Asymmetric Conjugate Addition of Grignard Reagents to 3‐Silyl Unsaturated Esters for the Facile Preparation of Enantioenriched β‐Silylcarbonyl Compounds and Allylic Silanes

A highly enantioselective conjugate addition of Grignard reagents to 3‐silyl unsaturated esters to deliver synthetically useful chiral β‐silylcarbonyl compounds was developed. The synthetic value of this methodology was further illustrated by the synthesis of enantioenriched β‐hydroxyl esters and the facile access granted to various α‐chiral allylic silanes. A plethora of diastereoselective transformations of β‐silylenolates were also investigated and afforded manifold organosilanes that contained contiguous stereogenic centers with excellent enantioselectivity.     

Heat‐Induced Supramolecular Organogels Composed of α‐Cyclodextrin and “Jellyfish‐Like” β‐Cyclodextrin–Poly(ε‐caprolactone)

In general, the complexation and gelation behavior between biocompatible poly(ε‐caprolactone) (PCL) derivatives and α‐cyclodextrin (α‐CD) is extensively studied in water, but not in organic solvents. In this article, the complexation and gelation behavior between α‐CD and multi‐arm polymer β‐cyclodextrin‐PCL (β‐CD‐PCL) with a unique “jellyfish‐like” structure are thoroughly investigated in organic solvent N,N‐dimethylformamide and a new heat‐induced organogel is obtained. However, PCL linear polymers cannot form organogels under the same condition. The complexation is characterized by rheological measurements, DSC, XRD, and SEM. The SEM images reveal that the complexes between β‐CD‐PCL and α‐CD present a novel topological helix porous structure which is distinctly different from the lamellar structure formed by PCL linear polymers and α‐CD, suggesting the unique “jellyfish‐like” structure of β‐CD‐PCL is crucial for the formation of the organogels. This research may provide insight into constructing new supramolecular organogels and potential for designing new functional biomaterials. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2013 , 51, 1598–1606     

Enantioselective Construction of Silicon‐Stereogenic Silanes by Scandium‐Catalyzed Intermolecular Alkene Hydrosilylation

The catalytic asymmetric construction of silicon‐stereogenic silanes is of great interest and significance, but has met with only limited success to date. We herein report the enantioselective hydrosilylation of alkenes with dihydrosilanes by a chiral half‐sandwich scandium catalyst, which constitutes an efficient and general route for the synthesis of a wide range of enantioenriched silicon‐stereogenic silanes from easily accessible starting materials. This reaction features a broad substrate scope, high yields, and high enantioselectivity. Some of the chiral tertiary silane products were also converted into valuable derivatives, such as chiral silanol, quaternary silane, and benzosilole compounds.     

Self‐Assembly of α‐Helical Polypeptides Driven by Complex Coacervation

Reported is the ability of α‐helical polypeptides to self‐assemble with oppositely‐charged polypeptides to form liquid complexes while maintaining their α‐helical secondary structure. Coupling the α‐helical polypeptide to a neutral, hydrophilic polymer and subsequent complexation enables the formation of nanoscale coacervate‐core micelles. While previous reports on polypeptide complexation demonstrated a critical dependence of the nature of the complex (liquid versus solid) on chirality, the α‐helical structure of the positively charged polypeptide prevents the formation of β‐sheets, which would otherwise drive the assembly into a solid state, thereby, enabling coacervate formation between two chiral components. The higher charge density of the assembly, a result of the folding of the α‐helical polypeptide, provides enhanced resistance to salts known to inhibit polypeptide complexation. The unique combination of properties of these materials can enhance the known potential of fluid polypeptide complexes for delivery of biologically relevant molecules.     

Stereoselective Synthesis of the Halaven C14–C26 Fragment from D‐Quinic Acid: Crystallization‐Induced Diastereoselective Transformation of an α‐Methyl Nitrile

Crystallization‐induced diastereoselective transformation (CIDT) of an α‐methyl nitrile completes an entirely non‐chromatographic synthesis of the halichondrin B C14–C26 stereochemical array. The requisite α‐methyl nitrile substrate is derived from D ‐quinic acid through a series of substrate‐controlled stereoselective reactions via a number of crystalline intermediates that benefit from a rigid polycyclic template. Therefore, all four stereogenic centers in the Halaven C14–C26 fragment were derived from the single chiral source D ‐quinic acid.     

