Phase‐Transfer‐Catalyzed Enantioselective Mannich Reaction of Malonates with α‐Amido Sulfones

The highly enantioselective reaction between in situ generated, Cbz‐protected azomethines and malonates in the presence of 150 mol % of potassium carbonate (50 % w/w) and 1 mol % of quinine‐derived quaternary ammonium bromides as phase‐transfer organocatalysts has been developed. This study reports a novel approach for the asymmetric Mannich‐type reaction and a wide range of azomethines, including those derived from enolizable aldehydes, is tolerated by the present system. The adducts, obtained in excellent yields with ee up to 98 %, are suitable precursors of optically pure β‐amino acids.     

One‐Step Catalytic Enantioselective α‐Quaternary 5‐Hydroxyproline Synthesis: An Asymmetric Entry to Highly Functionalized α‐Quaternary Proline Derivatives

The highly enantioselective cascade reaction between N‐protected α‐cyanoglycine esters and α,β‐unsaturated aldehydes is disclosed. The reaction represents a one‐step entry to polysubstituted 5‐hydroxyproline derivatives having a quaternary α‐stereocenter generally in high yields with up to >95:5 dr and 99:1 er. It is also a direct catalytic two‐step entry to functionalized α‐quaternary proline derivatives.     

Highly Efficient Asymmetric Three‐Component Vinylogous Mannich Reaction Catalyzed by a Chiral Scandium(III)‐ N,N′‐Dioxide Complex

The asymmetric three‐component vinylogous Mannich reaction of an acyclic silyl dienol ester, an aldehyde and 2‐aminophenol was accomplished using a chiral N,N′‐dioxide‐scandium(III) complex as the catalyst. A variety of aldehydes were found to be suitable substrates for the reaction and the desired δ‐amino‐α,β‐unsaturated esters were obtained in 90–99% yields with good to excellent enantioselectivities (up to >99% ee) and complete regioselectivities. Moreover, the simple experimental procedures were air‐tolerant and convenient. The present catalytic process provides the potential for large‐scale syntheses of the chiral δ‐amino‐α,β‐unsaturated esters.     

Organocatalyzed Highly Enantioselective and anti‐Selective Construction of γ‐Butenolides through Vinylogous Mukaiyama Aldol Reaction

The formation of chiral γ‐butenolides has been achieved with good yields (up to 90%), high enantioselectivity (up to 91%) and diastereoselectivity (up to 9/1, anti‐selective) through an organocatalyzed vinylogous Mukaiyama aldol reaction of 2‐(trimethylsilyloxy)furan and aldehydes. A wide range of chiral γ‐butenolides was obtained under mild conditions by this methodology.     

Enantioselective Vanadium‐Catalyzed Oxidation of 1,3‐Dithianes from Aldehydes and Ketones using β‐Amino Alcohol Derived Schiff Base Ligands

The asymmetric vanadium‐catalyzed oxidation of 1,3‐dithianes from aldehydes and ketones by β‐amino alcohol‐derived Schiff base ligands with two stereogenic centers was investigated. Using aqueous hydrogen peroxide as the oxidant and the Schiff base 3b as a chiral ligand, a variety of 1,3‐dithianes derived from aldehydes were easily converted into the corresponding mono‐sulfoxides in good yields (81–88%) with excellent enantioselectivities (up to 99% ee). Additionally, 99% ee was obtained for the enantioselective vanadium‐catalyzed oxidation of the 1,3‐dithianes derived from ketones. We found a slight kinetic resolution when using a higher ratio of hydrogen peroxide during the oxidation of the aldehyde‐derived 1,3‐dithianes but not in the ketone‐derived 1,3‐dithianes.     

Synthesis of an Enantiocomplementary Catalyst of β‐Isocupreidine (β‐ICD) from Quinine

Compound 20 , a pseudoenantiomer of β‐isocupreidine (β‐ICD), was synthesized from quinine employing a Barton reaction of nitrosyl ester 13 and acid‐catalyzed cyclization of carbinol 18 as key steps. The Baylis–Hillman reaction of benzaldehyde, p‐nitrobenzaldehyde, and hydrocinnamaldehyde with 1,1,1,3,3,3‐hexafluoroisopropyl acrylate (HFIPA) using 20 as a chiral amine catalyst was found to give the corresponding S‐enriched adducts in high optical purity (>91% ee) in contrast to the β‐ICD‐catalyzed reaction which affords R‐enriched adducts. This result suggests that compound 20 can serve as an enantiocomplementary catalyst of β‐ICD in the asymmetric Baylis–Hillman reaction of aldehydes with HFIPA.     

