Pyrazino quinazoline-3,6-diones

Reaction of 1 -methylene-1,2,3,4-tetrahydro-5//-pyrazino[2,1 -Z)]quina-zoline-3,6-diones (435) with PhLi and MeMgBr in THE at —78°C gave a mixture of 1 l//-pyrido[2,l-Z)]-quinazolin-l 1-ones 435-439 (01T1987). 

Reduction of the N(ll)=C(lltf) double bond of l,4-dihydro-2//-pyrazino[2,l-A quinazoline-3,6-diones 30 (R1 = indol-3-ylmethyl R2 = Me) and 31 (R1 = CH2-C6H4-C1- z Rz = Me) was effected with NaBH4. While the m-diastereomer, 30, retained its configuration, the /razw-diastereomer, 31, epimerized during the reaction. <1999JOC7233>. 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

C(l)-Acylation of the l,4-dihydro-277-pyrazino[2,TA]quinazoline-3,6-diones 57 (R4 = Me, Rz = Bn, CH2-C6H4-MeO-/>) by treatment with LHDMS at — 78 °C followed by addition of acyl chlorides resulted in the as- 1-acyl derivatives with de > 95% in good yield. Formation of the air-product was explained by equilibration through the anion formed by deprotonation at C-l. The 1-acyl compounds were unstable and easily retransformed into the starting 57 <1998TA249>. 

The syntheses of l,4-dihydro-2/7-pyrazino[2,l-7]quinazoline-3,6-diones can be divided into three groups, depending on how the pyrimidine and the pyrazine rings are constructed. 

Tripeptides with N-terminal anthranilic acid part were used as starting materials in the solid-phase synthesis carried out on TentaGel resin to prepare 1,4,11,1 l -tetrahydro-2//-pyrazino[2,l-3]quinazoline-3,6-diones with various N-l and N-3 substituents <2003EPP1471066>. Tandem cyclization from [6+0] atom fragments took place in the solid-phase synthesis of 143 from 142. Intermediate 141 was built on bromoacetal resin (Scheme 17) <1998JOC3162>. 

Fig. 7 Natural products with a pyrazino[2,l- ]quinazoline-3,6-dione skeleton...

Polyheterocyclic systems have been efEdently synthesized by cyclocondensation between anthranilic add and lactim ethers derived from 2,5-piperazinediones. This reaction leads to pyrazino[2,l-b]quinazoline-3,6-diones. When applied to bis(lactim) ethers the procedure again works better under the action of microwaves, with reaction times reduced from hours to minutes and enhancement of yields [232]. 

Several groups of quinazoline alkaloids involving pyrazino[2,l-fo]quinazoline-3,6-dione substructure are found in fungal metabolites. These include glyantrypine (21) [87], fumiquinazolines A-E, F (22), G (23) [88,89], H and I [90], and fiscalines A-C [91,92]. Novel spiro-type pyrazinoquina-... 

The Diels-Alder reaction of azadiene 106 prepared from l-methyl-2,4-dihydro-lH-pyrazino[2,l-fo]quinazoline-3,6-dione [255] with 3-methyleneoxindole 107 proceeds smoothly in chloroform at rt to afford exo- (108) and endo-isomer (109) in 55 and 18% yields, respectively. Mild hydrolysis of... 

FIGURE 11.3 Biological active compounds containing the pyrazino[2, l-fc]quinazoline-3,6-dione core 27. 

The base-induced rearrangement of the 1,3-dipolar cycloadducts of 2,5-di-f-butyl-/ -benzoquinone with 2,6-dichlorobenzonitrile oxide has been shown to afford isoxazole-fused / -quinol derivatives (250) by way of the pathway outlined in Scheme 64. Reduction of 2,4-dihydro-l//-pyrazino[2,l-fc]quinazoline-3,6-diones (251) with sodium borohydride has been reported to yield 11,1 la-dihydro derivatives... 

---