Electrophilicity aldehydes

Deprotonation of allylic aryl sulfoxides leads to allylic carbanions which react with aldehyde electrophiles at the carbon atom a and also y to sulfur . With benzaldehyde at — 10 °C y-alkylation predominates , whereas with aliphatic aldehydes at — 78 °C in the presence of HMPA a-alkylation predominates . When the a-alkylated products, which themselves are allylic sulfoxides, undergo 2,3-sigmatropic rearrangement, the rearranged compounds (i.e., allylic sulfenate esters) can be trapped with thiophiles to produce overall ( )-l,4-dihydroxyalkenes (equation 24). When a-substituted aldehydes are used as electrophiles, formation of syn-diols 27 occurs in 40-67% yields with diastereoselectivities ranging from 2-28 1 (equation 24) . ... 

Includes rearrangement products (19-24% overall yield) with aldehyde electrophiles. 

This approach to C (1) nucleophiles has been recently extended. The Lichten-thaler zinc enolate reacts efficiently with more demanding aldehyde electrophiles to provide C-disaccharides [108,109], and activation of the C(l) bromide 276 can also be carried out using CeCl3/NaI (Scheme 72). The latter method is based on the earlier work of Ftdcuzawa [110] and others [111], although the mechanism of this cerium-mediated reaction has yet to be fully understood. 

Originally, Stahly [34] showed that deprotonation and trapping with aldehyde electrophiles could be achieved in concentrated sodium hydroxide solution ... 

Methyl ketone enolates bearing a /1-heteroatom substituent have been designed to effect highly 1,5-diastereoselective additions to aldehyde electrophiles and used to achieve double-stereodifferentiating aldol reactions.30... 

Regio- and stereo-selective allylation of sulfonylimines has been carried out with trifluoro(allyl)borates and allylstannanes, using palladium-pincer complexes as catalysts.47 Syn products predominate, in contrast to the corresponding reaction of aldehyde electrophiles DFT calculations have been employed to probe the mechanistic differences. 

A substantial acceleration of the Baylis-Hillman reaction has been observed when the reaction was conducted in water [19, 20]. Several different amine catalysts were tested by Aggarwal and coworkers, and as with reactions conducted in the absence of solvent, 3-hydroxyquinudidine was found to be the optimum catalyst in terms of rate [19]. The reaction has been extended to other aldehyde electrophiles including pivaldehyde. Further studies on the use of polar solvents revealed that formamide also provided significant acceleration. 

There are several enzymes that form a Schiff base between their substrates and either a lysine -amino group from the protein, the aldehyde electrophile of pyridoxal-5-phosphate or the keto group of a covalently bound pyruvyl moiety. The electron sink under all these conditions is either the imine or its protonated iminium form, that in many cases leads to the formation of an enamine by the variety of pathways outlined below. 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

Oxazoles can react at the C-4 position with aromatic aldehyde electrophiles under Friedel-Crafts conditions when the C-5 position is substituted with an alkoxy group. This feature has been exploited in a chiral Lewis acid-catalyzed formal [3-1-2] cycloaddition of aromatic aldehydes and 2-aryl-5-methoxyoxazoles 45 to generate enantiomerically enriched 2-oxazoline-4-carboxylates 46 (Scheme 4) <2001AGE1884>. These products can serve as masked /3-hydroxy a-amino acids, which are useful synthetic intermediates and have been found in peptide-based natural... 

One of the most successful and widely used methods for diastereoselective aldol addition reactions employs Evans imides 17 and the derived dialkyl boryleno-lates [8J. The 1,2-svn aldol adducts are typically isolated in high diastereoisomeric purity (>250 1 dr) and useful yields. More recent investigations of Ti(IV) and Sn(II) enolates by Evans and others have considerably expanded the scope of the aldol process [9], In 1991, Heathcock documented that diverse stereochemical outcomes could be observed in the aldol process utilizing acyl oxazolidinone imides by variation of the Lewis acid in the reaction mixture [10]. Thus, for example, in contrast to the, l-syn adduct (21) isolated from traditional Evans aldol addition, the presence of excess TiCL yields the complementary non-Evans 1,2-syn aldol diastereomer. This and related observations employing other Lewis acids were suggested to arise from the operation of open transition-state structures wherein a second metal independently activates the aldehyde electrophile. 

