Synthesis of 2-azido-2-deoxy- and 2-acetamido-2-deoxy-D-manno derivatives as versatile building blocks

Reported herein is the synthesis of a number of building blocks of 2-amino-2-deoxy-d-mannose from common d-glucose precursors.Bio-organic Synthesi

Halogen atom participation in guiding the stereochemical outcomes of acetal substitution reactions

Bio-organic Synthesi

Teichoic Acids: Synthesis and Applications

Bio-organic Synthesi

Synthesis of the Staphylococcus aureus Strain M Capsular Polysaccharide Repeating Unit

Bio-organic Synthesi

Regioselectivity of Epoxide Ring-Openings via S(N)2 Reactions Under Basic and Acidic Conditions

We have quantum chemically analyzed the ring-opening reaction of the model non-symmetrical epoxide 2,2-dimethyloxirane under basic and acidic conditions using density functional theory at OLYP/TZ2P. For the first time, our combined activation strain and Kohn-Sham molecular orbital analysis approach have revealed the interplay of physical factors that control the regioselectivity of these chemical reactions. Ring-opening under basic conditions occurs in a regime of strong interaction between the nucleophile (OH-) and the epoxide and the interaction is governed by the steric (Pauli) repulsion. The latter steers the attack preferentially towards the sterically less encumbered C-beta. Under acidic conditions, the interaction between the nucleophile (H2O) and the epoxide is weak and, now, the regioselectivity is governed by the activation strain. Protonation of the epoxide induces elongation of the weaker (CH3)(2)C-alpha-O bond, and effectively predistorts the substrate for the attack at the sterically more hindered side, which goes with a less destabilizing overall strain energy. Our quantitative analysis significantly builds on the widely accepted rationales behind the regioselectivity of these ring-opening reactions and provide a concrete framework for understanding these indispensable textbook reactions.Bio-organic Synthesi

How Lewis acids catalyze ring-openings of cyclohexene oxide

We have quantum chemically studied the Lewis acid-catalyzed epoxide ring-opening reaction of cyclohexene epoxide by MeZH (Z = O, S, and NH) using relativistic dispersion-corrected density functional theory. We found that the reaction barrier of the Lewis acid-catalyzed epoxide ring-opening reactions decreases upon ascending in group 1 along the series Cs+ > Rb+ > K+ > Na+ > Li+ > H+. Our activation strain and Kohn-Sham molecular orbital analyses reveal that the enhanced reactivity of the Lewis acid-catalyzed ring-opening reaction is caused by the reduced steric (Pauli) repulsion between the filled orbitals of the epoxide and the nucleophile, as the Lewis acid polarizes the filled orbitals of the epoxide more efficiently away from the incoming nucleophile. Furthermore, we established that the regioselectivity of these ring-opening reactions is, aside from the "classical" strain control, also dictated by a hitherto unknown mechanism, namely, the steric (Pauli) repulsion between the nucleophile and the substrate, which could be traced back to the asymmetric orbital density on the epoxide. In all, this work again demonstrates that the concept of Pauli-lowering catalysis is a general phenomenon.Bio-organic Synthesi

Mimetics of ADP-ribosylated histidine through copper(I)-catalyzed click chemistry

A convergent synthesis provided nearly perfect tau-ADP-ribosylated histidine isosteres (His*-tau-ADPr) via a copper(I)-catalyzed cycloaddition between an azido-ADP-ribosyl analogue and an oligopeptide carrying a propargyl glycine. Both alpha- and beta-configured azido-ADP-ribosyl analogues have been synthesized. The former required participation of the C-2 ester functionality during glycosylation, while the latter was obtained in high stereoselectivity from an imidate donor with a nonparticipating para-methoxy benzyl ether. Four His*-tau-ADPr peptides were screened against a library of human ADP-ribosyl hydrolases.Bio-organic Synthesi

Doxorubicin and aclarubicin: shuffling anthracycline glycans for improved anticancer agents

Anthracycline anticancer drugs doxorubicin and aclarubicin have been used in the clinic for several decades to treat various cancers. Although closely related structures, their molecular mode of action diverges, which is reflected in their biological activity profile. For a better understanding of the structure-function relationship of these drugs, we synthesized ten doxorubicin/aclarubicin hybrids varying in three distinct features: aglycon, glycan, and amine substitution pattern. We continued to evaluate their capacity to induce DNA breaks, histone eviction, and relocated topoisomerase II alpha in living cells. Furthermore, we assessed their cytotoxicity in various human tumor cell lines. Our findings underscore that histone eviction alone, rather than DNA breaks, contributes strongly to the overall cytotoxicity of anthracyclines, and structures containing N,N-dimethylamine at the reducing sugar prove that are more cytotoxic than their nonmethylated counterparts. This structural information will support further development of novel anthracycline variants with improved anticancer activity.Bio-organic Synthesi