Achiral Aldol Reactions

Various magnesium oxide crystals were initially screened in the achiral aldol reaction between p-nitrobenzaldehyde and acetone at room temperature, and NAP-MgO was found to be superior compared to CP-MgO and CM-MgO (Table 5.8). Based on the results of the achiral aldol reaction, the work was further extended to the direct... 

TABLE 5.8. Achiral Aldol Reaction Catalyzed by Different Crystallites of MgO Between p-Nitrobenzaldehyde and Acetone at Room Temperature"... 

The achiral molybdenum enolate 2 reacts with benzophenone and benzaldehyde at —78 °C to yield the x,/i-unsaturated molybdenum-acyl complexes34, which presumably arise via elimination of hydroxide from unobserved aldolate intermediates such as 3. No examples of such aldol reactions with complexes that are chiral at molybdenum have been reported. 

Analogous to the closely related aldol reactions, reactions of achiral a-substituted enolates and imines lead to mixtures of syn- and rwd-diastereomers. The following diagram shows the postulated pericyclic transition states involved in enolate-iminc condensations10. 

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. 

Double asymmetric induction (See section 1.5.3) can also be employed in aldol reactions. When chiral aldehyde 15 is treated with achiral boron-mediated enolate 14, a mixture of diastereomers is obtained in a ratio of 1.75 1. However, when the same aldehyde 15 is allowed to react with enolates derived from Evans auxiliary 8, a syn-aldol product 16 is obtained with very high stereo-... 

Most of the asymmetric aldol reactions discussed thus far deal with the nucleophilic addition of a chiral or achiral enolate onto a chiral or achiral aldehyde,... 

Scheme 72 Asymmetric nitroso aldol reactions of achiral enamines...

An advantage of these enzymes is that they are stereocomplementary, in that they can synthesize the four possible diastereoisomers of vicinal diols from achiral aldehyde acceptors and DHAP (Scheme 4.2). Although this statement is generally used and accepted, it is not completely true since tagatose-l,6-bisphosphate aldolase (TBPA) from Escherichia coli-the only TBPA that has been investigated in terms of its use in synthesis-does not seems to control the stereochemistry of the aldol reaction when aldehydes different from the natural substrate were used as acceptors [7]. However, this situation could be modified soon since it has been demonstrated that the stereochemical course of TBPA-catalyzed C—C bond formation may be modified by enzyme-directed evolution [8]. 

Nitroso-Aldol Reaction In the course of the Yamamoto group s studies on the nitroso-aldol (NA) reachon of enamines substantial rate increases were observed upon addihon of stoichiometric amounts of achiral Br0nsted acid. Furthermore, exclusive regioselective formation of the N- versus 0-adducts could be controlled by the choice of MeOH or AcOH, respechvely, as Br0nsted acids (Scheme 5.60) [113]. Subsequently, enantioselechve versions of both N- and 0-nitroso aldol... 

An interesting problem in stereoisomerism is found in the aldol reactions of the achiral aldehydes which are obtained by ozonolysis of the homoallylic alcohols 174. After stereospecific conversion by the FruA [230], the products can be readily induced to form an intramolecular glycoside 175 by acidic (R=OH) or alkaline treatment (R=C1), under which conditions the two equatorial ring hydroxyl groups completely direct the stereogenic acetal formation [234]. The corresponding RhuA catalyzed reactions deliver the enantiomeric... 

For a previous related work on the achiral amine-catalyzed aldol reaction, see S. Bahmanyar, K. N. Hour,/. Am. Chem. Soc. 2001, 123, 11273-11283. 

The concept of the proline-catalyzed aldol reaction has been recently extended by List et al. towards the synthesis of aldol products with two stereogenic centers [9]. The desired anti-diols 4 have been obtained in a regio-, diastereo- and enantioselective step starting from achiral compounds. Impressive diastero- and enantioselectivities were observed, with a dia-stereomeric ratio up to dr > 20 1 and ee-values of up to >99% ee (Scheme 2, reaction 2). In addition, the reaction leads to a high regioselectivity of >20 1. 

To make the DERA-catalyzed process commercially attractive, improvements were required in catalyst load, reaction time, and volumetric productivity. We undertook an enzyme discovery program, using a combination of activity- and sequence-based screening, and discovered 15 DERAs that are active in the previously mentioned process. Several of these enzymes had improved catalyst load relative to the benchmark DERA from E. coli. In the first step of our process, our new DERA enzymes catalyze the enantioselective tandem aldol reaction of two equivalents of acetaldehyde with one equivalent of chloroacetaldehyde (Scheme 20.6). Thus, in 1 step a 6-carbon lactol with two stereogenic centers is formed from achiral 2-carbon starting materials. In the second step, the lactol is oxidized to the corresponding lactone 7 with sodium hypochlorite in acetic acid, which is crystallized to an exceptionally high level of purity (99.9% ee, 99.8% de). 

In the crossed aldol reaction between acetaldehyde and propiophenone, two chirality centres are created and consequently, four stereoisomers will be produced. Compounds A and B are enantiomers of each other and can be described with the stereo descriptor u. Similarly, C and D are enantiomers and are /-configured. Since both starting materials are achiral, without the use of a chiral base or chiral auxiliary, racemates will be produced. Likewise the choice of base, the addition of a Lewis acid and the reaction conditions used to form the enolate can control which diastereomer is preferentially formed. If the Z enolate is formed, the u product is the preferred product, whilst the E enolate yields predominately the / product. 

The asymmetric aldol reaction of enol silyl ethers of thioesters with aldehydes is performed in high enantiomeric excess by employing a chiral promoter, tin(II) trifluoromethanesulfonate coordinated with chiral diamine 1 and tri-n-butyltin fluoride (eqs 20 and 21). Highly enantioselective aldol reactions of achiral ketene silyl acetals with achiral aldehydes are carried out by means of the same chiral promoter (eq 22). ... 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

Kobayashi, S, Kawasuji, T, A new synthetic route to monosaccharides from simple achiral compounds by using a catalytic asymmetric aldol reaction as a key step, Synlett, 911-913, 1993. 

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. 

Activation of the (f )-binolato-Ti(OiPr)2 (2) by highly acidic and sterically demanding alcohols as achiral rather than chiral activators is also effective to provide higher levels of enantioselectivity than those attained by the parent enantio-pure binolato-Ti(OiPr) catalyst (2) in the Mukaiyama aldol reaction of silyl enol ethers (Eq. (7.22)) [55]. 

While the aldol reaction of benzaldehyde with (Z)-3-trimethylsiloxy-2-pentene proceeded smoothly in water-ethanol (1 9) at -15 C to afford the desired adduct in a high yield with good selectivities (quant., syn/anti-33/, syn=15% ee), much lower yield and selectivities were observed in ethanol (without water) under the. same conditions (10% yield, synfanti=2.3l, , vyn=41% ee). Furthermore, when the reaction was performed in dichloromethane at -15 °C, the aldol adduct was obtained in 11% yield with syn/anti=2.ll [.yy =20% ee (the opposite absolute configuration)]. From these results, we assume that desired chiral reactions are accelerated by water and that undesired achiral side reactions which proceed rapidly in aprotic solvents [32] are suppressed in aqueous media. 

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