Highly Diastereo‐ and Enantioselective Catalytic Domino Thia‐Michael/Aldol Reactions: Synthesis of Benzothiopyrans with Three Contiguous Stereocenters

Highly enantioselective organocatalytic domino thia‐Michael/aldol reactions between 2‐mercaptoacetophenone and α,β‐unsaturated aldehydes are presented. The reactions proceed with excellent chemo‐, diastereo‐ and enantioselectivity to give the corresponding benzothiopyran derivatives in high yields with up to >15:1 dr and 96 to >99 % ee.     

Organocatalytic Asymmetric syn‐Aldol Reactions of Aldehydes with Long‐Chain Aliphatic Ketones on Water and with Dihydroxyacetone in Organic Solvents

An on‐water, asymmetric, and direct syn‐aldol reaction of aliphatic ketones with aromatic aldehydes catalyzed by a primary amino acid‐based organocatalyst afforded the syn‐aldol adducts in high yields with excellent diastereo‐ and enantioselectivities (up to > 20/1 dr, >99% ee), and a highly enantioselective syn‐aldol reaction of dihydroxyacetone with a variety of aldehydes in THF proceeded with 14/1 to >20/1 dr and 92 to >99% ee. Water not only accelerated the reaction, but also enhanced the enantioselectivity. This positive water effect might arise from the hydrogen bond formed between a pendant hydroxy group of surface water molecules at the hydrophobic interface with the amide oxygen of the organocatalyst, which increases the acidity of the amide NH and thereby strengthens the related hydrogen bond formed with the aldehyde.     

A Highly Enantioselective Catalytic Domino Aza‐Michael/Aldol Reaction: One‐Pot Organocatalytic Asymmetric Synthesis of 1,2‐Dihydroquinolidines

The highly enantioselective organocatalytic domino aza‐Michael/aldol reaction is presented. The unprecedented, chiral amine‐catalyzed asymmetric domino reactions between 2‐aminobenzaldehydes and α,β‐unsaturated aldehydes proceed with excellent chemo‐ and enantioselectivity to give the corresponding pharmaceutically valuable 1,2‐dihydroquinolines derivatives in high yields with 90 to >99 % ee.     

Highly Enantioselective Co‐Catalytic Direct Aldol Reactions by Combination of Hydrogen‐Bond Donating and Acyclic Amino Acid Catalysts

Highly enantioselective co‐catalytic direct aldol reactions by a combination of simple hydrophobic acyclic amino acid and hydrogen‐bond donating catalysts are presented. The corresponding aldol products are formed in high yields with high regio‐, diastereo‐ (anti or syn) and enantioselectivity (up to 99.5:0.5 er). The catalyst loadings can be decreased to as little as 2 mol%.     

Aqueous Asymmetric Mukaiyama Aldol Reaction Catalyzed by Chiral Gallium Lewis Acid with Trost‐Type Semi‐Crown Ligands

The combination of Ga(OTf)₃ with chiral semi‐crown ligands ( 1a – e ) generates highly effective chiral gallium Lewis acid catalysts for aqueous asymmetric aldol reactions of aromatic silyl enol ethers with aldehydes. A ligand‐acceleration effect was observed. Water is essential for obtaining high diastereoselectivity and enantioselectivity. The p‐phenyl substituent in aromatic silyl enol ether ( 2 h ) plays an important role and increases the enantioselectivity up to 95% ee. Although aliphatic silyl enol ethers provided low enantioselectivities and silylketene acetal is easily hydrolyzed in aqueous alcohol, the aldol reactions of silylketene thioacetal ( 12 ) with aldehydes in the presence of gallium‐Lewis acid catalysts give the β‐hydroxy thioester with reasonable yields and high diastereo‐ (up to 99 : 1) and enantioselectivities (up to 96% ee).     

Studies of the Deracemization of (±)‐2‐Hydroxy‐1‐tetralone by Trichosporon cutaneum

The diastereo‐ and enantioselective bioreduction of (±)‐2‐hydroxy‐1‐tetralone ( 6 ) to the corresponding enantiopure (1S,2R)‐cis‐1,2‐dihydroxy‐1,2,3,4‐tetrahydronaphthalene ( 1 ) (83 % isolated yield, >99 % ee), mediated by resting cells of the yeast Trichosporon cutaneum CCT 1903 through dynamic kinetic resolution is reported. Deracemization of (±)‐ 6 was observed in kinetic studies on the biotransformation of the enantiomers (R)‐ 6 and (S)‐ 6 .     