Asymmetric Synthesis of Silicon‐Stereogenic Vinylhydrosilanes by Cobalt‐Catalyzed Regio‐ and Enantioselective Alkyne Hydrosilylation with Dihydrosilanes

The strategic carbon‐to‐silicon substitution at a stereogenic center can produce chiral silanes with significantly improved properties relative to their carbon congeners. We herein report an unprecedented cobalt‐catalyzed asymmetric hydrosilylation of unsymmetric alkynes with dihydrosilanes that furnishes silicon‐stereogenic vinylhydrosilanes with high regio‐ and enantioselectivity. The absolute configurations of the products were determined by chiroptical methods in combination with DFT calculations. The synthetic versatility of the vinylhydrosilanes as chiral building blocks was further demonstrated by asymmetric Si?H insertion and catalytic hydroboration reactions.     

Enantioselective Construction of α‐Chiral Silanes by Nickel‐Catalyzed C(sp3)−C(sp3) Cross‐Coupling

An enantioselective C(sp³)?C(sp³) cross‐coupling of racemic α‐silylated alkyl iodides and alkylzinc reagents is reported. The reaction is catalyzed by NiCl₂/(S,S)‐Bn‐Pybox and yields α‐chiral silanes with high enantiocontrol. The catalyst system does not promote the cross‐coupling of the corresponding carbon analogue, corroborating the stabilizing effect of the silyl group on the alkyl radical intermediate (α‐silicon effect). Both coupling partners can be, but do not need to be, functionalized, and hence, even α‐chiral silanes with no functional group in direct proximity of the asymmetrically substituted carbon atom become accessible. This distinguishes the new method from established approaches for the synthesis of α‐chiral silanes.     

Chiral Primary‐Amine‐Catalyzed Conjugate Addition to α‐Substituted Vinyl Ketones/Aldehydes: Divergent Stereocontrol Modes on Enamine Protonation

Enantioselective protonation with a catalytic enamine intermediate represents a challenging, yet fundamentally important process for the synthesis of α‐chiral carbonyls. We describe herein chiral primary‐amine‐catalyzed conjugate additions of indoles to both α‐substituted acroleins and vinyl ketones. These reactions feature enamine protonation as the stereogenic step. A simple primary–tertiary vicinal diamine 1 with trifluoromethanesulfonic acid (TfOH) was found to enable both of the reactions of acroleins and vinyl ketones with good activity and high enantioselectivity. Detailed mechanistic studies reveal that these reactions are rate‐limiting in iminium formation and they all involve a uniform H₂O/acid‐bridged proton transfer in the stereogenic steps but divergent stereocontrol modes for the protonation stereoselectivity. For the reactions of α‐branched acroleins, facial selections on H₂O‐bridged protonation determine the enantioselectivity, which is enhanced by an OH???π interaction with indole as uncovered by DFT calculations. On the other hand, the stereoselectivity of the reactions with vinyl ketones is controlled according to the Curtin–Hammett principle in the C? C bond‐formation step, which precedes a highly stereospecific enamine protonation.     

Enantio‐ and Diastereoselective 1,2‐Additions to α‐Ketoesters with Diborylmethane and Substituted 1,1‐Diborylalkanes

The catalytic enantioselective synthesis of boronate‐substituted tertiary alcohols through additions of diborylmethane and substituted 1,1‐diborylalkanes to α‐ketoesters is reported. The reactions are catalyzed by readily available chiral phosphine/copper(I) complexes and produce β‐hydroxyboronates containing up to two contiguous stereogenic centers in up to 99:1 e.r. and greater than 20:1 d.r. The utility of the organoboron products is demonstrated through several chemoselective functionalizations. Evidence indicates the reactions occur via an enantioenriched α‐boryl‐copper‐alkyl intermediate.     

Detection and Chiral Recognition of α‐Hydroxyl Acid through 1H and CEST NMR Spectroscopy Using a Ytterbium Macrocyclic Complex

Chiral α‐hydroxyl acids are of great importance in chemical synthesis. Current methods for recognizing their chirality by ¹H NMR are limited by their small chemical shift differences and intrinsic solubility problem in organic solvents. Herein, we developed three YbDO3A(ala)₃ derivatives to recognize four different commercially available chiral α‐hydroxyl acids in aqueous solution through ¹H NMR and chemical exchange saturation transfer (CEST) spectroscopy. The shift difference between chiral α‐hydroxyl acid observed by proton and CEST NMR ranged from 15–40 and 20–40 ppm, respectively. Our work demonstrates for first time, that even one chiral center on the side‐arm chain of cyclen could set the stage for rotation of the other two non‐chiral side chains into a preferred position. This is ascribed to the lower energy state of the structure. The results show that chiral YbDO3A‐like complexes can be used to discriminate chiral α‐hydroxyl acids with a distinct signal difference.     

