Metal-Catalyzed Asymmetric Aldol Reactions

A reação aldólica é uma das ferramentas mais poderosas e versáteis para a construção de ligações C−C. Tradicionalmente, esta reação foi desenvolvida em sua versão estequiométrica, no entanto, grandes esforços no desenvolvimento de catalisadores quirais para reações aldólicas foram realizados nos últimos anos. Desta forma, neste artigo de revisão, é discutido o desenvolvimento de catalisadores metálicos em reação aldólica do tipo Mukaiyama, reação aldólica redutiva e reação aldólica direta. Além disto, a aplicação destes catalisadores na síntese total de moléculas complexas será abordada.


Introduction
The aldol reaction is one of the most powerful and versatile methods in the chemistry of carbonyl compounds for the construction of C-C bonds in a regio-, stereo-and enantioselective manner. 1 It is well known that the relative configuration of the aldol adduct (in those reactions that proceed by a cyclic six member transition state) is controlled by the geometry of the propionate-type enolate, in which Z-enolates lead to preferential formation of the 1,2-syn products and E-enolates to 1,2-anti products.These observations can be rationalized from the Zimmerman-Traxler model.In this proposal, the aldol reaction undergoes a chair-type six-membered cyclic transition state, being diastereoselectivity dependent on the steric demand of the enolate and the aldehyde substituents (Scheme 1). 2 According to this model, the R 3 aldehyde substituent occupies, preferably, the pseudo-equatorial position, eliminating unfavorable 1,3-diaxial interactions between the R 3 group and the R 1 and L substituents, thus providing a transition state of lower energy.In the case of the E-enolates, 1,2-anti aldol adducts are preferably formed, since in the transition state TS1 the 1,3-diaxial interactions are minimized with respect to transition state TS2, which leads to the formation of 1,2-syn aldol adduct.
In the case of the Z-enolates, the formation of 1,2-anti aldol adduct is disfavored due to 1,3-diaxial interactions present in the transition state TS3.Thus, the 1,2-syn aldol adduct is formed preferentially, since in the transition state TS4 these repulsions are minimized.Thus, when preformed chiral enolates are employed together with aldehydes, it is possible to obtain aldol adducts with excellent levels of asymmetric induction. 3he aim of this review article is to discuss representative studies involving stereoselective aldol reactions using metal-mediated chiral catalysis with special attention to selectivity, substrate scope, current limitations and application in the total synthesis of natural products. 4,5The literature is covered up to early 2012.rare earth metal triflates (RE(OTf) 3 ), which are watertolerant Lewis acids, have been used in aldol reactions and can be effortlessly recovered and reused. 6obayashi and co-workers 7 showed that in the Mukaiyama aldol reactions involving chiral crown ether ligands that bind strongly with the larger rare earth metal cations (such as La, Ce, Pr and Nd), the ligands do not decrease the Lewis acid ability for the enantioselective transformations.The Mukaiyama aldol reactions in aqueous media between enolsilanes 1 and 2 and α,β-unsaturated aldehydes, mediated by Pr(OTf) 3 and bis-pyridino-18-crown-6 ether 15, gave good to high yields and high diastereo-and enantioselectivities in favor of the corresponding syn aldol adducts (Table 1, entries 1-13).However, aliphatic aldehyde 12 was not a suitable substrate for this transformation (entry 14).
For ligand 15, the authors proposed transition state TS5, taking into account the coordination of the aldehyde to the Pr 3+ cation and the shielding of the Si face of the aldehyde by the axially oriented methyl substituent of the Pr 3+ •15 complex, thus directing the attack of the enolate to the Re face of the aldehyde (Scheme 2). 7For ligand 16, in which the aldehyde is complexed with the Eu 3+ cation, the authors proposed that the Si face of the aldehyde is blocked by the ester substituent, and the Re face of the aldehyde becomes proper for the enol attack. 8 2012, Allen and co-workers 9 applied crown ether 16 as a ligand for neodymium-catalyzed Mukaiyama aldol reactions (Table 2).
As becomes evident from the results presented in Table 2, the Mukaiyama aldol reactions between enolsilane 1 and aromatic and α,β-unsaturated aldehydes, mediated by Nd(OTf) 3 , gave good to high yields and high diastereo-and enantioselectivities in favor of the corresponding syn aldol adducts (Table 2, entries 1-6).The aldol reactions using aliphatic aldehyde 14 (Table 2, entry 7) led to the formation of aldol adduct with good diastereo-and enantioselectivities in favor of the syn isomer, but in low yield.