Prolinamides versus Prolinethioamides as Recyclable Catalysts in the Enantioselective Solvent‐Free Inter‐ and Intramolecular Aldol Reactions

A solvent‐free asymmetric and direct anti‐aldol reaction of aliphatic ketones with aromatic aldehydes catalyzed by recyclable L ‐prolineamides and L ‐prolinethioamides 3 is studied. The L ‐prolinethioamide 3d (5 mol%), derived from L ‐Pro and (R)‐1‐aminoindane, is the most efficient catalyst for this process affording the anti‐aldol adducts in high yields with excellent diastereo‐ and enantioselectivities (up to >98/2 dr, up to 98% ee) at 0 °C or room temperature. Prolinethioamide 3d is an effective organocatalyst for the first asymmetric, solvent‐free, intramolecular Hajos–Parrish–Eder–Sauer–Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee) to reported catalysts in organic solvents. Moreover, organocatalyst 3d can be easily recovered and reused by a simple acid/base extraction.     

Reusable Chiral Dicationic Chromium(III) Salen Catalysts for Aminolytic Kinetic Resolution of trans‐Epoxides

A series of new recyclable chiral dicationic chromium(III) salen complexes 1 – 10 bearing different substituents, viz., hydrogen, methyl, tert‐butyl, triphenylphosphinomethyl, triethylaminomethyl, methylimidazolium, methylpyridinium, methyl‐N,N‐dimethylpyridinium at the 3,3′‐ and 5,5′‐ positions of the salen unit with (1S,2S)‐(+)‐1,2‐diaminocyclohexane, (1S,2S)‐(−)‐1,2‐diphenyl‐1,2‐diaminoethane, and (S)‐(−)‐1,1′‐binaphthyl‐2,2′‐diamine collars have been synthesized and characterized by various physico‐chemical methods. These complexes were used as catalysts for the highly enantioselective aminolytic kinetic resolution of racemic trans‐epoxides with different anilines as nucleophiles at room temperature. With the use of catalyst 3 , anti‐β‐amino alcohols were obtained in excellent yields (>99% with respect to the nucleophile) and enantioselectivities (ee>99%) with the concomitant recovery of corresponding epoxides in high optical purity (ee up to >99%) and quantitative yields in 12 h. The catalyst 3 is recyclable in the aminolytic kinetic resolution process and worked well up to six cycles with retention of enantioselectivity.     

Facile Construction of Vicinal Quaternary and Tertiary Stereocenters via Regio‐ and Stereoselective Organocatalytic Michael Addition to Nitrodienes

A highly regio‐ and stereoselective protocol for the synthesis of vicinal quaternary and tertiary stereocenters has been developed. The 6′‐OH Cinchona alkaloids ( BnCPN or BnCPD ) at low catalyst loading (0.5–5 mol%) catalyze the Michael addition of trisubstituted carbon nucleophiles to nitrodienes in good to excellent yield (up to >99), high enantioselectivity (up to 99% ee) and high diastereoselectivity (up to >99:1 dr) under mild reaction conditions.     

The Catalytic Diastereo‐ and Enantioselective Claisen Rearrangement of 2‐Alkoxycarbonyl‐Substituted Allyl Vinyl Ether

The catalytic asymmetric Claisen rearrangement of 2‐alkoxycarbonyl‐substituted allyl vinyl ethers that contain two stereogenic double bonds is described. A combination of the highly Lewis acidic [Cu{(S,S)‐tert‐Bu‐box}](H₂O)₂(SbF₆)₂ complex and molecular sieves served as catalyst and afforded the Claisen rearrangement products, substituted and functionalized α‐keto esters, in high yield with a remarkable diastereo‐ and enantioselectivity. The influence of ligand structure, counterion and allyl vinyl ether double bond configuration on the stereoselectivity of the rearrangement was briefly investigated. We propose an explanation for the rate accelerating effect of the Lewis acid as well as a stereochemical model which serve to explain and predict the stereochemical course of the copper bis(oxazoline) catalyzed Claisen rearrangement.     

