We report a simple, efficient, and general method for the indium-mediated enantioselective propargylation of aromatic and aliphatic aldehydes under Barbier-type conditions in a one-pot synthesis affording the corresponding chiral alcohol products in very good yield (up to 90%) and enantiomeric excess (up to 95%). The extension of this methodology to ketones demonstrated the need for electrophilic ketones more reactive than acetophenone as the reaction would not proceed with just acetophenone. Using the Lewis acid indium triflate [In(OTf)3] induced regioselective formation of the corresponding homoallenic alcohol product from acetophenone. However, this methodology demonstrated excellent chemoselectivity in formation of only the corresponding secondary homopropargylic alcohol product in the presence of a ketone functionality. Investigation of the organoindium intermediates under our reaction conditions shows the formation of allenylindium species, and we suggest that these species contain an indium(III) center. In addition, we have observed the presence of a shiny, indium(0) nugget throughout the reaction, irrespective of the stoichiometry, indicating disproportionation of indium halide byproduct formed during the reaction.

We report the first one-pot process for the asymmetric addition of allyl, methallyl, and propargyl groups to aldehydes and ketones using B-chlorodiisopinocampheylborane (dDIP-Cl) and indium metal. Under Barbier-type conditions, indium metal was used to generate allyl- and allenylindium intermediates, and subsequent reaction with dDIP-Cl successfully promoted the transfer of these groups to boron forming the corresponding chiral borane reagents. The newly formed borane reagents were reacted with aldehydes and ketones to produce the corresponding alcohol products in high yields and up to excellent enantioselectivity (98% ee). This method produced excellent enantioenriched secondary homoallylic alcohols from the allylation and methallylation of benzaldehyde. Using this method, the methallylation and cinnamylation of ketones afforded the highest enantioselectivities, while the propargylation of both aldehydes and ketones provided low enantiomeric excesses. In addition, this procedure provided the first synthesis of B-allenyldiisopinocampheylborane, which was characterized by 1H and 11B NMR spectroscopy. This is the first example of the direct synthesis of allylboranes that contained substitutions from the corresponding allyl bromide and indium, thereby expanding the utility of the DIP-Cl reagent. Hence, a general and straightforward route to these chiral organoborane reagents in one-pot has been developed along with the asymmetric Barbier-type allylation and propargylation of aldehyde and ketone substrates using these chiral organoborane reagents in subsequent coupling reactions.

Grignard reagents (aliphatic, aromatic, heteroaromatic, vinyl, or allylic) react with 1 equiv of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (pinacolborane, PinBH) at ambient temperature in tetrahydrofuran (THF) to afford the corresponding pinacolboronates. The initially formed dialkoxy alkylborohydride intermediate quickly eliminates hydridomagnesium bromide (HMgBr) and affords the product boronic ester in very good yield. Hydridomagnesium bromide (HMgBr) in turn disproportionates to a 1:1 mixture of magnesium hydride (MgH2) and magnesium bromide (MgBr2) on addition of pentane to the reaction mixture. DFT calculations (Gaussian09) at the B3LYP/6-31G(d) level of theory show that disproportionation of HMgBr to MgH2 and MgBr2 is viable in the coordinating ethereal solvents. This reaction also can be carried out under Barbier conditions, where the neat PinBH is added to the flask prior to the in situ formation of Grignard reagent from the corresponding organic halide and magnesium metal. Pinacolboronic ester synthesis under Barbier conditions does not give Wurtz coupling side products from reactive halides, such as benzylic and allylic halides. The reaction between PinBH and various Grignard reagents is an efficient, mild, and general method for the synthesis of pinacolboronates.

A facile and mild reduction procedure is reported for the preparation of chiral secondary alcohols prepared from α-substituted ketones using sodium borohydride and the chiral boronate ester (l)-TarB-NO2. Direct reduction of substituted ketones bearing Lewis basic heteroatoms generally provided secondary alcohols of only modest enantiomeric excess likely due to either competition between the target carbonyl and the functionalized sidechains at the Lewis acidic boron atom in TarB-NO2 or the added steric bulk of the α-sidechain. As an alternative method, these substrates were synthesized using TarB-NO2 via a two-step procedure involving the reduction of an α-halo ketone to a chiral terminal epoxide, followed by regioselective/regiospecific epoxide opening by various nucleophiles. This procedure provides access to a variety of functionalized secondary alcohols including β-hydroxy ethers, thioethers, nitriles, and amines with enantiomeric excesses of 94% and yields up to 98%.

