The One‐Pot Wittig Reaction: A Facile Synthesis of α,β‐Unsaturated Esters and Nitriles by Using Nanocrystalline Magnesium Oxide

Nanocrystalline magnesium oxide was found to be an effective heterogeneous, solid base catalyst for the one‐pot Wittig reaction to afford α,β‐unsaturated esters and nitriles in excellent yields with high E‐stereoselectivity in the presence of triphenylphosphine under mild conditions.     

Chemoselective Reduction of α,β‐Unsaturated Carbonyls over Novel Mesoporous CoHMA Molecular Sieves under Hydrogen Transfer Conditions

Chemoselective reduction of α,β‐unsaturated carbonyls to the corresponding alcohols was achieved by a catalytic transfer hydrogenation (CTH) method using cobalt(II)‐substituted hexagonal mesoporous aluminophosphate (CoHMA) molecular sieve catalyst. Further, the catalyst was found to be promising as a heterogeneous catalyst as the yield was practically unchanged after up to six cycles.     

Highly Enantioselective Michael Addition of Cyclic 1,3‐Dicarbonyl Compounds to β,γ‐Unsaturated α‐Keto Esters

A highly enantioselective Michael addition of cyclic 1,3‐dicarbonyl compounds to β,γ‐unsaturated α‐keto esters catalyzed by amino acid‐derived thiourea‐tertiary‐amine catalysts is presented. Using 5 mol% of a novel tyrosine‐derived thiourea catalyst, a series of chiral coumarin derivatives were obtained in excellent yields (up to 99%) and with up to 96% ee under very mild conditions within a short reaction time.     

The Synthesis of trans‐Perhydroindolic Acids and their Application in Asymmetric Domino Reactions of Aldehyde Esters with β,γ‐Unsaturated α‐Keto Esters

(2S,3aR,7aS)‐Perhydroindolic acid, the key intermediate in the synthesis of trandolapril, and its trans‐isomers, were readily prepared. These proline‐like molecules are unique in that they contain a rigid bicyclic structure, with two hydrogen atoms trans to each other at the bridgehead carbon atoms. These molecules were used successfully as chiral organocatalysts in asymmetric domino Michael addition/cyclization reactions of aldehyde esters with β,γ‐unsaturated α‐keto esters. They proved to have excellent catalytic behavior, allowing for the synthesis of multi‐substituted, enantiomerically enriched hemiacetal esters. Under optimal conditions (using 10 mol% catalyst loading), a series of β,γ‐unsaturated α‐keto esters was examined with up to 99% de, ee and yield, respectively. Additionally, the enantiomerically enriched hemiacetal esters could be readily transformed into their corresponding bioactive pyrano[2,3‐b]pyrans (possessing a multi‐substituted bicyclic backbone).     

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.     

Bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol: an Improved Organocatalyst for the Asymmetric Epoxidation of α,β‐Enones

The asymmetric epoxidation of α,β‐enones by the readily available bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol and tert‐butyl hydroperoxide (TBHP) is described. Stereoelectronic substitution on the aryl moiety of diaryl‐2‐pyrrolidinemethanols was found to significantly affect the efficiency with respect to the previously reported (S)‐diphenyl‐2‐pyrrolidinemethanol. Improved reactivity and enantioselectivity were achieved with bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol at reduced catalyst loading (20 mol %) with ees up to 94% for chalcone epoxides under mild reaction conditions, whereas (S)‐diphenyl‐2‐pyrrolidinemethanol afforded a maximum ee of 80%. Interestingly, the methodology is applicable to the epoxidation of more challenging aliphatic or enolizable enones with good control of the asymmetric induction (up to 87% ee).     

