Ketone directed aldol reactions with aldehydes

Marhwald reported that ligand exchange of Ti(rac-BINOLate)(Of-Bu)2 with optically active a-hydroxy acids presents an unexpected and novel approach to enantio-selective direct aldol reactions of aldehydes and ketones (Scheme 12.19). The aldol products have been isolated with a high degree of syn diastereoselectivity. High enantioselectivities have been observed when using simple optically pure a-hydroxy acids. 

Trichlorotitanium enolates are directly prepared from a ketone, TiCU, and a tertiary amine [122,123] and undergo aldol reactions with aldehydes [124-129], ketones [129], and imines [130,131], Intramolecular condensation with esters is also known [132-137], Although these reactions, based on a titanium enolate [16], which often results in high diastereoselectivity in aldol and related reactions [122], will not be discussed in detail in this article, the success of the alkylation of this titanium enolate with SNl-active electrophiles should be discussed owing to the high Lewis acidity of the metal center [123], Equation (37) shows stereoselective alkylation with an orthoacetate, which is usually inert to alkali metal enolates [138], Aminoalkylation of trichlorotitanium enolates with (a-chloroalkyl)amine has been performed analogously [139,140],... 

It is clear that the presence of the benzeneselenoethyl moiety in 21 or 22 is not required as a latent double bond in subsequent transformations. It would thus be synthetically more attractive to be able to prepare the unsaturated ketones directly. Reaction of AS-hexahy-dromandelic acid (3) with either (E)- or (Z)-propenyllithium followed by hydroxy silylation opens the way to both 34 and 35. Boron enolates of either 34 or 35, prepared in situ, undergo reaction with aldehydes to afford aldol products, albeit with low selectivity when R=TBS. Interestingly, the -isomer 34 provides mainly the 2,3-anti products 36 (1 3.5 syn. anti), while the Z-isomer 35 affords mainly the syn products 37 (3 1 to 10 1 syn anti). However, the corresponding O-triethylsilyl-protected boron enolates of 34 or 35 undergo smooth aldol reaction with aldehydes to yield the 1,3-syn products 37 with high diastereoselectivity (>100 1) (Scheme 6) [7]. 

In the same group, calcium, or barium, also played an acceptable catalytic activity in a certain aldol reaction. Early in 1998, Yamada and Shibasaki (145) have first found a chiral barium catalyst promoted a direct aldol reaction of aldehydes and unmodified ketones efficiently with good conversions (77-99% yield) and enantioselectivities (50-70% ee) (Scheme 30). The barium catalyst was prepared from Ba(0-fPr)2 and 2.5 equiv of ligand 96 (i2)-2-hydroxy-2 -methoxy-l,l -binaphthyl(BINOL-Me) in dimethyl ether, and the sideproduct of f-PrOH was removed by evaporation. 

Lanthanoid triisopropoxides are active catalysts for aldol reactions of aldehydes (209). In addition, it is useful reagent for the preparation of Ln-based heter-obimetallic catalysts, such as LLB 160. Shibasaki and co-workers contributed an important progress in the Ln-based heterobimetallic catalysts promoted organic transformations, including the aldol reactions (210-212). For example, early in 1997, they reported the (i )-LLB catalyzed direct aldol reaction with good enantioselectivities (up to 94% ee) and yields (up to 90%) for the direct aldol reaction of ketones to aldehydes (Scheme 55) (213). 

Brigaud and Portella et al. applied Yb(OTf)3 to aldol reaction of a,a-difluoroenol silyl ether (2) affording difluoromethylene ketones, a common structural motif of HlV-1 protease inhibitor [4], (2) was generated from acylsilane and trifluo-romethyltrimethylsilane and directly subjected to the aldol reaction with aldehydes with 10 mol% ofYb(OTf)3 in a one-pot procedure (Scheme 13.1). The same reaction with other Lewis acids such as TiCU or BF3-OEt2 required more than stoichiometric amount. 

Enantioselective direct aldol reaction with dynamic kinetic resolution can be performed in the presence of proline or its derivatives as an organocatalyst. " Ward and coworkers reported on an aldol reaction of cyclic ketone 101 with (+/—)-aldehyde 102 in the presence of L-proline to give adduct 104 with high enantioselectivity. For large-scale reaction, the more soluble catalyst 103 bearing tetra-zole was effective without lowering the yield (75%, with >98% ee) (Scheme 27.18). The aldol adduct 104 was further elaborated to serricomin 105, a sex pheromone of the female cigarette beetle. 

In general the reaction of an aldehyde with a ketone is synthetically useful. Even if both reactants can form an enol, the a-carbon of the ketone usually adds to the carbonyl group of the aldehyde. The opposite case—the addition of the a-carbon of an aldehyde to the carbonyl group of a ketone—can be achieved by the directed aldol reaction The general procedure is to convert one reactant into a preformed enol derivative or a related species, prior to the intended aldol reaction. For instance, an aldehyde may be converted into an aldimine 7, which can be deprotonated by lithium diisopropylamide (EDA) and then add to the carbonyl group of a ketone ... 