An Enantioselective Three‐Component Sulfa‐Michael/Aldol Cascade Reaction and its Application to the Synthesis of Thioaryl Substituted (−)‐Bestatin Derivatives

An efficient catalytic asymmetric three‐component sulfa‐Michael/aldol cascade reaction has been developed using a chiral multi‐functional catalyst. This reaction provided facile access to γ‐sulfur‐β‐nitro‐α‐hydroxy esters bearing three consecutive linear stereocenters in high yields (up to 97%) with excellent diastereo‐ (up to >97:3 dr) and enantioselectivities (>99% ee). These compounds were readily converted into 2‐nitroallylic alcohols and potentially bioactive γ‐sulfur‐β‐amino‐α‐hydroxy esters, which could be further used for the synthesis of Bestatin derivatives.

     

Organocatalytic Asymmetric Michael Addition of Pyrazolin‐5‐ones to Nitroolefins with Bifunctional Thiourea: Stereocontrolled Construction of Contiguous Quaternary and Tertiary Stereocenters

The first organocatalytic diastereo‐ and enantioselective Michael addition reaction of 4‐substituted‐pyrazolin‐5‐ones to nitroolefins has been developed with a chiral bifunctional thiourea as organocatalyst. A wide variety of desired multi‐substituted pyrazolin‐5‐one derivatives with contiguous quaternary and tertiary stereocenters are smoothly obtained in very good yields (up to 98%) with excellent enantioselectivities (up to>99% ee) and acceptable diastereoselectivities (up to 80:20). This experimentally simple process facilitates the access to various enantioenriched, multiply substituted pyrazolin‐5‐one derivatives, potential biologically active molecules, starting from readily available starting materials.     

Storable and Air‐Stable Zirconium Complex‐Catalyzed Highly Enantioselective Darzens Reaction of Diazoacetamide with Aldehydes

An asymmetric Darzens reaction of aldehydes with diazo‐N,N‐dimethylacetamide ( 3 ) catalyzd by an air‐stable and storable chiral zirconium Lewis acid catalyst, which is formed from 3,3′‐diiodobinaphthol and tetrabutoxyzirconium, gives solely the cis‐glycidic amides in high yields with excellent enantioselectivity (up to 97% yield, >99% ee).     

Cinchona Alkaloid‐Derived Thiourea‐Catalyzed Diastereo‐ and Enantioselective [3+2] Cycloaddition Reaction of Isocyanoacetates to Isatins: A Facile Access to Optically Active Spirooxindole Oxazolines

An efficient diastereo‐ and enantioselective [3+2] cycloaddition reaction of α‐aryl isocyanoacetates to isatins catalyzed by a quinine‐derived bifunctional amine‐thiourea‐bearing sulfonamide as multiple hydrogen‐bonding donor catalyst has been investigated. The corresponding adducts, which bear a spirocyclic quaternary stereocenter at the C‐3 position of the oxindole, were obtained in good yields (51–95%), high diastereoselectivities (up to >20:1 dr) and good to excellent enantioselectivities (up to 97% ee).     

Yeast‐mediated enantioselective synthesis of chiral R‐(+)‐ and S‐(−)‐1‐phenyl‐1‐butanol from prochiral phenyl n‐propyl ketone in hexane–water biphasic culture