We report a simple, efficient, and general method for the indium-mediated enantioselective allylation of aromatic and aliphatic aldehydes and ketones under Barbier-type conditions in a one-pot synthesis affording the corresponding chiral alcohol products in very good yield (up to 99%) and enantiomeric excess (up to 93%). Our method is able to tolerate various functional groups, such as esters, nitriles, and phenols. Additionally, more substituted allyl bromides, such as crotyl and cinnamyl bromide, can be used providing moderate enantioselectivity (72% and 56%, respectively) and excellent diastereoselectivity when employing cinnamyl bromide (>95/5 anti/syn). However, the distereoselectivity when using crotyl bromide was poor and other functionalized allyl bromides under our method afforded low enantioselectivities for the alcohol products. In these types of indium-mediated additions, solvent plays a major role in determining the nature of the organoindium intermediate and we observed the susceptibility of some allylindium intermediates to hydrolysis in protic solvents. Under our reaction conditions using a polar aprotic solvent, we suggest that an allylindium(III) species is the active allylating intermediate. In addition, we have observed the presence of a shiny, indium(0) nugget throughout the reaction, irrespective of the stoichiometry, indicating disproportionation of indium halide byproduct formed during the reaction.

A facile and mild reduction procedure is reported for the preparation of chiral allylic and propargyl alcohols in high enantiomeric purity. Under optimized conditions, alkynyl and alkenyl ketones were reduced by TarB-NO2 and NaBH4 at 25 °C in 1 h to produce chiral propargyl and allylic alcohols with enantiomeric excesses and yields up to 99%. In the case of α,β-unsaturated alkenyl ketones, α-substituted cycloalkenones were reduced with up to 99% ee, while more substituted and acyclic derivatives exhibited lower induction. For α,β-ynones, it was found that highly branched aliphatic ynones were reduced with optimal induction up to 90% ee, while reduction of aromatic and linear aliphatic derivatives resulted in more modest enantioselectivity. Using the (l)-TarB-NO2 reagent derived from (l)-tartaric acid, we routinely obtained highly enantioenriched chiral allylic and propargyl alcohols with (R) configuration. Since previous models and a reduction of a saturated analogue predicted propargyl products of (S) configuration, a series of new mechanistic studies were conducted to determine the likely orientation of aromatic, alkenyl, and alkynyl ketones in the transition state.

Asymmetric 1,2-reduction of α,β-unsaturated ketones using TarB-NO2 and NaBH4 is reported. Simple cycloalkenones give products in low enantiomeric excess. However, cycloalkenones with α-substituents, such as halides, alkyl, and aryl, have been enantioselectively reduced with this system to yield chiral allylic alcohols in enantiomeric excess up to 99%. The starting materials for TarB-NO2 are inexpensive, and the boronic acid can be easily recovered in high yield by a simple acid extraction.

In-vitro fluorescent enzyme assays have been developed for sucrose phosphorylase (SPO) and phosphoglucomutase (PGM). These assays make use of a selective carbohydrate sensing system that detects the unlabeled enzymatic products fructose and glucose-6-phosphate. The system comprises 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt as the reporter unit and boronic acid appended viologens as selective receptors with working ranges from 70 μM to 1.0 mM for fructose (SPO) and 190 μM to 2.0 mM for glucose-6-phosphate (PGM). The change in fluorescence can be converted into product concentration, allowing initial reaction velocities and Michaelis–Menten kinetics to be calculated. The assays are also carried out in multiwell plate formats, making them suitable for high-throughput screening of enzyme inhibitors. Rapid PGM inhibition screening is demonstrated with EDTA and LiCl. The PGM assay can also be used for enzyme quantification with a detection limit of 50 ng mL−1.

The anionic fluorescent dye, aminopyrene trisulfonic acid (APTS), was synthesized and used in a solution-based two-component glucose-sensing system comprising the dye and a boronic acid-appended viologen. The fluorescence of the dye was quenched in the presence of the viologen and the fluorescence restored upon glucose addition. An important feature of this fluorophore is that it can be covalently bonded to a polymer through the amine group without a significant effect on optical properties. Two APTS derivatives, functionalized with polymerizable groups, were synthesized and immobilized in hydroxyethyl methacrylate (HEMA)-based hydrogels. The latter were used to continuously monitor glucose. The fluorescence signal modulation, signal stability, reversibility, reproducibility, and pH sensitivity of the hydrogels were evaluated. The APTS dyes described herein are insensitive to pH changes within the physiological range, both in solution and when immobilized in a hydrogel. When APTS is used in conjunction with boronic acid-appended viologens to sense glucose, the system displays some pH sensitivity because of the presence of the boronic acid.

