Enantioselective, NHC-Catalyzed Annulations of Trisubstituted Enals and Cyclic N-Sulfonylimines via α,β-Unsaturated Acyl Azoliums

All aboard please! A new reaction of enals and cyclic sulfonylimines, as the nucleophiles(!), is the first highly enantioselective NHC-catalyzed annulation of trisubstituted enals. The catalytically generated α,β-unsaturated acyl azolium undergoes a reaction with the enamine tautomer of the imine via an aza-Claisen rearrangement as the key C?C bond-forming step. High yields and enantioselectivities were achieved using β-, α,β-, and β,β'-substituted enals.     

Concise and divergent total synthesis of swainsonine, 7-alkyl swainsonines, and 2,8a-diepilentiginosine via a chiral heterocyclic enaminoester intermediate

The concise and divergent total syntheses of (−)-swainsonine, (−)-7-alkyl swainsonines, and (−)-2,8a-diepilentiginosine from a common chiral heterocyclic enaminoester intermediate in five-step sequences are presented. The highly efficient annulation reaction of the chiral heterocyclic enaminoester with various α,β-unsaturated carboxylates, and a straightforward carboxy inversion constituted the key features of the synthetic pathway. This work provides an example for divergent synthesis of different natural and unnatural polyhydroxylated indolizidines from a readily available platform.     

Reaction of α,β-unsaturated Fischer carbene complexes with allyl alkoxide

Optically enriched homo-binuclear Fischer chromium carbene complexes with planar chiral arene chromium complexes gave α-allyl β-arylpropionates up to 97% ee by reaction with allyl alkoxide and subsequent photo-oxidative demetalation. The chiral hetero-binuclear tungsten carbene complexes afforded anti α-allyl β-hydroxy β-arylpropionates as a major product up to 92/8 dr by the same reaction sequence. High diastereoselectivity in these reactions is contributed to the planar chirality of the arene chromium complex, even though the reaction was carried out under vigorous basic media. The reaction products, α-allyl β-arylpropionates were derived by 1,3-M(CO)₅ shift and subsequent [3,3]-sigmatropic rearrangement. Also, the corresponding chromium-uncomplexed α,β-unsaturated Fischer carbene complexes afforded α-allyl β-arylpropionates under the same conditions. Formation of β-allyl β-arylpropionates via 1,2-M(CO)₅ shift followed by [3,4]-sigmatropic rearrangement was not observed in both reactions of chromium-coordinated and the corresponding chromium-uncoordinated α,β-unsaturated Fischer carbene complexes with allyl alkoxide in the presence of base.     

A novel and expedient synthesis of optically active fluoroalkylated amino acids via palladium-catalyzed allylic rearrangement and Ireland–Claisen rearrangement

The allylic substitution reactions of various chiral α-fluoroalkylated mesylates with carboxylic acids in the presence of a palladium catalyst proceeded smoothly to give γ-fluoroalkylated allyl esters in excellent yields. The esters were subsequently subjected to Ireland–Claisen rearrangement without isolation, leading to the corresponding homochiral α-fluoroalkylated-β,γ-unsaturated amino acids in good yields.     

N-Heterocyclic carbene (NHC) catalyzed annulation of enals and vinyl ketones: a novel synthesis of [2H]-pyranones

Homoenolate annulation of vinyl ketones led to the synthesis of dihydropyranones in contrast to cyclopentenes obtained by the homoenolate annulation of chalcones, another class of α,β-unsaturated ketones.     

Enantioselective organocatalytic conjugate addition of α-nitroacetate to α,β-unsaturated ketones in water

The catalytic enantioselective conjugate addition reaction of α-nitroacetate to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of α-nitroacetate to α,β-unsaturated ketones under aqueous-phase reaction conditions afforded the corresponding Michael adducts with high enantioselectivity. The conjugate addition adducts are easily converted to chiral δ-keto nitroalkanes and δ-keto esters.     

Asymmetric synthesis of allylic secondary alcohols: a new general approach for the preparation of α-amino acids

A new general approach for the synthesis of optically active α-amino acids has been developed. The key steps involve a ruthenium catalysed cross-coupling reaction to give a range of α,β-unsaturated ketones, which were then reduced to allylic secondary alcohols in the presence of a chiral CBS oxazaborolidine. A thermal Overman rearrangement was used to prepare a series of allylic trichloroacetimidates and these were converted under standard conditions to the target α-amino acids in good overall yields.     

