄⋅H₂O (2⋅H₂O), were isolated and structurally characterized. The continuous wave EPR and 2D ESEEM (HYSCORE; hyperfine sublevel correlation) spectroscopy parameters obtained for 1 and 2⋅H₂O provide spectroscopic signatures that enable the assignment of the cis-[V^IVO(OH)]⁺ center in biomolecules.

An unexplored family of polyoxometalates has evolved through the synthesis and structural characterization of the first examples of Mo^V sulfite heteropolyanions. The dodecanuclear molybdenum(V) sulfite exhibits a unique structural motif among polyoxometalates (see picture; gray polyhedra represent Mo^VO₆ octahedral units, black, white, and gray balls are sulfur, oxygen, and nitrogen atoms, respectively).

Big rings and nanocleavage: Whereas a variety of molybdenum oxide based nanoobjects can be obtained by self-assembly concomitant with a variety of modifications of a parent cluster system under alterable boundary conditions, drastic changes—comparable to a molecular-scissors-type activity—can even cause splitting of the parent cluster to (large) fragments which subsequently can be linked in fascinating ways even with the option of generating giant cluster collectives (see picture {Mo}≡{MoO₇(H₂ O)}³⁻).

Interconnecting rings: The first pyrophosphate/Mo^V complex Na₂₄{Na₄(H₂O)₆⊂[(Mo₂O₄)₁₀(P₂O₇)₁₀(CH₃COO)₈(H₂O)₄]}⋅97 H₂O is synthesized in mild conditions, and has been characterized by X-ray diffraction (see polyhedral representation) and ³¹P NMR spectroscopy. This molecular compound is formed of two nearly perpendicular interconnected wheels, an unprecedented topology for an inorganic compound.

Coupling of anatase and rutile TiO₂ in a bilayer form significantly increases photocatalytic activity relative to the individual components. Reducing the dimensions of the junction to the charge-separation distance is of importance in increasing this activity. The interfacial electron transfer from anatase to rutile (<10 μm) was revealed by labeling and visualizing the reduction sites by deposition of Ag nanoparticles (see picture).

Molecular sieving to take your breath away: The breathing ionic crystal 1 is synthesized by the complexation of Keggin-type [α-SiW₁₂O₄₀]⁴⁻ (red) polyoxometalate with a macro cation [Cr₃O(OOCH)₆(H₂O)₃]⁺ (green and white). The water of crystallization is easily removed from 1 by evacuation to form a guest-free phase 2. Compound 2 reversibly adsorbs small alcohols and nitriles as well as water, while longer-chain alcohols and nitriles were excluded, which shows the novel molecular sieving of small hydrophilic molecules by 2.

Box clever: A very stable box-shaped cyclic tetramer (see picture) was formed from meso-pyridyl substituted meso–meso-linked zinc(II) diporphyrin, in which the porphyrin subunits are held in a rigorous perpendicular orientation.

Self-assembly of triangular nanoscale secondary building units affords a Kagomé lattice (see picture) that exhibits room-temperature magnetic hysteresis. This phenomenon is caused by spin frustration imparted by the triangular lattice topology, which is exemplified by direct comparison to a network having the same composition, but different topology.

The conformational reaction pathway for β-mannosidases proposed here is distinct from that of glucosidases and cellulases. The proposal is based on substrate distortions along the reaction pathway of a β-mannosidase (see picture) that were revealed by X-ray crystallography and are close in conformational space to known β-mannosidase inhibitors.

Chiral side chains installed into the stacks of overcrowded arenes enforce helical conformations (see picture). The assembly process can be directed with electric fields as a result of a dipole moment parallel to the stacking direction. In concentrated solutions, superhelices emerge that reflect circularly polarized light.

The enantioselective alkylation of the Schiff base 2 was carried out in the presence of a novel phase-transfer catalyst, the guanidine-containing pentacyclic compound 1. The product 3 was obtained with enantiomeric excesses of 76–90 % (see scheme).

An electronic spectator in stable carbenes: A weak π-donor substituent such as a phosphanyl group brings enough stabilization to singlet phosphanyl(mesityl)carbenes prepared by photolysis of diazo precursors that the mesityl group remains an electronic spectator. The carbenes are sufficiently stable to allow characterization of the phosphanyl(tert-butyl)- and even phosphanyl(methyl)carbenes (see picture) by NMR spectroscopy (mesityl=2,4,6-trimethylphenyl).

Retention of the configuration is observed in the pinacol-type rearrangement of 2,3-epoxy alcohols 1 in the presence of bis(iodozincio)methane (2). The 1,3-migration of the hydroxymethyl group affords an intermediate 2-hydroxyaldehyde, which is methylenated by 2 in situ to give homoallyl alcohol 3.

Synthetic anchor: An incorporated allyl group may act in this way to allow protein modification in a site-specific fashion. The nonnatural amino acid O-allyl-L-tyrosine (1) has been site-specifically incorporated into protein in E. coli. The yield of full-length mutant Z-domain protein is 5.6 mg L⁻¹, in comparison to 9.2 mg L⁻¹ of native Z-domain protein. A high-resolution mass spectrum suggests the fidelity for the incorporation of 1 is better than 99.8 %.

A GaGa bond order considerably less than unity in the “digallene” Ar′GaGaAr′ (Ar′=2,6-Dipp₂C₆H₃, Dipp=2,6-iPr₂C₆H₃; see structure) is indicated by its structure and solution behavior.