Diastereo-and Enantioselective Catalytic Reductive Aldol Reactions
Catalytic reductive aldol reactions employing chiral ligands consist in a very exciting method to obtain aldol adducts in high diastereo-and enantioselective fashion. 10The aldol coupling between α,β-unsaturated ester or ketone and aldehydes are promoted using catalytic amounts of a transition metal complex under hydrogenation conditions.The tremendous advantage of this method is that the regioselective reductive formation of a transition metal enolate, required to the aldol reaction, is generated in situ by conjugated addition of a metal hydride to an unsaturated carbonyl compound (Scheme 3). 11The most common reductive agents are molecular hydrogen, silanes and stannanes in stoichiometric amounts.Among the reports involving Co-, Pt-, Pd-, Ni-, Cu-, Ir-and Rh-catalyzed reductive aldol reactions, so far Rh, Ir and Cu transition  metals and chiral ligand partners are the most prominent for this transformation.Efforts in order to get better diastereo-and enantioselective aldol adducts under milder conditions reaching high turnover and avoiding carbonyl reduction of the substrates are the driving forces of this field.
A few examples are showed in Scheme 5.
Nishiyama and co-workers 17 showed the possibility to achieve aldol adducts in high anti-selectivity (Table 4).
The reductive aldol reactions between acrylate 42 and a number of aldehydes were promoted by the chiral Rh-Phebox (44) catalyst and alkoxyhydrosilane providing anti-43 in good to high levels of diastereo-and enantioselectivities.
The supposed stereochemical pathway for this transformation, supported by theoretical calculations, involves the Rh-(E)-enolate (identified by 1 H NMR) in a Zimmerman-Traxler-type transition state TS7, with attack to the complexed aldehyde from the less sterically hindered face of the enolate (Scheme 6). 18

