Asymmetric Reduction of α‐Amino Ketones with a KBH4 Solution Catalyzed by Chiral Lewis Acids

An efficient enantioselective reduction of α‐amino ketones with potassium borohydride solution catalyzed by chiral N,N′‐dioxide–metal complex catalysts was accomplished under mild reaction conditions for the first time. It provided a simple, convenient, and practical approaches for obtaining synthetically important chiral β‐amino alcohols in good to excellent yields (up to 98 %) and enantioselectivities (up to 97 % ee).     

Chiral proton donor reagents: tin tetrachloride--coordinated optically active binaphthol derivatives

The Lewis acid–assisted chiral Brønsted acids (chiral LBAs), which are prepared from tin tetrachloride and optically active binaphthol derivatives, are highly effective chiral proton donor reagents for enantioselective protonation and biomimetic polyene cyclization. These chiral LBAs can directly protonate various silyl enol ethers and ketene disilyl acetals to give the corresponding α‐aryl or α‐halo ketones and α‐arylcarboxylic acids, respectively, with high enantiomeric excess (up to 98% ee). A catalytic version of enantioselective protonation was also achieved using stoichiometric amounts of 2,6‐dimethylphenol and catalytic amounts of monomethyl ether of optically active binaphthol in the presence of tin tetrachloride. The biomimetic cyclization of simple isoprenoids to polycyclic isoprenoids using chiral LBA is also described. This is the first example of a chiral Brønsted acid–induced enantioselective ene cyclization in synthetic chemistry. Geranyl phenyl ethers, o‐geranylphenols, and homogeranylphenol derivatives were directly cyclized in the presence of (R)‐binaphthol derivatives and tin tetrachloride (up to 90% ee). Compounds bearing a farnesyl group could also be cyclized under the same conditions to give the natural products (?)‐ambrox^® and (?)‐chromazonarol, and (?)‐tetracyclic polyprenoids of sedimentary origin. These chiral LBAs recognize the prochiral face of a trisubstituted terminal olefin and site selectively generate carbocations on the substrates. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 2: 177–188,2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10020     

A Solid State Polymer‐Coated Electrode Containing a Chiral Crown Ether Derivative for Enantioselective Detection of Phenylglycine Methyl Ester Isomer

All solid‐state enantioselective electrode (ASESE) based on a newly synthesized chiral crown ether derivative ((R)‐(?)‐(3,3′‐diphenyl‐1,1′‐binaphthyl)‐23‐crown‐6 incorporating 1,4‐dimethoxybenzene) was prepared and characterized by potentiometry. The ASESE clearly showed enantiomer discrimination for methyl esters of alanine, leucine, valine, phenylalanine, and phenylglycine, where the enantioselectivity for phenylglycine methyl ester was the highest (K_R,S=8.5±7.1%). Experimental parameters of ASESE for the analysis of (R)‐(?)‐phenylglycine methyl ester were optimized. The optimized ASESE showed a slope of 55.3±0.2 mV/dec for (R)‐(?)‐phenylglycine methyl ester in the concentration range of 1.0×10^?5–1.0×10^?2 M and the detection limit was 9.0×10^?6 M. The ASESE showed good selectivity for (R)‐(?)‐phenylglycine methyl ester against inorganic cations and various amino acid methyl esters. The concentration of (R)‐(?)‐phenylglycine methyl ester was determined in the mixture of (R)‐(?) and (S)‐(+)‐phenylglycine methyl ester, which ratios varied from 2 : 1 to 1 : 9. The lifespan of the electrode was alleged to be 30 days.     

Organoiodine‐Catalyzed Enantioselective Alkoxylation/Oxidative Rearrangement of Allylic Alcohols

An enantioselective catalytic alkoxylation/oxidative rearrangement of allylic alcohols has been established by using a Brønsted acid and chiral organoiodine. The presence of 20 mol % of an (S)‐proline‐derived C₂‐symmetric chiral iodine led to enantioenriched α‐arylated β‐alkoxylated ketones in good yields and with high levels of enantioselectivity (84–94 % ee).     

Enantioselective Syntheses of Strychnos and Chelidonium Alkaloids through Regio‐ and Stereocontrolled Cooperative Catalysis

We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α‐alkylation. This provides products containing indole‐bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N‐substituent. This led to concise syntheses of (?)‐akuammicine and (?)‐strychnine. In the second case, the poor performance of ortho‐substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α‐alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)‐chelidonine, (+)‐norchelidonine, and (+)‐chelamine.     

