Disconnection rearrangement

The disconnection is obvious, and gives us one way of making symmetrical 1,2-diols. What makes it more than trivial is that the products undergo the pinacol rearrangement ... 

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) ... 

Rearrangement of skeleton, which normally does not simplify structure, can also facilitate molecular disconnection, as is illustrated by examples 17 => 18 + 19 and 20 => 21. 

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... 

Antithetic conversion of a TGT by molecular rearrangement into a symmetrical precursor with the possibility for disconnection into two identical molecules. This case can be illustrated by the application of the Wittig rearrangement transform which converts 139 to 140 or the pinacol rearrangement transform which changes spiro ketone 141 into diol 142. 

The retrosynthetic simplification of 164 which has just been outlined was initiated by the application of a [3,3] sigmatropic rearrangement transform. Other tactical combinations involve the use of such rearrangement transforms to link a pair of disconnective transforms. 

Some insect pheromones are internal ketals. We have already mentioned multistriatin (pp T 2 and 99) and frontalin p 193). Brevicomin (22) is another example. Disconnection of the ketal gives (23) containing a 1,2-diol. Among other syntheses, hydroxy-lation of protected enone (24) by epoxidation and acid catalysed rearrangement gives brevicomin stereo-specifically,... 

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. 

In a pericyclic reaction, the electron density is spread among the bonds involved in the rearrangement (the reason for aromatic TSs). On the other hand, pseudopericyclic reactions are characterized by electron accumulations and depletions on different atoms. Hence, the electron distributions in the TSs are not uniform for the bonds involved in the rearrangement. Recently some of us [121,122] showed that since the electron localization function (ELF), which measures the excess of kinetic energy density due to the Pauli repulsion, accounts for the electron distribution, we could expect connected (delocalized) pictures of bonds in pericyclic reactions, while pseudopericyclic reactions would give rise to disconnected (localized) pictures. Thus, ELF proves to be a valuable tool to differentiate between both reaction mechanisms. 

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 synthetic applications of sigmatropic rearrangements to the synthesis of dissonant molecules (mainly 1,6-D) were extensively studied by Evans [22]. Although such a methodology meets the first two requirements of "logical disconnections", it does not meet the third one since it lacks simplicity. 

Let us now consider a dissonant 1,6-dicarbonyl system, which provides a good example of a [3,3]-sigmatropic rearrangement. The "illogical disconnection" would lead to an a,p-unsaturated ketone and a "homoenolate" anion ... 

This methodology, as in the cases of rearrangements and of plausible disconnections, does not meet the criterium of maximum simplicity, since the reconnection represents an increase of the "cyclic order" and therefore of the complexity of the molecule. 

With respect to the above-mentioned unsaturated carbonyl compounds with a double bond and a carbonyl group separated by three carbon atoms (14), it can be stated here that they may be disconnected to an alkyl vinyl ketone and an allylic anion (Scheme 7.5), through an oxy-Cope rearrangement (C/. Scheme 5.22). 

However, if only two carbon atoms are present (15) they may be disconnected to give an allylic alcohol 16 and the acetoacetic ester, through a retro-Carroll rearrangement [6] (Scheme 7.6). 

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]. 

Both target compounds discussed in this review, kelsoene (1) and preussin (2), provide a fascinating playground for synthetic organic chemists. The construction of the cyclobutane in kelsoene limits the number of methods and invites the application of photochemical reactions as key steps. Indeed, three out of five completed syntheses are based on an intermolecular enone [2+2]-photocycloaddition and one—our own—is based on an intramolecular Cu-catalyzed [2+2]-photocycloaddition. A unique approach is based on a homo-Favorskii rearrangement as the key step. Contrary to that, the pyrrolidine core of preussin offers a plentitude of synthetic alternatives which is reflected by the large number of syntheses completed to date. The photochemical pathway to preussin has remained unique as it is the only route which does not retrosynthetically disconnect the five-membered heterocycle. The photochemical key step is employed for a stereo- and regioselective carbo-hydroxylation of a dihydropyrrole precursor. 

Pericyclic disconnections and sigmatropic and other rearrangements give rise to synthons which are themselves reagents. Such disconnections greatly simplify the target molecule (e.g. the refro-Diels-Alder reaction). These disconnections are most commonly applied in alicyclic and heterocyclic systems. 

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