The solution-phase sensor array of three cationic bis-boronic acid appended benzyl viologens (BBV) and the anionic fluorescent dye, 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS), is able to discriminate among five phospho sugars, four nucleotides and three neutral saccharides in aqueous buffered solution at low mM concentrations. Linear discriminant analysis, principal component analysis, and hierachical cluster analysis studies showed the “discrimination limit” (lowest analyte concentration where the discrimination is still 100%) to be 4 mM. Calculated Kb and Fmax/F0 values from binding curves of the three BBVs with 1–12 were also used to perform multi-variate analyses with very good discrimination results.

Catalytic asymmetric transfer hydrogenations of aromatic alkyl ketones have been studied using [RuCl2(p-cymeme)]2 and terpene-based β-amino alcohols. The limonene derived amino alcohol, (1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(methylamino)cyclohexanol gave the most promising results. Chiral secondary alcohols were obtained in good to excellent yields and moderate enantioselectivities (up to 71%).{(S)-1-[(1S,2S,5R)-2-Hydroxy-2-methyl-5-(1-methylethenyl)cyclohexylcarbamoyl]-2-methylpropyl}-carbamic acid tert-butyl esterC20H36N2O4[α]D25=+18.1 (c 2.0, methanol)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,1′S,2′S,5′R)1-tert-Butyl-3-[(1S,2S,5R)-2-hydroxy-2-methyl-5-(1-methylethenyl)cyclohexyl]ureaC15H28N2O2[α]D25=+22.4 (c 2.0, methanol)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,5R)1-[(1S,2S,5R)-2-Hydroxy-2-methyl-5-(1-methylethenyl)cyclohexyl]-3-phenylureaC17H24N2O2[α]D25=+9.7 (c 2.0, methanol)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,5R)[(1S,2S,5R)-2-Hydroxy-2-methyl-5-(1-methylethenyl)cyclohexyl]carbamic acid isobutyl esterC15H27NO3[α]D25=+13.5 (c 1.0, methanol)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,5R)

A very general system is described in which anionic fluorescent dyes possessing a wide range of absorbance and emission wavelengths are used in combination with a boronic acid-modified viologen quencher to sense glucose at pH 7.4 in buffered aqueous solution. The present study demonstrates this capability with the use of eleven anionic fluorescent dyes of various structural types. Signal modulation occurs as the monosaccharide binds to the viologen quencher and alters its efficiency in quenching the fluorescence of the anionic dyes. The degree of quenching and the magnitude of the glucose signal were found to correlate roughly with the number of anionic groups on the dye. Optimal quencher : dye ratios were determined for each dye to provide a fairly linear signal in response to changes in glucose concentration across the physiological range.

Novel homochiral vinyloxazaborolidines have been synthesized and subsequently hydrogenated using palladium on carbon under ambient conditions to produce, after oxidation of the boronate group, enantiomerically enriched secondary alcohols (up to 20% ee). Herein, the first example of asymmetric hydrogenation utilizing oxazaborolidines as chiral auxiliaries is reported.(1S,2R)-2-Methylamino-1,2-diphenylethanolC15H17NOEe = 100%[α]D25=-6.8 (c 4.4, CHCl3)Source of chirality: (1S,2R)-(+)-2-amino-1,2-diphenylethanol(1S,2R,1′R)-2-(1′-Phenylethyl)amino-1,2-diphenylethanolC22H23NOEe = 100%[α]D25=+40 (c 4.0, CHCl3)Source of chirality: (R)-(+)-α-methylbenzylamine

Enantioselective alkynyl zinc additions to aromatic and aliphatic aldehydes have been studied using terpene derived chiral amino alcohol ligands. The limonene derived amino alcohol (1R,2R,5S)-2-methyl-5-(1-methylethenyl)-2-(1-pyrrolidinyl)cyclohexanol gave the most promising results. Chiral propargylic alcohols were obtained in good yields and moderate enantioselectivities (up to 60%).(1S,2S,4R)-2-Amino-1-methyl-4-(1-methylethenyl)cyclohexanol 4-toluenesulfonamideC17H25NO3S[α]D28=+36.4 (c 2.0, methanol)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,4R)(1S,2S,5R)-2-Amino-2-methyl-5-(1-methylethenyl)cyclohexanol 4-toluenesulfonamideC17H25NO3S[α]D25=+11.9 (c 4.0, chloroform)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,5R)(1R,2R,5S)-2-Methyl-5-(1-methylethenyl)-2-(1-pyrrolidino)cyclohexanolC14H25NO[α]D23=-29.8 (c 4.0, methanol)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,5S)

