Claisen reaction retro

The retro-acylation reactions of B-ketoaldehydes (388, X=H), B-diketones (388, X=alkyl) and the retro-Clai sen reaction of B-ketoesters (3M, X=0R) occur through the formation of an intermediate 389 v/hich gives an ester 390 and the enolate ion 391. Protonation of 391 then gives the corresponding aldehyde (392, X=H), ketone (392, X=a1ky1) or ester (, X=0R). 

This process can take place with stereoelectronic control only if the two oxygen atoms at C3 in 389 have each an electron pair oriented anti peri planar to the C3 -C2 bond and if this bond is parallel to the system of the carbonyl group. Thus a conformation such as 393 Is required for this reaction. Consequently, in the reverse process 394+393, the two reactants should approach each other as shown by 394. 

It is well known that bicyclic B-diketones are readily cleaved by hydroxide or alkoxide nucleophiles. For instance, diketone 395 gives readily the keto-acid SW vi intermediate 396 (112). This is a stereoelectronically allowed process. 

The reactivity of triketone orthocarbonate 403 is very interesting. The most hindered carbonyl group, i. e. C- = 0, is the most reactive one towards nucleophilic addition. This behavior can be rationalized by the fact that the C l - Cg bond is parallel to the u system of the carbonyl group at C-8. Indeed, this compound can be viewed as the hybrid of resonance structures 403— 404. 

Compound 403 is readily reduced with sodium borohydride at -7B°C and yields the monoalcohol 405 (115). It also reacts with potassium t-butyl hydroperoxide at -BO C and gives the cis-enone-perester carbonate 406 in high yield (116). This last transformation can be explained by retro-Claisen fragmentation of intermediate 407 followed by the elimination of methoxide ion from 408. It is also possible that 407 undergoes a direct stereoelectronically controlled Grob type fragmentation to compound 406. 

---

The four steps of the /3-oxidation pathway, resulting in the cleavage of an acetyl group from the end of the fatty-acid chain. The key chain-shortening step is a retro-Claisen reaction of a /3-keto thioester. Individual steps are explained in the text. 

Step 4 of Figure 29.3 Chain Cleavage Acetyl CoA is split off from the chain in the final step of /3-oxidation, leaving an acyl CoA that is two carbon atoms shorter than the original. The reaction is catalyzed by /3-ketoacyl-CoA thiolase and is mechanistically the reverse of a Claisen condensation reaction (Section 23.7). In the forward direction, a Claisen condensation joins two esters together to form a /3-keto ester product. In the reverse direction, a retro-Claisen reaction splits a /3-keto ester (or /3-keto thioester) apart to form two esters (or two thioesters). 

The retro-Claisen reaction occurs by initial nucleophilic addition of a cysteine -SH group on the enzyme to the keto group of the /3-ketoacyl CoA to yield an alkoxide ion intermediate. Cleavage of the C2-C3 bond then follows, with expulsion of an acetyl CoA enolate ion. Protonation of the enolate ion gives acetyl CoA, and the enzyme-bound acyl group undergoes nucleophilic acyl substitution by reaction with a molecule of coenzyme A. The chain-shortened acyl CoA that results then enters another round of tire /3-oxidation pathway for further degradation. 

Grogan G, GA Roberts, D Bougioukou, NJ Turner, SL Flitsch (2001) The desymmetrization of bicyclic P-diketones by an enzymatic retro-claisen reaction. J Biol Chem 276 12565-12572. 

Moreover, compounds of type 7-127, which were obtained from 7-125 by reaction with Pb(OAc)4, can undergo a further domino process when treated with potassium carbonate in a mixture of water and methanol [57]. This includes saponification of the acetate moieties in 7-127 to provide 7-129 via the unstable cyclic hemiacetal 7-128 (Scheme 7.35). Retro-Claisen reaction and ring closure with the proposed intermediates 7-130 and 7-131 led to the bridged ring-system 7-132 as a mixture of di-astereomers with preference of the (3-isomer. 

Hill, C.L., Verma, C.S. and Grogan, G., Des3mimetrisations of l-alkylbicyclo[3.3.0]octane-2,8-diones by enzymatic retro-Claisen reaction yield optically enriched 2,3-substituted cyclopenta-nones. Adv. Synth. Catal. 2007, 349, 916. 

Retro-Claisen reaction, 49 Rigid analogues, 50, 223, 284, 296, 451 Rimantadine, 19 Rimiterol, 278... 

Q ,Q -disubstituted /1-ketoesters like 9, when treated with an alkoxide, can be cleaved into ordinary esters by the reverse of the condensation reaction, the retro-Claisen reaction. However the condensation of esters with only one a-hydrogen is possible in moderate yields by using a strong base, e.g lithium diisopropyl amide (LDA). ... 

It has also been reported that ozonolysis of 6-methyl-8-mcthylcne-m-3-oxabicyclo[4.2.0]octan-2-one in methanol gave methyl 2-(4-methyl-2-oxo-4-tetrahydropyranyl)acetate by retro-Claisen reaction, whereas in dichloromethane 6-methyl-ra-3-oxabicyclo[4.2.0]octane-2,8-dione was isolated in good yield (see Section 5.1.3.).16... 

Ozonolysis of diketone carbonate 417 in methanol afforded an almost quantitative yield of the bicyclic diene triketone hydroxy-ester 418 (119). This remarkable transformation can also be readily explained. Ozonolysis of 417 produces the tetraketone intermediate 419 followed by methanol addition to produce the hemi-ketal 420 which undergoes a retro-Claisen reaction to 421. Then, loss of carbon dioxide from 421 yields 418. Again, 420 could also undergo a Grob type fragmentation to yield 418 directly. 

Grogan, G., Graf, J., Jones, A., Parsons, S., Turner, N. J. and Flitsch, S. L An asymmetric enzyme-catalyzed retro-Claisen reaction for the desymmetrization of cyclic diketones. Angew. Chem. 2001,113 1145-1148 [Angew. Chem. Int. Ed. 40 1111-1114]. 

The final step is a retro-Claisen reaction, whose mechanism is pictured in Section 29.3 as Step 4 of (3-oxidation of fatty acids. 

Certain CoA thioester using enzymes catalyze reactions at the fS-carbon or other carbons of the acyl group more distant from the thioester functionality. The fatty acid fi-oxidation cycle provides some examples (Fig. 3). Fatty acids 7 enter the cycle by initial conversion to the CoA ester 8, which is then oxidized to the a,P-unsaturated thioester 9 by a flavin-dependent enzyme. Addition of water to the double bond to form the fi-hydroxy thioester 10 is catalyzed by the enzyme crotonase, which is the centerpiece of the crotonase superfamily of enzymes that catalyze related reactions (37), which is followed by oxidation of the alcohol to form the fi-keto thioester 11. A retro-Claisen reaction catalyzed by thiolase forms acetyl-CoA 12 along with a new acyl-CoA 13 having a carbon chain two carbons shorter than in the initial or previous cycle. 

Reaction of 9-substituted 6-chloropurine with ethyl acetoacetate in the presence of sodium hydride gives 9-substituted purine-6-acetate 1, via a retro Claisen reaction. 

STEP 4 The bond between C2 and C3 is broken by nucleophilic attack of coenzyme A on the C3 carbonyl group in a retro-Claisen reaction to yield acetyl CoA and a chain-shortened fatty acid. 

---