Highly stereoselective hydrocyanation of optically pure α-sulfinylaldehydes

Diastereoselective hydrocyanation of enantiomerically pure 2-p-tolylsulfinylacetaldehyde and 2-p-tolylsulfinylpropanal with Et₂AlCN catalyzed by ZnBr₂ is described. The sulfur configuration controls the stereochemical course of the reaction. Hydrolysis of the resulting cyanohydrins and further desulfurization yielded the corresponding α-hydroxyamides in high ees (90%).     

An efficient synthesis of 1-cyano-2,3-unsaturated sugars via the reaction of glycals with Et2AlCN

The reaction of glycals 1a-d with Et₂AlCN in benzene at room temperature leads to formation of the corresponding 1-cyano-2,3-unsaturated sugars 2a-d and 3a-d in good to excellent yields.     

Remote stereocontrol by sulfinyl groups: hydrocyanation of δ-ketosulfoxides

Reactions of (2-p-tolylsulfinyl)benzyl alkyl (and aryl) ketones (δ-ketosulfoxides) with Et₂AlCN in the presence of Yb(OTf)₃ take place in a completely stereoselective manner, demonstrating the efficiency of the sulfinyl group in the control of the stereoselectivity of 1,5-asymmetric hydrocyanation processes as well as the ability of Yb(OTf)₃ to form chelated species with ketosulfoxides. The behavior of their methyl derivatives at the benzylic position is dependent on the configuration at the chiral carbon. The resulting sulfinyl cyanohydrins were readily transformed into α-hydroxyamides by hydrolysis of the CN group and hydrogenolysis of the C-S bond.     

Asymmetric alkyne addition to aldehydes catalyzed by Schiff bases made from 1,1′-bi-2-naphthol and chiral benzylic amines

Several 1,1′-bi-2-naphthol (BINOL)-based Schiff bases were prepared from the condensation of (R)-3,3′-diformyl BINOL with chiral benzylic amine derivatives. These compounds were used to catalyze the reaction of phenylacetylene with aldehydes in the presence of ZnEt₂ with up to 85% ee and 83% yield.     

Synthesis of new bis-BINOL-2,2′-ethers and bis-H8BINOL-2,2′-ethers evaluation of their Titanium complexes in the asymmetric ethylation of benzaldehyde

The preparation by means of different synthetic paths of a series of bis-BINOL and bis-H₈BINOL ligands is described. The ligands consist of two BINOL or H₈BINOL fragments, joined by diverse linkages through the oxygen at the 2′-position of the arylic fragments. These ligands were applied to the Ti(OⁱPr)₄ catalyzed asymmetric alkylation of benzaldehyde with Et₂Zn. The performance of these catalysts is very sensitive to the nature of the ether linkage. The ligand with a propylene link shows better enantioselectivity (ca. 70%) than those with two or four carbon atoms joining the BINOL fragments. Furthermore, using the propylene link, but replacing (R)-BINOL by (R)-H₈BINOL, a significant improvement in the stereoselectivity of the catalysts was achieved (ca. 80% ee in (R)-1-phenylpropan-1-ol). A cooperative effect was observed between the chirality at the BINOL fragment and that of a (S,S)-4,5-bis(methylene)-2,2-dimethyl-1,3-dioxolane link, derived from tartaric acid. When this chiral link combines with two (S)-BINOL fragments, the alkylation of benzaldehyde in toluene produces 70% ee of (S)-1-phenylpropan-1-ol, while the (R)-BINOL derivative ligand with the same link, in identical conditions, yields only 40% ee of the (R)-alcohol.     

Synthesis and catalytic applications of soluble polymer-supported BINOL

The synthesis of a soluble polymer containing BINOL residues is described. Titanium-BINOLate and AlLibis(binaphthoxide) catalysts are easily generated from this polymer and applied to the asymmetric reaction of Et₂Zn with benzaldehyde and the asymmetric Michael addition, respectively. The products are obtained in good yields with high enantioselectivities.     

γ-Amino vinyl sulfoxides in asymmetric synthesis. Synthesis of optically pure α-substituted β-amino nitriles

The synthesis of optically pure (E)- and (Z)-γ-amino vinyl sulfoxides derived from commercially available protected α-amino esters is reported. Hydrocyanation of the double bond with Et₂AlCN is completely stereoselective and provides enantiomerically pure α-substituted β-amino nitriles with complete control of the configuration at the α-carbon being exerted by the sulfinyl group.     

