Aldol, retro

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. 

This cleavage is a retro aldol reaction It is the reverse of the process by which d fruc tose 1 6 diphosphate would be formed by aldol addition of the enolate of dihydroxy acetone phosphate to d glyceraldehyde 3 phosphate The enzyme aldolase catalyzes both the aldol addition of the two components and m glycolysis the retro aldol cleavage of D fructose 1 6 diphosphate... 

Cleavage reactions of carbohydrates also occur on treatment with aqueous base for prolonged periods as a consequence of base catalyzed retro aldol reactions As pointed out m Section 18 9 aldol addition is a reversible process and (3 hydroxy carbonyl com pounds can be cleaved to an enolate and either an aldehyde or a ketone... 

A number of other valuable aroma chemicals can be isolated from essential oils, eg, eugenol from clove leaf oil, which can also, on treatment with strong caustic, be isomerked to isoeugenol, which on further chemical treatment can be converted to vanillin (qv). Sometimes the naturally occurring component does not requke prior isolation or concentration, as in the case of cinnamaldehyde in cassia oil which, on dkect treatment of the oil by a retro-aldol reaction, yields natural ben2aldehyde (qv). This product is purified by physical means. 

In E. coli GTP cyclohydrolase catalyzes the conversion of GTP (33) into 7,8-dihydroneoptetin triphosphate (34) via a three-step sequence. Hydrolysis of the triphosphate group of (34) is achieved by a nonspecific pyrophosphatase to afford dihydroneopterin (35) (65). The free alcohol (36) is obtained by the removal of residual phosphate by an unknown phosphomonoesterase. The dihydroneoptetin undergoes a retro-aldol reaction with the elimination of a hydroxy acetaldehyde moiety. Addition of a pyrophosphate group affords hydroxymethyl-7,8-dihydroptetin pyrophosphate (37). Dihydropteroate synthase catalyzes the condensation of hydroxymethyl-7,8-dihydropteroate pyrophosphate with PABA to furnish 7,8-dihydropteroate (38). Finally, L-glutamic acid is condensed with 7,8-dihydropteroate in the presence of dihydrofolate synthetase. 

Cinnamaldehyde has been efficiently isolated in high purity by fractional distillation from cassia and cinnamon bark essential oils. This material has been utili2ed in several manufacturing protocols (39—41) for the preparation of natural ben2aldehyde through a retro-aldol process. Since the late 1970s the demand for natural flavors has increased dramatically. This demand has led to a corresponding requirement for a more extensive line of readily available natural aroma chemicals for flavor creation. 

In systems which preclude retro-aldol condensations, benzilic acid rearrangement of 11,12-diketones affords normal C-norsteroids in fair yields. For example, 11,12-diketotigogenin (82) is converted to the C-nor-(5oc,9(, 22a)-spirostane (83) in 65 % yield by barium oxide in boiling aqueous methyl-cellosolve. ... 

Trimethylsilyl cyanide. This reagent readily silylates alcohols, phenols, carboxylic acids, and, more slowly, thiols and amines. Amides and related compounds do not react with it. The reagent has the advantage that a volatile gas (HCN is highly toxic) is the only by-product. In the following case, the use of added base resulted in retro aldol condensation ... 

The ratio of products 15 and 16 is dependent on the structures, base, and the solvent. The kinetics of the reaction is likewise dependant on the structures and conditions of the reaction. Thus addition or cyclization can be the rate-determining step. In a particularly noteworthy study by Zimmerman and Ahramjian, it was reported that when both diastereomers of 20 were treated individually with potassium r-butoxide only as-epoxy propionate 21 was isolated. It is postulated that the cyclization is the rate-limiting step. Thus, for these substrates, the retro-aldolization/aldolization step reversible. ... 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

The reducdon of fl-rdtro alcohols v/ith LLAiH) residts in low yields of fl-amino alcohols due to the occurrence of a retro-aldol reacdon. This problem is resolved by protecdng of OH of fi-nitro alcohols, as shovm in Eq. 6.53. ... 

The following reaction involves an intramolecular aldol reaction followed by a retro aldol-like reaction. Write both steps, and show their mechanisms. 

Fructose 1,6-bisphosphate undergoes ring opening and is cleaved by a retro-aldol reaction into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP). 

Step 2 of Figure 29.13 Decarboxylation and Phosphorylation Decarboxylation of oxaloacetate, a jB-keto acid, occurs by the typical retro-aldol mechanism like that in step 3 in the citric acid cycle (Figure 29.12), and phosphorylation of the resultant pyruvate enolate ion by GTP occurs concurrently to give phosphoenol-pyruvate. The reaction is catalyzed by phosphoenolpyruvate carboxykinase. 

The reactions that accomplished the conversion of intermediate 16 into intermediate 23 have taken place very smoothly. It is worth acknowledging that the //-hydroxy lactam moiety did not, at any stage, participate in any undesirable side reaction processes. The stability of the //-hydroxy lactam substructure in the presence of basic reagents is particularly noteworthy since a destructive retro-aldol cleavage reaction could have conceivably occurred on several occasions. The stability of this potentially labile moiety permits all of the desired transformations leading from 16 to 23 to be conducted without prior protection of the C-8 hydroxyl group. 

This retro-aldol-typc fragmentation is possible because the chlorin chromophore stabilizes the anion formed on loss of the a-oxo acid residue. A related reactivity is observed in the reduction of 3-vinylchlorins, e.g. 24, to 3-ethylporphyrins, e.g. 25, in the presence of hydrogen iodide in acetic acid. The mechanism of this reaction can be represented as a sequence of tautomeric reactions which lead to the completely conjugated porphyrin system.32c-40-54... 

Scheme 8.52 Retro-aldol fragmentation of an epoxide-derived hemiacetal.

The classical aldol addition, which is usually run in protic solvents, is reversible. Most modern aldol methodologies, however, rely on highly reactive preformed metal enolates, whereby proton donors are rigorously excluded. As a consequence, the majority of recent stereoselective aldol additions are performed under kinetic control. Despite this, reversibility and, as a consequence, an equilibration of yrn-aldolates to a t/-aldolates by retro-aldol addition, should not be excluded a priori. 

In general, the rate of syn/anti equilibration increases with decreasing basicity of the enolate and with increasing steric repulsion in the enolate. The first point is illustrated by the fact that aldolates derived from ketones (X = aryl, alkyl) undergo syn/anti equilibration more readily than those derived from amides or carboxylates (X = NR2,0-). It appears that the rate of the retro-aldol addition is higher when the enolate thereby generated is more stable. 

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