A general organocatalytic enantioselective malonate addition to alpha,beta-unsaturated enones

A general enantioselective organocatalytic conjugate addition procedure of a variety of malonates to alpha,beta-unsaturated enone systems is presented. The reaction is efficiently catalysed by the pyrrolidinyl tetrazole catalyst 1. Cyclic, acyclic and aromatic enones can be used and the reaction with ethyl malonates 3 b provides the Michael addition products in high yields with good to excellent enantioselectivities. Since only 1.5 equivalents of malonate are used as a reagent, the reaction is readily scaled and practical to operate. Furthermore, the malonate addition products can be easily mono decarboxylated without loss in enantiomeric excess by enzymatic or sodium hydroxide mediated methods.     

Novel imidazolidine-tetrazole organocatalyst for asymmetric conjugate addition of nitroalkanes

The Michael addition of nitroalkanes to alpha,beta-unsaturated enones catalyzed by a novel chiral imidazolidine-2-yltetrazole organocatalyst has been investigated. The new more soluble organocatalyst decreases reaction times and improves enantioselectivities compared to other catalysts. The Michael addition adducts were obtained with up to 92% ee. [reaction: see text]     

Rhodium-catalyzed enantioselective conjugate addition of organoboronic acids to alpha,beta-unsaturated sulfones

[reaction: see text] A general method for the enantioselective catalytic conjugate addition to acyclic alpha,beta-unsaturated sulfones is described. Using metal-chelating alpha,beta-unsaturated pyridyl sulfones as substrates, the rhodium-catalyzed chiraphos-mediated addition of organoboric acids takes place in excellent yield and high enantioselectivity. The subsequent elimination of the pyridylsulfonyl group by Julia-Kociensky olefination provides a novel approach to the enantioselective synthesis of allylic substituted alkenes.     

Design and synthesis of new chiral pyridine–phosphite ligands for the copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones

A series of new chiral pyridine–phosphite ligands have been prepared from (R)-pyridyl alcohols and BINOL-derived chlorophosphite, and successfully employed in the copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones. Using the simple and inexpensive CuBr₂ as a precursor, the enantioselective additions to various substituted acyclic enones afforded products in high yields and good enantioselectivities (up to 92% ee).     

Diphenylprolinol silyl ether as catalyst of an asymmetric, catalytic, and direct Michael reaction of nitroalkanes with alpha,beta-unsaturated aldehydes

A catalytic enantioselective direct conjugate addition of nitroalkanes to alpha,beta-unsaturated aldehydes using diphenylprolinol silyl ether as an organocatalyst has been developed. Using this methodology as a key step, short syntheses of therapeutically useful compounds have also been accomplished.     

Chiral ligand-controlled asymmetric conjugate addition of alpha-trimethylsilanylacetate to acyclic and cyclic enones

The reaction of lithium ester enolate with enones provides a challenge for chemoselectivity, that is, discrimination between a conjugate addition and a 1,2-addition. Asymmetric conjugate addition of a lithium enolate of alpha-trimethylsilanylacetate to acyclic and cyclic alpha,beta-unsaturated ketones was mediated by an external chiral ligand to give the corresponding 1,4-adducts in good enantioselectivity of 74% and good chemoselectivity.     

Highly enantioselective conjugate additions to alpha,beta-unsaturated ketones catalyzed by a (salen)Al complex

Chiral (salen)Al complex 1a catalyzes the highly enantioselective conjugate addition of carbon- and nitrogen-based nucleophiles to acyclic alpha,beta-unsaturated ketones. This methodology is tolerant of substantial variation of the ketone structure, providing access to a wide range of useful chiral building blocks in high yield and enantiomeric excess. Synthetic manipulations of the conjugate addition products are demonstrated, including the straightforward preparation of beta-amino ketones and highly enantioenriched carbo- and heterocyclic compounds.     

The effects of solvent on switchable stereoselectivity: copper-catalyzed asymmetric conjugate additions using D2-symmetric biphenyl phosphoramidite ligands

A highly enantioselective copper-catalyzed conjugate addition of diethylzinc to acyclic aromatic enones was developed with phosphoramidite ligands bearing a D(2)-symmetric biphenyl backbone. This type of reaction demonstrated that toluene and THF solvents can completely reverse the absolute configuration of the products, thus simplifying the process of accessing either enantiomer (S: 92% ee, 94% yield; R: 99% ee, 96% yield).     

