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Structural constraints for C 2-symmetric heterocyclic organocatalysts in asymmetric aldol reactions
Abstract
Asymmetric aldol reactions were studied in the presence of heterocyclic bimorpholine- and bipiperidine-type organocatalysts. Bimorpholine derivatives were found to be more reactive and more selective in intramolecular, as well as intermolecular, reactions.
... Subsequently, the same authors studied bipiperidine C-15 analogue to bimorpholine C-14 with the aim to identify catalysts that could be obtained with a simpler synthetic route [67]. Unfortunately, the bipiperidine derivative was a much less efficient catalyst than the corresponding bimorpholine derivative, both for reactivity and selectivity. ...
The Wieland–Miescher ketone, Hajos–Parrish–Eder–Sauer–Wiechert ketone, and their analogues are bicyclic diketones essential as building blocks for the synthesis of several natural and bioactive molecules. For this reason, since 1971, when Hajos and Parrish and Eder, Sauer, and Wiechert reported the stereoselective synthesis of these compounds promoted by L-proline, numerous methodologies and organocatalysts have been studied over the years with the aim of identifying increasingly efficient asymmetrical syntheses of these bicyclic ketones. This review will outline the methodological and stereochemical features of the organocatalytic stereoselective synthesis of these bicyclic scaffolds based on the different organocatalysts employed from 1971 until today. Particular emphasis will be given to the structural features of the catalysts and to the reaction conditions.
Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.
A polystyrene-supported, recyclable, BINOL-derived chiral phosphoric acid has been applied to the desymmetrization of meso -diones to produce enantioenriched cyclohexenones.
Some simple L-proline derivatives were designed as the organocatalysts for asymmetric synthesis of (S)-Wieland-Miescher Ketone. Their catalytic efficiencies were predicted based on DFT (Density Functional Theory) calculations. The results of DFT calculations were in good agreement with that of experiment. In order to further investigate the effects of substituent groups attached to CONH on catalytic efficiencies, 12 other L-proline derivatives were designed, synthesized and tested the catalytic efficiencies. Some of title organcatalysts (C04 and D01) exhibited excellent catalytic efficiencies (up to 93% ee and 88% yield) with a very low loading (0.5-1 mol%) under solvent-free conditions. Meanwhile, microwave irradiation was used for accelerating the reaction, and the reaction time had been decreased to 3 hours. Organocatalysts D01 derived from cheap isopropylamine would make the preparation of (S)-Wieland-Miescher Ketone a lot easier and cheaper.
The Hajos-Parrish-Eder-Sauer-Wiechert reaction can be considered as the origin of asymmetric organocatalysis, giving rise to the Wieland-Miescher ketone 1 (WMK), a versatile building block. Although 40 years have passed since its discovery, a highly enantioselective and scalable synthesis of the WMK has remained elusive. This account details a solution to that problem that came about in the development of methodology towards C-8a WMK analogues as part of the total synthesis of complex diterpene natural products. The work has been placed in the context of the historical background and reactivity of this important building block, highlighting the challenges faced by organocatalysis in large-scale reactions.
1 Introduction
2 The Wieland-Miescher Ketone
2.1 The Hajos-Parrish-Eder-Sauer-Wiechert Reaction: A Historical Perspective
2.2 Practicalities of the Wieland-Miescher Ketone Synthesis Using Proline
2.3 Alternative Catalysts for the Synthesis of the Wieland-Miescher Ketone
3 Background to Developing a New Wieland-Miescher Ketone Synthesis
4 Optimization of Method and Conditions
5 Key Reactions of the Wieland-Miescher Ketone
5.1 Reduction, Oxidation, Protection, and Non-C-C-Bond-Forming Reactions
5.2 C-C-Bond-Forming Reactions
5.3 Ring-Expansion and -Contraction Reactions
6 Conclusions and Future Considerations
Known and new N-(2-pyrrolidinylmethyl)amines, e.g. (I), containing alkyl, cycloalkyl, branched alkyl and arylalkyl substituents are applied as alternative chiral amine mediators in the HPESW reaction to get the Wieland—Miescher ketone (III).
A novel prolylsulfonamide derived from ethylene diamine and its supported counterpart has been prepared and tested as enantioselective intramolecular aldol reaction of cyclic and acyclic triketones. Good to excellent yields and enantioselectivities have been obtained in water and under solvent free conditions.
