Research on Asymmetric Michael Addition Part I: Addition of Menthone Imines of Glycinates to Alkyl Acrylates Under the Solid Base Conditions

Asymmetric Michael addition of (S)-menthone imines of glycinates to alkyl acrylates can be performed in solid base conditions. The reactions gave adducts in yields of 40–60% and enantiomeric excesses of 23–45%. The results are best explained by a cyclic transition state mechanism.     

A method for the asymmetric hydrosilylation of N-aryl imines

[reaction: see text] The asymmetric reduction of N-aryl imines to yield chiral amines with enantiomeric excesses above 90% was achieved. Ethylenebis(eta5-tetrahydroindenyl)titanium difluoride ((EBTHI)TiF2, 1) was employed as the precatalyst with polymethylhydrosiloxane (PMHS) as the stoichiometric reducing agent. A variety of N-aryl imines derived from nonaromatic ketones were reduced with high ee.     

Asymmetric allylboration of acyl imines catalyzed by chiral diols

Chiral BINOL-derived diols catalyze the enantioselective asymmetric allylboration of acyl imines. The reaction requires 15 mol % (S)-3,3'-Ph2-BINOL as the catalyst and allyldiisopropoxyborane as the nucleophile. The reaction products are obtained in good yields (75-94%) and high enantiomeric ratios (95:5-99.5:0.5) for aromatic and aliphatic imines. High diastereoselectivities (diastereomeric ratio > 98:2) and enantioselectivities (enantiomeric ratio > 98:2) are obtained in the reactions of acyl imines with crotyldiisopropoxyboranes. This asymmetric transformation is directly applied to the synthesis of Maraviroc, the selective CCR5 antagonist with potent activity against HIV-1 infection. Mechanistic investigations of the allylboration reaction including IR, NMR, and mass spectrometry studies indicate that acyclic boronates are activated by chiral diols via exchange of one of the boronate alkoxy groups with activation of the acyl imine via hydrogen bonding.     

Asymmetric Au-catalyzed domino cyclization/nucleophile addition reactions of enynes in the presence of water, methanol and electron-rich aromatic derivatives

An efficient Au(I) catalytic system is described for the asymmetric domino cyclization/functionalization reactions of functionalized 1,6-enynes in the presence of an external nucleophile. The use of (R)-4-MeO-3,5-(t-Bu)₂-MeOBIHEP ligand associated with gold led to clean rearrangements implying the formal addition of an oxygen or carbon nucleophile to an alkene followed by a cyclization process. The enantiomeric excesses were highly dependant on the substrate/nucleophile combination. Very good enantiomeric excesses up to 98% were obtained in the case of substrates bearing larger groups (hindered diesters and disulfones) and in the case of hindered carbon nucleophiles.     

An enantioselective chiral Brønsted acid catalyzed imino-azaenamine reaction

The enantioselective Br?nsted acid catalyzed addition of methyleneaminopyrrolidine to N-Boc imines has been achieved in the presence of chiral phosphoric acids derived from 3,3'-di(phenanthryl)-H8-BINOL. The corresponding aminohydrazones have been isolated in good yields with enantiomeric excesses up to 90%. [reaction: see text]     

Asymmetric catalytic aza-Morita-Baylis-Hillman reaction using chiral bifunctional phosphine amides as catalysts

The asymmetric catalytic aza-Morita-Baylis-Hillman reaction of N-sulfonated imines with α,β-unsaturated ketones has been successfully conducted by using chiral bifunctional phosphine amides as catalysts. A series of new chiral bifunctional phosphine amides were designed, synthesized, and systematically studied for this asymmetric reaction. The corresponding aza-MBH adducts were obtained in good yields (75-99%) and up to very good enantiomeric excesses (51-95% ee) under mild conditions.     

Sc(BINOL)2Li: a new heterobimetallic catalyst for the asymmetric Strecker reaction

The new chiral heterobimetallic complex Sc(BINOL)₂Li 1 was prepared and used as a catalyst in the enantioselective addition of a cyanide source (HCN or TMSCN) to several imines. High conversion rates and enantiomeric excesses (e.e.s) as high as 95% were obtained.     

Palladium-catalyzed asymmetric silaboration of allenes

An enantioselective silaboration of allenes was achieved using an achiral silylborane in the presence of a palladium catalyst bearing a chiral monodentate phosphine ligand. (R)-2-Bis(3,5-dimethylphenyl)phosphino-1,1'-binaphthyl gave the highest enantioselectivities in the addition of (diphenylmethylsilyl)pinacolborane to the internal C=C bond of terminal allenes at 0 degrees C, giving the corresponding beta-borylallylsilanes in high yields with high enantiomeric excesses. The enantioselectivity depended on the bulkiness of substituents of allenes: the enantiomeric excesses were found to be 91-93% ee (R = tert- and sec-alkyl), 88-90% ee (R = aryl), and 80-82% ee (R = prim-alkyl and Me) at 0 degrees C. Perfect chirality transfer was observed in the intramolecular cyclization reactions of the functionalized allylsilanes, affording highly enantioenriched cyclic alkenylboranes, which underwent Suzuki-Miyaura coupling with aryl halides.     

