Stoichiometric Enantioselective Aldol Reaction

Many aldehydes react with the (E) silicon enolate [63] derived from propionic acid thioester 79, to give syn aldol adducts in high yield and with perfect stereochemical control, by combined use of tin(II) trifiate, chiral diamine 80, and dibutyltin acetate (Eq. (41)) [64-66] 

The formation of an active complex 81 consisting of three components, tin(II) trifiate, chiral diamine 80, and dibutyltin acetate is assumed in these aldol reactions. The three-component complex would activate both aldehyde and silyl enolate (double activation), i.e. the chiral diamine-coordinated tin(II) trifiate activates aldehyde while oxygen atoms of the acetoxy groups in dibutyltin acetate interact with the silicon atom of the silicon enolate. Because it has been found that the reaction does not proceed via tin(II) or tin(IV) enolates formed by silicon-metal exchange, silicon enolate is considered to attack the aldehydes directly [65]. The problem of this aldol reaction is that (Z) enolates [63] react with aldehydes more slowly, consequently affording the aldols in lower yield and with lower diastereo- and enantio-selectivity. 

Because optically active molecules containing 1,2-diol units are often observed in nature (e.g. carbohydrates, macrolides, polyethers), asymmetric aldol reaction of the silyl enolate of a-benzyloxythioacetate 82 with aldehydes has been investigated for simultaneous introduction of two vicinal hydroxy groups with stereoselective carbon-carbon bond-formation. It has, interestingly, been found that the anti-a,fd-dihydroxy thioester derivatives 83 are 

To examine this hypothesis silicon enolate 85, which has bulky tert-butyldimethylsilyl group, was prepared, to prevent coordination of the a oxygen atom to tin(II). As expected, syn aldol 86 is obtained in high stereoselectivity by reaction of the above-mentioned hindered silicon enolate 85, tin(II) triflate, a chiral diamine 87, and dibutyltin acetate (Eq. (43)) [68]. 

3 Crossed Aldol Reactions Using Silicon Enolates I 153 

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Typical Procedure for Stoichiometric Enantioselective Aldol Reaction Using a Chiral Tin(ll) Catalyst System (Eq. (44)) [67]... 

After the report by Kiyooka et al. in 1991 [43] of the enantioselective aldol reaction by use of CAB 3f under stoichiometric conditions, Masamune and co-workers [44], Kiyooka et al. [45a], and Corey et al. [46] all independently developed CAB-cata-lyzed systems for enantioselective aldol reactions (Eq. 59). 

The original methods for directed aldol and aldol-type reactions of aldehydes and acetals with silyl enolates required a stoichiometric amount of a Lewis acid such as TiCh, Bl i-OI y, or SnCl.j [18]. Later studies have introduced many Lewis acids which accelerate these processes with a catalytic quantity (vide infra). In addition, it has been found that fluoride ion sources also work as effective catalysts of the aldol reaction [19]. In the last decade, much attention has been paid for the development of diastereo- and enantioselective aldol reactions [20, 21], aqueous aldol reactions using water-stable Lewis acids [22], and novel types of silyl enolate with unique reactivity. 

Kiyooka et al. have reported that stoichiometric use of chiral oxazaborolidines (e.g. (S)-47), derived from sulfonamides of a-amino acids and borane, is highly effective in enantioselective aldol reactions of ketene TMS acetals such as 48 and 49 (Scheme 10.39) [117]. The use of TMS enolate 49 achieves highly enantioselective synthesis of dithiolane aldols, which can be readily converted into acetate aldols without epimerization. The chiral borane 47-promoted aldol reaction proceeds with high levels of reagent-control (Scheme 10.40) [118] - the absolute configuration of a newly formed stereogenic center depends on that of the promoter used and not that of the substrate. 

In 1989, a highly enantioselective aldol reaction of achiral silyl enol ethers of thiol esters with achiral aldehydes was developed by using a novel chiral promoter system consisting of chiral diamine-coordinated tin(II) triflate and tributyltin fluoride (or dibutyltin diacetate) [23]. When the silyl enol ether 16 of S-ethyl ethanethioate was treated with PhCHO in the presence of stoichiometric amounts of tin(II) triflate, (S)-l-methyl-2-[(piperidin-l-yl)-methyl]-pyrrolidine (18), and tributyltin fluoride, the aldol reaction proceeded at -78 °C to afford the corresponding adduct 17 in 78% yield with 82% ee (Scheme 4). 

