Investigations of enantioreversal in both direct and directed enantioselective aldol reactions catalyzed by CuCl2[(−)-sparteine] and NiCl2[(−)-sparteine] complexes

The use of structurally well-defined chiral [CuCl₂(sparteine)] 1 and [NiCl₂(sparteine)] 2 complexes as catalysts under fluoride anion-promoted double catalytic activation (DCA) conditions cause enantioreversal in the asymmetric Mukaiyama aldol reaction of 1-phenyl-1-trimethylsiloxyethylene with various aromatic aldehydes. A similar enantioreversal also occurs in the direct aldol reaction between methyl vinyl ketone and various aromatic aldehydes under Et₃N promoted DCA conditions. We have quantitatively analyzed using group theoretical analysis via symmetry deformation coordinates, the molecular structures of 1 and 2 from the X-ray structural data; the results from the study show that the innate stereochemical differences that are present in their molecular structures, form the basis for the enantioreversal phenomenon in the asymmetric C–C bond-forming aldol reactions.     

Asymmetric Mukaiyama aldol reaction of silyl enol ethers with aldehydes using a polymer-supported chiral Lewis acid catalyst

Chiral N-sulfonylated α-amino acid monomer (5) derived from (S)-tryptophan was copolymerized with styrene and divinylbenzene under radical polymerization conditions to give a polymer-supported N-sulfonyl-(S)-tryptophan (6). Treatment of the polymer-supported chiral ligand with 3,5-bis(trifluoromethyl)phenyl boron dichloride afforded a polymeric Lewis acid catalyst (16) effective for asymmetric Mukaiyama aldol reaction of silyl enol ethers and aldehydes. Various aldehydes were allowed to react with silyl enol ethers in the presence of the polymeric chiral Lewis acid to give the corresponding aldol adducts in high yield with high levels of enantioselectivity.     

Highly enantioselective hetero-Diels-Alder reaction between trans-1-methoxy-2-methyl-3-trimethylsiloxybuta-1,3-diene and aldehydes catalyzed by (R)-BINOL-Ti(IV) complex

An efficient enantioselective approach to 2,5-disubstituted dihydropyrones was developed. Some easily accessible inexpensive diol ligand metal complexes were employed, and [(R)-BINOL]₂-Ti(OiPr)₄ complex was found to be the most effective catalyst (up to 99% yield and 99% ee in the presence of 5 mol% catalyst) for the hetero-Diels-Alder reaction between trans-1-methoxy-2-methyl-3-trimethylsiloxybuta-1,3-diene (1) and aldehydes. The potential and generality of this catalyst were evaluated by a variety of aldehydes including aromatic, heteroaromatic, α,β-unsaturated and aliphatic aldehydes. Based on the isolated intermediate from the reaction of benzaldehyde being confirmed by ¹H, ¹³C NMR and HRMS data, the mechanism was proposed as a Mukaiyama aldol pathway.     

Iron‐ and Bismuth‐Catalyzed Asymmetric Mukaiyama Aldol Reactions in Aqueous Media

We have developed asymmetric Mukaiyama aldol reactions of silicon enolates with aldehydes catalyzed by chiral Fe^II and Bi^III complexes. Although previous reactions often required relatively harsh conditions, such as strictly anhydrous conditions, very low temperatures (?78 °C), etc., the reactions reported herein proceeded in the presence of water at 0 °C. To find appropriate chiral water‐compatible Lewis acids for the Mukaiyama aldol reaction, many Lewis acids were screened in combination with chiral bipyridine L1 , which had previously been found to be a suitable chiral ligand in aqueous media. Three types of chiral catalysts that consisted of a Fe^II or Bi^III metal salt, a chiral ligand ( L1 ), and an additive have been discovered and a wide variety of substrates (silicon enolates and aldehydes) reacted to afford the desired aldol products in high yields with high diastereo‐ and enantioselectivities through an appropriate selection of one of the three catalytic systems. Mechanistic studies elucidated the coordination environments around the Fe^II and Bi^III centers and the effect of additives on the chiral catalysis. Notably, both Brønsted acids and bases worked as efficient additives in the Fe^II‐catalyzed reactions. The assumed catalytic cycle and transition states indicated important roles of water in these efficient asymmetric Mukaiyama aldol reactions in aqueous media with the broadly applicable and versatile catalytic systems.     

Asymmetric routes towards polyfunctionalized pyrrolidines: application to the synthesis of alkaloid analogues

The Mukaiyama aldol type condensation of t-butyldimethylsilyloxypyrrole 1b with methyl 2-formylbenzoate furnished the aldol adduct 9 with high yield and complete stereoselectivity. An erythro (anti) configuration was established (X-ray) in sharp contrast with the reaction of 1b with aliphatic aldehydes. Simple chemical transformations were used to transform 9 into original phthalidopyrrolidine compound analogous of bicuculline alkaloids.     