Amine‐Catalyzed Asymmetric Epoxidation of α,β‐Unsaturated Aldehydes

The direct organocatalytic enantioselective epoxidation of α,β‐unsaturated aldehydes with different peroxides is presented. Proline, chiral pyrrolidine derivatives, and amino acid‐derived imidazolidinones catalyze the asymmetric epoxidation of α,β‐unsaturated aldehydes. In particular, protected commercially available α,α‐diphenyl‐ and α,α‐di(β‐naphthyl)‐2‐prolinols catalyze the asymmetric epoxidation reactions of α,β‐unsaturated aldehydes with high diastereo‐ and enantioselectivities to furnish the corresponding 2‐epoxy aldehydes in high yield with up to 97:3 dr and 98 % ee. The use of non‐toxic catalysts, water and hydrogen peroxide, urea hydroperoxide or sodium percarbonate as the oxygen sources could make this reaction environmentally benign. In addition, one‐pot direct organocatalytic asymmetric tandem epoxidation‐Wittig reactions are described. The reactions were highly diastereo‐ and enantioselective and provide a rapid access to 2,4‐diepoxy aldehydes. Moreover, a highly stereoselective one‐pot organocatalytic asymmetric cascade epoxidation‐Mannich reaction, which proceeds via the combination of iminium and enamine activation, is presented. The mechanism and stereochemistry of the amino acid‐ and chiral pyrrolidine‐catalyzed direct asymmetric epoxidation of α,β‐unsaturated aldehydes are also discussed.     

Enantioselective Synthesis of cis‐4‐Formyl‐β‐lactams via Chiral N‐Heterocyclic Carbene‐Catalyzed Kinetic Resolution

An efficient synthesis of optically pure cis‐4‐formyl‐β‐lactams (up to 99% ee) by a chiral NHC‐catalyzed ring expansion reaction has been realized, featuring the ready availability of both the substrate and the catalyst, and the mild reaction conditions. The current method is also suitable for the synthesis of enantioenriched 4‐formyl‐β‐lactams and succinimides containing quaternary carbon centers.     

Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

Asymmetric Aza‐Morita–Baylis–Hillman‐Type Reactions: The Highly Enantioselective Reaction between Unmodified α,β‐ Unsaturated Aldehydes and N‐Acylimines by Organo‐co‐catalysis

The highly enantioselective organo‐co‐catalytic aza‐Morita–Baylis–Hillman (MBH)‐type reaction between N‐carbamate‐protected imines and α,β‐unsaturated aldehydes has been developed. The organic co‐catalytic system of proline and 1,4‐diazabicyclo[2.2.2]octane (DABCO) enables the asymmetric synthesis of the corresponding N‐Boc‐ and N‐Cbz‐protected β‐amino‐α‐alkylidene‐aldehydes in good to high yields and up to 99% ee. In the case of aza‐MBH‐type addition of enals to phenylprop‐2‐ene‐1‐imines, the co‐catalytic reaction exhibits excellent 1,2‐selectivity. The organo‐co‐catalytic aza‐MBH‐type reaction can also be performed by the direct highly enantioselective addition of α,β‐unsaturated aldehydes to bench‐stable N‐carbamate‐protected α‐amidosulfones to give the corresponding β‐amino‐α‐alkylidene‐aldehydes with up to 99% ee. The organo‐co‐catalytic aza‐MBH‐type reaction is also an expeditious entry to nearly enantiomerically pure β‐amino‐α‐alkylidene‐amino acids and β‐amino‐α‐alkylidene‐lactams (99% ee). The mechanism and stereochemistry of the chiral amine and DABCO co‐catalyzed aza‐MBH‐type reaction are also discussed.     