cis- and trans-Diastereomers of (R)-(+)-limonene oxide can be purified by simple kinetic separation of the commercially available (1:1) diastereomeric mixture of limonene oxides. Nucleophilic amines, such as pyrrolidine and piperidine, selectively open the epoxide ring of the trans-isomer, leaving the cis-limonene oxide largely unreacted. The unreacted cis-(R)-limonene oxide is recovered in up to 88% yield. On the other hand, less nucleophilic amines, such as triazole or pyrazole, selectively catalyze hydrolysis of the cis-limonene oxide to 1,2-limonene diol leaving the trans-limonene oxide largely unreacted. The unreacted trans-limonene oxide is recovered in up to 80% of the theoretical yield by a simple workup procedure. The cis- and trans-diastereomers of (R)-(+)-limonene oxide thus isolated were found to be >98% pure by both GC and NMR analyses. Thus, depending on the choice of amine, either cis- or trans-limonene oxide may be obtained in high diastereomeric purity by this simple and environmentally friendly method.Graphic

A series of β-amino alcohols, conveniently prepared from limonene oxide, were evaluated as catalysts for the enantioselective addition of dialkylzinc to benzaldehyde. These limonene-based amino alcohols are of particular interest because they are easily synthesized in both enantiomeric forms. Ethylation of benzaldehyde using diethylzinc and catalyzed by limonene derived amino alcohols proceeded with enantioselection of up to 87% ee. This is an unusually high level of induction for amino alcohols possessing a trans relationship between the amino and alcohol functionalities. Both enantiomers of 1-phenyl-1-propanol can be synthesized with equal control since both enantiomers of the chiral catalyst are readily available. When (1S,2S,4R)-limonene amino alcohols are used as chiral catalysts, (R)-1-phenyl-1-propanol is obtained as the major product. A plausible mechanism is proposed to explain the facial selectivity determining the asymmetric induction observed in these reactions.Graphic(1R,2R,4S)-1-Methyl-4-(1-methylethenyl)-2-[2-(1,2,3,4-tetrahydroisoquinolinyl)]cyclohexanolC19H27NOMp=86–88°C[α]23D=−5.2 (c, 4.0, methanol)Source of chirality: (−)-(4S)-limonene oxideAbsolute configuration: 1R,2R,4S(1S,2S,4R)-1-Methyl-4-(1-methylethenyl)-2-(4-methyl-1-piperazinyl)cyclohexanolC15H28N2OBp 143–147°C (2.6 torr)[α]23D=+27.1 (c, 4.0, methanol)Source of chirality: (+)-(4R)-limonene oxideAbsolute configuration: 1S,2S,4R(1S,2S,4R)-1-Methyl-4-(1-methylethenyl)-2-(4-morpholinyl)cyclohexanolC14H25NO2Mp 43–44°C[α]23D=+37.5 (c, 4.0, methanol)Source of chirality: (+)-(4R)-limonene oxideAbsolute configuration: 1S,2S,4R(1R,2R,4S)-1-Methyl-4-(1-methylethenyl)-2-(4-benzyl-1-piperidinyl)cyclohexanolC22H33NOMp 71–78°C[α]23D=−14.5 (c, 4.0, methanol)Source of chirality: (−)-(4S)-limonene oxideAbsolute configuration: 1R,2R,4SC15H27NO(1R,2R,4S)-1-Methyl-4-(1-methylethenyl)-2-(1-piperidinyl)cyclohexanolBp 133–135°C (3.5 torr)[α]23D=−13.5 (c, 4.0, methanol)Source of chirality: (−)-(4S)-limonene oxideAbsolute configuration: 1R,2R,4S(1R,2R,4S)-1-Methyl-4-(1-methylethenyl)-2-(1-pyrrolidinyl)cyclohexanolC14H25NOBp 128–131°C (3.0 torr)[α]23D=−34.9 (c, 4.0, methanol)Source of chirality: (−)-(4S)-limonene oxideAbsolute configuration: 1R,2R,4S

The anionic fluorescent dye, aminopyrene trisulfonic acid (APTS), was synthesized and used in a solution-based two-component glucose-sensing system comprising the dye and a boronic acid-appended viologen. The fluorescence of the dye was quenched in the presence of the viologen and the fluorescence restored upon glucose addition. An important feature of this fluorophore is that it can be covalently bonded to a polymer through the amine group without a significant effect on optical properties. Two APTS derivatives, functionalized with polymerizable groups, were synthesized and immobilized in hydroxyethyl methacrylate (HEMA)-based hydrogels. The latter were used to continuously monitor glucose. The fluorescence signal modulation, signal stability, reversibility, reproducibility, and pH sensitivity of the hydrogels were evaluated. The APTS dyes described herein are insensitive to pH changes within the physiological range, both in solution and when immobilized in a hydrogel. When APTS is used in conjunction with boronic acid-appended viologens to sense glucose, the system displays some pH sensitivity because of the presence of the boronic acid.