Stereoselective titanium-mediated syn-aldol reaction from a lactate-derived chiral ethyl ketone

Stereoselectivity of the titanium-mediated aldol process based on (S)-2-benzyloxy-3-pentanone, 1, is dramatically modified by the presence of a Lewis acid. Among the Lewis acids surveyed, TiCl₄ has given access to the corresponding 2,4-anti-4,5-syn aldol adducts with the highest diastereomeric ratios. The excellent stereocontrol exerted by the aforementioned ketone has been demonstrated in double asymmetric reactions involving chiral α-methyl-β-OTBDPS aldehydes.     

New indenyl phosphinooxazoline complexes of iron and their catalytic activity in the Mukaiyama aldol reaction

New phosphinooxazoline (PHOX) η⁵-indenyl complexes of iron were synthesized and applied as catalysts in the Mukaiyama aldol reaction. Reaction of three different PHOX ligands with [Fe(η⁵-Ind)I(CO)₂] afforded the iodide salts of three complexes of the general formula [Fe(η⁵-Ind)(CO)(PHOX)]⁺ in 73-81% isolated yields. The molecular structure of one of the new complexes was determined, revealing a pseudo octahedral coordination geometry about the iron center. The iron complexes are catalytically active in the Mukaiyama aldol reaction between aldehydes and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene to give the corresponding aldol adducts (3 mol % catalyst, 15 min, room temperature, 48-83% isolated yields). A previously synthesized iron complex of the general formula [Fe(η⁵-Cp)(CO)(PHOX)]⁺ was found to be catalytically active in the title reaction as well, but needed three hours at room temperature to convert the starting materials to the products.     

Highly enantioselective vinylogous addition of 2-trimethylsilyloxyfuran to aldehydes promoted by the SiCl4/chiral Lewis base system

This paper reports the regio-, diastereo- and highly enantioselective vinylogous aldol reaction of 2-trimethylsilyloxyfuran (TMSOF) promoted by the SiCl₄/Lewis base catalytic system. Several electron-pair donors proved to be effective as SiCl₄ activators versus the TMSOF γ-selective addition to aldehydes giving rise to different diastereoisomeric ratios, while Denmark’s chiral bis-phosphoramide (R,R)-7 gave the highest enantioselectivity for both the anti- and syn-diastereoisomers. Furthermore, by using ambident electrophiles such as α,β-unsaturated aldehydes, the SiCl₄/Lewis base-promoted process leads exclusively to the 1,2-addition products.     

Combining prolinamides with 2-pyrrolidinone: Novel organocatalysts for the asymmetric aldol reaction

Peptides and especially prolinamides have been identified as excellent organocatalysts for the aldol reaction. The combination of prolinamides with derivatives bearing the 2-pyrrolidinone scaffold, deriving from pyroglutamic acid, led to the identification of novel organocatalysts for the intermolecular asymmetric aldol reaction. The new hybrids were tested both in organic and aqueous media. Among the compounds tested, 22 afforded the best results in petroleum ether, while 25 afforded the products in brine in high yields and selectivities. Then, various ketones and aldehydes were utilized and the products of the aldol reaction were obtained in high yields (up to 100%) with excellent diastereo- (up to 97:3 dr) and enantioselectivities (up to 99% ee).     

Constructing chiral diazoacetoacetates by enantioselective catalytic Mukaiyama aldol reactions

Asymmetric catalysis of Mukaiyama aldol addition reactions of methyl 3-TMSO-2-diazo-3-butenoate 4 with aromatic aldehydes using AgF/(R)-BINAP at −20 °C produces chiral diazoacetoacetates in high chemical yields and with high enantiocontrol.     

The Mukaiyama Aldol Reaction: 40 Years of Continuous Development

A directed cross‐aldol reaction of silyl enol ethers with carbonyl compounds, such as aldehydes and ketones, promoted by a Lewis acid, a reaction which is now widely known as the Mukaiyama aldol reaction. It was first reported in 1973, and this year marks the 40th anniversary. The directed cross‐aldol reactions mediated by boron enolates and tin(II) enolates also emerged from the Mukaiyama laboratory. These directed cross‐aldol reactions have become invaluable tools for the construction of stereochemically complex molecules from two carbonyl compounds. This Minireview provides a succinct historical overview of their discoveries and the early stages of their development.     

