Reductive claisen rearrangements of anthraquinone allyl ethers

Gentle heating of allyloxyanthraquinones with sodium dithionite in dimethylformanide - water effects a rapid and controlled rearrangement to give high yields of 2-allyanthraquinones.     

Precursor-directed biosynthesis of epothilone in Escherichia coli

Engineered biosynthetic pathways provide a powerful method for generating complex molecules. Precursor-directed biosynthesis, which combines chemical synthesis and enzymatic transformations, allows non-native starting materials to be incorporated into biosynthetic pathways. Using this approach, we achieved the production of the anticancer agent epothilone C in Escherichia coli. An E. coli strain was engineered to express the last three modules of the epothilone biosynthetic pathway (epoD-M6, epoE, and epoF) and the substrate required to complement the biosynthetic enzymes was obtained by chemical synthesis. Under high-density cell culture conditions, the E. coli strain processed exogenously fed synthetic substrate into epothilone C at levels comparable to the native host (1 mg/L) and at higher levels than other heterologous hosts. Importantly, this precursor-directed approach will allow chemical modifications to be introduced into the polyketide backbone and may ultimately provide access to epothilone analogues with improved pharmacological properties in quantities sufficient for clinical development.     

An evaluation of a new neutron tube (Philips Type 18604) for total body in vivo activation analysis

A 14 MeV neutron generator system with a new sealed tube (Philips 18604) was evaluated for total body in vivo neutron activation analysis (TBIVNAA). The neutron output, angular distribution, rise time, reproducibility of short irradiations and leakage of tritium were investigated. The 18604 tube meets all the requirements of TBIVNAA within its normal operating specification.     

Hexanes/acetonitrile: a binary solvent system for the efficient monosilylation of symmetric primary and secondary diols

Symmetric diols are useful compounds in the synthesis of natural products, their value often dependent on their successful monoprotection. A general and simple method for the monosilylation of symmetrical primary and secondary diols is reported. The method exploits the solubility differential of diols and their monosilylated counterparts in a binary hexanes/acetonitrile solvent system.     

Lanthanide Shift Reagents. Paper 21. Interaction of Arenes with Silver/Lanthanide Shift Reagent and Comparison with Chromium Tricarbonyl Complexes

Lanthanide shift reagents can bring about dramatic simplifications of highly complex NMR spectra^1,2. The applicability of the commonest of these (the thd and fod chelates of Eu, Pr and Yb) has been restricted to those molecules possessing a suitable N, O or S donor atom, although they may turn up in unusual guises, e.g. in quaternary ammonium compounds³.     

Rapid Assembly of Saturated Nitrogen Heterocycles in One‐Pot: Diazo‐Heterocycle “Stitching” by N–H Insertion and Cyclization

Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2‐disubstituted azetidines, pyrrolidines, piperidines, and azepanes bearing ester and diverse aryl substituents. A one‐pot rhodium catalyzed N–H insertion and cyclization sequence uses diazo compounds to stitch together linear 1,m‐haloamines (m=2–5) to rapidly assemble 4 ‐, 5 ‐, 6 ‐, and 7 ‐membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including examples with diazo compounds derived from biologically active compounds. The products can be functionalized to afford α,α‐disubstituted amino acids and applied to fragment synthesis.     

Total Biosynthesis of Legionaminic Acid,a Bacterial Sialic Acid Analogue

Legionaminic acid, Leg5,7Ac₂, a nonulosonic acid like 5‐acetamido neuraminic acid (Neu5Ac, sialic acid), is found in cell surface glycoconjugates of bacteria including the pathogens Campylobacter jejuni, Acinetobacter baumanii and Legionella pneumophila. The presence of Leg5,7Ac₂ has been correlated with virulence in humans by mechanisms that likely involve subversion of the host's immune system or interactions with host cell surfaces due to its similarity to Neu5Ac. Investigation into its role in bacterial physiology and pathogenicity is limited as there are no effective sources of it. Herein, we construct a de novo Leg5,7Ac₂ biosynthetic pathway by combining multiple metabolic modules from three different microbial sources (Saccharomyces cerevisiae, C. jejuni, and L. pneumophila). Over‐expression of this de novo pathway in Escherichia coli that has been engineered to lack two native catabolic pathways, enables significant quantities of Leg5,7Ac₂ (≈120 mg L^?1 of culture broth) to be produced. Pure Leg5,7Ac₂ could be isolated and converted into CMP‐activated sugar for biochemical applications and a phenyl thioglycoside for chemical synthesis applications. This first total biosynthesis provides an essential source of Leg5,7Ac₂ enabling study of its role in prokaryotic and eukaryotic glycobiology.     

6-Deoxyerythronolide B synthase thioesterase-catalyzed macrocyclization is highly stereoselective

Macrocyclic polyketide natural products are an indispensable source of therapeutic agents. The final stage of their biosynthesis, macrocyclization, is catalyzed regio- and stereoselectively by a thioesterase. A panel of substrates were synthesized to test their specificity for macrocyclization by the erythromycin polyketide synthase TE (DEBS TE) in vitro. It was shown that DEBS TE is highly stereospecific, successfully macrocyclizing a 14-member ring substrate with an R configured O-nucleophile, and highly regioselective, generating exclusively the 14-member lactone over the 12-member lactone.