Aldol addition reactions retro

Mg enolates generated from Mg bisamides can be used in aldol addition reactions with alkyl, aryl, and cyclic ketones. As shown in Scheme 3.40, these reactions are significant in that the self-coupling of ketones in aldol reactions to give tertiary yS-hydroxyketones are also possible. More specifically, these transformations are achieved principally by the use of relatively high reaction temperatures between 25 °C and 60 °C. Such conditions are a notable departure from the widely used lithium-mediated aldol additions, where increasing the reaction temperature results in retro-aldol processes and also elimination of LiOH to give enone products [30]. 

There are few cases in which the stereochemistry of cyclic aldol addition reactions has been carefully examined. The situation is complicated by the problem of retro-aldolization and by the propensity of such aldols to dehydrate to the enone. There is a suggestion that under strictly kinetic conditions, aldols in which the carbonyl and hydroxy groups can chelate a metal cation are favored. However, in protic medium, it does not appear that the kinetic product is generally the more stable one. A particularly instructive example is seen in equation (135). The complex keto aldehyde (101) was treated with dilute KOH in methanol for 15 min at various temperatures. At -20 °C, +25 °C, and +65 °C, the (102) (103) ratios were 93 7,50 50 and 0 100, respectively. 

Therefore, we consider preparing the product via either an aldol reaction or a Claisen condensation. In this case, an aldol addition reaction can be employed, as shown in the following retro synthetic analysis. 

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... 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

Another interesting example is SHMT. This enzyme catalyzes decarboxylation of a-amino-a-methylmalonate with the aid of pyridoxal-5 -phosphate (PLP). This is an unique enzyme in that it promotes various types of reactions of a-amino acids. It promotes aldol/retro-aldol type reactions and transamination reaction in addition to decarboxylation reaction. Although the types of apparent reactions are different, the common point of these reactions is the formation of a complex with PLP. In addition, the initial step of each reaction is the decomposition of the Schiff base formed between the substrate and pyridoxal coenzyme (Fig. 7-3). 

Leaving the (retro-)aldol addition-initiated threefold anionic domino processes, we are now describing sequences which are initiated by a SN-type transformation. In particular, domino reactions based on SN/1,4-Brook rearrangement/SN reactions are well known. For example, the group of Schaumann obtained functionalized cyclopentanols of type 2-461 by addition of lithiated silyldithioacetals 2-458 to epoxy-homoallyl tosylates 2-459 in 41-75% yield (Scheme 2.106) [248]. 

It can be assumed that, upon irradiation, tautomer 5-40-II reacts with the alkene 5-41 in a highly regioselective [2+2] cycloaddition to give the cyclobutane 5-42 as an intermediate. Subsequent retro-aldol-type reaction and hemiacetal formation produces 5-44 via 5-43. After addition of the Lewis acid (BF3-Et20), cyclization takes place to give the desired products. It should be noted that the excess of alkene must be removed under reduced pressure before addition of the Lewis acid in order to avoid polymerization. 

The structural similarity between claenone (42) and stolonidiol (38) enabled Yamada to exploit an almost identical strategy for the total synthesis of (-)-stolonidiol (38) [40]. A short retrosynthetic analysis is depicted in Fig. 12. An intramolecular HWE reaction of 68 was successfully applied for the macrocyclization. The highly substituted cyclopentanone 69 was made available by a sequence that is highlighted by the sequential Michael-Mi-chael addition between the enolate 53 and the a, -unsaturated ester 70 followed by a retro-aldol addition. However, as is the case for the claenone (42) synthesis, the synthesis of stolonidiol (38) is characterized by numerous functional and protecting group transformations that are a consequence of Yamada s synthetic strategy. 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

In this system, the chiral phase transfer catalyst (PTC) is able to recognize one aldolate selectively. There is an equilibrium between syn- and anti-aldolates via retro-aldol addition, and the formation of a stable, chelated lithium salt blocks the non-catalyzed subsequent reaction from yielding the epoxide product ... 

Heteroarylamines, for example 1195, react with (dimethylamino)propenoate 1196 to yield an imidazolecarboxylate 1199. The imidazole ring is formed via the intermediate diaminoalkenoate 1197, which undergoes an intramolecular Michael addition followed by a retro-aldol-like reaction (Scheme 294) <1998JHC1527>. Similarly, 4-dimethyl-amino-2-aza-l,3-dienes 1200, serving as y-dielectrophiles, condense with amines or hydrazines neat at 70 °C to form A -substituted imidazole-4-carboxylates 1201 in 60-75% yields (Scheme 294) <1999TL8097>. 

Aldolase antibodies 38C2 and 33F12 are able to catalyze both the aldol addition and the retro-aldol reaction [99]. These catalysts have been employed to carry out the kinetic resolution of /3-hydroxyketones [100] and have been found to catalyze the asymmetric aldol reactions of 23 donors (ketones) and 16 acceptors (aldehydes) [101]. A highly efficient enantioselective... 

This reaction is very closely related to Acetoacetic Ester Condensation, and mechanistically, the cleavage of /3-ketoesters under strong base conditions is similar to the Retro-Aldol Addition. 

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