Conformational analysis of the disaccharide methyl α‐d‐mannopyranosyl‐(1→3)‐2‐O‐acetyl‐β‐d‐mannopyranoside monohydrate

The crystal structure of methyl α‐d ‐mannopyranosyl‐(1→3)‐2‐O‐acetyl‐β‐d ‐mannopyranoside monohydrate, C₁₅H₂₆O₁₂·H₂O, ( II ), has been determined and the structural parameters for its constituent α‐d ‐mannopyranosyl residue compared with those for methyl α‐d ‐mannopyranoside. Mono‐O‐acetylation appears to promote the crystallization of ( II ), inferred from the difficulty in crystallizing methyl α‐d ‐mannopyranosyl‐(1→3)‐β‐d ‐mannopyranoside despite repeated attempts. The conformational properties of the O‐acetyl side chain in ( II ) are similar to those observed in recent studies of peracetylated mannose‐containing oligosaccharides, having a preferred geometry in which the C2—H2 bond eclipses the C=O bond of the acetyl group. The C2—O2 bond in ( II ) elongates by ～0.02 Å upon O‐acetylation. The phi (?) and psi (ψ) torsion angles that dictate the conformation of the internal O‐glycosidic linkage in ( II ) are similar to those determined recently in aqueous solution by NMR spectroscopy for unacetylated ( II ) using the statistical program MA′AT, with a greater disparity found for ψ (Δ = ～16°) than for ? (Δ = ～6°).     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Highly Enantioselective Tandem Michael Addition of Tryptamine‐Derived Oxindoles to Alkynones: Concise Synthesis of Strychnos Alkaloids

A highly enantioselective tandem Michael addition of tryptamine‐derived oxindoles to alkynones was developed by taking advantage of a chiral N,N′‐dioxide Sc(OTf)₃ catalyst. The reaction enables the facile preparation of enantioenriched spiro[pyrrolidine‐3,3′‐oxindole] compounds, which provides a novel strategy for the synthesis of monoterpenoid indole alkaloids. As a demonstration, the asymmetric synthesis of strychnos alkaloids [(?)‐tubifoline, (?)‐tubifolidine, (?)‐dehydrotubifoline] was achieved in 10–11 steps.     

Efficient Synthesis of (−)‐Corynoline by Enantioselective Palladium‐Catalyzed α‐Arylation with Sterically Hindered Substrates

Sterically hindered substrates can be employed in an enantioselective palladium‐catalyzed α‐arylation with the chiral monophosphorus ligand BI‐DIME. This process enabled an efficient synthesis of the antidepressant (S)‐nafenodone, a four‐step enantioselective synthesis of the Sceletium alkaloid (+)‐sceletium A‐4, a concise five‐step enantioselective synthesis of (?)‐corynoline, as well as a three‐step preparation of (?)‐DeN‐corynoline.     

Catalytic Asymmetric Three‐component Hydroacyloxylation/ 1,4‐Conjugate Addition of Ynamides

A highly enantioselective three‐component hydroacyloxylation/1,4‐conjugate addition of ortho‐hydroxybenzyl alcohols, ynamides and carboxylic acids was developed under mild reaction conditions in the presence of a chiral N,N′‐dioxide/Sc(OTf)₃ complex, which went through in situ generated ortho‐quinone methides with α‐acyloxyenamides, delivering a range of corresponding chiral α‐acyloxyenamides derivatives containing gem(1,1)‐diaryl skeletons in moderate to good yields with excellent ee values. The scale‐up experiment and further derivation showed the practicality of this catalytic system. In addition, a possible catalytic cycle and transition state model was proposed to elucidate the origin of the stereoselectivity based on X‐ray crystal structure of the α‐acyloxyenamide intermediate and product.     

Phosphoric Acid Catalyzed Desymmetrization of Bicyclic Bislactones Bearing an All‐Carbon Stereogenic Center: Total Syntheses of (−)‐Rhazinilam and (−)‐Leucomidine B

In the presence of a catalytic amount of an imidodiphosphoric acid, enantioselective desymmetrization of bicyclic bislactones by reaction with alcohols took place smoothly to afford enantiomerically enriched monoacids having an all‐carbon stereogenic center. Concise catalytic enantioselective syntheses of both (?)‐rhazinilam and (?)‐leucomidine B were subsequently developed using (S)‐methyl 4‐ethyl‐4‐formylpimelate monoacid as a common starting material.     