New or known N-benzyl-N-(2-pyrrolidinylmethyl)amine derivatives bearing a variety of substituents on the aromatic ring were easily prepared from N-Boc-proline or N-Boc-prolinol. The enantioselectivity of the intramolecular asymmetric aldol reaction mediated by a combination of the amine derivative and Bronsted acid to prepare Wieland-Miescher ketone was examined in detail. During the examination, remarkable substitutional effects on the aromatic ring were observed. Development of a catalytic version of the reaction was successfully achieved by the use of N-[(9-anthracenyl)methyl]-N-(2-pyrrolidinylmethyl)amine in the presence of dichloroacetic acid.
Bimorpholine and bipiperidine are efficient organocatalysts. Stereoselectivity of reactions catalysed by bimorpholine and bipiperidine strongly depend on their protonation – only the protonated form of the catalyst leads to stereoselective reactions. In this study the conformations of these compounds, as well as some reaction intermediates, are investigated computationally. Significant changes in the conformations are observed when the compounds are protonated, caused by intramolecular hydrogen bonding.
A general method for the synthesis of 5,5′-disubstituted bimorpholines is proposed. According to the method, methyl-substituted and benzyl-substituted compounds were synthesized, starting from tartaric ester acetal. Target compounds were obtained in good yield and high enantiomeric purity.
A general three-component triple cascade reaction through an iminium-enamine-iminium sequential activation initiated by a hetero-Michael addition to alpha,beta-unsaturated aldehyde affords [3.2.0]heterobicycles in high diastereoselectivity. The rate and diastereoselectivity of the reaction depended on the (E)-4-heterocrotonate and size of the secondary amine. The enantiomers of the major diastereoisomer of oxa- and azabicyclo[3.2.0]heptane derivatives were separated by enzymatic kinetic resolution with immobilized Candida Antarctica Lipase B (CALB), with E values up to 153. The absolute configuration of the nonacylated enantiomer of oxabicyclo[3.2.0]heptane was determined by single crystal X-ray analysis.
Organocatalytic double Michael reaction and the subsequent aldol condensation of (E)-7-oxooct-5-enal and 3-arylpropenal (e.g., cinnamaldehyde) provided octahydro-6-oxo-1-phenylnaphthalene-2-carbaldehyde in high diastereoselectivity and high enantioselectivity (>99% ee). Structures of the adducts 5a and 5j were confirmed unambiguously by X-ray analysis.
Since the thriving use of simple (S)-proline as organocatalyst in the intermolecular direct aldol reaction in 2000, new reaction conditions have been investigated
with this molecule to overcome the initial reaction inconveniences such as slow reaction rate, high catalyst loading, need
of high polar solvents and huge excesses of reagents. At the same time, an arsenal of new catalytic systems have been designed
to improve the early reported proline efficiency, increasing the substrate scope of the reaction and facilitating their application
to a large scale or natural product synthesis. Throughout this chapter these new inputs for this well-known process as well
as the related C-C bond formation Morita-Baylis-Hillman reaction, in which the last step of the overall reaction is also an
aldol process, will be discussed.
In the title compound, C10H22N2
2+·2Br−, a precursor in the synthesis of organocatalysts, the bipiperidinium ion is located on a twofold rotation axis which passes through the mid-point of the central C—C bond. The piperidinium ring adopts a chair conformation. In the crystal, the cations are linked together by Br− ions through N—H⋯Br hydrogen bonds, forming layers parallel to the ab plane.
Asymmetric organocatalysis has been providing powerful and practical methods for the highly stereo-controlled construction of a huge variety of carbo- and heterocyclic compounds. In the case of polycyclic systems, either fused, bridged, or spiranic ring arrangements can be accessed. Around 150 different small chiral organic molecules have been proven to be useful catalysts in asymmetric cyclization, annulation, and cycloaddition processes. Some of these processes such as ntramolecular aldol reactions, intramolecular aza-Michael reactions, or Diels-Alder cycloadditions, have reached impressive levels of stereoselective control and are increasingly being used in enantioselective total syntheses. Polyene cyclizations, domino processes, combination of organocatalysis with transition metal-based catalysis and/or biocatalysis, polymer-supported and supramolecular-gel-supported catalysts, self-assembled organocatalysts, and multiphase homogeneous catalysis and flow chemistry are experiencing a fast growth.