Enantioselective conjugate addition of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones catalyzed by chiral bifunctional organocatalysts

The catalytic enantioselective conjugate addition reaction of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones under mild reaction conditions afforded the corresponding Michael adducts with high enantioselectivity. The conjugate addition adducts are useful for the synthesis of chiral monofluoromethylated compounds.     

Lewis acid-catalyzed Meyer-Schuster reactions: methodology for the olefination of aldehydes and ketones

In principle, the most efficient and atom-economical means of converting an aldehyde or ketone into the homologated α,β-unsaturated ester is through addition/rearrangement sequences involving acetylenic π-bonds (Scheme 1). Implementation of such a strategy for the synthesis of α,β-unsaturated esters is presented: addition of ethoxyacetylene followed by scandium(III) triflate-catalyzed Meyer-Schuster rearrangement reaction. Stereoselectivities range from good to excellent in the formation of disubstituted α,β-unsaturated esters from aldehydes (Table 3). The two-stage olefination of even the most hindered ketones proceeds with near perfect efficiency (Table 4).     

Enantioselective cyclopropanation of enals by oxidative N-heterocyclic carbene catalysis

Carbene catalysed redox activation of α,β-unsaturated aldehydes is applied for generation of α,β-unsaturated acyl azoliums which undergo cyclopropanation upon reaction with a sulfur ylide and an alcohol to give the corresponding cyclopropanecarboxylic acid esters. With chiral carbenes good to excellent diastereo and enantioselectivities are obtained.     

Preparation and Reactions of Amino Acid Ester Sulfones as New Remote Asymmetrical Induced Reagents

The development of chiral auxiliary-controlled asymmetric synthesis has been receiving increasing interest in recent yearsfi,2] Various chiral auxiliary reagents have been observed[3] and a lot of results showed that variation of the chiral auxiliary could influence asymmetric induction. Recently, it has been reported the reaction of the aminated sulfones as a remote chiral auxiliary with α,β-unsaturated carbonyl compounds.[4] Here we would like to report the preparation of amino acid ester sulfones as new remote asymmetrical induced reagents and their reactions with α,β-unsaturated esters.     

Brønsted acid-mediated annulations of pyrroles featuring N-tethered α,β-unsaturated ketones and esters: Total syntheses of (±)-tashiromine and (±)-indolizidine 209I

This study provides the first report of the construction of tetrahydroindolizines and tetrahydropyrrolo[1,2-a]azepines via Brønsted acid-mediated annulation of pyrroles featuring N-tethered α,β-unsaturated esters. In addition, the Brønsted acid-catalyzed cyclization of pyrroles featuring pendant α,β-unsaturated ketones was applied to complete total syntheses of the indolizidine alkaloids (±)-tashiromine and (±)-indolizidine 209I.     

Vinylsilane mediated regiospecific cyclopentenone annulation of ketones

The development of a new cyclopentenone annulation sequence of general scope which involves Friedel-Crafts acylation of a vinylsilane with an α,β-unsaturated acid chloride followed by Nazarov cyclization is reported.     

Gold(III)-catalyzed tandem conjugate addition/annulation of 4-hydroxycoumarins with α,β-unsaturated ketones

An efficient and selective approach for the synthesis of functionalized pyranocoumarins has been developed via a gold(III)-catalyzed tandem conjugate addition/annulation reaction of 4-hydroxycoumarins with α,β-unsaturated ketones.     

Iodine-mediated Z-selective oxidation of ketones to α,β-unsaturated esters: synthesis and mechanistic studies

The Z-selective oxidation of simple acyclic ketones to Z-2,3-trisubstituted α,β-unsaturated esters is described. Enolates generated under the reaction conditions undergo double iodination followed by a Favorskii-related rearrangement to the unsaturated ester. This reaction represents the first stereoselective one-step transformation of ketones to α,β-unsaturated esters. Mechanistic studies suggest that an electrocyclic reaction governs the Favorskii-related rearrangement.     

