Reverse Aldol-type reaction

In antithetical analyses of carbon skeletons the synthon approach described in chapter I is used in the reverse order, e.g. 1,3-difunctional target molecules are "transformed" by imaginary retro-aldol type reactions, cyclohexene derivatives by imaginary relro-Diels-Alder reactions. 

The fragment attached to pyridoxal will be the same in both cases, and after hydrolysis it is released as the amino acid glycine. In case this seems a bit complicated, consider the reverse reaction, which would be attack of an electron-rich system on to the carbonyl group of an aldehyde, i.e. an aldol reaction. Therefore, what we are seeing here is merely a reverse aldol-type reaction (see Section 10.3). 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

The reactions of enolates with aldehydes (aldol reactions) or with imines have been widely developed since the 1970s. Asymmetric aldol-type reactions are very important in the multistep synthesis of complex molecules such as ionophores or p-lactam antibiotics. Chirality has been introduced either on the substituents of boron, on the metal ligands or on the carbon skeleton of the enolate. Aldol reactions are usually run at low temperatures, and when metal enolates are used, the reactions are sometimes easily reversible [160, 209],... 

To explain all the results it was necessary to assume that the aromaticity of the arylamine had to be broken by adding an ammonia molecule to the arylamine (Scheme 6). This explains why a high NH3 pressure is required and why the reaction runs better with naphthylamine than with aniline. Then ring opening occurs through a reverse aldol-type reaction (Scheme 7) and ring closure might occur... 

The autoxidation of an alcohol gives the corresponding ketone or aldehyde and hydrogen peroxide, and the yield of hydrogen peroxide in the autoxidation of PVA is of interest. It is also expected that photochemical cleavage of ketone will reduce the molecular weight. Another product of interest is acetaldehyde, formed by the reverse aldol-type reaction, (19,20) where /Miydroxyaldehyde or ketone is cleaved in alkaline aqueous solution. 

Alternatively, Li et al. reported a RUCI2 (PPhs) 3 -catalyzed reshuffling of functional groups of homoallylic alcohols in water (Eq. 4.61). The reaction led to an aldol-type reaction by reacting allyl alcohols with aldehyde (Scheme 4.23). The presence of In(OAc)3 promoted the aldol reaction with a -vinylbenzyl alcohol and aldehyde. An indium hydride-promoted reductive aldol reaction of unsaturated ketones in aqueous media was developed. The use of water/methanol as a solvent dramatically reverses stereochemistry from anti to syn. Boron enolates have been used for aldol reactions in water using catalytic amounts of boron reagents. 

Aromatic A-TMS-ketene imines undergo efficient aldol-type reaction with O-protected a-hydroxy aldehydes, giving iy -selectivity at ambient temperature, reversing at -78 °C to anti- Transfer of the TMS group from the ketene imine prevents (g) retro-reaction. 

P-Pyranone is not a stable end product of the maltose degradation, but reacts in the presence or absence of amines to give a wide range of advanced products (8). In aqueous solution P-pyranone isomerizes to a certain extent to cyclopentenone (2) (Figure 5). The reversible transformation represents an intramolecular aldol type reaction. 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

The metabolism of P-hydroxy-a-amino adds involves pyridoxal phosphate-dependent enzymes, dassified as serine hydroxymethyltransferase (SHMT) (EC 2.1.2.1) or threonine aldolases (ThrA L-threonine selective = EC 4.1.2.5, L-aHo-threonine selective = EC 4.1.2.6). Both enzymes catalyze reversible aldol-type deavage reactions yielding glycine (120) and an aldehyde (Eigure 10.45) [192]. 

An asymmetric C-C coupling, one of the most important and challenging problems in synthetic organic chemistry, seems to be most appropriate for the creation of a complete set of diastereomers because of the applicability of a convergent, combinatorial strategy [38-40]. In Nature, such reactions are facilitated by lyases which catalyze the (usually reversible) addition of carbo-nucleophiles to C=0 double bonds, in a manner mechanistically most often categorized as aldol and Claisen additions or acyloin reactions [41], The most frequent reaction type is the aldol reaction, and some 30 lyases of the aldol type ( aldolases ) have been identified so far [42], of which the majority are involved in carbohydrate, amino acid, or hydroxy acid metabolism. This review will focus on the current state of development of this type of enzyme and will outline the scope and limitations for their preparative application in asymmetric synthesis. 

Substituted 3-phenylsulfonyl-5-hydroxymethyl-THFs (e.g. 44) have been prepared chemo-, regio-, and diastereo-selectively via reaction of a y,5-cpoxycarbanion with aldehydes, RCHO.156 The initial aldol-type addition is non-diastereoselective, but reversible. The subsequent cyclization is selective, and exerts overall thermodynamic control. 

Hydroxymethyl-substituted tetrahydrofurans have been prepared with high diastere-oselectivity by reaction of the carbanion derived from 3,4-epoxybutyl phenyl sulfone (g) with aldehydes in the presence of a mixture of lithium and potassium /-buloxidcs (Scheme 8).48 Initial formation of aldol-type adducts is a non-diastereoselective but reversible process thus, subsequent formation of one main diastereoisomer is controlled by the relative rates of cyclization. The configuration of the carbon stereocentre at the oxirane ring is inverted in the course of the 5 2 process, and two new centres are created diastereoselectively (up to 87 13 0 0). 

This outcome (23) is consistent with aldol-type 0-addition with oxygen retention reversal (ref. 14), as shown in reaction sequence (24). 

FDP aldolase catalyzes the reversible aldol addition reaction of DHAP and d-glyceraldehyde 3-phosphate (D-Gly 3-P) to form d-FDP (Fig. 14.1-1). The equilibrium constant for this reaction has a value of -104 m-1 in favor of FDP formation. The enzyme has been isolated from a variety of eukaryotic and prokaryotic sources, both in type I and type II forms[7 21). Generally, the type I FDP aldolases exist as tetramers (M.W. 160 KDa), while the type II enzymes are dimers (M. W. 80 KDa). For the... 

The synthons of porphyrin syntheses are the pyrroles, which in turn must be made from 1,4-difunctional synthons. These carbon skeletons are available by an aldol-type condensation of the enol of a 1,3-diketone with an a-nitrosylated acetoacetate (Knorr pyrrole synthesis. Scheme 1.3.4). The final reductive ring closure by Schiff base formation is again a reversible condensation reaction. After dehydration, however, a stable 7i-electron sextet is formed, which gives the resulting pyrrole aromatic stability. Hydrolysis of this enamine can now only occur in very strong acid. In water of modest acidity or basicity it is perfectly stable. 

Zn complexes " have been prepared that model type-II aldolases, which catalyze reversible aldol addition reactions. Enolizations are essential for the carbon-carbon bond formation in an aldol reaction, and Zn may play a role in such processes. For example, activation of the carbonyl of DHAP in the active site of type-II aldolases was performed by a Zn complex of l-(4-bromophenacyl)-cyclen (59) (Scheme 38). The pAa value for the acidic protons of the carbonyl a-position was 8.4. 

Formally, the MBH reaction involves a sequence of Michael addition, aldol reaction and P-elimination. The commonly proposed mechanism consists in a reversible conjugate addition of the nncleophile to the starting enone 237, generating an intermediate enolate 238. This enolate reacts with the electrophilic aldehyde in an aldol-type process, in which two stereogenic centers are formed, to give 239, which suffers an intramolecnlar acid-base eqnilibrinm to give another enolate 240. From this intermediate, the p-elimination of the nncleophile provides the MBH product... 

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