Chiral Lewis Base Catalysis in Enantioselective Aldol Reactions
The concept of Lewis base catalysis in aldol reactions involving trichlorosilyl enolates with aldehydes has   been extensively explored by Denmark et al. 19,20 since the first report in 1996 (Scheme 7). 21In the context of stereoselective aldol transformations, the electron-pair of a chiral Lewis base catalyst interacts with an acceptor silicon atom of the enolate making it more reactive.In addition, the new chiral complex should interact with the carbonyl oxygen of aldehyde producing aldol adducts in a stereoselective manner.
The scope and generality of this transformation were extensively studied by Denmark et al. 19,20 using phosphoramide organocatalysts.Mukaiyama aldol reactions involving Lewis base catalysis were also reported involving trimethoxysilyl enol ethers activated by binaphtholate organocatalysts. 22n alternative strategy involving Lewis base catalysis in Mukaiyama aldol reactions involves the fluorine-catalyzed bifunctional approach reaction with chiral Lewis acid catalysts, examined by Yamamoto and co-workers 23 using the catalyst system BINAP/AgOTf/KF/ [18]crown-6 (Scheme 8).In this strategy, the fluoride ions act as an achiral Lewis base forming an anionic hypervalent silicate activating the trimethoxysilyl enol ether, as represented by the cyclic transition state TS8, explaining the diastereoselectivities of aldol adducts syn-50c or anti-50a-b from Z-or E-enolates, respectively. 23nother successful example involving catalytic enantioselective aldol reactions combines a weak achiral Lewis acid (SiCl 4 ) with a chiral phosphoramide (R,R)-53 Lewis base catalyst generating a strong and activated chiral Lewis acid (Scheme 9).Denmark and Chung 24 developed Mukaiyama aldol reactions version using this concept.The sense of diastereoselectivity is modulated by the size of the protecting group of silyl ketene acetals and high levels of diastereo-and enantioselectivities were obtained (Scheme 9).Theoretical calculations support the cationic opening transition states TS9 and TS10 for aldol reactions involving enolates 51 and 54, respectively. 25 2012, Nakajima, Kotani and co-workers 26 presented an efficient method for the enantioselective reductive aldol reaction of α,β-unsaturated ketones with aldehydes (Table 5).The conjugated reduction was performed using a tertiary amine and trichlorosilyl triflate.Then, the aldol reaction was made in the presence of BINAP dioxide (BINAPO).
As evident from the results presented in Table 5, the reductive aldol reactions with the chalcone derivatives proceeded smoothly to give the corresponding products in good yields with high diastereo-and enantioselectivities (entries 2-7).Isopropyl ketone 63 provided the aldol product in high yield and selectivity (entry 8), whereas the stereoselectivity of the reaction with cyclopropyl ketone 64 was found to decrease (entry 9).
In addition, reductive aldol reactions between various aldehydes and chalcone (56) were conducted (entries 10-15).The aromatic aldehydes tended to give the aldol adducts with good yields and high stereoselectivities (entries 10-12).The conjugate aldehyde 9 furnished the product in high yield with high selectivity (entry 13).Strikingly, the aliphatic aldehydes 12 and 28, which were generally less reactive in Lewis base-catalyzed reactions, gave the corresponding aldol adducts in good yields with high diastereoselectivities (entries 14 and 15).The rationalization for the observed selectivity is shown in Scheme 10.
The conjugate reduction of ketone gave the (Z)-trichlorosilyl enol ether (Scheme 10).The aldol reaction of (Z)-trichlorosilyl enol ether with aldehyde proceeded via a six-membered transition state TS11 involving hypervalent silicon species to afford the corresponding aldol adduct with high syn-diastereo-and enantioselectivities.