Phosphahelicenes in Asymmetric Organocatalysis: [3+2] Cyclizations of γ‐Substituted Allenes and Electron‐Poor Olefins

The first use of phosphahelicene in enantioselective organocatalysis is reported. New chiral phosphahelicenes have been prepared and enable highly enantioselective [3+2] cyclization reactions between arylidene‐ or alkylidenemalononitriles and γ‐substituted allenoates or cyanoallenes. These reactions afford cyclopentene derivatives in both high yields and diastereoselectivities, with enantiomeric excesses of up to 97 %.     

Systematic Studies using 2‐(1‐Adamantylethynyl)pyrimidine‐5‐carbaldehyde as a Starting Material in Soai’s Asymmetric Autocatalysis

Herein, we present a new substrate for the Soai reaction, which has an adamantylethynyl residue ( 1 g ) and exhibits asymmetric autocatalysis, yielding products with enantiomeric excesses above 99 %. For the first time, all reactions were performed on a parallel synthesizer system to ensure identical reaction conditions. A detailed systematic study of reaction parameters was performed and we report the highest enhancements of enantiomeric excess reported so far in the Soai reaction in one reaction cycle (7.2→94.1 % ee or 3.1→92.1 % ee). Our results led to a set of reaction parameters that yield reproducible results. Therefore, our new starting material 1 g is suitable for systematic and mechanistic studies on this remarkable reaction. A series of experiments designed to quantify the amplification of enantiomeric excess demonstrated that the reaction can be used in principle as a tool for the detection of low enantiomeric excesses: under definite conditions, an unknown low enantiomeric excess (0.1–7 %) was amplified to a detectable one. A back calculation to the original value offers a new method for the determination of small enantiomeric excesses.     

A convenient route to enantiopure 3-aryl-2,3-diaminopropanoic acids by diastereoselective Mannich reaction of camphor-based tricyclic iminolactone with imines

A novel and convenient route to the asymmetric synthesis of 2,3-diamino acids via Mannich reaction of iminolactones 1a and 1b with N-protected imines has been achieved in good yields (up to 95%) and high diastereoselectivity (dr: >99:1). Hydrolysis of the Mannich adducts under acidic conditions furnished the desired 3-aryl-2,3-diaminopropanoic acids in good yields (up to 85%) with excellent enantiomeric excesses (99% ee).     

Bioreduction of β-carboline imines to amines employing Saccharomyces bayanus

β-Carboline imine reductions mediated by Saccharomyces bayanus have been described achieving moderate to good enantiomeric excesses of the amine products. The enantiomeric excesses of the bioreduction showed a dependence on the imine substituents. Compounds presenting C₁–C₁₁ aliphatic substituent groups afforded amines with an (S)-configuration, whereas C₁₅ and higher aliphatic- and aromatic-substituted β-carboline imines achieved inversion of the configuration in the final (R)-2 amine products. Based on this data, a model for the Saccharomyces reduction is proposed.     

Screening of chiral phosphines as catalysts for the enantioselective [3+2] annulations of N-tosylimines with allenic esters

The use of chiral, binaphthyl-based phosphepines as catalysts improves previous results for the enantioselective [3+2] cyclisation reactions between allenic esters and N-tosylimines, both in terms of conversion rate and enantioselectivity. Pyrrolines bearing 1-naphthyl, phenyl, o-tolyl and p-MeO-phenyl substituents on the stereogenic alpha-carbon have been obtained with enantiomeric excesses up to 64-80%.     

On the way to chiral epoxidations with methyltrioxorhenium(VII) derived catalysts

Methyltrioxorhenium(VII) (MTO) is successfully applied as chiral epoxidation catalysts in the presence of H₂O₂ as oxidizing agent and excess chiral Lewis base ligands derived from pyrazole. Moderate enantiomeric excesses up to ca. 30% can be reached at low reaction temperatures (−30 °C), the conversions however, being quite low (<25%). The reason for this may be the fluctionality of the N-base ligand. Glycolate complexes of MTO, applied under the same conditions reach somewhat higher enantiomeric excesses (up to ca. 40%), however, again associated with low conversions (<30%). In this case the sensitivity of the catalyst to water induced ligand removal as well as to ligand exchange with other diols is the most likely reason. Nevertheless, the enantiomeric excesses reported here are among the best observed for MTO derived catalytic systems reported to date and more active and selective systems seem feasible.     