Supramolecular inclusion complexes of star‐shaped poly(ε‐caprolactone) with α‐cyclodextrin

Both star‐shaped poly(ε‐caprolactone) (PCL) having 4 arms (4sPCL) and 6 arms (6sPCL) and linear PCL having 1 arm (LPCL) and 2 arms (2LPCL) were synthesized and then investigated for inclusion complexation with α‐cyclodextrin (α‐CD). The supramolecular inclusion complexes (ICs) were in detail characterized by ¹H NMR, differential scanning calorimetry, thermogravimetric analysis, wide angle X‐ray diffraction, solid‐state carbon nuclear magnetic resonance spectroscopy using cross‐polarization and magic‐angle spinning, and Fourier transform infrared, respectively. The stoichiometry (CL:CD, mol:mol) of all ICs increased with the increasing branch arm of PCL polymers, and it was in the order of α‐CD‐6sPCL1 ICs > α‐CD‐4sPCL ICs > α‐CD‐2LPCL ICs > α‐CD‐LPCL ICs. All analyses indicated that the branch arms of star‐shaped PCL polymers were included into the hydrophobic α‐CD cavities and their original crystalline properties were completely suppressed. Moreover, the ICs of star‐shaped PCL with α‐CD had a channel‐type crystalline structure similar to that formed between the linear PCL and α‐CD. Furthermore, the thermal stability of the free PCL polymers probably controlled that of the guest polymers included in the ICs. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4721–4730, 2005     

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.     

Cu/Pd Synergistic Dual Catalysis: Asymmetric α‐Allylation of an α‐CF3 Amide

Despite the burgeoning demand for fluorine‐containing chemical entities, the construction of CF₃‐containing stereogenic centers has remained elusive. Herein, we report the strategic merger of Cu^I/base‐catalyzed enolization of an α‐CF₃ amide and Pd⁰‐catalyzed allylic alkylation in an enantioselective manner to deliver chiral building blocks bearing a stereogenic carbon center connected to a CF₃, an amide carbonyl, and a manipulable allylic group. The phosphine complexes of Cu^I and Pd⁰ engage in distinct catalytic roles without ligand scrambling to render the dual catalysis operative to achieve asymmetric α‐allylation of the amide. The stereoselective cyclization of the obtained α‐CF₃‐γ,δ‐unsaturated amides to give tetrahydropyran and γ‐lactone‐fused cyclopropane skeletons highlights the synthetic utility of the present catalytic method as a new entry to non‐racemic CF₃‐containing compounds.     

Mono‐6A‐(4‐methoxybutylamino)‐6A‐β‐cyclodextrin as a chiral selector for enantiomeric separation

A new member of the family of methoxylalkylamino monosubstituted β‐cyclodextrins, mono‐6^A‐(4‐methoxybutylamino)‐6^A‐β‐cyclodextrin, has been developed as a chiral selector for enantioseparation in capillary electrophoresis. This amino cyclodextrin exhibited good enantioselectivities for 16 model acidic racemates including three dansyl amino acids at an optimum pH of 6.0. Excellent chiral resolutions over six were obtained for α‐hydroxy acids and 2‐phenoxypropionic acids with 3.0 mM chiral selector. The good chiral recognition for α‐hydroxyl acids was attributed to inclusion complexation, electrostatic interactions, and hydrogen bonding. The hydrogen‐bonding‐enhanced chiral recognition was revealed by NMR spectroscopy. The chiral separation of acidic racemates was further improved with the addition of methanol (≤10 vol%) as an organic additive.     

Poly(ethylene imine)‐graft‐poly(ethylene oxide) brush‐like copolymers: Preparation,thermal properties,and selective supramolecular inclusion complexation with α‐cyclodextrin

Poly(ethylene imine)‐graft‐poly(ethylene oxide) (PEI‐g‐PEO) copolymers were synthesized via Michael addition reaction between acryl‐terminated poly(ethylene oxide) methyl ether (PEO) and poly(ethylene imine) (PEI). The brush‐like copolymers were characterized by means of Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. It is found that the crystallinity of the PEO side chains in the copolymers remained unaffected by the PEI backbone whereas the crystal structure of PEO side chains was altered to some extent by the PEI backbone. The crystallization behavior of PEO blocks in the copolymers suggests that the bush‐shaped copolymers are microphase‐separated in the molten state. The PEO side chains of the copolymers were selectively complexed with α‐cyclodextrin (α‐CD) to afford hydrophobic side chains (i.e., PEO/α‐CD inclusion complexes). The X‐ray diffraction (XRD) shows that the inclusion complexes (ICs) of the PEO side chains displayed a channel‐type crystalline structure. It is identified that the stoichiometry of the inclusion complexation of the PEI‐g‐PEO with α‐CD is close to that of the control PEO with α‐CD. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 2296–2306, 2008     

Regio‐ and Stereoselective Modification of Chiral α‐Amino Ketones by Pd‐Catalyzed Allylic Alkylation

Chiral α‐amino ketones are excellent nucleophiles for stereoselective palladium‐catalyzed allylic alkylations. Both chiral as well as achiral allylic substrates can be applied, while the stereochemical outcome of the reaction is controlled by the chiral ketone enolate. The substituted amino ketones formed can be reduced stereoselectively, and up to five consecutive stereogenic centers can be obtained. This approach can be used for the synthesis of highly substituted piperidine derivatives.     