The aldol reaction is one of the most useful carbon-carbon bond forming reactions in which one or two stereogenic centers are constructed simultaneously. Diastereo-and enantioselective aldol reactions have been performed with excellent chemical yield and stereoselectivity using chiral catalysts [142]. Most cases, however, required the preconversion of donor substrates into more reactive species, such as enol silyl ethers or ketene silyl acetals (Scheme 13.45, Mukaiyama-type aldol addition reaction), using no less than stoichiometric amounts of silicon atoms and bases (Scheme 13.45a). From an atom-economic point of view [143], such stoichiometric amounts of reagents, which afford wastes such as salts, should be excluded from the process. Thus, direct catalytic asymmetric aldol reaction is desirable, which utilizes unmodified ketone or ester as a nucleophile (Scheme 13.45b). Many researchers have directed considerable attention to this field, which is reflected in the increasing... 

As described above, optically active aldol adducts are easily obtained by using a stoichiometric amount of chiral diamine, tin(II) triflate, and dibutyltin acetate. To perform the enantioselective aldol reaction by using a catalytic amount of the chiral catalyst, transmetalation of initially formed tin(II) alk-oxide 91 to silyl alkoxide 92 tvith silyl triflate is an essential step (Figure 3.6). When the aldol reaction vas conducted simply by reducing the amount of the chiral catalyst, aldol adducts vere obtained vith low stereoselectivity because Sn-Si exchange occurs slovrly and undesired Me3SiOTf-promoted aldol reaction affords racemic aldol adducts. 

Reetz and coworkers introduced the cyclic chlorodialkylboron Lewis acid (75) (Equation 48) [46], and Kiyooka and coworkers made use of acyloxyborane (76) (Equation 49) [47] in enantioselective Mukaiyama-aldol reactions that employ stoichiometric amounts of the respective boron Lewis acids. Both species give high enantioselectivity in the formation of the desired aldol adducts. After Kiyooka s report of (76), various boron catalysts derived from chiral amino acids appeared in the literature. As such, Masamune and coworkers introduced (77) and (78) [48], Kiyooka and co workers introduced (79) [49], and Corey and co workers introduced (80) [50] as chiral acyloxy borane catalysts for enantioselective aldol reactions (Figure 5.7). 

Shibasaki et al. also developed catalytic reactions of copper, some of which can be applied to catalytic asymmetric reactions. Catalytic aldol reactions of silicon enolates to ketones proceed using catalytic amounts of CuF (2.5 mol%) and a stoichiometric amount of (EtO)3SiF (120 mol%) (Scheme 104).500 Enantioselective alkenylation catalyzed by a complex derived from CuF and a chiral diphosphine ligand 237 is shown in Scheme 105.501 Catalytic cyanomethyla-tion by using TMSCH2CN was also reported, as shown in Scheme 106.502... 

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. 

Fujiwara has reported a unique chiral lanthanoid(II) alkoxide-promoted asymmetric Mukaiyama aldol reaction.38 Stoichiometric amounts of the chiral alkoxide, however, were required for good enantioselectivity. 

D. The use of chiral oxazaborolidines as enantioselective catalysts for the reduction of prochiral ketones, imines, and oximes, the reduction of 2-pyranones to afford chiral biaryls, the addition of diethylzinc to aldehydes, the asymmetric hydroboration, the Diels-Alder reaction, and the aldol reaction has recently been reviewed.15b d The yield and enantioselectivity of reductions using stoichiometric or catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13 The above procedure demonstrates the catalytic use of the oxazaborolidine-borane complex for the enantioselective reduction of 1-indanone. The enantiomeric purity of the crude product is 97.8%. A... 

A stoichiometric amount of 3f catalyzed the asymmetric aldol reaction of aldehydes with enol silyl ethers and subsequent asymmetric reduction, in one pot, to afford syn 1,3-diols with high enantioselectivity (Eq. 49) [43b]. With a variety of aldehydes, 1,3-diols were obtained in moderate yields (53-70 %) with high syn diastereoselectivity. The syn 1,3-diols prepared from aliphatic aldehydes in the reaction (in EtCN as sol-... 