A novel multicomponent cascade reaction led to the formation of a strained 3-azabicyclo[3.2.0]heptane derivative 4. The unstable ester 4 was reduced in a one-pot procedure to a stable alcohol 6. The formation of the bicyclic product is highly diastereoselective, predominantly affording one diastereoisomer. The obtained azabicycloheptanes are important pharmacophores.
A complex derived from the enantiomeric bipiperidine and copper(II) acetate hydrate is an efficient catalyst for the enantioselective Henry reaction. The easy availability of both catalyst components, mild reaction conditions, high yield, and good to excellent enantioselectivity make the catalyst useful for everyday practice.
The utility of C(2)-symmetric bipiperidine and bimorpholine derivatives as organocatalysts in the Michael addition of enamine intermediates formed from aldehydes to nitroolefins has been demonstrated. The best results were obtained when the reaction was run in the presence of (2R,2'R)-N-iPr-bipiperidine. The products were formed via an enamine intermediate with high diastereo- and enantioselectivity with relatively short reaction times.
The first total synthesis of AB-ring system of an antipro-liferative and cytotoxic 9,11-secosterol 1 is described. Enantiomer-ically pure (3S,5S,6S,10S)-3,6-diacetoxy-10-methylbicyclo[4.4.0]-decan-9-one 8 (steroidal numeration) was prepared from (S)-Wieland-Miescher ketone.
The reaction of enantiopure 4-oxoazetidine-2-carbaldehydes with unmodified ketones was catalyzed by L-proline as well as by D-proline, to give the corresponding gamma-amino-beta-hydroxy ketones with good yields and diastereoselectivities. The obtained results implied that (2R,3R)-4-oxoazetidine-2-carbaldehydes and L-proline are a matched pair for diastereoselective induction.
PEP and aldolase mimicry is the key for a direct organocatalytic entry to precursors of ulosonic acids, biomolecules of enormous importance in biology, chemistry and medicine; in the key aldol reaction the dimethylacetal of pyruvic aldehyde is used as phosphoenolpyruvate (PEP) equivalent and the amino acid proline functions as an organocatalyst, imitating the enzyme.
This review is intended to update the impressive amount of recent developments of asymmetric organocatalysis in numerous reaction types, such as nucleophilic additions to electron-deficient CC double bonds, nucleophilic additions to CO double bonds, nucleophilic additions to CN double bonds, nucleophilic additions to unsaturated nitrogen, nucleophilic substitutions at aliphatic carbon, cycloaddition reactions, oxidations, reductions, kinetic resolutions and miscellaneous reactions, covering the literature from 2005 to 2007. This review clearly demonstrates the explosive growth and power of this new field of organic chemistry, which has become, in the last few years, the third methodology of asymmetric catalysis besides organometallic and enzymatic catalysis.Figure optionsView in workspaceDownload full-size imageDownload as PowerPoint slide
The synthesis of 3,3′-bimorpholine and its N-alkyl derivatives is described. These new diamine derivatives were revealed to be efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitroalkenes with excellent enantioselectivity (up to 90% ee). The potential of these organocatalysts was also demonstrated for the highly enantioselective intramolecular aldol reaction affording the Wieland-Miescher ketone with tremendous enantioselectivity (up to 95% ee).
The effect of bases, acids, and water as additives in proline-catalyzed ketone–aldehyde aldol reactions has been studied. While the reaction appears to be relatively tolerant to small amounts of tertiary amine bases or weak acids, it stops completely with strong acids. The use of water as an additive had a highly beneficial effect on reactions that were conducted with a stoichiometric ratio of ketone to aldehyde, especially with cyclic ketones. This allows the efficient use of more precious ketones such as 4-thianone as donors in the direct enantioselective aldol and facilitates purification.
Enamines react with aldehydes in the presence of Lewis acids such as BF3·OEt2 to give the corresponding crossed aldol products in good yields. Reaction of dienamines with aldehydes gives the corresponding β,γ-unsaturated α-(1-hydroxyalkyl) carbonyl compounds.