We have already seen how relative stereocontrol may be achieved in aldol reactions at the positions labelled 1 and 2 in 194 (chapters 4 and 27). One of these chiral centres is formed from the aldehyde electrophile and the geometry of the double bond of the enolate determined whether we got anti or syn geometry (chapters 4 and 21). The absolute stereochemistry at these centres could be controlled by a variety of methods (chapters 23-29), including the use of a chiral auxiliary (chapter 27). 

This compound can form a cyclic hemiacetal because it has an alcohol nucleophile and an aldehyde electrophile in the same molecule. Although hemiacetals are normally not favored at equilibrium, formation of a six-membered cyclic hemiacetal has a larger equilibrium constant than a comparable intermolecular reaction. In this case the equilibrium favors the cyclic hemiacetal, there is no carbonyl band in the IR spectrum. 

Thiourea catalyst with additional thoiurea functionality can act as possible bifunctional thiourea catalyst due to the hydrogen bonding ability of the thiourea function. C2-symmetric bisthiourea has been applied to the Baylis-Hillman reaction of cyclohexenone [42] (Table 9.14). Adduct is obtained in moderate to good yields (runs 1-6), but asymmetric induction is dependent upon the aldehyde electrophile (90% ee in run 6). The use of monothiourea as a catalyst results in low conversion (20%). Thus, it could be reasonably deduced that each thiourea function of bisthiourea independently and effectively interact with cyclohexenone and aldehyde in the transition state (Figure 9.10). 

Scheme 10)/ In the case of aldehyde electrophiles, a reaction reminiscent of that with dimedone occurs, and bimetallic complexes may be obtained (Scheme 11). 

The aldolases are a diverse class of enzymes that catalyse the coupling of a carbonyl-containing compound (nucleophile), containing one, two or three carbons, with an aldehyde (electrophile). In most cases the nucleophile is either pyruvic acid or dihydroxyacetone phosphate, whereas the electrophilic aldehyde is much more variable in structure. In many cases the reaction generates two new stereogenic centres in the product. In general, only one isomer is obtained from the four possible stereoisomeric products (Scheme 5.1). 

The direct catalytic intermolecular aldol reaction of ketone electrophiles is difficult due to the small equilibrium constants for ketone electrophiles compared with those of aldehyde electrophiles (142). Very recently, Shibasaki and co-workers overcome the inherent instability of the aldol adducts of ketones by using a-isothiocyanato esters (143) to produce protected a-amino-y3-hydroxy esters (Scheme 29). The screening of chiral ligands and metal sources proved that a 1 1 Bu2Mg/ligand 93 complex effectively promoted the reaction in excellent jdelds... 

Reaction of a 1,3-dithiane anion nucleophile with a ketone or aldehyde electrophile, followed by a mercury-assisted hydrolysis, affords an a-hydroxy ketone. 

The scope of the aldehyde electrophile is limited to unsaturated aldehydes (Scheme 10). This fact is not surprising because of the low N value of these silyl enol ethers (N 4 [43]). Yield and enantioselectivity are uniformly high with... 

The high rate of the epoxide-opening reaction made a thorough kinetic analysis challenging. Reexamination of the kinetic profile of a phosphoramide/SiCLi-catalyzed reaction with an aldehyde electrophile proved more feasible because the broad substrate scope of these reactimis allowed for the selection of reaction partners that give reasonable reactiOTi rates and a more detailed analysis to be obtained without moving away from synthetically relevant reaction cmiditions. 

The abiUty of enals to react as homoenolates [84] in the presence of NHC catalysts was first noted in 2004 independently by the groups of Glorius and Bode [85]. In both cases, the use of stericaUy-hindered catalyst 99 and a strong base (DBU or Bu OK) allowed a -d umpolung through the extended Breslow intermediate (101), thereby attacking an aldehyde electrophile and ultimately forming a y-lactone diastereoselectively (105, = H) (Scheme 18.18). Whereas two aldehydes can... 

The selectivity observed with hydroxyacetone (206) in proline-catalyzed aldol additions is particularly remarkable, as the scope includes a wide range of aldehydes to furnish a,/i-ketone diols such as 207 under mild conditions (Equation 19) [102]. The addition reactions of protected derivatives of a-hydrox) aldehydes as nucleophile coupling partners and aldehyde electrophiles in proline-catalyzed aldol reactions have recently been used to provide access to fragments that can be converted into a variety of carbohydrates [103). 

---