Phase‐Transfer‐Catalyzed Olefin Isomerization/α‐Alkylation of α‐Alkynylcrotonates as a Route for 1,4‐Enynes

The phase‐transfer‐catalyzed alkylation of α‐alkynylcrotonates was developed as a means to provide 1,4‐enynes deconjugated by an all‐carbon quaternary center. Extension to the asymmetric version using the chiral phase‐transfer catalyst (S)‐ 3 provided the alkylated compounds with up to 87% ee.     

Catalytic Enantioselective Arylative Dearomatization of 3‐Methyl‐2‐vinylindoles Enabled by Reactivity Switch

The first catalytic asymmetric dearomatization of 3‐methyl‐2‐vinylindoles has been established by using quinone monoimides as suitable electrophiles in the presence of chiral phosphoric acid, which afforded chiral indole derivatives bearing a quaternary stereogenic center in a chemospecific and highly enantioselective fashion (up to 81% yield, >99% ee). The success of this reaction was enabled by the reactivity switch of 3‐methyl‐2‐vinylindoles, which has not been reported before. This reaction also represents the first catalytic asymmetric arylative dearomatization of vinylindoles, which will help confront the challenges in catalytic asymmetric arylative dearomatization and dearomatization of vinylindoles.

     

Step‐growth polymerization of 5‐[(9,10‐dihydro‐9,10‐ethanoanthracene‐11,12‐dicarboximido)‐3‐methylbutanoyl‐amino]isophthalic acid with aromatic diols

cis‐9,10‐dihydro‐9,10‐ethanoanthracene‐11,12‐dicarboxylic acid anhydride ( 1 ) was converted to imide acid ( 2 ) by reaction with S‐valine. Compound 2 was converted to the acid chloride ( 3 ) by reaction with thionyl chloride and then treated with 5‐aminoisophthalic acid in dry N,N‐dimethylacetamide to obtain 5‐[(9,10‐dihydro‐9,10‐ethanoanthracene‐11,12‐dicarboximido)‐3‐methylbutanoylamino]isophthalic acid ( 4 ). Direct step‐growth polymerization of this novel chiral diacid monomer 4 with a series of different diols in a system of tosyl chloride, pyridine, and N,N‐dimethylformamide was carried out. The optically active polyesters (PEs) were obtained with good yield and moderate inherent viscosity ranging from 0.23 to 0.48 dL/g. The resulting polymers were characterized with FTIR, ¹H‐NMR, and elemental analysis techniques. The prepared PEs showed good thermal stability up to 320°C as measured by thermogravimetric analysis. Specific rotation experiments demonstrated the induction of optical activity due to successful insertion of S‐valine in the structure of pendant groups. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Iron(III) Chloride‐Catalyzed Tandem Aza‐Prins/Friedel–Crafts Cyclization of 2‐Arylethyl‐2,3‐butadienyl Tosylamides and Aldehydes‐An Efficient Synthesis of Benzo[f]isoquinolines

An efficient approach for the synthesis of 1,2,3,4,5,6‐hexahydrobenzo[f]isoquinolines via a tandem aza‐Prins/Friedel–Crafts cyclization from 2‐arylethyl‐2,3‐butadienyl tosylamides and aldehydes has been developed. This iron(III) chloride‐catalyzed cascade cyclization at the room temperature with different types of aldehydes, such as aromatic and heteroaromatic aldehydes, alkyl aldehydes, and α,β‐unsaturated aldehydes, affords the products in moderate to excellent yields (up to 97 %). In this reaction, chlorotrimethylsilane was applied to activate the aldehydes. The cheap catalyst, the mild reaction conditions, and the broad scope of the substrates make this method highly useful.

     

Direct Enantioselective Three‐Component Kabachnik–Fields Reaction Catalyzed by Chiral Bis(imidazoline)‐Zinc(II) Catalysts

A direct three‐component reaction of aldehydes, amines and diaryl phosphites was catalyzed by a zinc(II) complex of 1,3‐bis(imidazolin‐2‐ly)pyridine (pybim) giving the corresponding α‐aminophosphonates in good yield with good enantioselectivity. The reaction was applied to a wide variety of aromatic aldehydes to give products with excellent yields (up to 99%) and enantiomeric excesses (up to 93% ee).     