Novel C2-symmetric chiral O,N,N,O-tetradentate 2,2-bipyridyldiolpropane ligands: synthesis and application in asymmetric diethylzinc addition to aldehydes

First synthesis of C₂-symmetric chiral O,N,N,O-tetradentate 2,2-bipyridyldiolpropane ligands is described. The Mukaiyama–Michael reaction was applied as an important reaction for the synthesis of 2,2-bipyridylpropane 9. Among the ligands synthesized, ligand 11 exhibits excellent chiral induction (up to 97% ee) in diethylzinc addition to various aldehydes. The use of additional Lewis acid such as Ti(OⁱPr)₄ in diethylzinc addition reaction is not required for the present catalytic system.     

l-Proline amides catalyze direct asymmetric aldol reactions of aldehydes with methylthioacetone and fluoroacetone

Direct aldol reactions of aldehydes with methylthio- and fluoroacetone catalyzed by proline amides have been investigated. l-Prolinamide 5e was found to be the best catalyst. Under the optimized reaction conditions, a series of aromatic and aliphatic aldehydes reacted smoothly with methylthioacetone, to generate 1-methylthio-4-hydroxyketones 3 in good yields and with high regio- and enantioselectivities. Excellent enantioselectivities of up to 98% ee were observed for aromatic aldehydes and even higher enantioselectivities of >99% ee were observed for aliphatic aldehydes. Asymmetric direct aldol reactions of fluoroacetone with aldehydes in the presence of 20 mol % of 5e preferentially occurred at the fluoromethyl group, yielding products with high enantioselectivities (up to 98% ee).     

Chiral Catalysts Dually Functionalized with Amino Acid and Zn2+ Complex Components for Enantioselective Direct Aldol Reactions Inspired by Natural Aldolases: Design,Synthesis, Complexation Properties,Catalytic Activities,and Mechanistic Study

Aldolases are enzymes that catalyze stereospecific aldol reactions in a reversible manner. Naturally occurring aldolases include class I aldolases, which catalyze aldol reactions via enamine intermediates, and class II aldolases, in which Zn²⁺ enolates of substrates react with acceptor aldehydes. In this work, Zn²⁺ complexes of L ‐prolyl‐pendant[15]aneN₅ (ZnL³), L ‐prolyl‐pendant[12]aneN₄ (ZnL⁴), and L ‐valyl‐pendant[12]aneN₄ (ZnL⁵) were designed and synthesized for use as chiral catalysts for enantioselective aldol reactions. The complexation constants for L³ to L⁵ with Zn²⁺ [logK_s(ZnL)] were determined to be 14.1 (for ZnL³), 7.6 (for ZnL⁴), and 9.6 (for ZnL⁵), indicating that ZnL³ is more stable than ZnL⁴ and ZnL⁵. The deprotonation constants of Zn²⁺‐bound water [pK_a(ZnL) values] for ZnL³, ZnL⁴, and ZnL⁵ were calculated to be 9.2 (for ZnL³), 8.2 (for ZnL⁴), and 8.6 (for ZnL⁵), suggesting that the Zn²⁺ ions in ZnL³ is a less acidic Lewis acid than in ZnL⁴ and ZnL⁵. These values also indicated that the amino groups on the side chains weakly coordinate to Zn²⁺. We carried out aldol reactions between acetone and 2‐chlorobenzaldehyde and other aldehydes in the presence of catalytic amounts of the chiral Zn²⁺ complexes in acetone/H₂O at 25 and 37 °C. Whereas ZnL³ yielded the aldol product in 43 % yield and 1 % ee (R), ZnL⁴ and ZnL⁵ afforded good chemical yields and high enantioselectivities of up to 89 % ee (R). UV titrations of proline and ZnL⁴ with acetylacetone (acac) in DMSO/H₂O (1:2) indicate that ZnL⁴ facilitates the formation of the ZnL⁴ ? (acac)^? complex (K_app=2.1×10² M ^?1), whereas L ‐proline forms a Schiff base with acac with a very small equilibrium constant. These results suggest that the amino acid components and the Zn²⁺ ions in ZnL⁴ and ZnL⁵ function in a cooperative manner to generate the Zn²⁺‐enolate of acetone, thus permitting efficient enantioselective C? C bond formation with aldehydes.     

Development of N,N-bis(perfluoroalkanesulfonyl)squaramides as new strong Brønsted acids and their application to organic reactions

New strong Brønsted acids derived from a squaric acid scaffold bearing different perfluoroalkanesulfonyl groups have been developed and applied to several organic reactions. These squaramides are bench-stable and exhibit much higher reactivities in several organic reactions than squaric acid itself. N,N-Bis(trifluoromethanesulfonyl)squaramide 2a was applied to the Mukaiyama aldol reaction and Mukaiyama Michael reaction. Mechanistic studies revealed that the Brønsted acid might be the predominant catalyst through direct protonation of carbonyl compound by the acid itself rather than the silylated Brønsted acid. The utility of this acid 2a was further extended to Hosomi-Sakurai allylation of aldehydes and a carbonyl-ene reaction. Furthermore, other squaramides 2b and c bearing longer perfluoroalkyl chains have been developed, which are also bench-stable and displayed similar reactivities with squaramide 2a in several organic reactions.     