Enamines, prepared readily from various carbonyl compounds, react with acetals or trialkyl orthoformates in the presence of Lewis acids such as BF3·OEt2 to give corresponding β-alkoxy carbonyl compounds or α-dialkoxymethyl carbonyl compounds in good yields. The reaction of dienamines with acetals or trialkyl orthoformates also selectively gives corresponding β,γ-unsaturated α-(α-alkoxyalkyl) carbonyl compounds or β,γ-unsaturated α-diakoxymethyl carbonyl compounds in good yields.
Second-order rate constants (KNu) have been measured for the addition of 44 primary amines (including five α-effect amines), 28 secondary amines, 19 tertiary amines, ammonia and hydroxide ion to the vinyl group of the 1-methyl-4-vinylpyridinium cation (1) in aqueous solution at 25° C (ionic strength 0.1 mol dm–3). Nucleophilic attack is shown to be rate-determining for primary and secondary amines, with secondary amines being generally more reactive than primary amines of the same basicity. After classification of these species in terms of structure, they describe a number of Brønsted-type correlations having βnuc in the range 0.35–0.54 for six structural classes of primary amine, βnuc= 0.48 for α-effect amines, and βnuc in the range 0.23–0.34 for four structural classes of secondary amine. Substitution upon the α-carbon atom reduces amine nucleophilicity of both primary and secondary amines. The presence of an unsaturated carbon atom (either sp2- or sp-hybridized) as the β-carbon atom leads to an enhanced reactivity relative to the corresponding β-sp3 species in all cases. Tertiary amines are in general less reactive than other amines of the same basicity. Brønsted-type plots for tertiary amines present the appearance of random scatter which is not readily decipherable in terms of structure. β-Hydroxy and β-amino tertiary amines are unusually reactive relative to their basicity. All of these phenomena suggest that protonation of the carbanionic intermediate by a molecule of water is the rate-determining step for the addition of tertiary amines to 1.
A highly efficient enantioselective synthesis of protected trans-hydrindenol diene 1 is described starting from the readily available Hajos–Parrish ketone. The reported methodology represents the most convenient route (10 steps, 31% overall yield) to both enantiomeric forms of a steroid (estrogenic) CD-ring diene precursor.
An anchimeric effect of vicinal dimesylate in the intramolecular nucleophilic substitution by amine is described. One sulfonate group of the dimesylate acts as an internal nucleophile and the other as a leaving group, affording meso-bimorpholine in the intramolecular cyclization. omega,omega'-Dimesylate omits this effect and the target compound is obtained with high ee.
A convenient method for proline-catalyzed asymmetric aldol reactions using synthons of straight-chain aliphatic aldehydes, and aldehydes bearing a 1,3-dithiane moiety at the β-position, has been developed. This method was successfully applied to the synthesis of (−)-(5R,6S)-6-acetoxyhexadecanolide, an oviposition attractant pheromone of the female Culex mosquito.
Novel bimorpholine-derived organocatalysts have been used for highly enantioselective intramolecular aldol reaction affording Wieland-Miescher ketone in high yield and enantioselectivity (up to 92% and 95%, respectively).
The separation of racemic 2,2′-bipiperidine and the meso form has been performed through the dihydrochloride salt of the diamine. The reaction of racemic 2,2′-bipiperidine with [Co(NO2)6]3– has been shown to yield only one DL pair of trans-bis(2,2′-bipiperidine)dinitrocobalt(III) complexion. The dinitro-complex has been characterized and optically resolved using ammonium D-2- bromo-4,7-dimethyl-3-oxobicyclo[2.2.1]heptane-7-methanesulphonate. Optically pure (–)589-2,2′-bipiperidine was recovered from the less soluble diastereoisomer and shows a specific rotation of –12.2°. The stereoselective formation of the trans-dinitro-complex is discussed in relation to the predictions of strain energy minimization calculations.
New and reliable procedures for the preparation of both enantiomers of 2,2‘-bipiperidine have been developed. Chiral imidazolinium salts derived from 2,2‘-bipiperidine and partially reduced biisoquinoline were prepared in high yields. Rhodium and iridium complexes of new chiral N-heterocyclic carbenes were obtained by transmetalation from corresponding silver(I) complexes. The structures of these complexes were verified by X-ray diffraction. The novel carbenes seem to range between the very electron-rich bis(amido)carbenes and the imidazole-derived carbenes with regard to the electronic ligand properties (IR evidence). Rhodium and iridium complexes were applied to a variety of catalytic asymmetric reactions. Modest enantioselectivities of up to 28% ee were observed.