This is known as the directed aldol reaction. Similar reactions have been performed with oc-lithiated dimethylhydrazones of aldehydes or ketones and with a-lithiated... 

The values of x = 0.5 and = 1 for the kinetic orders in acetone [1] and aldehyde [2] are not trae kinetic orders for this reaction. Rather, these values represent the power-law compromise for a catalytic reaction with a more complex catalytic rate law that corresponds to the proposed steady-state catalytic cycle shown in Scheme 50.3. In the generally accepted mechanism for the intermolecular direct aldol reaction, proline reacts with the ketone substrate to form an enamine, which then attacks the aldehyde substrate." A reaction exhibiting saturation kinetics in [1] and rate-limiting addition of [2] can show apparent power law kinetics with both x and y exhibiting orders between zero and one. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

In principle, L-proline acts as an enzyme mimic of the metal-free aldolase of type I. Similar to this enzyme L-proline catalyzes the direct aldol reaction according to an enamine mechanism. Thus, for the first time a mimic of the aldolase of type I was found. The close relation of the reaction mechanisms of the aldolase of type 1 [5b] and L-proline [4] is shown in a graphical comparison of both reaction cycles in Scheme 3. In both cases the formation of the enamines Ila and lib, respectively, represents the initial step. These reactions are carried out starting from the corresponding ketone and the amino functionality of the enzyme or L-proline. The conversion of the enamine intermediates Ha and lib, respectively, with an aldehyde, and the subsequent release of the catalytic system (aldolase of type I or L-proline) furnishes the aldol product. 

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

Epothilone A (2) is a natural product that exhibits taxoterelike anticancer activity. A new synthesis of the ketoacid 6, a common C1-C6 fragment used in the total synthesis of epothilone A, was accomplished by directed aldol reaction of acetone with the aldehyde 34 (Scheme 2.3c). The aldol reaction of acetone with the aldehyde 3 in the presence of D-proline proceeded smoothly to furnish the expected aldol product (4) in 75% yield and with greater than 99% ee. Intramolecular aldol reaction of the hydroxy ketone 4 in the presence of pyrrolidine gave the cyclohexenone 5 in good yield. Protection of the alcohol as a TBS ether followed by oxidation of the alkene then produced the desired ketoacid (6). 

Northrup AB, MacMillan DWC (2002a) The first direct and enantioselective cross-aldol reaction of aldehydes. J Am Chem Soc 124 6798-6799 Northrup AB, MacMillan DWC (2002b) First general enantioselective catalytic Diels-Alder reaction with simple alpha,beta-unsaturated ketones. J Am Chem Soc 124 2458-2460... 

Yamada YM, YoshikawaN, SasaiH, Shibasaki M (1997) Direct catalytic asymmetric aldol reactions of aldehydes with unmodified ketones. Angew Chem Int Ed Engl 36 1871-1873... 

The mechanism is similar to that of the barium-catalyzed direct aldol reaction (Scheme 16). The reaction commences with deprotonation of the ketone (2) by the Br0nsted base unit of the catalyst under generation of the enolate 81. After addition of the aldehyde 1 the Lewis acid-base adduct 82 is formed. Then the reaction of the aldehyde and the enolate occurs (82 83). After... 

The directed aldol reaction is an important means of selective carbon-carbon bond formation. This reaction is efficiently achieved by the transformation of one carbonyl group to a silylated enol derivative, which subsequently couples with another carbonyl compound with the aid of a Lewis acid, typically TiCl4, as formulated in Eq. (2). This type of directed aldol reaction is called the Mukaiyama aldol reaction, a standard and practical synthetic protocol with broad application which has, accordingly, been reviewed extensively [38-42] in addition to the reviews cited in the introductory section. The fundamental reactions between enol silyl ethers and an aldehyde or a ketone... 

Although both aldehydes and ketones also participate in the directed aldol reaction, the former are generally more reactive, as is exemplified in Eq. (6) [45]. Thus, the aldol reaction of an enol silyl ether with an aldehyde could be performed in the presence of a ketone. Equation (6) also demonstrates that the base (LDA)-mediated aldol reaction and the Mukaiyama-type reaction took place at the different position in a complementary manner to give the isomeric aldols. 

In the proline-catalyzed aldol reactions, enolizable achiral aldehydes and ketones are transformed into the corresponding enamines, which can then react with less enolizable carbonyl compounds, even in one-pot protocols. These reactions, unlike most catalytic aldol reactions, do not require preformed enolates, and constitute direct aldol reactions. 

In combination wifh t-butyldimethylsilyl chloride, InClj catalyzes the aldol reaction between aldehydes and t-butyldimethylsilyl enol ethers in anhydrous organic solvents [140]. It has recently been found that the InCh-catalyzed Mukaiyama aldol reaction proceeds in water (Tab. 8.26) [141]. The reaction proceeds cleanly under almost neutral conditions to give /1-hydroxy ketones. The aqueous phase with IriClj can be reused. Water-soluble aldehydes such as glyoxylic acid and a commercial formaldehyde solution can be used directly for these reactions. 

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