Disconnections heterocyclic compounds

Since in the synthesis of heterocyclic compounds the ring closure usually involves the formation of the carbon-heteroatom bond, in the retrosynthetic analysis the first bond to be disconnected is the carbon-heteroatom bond (Cf. heuristic principle HP-8), either directly or after the pertinent (FGI or FGA) functional group manipulation. For instance, compound 17 -which is the starting material for Stork s synthesis of Aspidosperma alkaloids [30]- may be disconnected as shown in Scheme 6.11. 

The disconnection or synthon approach now integrated into the text, and the principles of retrosynthetic analysis applied to relevant aliphatic, aromatic, alieyelic and heterocyclic compounds. 

The complicated heterocyclic compound 32 is symmetrical about a vertical plane and two aldol disconnections give the symmetrical ketone 34 and two molecules of the unenolisable aldehyde 33. Condensation with KOH gives7 93% of 32. 

The rearrangement also works well with heterocycles compound (33), wanted for an alkaloid synthesis, disconnects to imine (34) which can be made from a benzylic cyanide (3S). The synthesis is uneventful. 

We consider the key building blocks with two heteroatoms as the results of contemporaneous disconnections of two C-heteroatom bonds in the heterocyclic ring. This retrosynthetic step corresponds to cyclization by contemporaneous formation of two C-heteroatom bonds, a usual step in the synthesis of heterocyclic compounds. Depending on 1,2-, 1,3- or 1,4 relation of hetereoatoms in the heterocyclic ring, the corresponding building blocks possess heteroatoms bound directly in the germinal or vicinal position (Fig. 7.1). 

Figure 10.42 Use of the 0s04-Nal04 cleavage of C C bonds in the disconnection/reconnection synthesis of labeled heterocyclic compounds...

One extra disconnection is all we need to cope with misaturated heterocycles. If a nitrogen atom is joined to a double bond in a ring, we have a cyclic enamine. This is made from an amine and a carbonyl compound in the same way as ordinary enamines ... 

Methoxatin, now known as coenzyme PQQ, was originally obtained from methylotrophic bacteria but is now known to be a mammalian cofactor, for example, for lysyl oxidase and dopamine p-hydroxylase. The first synthesis of this rare compound was accomplished by the route outlined below. In the retrosynthetic analysis both of the heterocyclic rings were disconnected using directly keyed transforms. 

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. 

It turns out that we must protect the phenol as its methyl ether 127 and that 126 is best used as an amidine-ester rather than the double enamine. The synthesis is then quite short. We have barely scratched the surface of aromatic heterocyclic synthesis in this chapter but the encouraging message is that cyclisation is easy and that cyclisations to form aromatic compounds are the easiest of all. Disconnect with confidence ... 

The disconnection approach to synthesis essentially involves working backwards from a target compound in a logical manner (so-called retrosynthesis), so that a number of possible routes and starting materials are suggested. This approach has been applied mainly to alicyclic, carbocyclic, and saturated heterocyclic systems. Retrosynthetic analyses are presented in this text not as an all-embracing answer to synthetic problems, but rather as an aid to understanding the actual construction of unsaturated heterocycles. 

The diester has a 1,3-diCO relationship and could be disconnected but we have in mind using malonate so we would rather disconnect the alternative 3-amino carbonyl compound (the MezN group has a 1,3-relationship with both ester groups) by a 1,3-diX disconnection giving an unsaturated ester. This ot,p-unsaturated ester disconnects nicely to a heterocyclic aldehyde and diethyl malonate, doxplcomlne retrosynthetic analysis II... 

Many natural compounds include heterocyclic systems constructed by hemiacetal formation between a hydroxyl group and a keto group of the chain in a 1,4- or 1,5-relative disposition. It is advantageous in a retrosynthetic analysis to take this point into account and to devise a disconnection next to the carbonyl group. Moreover, the synthetic connection does not involve chiral center formation. An obvious translation of this principle in carbohydrate chemistry is the formation of a carbon-carbon bond at the anomeric center by nucleophilic addition to lactones. However, other methods have also been devised to reach this goal. 

Other compounds may need FGl before disconnection. Meyer s heterocyclic reagent (21) is made from diol (20) in a Ritter reaction (Chapter 8) and this comes from a S-hydroxy ketone by reduction. Disconnection again reveals two molecules of the same compound. 

Abstract Compounds with a 1,2-, 1,4- and 1,6-dioxygen pattern and related bifunctional structures are presented. Disconnection of the internal bonds results in illogical synthons because of the mismatch of charges in the patterns with an even number of C atoms between the functional groups. Three-membered heterocyclic rings are presented as an important class of illogical nucleophiles in the retrosyn-thesis of the 1,2-difunctional pattern. Retrosynthesis of the 1,6-dicarbonyl pattern by reconnection and rctro-Birch reduction of the aromatic building block is related to chemoselective Birch reduction and ozonolysis in the synthetic route. The retrosynthesis and synthesis of salbutamol and asymmetric synthesis of —)-frontalin are presented. 

---