Aldol enantioselective version

The chiral ligand (5,5)-Jl, derived from chiral 13., is a controller group that has shown to provide a highly enantioselective version of several powerful synthetic methods, as Diels-Alder, aldol and carbonyl allylation processes. 

Morken and co-workers have reported the highly enantioselective version of this reaction, albeit with low efficacy in the aldol-type coupling [8d, e]. Unfortunately, we obtain low enantioselectivity ee 2-4%) using chiral rhodium complexes under our reaction conditions. An intramolecular adaptation has led to new opportunities in cobalt-catalyzed carbocyclizations, wherein the use of PhSiHs was essential for smooth ring formation (Eq. 4) [9]. The identical products were also formed by a combination of [Rh(COD)2]OTf/(p-CE3Ph)3P and molecular hydrogen [10]. 

The condensation reaction of (3-dicarbonyl compounds with a-haloketones to generate hydroxydihydrofuran is known as an interrupted Feist-Benary reaction. Calter et al. reported an enantioselective version of this reaction [26]. The aldol reaction of diketone with a-bromo-a-ketoester followed by cyclization proceeded in the presence of dimeric cinchona alkaloid catalyst to give cyclized product in high yield with high ee... 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

Lithium diphenylbinaphtholate catalyses enantioselective aldol-Tishchenko reactions to give 1,3-diols with three contiguous chiral centres. A successive aldol-aldol-Tishchenko version gave a triol (79) with five contiguous centres. An Evans-Tishchenko reduction is also described. " ... 

Lipshutz and co-workers have developed an enantioselective version of the silane-mediated intramolecular reductive aldol cyclization catalyzed by Cu complexes (Scheme 112) (182). The reaction of enones 251 with Cu-Josiphos complexes L3 or L4 in the presence of diethoxymethylsilane (DBMS) gave a single diastereomers of the products 252 in high enantiomeric excess (up to 98% ee). 

Zirconium alkoxide catalysts were used for the aldol-Tishchenko reaction shown in Equation 18 [23]. In the reaction, diacetone alcohol (55) is converted to the corresponding enol by removal of acetone, and adds to an aldehyde. Enantioselective version of the reaction was also examined [24]. 

Sasai has recently described an interesting entry into chiral tetrahydropyridines 37 from acrolein and aromatic tosylimines [29], which involves an enantioselective version of a domino process previously reported by Huang [30] that can be classified as an ABB multicomponent reaction because of the participation of two molecules of acrolein, each of them with a different role in the overall transformation. The best results were obtained with catalyst 36, which contains both Lewis base and Brpnsted acid structural fragments, and the reaction was rationalized as the result of an aza Morita-Baylis-Hillman/aza Michael/aldol sequence (Scheme 3.8). 

The Reformatsky reaction, the zinc-mediated reaction of a-halo esters with aldehydes or ketones, may be considered an alternative to the aldol addition. As far as enantioselective versions are concerned, this method was much less developed than the aldol protocols [155]. In an early approach, Guette and coworkers explored the Reformatsky reaction of ethyl bromoacetate in the presence of stoichiometric amounts of sparteine although a high enantiomeric excess was observed with benzaldehyde (94% ee), the method was much less satisfactory for other carbonyl compounds [156]. According to a report of Yamano and coworkers, high enantioselectivity (up to 97% ee) was obtained when the Reformatsky reagent generated from ethyl bromoacetate was allowed... 

Connon, Zeitler, and coworkers showed a-ketoesters to be competent reaction partners when using N-C Fs triazolium salt 17 [31]. Even aliphatic a-ketoesters could serve as substrates while avoiding possible competing aldol pathways. The enantioselective version of the reaction proved challenging, and cross-benzoin product 44 could be obtained in only moderate yield and enantioselectivity (Scheme 18.6). Intermolecular formal cross-benzoin reactions using pyruvate as an aldehyde equivalent were also shown to be possible, using a thiamine-dependent enzyme, with broad substrate scope [32]. 

Transannular aldolization is a powerful method for creating two new rings with at least two new stereogenic centers. Chandler and List reported on an enantioselective version of transannular aldolization of cyclic diketone catalyzed by proline derivative 87. 1,4-Cyclooctadione 86 was subjected to the intramolecular aldol reaction in the presence of /ra 5-4-fluoroproline 87 to give the transannular aldol product, (3-hydoxy ketone 88, in 84% yield with 96% ee (Scheme 27.15). In this reaction, proline catalyst bearing a substituent at the 4-position was effective for increasing enantioselectivity. The polycyclic product of 88 was further elaborated into (-l-)-hirustene 89, which is a... 

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

It is well known that acrylates undergo transition metal catalyzed reductive aldol reaction, the silanes R3SiH first reacting in a 1,4 manner and the enolsilanes then participating in the actual aldol addition.57,58 A catalytic diastereoselective version was discovered by arrayed catalyst evaluation in which 192 independent catalytic systems were screened on 96-well microtiter plates.59 Conventional GC was used as the assay. A Rh-DuPhos catalyst turned out to be highly diastereoselective, but enantioselectivity was poor.59... 