Enantioselective conjugate addition of dialkylzinc and diphenylzinc to enones catalyzed by a chiral copper(I) binaphthylthiophosphoramide or binaphthylselenophosphoramide ligand system

The enantioselective conjugate addition of dialkylzinc or diphenylzinc to enones was catalyzed by a copper(I)-axially chiral binaphthylthiophosphoramide or binaphthylselenophosphoramide ligand system at room temperature (20 degrees C) or 0 degrees C, affording the Michael adducts in high yields with excellent ee for cyclic and acyclic enones. The enantioselectivity and reaction rate achieved here are one of the best results yet for the Cu-catalyzed conjugate addition to enones. It was revealed that this series of chiral phosphoramides was a novel type of S,N-bidentate ligands on the basis of (31)P NMR and (13)C NMR spectroscopic investigations. The mechanism of this asymmetric conjugate addition system has been investigated as well. We found that the acidic proton of phosphoramide in these chiral ligands play a significant role in the formation of the active species. A bimetallic catalytic process has been proposed on the basis of previous literature. The linear effect of product ee and ligand ee further revealed that the active species is a monomeric Cu(I) complex bearing a single ligand [Cu(I):ligand 1:1].     

Epi-cinchona based thiourea organocatalyst family as an efficient asymmetric Michael addition promoter: enantioselective conjugate addition of nitroalkanes to chalcones and alpha,beta-unsaturated N-acylpyrroles

A small set of easily available epi-cinchona based thiourea organocatalysts have been synthesized and tested in enantioselective Michael addition of nitroalkanes to chalcones. These bifunctional catalyst systems promoted the conjugate additions with high enantioselectivities and chemical yields. The extension of this methodology was further explored to encompass alpha,beta-unsaturated N-acylpyrroles, as a chalcone mimic. Functionally, the N-acylpyrrole moiety in the adduct acts as an ester surrogate; therefore, it can easily be transformed to various valuable and biologically relevant compounds. This approach allowed the concise stereoselective synthesis of (R)-rolipram.     

Michael addition of stannyl ketone enolate to alpha,beta-unsaturated esters catalyzed by tetrabutylammonium bromide and an ab initio theoretical study of the reaction course

Michael addition of stannyl ketone enolates to alpha,beta-unsaturated esters was accomplished in the presence of a catalytic amount of tetrabutylammonium bromide (Bu(4)NBr). Other typical systems using lithium enolate or silyl enolate with catalysts (TiCl(4) or Bu(4)NF) failed to give the desired products. The bromide anion from Bu(4)NBr coordinates to the tin center in enolate to accelerate the conjugate addition where a five-coordinated tin species was generated. The coordination of the bromide anion significantly raises the HOMO level of tin enolate and enhances its nucleophilicity. The conjugate addition provides the intermediate Michael adduct, which has an ester enolate moiety, and the adduct immediately transforms to alpha-stannyl gamma-ketoester by keto-enol tautomerization. This step contributes to the stabilization of the product system and leads to a thermodynamically favorable reaction course. An ab initio calculation reveals that the activation energy in the reaction using the bromide anion is lower than that of the reaction without using it. The transition state in either reaction course has a linear structure, not a cyclic one. This system can be applied to a variety of tin enolates and alpha,beta-unsaturated carbonyls involving enoates, enones, and unsaturated amides.     

Enantioselective formal hydration of alpha,beta-unsaturated imides by Al-catalyzed conjugate addition of oxime nucleophiles

The (salen)Al-catalyzed asymmetric conjugate addition of salicylaldoxime to alpha,beta-unsaturated imides is the key step in an efficient and highly enantioselective two-step formal hydration of these electron-deficient olefins. This reaction constitutes the first example of an enantioselective conjugate addition of an oxygen-centered nucleophile to alpha,beta-unsaturated carboxylic acid derivatives. Application of this method to chiral, nonracemic substrates revealed a high level of catalyst-induced diastereoselectivity, underscoring its potential utility for polyketide natural product synthesis.     

Highly enantioselective Michael addition of malononitrile to alpha,beta-unsaturated ketones

The highly enantioselective Michael addition of malononitrile to acyclic and cyclic alpha,beta-unsaturated ketones has been developed. The Michael reaction catalyzed by a primary amine derived from quinidine proceeded smoothly and provided the desired adducts with excellent enantioselectivities (83-97% ee).     

The thiazolium-catalyzed Sila-Stetter reaction: conjugate addition of acylsilanes to unsaturated esters and ketones

A new acyl anion addition reaction between acylsilanes and alpha,beta-unsaturated conjugate acceptors promoted by a nucleophilic organic catalyst has been disclosed. The 1,4-dicarbonyl products produced in this reaction are highly useful synthons. Neutral carbenes (or zwitterions) generated in situ from commercial thiazolium salts are used as effective catalysts for the reaction which is in contrast to established anionic catalysts typically employed to promote the required Brook rearrangement (1,2-silyl shift from carbon to oxygen) involved in the reported reaction. This process successfully utilizes acylsilanes as tunable acyl anion progenitors and is tolerant of a wide range of structural diversity on the acylsilane or the conjugate acceptor.     

Enantioselective Cu-catalyzed conjugate addition of diethylzinc to acyclic aliphatic enones

[reaction: see text] A new P-chiral phosphine bis(sulfonamide) ligand has been developed that allows the Cu-catalyzed enantioselective conjugate addition of Et(2)Zn to acyclic aliphatic enones. The reactions proceed with excellent levels of enantioselectivity (90-95% ee) with a range of enone substrates, involve the use of only 1.2 equiv of Et(2)Zn, and give best results at ambient temperature.     

