Claisen disconnection

Several ester disconnections are covered in this chapter. The Claisen condensation gives a keto-ester and the Claisen disconnection is shown. The cyclic version of this reaction is the Dieckmann condensation, and the Dieckmann disconnection is also shown. 

The Diels-Alder disconnection is actually a two-carbon disconnection. If a molecule has cyclohexene unit, the Diels-Alder disconnection leads to a diene and alkene for precursors as shown. A Cope disconnection has a 1,5-diene target with a 1,5-diene precursor. The oxy-Cope disconnection has an alkene aldehyde or an alkene-ketone target with a diene-alcohol precursor. The Claisen disconnection also has an alkene-aldehyde target, but the precursor is an allyl vinyl ether. The Ireland-Claisen disconnection is included, with an alkene-acid target and an alkene-ester precursor. 

The self-aldol reaction of aldehydes and ketones gives either P-hydroxy carbonyl or a,P-unsaturated carbonyl products. When the same reaction mechanism is applied to esters, the reaction is called the Claisen condensation. Like the aldol reaction, the Claisen condensation involves the attack of an enolate (or enol) nucleophile on a carbonyl electrophile. However, subsequent elimination of the leaving group creates a P-keto ester product. If this 1,3-dicarbonyl pattern is present in a TM, it is an indication that the TM might be the product of a Claisen condensation, and a Claisen disconnection will be one option for retrosynthesis. 

You have already seen that a carbon-heteroatom bond is easy to make, since we used such bonds as natural places for disconnections (frames 234 ft). It is good strategy therefore to make a carbon-heteroatom bond and then to transform it into a carbon-earbon bond. The Claisen rearrangement is one way to do this an ortho allyl phenol (B) made from an allyl ether (A) ... 

The retron for the Claisen rearrangement transform (see above) is easily established by the application of a Wittig disconnection at each of the equivalent terminal double bonds of 57... 

The category of 2-Gp-keyed transforms which disconnect C-C bonds is among the most important of all transform types. These transforms, especially in their stereoselective versions, are workhorses of retrosynthetic planning as their names alone attest aldol, Michael, Claisen,... 

We might have recognised this as a Claisen-Cope product since it is a y > < -unsaturaLed ester. Disconnecting and inverting the allylic group from the ester enolate gives the start ing material 32), Ortho esters are usually used as the reagents. 

Bicyclic ketone (33) was needed for a chrysanthemic acid synthesis. tarbene disconnection next to the ketone group (Chapter T30) reveals y. (5-unsaturated acid (35) as an intermediate, available by a Claisen-Cope rearrangement. 

The retrosynthetic concept of the Nicolaou group is shown in Scheme 22. The target molecule 36 is disconnected via an IMDA cyclization of the diene quinone precursor 138, which would be generated from the tetraline derivative 139 using Wittig chemistry followed by aromatic oxidation. A Claisen-type rearrangement would provide access to 139 whereby the side chain required for the rearrangement of 140 would be introduced by 0-acylation. The core of 141 would be formed via an intermolecular Diels-Alder reaction between diene 142 andp-benzoquinone 130 [42]. 

The recognition of consonant bifunctional relationships in the target molecule allows their disconnection by a retro-Claisen, a retro-aldol or a retro-Mannich condensation or by retro-Michael addition [equivalent, according to Corey s formalisation, to the application of the corresponding transforms (= operators) to the appropriate retrons]. 

Bifunctional systems In the case of bifunctional systems (or molecules) only two alternatives are possible the bifunctional relationships are either "consonant" or "dissonant" (apart from molecules or systems with functional groups of type A to which we have referred to as "assonant"). In the first case, the synthetic problem will have been solved, in principle, in applying the "heuristic principle" HP-2 that is to say, the molecule will be disconnected according to a retro-Claisen, a retro-aldol or a retro-Mannich condensation, or a retro-Michael addition, proceeding if necessary by a prior adjustment of the heteroatom oxidation level (FGI). 

In the particular case in which the carbonyl group belongs to a carboxylic acid derivative, such as an ester (17) or an amide (18) (or other functional groups which may be converted into it by a FGI), then they may be disconnected according to the "orthoacetate-modification" of the retro-Claisen rearrangement (Schemes 7.7 and 7.8) developed mainly by Eschenmoser [7] and Ziegler [8], independently, in the synthesis of alkaloids, and Johnson in a very simple and yet highly stereoselective synthesis of squalene [9]. 

The typical / -keto ester is ethyl acetoacetate (ethyl 3-oxo-butanoate). A retro-synthetic disconnection on this compound points to one of the most common methods for its synthesis, namely the Claisen ester condensation. 

The ether 52 was needed to study the Claisen rearrangement and can be disconnected in 1,2-diX fashion as the epoxide 54 will be attacked at the less hindered end by the anion of 53. 

The disconnection for the aromatic Claisen is to reverse the rearrangement. This is a little simpler than those we have seen so far as one C-C bond is broken 59 and one C-0 bond made. But you must remember to turn the allylic system back to front. This is easily seen if the starting material is drawn as 59a with the dotted line representing a reconnection. The rest is a normal ether disconnection. 

The Claisen ester disconnection a 1,3-diO relationship needing two carbonyl groups... 

In this second synthesis of the problematic steroid trans ring junction, the idea is to make the five-membered ring by a Claisen ester condensation and to direct the stereochemistry by tethering the cis groups with a sulfur atom. We can represent this easily in disconnection terms (Chapter 31). The cis-carbons to be joined through sulfur are shown in black. 

Following the methods we have established so far in this chapter, we can remove the hydrazine portion to reveal a 1,3-dicarbonyl compound. In fact, this is a tricarbonyl compound, a diketo-estcr, because of the ester already present and it contains 1,2- 1,3-, and 1,4-dicarbonyl relationships. The simplest synthesis is by a Claisen ester condensation and we choose the disconnection so that the electrophile is a reactive (oxalate) diester that cannot enolize. The only control needed will then be in... 

After the reaction mixture has cooled somewhat the flask is disconnected from the column, a Claisen head is attached, and the product is distilled at reduced pressure (Note 4). After a fore run of about 20 g. (not readily condensed below 40 mm. pressure), the faintly yellow product is collected at 124-126°/3 mm., weight 73-79 g. (80-86%), 1.5525-1.5540 (Note 4). 

This disconnection led to the C3 synthon 48 (and hence to its already familiar synthetic equivalent 44) and C9 amino dialdehyde 47. The Michael addition of malonic ester to acrolein was employed for the synthesis of the key starting material 49. The Claisen ester condensation of the latter followed by decarboxylation and reductive aminolysis led to the preparation of amino-bis-acetal 47a. The respective amino dialdehyde 47, generated in situ by a controlled hydrolysis of the acetal groups of 47a, reacted smoothly with acetonedicarboxylic diester and gave the required adduct 46 in a good yield and nearly complete stereoselectivity. 

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