The supposed color reaction of α,α′-dipiperidyl with ferrous salts is shown to be due to an oxidation or dehydrogenation product of this base, probably α,α′-bis-Δ1-piperideine. Based on the α-diimine structure of that compound stable ferrous complexes of glyoxal and biacetyl bis-N-methylimine have been prepared. Their absorption spectra are similar to the spectra of the ferrous complexes of α,α′-dipyridyl and o-phenantholine. Possible relations between the structure and the color of the α-diimine complexes are briefly discussed.
The direct Michael addition of aldehydes and ketones to nitroolefins, catalyzed by N-i-Pr-2,2′-bipyrrolidine, is described. The desired 1,4-adducts are obtained in excellent yields with enantioselectivities up to 95% ee and dr up to 95 : 5 of the syn aldehyde addition product. An unexpected inversion of diastereoselectivity was observed for the addition of α-hydroxy ketones to β-arylnitroolefins with enantioselectivities up to 98% ee. The formation of an internal hydrogen bond between the OH group of the α-hydroxy ketone and the tertiary nitrogen of the catalyst leads to the formation of a rigid cis enamine intermediate that accounts for the inversion of the expected diastereoselectivity and the very high ees.
Novel heterocycles—(2S,2′S)-bimorpholine 1 and (3S,3′S)-bimorpholine 2—were synthesised in >98% e.e. starting from tartaric acid ester.
The use of simple (S)-proline as catalyst for the intermolecular direct aldol reaction at the beginning of this century became a true milestone in the growth of organocatalysis as a useful synthetic strategy. Since then, a plethora of new organocatalytic systems have been developed allowing to reach extraordinary levels of efficiencies, widening the scope of substrates used. Several modifications have been introduced to overcome some of the initial drawbacks, such as long reaction times, high catalyst loading, excess of reagents, etc., improving the expectations for their use in large scale synthesis. All these achievements would not be possible without a partial understanding of the involved mechanism. The acquired knowledge in this area has allowed the application of this strategy to be used in the synthesis of natural products. Within this review, a comprehensive look of all these aspects will be discussed. We are grateful to the Spanish Ministerio de Educación y Ciencia, as well as to Generalitat Valenciana and University of Alicante, for their continuous financial support.
The kinetics of the reactions of the nitrogen-sulfur(VI) esters 4-nitrophenyl N-methylsulfamate (NPMS) with a series of pyridines and a series of alicyclic amines and of 4-nitrophenyl N-benzylsulfamate (NPBS) with pyridines, alicyclic amines, and a series of quinuclidines have been investigated in acetonitrile (ACN) in the presence of excess amine at various temperatures. Pseudo-first-order rate constants (k(obsd)) have been obtained by monitoring the release of 4-nitrophenol/4-nitrophenoxide. From the slope of a plot of k(obsd) vs [amine], second-order rate constants (k'(2)) have been obtained for the pyridinolysis of NPMS, and a Brønsted plot of log k'(2) vs pK(a) of pyridine gave a straight line with beta = 0.45. However, aminolysis with alicyclic amines of NPMS gave a biphasic Brønsted plot (beta(1) = 0.6, beta(2) approximately equal to 0). Pyridinolysis and aminolysis with alicyclic amines and quinuclidines of NPBS also gave similar biphasic Brønsted plots. This biphasic behavior has been explained in terms of a mechanistic change within the E1cB mechanism from an (E1cB)(irrev) (less basic amines) to an (E1cB)(rev) (more basic amines), and the change occurs at approximately the pK(a)'s (in ACN) of NPMS (17.94) and NPBS (17.68). The straight line Brønsted plot for NPMS with pyridines occurs because the later bases are not strong enough to substantially remove the substrate proton and initiate the mechanistic change observed in the reaction of NPMS with the strong alicyclic amines and quinuclidines. An entropy study supports the change from a bimolecular to a unimolecular mechanism. This is the first clear demonstration of this E1cB mechanistic changeover involving a nitrogen acid substrate.