Diastereoselective conjugate addition to chiral alpha,beta-unsaturated carbonyl systems in aqueous media: an enantioselective entry to alpha- and gamma-hydroxy acids and alpha-amino acids

The stereoselectivity of the ultrasonically induced zinc--copper conjugate addition of iodides to chiral alpha,beta-unsaturated carbonyl systems under aqueous conditions was studied. Alkyl iodides add diastereoselectively to methylenedioxolanone 1 and methyleneoxazolidinone 2 to afford the 1,4-addition products in good yields (38-95 %) and with high diastereomeric excess (44-90 % de). The 1,4-addition to chiral gamma,delta-dioxolanyl-alpha,beta-unsaturated esters 3-5 also proceeds with good yields (51-99 %). The diastereoselectivity is dependent on the geometry of the olefin: the Z isomer 3 gives high diastereoselectivity, while the reactions with the E isomer 4 are nonstereoselective. The reaction proceeds with excellent chemoselectivity and allows the use of iodides bearing ester, hydroxy, and amino groups. Since the 1,4-addition products can be readily hydrolyzed, this methodology constitutes a novel entry for the enantioselective synthesis of alpha- and gamma-hydroxy acids and alpha-amino acids in aqueous media. The results obtained support the radical mechanism proposed by Luche, and represent one of the few examples of a radical stereoselective conjugate addition in aqueous medium.     

Tandem asymmetric conjugate addition--silylation of enantiomerically enriched zinc enolates. Synthetic importance and mechanistic implications

[formula: see text] The zinc enolates, resulting from the copper-catalyzed enantioselective conjugate addition of dialkyl zinc reagents to cyclic and acyclic enones, could be trapped, quantitatively, as silyl enol ethers with TMSOTf in apolar solvents or with TMSCI and NEt3. These enantiomerically enriched silyl enol ethers were submitted to four synthetic transformations to show their synthetic utility. The zinc enolates obtained from acyclic enones were found to be configurationally stable, as shown by the stereochemistry of the silyl enol ethers.     

The first enantioselective organocatalytic Mukaiyama-Michael reaction: a direct method for the synthesis of enantioenriched gamma-butenolide architecture

The first enantioselective organocatalytic Mukaiyama-Michael reaction using alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective addition of 2-silyloxy furans to unsaturated aldehydes to generate a variety of butenolide systems, an important chiral synthon found among many natural isolates. The (2S,5S)-5-benzyl-2-tert-butyl-imidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted silyloxy furans to unsaturated aldehydes. A diverse range of aldehyde substrates can be accommodated in this new organocatalytic transformation. Application of this new asymmetric technology to the enantioselective total synthesis of spiculisporic acid and the corresponding 5-epi-spiculisporic acid analogue is also discussed.     

Recent topics on catalytic asymmetric 1,4-addition

Catalytic asymmetric 1,4-addition (conjugate addition; Michael addition) is one of the most powerful methods for carbon-carbon bond formation. Following the first efficient catalyst system developed by Feringa, which is composed of Cu(OTf)₂ and phosphoramidite with dialkylzincs, a variety of chiral catalysts have been reported for the catalytic asymmetric conjugate addition. In this digest review, we will first summarize novel chiral ligands that work efficiently for cyclic and acyclic enones and demonstrate the wide applicability of Michael acceptors. We will also introduce unique phenomena that include the nonlinear effect and reversal of enantioselectivity. Organomagnesium reagents have also been used instead of organozincs. Finally, we introduce the recent examples of the synthesis of natural products based on the catalytic asymmetric reaction. The rare experimental studies into the mechanism of copper-catalyzed 1,4-addition reported by Kitamura and Noyori’s group are also introduced.     

Asymmetric aza-Henry reaction under phase transfer catalysis: an experimental and theoretical study

An efficient catalytic asymmetric aza-Henry reaction under phase transfer conditions is presented. The method is based on the reaction of the respective nitroalkane with alpha-amido sulfones effected by CsOH x H2O base in toluene as solvent and in the presence of cinchone-derived ammonium catalysts. This direct aza-Henry reaction presents as interesting features its validity for both nonenolizable and enolizable aldehyde-derived azomethines and the tolerance of nitroalkanes, other than nitromethane, for the production of beta-nitroamines. The synthetic value of the methodology described is demonstrated by providing (a) a direct route for the asymmetric synthesis of differently substituted 1,2-diamines and (b) a new asymmetric synthesis of gamma-amino alpha,beta-unsaturated esters through a catalytic, highly enantioselective formal addition of functionalized alkenyl groups to azomethines. Finally, a preferred TS that nicely fits the observed enantioselectivity has been identified. Most remarkable, an unusual hydrogen bond pattern for the catalyst-nitrocompound-imine complex is predicted, where the catalyst OH group interacts with the NO2 group of the nitrocompound.