Enantioselective Synthesis of Cyclic Nitrones and Oxime Ethers by Chemoselective Allylic Alkylation of Oximes

The enantio- and chemoselective iridium-catalyzed <i>N</i>- and<i> O</i>-allylation of oximes is described for the first time. Kinetic resolution in an intramolecular setting provides access to cyclic nitrones, oxime ethers and enantioenriched aliphatic allylic alcohols. Salient features of this transformation are its ability to employ <i>E</i>/<i>Z</i>-isomeric mixtures of oxime starting materials convergently, high functional group tolerance, and divergent <i>N</i>- or <i>O</i>-allylation by choice of the reaction conditions. The implementation of <i>N</i>-allylation/1,3-dipolar cycloaddition reaction cascades furnish tricyclic isoxazolidines in highly enantio- and diastereoselective fashion. Expansion of this approach to the selective allylation of hydrazones allows enantioselective preparation of azomethine imines. The synthetic utility of the approach is demonstrated by the efficient, formal syntheses of glycoprotein GP IIb‐IIIa receptor antagonist (–)-roxifiban and marine natural product (+)-halichlorine.

Enantioselective Synthesis of Cyclic Nitrones and Oxime Ethers by Chemoselective Allylic Alkylation of Oximes

The enantio- and chemoselective iridium-catalyzed <i>N</i>- and<i> O</i>-allylation of oximes is described for the first time. Kinetic resolution in an intramolecular setting provides access to cyclic nitrones, oxime ethers and enantioenriched aliphatic allylic alcohols. Salient features of this transformation are its ability to employ <i>E</i>/<i>Z</i>-isomeric mixtures of oxime starting materials convergently, high functional group tolerance, and divergent <i>N</i>- or <i>O</i>-allylation by choice of the reaction conditions. The implementation of <i>N</i>-allylation/1,3-dipolar cycloaddition reaction cascades furnish tricyclic isoxazolidines in highly enantio- and diastereoselective fashion. Expansion of this approach to the selective allylation of hydrazones allows enantioselective preparation of azomethine imines. The synthetic utility of the approach is demonstrated by the efficient, formal syntheses of glycoprotein GP IIb‐IIIa receptor antagonist (–)-roxifiban and marine natural product (+)-halichlorine.

Enhanced Activity in the Tosylation of Tolanophanes via Supramolecular HgCl2 Recognition

The ‘self-activation’ of host molecules via the incorporation of a guest has received considerable attention in supramolecular catalysis. Here, we demonstrate how HgCl2 effects the tosylation rate of tolanophanes (1a–c: n=2−4) with different alkyl chain lengths. Among these substrates, 1a has the highest strain in sp carbons and, therefore, is active even without assistance of HgCl2. In contrast, 1c is inert and needs to be activated in the presence of HgCl2. Therefore, the averaged reaction rate is in the following order: 1c&gt;1b&gt;1a, confirming the role of the supramolecular cavity of 1 over the strain of alkyne bonds. Ab initio calculations are consistent with the experimentally derived reactivity, supporting our size-fitting hypothesis. In contrast, acyclic analogues showed lower activity in the presence of HgCl2 to confirm the effect of the ring cavity. To gain more information, the HgCl2 complexation of 1b was examined by using 1H NMR and UV-vis spectroscopies. All products 5 are new and well characterized. The hydration of isomeric mixtures of 5b,c gave the corresponding single products 4b,c.

Salt-free fractionation of complex isomeric mixtures of glycosaminoglycan oligosaccharides compatible with ESI-MS and microarray analysis

Heparin and heparan sulfate (Hp/HS) are linear complex glycosaminoglycans which are involved in diverse biological processes. The structural complexity brings difficulties in separation, making the study of structure-function relationships challenging. Here we present a separation method for Hp/HS oligosaccharide fractionation with cross-compatible solvent and conditions, combining size exclusion chromatography (SEC), ion-pair reversed phase chromatography (IPRP), and hydrophilic interaction chromatography (HILIC) as three orthogonal separation methods that do not require desalting or extensive sample handling. With this method, the final eluent is suitable for structure-function relationship studies, including tandem mass spectrometry and microarray printing. Our data indicate that high resolution is achieved on both IPRP and HILIC for Hp/HS isomers. In addition, the fractions co-eluted in IPRP could be further separated by HILIC, with both separation dimensions capable of resolving some isomeric oligosaccharides. We demonstrate this method using both unpurified reaction products from isomeric synthetic hexasaccharides and an octasaccharide fraction from enoxaparin, identifying isomers resolved by this multi-dimensional separation method. We demonstrate both structural analysis by MS, as well as functional analysis by microarray printing and screening using a prototypical Hp/HS binding protein: basic-fibroblast growth factor (FGF2). Collectively, this method provides a strategy for efficient Hp/HS structure-function characterization.

Salt-free fractionation of complex isomeric mixtures of glycosaminoglycan oligosaccharides compatible with ESI-MS and microarray analysis

Heparin and heparan sulfate (Hp/HS) are linear complex glycosaminoglycans which are involved in diverse biological processes. The structural complexity brings difficulties in separation, making the study of structure-function relationships challenging. Here we present a separation method for Hp/HS oligosaccharide fractionation with cross-compatible solvent and conditions, combining size exclusion chromatography (SEC), ion-pair reversed phase chromatography (IPRP), and hydrophilic interaction chromatography (HILIC) as three orthogonal separation methods that do not require desalting or extensive sample handling. With this method, the final eluent is suitable for structure-function relationship studies, including tandem mass spectrometry and microarray printing. Our data indicate that high resolution is achieved on both IPRP and HILIC for Hp/HS isomers. In addition, the fractions co-eluted in IPRP could be further separated by HILIC, with both separation dimensions capable of resolving some isomeric oligosaccharides. We demonstrate this method using both unpurified reaction products from isomeric synthetic hexasaccharides and an octasaccharide fraction from enoxaparin, identifying isomers resolved by this multi-dimensional separation method. We demonstrate both structural analysis by MS, as well as functional analysis by microarray printing and screening using a prototypical Hp/HS binding protein: basic-fibroblast growth factor (FGF2). Collectively, this method provides a strategy for efficient Hp/HS structure-function characterization.