Aldol-type addition

Substituted 3-Hydroxyalkanal Dimethylhydrazones 2 General Procedure for Aldol-Type Addition of Ti-tanated Dimethylhydrazones2 ... 

These results show that chemical yields are generally higher than for most aldol-type additions of ester cnolates. mainly because of the chemical activation of the methylene group by the sulfoxide, which makes this reaction suitable for any aldehyde or ketone. High asymmetric induction is also generally observed. The aldol adducts obtained by addition to aldehydes have been transformed into optically active four- and five-membered lactones38. 

The major difference, when compared with simple diastereoselection in aldol-type additions, is the E- and Z-geometrical isomers of the Michael acceptor. Model transition state G shows one of the orientations of the enantiofaces of an (A)-enolate with a (Z)-enone. These additions, again, result in the same. vyn/an/i-adducts, as in the case of an (A)-enone, but the substituent interactions will be different. 

Darzens reaction, the reaction between a carbonyl compound and an a-halo ester in the presence of a base, consists of an initial aldol-type addition and a subsequent intramolecular Sn2 reaction, forming an epoxide as its final product. Its high stereoselectivity thus relies on the stereoselectivity of the nucleophilic addition of an a-halo ester onto the carbonyl substrate, which can be either an aldehyde or a ketone. 

The carbene-bound alkyl groups are acidic pX [(CO)5Cr=C(OMe)Me in H2O] 12.3 and can be easily deprotonated and alkylated [45,211,212] or acylated [213] (Figure 2.16). Stereoselective aldol-type additions can be realized with the aid of Fischer-type alkylcarbene complexes [214-216]. In these reactions the metallic fragment can either play the role of a bulky carbonyl group or stabilize a given conformation of the substrate by chelate formation [216,217]. 

A different behavior is exhibited by naphthalene-1,8-dicarbocal-dehyde (73). No m-naphthane derivatives are obtained on reaction with nitromethane, nitroethane or other methylene components. The basic medium, required for aldol type additions, causes the dialdehyde to undergo Cannizzaro reaction to the naphthopyranon (74) via an intramolecular 1,5-hydride shift, which is sterically favoured by the peri-position of the two aldehyde functions 28). 

The estimation of the conditions, suppressing the silyl-mediated catalysis and preferable for the carbenium-promoting catalysis, is of significant importance to introduce the chiral information in the product. Since it was observed that a carbe-nium salt promoted the reaction and thus provided the enantioselectivity in the outcome, the rigid conformation and the enhanced reactivity of the carbocation may be the key requirement for the productive enantioselective carbenium catalysis in the aldol-type additions. 

It seems unlikely that this reaction could occur in quite the same way as in the laboratoryaldol reaction, because the enolate anion of the donor molecule (dihydroxypropanone) is not expected to be formed in significant amount of the pH of living cell. In fact there is strong evidence that the enzyme behaves as amino (ENH2) compound and reacts with carbonyl group of dihydroxy propanone to form an imine. This implies that the imine form of dihydroxy propanone is a key intermediate in the overall aldol-type addition. 

Most, but not all, pertinent examples concern the formation of stereogenic units by additions to olefins or face-to-face combinations of trigonal planar units, c.g., aldol-type additions, as illustrated in Table 15. 

The following examples show how open and closed transition states may be invoked by the choice of the reaction type. For instance, aldol-type addition normally proceeds via a closed transition state because the metal ion is shifted from the enolate oxygen to the carbonyl oxygen in an ene-like mechanism ( Zimmerman-Traxler transition state 9). The crucial interactions in the Zimmerman-Traxler transition state 16 are those between the 1,3-diaxially oriented substituents around the chair-like structure. R2 adopts the location shown, thus R3 avoids the 1,3-interaction and assumes an equatorial position. Therefore, the diastereomeric ratio depends mainly on the ( )/(Z) configuration of the enolate. Whereas (Z)-enolates 13 afford syn-config-urated enantiomers, 17 and 18, the corresponding ( )-enolates 14 lead to anti-configurated adducts 19 and 20 10. 

Open transition states have been postulated in the aldol-type additions of ( )- and (Z)-crotyl-stannanes (21/22) to aldehydes. Irrespective of the ( ) or (Z) configuration of the stannane only. yyn-adducts 23/24 are formed. Due to the Lewis acid (LA) complexation of the carbonyl oxygen, a cyclic ( closed ) transition state cannot be adopted. Instead, an open geometry is preferred, in which the methyl and the R group move apart as far as possible to generate the enantiomorphous arrangements 25/2611. 

Early examples of successful, highly diastereoselective alkylations of bicyclic /1-lactams include reactions of the enolates from penicillin and cephalosporin derivatives (e.g., 1 and 4). These enolates have also been used in aldol-type additions, acylations and in the preparation of hetero-substituted penicillins and cephalosporins1. 

This implies that the imine form of dihydroxypropanone is a key intermediate in the overall aldol-type addition. 

Devise a synthesis of each of the following compounds using as a key step an aldol-type addition reaction ... 

This reaction is quite special in that it is an aldol-type addition in which a thioester is the donor (nucleophile) and a keto acid is the acceptor (electrophile). From the discussion in Section 18-8E, you will see that reactions of this kind involving an ester as the donor and an aldehyde or ketone as the acceptor can be achieved in the laboratory only under rather special conditions. For the thioester to function as a nucleophile at the a carbon under the restraints imposed by having the reaction occur at the physiological pH, the catalyzing enzyme almost certainly must promote formation of the enol form of the thioester. The enol then could add to the ketone carbonyl with the assistance of a basic group on the enzyme. This kind of catalysis by enzymes is discussed in Section 25-9C. 

This obviously is unlikely for the given example because there is no reason for cyanide ion to have anything other than an exactly equal chance of attacking above or below the plane of the ethanal molecule, producing equal numbers of molecules of the enantiomers, 21 and 22. However, when a chiral center is created through reaction with a dissymmetric (chiral) reagent, we should not expect an exactly 1 1 mixture of the two possible isomers. For example, in an aldol-type addition (Section 18-8E) of a chiral ester to a pro-chiral ketone the two configurations at the new chiral center in the products 23 and 24 are not equally favored. That is to say, asymmetric synthesis is achieved by the influence of one chiral center (R ) on the development of the second ... 

The entry point is the reaction between acetyl CoA and a four-carbon unit, 2-oxobutanedioic acid. An aldol-type addition of the CH3CO group to this C4... 

It is not difficult to visualize how sugars such as ribose may be formed. Methanal is known to be converted by bases through a series of aldol-type additions to a mixture of sugarlike molecules called formose. Formation of racemic ribose along with its stereoisomers could occur as follows ... 

As to the mechanism of benzoin formation, cyanide ion adds to the aldehyde to form 12. This anion is in equilibrium with 13, wherein the negative charge can be delocalized over the phenyl and nitrile groups. A subsequent aldol-type addition of 13 to the carbonyl carbon of a second aldehyde molecule gives the addition product 14, and loss of HCN from 14 leads to the benzoin ... 

Ab initio MO methods have been used to predict the stereochemistry of aldol-type addition of boron enolates to imines, with due allowance for the degree and type of substitution, and the geometry (E or Z) of both the enolate and imine reactants.39 Only two important transition states were identified—both cyclic—one chair-like and the other boat-like. The results are compared with the stereo selections reported in various experimental methodologies. 

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