Cationic copolymers of α,β‐poly‐(N‐2‐hydroxyethyl)‐DL‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy): synthesis and characterization

In the present study the derivatization of two water‐soluble synthetic polymers, α,β‐poly(N‐2‐hydroxyethyl)‐DL ‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy), with glycidyltrimethylammonium chloride (GTA) is described. This reaction permits the introduction of positive charges in the macromolecular chains of PHEA and PAHy in order to make easier the electrostatic interaction with DNA. Different parameters affect the reaction of derivatization, such as GTA concentration and reaction time. PHEA reacts partially and slowly with GTA; on the contrary the reaction of PAHy with GTA is more rapid and extensive. The derivatization of PHEA and PAHy with GTA is a convenient method to introduce positive groups in their chains and it permits the preparation of interpolyelectrolyte complexes with DNA. © 2000 Society of Chemical Industry     

Efficient Lipase‐Catalyzed Kinetic Resolution and Dynamic Kinetic Resolution of β‐Hydroxy Nitriles. Correction of Absolute Configuration and Transformation to Chiral β‐Hydroxy Acids and γ‐Amino Alcohols

Chemoenzymatic dynamic kinetic resolution of β‐hydroxy nitriles 1 has been carried out using Candida antarctica lipase B and a ruthenium catalyst. The use of a hydrogen source to depress ketone formation in the dynamic kinetic resolution yields the corresponding acetates 2 in good yield and high enantioselectivity. It is shown that the ruthenium catalyst and the enzyme can be recycled when used in separate reactions. We also report on the preparation of various enantiomerically pure β‐hydroxy acid derivatives and γ‐amino alcohols from 1 and 2. The latter compounds were also used to establish the correct absolute configuration of 1 and 2.     

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.     

Ruthenium(II)‐Catalyzed Protocol for Preparation of Diverse α,β‐ and β,β‐Dihaloenones from Diazodicarbonyls

Efficient one‐step syntheses of α,β‐ and β,β‐dihaloenones were achieved by ruthenium(II)‐catalyzed reactions between cyclic or acyclic diazodicarbonyl compounds and oxalyl chloride or oxalyl bromide in moderate to good yields. This methodology offers several significant advantages, which include ease of handling, mild reaction conditions, one‐step reaction, and the use of an effective and non‐toxic catalyst. The synthesized compounds were further transformed into highly functionalized novel molecules bearing aromatic rings on the enone moiety using the Suzuki reaction.

     

Enantioselective Aza‐Morita–Baylis–Hillman Reaction Using Aliphatic α‐Amidosulfones as Imine Surrogates

The bifunctional catalyst 6′‐deoxy‐6′‐acylamino‐β‐isocupreidine ( 1 ) served both as a base to trigger the in situ generation of N‐sulfonylimine from readily available α‐amidosulfones and as a chiral nucleophile to initiate the enantioselective aza‐Morita–Baylis–Hillman (aza‐MBH) reaction. α‐Methylene‐β‐amino‐β‐alkyl carbonyl compounds, difficultly accessible previously, can now be synthesized in excellent yields and enantioselectivities.     

Multi‐Enzymatic Synthesis of Optically Pure β‐Hydroxy α‐Amino Acids

A novel enzymatic production system of optically pure β‐hydroxy α‐amino acids was developed. Two enzymes were used for the system: an N‐succinyl L ‐amino acid β‐hydroxylase (SadA) belonging to the iron(II)/α‐ketoglutarate‐dependent dioxygenase superfamily and an N‐succinyl L ‐amino acid desuccinylase (LasA). The genes encoding the two enzymes are part of a gene set responsible for the biosynthesis of peptidyl compounds found in the Burkholderia ambifaria AMMD genome. SadA stereoselectively hydroxylated several N‐succinyl aliphatic L ‐amino acids and produced N‐succinyl β‐hydroxy L ‐amino acids, such as N‐succinyl‐L ‐β‐hydroxyvaline, N‐succinyl‐L ‐threonine, (2S,3R)‐N‐succinyl‐L ‐β‐hydroxyisoleucine, and N‐succinyl‐L ‐threo‐β‐hydroxyleucine. LasA catalyzed the desuccinylation of various N‐succinyl‐L ‐amino acids. Surprisingly, LasA is the first amide bond‐forming enzyme belonging to the amidohydrolase superfamily, and has succinylation activity towards the amino group of L ‐leucine. By combining SadA and LasA in a preparative scale production using N‐succinyl‐L ‐leucine as substrate, 2.3 mmol of L ‐threo‐β‐hydroxyleucine were successfully produced with 93% conversion and over 99% of diastereomeric excess. Consequently, the new production system described in this study has advantages in optical purity and reaction efficiency for application in the mass production of several β‐hydroxy α‐amino acids.

