Chiral phosphoramide-catalyzed, enantioselective, directed cross-aldol reactions of aldehydes

Abstract

Catalytic, enantioselective, directed cross-aldol reactions of aldehydes are described. The addition of isobutyraldehyde trichlorosilyl enolate 2 to various aldehydes in the presence of 10 mol % bisphosphoramide 4 provides aldol products in high yields with moderate to good enantioselectivities. The reaction works well with a wide range of aromatic, olefinic, and aliphatic aldehydes. Enantioselectivities are highly dependent on the electronic nature of the aldehyde substituent. Hammett studies reveal that enantioselectivity increases as aldehydes become either more electron rich or more electron poor. T he catalytic enantioselective aldol reaction has achieved ''strategy level'' status in organic synthesis (1-6). In this process, a new carbon-carbon bond is formed with the creation of up to two new stereogenic centers. The relative and absolute configurations of the newly created stereocenters are usually controlled through the use of chiral Lewis acids (7) or through enzymatic methods (3,8). Chiral Lewis acid-catalyzed aldol reactions generally afford aldol products from enoxysilane derivatives of ketones or esters [directed aldol reaction (9)] in high yields with good to excellent selectivity. A few notable examples of chiral Lewis acids used in these catalytic aldol processes include bisoxazoline copper(II) complexes (10, 11) and Schiff base titanium(IV) complexes (12, 13), which have been developed by Evans et al. and Carreira et al., respectively. Recent advances also include the development of direct catalytic enantioselective aldol reactions that employ the two unmodified carbonyl components. Early reports on this type of aldol reaction using LaLi 3 tris(binaphthoxide) as a catalyst were disclosed by . Moderate to good yields and selectivities were obtained in these studies, albeit at long reaction times. Further, Trost et al. (17,18) have developed dinuclear zinc catalysts for direct catalytic enantioselective aldol reactions. These catalysts, which mimic class II aldolases, have been shown to catalyze aldol reactions of unmodified ketones with aldehydes in moderate to good yields with excellent levels of stereocontrol. Parallel to these successful developments is the finding of proline and its derivatives as effective catalysts for direct enantioselective aldol reactions (19-21). These simple cyclic amine catalysts are capable of mimicking class I aldolases, and they provide another approach to asymmetric aldol reactions (22,23).Besides these methods, the use of enzymes (3, 24) and monoclonal antibodies (8) in enantioselective aldol reactions has also been described with success. Wong et al. (24) have demonstrated the use of natural aldolase-catalyzed aldol reactions as a means to effectively and selectively synthesize highly oxygenated carbon chains, allowing a rapid access to various carbohydrates. However, broadening enzyme specificities and being able to perform enzymatic transformations on a preparative scale remain challenges for further development.For the directed aldol reaction, silyl enol et...

Development and Application of Asymmetric Organocatalytic Mukaiyama and Vinylogous Mukaiyama‐Type Reactions

“…[22] The reactionp roceeded in the presence of 10 mol %b isphosphoramide 30 without any addition of SiCl 4 or base, giving dimethyl acetals 39 in high yields with moderate enantiomeric purity.I ng eneral,t he rate of the reaction with electron-poora romatic aldehydes was faster than with electron-rich aromatic aldehydes, as well as more enantioselective. [22] The reactionp roceeded in the presence of 10 mol %b isphosphoramide 30 without any addition of SiCl 4 or base, giving dimethyl acetals 39 in high yields with moderate enantiomeric purity.I ng eneral,t he rate of the reaction with electron-poora romatic aldehydes was faster than with electron-rich aromatic aldehydes, as well as more enantioselective.…”

“…As another example of this approach, organocatalysis has been employed to conduct the addition of isobutyraldehyde trichlorosilyl enolate( 38)t oawide range of aldehydes 16 (Scheme8). [22] The reactionp roceeded in the presence of 10 mol %b isphosphoramide 30 without any addition of SiCl 4 or base, giving dimethyl acetals 39 in high yields with moderate enantiomeric purity.I ng eneral,t he rate of the reaction with electron-poora romatic aldehydes was faster than with electron-rich aromatic aldehydes, as well as more enantioselective. Addition to olefinic aldehydes displayed low enantioselectivity,w hereas aliphatic aldehydesr equired higher tempera-Scheme5.Aldol reaction of trichlorosilyl enolates with various aldehydes catalyzed by aphosphoramide derivative.…”

Atherton–Todd reaction: mechanism, scope and applications

“…They obtained the aldol products in high yields with moderate to good enantioselectivities [ 101 ]. The chiral phosphoramidates used in this study and tested in many other enantioselective reactions (aldol reaction [ 102 ], Michael addition [ 103 ], Diels–Alder reaction [ 104 ], Friedel–Crafts alkylation [ 105 ]) illustrate the use of phosphoramidates as organocatalysts. These phosphoramidates were not synthesized by an AT reaction.…”

Supersilyl Protective Groups in Aldol Reactions

“…Indeed, the TES-type super silyl group [Si(TES) 3 ] gave higher selectivity than the TMS-type super silyl group [Si(TMS) 3 ]. The reaction has broad scope, with a variety of methyl ketones and aldehydes showing high selectivity (entries [3][4][5][6][9][10][11][12]. A particular advantage of this method is that the products of the Mukaiyama aldol reactions can be used directly.…”

“…Denmark and coworkers [10][11][12] developed an elegant asymmetric aldol addition of the trichlorosilyl enol ethers of acetaldehyde and propionaldehyde to aldehydes catalyzed by a chiral phosphoramidate Lewis base. Following MacMillan's seminal report [13], enamine activation has emerged as powerful strategy for the aldehyde crossed-aldol reaction, with a number of groups reporting the addition of acetaldehyde and propionaldehyde to various aldehydes using proline and other organocatalysts.…”