Mukaiyama and Kobayashi et al. have developed the use of Sn(OTf)2 in diastereose-lective and enantioselective aldol-type reactions [26,27]. Initially, the stereoselective aldol reactions were performed with a stoichiometric amount of Sn(OTf)2 [28], The reaction between 3-acylthiazolidine-2-thione and 3-phenylpropionaldehyde is a representative example of a diastereoselective syn-aldol synthesis (Eq. 17). 

In all of the examples considered so far, the chiral element has been employed in stoichiometric quantities. Ultimately, it would be desirable to require only a small investment from the chirality pool. This is only possible if the chiral species responsible for enantioselectivity is catalytic. It is worth stating explicitly that, in order to achieve asymmetric induction with a chiral catalyst, the catalyzed reaction must proceed faster than the uncatalyzed reaction. One example of an asymmetric aldol addition that has been studied is variations of the Mukaiyama aldol reaction [110] whereby silyl enol ethers react with aldehydes with the aid of a chiral Lewis acid. These reactions proceed via open transition structures such as those shown in Figure... 

In contrast to the number of studies on asynunetric HWE reactions using chiral phosphonates, only a few enantioselective HWE reactions using a combination of achiral phosphonates and chiral Ugands are known [69,70]. Koga and coworkers reported the first enantioselective HWE reaction of diethylphospho-noacetonitrile and 4-terf-butylcyclohexanone using a stoichiometric amount of lithium 2-aminoalkoxides as a chiral base [Eq. (23)] [71]. The a,P-unsaturated nitrile was obtained in 92% yield with 52% ee. When the racemic aldolate intermediate was treated with a chiral diamine, a similar result was obtained. These results show that dissociation of the Uthium aldolate to the a-hthiated phospho-noacetonitrile and recombination to the aldolate reversibly occurs during the reaction, and the enantioselectivity is controlled by the rate of the eUmination reaction of the phosphate. 

The role of stoichiometric amount of zinc compounds in the aldol reaction was studied 30 years ago (107). The first study of asymmetric zinc-catalyzed aldol reaction was carried out by Mukaiyama and co-workers the chiral zinc catalyst was prepared from diethylzinc and chiral sulfonamides and was effective in the reaction of ketene silyl ethers with aldehydes (108). Among the subsequent studies on zinc-catalyzed aldol reactions, Trost s group gave important contribution to zinc/prophenol ligand complexes (109,110). The chiral dinuclear zinc catalyst promotes the direct aldol reaction of ketones, including a-hydroxyketones, and aldehydes with excellent enantioselectivity (Scheme 17). It is proposed that one zinc metal coordinated different substrates to form zinc enolate, and another zinc metal center provided the bridge between the interaction of donor and acceptor. 

The first amine-catalyzed, asymmetric intermolecular aldol reactions were developed by List et al. in 2000 [29-33]. Initially it was found that excess acetone in DMSO containing sub-stoichiometric amounts of (S)-proline reacted with some aromatic aldehydes and isobutyraldehyde to give the corresponding acetone aldols (134) with good yields and enantioselectivity (Scheme 4.25). Particularly high ee were achieved with a-branched aldehydes. Similarly to the intramolecular enolendo variant, the only side-product in proline-catalyzed intermolecular aldol reactions are the condensation products (Scheme 4.25). 

At the time the chemistry of main group enolates flourished already for a while, that of late transition metals had a shadowy existence in synthetic organic chemistry. Their stoichiometric preparation and the sluggish reactivity - tungsten enolates, for example, required irradiation to undergo an aldol addition [24a] - did not seem to predestine them to become versatile tools in asymmetric syntheses [27]. The breakthrough however came when palladium and rhodium enolates were discovered as key intermediates in enantioselective catalyses. After aldol reactions of silyl enol ethers or silyl ketene acetals under rhodium catalysis were shown to occur via enolates of the transition metal [8] and after the first steps toward enantioselective variants were attempted [28], palladium catalysis enabled indeed aldol additions with substantial enantioselectivity... 

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