Synthesis and characterization of optically active helical vinyl polymers via free radical polymerization

A facile synthetic route to prepare the dual‐functional molecule, 2,5‐bis(4′‐carboxyphenyl)styrene, was developed. The esterification of this compound with chiral alcohols, that is, (S)‐(+)‐sec‐butanol/(R)‐(?)‐sec‐butanol, (S)‐(+)‐sec‐octanol/(R)‐(?)‐sec‐octanol, and D ‐(+)‐menthol/L ‐(?)‐menthol, respectively, yielded three enantiomeric pairs of novel vinyl monomers, which underwent radical polymerization to obtain helical polymers with an excess screw sense. These polymers exhibited optical rotations as large as fourfold those of the corresponding monomers. Their helical conformations were quite stable as revealed by the almost unchanged chiroptical properties measured at different temperatures. The polymers with linear alkyl tails in the side‐groups formed irreversibly columnar nematic phases in melt although the corresponding monomers were not liquid crystalline. Whereas, the polymers with cyclic tails generated no mesophase. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2408–2421, 2009     

Non‐iterative Asymmetric Synthesis of C15 Polyketide Spiroketals

The 2,2′‐methylenebis[furan] ( 1 ) was converted to 1‐{(4R,6S))‐6‐[(2R)‐2,4‐dihydroxybutyl]‐2,2‐dimethyl‐1,3‐dioxan‐4‐yl}‐3‐[(2R,4R)‐tetrahydro‐4,6‐dihydroxy‐2H‐pyran‐2‐yl)propan‐2‐one ((+)‐ 18 ) and its (4S)‐epimer (?)‐ 19 with high stereo‐ and enantioselectivity (Schemes 1–3). Under acidic methanolysis, (+)‐ 18 yielded a single spiroketal, (3R)‐4‐{(1R,3S,4′R,5R,6′S,7R)‐3′,4′,5′,6′‐tetrahydro‐4′‐hydroxy‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐6′‐yl}butane‐1,3‐diol ((?)‐ 20 ), in which both O‐atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (?)‐ 20 (methyl pyranoside formation). Compound (?)‐ 19 was converted similarly into the (4′S)‐epimeric tricyclic spiroketal (?)‐ 21 that also adopts a similar (3S)‐configuration and conformation. Spiroketals (?)‐ 20 , (?)‐ 21 and analog (?)‐ 23 , i.e., (1R,3S,4′R,5R,6′R)‐3′,4′,5′,6′‐tetrahydro‐6′‐[(2S)‐2‐hydroxybut‐3‐enyl]‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐4′‐ol, derived from (?)‐ 20 , were assayed for their cytotoxicity toward murine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic (±)‐ 21 showed evidence of cancer‐cell‐growth inhibition (P388, ED₅₀: 6.9 μg/ml).     

Enantioselective Addition of Dialkylzincs to Aldehydes Catalyzed by (−)‐MITH

An effective catalytic system that imparts high enantioselectivity has been disclosed for the synthesis of optically active alcohols, which may undergo further chemical transformations. The enantioselective alkylation of aldehydes with dialkylzincs to afford the corresponding optically active alcohols with excellent enantioselectvities has been achieved in the presence of 0.1–0.5 mol % of the camphor‐derived chiral ligand (?)‐2‐exo‐morpholinoisobornane‐10‐thiol (MITH) ( 1 ) at room temperature or at 0 °C.     

Construction of Optically Active Quaternary Propargyl Amines by Highly Enantioselective Zinc/BINOL‐Catalyzed Alkynylation of Ketoimines

A general and efficient method for the highly enantioselective alkynylation of ketoimines through a zinc/1,1′‐bi‐2‐naphthol (BINOL)‐catalyzed process has been developed. A variety of ketoimines, including α‐fluoroalkyl α‐imine esters, α‐aryl α‐imine esters, and trifluoromethyl aryl ketoimines, are applicable and provide their corresponding quaternary propargyl amines in excellent yields with high ee values (up to 99 % ee). Both the steric and electronic effects of substituents at the 3,3′ positions of BINOL are critical for the reaction efficiency and enantioselectivity. To demonstrate the usefulness of the method, (R)‐α‐CF₃ α‐proline has been prepared in a highly efficient manner. The notable features of this protocol are its broad substrate scope, high reaction efficiency (up to 99 %) and enantioselectivity (up to 99 % ee), low catalyst loading (5 mol % of BINOL derivative), and mild reaction conditions.     