Enantioselective Diels-Alder approach to C-3-oxygenated angucyclinones from (SS)-2-(p-tolysulfinyl)-1,4-naphthoquinone

Chiral racemic vinylcyclohexenes 2, bearing oxygenated substituents and/or a methyl group at the C-5 position of the cyclohexene ring, were submitted to Diels-Alder reactions with enantiomerically pure (SS)-(2-p-tolylsulfinyl)-1,4-naphthoquinone [(+)-1]. The domino cycloaddition/pyrolytic sulfoxide elimination process led to the formation of enantiomerically enriched angularly tetracyclic quinones anti-6 and syn-7, which were obtained from the kinetic resolution of the racemic diene. In all cases, (SS)-(2-p-tolylsulfinyl)-1,4-naphthoquinone reacted from the less hindered face of the more reactive s-cis conformation, to form products in good enantiomeric excesses. Steric effects and torsional interactions in the corresponding approaches account for the observed pi-facial diastereoselectivities at both partners. The usefulness of this methodology is illustrated with the four-step totally asymmetric synthesis of the C-3-oxygenated angucyclinone derivative (-)-8-deoxytetrangomycin 10 in 26% overall yield and with 50% enantiomeric purity.     

Studies of Diastereoselectivity in Diels-Alder Reactions of Enantiopure (SS)-2-(p-Tolylsulfinyl)-1,4-naphthoquinone and Chiral Racemic Acyclic Dienes

Enantiopure sulfinylnaphthoquinone (+)-5 reacted with racemic acyclic dienes 1a-f bearing a stereogenic allylic center, through a tandem cycloaddition/pyrolytic sulfoxide elimination, to afford optically enriched compounds 8a-f and 9a-f with good like/unlike selectivities (ca. 75:25) and good enantiomeric excesses (68-82%), arising from the partial kinetic resolution of the racemic dienes. The opposite diastereoselection (8g-i: 9g-i, up to 5:95) was observed in reactions with dienes 1g-i, having an additional methyl group at C-3, the enantiomeric purities being moderate (14-25%). Steric effects and torsional interactions in the corresponding approaches account for the observed diastereoselectivities.     

Organosilanols as catalysts in asymmetric aryl transfer reactions

[reaction: see text] Various ferrocene-based organosilanols have been synthesized in four steps starting from achiral ferrocene carboxylic acid. Applying these novel planar-chiral ferrocenes as catalysts in asymmetric phenyl transfer reactions to substituted benzaldehydes afforded products with high enantiomeric excesses. The best result (91% ee) was achieved in the addition to p-chlorobenzaldehyde with organosilanol 2b, which has a tert-butyl substituent on the oxazoline ring and an isopropyl group on the silanol fragment.     

One-pot enantioselective aziridination of olefins catalyzed by a copper(I) complex of a novel diimine ligand by using PhI(OAc)(2) and sulfonamide as nitrene precursors

A novel chiral C(2)-symmetric 1,4-diamine with multistereogenic centers at the backbone of the ligand has been synthesized from cheap natural product D-mannitol through multistep transformations. Its diimine derivative (3 a) was found to be highly effective for the enantioselective control of the copper-catalyzed asymmetric aziridination of olefin derivatives with PhI==NTs as the nitrene source, affording the corresponding N-sulfonylated azirindine derivatives in good to excellent yields with up to 99 % ee (ee=enantiomeric excess). The catalyst system discovered in the present work was also extended to a one-pot enantioselective aziridination by using sulfonamide/iodobenzene diacetate as the nitrene source. In this case, most reactions proceeded smoothly to give the corresponding products in moderate yields with good to excellent enantiomeric excesses (75-96 % ee).     

Rhodium-catalyzed Asymmetric Ring-opening Reactions of N-Boc-azabenzonorbornadiene with N-Substituted Piperazine Nucleophiles

Asymmetric ring‐opening reactions of N‐Boc‐azabenzonorbornadiene with N‐substituted piperazine nucleophiles in the presence of 5 mol% of [Rh(COD)Cl]₂ and 10 mol% of chiral ligand, (R,S)‐PPF‐P‐t‐Bu₂, gave the corresponding 1,2‐diamine product in moderate to excellent yields (up to 95%) with reasonable enantiomeric excesses (up to 70% ee). The results showed that the nature of ligands had significant influence on the yields and the enantiomeric excesses.     

Phosphine-catalyzed [4+2] cycloaddition of sulfamate-derived cyclic imines with allenoates: synthesis of sulfamate-fused tetrahydropyridines

Using n-PrPPh₂ as the nucleophilic catalyst, the [4+2] cycloaddition reaction of the sulfamate-derived cyclic imines with allenoates works efficiently to yield various sulfamate-fused tetrahydropyridines in high yields with excellent diastereoselectivities. Using amino acid-based bifunctional phosphine as chiral catalyst, an asymmetric [4+2] cycloaddition reaction was achieved, giving chiral sulfamate-fused tetrahydropyridines in high yields with good enantiomeric excesses.