Highly enantioselective Cu(I)-Tol-BINAP-catalyzed asymmetric conjugate addition of Grignard reagents to α,β-unsaturated esters

The copper-catalyzed conjugate addition (CA) of organometallic reagents to α,β-unsaturated carbonyl compounds is one of the most versatile synthetic methods for the construction of C-C bonds. Interestingly, the application of Grignard reagents, which are among the most widely used of organometallic compounds, in asymmetric conjugate addition (CA) reactions has received less attention. Therefore, our group and others have been exploring better catalytic systems to effect the asymmetric 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters. It is only in the past decade that significant breakthroughs have been made in this field. In our studies, we found that CuI-Tol-BINAP could catalyze the asymmetric conjugate addition (CA) reactions of Grignard reagents, including the addition of MeMgBr to α,β-unsaturated esters to afford the β-methylated esters in good yields with excellent regio- and enantioselectivities. Both enantiomers of the products could be obtained by either using the enantiomers of the chiral Tol-BINAP or by using the geometrical isomer of the starting material. This method is also suitable for other Michael acceptors. In this article, we describe the development of the asymmetric Cu(I)-Tol-BINAP catalyzed 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters and applications of this chemistry. This method provides a convenient method to synthesize β-alkyl esters with high enantioselectivity or diastereoselectivity using CuI and the inexpensive chiral ligand, Tol-BINAP.     

Asymmetric Catalytic Synthesis of Hexahydropyrrolo-isoquinolines via Three-Component 1,3-Dipolar-Cycloaddition

An asymmetric three-component 1,3-dipolar cycloaddition of 3,4-dihydroisoquinolines, bromoacetates and α,β-unsaturated pyrazole amide is realized by using a chiral N,N’-dioxide-Y(OTf)₃ complex as the catalyst. The process includes a base-promoted formation of dihydroisoquinolium ylides in situ, and a chiral Lewis acid-catalyzed asymmetric [3+2] cycloaddition with α,β-unsaturated pyrazole amides. A series of hexahydropyrrolo-isoquinolines are obtained in moderate to good yields with excellent diastereo- and enantioselectivities.     

Phosphine-catalyzed [4 + 1] annulation between α,β-unsaturated imines and allylic carbonates: synthesis of 2-pyrrolines

In this report, a phosphine-catalyzed [4 + 1] annulation between α,β-unsaturated imines and allylic carbonates is described. This reaction represents the first realization of catalytic [4 + 1] cyclization of 1,3-azadienes with in situ formed phosphorus ylides, which provides highly efficient and diastereoselective synthesis of 2-pyrrolines.     

HBTU Mediated Synthesis of α,β-Unsaturated γ-Lactams from E-α,β-Unsaturated γ-Amino Acids

The α,β-unsaturated γ-lactams have been found in many biologically active peptide natural products. Due to their biological activities, extensive efforts have been made in the literature to synthesize the α,β-unsaturated γ-lactams. Here, we are reporting the spontaneous transformation of E-α,β-unsaturated γ-amino acids into α,β-unsaturated γ-lactam through in-situ activation of free carboxylic acid using peptide coupling reagent HBTU and base DIPEA at room temperature. The transformation also involves the E→Z isomerization of α,β-unsaturated γ-amino acids. The reaction is also compatible with the peptides consisting of E-α,β-unsaturated amino acids at the C-terminus. The α,β-unsaturated γ-lactams were isolated in very good yields. Even though the reaction required very mild conditions, the products were isolated in the form of a racemic mixture. However, the products can be separated under a chiral environment. No α,β-unsaturated γ-lactams were observed if the reaction was performed in the presence of free amines. In addition, no racemization was observed during the peptide synthesis. The analysis of the reactions of various substrates revealed that amide NH and γ-CH are important for lactamization. No α,β-unsaturated γ-lactams or E→Z isomerization products were observed in the case of N-Me-(E)-α,β-unsaturated γ-amino acids, whereas in the case of E-α,β-unsaturated γ,γ-dimethyl amino acid α,β-unsaturated γ-lactam was isolated, however, with low yield.     

α-Bromo-β,γ-unsaturated ketenes for the synthesis of α-benzylamino-β,γ-unsaturated acids

The synthesis of α-benzylamino-β,γ-unsaturated acids has been developed starting from α-bromo-α,β-unsaturated chlorides. Via treatment of the acyl chlorides with (R)-pantolactone in the presence of TEA, the in situ formation of the deconjugated ketenes and their direct transformation into chiral esters was performed. The substitution of bromine with benzylamine, followed by acid hydrolysis, allowed to us obtain enantiomerically enriched α-benzylamino-β,γ-unsaturated acids.