Diastereo‐ and Enantioselective Intramolecular [2+2] Photocycloaddition Reactions of 3‐(ω′‐Alkenyl)‐ and 3‐(ω′‐Alkenyloxy)‐Substituted 5,6‐Dihydro‐1H‐pyridin‐2‐ones

3‐(ω′‐Alkenyl)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 2 – 4 were prepared as photocycloaddition precursors either by cross‐coupling from 3‐iodo‐5,6‐dihydro‐1H‐pyridin‐2‐one ( 8 ) or—more favorably—from the corresponding α‐(ω′‐alkenyl)‐substituted δ‐valerolactams 9 – 11 by a selenylation/elimination sequence (56–62 % overall yield). 3‐(ω′‐Alkenyloxy)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 5 and 6 were accessible in 43 and 37 % overall yield from 3‐diazopiperidin‐2‐one ( 15 ) by an α,α‐chloroselenylation reaction at the 3‐position followed by nucleophilic displacement of a chloride ion with an ω‐alkenolate and oxidative elimination of selenoxide. Upon irradiation at λ=254 nm, the precursor compounds underwent a clean intramolecular [2+2] photocycloaddition reaction. Substrates 2 and 5 , tethered by a two‐atom chain, exclusively delivered the respective crossed products 19 and 20 , and substrates 3 , 5 , and 6 , tethered by longer chains, gave the straight products 21 – 23 . The completely regio‐ and diastereoselective photocycloaddition reactions proceeded in 63–83 % yield. Irradiation in the presence of the chiral templates (?)‐ 1 and (+)‐ 31 at ?75 °C in toluene rendered the reactions enantioselective with selectivities varying between 40 and 85 % ee. Truncated template rac‐ 31 was prepared as a noranalogue of the well‐established template 1 in eight steps and 56 % yield from the Kemp triacid ( 24 ). Subsequent resolution delivered the enantiomerically pure templates (?)‐ 31 and (+)‐ 31 . The outcome of the reactions is compared to the results achieved with 4‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones and quinolones.     

Pd(II)-catalyzed and diethylzinc-mediated asymmetric umpolung allylation of aldehydes in the presence of chiral phosphine-Schiff base type ligands

Chiral phosphine-Schiff base type ligand L3 prepared from (R)-(?)-2-(diphenylphosphino)-1,1′-binaphthyl-2′-amine was found to be a fairly effective chiral ligand for the Pd(II)-catalyzed and diethylzinc-mediated enantioselective umpolung allylation of aldehydes to give homoallylic alcohols in good yields, moderate enantioselectivities and high syn diastereoselectivities.     

Divergent Synthesis of 3‐Deoxy‐d‐manno‐oct‐2‐ulosonic Acid (Kdo) Glycosides Containing α‐(2→4)‐Linked Kdo‐Kdo Unit

A convenient and divergent approach was developed to prepare diverse bacterial 3‐deoxy‐d ‐manno‐oct‐2‐ulosonic acid (Kdo) oligosaccharides containing a Kdo‐α‐(2→4)‐Kdo fragment. The orthogonal protected α‐(2→4) linked Kdo‐Kdo disaccharide 3 , serving as a common precursor, was divergently transformed into the corresponding 8‐, 8′‐, and 4′‐hydroxy disaccharides 5 , 7 , and 14 , respectively. Then, these alcohols were glycosylated, respectively, with the 5,7‐O‐di‐tert‐butylsilylene (DTBS) protected Kdo thioglycoside donors 1 or 2 in an α‐stereoselective and high‐yielding manner to afford a range of Kdo oligosaccharides. Finally, removal of all protecting groups of the newly formed glycosides resulted in the desired free Kdo oligomer.     

Pharmacokinetic study of ofloxacin enantiomers in Pagrosomus major by chiral HPLC

(S)‐(?)‐Ofloxacin and (R)‐(+)‐ofloxacin concentrations in the plasma of Pagrosomus major after drug treatment were detected by chiral high‐performance liquid chromatography, and various pharmacokinetic parameters were calculated from these data. The elimination half‐life of (S)‐(?)‐ofloxacin was significantly shorter than that of the (R)‐(+) enantiomer. (S)‐(?)‐Ofloxacin also had a significantly lower maximum plasma concentration, area under the concentration–time curve from zero to infinity, and mean residence time than (R)‐(+)‐ofloxacin. However, the apparent volume of distribution and total body clearance of (S)‐(?)‐ofloxacin were greater than those of (R)‐(+)‐ofloxacin. The ratio of the (S)‐(?)‐ to (R)‐(+)‐ofloxacin plasma concentration was always <1.0. Together, these data suggest that (S)‐(?)‐ofloxacin was preferentially excreted and (R)‐(+)‐ofloxacin was preferentially absorbed. Although the difference in pharmacokinetic parameters was small, the metabolic behavior of the ofloxacin enantiomers in P. major was enantioselective. Copyright © 2015 John Wiley & Sons, Ltd.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.