The mechanisms, transition states, relative rates, and stereochemistries of amine-catalyzed aldol reactions involving enamine intermediates have been explored with density functional theory (B3LYP/6-31G*) and CPCM solvation models. Primary enamine-mediated aldol reactions involve half-chair transition states with hydrogen bonding leading to proton transfer. This leads to charge stabilization and low activation energies as compared to secondary enamine-mediated aldol reactions. Oxetane intermediates can be formed when C-C bond formation occurs without H-transfer in the transition state. The stereoselectivities of reactions of ketone enamines with aldehydes, including the facial stereoselectivity involving chiral aldehydes, were modeled and compared with experimental results. Transition states for the intramolecular aldol reactions leading to the formation of hydrindanone-beta-ketol and decalone-beta-ketol aldol products showed a preference for the formation of the cis-fused rings, in agreement with experimental results.
[reaction: see text] The enantioselective total synthesis and structure revision of spirodihydrobenzofuranlactam 1 and of its regioisomer 25 are presented. Optically pure (+)-Wieland-Miescher ketone was utilized to construct the AB bicyclic core in 10 steps. Introduction of the resorcylate D-ring unit was achieved by use of our tert-butyl ester metalation sequence. Subsequent stereoselective spirocyclization to form the C-ring was followed by regioselective ring cyanation and lactam formation to produce the pentacyclic structure 1 and its regioisomer 25.
The mechanism of the proline-catalyzed aldol reaction has stimulated considerable debate, and despite limited experimental data, at least five different mechanisms have been proposed. Complementary to recent theoretical studies we have initiated an experimental program with the goal of clarifying some of the basic mechanistic questions concerning the proline-catalyzed aldol reaction. Here we summarize our discoveries in this area and provide further evidence for the involvement of enamine intermediates.
Computational studies have led to models to understand some classic and contemporary asymmetric reactions involving organocatalysts. The Hajos-Parrish-Eder-Sauer-Wiechert reaction and intermolecular aldol reactions as well as Mannich reactions and oxyaminations catalyzed by proline and other amino acids, and Diels-Alder reactions catalyzed by MacMillan's chiral amine organocatalysts have been studied with density functional theory. Quantitative predictions for several new catalysts and reactions are provided.
A novel class of phenylpyrazole fused Wieland-Miescher ketone derivatives are high affinity, receptor specific, selective modulators of glucocorticoid receptor (GR) mediated transcription in vitro, dissociating transactivation, AP-1 repression, and NF-kappaB repression from each other.
The term "organocatalysis" describes the acceleration of chemical reactions through the addition of a substoichiometric quantity of an organic compound. The interest in this field has increased spectacularly in the last few years as result of both the novelty of the concept and, more importantly, the fact that the efficiency and selectivity of many organocatalytic reactions meet the standards of established organic reactions. Organocatalytic reactions are becoming powerful tools in the construction of complex molecular skeletons. The diverse examples show that in recent years organocatalysis has developed within organic chemistry into its own subdiscipline, whose "Golden Age" has already dawned.
A comparison of previously proposed models of the C-C bond-forming step of the title reaction with density functional methods indicate that the most favored one involves an enamine intermediate undergoing a concerted aldol cyclization with proton transfer from the proline carboxylic acid group (see structure). This step is equal in energy to the intramolecular deprotonation leading to the enamine, and both are partially rate-determining steps.
On the basis of the mechanistic insight that more than one Lewis basic moiety (phosphoramide) is involved in the rate- and stereochemistry-determining step of enantioselective allylation, bidentate chiral phosphoramides were developed. Different chiral phosphoramide moieties were connected by tethers of methylene chains of varying length. The rate and enantioselectivity of allylation with allyltrichlorosilane promoted by the bidentate phosphoramides was found to be highly dependent on the tether length. A new phosphoramide based on a 2,2'-bispyrrolidine skeleton has been designed and afforded good yield, efficient turnover, and high enantioselectivity in allylation reactions. The synthesis of enantiopure 2,2'-bispyrrolidine was easily accomplished on large scale by photodimerization of pyrrolidine followed by resolution with L(or D)-tartaric acid. The scope of the allylation reaction was examined with variously substituted allylic trichlorosilanes and unsaturated aldehydes. This method has been applied to the construction of stereogenic, quaternary centers by the addition of unsymmetrically gamma-disubstituted allylic trichlorosilanes.