Stereoselective Synthesis of cis,cis‐Configured Perhydroquinoxaline‐5‐Carbonitrile from Cyclohex‐2‐en‐1‐ol

cis,cis‐Configured perhydroquinoxaline‐5‐carbonitrile 10 was synthesized stereoselectively by ditosylation of trans,cis‐2,3‐dihydroxycyclohexane‐1‐carbonitrile 4 and subsequent reaction with ethylenediamine. The diol precursor 4 was stereoselectively obtained by regioselective opening of the epoxide 3 with KCN in water avoiding hazardous Et₂AlCN.     

Search for ideal sulfinyl dienophile and dipolarophile

By analysis, the advantages and drawbacks of the differently substituted vinyl sulfoxides so far reported, (Z)‐3‐p‐tolylsulfinyl acrylonitriles are proposed as the best sulfinyl dienophiles. The stereoselective synthesis of these compounds was optimized by hydrocyanation of sulfinyl alkynes with Et₂AlCN. Their behavior as chiral dienophiles and dipolarophiles is responsible for the high stereocontrol of Diels–Alder and 1,3‐dipolar reactions, respectively. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:453–462, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10066     

The synthesis of dendritic BINOL ligands and their applications in the enantioselective Lewis acid catalyzed addition of diethylzinc to aldehydes

Novel dendritic chiral BINOL ligands have been synthesized through coupling of MOM-protected 3,3′-dihydroxymethyl-binaphthol with Fréchet-type polyether benzyl bromide dendrons followed by deprotection of the MOM groups using TsOH. These dendritic chiral BINOL ligands were found to be effective in the enantioselective addition of diethylzinc to benzaldehyde both in the presence and absence of Ti(O-iso-Pr)₄. The enantioselectivity decreased with increasing generation in both cases. In the latter case, the dendritic chiral BINOL ligands showed much higher catalytic activity and enantioselectivity than BINOL.     

Enantioselective addition of Et2Zn to seven‐membered cyclic imines catalyzed by a (R)-VAPOL-Zn(II) complex

Various substituted dibenzo[b,f][1,4]oxazepines underwent an enantioselective alkylation with Et₂Zn catalyzed by a (R)-VAPOL-Zn(II) complex. The corresponding chiral 11-ethyl-10,11-dihydrodibenzo[b,f][1,4]oxazepine derivatives were obtained with good yields and moderate enantioselectivities. This represents the first example of enantioselective addition of Et₂Zn to cyclic aldimines.     

A Chiral Emissive Conjugated Corral for High-Affinity and Highly Enantioselective Recognition in Water

Accurately distinguishing between enantiomeric molecules is a fundamental challenge in the field of chemistry. However, there is still significant room for improvement in both the enantiomeric selectivity (K_R(S)/K_S(R)) and binding strength of most reported macrocyclic chiral receptors to meet the demands of practical application scenarios. Herein, we synthesized a water-soluble conjugated tubular host—namely, corral[4]BINOL—using a chiral 1,1′-bi-2-naphthol (BINOL) derivative as the repeating unit. The conjugated chiral backbone endows corral[4]BINOL with good fluorescent emission (QY=34 % ) and circularly polarized luminescence (|g_lum| up to 1.4×10⁻³) in water. Notably, corral[4]BINOL exhibits high recognition affinity up to 8.6×10¹⁰ M⁻¹ towards achiral guests in water, and manifested excellent enantioselectivity up to 18.7 towards chiral substrates, both of which represent the highest values observed among chiral macrocycles in aqueous solution. The ultrastrong binding strength, outstanding enantioselectivity, and facile accessibility, together with the superior fluorescent and chiroptical properties, endow corral[4]BINOL with great potential for a wide range of applications.     

Micelle-derived polymer supports for enantioselective catalysts

The BINOL moieties are successfully immobilized on the surface of a micelle-derived polymer. Ti-BINOLate complexes prepared from the polymer with Ti(O-i-Pr)₄ exhibited high catalytic activity for the asymmetric alkylation of benzaldehyde with Et₂Zn to afford the adduct in up to 96% yield with 84% ee.     

Enantioselective conjugate addition of dialkylzinc to cyclic enones catalyzed by chiral binaphthyldiamine-copper(I) complexes

The enantioselective conjugate addition of dialkylzinc (R₂Zn) to cyclic enones was examined using chiral binaphthyldiamine-copper(I) catalysts. Under the present reaction conditions, chiral C₂-symmetric [RZn(II)]₂-diamine-Cu(I) complexes were formed from chiral binaphthyldiamine, R₂Zn, and copper(I or II) chloride in situ. The reaction of 2-cyclohexenone with Et₂Zn proceeded smoothly in the presence of the corresponding chiral copper(I) complex (5 mol %) and achiral 2,6-diphenylaniline (10 mol %), and the desired Et-adduct was obtained with up to 76% ee in 95% yield.     