     

Rhodium‐Catalyzed Asymmetric Hydroformylation of 1,1‐Disubstituted Allylphthalimides: A Catalytic Route to β3‐Amino Acids

The high enantioselective rhodium‐catalyzed hydroformylation of 1,1‐disubstituted allylphthalimides has been developed. By employing chiral ligand 1,2‐bis[(2S,5S)‐2,5‐diphenylphospholano]ethane [(S,S)‐Ph‐BPE], a series of β³‐aminoaldehydes can be prepared with up to 95% enantioselectivity. This asymmetric procedure provides an efficient alternative route to prepare chiral β³‐amino acids and alcohols.     

Organoselenium‐Catalyzed Baeyer–Villiger Oxidation of α,β‐Unsaturated Ketones by Hydrogen Peroxide to Access Vinyl Esters

By carefully screening the organoselenium pre‐catalysts and optimizing the reaction conditions, simple dibenzyl diselenide was found to be the best pre‐catalyst for Baeyer–Villiger oxidation of (E)‐α,β‐unsaturated ketones with the green oxidant hydrogen peroxide at room temperature. The organoselenium catalyst used in this reaction could be recycled and reused several times. This new method was suitable not only for methyl unsaturated ketones, but also for alkyl and aryl unsaturated ketones. Therefore, it provided a direct, mild, practical, highly functional group‐tolerant process for the chemoselective preparation of the versatile (E)‐vinyl esters from the readily available (E)‐α,β‐unsaturated ketones. A possible mechanism was also proposed to rationalize the activity of the organoselenium catalyst in the presence of hydrogen peroxide in this Baeyer–Villiger oxidation reaction.

     

Poly‐α,β‐(3‐hydroxypropyl)‐DL‐aspartamide: A new drug carrier

Poly‐α,β‐(3‐hydroxypropyl)‐DL ‐aspartamide (PHPA) was synthesized by the ring‐open reaction of polysuccinimide (PSI) and 3‐hydroxypropylamine. The polymer was characterized by ¹H‐NMR, ¹³C‐NMR, FTIR, and GPC. Mark–Houwink coefficients were obtained from viscometry and GPC measurements, K = 5.53 × 10⁻³ and α = 0.78 in water. The acute toxicity of PHPA was examined and it revealed no death in ICR mice up to the dose treated of 15.3 kg/kg, and hematological parameters showed no significant difference between treated and control animals. The potential use of PHPA as a drug carrier was also investigated. In a typical case, a contraceptive drug, norethindrone (NET), was bonded to PHPA, and the drug sustained released as long as 120 days an in vitro test. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 2411–2417, 2000     

Efficient and Green Route to γ‐Lactams by Copper‐Catalysed Reversed Atom Transfer Radical Cyclisation of α‐Polychloro‐N‐allylamides,using a Low Load of Metal (0.5 mol%)

The cyclisation of N‐allyl‐N‐substituted‐α‐polychloroamides is efficiently obtained through a copper‐catalysed activators regenerated by electron transfer–atom transfer radical cyclisation process, with a metal load of only 0.5 mol%. The redox catalyst is introduced in its inactive form as copper(II) chloride/[nitrogen ligand] complex, and continuously regenerated to the active copper(I) chloride/[nitrogen ligand] species by ascorbic acid. To preserve the catalyst integrity, the hydrochloric acid, released after each regeneration cycle, has been quenched by carbonate. The choice of the solvent is critical, the best performance being observed in ethyl acetate‐ethanol (3:1).     

