Bartosz Lewandowski

Sequence-Specific Peptide Synthesis by an Artificial Small-Molecule Machine

Ribosomal Rotaxane? The ribosome is an extraordinarily sophisticated molecular machine, assembling amino acids into proteins based on the precise sequence dictated by messenger RNA. Lewandowski et al. (p. 189) have now taken a step toward the preparation of a stripped-down synthetic ribosome analog. Their machine comprises a rotaxane—a ring threaded on a rod—in which the ring bears a pendant thiol that can pluck amino acids off the rod; the terminal nitrogen then wraps around to form a peptide bond and liberate the thiol for further reaction. The system was able to link three amino acids in order from the preassembled rod. A macrocycle threaded on a rod can catalytically insert several amino acids placed along its path into a peptide chain. The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ~1018 molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.

Sucrose chemistry and applications of sucrochemicals.

Publisher Summary This chapter discusses sucrose chemistry and the applications of sucrochemicals. The use of sucrose as a chemical raw material was first motivated by the desire to increase the small proportion of the total production dedicated to the applications of higher value, essentially for nonfood uses. The conformational structure of sucrose is essentially based on the intramolecular hydrogen-bond network that connects hydroxyl groups from the glucose and the fructose moieties. Some scales of relative acidity of the hydroxyl groups of sucrose, converging on the highest acidity for OH-2, can be established either by semi-empirical calculations or be deduced from the distribution of the regio-isomers after selective substitution. It is found that because of the high stability of the ether function, etherification of unprotected sucrose leads to a kinetic distribution of products directly reflecting the relative reactivity of the hydroxyl groups. Specific microorganisms, yeasts, and bacteria can also convert sucrose into other alcohols, as well as organic acids, amino acids, and vitamins. All these biological processes have been improved with the help of modern biotechnology, making them more chemically and economically efficient and to direct them toward new and useful chemical products.

Amino-acid templated assembly of sucrose-derived macrocycles.

C(2)-Symmetrical chiral macrocycles containing two sucrose units were prepared by an amino acid templated macrocyclization reaction between appropriate sucrose-based linear precursors and ethylenediamine.

Asymmetric catalysis with short-chain peptides.

Within this review article we describe recent developments in asymmetric catalysis with peptides. Numerous peptides have been established in the past two decades that catalyze a wide variety of transformations with high stereoselectivities and yields, as well as broad substrate scope. We highlight here catalytically active peptides, which have addressed challenges that had thus far remained elusive in asymmetric catalysis: enantioselective synthesis of atropoisomers and quaternary stereogenic centers, regioselective transformations of polyfunctional substrates, chemoselective transformations, catalysis in-flow and reactions in aqueous environments.

Synthesis of some halogenated tetraarylborates

The reactions of 3,4-dichlorophenylmagnesium bromide and 3,5-dichlorophenylmagnesium bromide with B(OEt) 3 and NaBF 4 were studied The corresponding tetraarylborates [(3,4-Cl 2 C 6 H 3 ) 4 B]NH 4 and [(3,5-Cl 2 C 6 H 3 ) 4 B]Na were obtained and characterized. The significant influence of the substituents inductive effect on the reaction course was revealed. NaBF 4 was found to be a valuable boron reagent in the synthesis of tetraarylborates containing highly electronegative substituents. The molecular structure of [(3-CF 3 C 6 H 4 ) 4 B]NH 4 obtained from the reaction of 3-trifluoromethylbromobenzene with NaBF 4 and Mg was determined using X-ray analysis.

Shape Persistence of Polyproline II Helical Oligoprolines

Oligoprolines are commonly used as molecular scaffolds. Past studies on the persistence length of their secondary structure, the polyproline II (PPII) helix, and on the fraction of backbone cis amide bonds have provided conflicting results. We resolved this debate by studying a series of spin-labeled proline octadecamers with EPR spectroscopy. Distance distributions between an N-terminal Gd(III) -DOTA (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) label and a nitroxide label at one of five evenly spaced backbone sites allowed us to discriminate between the flexibility of the PPII helix and the cis amide contributions. An upper limit of 2 % cis amide bonds per residue was found in a 7:3 (v/v) water/glycerol mixture, whereas cis amides were not observed in trifluoroethanol. Extrapolation of Monte Carlo models from the glass transition to ambient temperature predicts a persistence length of ≈3-3.5 nm in both solvents. The method is generally applicable to any type of oligomer for which the persistence length is of interest.

Synthetic Molecular Walkers

In biological systems, molecular motors have been developed to harness Brownian motion and perform specific tasks. Among the cytoskeletal motor proteins, kinesins ensure directional transport of cargoes to the periphery of the cell by taking discrete steps along microtubular tracks. In the past decade there has been an increasing interest in the development of molecules that mimic aspects of the dynamics of biological systems and can became a starting point for the creation of artificial transport systems.To date, both DNA-based and small-molecule walkers have been developed, each taking advantage of the different chemistries available to them. DNA strollers exploit orthogonal base pairing and utilize strand-displacement reactions to control the relative association of the component parts. Small-molecule walkers take advantage of the reversibility of weak noncovalent interactions as well as the robustness of dynamic covalent bonds in order to transport molecular fragments along surfaces and molecular tracks using both diffusional processes and ratchet mechanisms. Here we review both types of synthetic systems, including their designs, dynamics, and how they are being used to perform functions by controlled mechanical motion at the molecular level.

Application of 1′,2,3,3′,4,4′-Hexa-O-benzylsucrose in the Preparation of Sucrose Macrocycles via a Click Chemistry Route: Regioselectivity Study

Abstract 1′,2,3,3′,4,4′-Hexa-O-benzyl-sucrose was applied in the preparation of sucrose-based macrocycles via a click chemistry route. This was realized by protection of the 6′‒OH with silyl block followed by elongation of the glucose end with the ‒CH2CH2N3 unit. Removal of the silyl block and subsequent propargylation of the released C6′‒OH afforded the corresponding synthon, cyclization of which under the click condition provided the desired macrocycle with the expected 1,4-pattern of substituents at the triazole ring.

Sucrose Analogs Containing Sulfur Functionalities

Regioselective synthesis of sucrose monosulfides, with sulfur functionality placed either at the C-6 (glucose part) or C-6′ (fructose) ends, is presented. The performed model dimerization of the mercaptane into the disulfide opens a convenient route to the open-chain sucrose dimers.

New Methodology for the Differentiation of the Primary Hydroxyl Groups in 2,3,3′,4,4′-Penta-O-Benzylsucrose: Convenient Approach to Sucrose Monophosphines

Two new routes to derivatives of 2,3,3′,4,4′-penta-O-benzylsucrose with differently protected primary hydroxyl groups were elaborated. One of these compounds, 2,3,3′,4,4′-penta-O-benzyl-6′-O-mesylsucrose, was used in a model synthesis of the 6′-phosphine with sucrose scaffold. Elimination of the mesyloxy- group under the reaction conditions was also noted providing the 5′,6′-unsaturated sucrose derivative.