Metal-Catalyzed Direct Aldol Reactions
The so-called direct aldol reaction comprises an extraordinary category of aldol transformations developed aiming to atom economy through clean and economic reaction conditions. 27The exciting challenges involving this transformation are to find new catalytic systems that allow the C−C bond coupling by the reaction of enolizable carbonyl compounds with itself or with another carbonyl compound, without the preactivation of the enolate nucleophile, in high chemo-, regio-and stereoselective fashion.Despite the remarkable success of organocatalytic direct aldol processes, heterobimetallic-catalyzed direct aldol reactions shows milder conditions than enaminebased organocatalysts employing nucleophilic amines.However, the requirement of long times under low temperature conditions for these reactions remains as the biggest drawback of this methodology.New organocatalytic approaches involving chiral phosphoric Brønsted acid in direct aldol processes have also emerged as a very attractive alternative. 28umerous heterobimetallic complexes with chiral BINOL-based ligands have been emerged as very suitable catalysts for direct aldol reactions.A tremendous contribution was given by Shibasaki and co-workers 29 in this field.They reported the utilization of the heterobimetallic lanthanum-lithium-BINOL (LLB) complex catalyzing the aldol reaction between aromatic and aliphatic aldehydes with several equivalents of ketones in long reaction times.The heteropolymetallic catalyst LLB-KOH (70) was used in order to shorten the reaction times by enhancing the catalytic activity of LLB complex, giving aldol adducts 69a-d in modest to good enantioselectivities (Scheme 11). 30hibasaki and co-workers 31 reported the use of (S)-LLB (74) catalyst in the formal total synthesis of fostriecin (75) and 8-epi-fostriecin (8-epi-75).The best reaction condition to the system of interest for fostriecin (75) afforded the aldol adduct 73 in good yield using ketone 71 and aldehyde 72 and the two-center Lewis acid-Brønsted base catalyst (S)-LLB (74) (Scheme 12).On the other hand, a new study was performed in order to improve the selectivity for the desired aldol adduct 8-epi-73 used in the synthesis of 8-epi-fostriecin (8-epi-75), and the addictive LiOTf showed the best performance.
In early 2000, Trost and co-workers 32 reported a new chiral dinuclear zinc catalyst, prepared from Et 2 Zn and chiral ligand 78 (Scheme 13).
In these works, the authors obtained aldol adducts with excellent levels of enantioselectivities using the version of direct aldol reaction between various ketones and aldehydes, mediated by a chiral dinuclear zinc catalyst.These results can be consistently explained by the proposed catalytic cycle (Scheme 14).The catalyst 83, prepared in situ by treatment of ligand 78 with 2 equivalents of diethylzinc, involves initiation by liberation of 3 equivalents of ethane followed by a fourth by reaction with the active methylene partner (acetophenone in this case).The chiral space derives from the conformational preferences of the diphenylcarbinol moieties.Thus, the role of the two proximal zinc species is to provide both a zinc to form the requisite enolate (zinc functioning as a Brønsted base) and a second zinc to function as a Lewis acid to coordinate the aldehyde.
In 2005, Trost and co-workers 33 described a formal synthesis of fostriecin (75) (Scheme 15).One of the steps of the synthesis consisted in the direct aldol reaction between ketone 85 and aldehyde 84, mediated by chiral binuclear zinc catalyst 83, which led to the formation of aldol adduct 86 with excellent level of enantioselectivity.Compound 86 corresponds to the C8-C13 fragment of fostriecin (75).Recently, Kumagai, Shibasaki and co-workers 34 developed a direct catalytic asymmetric aldol reaction between thioamide 87 and aldehydes employing a soft Lewis acid/hard Brønsted base cooperative catalysis (Table 6).
As can be seen from Table 6, independently of the steric nature of the aldehyde, the aldol adducts were obtained with yields ranging from moderate to good and excellent level of enantiomeric excess.Vol. 23, No. 12, 2012 Scheme 13.Enantioselective aldol reactions between ketones and aldehydes in the presence of 78 and Et 2 Zn.
In 2012, Kumagai, Shibasaki and co-workers 35 reported the total synthesis of duloxetine (92), a dual serotonin and norepinephrine reuptake inhibitor in presynaptic cells.The key step of the synthesis was a direct catalytic aldol reaction between thioamide 90 and aldehyde 7, mediated by chiral catalyst ent-88, which provided the aldol adduct 91 with high enantioselectivity (ee = 92%) (Scheme 16).

