Controlling Reactivity and Selectivity in the Mizoroki-Heck Reaction: High Throughput Evaluation of 1,5-Diaza-3,7-diphosphacyclooctane Ligands.

We report a high throughput evaluation of the Mizoroki-Heck reaction of diverse olefin coupling partners. Comparison of different ligands revealed the 1,5-diaza-3,7-diphosphacyclooctane (P2N2) scaffold to be more broadly applicable than common "gold standard" ligands, demonstrating that this family of readily accessible diphosphines has unrecognized potential in organic synthesis. In particular, two structurally related P2N2 ligands were identified to enable the regiodivergent arylation of styrenes. By simply altering the phosphorus substituent from a phenyl to tert-butyl group, both the linear and branched Mizoroki-Heck products can be obtained in high regioisomeric ratios. Experimental and computational mechanistic studies were performed to further probe the origin of selectivity, which suggests that both ligands coordinate to the metal in a similar manner but that rigid positioning of the phosphorus substituent forces contact with the incoming olefin in a π-π interaction (for P-Ph ligands) or with steric clash (for P-tBu ligands), dictating the regiocontrol.

Photocatalytic, site-selective oxidations of carbohydrates.

Site-selective oxidations of carbohydrates, employing acridinium photocatalysis and quinuclidine hydrogen atom transfer catalysis, are presented. Protocols have been developed for oxidations of all-equatorial carbohydrates as well as those containing cis-1,2-diols. Site-selectivity reflects the relative rates of hydrogen atom transfer from the carbohydrate C-H bonds, and can be enhanced using a phosphate hydrogen-bonding or boronic acid catalyst.

Recent advances in the direct O-arylation of carbohydrates.

Methods for the O-arylation of hydroxyl and hemiacetal groups in carbohydrates via C(sp2)-O bond formation are discussed. Such methods provide an alternative disconnection to the traditional approach of nucleophilic substitution between a sugar-derived electrophile and a phenol or phenoxide nucleophile. They have led to new opportunities for stereoselectivity, site-selectivity and chemoselectivity in the preparation of O-aryl glycosides and carbohydrate-derived aryl ethers, compounds that are useful for a broad range of applications in medicinal chemistry, glycobiology and organic synthesis.

Site-selective redox isomerizations of furanosides using a combined arylboronic acid/photoredox catalyst system.

In the presence of an arylboronic acid and a hydrogen atom transfer mediator under photoredox conditions, furanoside derivatives undergo site-selective redox isomerizations to 2-keto-3-deoxyfuranosides. Experimental evidence and computational modeling suggest that the transformation takes place by abstraction of the hydrogen atom from the 2-position of the furanoside-derived arylboronic ester, followed by C3-O bond cleavage via spin-center shift. This mechanism is reminiscent of the currently accepted pathway for the formation of 3'-ketodeoxynucleotides by ribonucleotide reductase enzymes.

Copper-mediated anomeric O-arylation with organoboron reagents.

Copper-mediated couplings of arylboroxines with glycosyl hemiacetals furnish O-aryl glycosides via Csp2-O bond formation. The method enables the anomeric O-arylation of protected pyranose and furanose derivatives, and is tolerant of functionalized arylboroxine partners. Whereas mixtures of anomers are formed from glucopyranose, galactopyranose and arabinofuranose hemiacetals, the α-anomer is generated selectively from mannopyranose and mannofuranose-derived substrates.

Site-Selective and Stereoselective C-H Alkylations of Carbohydrates via Combined Diarylborinic Acid and Photoredox Catalysis.

Diphenylborinic acid serves as a cocatalyst for site- and stereoselective C-H alkylation reactions of carbohydrates under photoredox conditions using quinuclidine as the hydrogen atom transfer mediator. Products arising from selective abstraction of the equatorial hydrogens of cis-1,2-diol moieties, followed by C-C bond formation with net retention of configuration, are obtained. Computational modeling supports a mechanism involving formation of a tetracoordinate borinic ester, which accelerates hydrogen atom transfer with the quinuclidine-derived radical cation through polarity-matching and/or ion-pairing effects.

Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives.

Methods for site-selective transformations of hydroxyl groups in carbohydrate derivatives are reviewed. The construction of oligosaccharides of defined connectivity hinges on such transformations, which are also needed for the preparation of modified or non-natural sugar derivatives, the installation of naturally occurring postglycosylation modifications, the selective labeling or conjugation of carbohydrate derivatives, and the preparation of therapeutic agents or research tools for glycobiology. The review begins with a discussion of intrinsic factors and processes that can influence selectivity in reactions of unprotected or partially protected carbohydrate derivatives, followed by a description of transformations that engage two OH groups in cyclic adducts (acetals, ketals, boronic esters, and related species). An overview of the various classes of site-selective transformations of OH groups in sugars is then provided: the reactions discussed include esterification, thiocarbonylation, alkylation, glycosylation, arylation, silylation, phosphorylation, sulfonylation, sulfation, and oxidation. Emphasis is placed on recently developed methods that employ reagent or catalyst control to achieve otherwise challenging transformations or site-selectivities.

Site-Selective, Copper-Mediated O-Arylation of Carbohydrate Derivatives.

Site-selective functionalization of hydroxy groups in sugar derivatives is a major challenge in carbohydrate synthesis. Methods for achieving this goal will provide efficient access to new sugar-derived chemical building blocks and will facilitate the preparation or late-stage modification of complex oligosaccharides for applications in glycobiology research and drug discovery. Here, we describe site-selective, copper-promoted couplings of boronic acids with carbohydrate derivatives. These reactions generate sugar-derived aryl ethers, a structural class that is challenging to generate by other means and has not previously been accessed in a site-selective fashion. Experimental evidence and computational modeling suggest that the formation of a sugar-derived boronic ester intermediate is crucial to the selectivity of these processes, accelerating the arylation of an adjacent hydroxy group. The results demonstrate how the interactions of sugars with boron compounds can be combined with transition metal catalysis to achieve new chemical reactivity.

Boronic acid/Brønsted acid co-catalyst systems for the synthesis of 2H-chromenes from phenols and α,ß-unsaturated carbonyls.

Protocols for the synthesis of substituted 2H-chromenes from α,ß-unsaturated carbonyls and phenols are described. Optimal combinations of arylboronic acids and Brønsted acids have been identified, such that both can be employed in catalytic quantities to accelerate these condensations. The method has been used to synthesize a variety of substituted 2H-chromenes, as well as photochromic naphthopyrans. The use of pentafluorophenylboronic acid and diphenylphosphinic acid enabled an expansion of the electrophile scope to include α,ß-unsaturated ketones. Hall's 'phase-switching' of boronic acids has been exploited to achieve the separation of the two co-catalysts from unpurified reaction mixtures by a simple liquid-liquid extraction.