Platinum(II) complex-catalyzed enantioselective aldol reaction with ketene silyl acetals in DMF at room temperature

[{(R)-binap}Pt(μ-OH)]₂2X is a weak Lewis acid, which can catalyze the enantioselective aldol reaction of aldehydes with ketene silyl acetals in DMF at room temperature. The platinum(II) complex-catalyzed the enantioselective aldol reaction of aldehydes with 1-methoxy-2-methyl-(1-trimethylsilyloxy)propene gave the corresponding aldols in high yields with enantioselectivity up to 92%. With 5 mol % loading of the complexes, the enantioselective aldol reaction of aldehydes with 1-benzyloxy-1-(trimethylsilyloxy)propene smoothly proceeded in DMF containing 10% HMPA as to predominantly give anti-propionates with enantioselectivity up to 89%, irrespective of the silyl nucleophile geometry.     

Water opportunities: catalyst and solvent in Mukaiyama aldol addition of Rawal’s diene to carbonyl derivatives

Addition reactions between Rawal’s diene and different carbonyl compounds are rapidly and efficiently promoted by water. No catalyst or any other additive, water as an eco-friendly medium, clean reaction conditions, a simple work-up, and short reaction times are the salient features in this procedure. The protocol is general, proceeding well with moderate to good yields for various aldehydes and activated ketones. Based on the experimental ¹H NMR results, a Mukaiyama aldol mechanism was proposed as the reaction pathway, affording open chain products.     

Unique chemoselective Mukaiyama aldol reaction of silyl enol diazoacetate with aldehydes and acetals catalyzed by MgI2 etherate

Functionalized diazo acetoacetates are prepared by an efficient Mukaiyama aldol reaction between 3-TBSO-2-diazo-3-butenoate with aldehydes and acetals under mild reaction conditions. A variety of substituted aldehydes and the corresponding acetals are both accessible in good to excellent yields through this methodology. MgI₂ etherate (MgI₂·(OEt₂)_n) is the preferred catalyst and, the addition proceeds without decomposition of the diazo moiety. In addition, this MgI₂·(OEt₂)_n-catalyzed Mukaiyama aldol reaction shows unique chemoselectivity towards aldehydes and acetals.     

Chiral Zn(II)-Bisamidine Complex as a Lewis-Brønsted Combined Acid Catalyst: Application to Asymmetric Mukaiyama Aldol Reactions of <em>α</em>-Ketoesters

Focusing on the steric and electronic properties of the resonance-stabilized amidine framework, a cationic metal-bisamidine complex was designed as a conjugated combined Lewis-Br?nsted acid catalyst. The chiral Zn(II)-bisamidine catalyst prepared from the 2,2'-bipyridyl derived bisamidine ligand, ZnCl₂, and AgSbF₆ promoted asymmetric Mukaiyama aldol reaction of α-ketoester and α,α-disubstituted silyl enol ether to afford the α-hydroxyester having sequential quarternary carbons in good yield, albeit with low enantioselectivity. Addition of 1.0 equivalent of the fluoroalcohol having suitable acidity and bulkiness dramatically increased the enantioselectivity (up to 68% ee). DFT calculations suggested that this additive effect would be caused by self-assembly of the fluoroalcohol on the Zn(II)-bisamidine catalyst.     

Chemoselective Catalysis with Organosoluble Lewis Acidic Polyoxotungstates

The preparation of new organosoluble Lewis acidic polyoxometalates (POMs) is reported. These complexes were prepared by the incorporation of Zr, Sc, and Y atoms into the corresponding monolacunary Dawson [P₂W₁₇O₆₁]^10? and Keggin [PW₁₁O₃₉]^7? polyoxotungstates. The catalytic activity of these compounds was evaluated for C? C bond formation in the Diels–Alder, Mannich, and Mukaiyama‐type reactions. Comparisons with previously described Lewis acidic POMs are reported. Competitive reactions between imines and aldehydes or between various imines demonstrated that fine tuning of the reactivity could be reached by varying the metal atom incorporated into the polyanionic framework. A series of experiments that employed pyridine derivatives allowed us to distinguish between the Lewis and induced Brønsted acidity of the POMs. These catalysts activate imines in a Lewis acidic way, whereas aldehydes are activated by indirect Brønsted catalysis.