Unsymmetrical pyrazines

The formation of pyridazines from 1,2-diaza-1,3-butadienes and electron-rich dienophiles has been reported [308] on the other hand, tetrazine and triazole derivatives have been prepared from these heterodienes and azo esters [309]. Aza Diels-Alder reactions of 1,4-diaza-1,3-butadienes have been employed for the synthesis of unsymmetrical pyrazine derivatives by Heathcock et al. [310]. 

Scheme 8. Synthesis of an unsymmetrical pyrazine via a Diels-Alder like reaction.

Scheme 11. Smith and Heathcock s synthesis of an unsymmetrical pyrazine.

On the synthetic front, the discovery of these alkaloids has sparked interest in the construction of unsymmetrical pyrazines, and the methods developed will be useful in other settings as well. The Fuchs group has successfully accomplished landmark syntheses of tetrahydrocephalostatin 12, cephalostatin 7, cephalostatin 12, and ritterazine K and is clearly close to a synthesis of dihydrocephalostatin 1. These efforts have added significantly to the areas of steroid and spiroketal chemistry. 

A limitation of the Gutknecht synthesis lies in the fact that the pyrazine products are necessarily symmetrically substituted. Thus the 2 and 5 substituents must be the same, as must the 3 and 6 substituents. Thus the reaction is not applicable to those situations in which an unsymmetrical pyrazine is the desired product. In addition, the Gutknecht synthesis does not provide a useful preparation of pyrazine itself. ... 

The ease of oxidation varies considerably with the nature and number of ring substituents thus, although simple alkyl derivatives of pyrazine, quinoxaline and phenazine are easily oxidized by peracetic acid generated in situ from hydrogen peroxide and acetic acid, some difficulties are encountered. With unsymmetrical substrates there is inevitably the selectivity problem. Thus, methylpyrazine on oxidation with peracetic acid yields mixtures of the 1-and 4-oxides (42) and (43) (59YZ1275). In favourable circumstances, such product mixtures may be separated by fractional crystallization. Simple alkyl derivatives of quinoxalines are... 

Structurally related quinoxalines have been identified as sub-micromolar HCV polymerase inhibitors in a high throughput screen (HTS). Derivatives that are unsymmetrically substituted with hydrophobic groups on the pyrazine moiety, and with a pendant hydroxy-tryptophan side-chain that has been reported previously (vide infra), provide the greatest activity (14, IC50 = 0.6 pM) [56]. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. It has been conducted on the pyrazine ring of quinoxaline and the resulting alkynyl- and dialkynyl-quinoxalines were subsequently utilized to synthesize condensed quinoxalines [52-55], Ames et al. prepared unsymmetrical diynes from 2,3-dichloroquinoxalines. Thus, condensation of 2-chloroquinoxaline (93) with an excess of phenylacetylene furnished 2-phenylethynylquinoxaline (94). Displacement of the chloride with the amine also occurred when the condensation was carried out in the presence of diethylamine. Treatment of 94 with a large excess of aqueous dimethylamine led to ketone 95 that exists predominantly in the intramolecularly hydrogen-bonded enol form 96. 

To access a pyrazine in this way one needs a 1,2-diamine and a 1,2-dicarbonyl compound, and a subsequent oxidation, but if both components are unsymmetrical, mixtures are formed. The dimerisation of 2-aminocarbonyl compounds also generates symmetrically substituted dihydro-pyrazines - perhaps the best known examples of such dimerisations involve the natural amino acids and their esters, which dimerise to give dihydropyrazine-2,5-diones - diketopiperazines . 

This method is well suited to the formation of symmetrical pyrazines, " but if both diketone and diamine are unsymmetrical, two isomeric pyrazines are formed. The dihydro-pyrazines can be dehydrogenated and they will also react with aldehydes and ketones, with introduction of another alkyl group at the same time as achieving the aromatic oxidation level. ... 

The synthesis of the pteridine ring system has been approached by two obvious routes one is the fusion of the pyrazine ring onto a pre-formed 4,5-diamino-pyrimidine, and the second, the elaboration of the pyrimidine ring on a pre-formed pyrazine. The first of these, the Isay synthesis, suffers from the disadvantage that condensation of the heterocyclic 1,2-diamine with an unsymmetrical 1,2-dicarbonyl compound... 

Four years after the isolation of cephalostatin A, the first synthetic studies in this area were reported. Fuchs etal. (38) reported the conversion of steroidal a-azidoketones 48 to the C-2 symmetrical nonacyclic and trisdecacyclic pyrazines 49 through catalytic reduction (Scheme 1). In the process they also observed an unusual azide-mediated formation of an unsymmetrical heterobenzyl azide (Scheme 2). Use of excess azide served as a base to generate the a-aminoenone 50. Dimerization of 50, followed by SN2 reaction with the hydrazoic acid coproduct yielded the unsymmetrical azidopyra-zine 51. 

C. Synthesis of Unsymmetrical Bis-Steroidal Pyrazines Related to Cephalostatin 1 (11)... 

In 1992 Heathcock and Smith developed efficient routes for the synthesis of symmetrical and unsymmetrical bis-steroidal pyrazines from readily available precursors such as 3-cholestanone and androstanone (40). In a later publication they synthesized the unsymmetrical bis-steroidal pyrazines by the reaction of appropriate a-acetoxy ketones with a-amino oximes. Heating either 2/3,17/3-dihydroxyandrostan-3-one diacetate or 2/3-17/3-dihydroxyhecogenin-3-one diacetate with 2-amino-3-methoxyimino-cholestane in toluene at 145°C gave the corresponding symmetrical pyrazine in moderate yields. 

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