BACKGROUND: The hydrophobic phenyl n‐propyl ketone was used as a model compound to examine alcohol dehydrogenase activity in Saccharomyces cerevisiae mediated cell culture. Parameters such as pH, hexane‐to‐water volume percentage, and the amount of cofactor Zn²⁺ ion for either cell growth or reduction were studied to see their effect on the enantioselectivity toward the product R‐(+)‐ or S‐(?)‐1‐phenyl‐1‐butanol. RESULTS: The pH for cell growth in aqueous culture was 7.0, while the pH for reduction in the aqueous portion of the biphasic culture was 5.0. Without Zn²⁺ ion the biphasic cultures of middle to high hexane‐to‐water volume percentage exhibited an R‐(+)‐1‐phenyl‐1‐butanol enantiomeric excess of 53.7% to > 99%. Without Zn²⁺ ion the biphasic cultures at low hexane‐to‐water volume percentage possessed an S‐(?)‐1‐phenyl‐1‐butanol enantiomeric excess of 14.5–46.5%. Exclusively, the enantioselectivity for biphasic cultures containing Zn²⁺ ion was an S‐(?)‐1‐phenyl‐1‐butanol enantiomeric excess of 27.5% to > 99%. Reduction mediated in aqueous culture with varied amount of Zn²⁺ ion by the yeast Candida utilis also showed an S‐(?)‐1‐phenyl‐1‐butanol enantiomeric excess of 79.2–95.4%. CONCLUSION: The enantioselectivity of S. cerevisiae mediated biphasic culture reduction of phenyl n‐propyl ketone can be manipulated through the cofactor Zn²⁺ ion and the hexane volume percentage of the biphasic culture. Copyright © 2008 Society of Chemical Industry     

A Protection Strategy Substantially Enhances Rate and Enantioselectivity in ω‐Transaminase‐Catalyzed Kinetic Resolutions

The kinetic resolution of 3‐aminopyrrolidine (3AP) and 3‐aminopiperidine (3APi) with ω‐transaminases was facilitated by the application of a protecting group concept. 1‐N‐Cbz‐protected 3‐aminopyrrolidine could be resolved with >99% ee at 50% conversion, the resolution of 1‐N‐Boc‐3‐aminopiperidine yielded 96% ee at 55% conversion. The reaction rate was up to 50‐fold higher by using protected substrates. Most importantly, enantioselectivity increased remarkably after carbamate protection compared to the unprotected substrates (86 vs. 99% ee). Surprisingly, benzyl protection of 3AP had no influence on enantioselectivity. A possible explanation for this observation could be the different flexibility of the benzyl‐ or carbamate‐protected 3AP as confirmed by NMR spectroscopy.     

Catalytic Asymmetric Five‐Component Tandem Reaction: Diastereo‐ and Enantioselective Synthesis of Densely Functionalized Tetrahydropyridines with Biological Importance

The first catalytic asymmetric five‐component tandem reactions of β‐keto esters, aromatic aldehydes and anilines have been established in the presence of a chiral phosphoric acid, affording densely functionalized tetrahydropyridines with concomitant generation of five σ bonds and two stereogenic centers in high diastereo‐ and enantioselectivities (up to >99:1 dr, 95:5 er). In addition, the first isolation and preparation of a diene species as the key intermediate of the reaction has been successfully realized, leading to the formation of the desired tetrahydropyridine via further condensation with in situ generated imine, which supported the proposed tandem [4+2] reaction pathway to some extent. This protocol not only represents the first enantioselective example of this five‐component tandem reaction, but also provides an unprecedented access to enantioenriched tetrahydropyridines with structural diversity, which holds great potential in medicinal chemistry.     

4,4′‐Disubstituted‐L‐proline Catalyzes the Direct Asymmetric Michael Addition of Aldehydes to Nitrostyrenes

In a search for small organic molecules as catalysts for the direct asymmetric Michael addition reaction of aldehydes to nitrostyrenes, 4,4′‐di(naphthalene‐1‐ylmethyl)‐L ‐proline 1c and a catalytic amount of 4‐dimethylaminopyridine (DMAP) were found to be an efficient system for the Michael addition of aldehydes to nitrostyrenes with high diastereo‐ and enantioselectivity and broad substrate range.     

Efficient Asymmetric Synthesis of 2,6‐Disubstituted 2H‐Dihydropyrans via a Catalytic Hetero‐Diels–Alder/Allylboration Sequence

[4+2] Cycloaddition of (E)‐3‐borylacrolein 1 with ethyl vinyl ether, catalysed by chromium complex (1R,2S) or (1S,2R) 2 , led to the corresponding cycloadducts with high diastereo‐ and enantioselectivities. Further reaction with aldehydes offers an attractive asymmetric route to synthetically useful substituted 3,4‐dihydro‐2H‐pyrans.     

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.