During the last six years the asymmetric catalysis of carbonyl transformations via iminium ion and enamine intermediates using chiral amines as organocatalysts has grown most remarkably. In this personal account an overview of this area is given. The field can be divided into two sub areas: (a) Iminium catalysis, which is typically used for cycloadditions and conjugate additions to enals and enones and (b) Enamine catalysis, which is commonly used in electrophilic alpha-substitution reactions of ketones and aldehydes. A common origin of the two catalysis principles is proposed and their recent merger in tandem sequences is discussed.
Dihydroxyacetone variants have been explored as donors in organocatalytic aldol reactions with various aldehyde and ketone acceptors. The protected form of dihydroxyacetone that was chosen for in-depth study was 2,2-dimethyl-1,3-dioxan-5-one, 1. Among the catalysts surveyed here, proline proved to be superior in terms of yield and stereoselectivities in the construction of various carbohydrate scaffolds. In a fashion analogous to aldolase enzymes, the de novo preparation of L-ribulose, L-lyxose, D-ribose, D-tagatose, 1-amino-1-deoxy-D-lyxitol, and other carbohydrates was accomplished via the use of 1 and proline. In reactions using 2,2-dimethyl-1,3-dioxan-5-one 1 as a donor, (S)-proline can be used as a functional mimic of tagatose aldolase, whereas (R)-proline can be regarded as an organocatalytic mimic of fuculose aldolase.
New N-alkyl-3,3'-bimorpholine derivatives (iPBM) were revealed to be efficient organocatalysts for the asymmetric direct Michael addition of aldehydes to nitroolefins and a vinyl sulfone. In these transformations using iPBM, 1,4-adducts were afforded in high yields, with good to high levels of diastereo- and enantioselectivity. The stereochemical outcome of the reaction could be explained by an acyclic synclinal model. [reaction: see text]
We report an efficient route to obtain azasugars from the enantiomerically pure L- and D-diethyltartrate. The key step is a proline-catalyzed aldol condensation, in which both enantiomers of proline have been used as catalyst, affording complementary anti-aldol products.
The current status of organic synthesis is hampered by costly protecting-group strategies and lengthy purification procedures after each synthetic step. To circumvent these problems, the synthetic potential of multicomponent domino reactions has been utilized for the efficient and stereoselective construction of complex molecules from simple precursors in a single process. In particular, domino reactions mediated by organocatalysts are in a way biomimetic, as this principle is used very efficiently in the biosynthesis of complex natural products starting from simple precursors. In this Minireview, we discuss the current development of this fast-growing field.
The kinetics of the reactions of 26 primary and secondary amines with benzhydrylium ions in water were investigated photometrically. Because the parallel reactions of the benzhydrylium ions with hydroxide and water are much slower, the second-order rate constants for the reactions of amines with benzhydrylium ions could be determined reliably. Reactivities of anilines were also studied in acetonitrile solution. Plots of log k2,N for these reactions vs the electrophilicity parameters E of the benzhydrylium ions were linear, which allowed us to derive the nucleophilicity parameters N and s for amines as defined by the equation log k(20 degrees C)=s(E+N). Because the slope parameters for the different amines are closely similar; the relative nucleophilicities are almost independent of the electrophiles and can be expressed by the nucleophilicity parameters N. The correlation between nucleophilicity N and pKaH values is poor, and it is found that secondary alkyl amines and anilines are considerably more nucleophilic, while ammonia is much less nucleophilic than expected on the basis of their pKaH values.
Monosalts of N-substituted bimorpholine derivatives are efficient organocatalysts in intramolecular and intermolecular aldol reactions. The properties of the catalysts can be tuned either by the selection of an appropriate acid for the salt formation or by the change of a substituent at the nitrogen atom. In aldol condensation, i-Pr-substituted bimorpholine is the most stereoselective catalyst affording products in high yield with enantioselectivities up to 95% ee.
One enigma leads in three directions: The Hajos–Wiechert reaction presented an enigma that went unsolved for three decades. With the unravelling of this enigma, organocatalysis plays a major role in the development of efficient catalytic asymmetric methodologies. The mechanisms of organocatalysis also shed light on the origin of homochirality essential for life and provide clues to yet-to-be-discovered biosynthetic mechanisms at work in living organisms today.
- Pihko