BINOL and Related Ligands in Catalytic Stereoselective Mukaiyama Aldol Reactions
The Lewis acid mediated aldol reactions involving silyl enol ethers with aldehydes are one of the most convenient methods to control the asymmetry in stereoselective catalytic aldol process.Catalytic asymmetric aldol reaction involving ligands possessing symmetry elements of pure rotation such as BINOL and derivatives have been extensively studied.Reetz et al. 36 firstly reported enantioselective Mukaiyama aldol reactions involving BINOL-Ti(IV) complex as Lewis acid.
The research groups of Mikami 37 and Keck 38 gave important contributions to the development of the catalytic thioacetate Mukaiyama aldol reactions, involving, for example, BINOL-Ti(IV) complexes (R)-98 and (S)-95, respectively (Scheme 17).In general, these reactions showed high enantioselectivities with several aldehydes.
In 1994, Carreira and co-workers 39 reported the design of a chiral tridentate Schiff base BINOL-derivative ligand 102 utilized for the preparation of the chiral complex 104 (Table 7).This complex presented a superior performance for Mukaiyama aldol reactions between silyl ketene acetals derived from O-alkyl acetates 105 and 106 and several aldehydes.As can be seen in Table 7, aromatic, unsaturated, and saturated aldehydes provided aldol adducts in high enatioselectivities in an in situ preparation of complex 104. 40he Carreira's catalyst 104 was successfully applied in the total synthesis of the antitumor dipsipeptide romidepsin (113) 41 and the polyene macrolide roflamycoin (116) 42 (Scheme 18).In both synthetic studies, the asymmetric aldol reaction furnished the aldol adducts in high yields, with high levels of enantioselectivities, which were utilized as precursors in the synthesis of the natural products.
In 2000, Kobayashi and co-workers 43 developed a Mukaiyama aldol reaction involving zirconium-Lewis acid complex 119 based on the chiral 3,3'-I 2 -BINOL ligand.The Mukaiyama aldol reactions between several aldehydes and either silyl enol ether derived from O-or S-alkyl acetates preceded in high levels of diastereo-and enantioselectivities in good yields (Scheme 19).Notably, the best reaction condition involves the preparation of catalyst 119 with a small amount of water and in the presence of a primary alcohol. 44The Z-and E-silylketene acetals (Z-120 and E-120) react in a stereoconvergent manner providing anti-121 aldol adduct in high diastereo-and enantioselectivities.Further studies showed the development of an air-stable and storable Scheme 16.Aldol reaction in the total synthesis of duloxetine (92).Zr-BINOL catalyst, remaining unaltered the yield and stereoselectivities of aldol adducts. 45hiral catalyst 119 was utilized by Inoue and co-workers 46 in the total synthesis of the potent toxin antillatoxin (125) (Scheme 20).The aldol reaction between aldehyde 123 and silyl enol ether 122 afforded the intermediate 124 in high diastereo-and enantioselectivity to set up the C4 and C5 stereocenters of antillatoxin (125).

Asymmetric Induction in Mukaiyama Aldol Reactions with Bis(oxazolinyl) (BOX) and Bis(oxazolinyl)pyridine (PYBOX) as Chiral Ligands
Early studies involving the C 2 -symmetric chiral Lewis acid complexes in aldol reactions, such as bis(oxazolinyl) Scheme 17. Catalytic asymmetric Mukaiyama aldol reactions involving BINOL-Ti(IV) complex.(BOX) and bis(oxazolinyl)pyridine (PYBOX) ligands have been developed by Evans and co-workers. 47In these works, the authors achieved excellent levels of regio-, diastereo-and enantioselectivities using electrophiles capable of chelation, for example, (benzyloxy)acetaldehyde (33) (Table 8). 47s can be seen, the reactions were found to be quite general with respect to the silylketene acetal structure.In all cases, excellent yields were obtained with enantiomeric excesses above 95%.
The requirement for a chelating substituent at the aldehyde partner is critical to catalyst selectivity, as (tert-butyldimethylsiloxy)-acetaldehyde gave low enantioselectivity (ee = 56%).Curiously, β-(benzyloxy) propionaldehyde provided racemic products, indicating a strict requirement for a five-membered catalyst-aldehyde chelate.The observed results can be rationalized based on a pyramidal square transition state TS12 with a penta-coordination geometry (Scheme 21).
As can be seen from the proposed transition state TS12, the aldehyde is preferentially attacked from the Si face, justifying the absolute configuration of the observed aldol adducts.The observed results can be rationalized by invoking a square planar transition state TS13 (Scheme 22).
As can be observed from the proposed transition state TS13, the Si face is exposed to suffer an attack of the nucleophile, which is consistent with the results.
In addition, Evans and co-workers 47 showed that the use of tin C 2 -symmetric complexes as chiral Lewis acid led to the formation of aldol adducts with 1,2-anti relationship in excellent levels of enantiomeric excess (Table 10).
The catalyzed addition to pyruvates is general with respect to the silyl enol ether.Both E-and Z-isomers of the silyl enol ether (Table 10, entries 1 and 2) react in a stereoconvergent manner providing the substituted succinate derivative with excellent diastereo-and enantioselectivity (dr = 99:01 1,2-anti:1,2-syn, ee > 96%).Variation in the size of the alkyl substituent of the enolsilane is possible Vol.23  48 reported the total synthesis of pectenotoxin-4 (139) and pectenotoxin-8 (140) (Scheme 23).The enantioselective Sn 2+ -catalyzed aldol reaction between silyl enol ether 133 and glyoxylate 134 led to the formation of aldol adduct 135, which corresponds to the C8-C11 fragment of pectenotoxins in excellent yields and enantiomeric excess (Scheme 23).Similarly, the aldol reaction between silyl enol ether 137 and glyoxylate 134, mediated by chiral Lewis acid 132, led to the formation of compound 138 (Scheme 23).This aldol adduct correspond to the C36-C39 fragment of pectenotoxins in excellent yields, diastereo-and enantiomeric excess.
In 2006, Jørgensen and co-workers 49 concluded the total synthesis of nonnatural indolizine alkaloid 145 (Scheme 24).For this purpose, the authors performed a Mukaiyama-type aldol reaction between silyl enol ether 142 and aldehyde 141, mediated by a chiral (S,S)-t-Bu-BOX 144, leading to the formation of the aldol adduct 143 in excellent levels of diastereo-and enantiomeric excess (Scheme 24).

