Aldehydes as electrophiles

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

On the other hand, if the allylsilane anion is first complexed with certain metals, a-regioselectivity then predominates, and a high degree of complementary diastereoselectjvity (19) can be attained with aldehydes as electrophiles. For example, boron, aluminium and titanium complexation all induce threo selectivity whereas the use of tin results in an erytbro... 

When 2,2-diphenyl-l,3-dioxolane (410, R = Ph) was lithiated with lithium and a catalytic amount of naphthalene (4%) in THF at —40°C (see Section VI.F.l) and then reacted with an aldehyde as electrophile, intermediates 437 were generated. The further lithiation of these compounds at the same temperature cleaved the second benzylic carbon-oxygen bond giving new organolithium intermediates 438, and a second electrophile could be introduced to give 439, after hydrolysis. In these products, two different electrophilic fragments have been incorporated, so the starting material behaves as the 1,1-diphenylmethane dianion synthon (Scheme 122) °. 

The substitution of aldehydes as electrophiles into activated nucleophilic positions of aromatic rings, such as the ortho or para positions in a phenol, is well known from the commercial importance of phenol-formal-... 

Hydrogen bond-promoted asymmetric aldol reactions and related processes represent an emerging facet of asymmetric proton-catalyzed reactions, with the first examples appearing in 2005. Nonetheless, given their importance, these reactions have been the subject of investigation in several laboratories, and numerous advances have already been recorded. The substrate scope of such reactions already encompasses the use of enamines, silyl ketene acetals and vinylogous silyl ketene acetals as nucleophiles, and nitrosobenzene and aldehydes as electrophiles. 

The simplest explanation of this result is that the chemical reaction has followed essentially the same course as the biological one. First, the hemiacetal is opened by the base to give the open-chain keto-aldehyde. Rotation about a C-C bond allows a simple aldol condensation between the enolate of the ketone as nucleophile and the aldehyde as electrophile. 

The rich, synthetically valuable chemistry of these carbanions is mainly due to the independent efforts of two groups ". As outlined in equation 129 addition of a ketone to the carbanion is the basis for the preparation of cyclobutanones obtained after acid treatment of the intermediate oxaspiropentanes. In contrast, aldehydes as electrophiles give isolable bromoalcohols, which undergo redox isomerization to cyclopropyl ketones. 

There is little to differentiate these derivatives from benzenoid acids and esters, save for the easy decarboxylation of quinoline-2- and isoquinoline-1-acids, via an ylide that can be trapped with aldehydes as electrophiles - the Hammick reaction. Loss of carbon dioxide from A-methylquinolinium-2- and -isoquinolinium-1-acids, and trapping of resulting ylides, can be achieved with stronger heating. ... 

Some initial studies have been made on KDPG aldolase (EC 4.1.2.14) which in vivo catalyzes the reversible condensation of the pyruvate with glyceraldehyde 3-phosphate (25) to form 2-keto-3-deoxy-6-phosphogluconate (KDPG - 26) (Scheme 9). The enzyme was found to accept a number of unnatural aldehydes as electrophiles. It was applied for the synthesis of KDG from glyceraldehyde [66]. 

Aldolases - Aldolases catalyze reversible aldol condensations of su-gars. A well-studied enzyme is fructose-1,6-dlphosphate aldolase from rabbit muscle. This enzyme exhibits a high specificity for dihydroxy-acetone phosphate as the nucleophile, but tolerates a range of aldehydes as electrophiles (Scheme II).This broad specificity allows synthesis of sugars such as 6-deoxyfructose and Isotopically labeled glucose... 

Pentacovalent 2,2,2-triethoxy-2,2-dihydro-5-methoxy-1,2-2 -oxapho-spholene (342) has been synthesized as a new type of enolate from a.jS-nn-saturated ketones (341) and trialkyl phosphites and then hydrolyzed to give a series of phosphonates (343) and (344) (Scheme 77). The aldol reaction of the oxaphospholene intermediate with several aldehydes as electrophiles under mild and neutral conditions produced phosphonate-containing aldol compounds. 

The scope of aldehydes as electrophiles has been extensively studied. For instance, aqueous formaldehyde reacted with only two equiv. of cyclic ketones... 

Whereas the intermolecular processes using ketones as source of nucleophile and aldehydes as electrophiles have been extensively stndied, other reactions, nsing either ketones or aldehydes as electrophiles, have been less studied, with reactions implying the use of aldehydes as source of nucleophile and ketones as electrophiles having scarcely investigated. Also the nse of poor reactive ketones such as a,p-unsaturated ketones or even alkyl aryl ketones is still elnsive. 

In organocatalytic cross-aldol reactions of two different aldehydes through the enamine intermediate first reported by MacMillan and Northrop, the a d-cross-aldol adduct could be obtained in a highly stereoselective fashion. However, most such reactions required the use of sterically hindered aliphatic aldehydes, from which the enamine intermediates are rather difficult to form, or aromatic aldehydes as electrophile. In the direct aldol reaction between simple aliphatic aldehydes (enolisable aldehydes), both aldehydes can perform the double role of nucleophile and electrophile, and consequently, two cross-aldol adducts and two homo-aldol adducts would be possible products with each having four stereoisomers. To differentiate two... 

The same diaryprolinol catalyst can be applied to the reaction of trifluorome-thylacetaldehyde ethyl hemiacetal with enolizable aldehydes as electrophiles. In this case, anti-selectivity was also observed though the level of diastereoselectivity was much lower [141]. 

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