Asymmetric 1,4‐Addition of Diethylzinc to Cyclic Enones Catalyzed by Cu(I)‐Chiral Sulfonamide‐Thiophosphoramide Ligands and Lithium Salts

The chiral sulfonamide‐thiophosphoramide ligand L1 , prepared from the reaction of (1R,2R)‐(−)‐1,2‐cyclohexanediamine with diphenylthiophosphoryl chloride and p‐toluenesulfonyl chloride, was used as a chiral ligand in Cu(MeCN)₄ClO₄‐promoted catalytic asymmetric addition of diethylzinc to cyclic enones using LiCl as an additive in which up to 90% ee can be realized under mild conditions within 0.5 h. This chiral ligand is stable and recoverable after usual work‐up and can be reused in the same catalytic asymmetric reaction. Moreover, it was found that this series of chiral ligands represents a type of S,O‐bidentate ligands on the basis of ¹H NMR, ³¹P NMR and ¹³C NMR spectroscopic investigations. The linear effect of ligand ee and product ee further revealed that the active species is a monomeric Cu(I) complex bearing a single ligand.     

Highly Enantioselective Michael Addition Reactions of 3‐Substituted Benzofuran‐2(3H)‐ones to Chalcones Catalyzed by a Chiral Alkyl‐Substituted Thiourea

A highly enantioselective Michael addition of 3‐substituted benzofuran‐2(3H)‐ones to chalcones catalyzed by a chiral bifunctional thiourea was developed. Several chiral 3,3′‐substituted benzofuran‐2(3H)‐ones derivatives, bearing adjacent quaternary‐tertiary stereocenters, were efficiently synthesized with excellent enantioselectivities.     

Stereoselective Lewis Base‐Catalyzed Asymmetric Hydrosilylation of α‐Acetamido‐β‐enamino Esters: Straightforward Approach for the Construction of α,β‐Diamino Acid Derivatives

The Lewis base‐organocatalyzed asymmetric hydrosilylation of α‐acetamido‐β‐enamino esters was investigated. Among various chiral Lewis base catalysts, a novel catalyst derived from L ‐serine was found to be the most efficient one which can promote the reaction to afford a series of α,β‐diamino acid derivatives with high yields (up to 99%), excellent enantioselectivities (up to 98% ee) and moderate diastereoselectivities (up to 80:20 dr). The absolute configuration of one of the products was determined by the X‐ray crystallographic analysis. In addition, the mechanism and the transition state of the reaction were proposed.     

Synthesis of Chiral 2‐Hydroxy‐1‐methylpropanoates by Rhodium‐Catalyzed Stereoselective Hydrogenation of α‐(Hydroxymethyl)‐acrylate Derivatives

The synthesis of chiral 3‐hydroxy‐2‐methylpropanoic acid esters (e.g., “Roche ester” 3a ) based on the rhodium‐catalyzed stereoselective hydrogenation of Baylis–Hillman reaction products was investigated. Full conversions and enantioselectivities of up to 99% at a substrate/catalyst ratio of up to 500/1 were achieved by application of bisphospholanes of the catASium M series as ancillary ligands. An interesting kinetic resolution was observed by the diastereoselective hydroxy‐directed hydrogenation of related racemic β‐branched precursors affording mainly anti‐isomers with up to 96%ee.     

Chiral Imidodiphosphoric Acids‐Catalyzed Friedel–Crafts Reactions of Indoles/Pyrroles with 3‐Hydroxy‐indolyloxindoles: Enantioselective Synthesis of 3,3‐Diaryloxindoles

The first enantioselective Friedel–Crafts alkylation of indoles and pyrroles with 3‐hydroxy‐3‐indolyloxindoles to access two novel types of 3,3‐diaryloxindoles catalyzed by chiral imidodiphosphoric acids has been reported. A range of quaternary carbon centered 3,3‐diaryloxindoles were synthesized in high yield (up to >99%) with excellent enantioselectivity (up to 98% ee) at low catalyst loadings (as low as 0.5 mol%). The Friedel–Crafts reaction between indoles and 3‐hydroxy‐3‐indolyloxindoles is amenable to gram scale syntheses.