Asymmetric Induction in Mukaiyama Aldol Reactions with Boron-Derivatives as Chiral Ligands
In the early 1990, Masamune and co-workers 51 and Corey et al. 52 developed, independently, an asymmetric aldol reaction catalyzed by amino acids derived oxazaborolidines (Scheme 26).In these works, the authors achieved good levels of enantioselectivities.
In 2010, Micoine and Fürstner 53 concluded the total synthesis of the potent cell migration inhibitor lactimidomycin (159) (Scheme 27).In this paper, the

Conclusions
In this review article, our group demonstrated representative examples of metal-mediated catalytic asymmetric aldol reactions.This type of aldol reactions using chiral catalysis are one of the most powerful methods to control the stereochemistry of aldol adducts.One of the major motivations for the development of new enantioselective catalysis is to reach higher catalytic efficiency under very mild reaction conditions.Thus, the design of new chiral catalyst systems continues to be an attractive field in organic synthesis.
Although, the applicability of the most asymmetric catalysis is limited in terms of substrate generality, we can predict a promising future for this field in the light of the search for synthetic ideality 54 and the green chemistry.

55
at the University of Campinas (IQ, UNICAMP, Brazil), under Prof. Dias guidance.Also in the same research group, Marco held his PhD, completed in 2012.After that, he began his post-doctoral studies in the laboratory of Professors Roberto R. Neto and Claudio F. Tormena (UNICAMP), where he is currently working on the development of new methods to determine the relative stereochemistry of organic systems by applying methods of quantum chemistry.His research interests are focused on the development of new synthetic methodologies and their application in the total synthesis of natural products with potential biological activity.Ellen C. Polo was born in São Bernardo do Campo, São Paulo State, Brazil, in 1985.She has a degree in Chemistry from the University of São Paulo (FFCLRP, USP, Brazil, 2007) and earned her MSc degree at the University of Campinas (IQ, UNICAMP, Brazil) in 2011 under the supervision of Prof. Dias.She is currently pursuing her doctorate in the same lab at the UNICAMP.

Table 6 .
Direct catalytic asymmetric aldol reaction between thioamide 87 and aldehydes

Table 7 .
Mukaiyama aldol reaction with the in situ preparation of catalyst 104
Scheme 23.Aldol reactions in the total synthesis of pectenotoxins 139 and 140.authors performed the late-stage Mukaiyama-type aldol reaction between the silyl enol ether prepared from ketone 156 and aldehyde 157 mediated by oxazaborolidine 158, after work-up with HF-pyridine leading to the formation of lactimidomycin (159) in 60% yield and excellent selectivity.Scheme 27.