Aldol and Claisen Reactions

The aldol and Claisen reactions both achieve carbon - carbon bond formation and in typical base-catalysed chemical reactions depend on the generation of a resonance-stabilized enolate anion from a suitable carbonyl system (Figure 2.7). Whether an aldol-type or Claisen-type product is formed depends on the nature of X and its potential as a leaving group. Thus, chemically, two molecules

secondary carbocation

1,2-hydride H shift y*

tertiary carbocation

1,2-methyl secondary carbocation tertiary carbocation

1,2-alkyl shift tertiary carbocation, but strained 4-membered ring secondary carbocation, but reduced ring strain in 5-membered ring

1,3-hydride shift

tertiary carbocation tertiary carbocation

1,3-hydride shift resonance-stabilized allylic cation resonance-stabilized allylic cation

H a series of concerted 1,2

-n^ hydride and methyl shifts

H a series of concerted 1,2

-n^ hydride and methyl shifts

Aldol and Claisen reactions

resonance-stabilized enolate anion

Ok nucleophilic addition on to carbonyl n o

R = X = H, acetaldehyde R = H, X = OEt, ethyl acetate

loss of leaving group aldol-type product R = X = H, aldol

O

'/

C

O

\

//

CH—

C

/

\

R

H, X = OEt, ethyl acetoacetate

Claisen-type product

H, X = OEt, ethyl acetoacetate if no suitable leaving group, protonation occurs

Figure 2.7

cysteamine ¡ pantothenic acid pantetheine

Coenzyme A HSCoA

PO OH

resonance decreases acidity of a-hydrogens

ester

resonance of this type is less favourable in the sulphur ester

H3C {S thioester

Figure 2.8

h3c s

of acetaldehyde yield aldol, whilst two molecules of ethyl acetate can give ethyl acetoacetate. These processes are vitally important in biochemistry for the elaboration of both secondary and primary metabolites, but the enzyme catalysis obviates the need for strong bases, and probably means the enolate anion has little more than transitory existence. Nevertheless, the reactions do appear to parallel enolate anion chemistry, and are frequently responsible for joining together of C2 acetate groups.

In most cases, the biological reactions involve coenzyme A esters, e.g. acetyl-CoA (Figure 2.8). This is a thioester of acetic acid, and it has significant advantages over oxygen esters, e.g. ethyl acetate, in that the a-methylene hydrogens are now more acidic, comparable in fact to those in the equivalent ketone, thus increasing the likelihood of generating the enolate anion. This is explained in terms of electron delocalization in the ester function (Figure 2.8). This type of delocalization is more prominent in the oxygen ester than in the sulphur ester, due to oxygen's smaller size and thus closer proximity of the lone pair for overlap with carbon's orbitals. Furthermore, the thioester has a much more favourable leaving group than the oxygen ester, and the combined effect is to increase the reactivity for both the aldol and Claisen-type reactions.

Claisen reactions involving acetyl-CoA are made even more favourable by first converting acetyl-CoA into malonyl-CoA by a carboxylation reaction with CO2 using ATP and the coenzyme biotin (Figure 2.9). ATP and CO2 (as bicarbonate, HCO3-) form the mixed anhydride, which car-boxylates the coenzyme in a biotin - enzyme complex. Fixation of carbon dioxide by biotin - enzyme complexes is not unique to acetyl-CoA, and another important example occurs in the generation of oxaloacetate from pyruvate in the synthesis of glucose from non-carbohydrate sources

(gluconeogenesis). The conversion of acetyl-CoA into malonyl-CoA means the a-hydrogens are now flanked by two carbonyl groups, and have increased acidity. Thus, a more favourable nucle-ophile is provided for the Claisen reaction. No acy-lated malonic acid derivatives are produced, and the carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation (Figure 2.9). An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base. Thus, the product formed from acetyl-CoA as electrophile and malonyl-CoA as nucleophile is acetoacetyl-CoA, which is actually the same as in the condensation of two molecules of acetyl-CoA. Accordingly, the role of the carboxylation step is clear cut: the carboxyl activates the acarbon to facilitate the Claisen condensation, and it is immediately removed on completion of this task.

O 11

ADP HO-P-O7C-OH 1

mixed anhydride

HN H

NH H

CoAS-C-CH2 acetyl-CoA ®N O"^ (enolate) O, /^Jl^

ADP HO-P-O7C-OH 1

mixed anhydride

CO-Enz

biotin-enzyme

NH H

CO-Enz

CO-Enz

N-carboxybiotin-enzyme nucleophilic attack on to carbonyl; loss of biotin-enzyme as leaving group

CO-Enz nucleophilic attack on to mixed anhydride biotin-enzyme

nucleophilic attack on carbonyl but with simultaneous loss of CO2

loss of CoAS ^ as leaving group

CH3-CrSCoA

N-carboxybiotin-enzyme

O 11

CO2H malonyl-CoA

+ biotin-enzyme

CH2-CO2Et enolate anion from ethyl acetate

NaOEt EtOH

CH3-C-OEt

CO2Et

enolate anion from diethyl malonate

NaOEt EtOH

Il H

CH3-C-CH2-CO2Et -

ethyl acetoacetate

O CO2Et il I H

acylated diethyl malonate

ch3-c-ch2-co2h acetoacetic acid

HO gem-diacid thermal decarboxylation

Figure 2.10

P-Oxidation of fatty acids dehydrogenation; hydrogen atoms passed to FAD

stereospecific hydration of double bond

R v SCoA

fatty acyl-CoA (chain length C2n)

FAD FADH2

SCoA

dehydrogenation; hydrogen atoms passed to NAD+

NAD+ NADH

SCoA

Il II

reverse Claisen reaction r

HSCoA

SCoA

fatty acyl-CoA (chain length C2n-2)

CH3^""SCoA acetyl-CoA

Figure 2.11

By analogy, the chemical Claisen condensation using the enolate anion from diethyl malonate in Figure 2.10 proceeds much more favourably than that using the enolate from ethyl acetate. The same acetoacetic acid product can be formed in the mal-onate condensation by hydrolysis of the acylated malonate intermediate and decarboxylation of the gem-diacid.

Both the reverse aldol and reverse Claisen reactions may be encountered in the modification of natural product molecules. Such reactions remove fragments from the basic skeleton already generated, but may extend the diversity of structures. The reverse Claisen reaction is a prominent feature of the P-oxidation sequence for the catabolic degradation of fatty acids (Figure 2.11), in which a C2 unit as acetyl-CoA is cleaved off from a fatty acid chain, leaving it two carbons shorter in length.

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