[2+2] Carbonylative cycloaddition catalyzed by palladium: stereoselective synthesis of β-lactams

[2+2] Carbonylative cycloaddition of chiral imines to various allyl halides, under CO pressure, in the presence of Et₃N, a catalytic amount of Pd(OAc)₂ and PPh₃ as ligand, are carried out. Separable diastereomeric mixtures of chiral alkenyl-β-lactams are isolated with good yields and high trans diastereoselections. Absolute configurations are assigned by X-ray measurements and ¹H NMR spectroscopy.     

Synthesis of Enantioenriched Indolines by a Conjugate Addition/Asymmetric Protonation/Aza‐Prins Cascade Reaction

A conjugate addition/asymmetric protonation/aza‐Prins cascade reaction has been developed for the enantioselective synthesis of fused polycyclic indolines. A catalyst system generated from ZrCl₄ and 3,3′‐dibromo‐BINOL enables the synthesis of a range of polycyclic indolines in good yields and with high enantioselectivity. A key finding is the use of TMSCl and 2,6‐dibromophenol as a stoichiometric source of HCl to facilitate catalyst turnover. This transformation is the first in which a ZrCl₄?BINOL complex serves as a chiral Lewis‐acid‐assisted Brønsted acid.     

Development of new methods toward efficient immobilization of chiral catalysts

BINOL moieties are efficiently immobilized onto the surface of a micelle-derived spherical polymer and a monolayer-protected Au cluster (Au-MPC). Ti-BINOLate complexes generated from the BINOL immobilized polymer and Au-MPC are found to promote catalytic asymmetric alkylation of benzaldehyde with Et₂Zn to afford the adduct in up to 84% ee and 86% ee, respectively. Au-MPC-supported multicomponent asymmetric catalyst was prepared and used in the Michael reaction of 2-cyclohexen-1-one with dibenzyl malonate affording the adduct in up to 67% yield and 98% ee.     

Total synthesis of resolvin E2

Resolvin E2 (2) was synthesized stereoselectively using the C1-8 and C15-20 aldehydes 6 and 9, which were connected to the C9-14 fragment by using Wittig reactions. The aldehyde 6 was prepared from the γ-silyl alcohol (S)-20 by a sequence of reactions involving ozonolysis, oxidation with NaIO₄, and the Wittig reaction of the resulting aldehyde with Ph₃PCHCHO, whereas the aldehyde 9 was synthesized from the corresponding γ-silyl alcohol through epoxidation, reaction with Et₂AlCN, and reduction with DIBAL-H.     

Temperature-induced inversion of elution order in the chromatographic enantioseparation of 1,1′-bi-2-naphthol on an immobilized polysaccharide-based chiral stationary phase

In this work, the enantioseparations of 1,1′-bi-2-naphthol (BINOL) and its three derivatives were performed on an immobilized polysaccharide-based chiral stationary phase, Chiralpak IA, under normal-phase mode. The effects of the content of polar modifier in the mobile phase and the column temperature on the retention and enantioseparation were investigated in detail. Temperature-induced inversion of elution order for BINOL was observed directly when n-hexane/2-propanol (92/8, v/v) was used as mobile phase. The isoenantioselective temperature (T_iso) was calculated to be 31.4 °C. When n-hexane/2-propanol/THF (93/2/5, v/v/v) was used as mobile phase, the T_iso value decreased to −8.2 °C. Entropically driven enantioseparation which had practical application was obtained successfully (separation factor being 1.189 and 1.332 at 25 °C and 50 °C, respectively). The corresponding thermodynamic parameters for other three binaphthyl compounds were compared with that for BINOL. Some inferences about chiral recognition mechanism were stressed.     

Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes

Cyclic products can be obtained through the intramolecular version of the Nicholas reaction, which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis of 1-oxa-3-cyclooctynes starting from commercially available (1R,3S)-camphoric acid. The strategy is based on the initial preparation of propargylic alcohols, complexation of the triple bond with Co₂(CO)₈, and treatment with BF₃·Et₂O to induce an intramolecular Nicholas reaction with the free hydroxyl group as nucleophile. Finally, oxidative deprotection of the alkyne afforded the cyclooctynes in good yields. Notably, large-sized R substituents at the chiral center connected to the O atom were oriented in such a way that steric interactions were minimized in the cyclization, allowing the formation of cyclooctynes exclusively with (R) configuration, in good agreement with theoretical predictions. Moreover, preliminary studies demonstrated that these cyclooctynes were reactive in the presence of azides yielding substituted triazoles.