Side‐Arm Effect of a Methyl α‐d‐Glucopyranoside Based Lariat Ether Catalysts in Asymmetric Syntheses

Methyl α‐d ‐glucopyranoside based monoaza‐15‐crown‐5 type lariat ethers with different heteroatom‐containing side arm attached to the nitrogen of the macrocyclic ring have been synthesized. These compounds were used as chiral phase transfer catalysts in a few asymmetric reactions, such as Michael additions, Darzens condensation, and epoxidation of chalcone. The side arms of the macrocycles had a significant impact on the chemical yields and the enantioselectivity. The effect of the lariat ethers with side arms having heteroatom (O, N, and S) was compared with the effect of the analogues having substituents without a heteroatom. The terminal allyl group also generated a significant enantioselectivity (79% enantiomeric excess) in one of the Michael additions. The application of crown ethers with substituents (CH₂)₃OH or (CH₂)₃OCH₃ leads to the best enantioselectivities 85% and 99%, respectively.     

Synthesis of a New Chiral Source, (1R,2S)‐1‐Phenylphospholane‐2‐carboxylic Acid,via a Key Intermediate α‐Phenylphospholanyllithium Borane Complex: Configurational Stability and X‐ray Crystal Structure of an α‐Monophosphinoalkyllithium Borane Complex

A synthetic route to enantiomerically pure (1R,2S)‐1‐phenylphospholane‐2‐carboxylic acid ( 1 ), which is a phosphorus analogue of proline, has been established. A key step is the deprotonation–carboxylation of the 1‐phenylphospholane borane complex 3 by using sBuLi/1,2‐dipiperidinoethane (DPE). Configurational stability of the key intermediate, the amine‐coordinated α‐phosphinoalkyllithium borane complex 4 , was investigated by employing lithiodestannylation–carboxylation of both diastereomers of the 1‐phenyl‐2‐trimethylstannylphospholane borane complex 7 in the presence of several kinds of amines, and as a result, 4 was found to be configurationally labile even at ?100 °C. The key intermediate, the DPE‐coordinated trans‐1‐phenyl‐2‐phospholanyllithium borane complex 9 , was isolated, and the structure was identified by X‐ray crystal structure analysis. This is the first X‐ray crystal structure determined for an α‐monophosphinoalkyllithium borane complex. Remarkably, the alkyllithium complex is monomeric and tricoordinate at the lithium center with a slightly pyramidalized environment, and the existence of a Li? C bond (2.170 Å) has been confirmed. Moreover, ¹H–⁷Li HOESY and ⁶Li NMR analyses suggested the structure of 9 in solution as well as the existence of an equilibrium between 9 , its cis isomer, and the ion pair 8 at room temperature, which was extremely biased towards 9 at ?100 °C. Finally, 1 was used as a chiral ligand in a palladium‐catalyzed allylic substitution, and the desired product was obtained in high yield with good enantioselectivity.     

Synthesis of Chiral Pyrazoles: A 1,3‐Dipolar Cycloaddition/[1,5] Sigmatropic Rearrangement with Stereoretentive Migration of a Stereogenic Group

The reactions between terminal alkynes and α‐chiral tosylhydrazones lead to the obtention of chiral pyrazoles with a stereogenic group directly attached at a nitrogen atom. The cascade reaction includes decomposition of the hydrazone into a diazocompound, 1,3‐dipolar cycloaddition of the diazo compound with the alkyne, and [1,5] sigmatropic rearrangement with migration of the stereogenic group. This strategy has been successfully applied to the synthesis of structurally diverse chiral pyrazoles through α‐chiral tosylhydrazones, obtained from α‐phenylpropionic acid, α‐amino acids, and 2‐methoxycyclohexanone. Notably, the stereoretention of the [1,5] sigmatropic rearrangements represent very rare examples of this stereospecific transformation.     

Mechanism of the Deprotonation Reaction of Alkyl Benzyl Ethers with n‐Butyllithium

Kinetic study of the α‐lithiation of benzyl methyl ether (BME) by nBuLi has revealed that increasing the concentration of the organolithium compound does not necessarily increase the reactivity, and this is a consequence of the reactivities of the different nBuLi aggregates present in solution. We propose a dimer‐based mechanism, in which a pre‐complexation step is a key process for substrates bearing a donor oxygen atom that can interact with the lithium cation to form mixed dimers. For these studies, we have developed a system based on UV/Vis spectroscopy that allows kinetic measurements to be conducted at ?80 °C under argon.