Heterocycles retrosynthetic analysis

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. 

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. 

As in the five-membered heterocyclic section the discussion of the relevant ring-forming reaction is related, as appropriate, to an overall strategy of skeletal assembly, and to a more rigorous retrosynthetic analysis. The reactions are conveniently discussed in relation to the synthesis of compounds belonging to the following groups of heterocycles. 

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 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... 

The intensity of activity in the field of thiazole and benzothiazole research reflects the importance of these heterocycles in organic and biological chemistry. There has therefore been a large volume of synthesis literature produced since 1995. The following section has been ordered according to the fragments generated by retrosynthetic analysis, which are shown in Scheme 53. 

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. 

There have been numerous syntheses of thiazoles and benzothiazoles reported since 1984 (for syntheses prior to 1984 see (CHEC-I <84CHEC-I(6)253 . These approaches are classified according to a retrosynthetic analysis taking into account the fragments which join to form the heterocyclic nucleus. For thiazoles, thiazolines, and thiazolidines the followed classification is shown in Scheme 66. 

Several methods exist for the preparation of furan. In this book, we shall use the method of retrosynthetic analysis (COREY and WARREN [5]) as a guiding principle for the heterocyclic synthesis of the most important target systems. This procedure leads to logical starting materials and methods for constructing the required heterocycles which can then be compared with existing and pre-paratively important methods. 

A simple retrosynthetic analysis reveals that the neonicotinoids consist of a chloromethyl-substituted heterocycle and in most cases a nitroguanidine part. For discovery research as for industrial synthesis, the accessibility to these budding blocks is of considerable importcmce. Prior to the emergence of neonicotinoids, heterocycles of this structural type had not drawn particular attention, what has clearly changed ever since. [143,144]... 

Retrosynthetic analysis of the target coumarin skeleton provides two major synthetic routes (Figure 10.1). Route A requires an aromatic o-hydroxy carbonyl compound and a two-carbon fragment observed in Knoevenagel and Perkin reactions reflecting the [4h-2] approach for the construction of six-membered heterocycles. Route B represents the reaction between phenols and three carbon fragments associated with the Pechmann cyclization. In recent years, newer synthetic methodologies have also been applied to the synthesis of a variety of coumarins that have avoided the use of concentrated sulfuric acid. The present chapter reviews various... 

Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 474 Substituent Effects in Electrophilic Aromatic Substitution Activating Substituents 476 Substituent Effects in Electrophilic Aromatic Substitution Strongly Deactivating Substituents 480 Substituent Effects in Electrophilic Aromatic Substitution Halogens 482 Multiple Substituent Effects 484 Retrosynthetic Analysis and the Synthesis of Substituted Benzenes 486 Substitution in Naphthalene 488 Substitution in Heterocyclic Aromatic Compounds 489... 

In this chapter, the retrosynthetic analysis and proposals for the synthesis of heterocyclic compounds with one to three heteroatoms in five- or six-membered heterocyclic rings are presented. Such heterocyclic rings are constituents of thousands of biologically active compounds. Compendia on the synthesis and structural properties of all classes of heterocyclic compounds are available [1 ]. Numerous syntheses of heterocycles and descriptions of their physico-chemical properties are presented in separate chapters of organic chemistry handbooks cited in the introduction chapter of this book. 

As a guiding principle for the synthesis the most important heterocyclic target molecules, in this book retrosynthetic analysis [18] will be used. This procedure leads to logical methods and starting materials for the construction of the required heterocycles, which then can be correlated with existing and preparatively relevant methods. 

Analysis of the efficiency of different methods of synthesis of imidazo[l,5-a] and imidazo[l,2-fl]quinoxalines demonstrates that there are currently 26 approaches corresponding to the retrosynthetic analysis of the stmcture of a heterocyclic system without including the benzene ring. Initial compounds are quinoxaline (see Figs. 4.3 and 4.6) or imidazole derivatives (see Figs. 4.4 and 4.7). For synthesis of imidazo[l,5-a]quinoxaline, seven approaches based on quinoxalines and four approaches based on imidazoles have been developed (Table 4.4) for synthesis of imidazo[l,2-a]quinoxalines, six approaches based on quinoxalines and five approaches based on imidazoles have been developed (Table 4.5). 

For the retrosynthesis of the isoxazole system (see Fig. 5.12), it is essential that the heterocycle possesses the functionality of an oxime and of an enol ether, and that C-3/C-5 are at the oxidation level of a carbonyl function. Therefore, a logical retrosynthetic route (a - c) leads by way of the monoxime 2 to the 1,3-diketone and hydroxylamine. If the retrosynthetic operation a to d is generalized, one arrives at the 4,5-dihydroisoxazole 1. Its analysis, according to a retroanalytically permitted cycloreversion, leads to an alkene unsubstituted by a leaving group and to a nitrile oxide 3. These fragments represent the two components of a 1,3-dipolar cycloaddition. 

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