Besides the silyl enolate-mediated aldol reactions, organotin(IY) enolates are also versatile nucleophiles toward various aldehydes in the absence or presence of Lewis acid.60 However, this reaction requires a stoichiometric amount of the toxic trialkyl tin compound, which may limit its application. Yanagisawa et al.61 found that in the presence of one equivalent of methanol, the aldol reaction of an aldehyde with a cyclohexenol trichloroacetate proceeds readily at 20°C, providing the aldol product with more than 70% yield. They thus carried out the asymmetric version of this reaction using a BINAP silver(I) complex as chiral catalyst (Scheme 3-34). As shown in Table 3-8, the Sn(IY)-mediated aldol reaction results in a good diastereoselectivity (,anti/syn ratio) and also high enantioselectivity for the major component. 

Related catalytic enantioselective processes [84] As the examples in Scheme 6.26 show, a wide variety of catalytic asymmetric aldol additions have been reported that can be considered as attractive alternatives to the Zr-catalyzed process summarized above. The Ti-cata-lyzed version due to Carreira (84) [85], the Cu-catalyzed variant of Evans (85) [86], and the protocol reported by Shibasaki (86) [87] have all been used in syntheses of complex molecules. More recently, Trost (87) [88] and Shibasaki (88) [89] have developed two additional attractive asymmetric catalytic aldol protocols. Other related technologies (not represented in Scheme 6.26) have been described by Morken [90] and Jorgensen [91]. 

The advantage of asymmetric activation of the racemic BINOL-Ti(OPr )2 complex ( 2) is highlighted in a catalytic version (Table 8C.3, entry 5) wherein high enantioselectivity (80.0% ee) is obtained by adding less than the stoichiometric amount (0.25 molar amount) of (R)-BI-NOL [42a], A similar phenomenon has been observed in the aldol [42c] and (hetero) Diels-Al-der [44] reactions catalyzed by the racemic BINOL-Ti(OPr )2 catalyst (+2). 

Other aromatic aldehydes provided products with similar enantiomeric excess. Although a-unbranched aldehydes such as pentanal did not yield any significant amount of the desired aldol products, the reaction of isobutyraldehyde gave the corresponding aldol product in 97% yield and 96% ee. The reaction is considered to proceed via an enamine mechanism. The enantioselectivity of the reaction can be explained in terms of a metal-free version of a six-membered transition state... 

A particularly attractive version of this reaction relies on the action of a catalytic chiral lithium binaphtholate and an excess of water on trimethoxysilylenol ether119. The tetralone enolate thus generated was directly employed in an aldol reaction, which turned out to be poorly diastereoselective but highly enantioselective for both diastereomers (Scheme 27). 

SCHEME 132. Substoichiometric catalytic version of the enantioselective aldol reaction using... 

One of the most powerful catalysts of the Mukaiyama aldol reaction is a chiral Ti(IV)-Schiff base complex 91 prepared from Ti(0 Pr)4 and enantiomerically pure salicylaldimine reported by Carreira [103-105]. This catalyst furnished aldol adducts in good yields and with excellent enantioselectivity. The Ti(IV)-Schiff base catalyst system is unique among the aldol catalysts yet reported in terms of operational simplicity, catalyst efficiency, chirality transfer, and substrate generality. Because the Ti(IV)-Schiff base complexes are remarkably efficient catalysts for the addition of ketene acetals to a wide variety of aldehydes, the polymeric version of catalyst 92 was prepared [106]. The activity and enantioselectivity of the polymer-supported chiral Ti(IV)-Schiff base complex were, however, much lower than were obtained from the low-molecular-weight catalyst (Eq. 28). 

A possible way to induce enantioselectivity in the aldol reaction is to empioy a chirai catalyst. M. Shibasaki and coworkers developed a bifunctional catalyst, (S)-LLB (L=lanthanum LB=lithium binaphthoxide), which could be successfully applied in direct catalytic asymmetric aldol reactions. An improved version of this catalyst derived from (S)-LLB by the addition of water and KOH was utilized in the formal total synthesis of fostriecin. ... 

Later, the scope of this methodology was successfully extended to the intramolecular version by List and coworkers [14]. By employing 9-amino-9-deoxyepiquinine 24 as a catalyst (20 mol%) and an acid cocatalyst (AcOH, 60 mol%), 5-substituted-3-methyl-2-cydohexene-l-ones (26) were obtained with high enantioselectivity (up to 94% ee) from the diketones 25 via the intramolecular aldol reaction (Scheme 8.8). The chiral enones 26 are valuable synthetic building blocks for the synthesis of many biologically important compounds (e.g., HIV-1 protease-inhibitive didemnaketals). The pseudoenantiomeric quinidine analogue 23 of 24 also provided the opposite... 

Kiyooka et al. succeeded in developing a catalytic version of the chiral borane-promoted aldol reaction of KSA by modification of the promoter (the use of 47 e) and the use of FtNO2 as solvent (Schemes 10.39 and 10.42) [122]. The solvent effect realizing an efficient catalytic cycle would arise from acceleration of Step II (Scheme 10.43) by nucleophilic assistance of the polar solvent. The 47e-catalyzed reaction of KSA 49 in EtNO2 can be used for enantioselective synthesis of both isomers of 1,3-diols (Scheme 10.44). 

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