Catalytic Hydrogenation of α‐Iminophosphonates as a Method for the Synthesis of Racemic and Optically Active α‐Aminophosphonates

It was shown that the catalytic hydrogenation of α‐iminophosphonates by molecular hydrogen can serve as a convenient method for the synthesis of racemic and optically active α‐aminophosphonates. Up to 94% ee was achieved in the rhodium‐catalyzed enantioselective hydrogenation using chiral ligand (R)‐BINAP.     

Chemoenzymatic Preparation of Enantiopure Homoadamantyl β‐Amino Acid and β‐Lactam Derivatives

Racemic cis‐10‐azatetracyclo[7.2.0.1^2,6.1^4,8]tridecan‐11‐one was prepared from homoadamant‐4‐ene by chlorosulfonyl isocyanate addition. The transformation of the β‐lactam to the corresponding β‐amino ester followed by Candida antarctica lipase A‐catalyzed enantioselective (E>>200) N‐acylation with 2,2,2‐trifluoroethyl butanoate afforded methyl (1R,4R,5S,8S)‐5‐aminotricyclo[4.3.1.1^3,8]undecane‐4‐carboxylate and the (1S,4S,5R,8R)‐butanamide with>99% ee at 50% conversion. Alternatively, transformation of the β‐lactam to the corresponding N‐hydroxymethyl‐β‐lactam and the following Pseudomonas cepacia (currently Burkholderia cepacia) lipase‐catalyzed enantioseletive O‐acylation provided the (1S,4S,6R,9R)‐alcohol (ee=87%) and the corresponding (1R,4R,6S,9S)‐butanoate (ee>99%). In the latter method, competition for the enzyme between the (1R,4R,6S,9S)‐butanoate, 2,2,2‐trifluoroethyl butanoate and the hydrolysis product, butanoic acid, tended to stop the reaction at about 45% conversion and finally gave racemization in the (1S,4S,6R,9R)‐alcohol with time.     

Effect of nucleating duality on the formation of γ‐phase in a β‐nucleated isotactic polypropylene copolymer

BACKGROUND: It is a challenge for polymer processing to promote the formation of γ‐phase under atmospheric conditions in isotactic polypropylene (iPP) copolymer containing chain errors. Incorporation of an α‐nucleator in iPP copolymer seems reasonable since it can enhance non‐isothermal crystallization. Up to now, however, the issue regarding a β‐nucleated iPP copolymer still remains unclear, which is the subject of this study. RESULTS: The results indicate that the γ‐phase indeed occurs in a β‐nucleated random iPP copolymer with ethylene co‐unit (PPR) sample and becomes predominant at slow cooling rates (e.g. 1 °C min^?1) where the formation of the β‐form is suppressed to a large extent. With detailed morphological observations the formation of γ‐phase in the β‐nucleated PPR sample at slow cooling rate is unambiguously attributed to the nucleating duality of the β‐nucleator towards α‐ and β‐polymorphs. The α‐crystals, induced by the β‐nucleator, serve as seeds for the predominant growth of the γ‐phase. Moreover, the presence of the β‐nucleator, acting as heterogeneous nuclei, promotes the formation of γ‐phase in the nucleated PPR sample, at least to some extent. CONCLUSION: The findings in this study extend our insights into the formation of γ‐phase in β‐nucleated iPP copolymer and, most importantly, provide an alternative route to obtain iPP rich in γ‐phase. Copyright © 2008 Society of Chemical Industry     

Copper‐Catalyzed Cyclization and Azidation of γ,δ‐Unsaturated Ketone O‐Benzoyl Oximes

An intramolecular imination/azidation sequence has been realized through the tetrakis(acetonitrile)copper(I) hexafluorophophate [Cu(CH₃CN)₄PF₆]‐catalyzed reaction of γ,δ‐unsaturated ketone O‐benzoyl oximes with trimethylsilyl azide (TMSN₃). The reaction proceeds via the copper‐mediated N O cleavage and subsequent C N forming 5‐exo cyclization. The thus formed intermediate is then azidated to afford the corresponding dihydropyrrole product. Preliminary mechanistic investigations suggest that the cyclization step does not involve a radical intermediate.