Pyrazino-quinazolines

Synthesis of the pyrazino[2,1 -bjquinazoline (557) was achieved by oxidative cyclization of the l-(2-aminobenzyl)-4-methylpiperazine (556) with manganese dioxide [68JCS(C)1722], the pyrimidine ring of 557 was formed during this synthesis. The pyrimidine ring of 559 was also formed upon cyclocondensation of anthranilic acids with the cyclic imidate ester (558), followed by removal of the protective group (66USP3280117). 

Consecutive formation of the two diazine rings was the approach for synthesizing the pyrazino[2,l-6]-quinazo ine (567) from methyl anthrani-late and the protected glycylglycine dipeptide (565), according to the indicated sequence of reactions (80MI4). 

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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>. 

The l,4-dihydro-pyrazino[2,l- ]quinazoline lactim ether 48 oxidized to give 49 with 2,3-dichloro-5,6-dicyano-/>-benzoquinone (DDQ) (Equation 3) <20030L3205>. 

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. 

The same approach was readily adaptable to solid-phase synthesis. A small library of unnatural derivatives of 140 was prepared with variation of the configuration and nature of R1 and R4 and with substitution on the benzene ring <2000JC0186>. Three natural alkaloids, Verrucine A, B, and Anacine, were synthesized by a similar pathway and the pyrazino[2,l- ]quinazoline as opposed to the benzodiazepine structure of Anacine was proved <2001JNP1497>. Fiscalin B and other derivatives were prepared by solid-phase synthesis using polyethylene glycol (PEG) resin <2002USP6376667>. 

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>. 

The fungal metabolite, 5-A-acetylardeemin, possessing a hexacyclic structure with a l,4-dihydro-3,6-dioxo-pyra-zino[2,l-A]quinazoline skeleton, is the best multidrug resistance reversal agent known to date <1998MI45>. Hexahydro-3,6-dioxo-pyrazino[2,l-7]quinazolines have been claimed as endothelial nitric oxide synthetase regulators useful in the treatment of cardiovascular disorders <2004EP1471066>. 

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

The methodology was successfully extended to a one-pot total synthesis of complex heterocyclic systems such as pyrazino [2,1-b] quinazolines 79, encountered in nature as alkaloids 80-82 (Scheme 50) [125]. To assemble the pyrazino[2,l-fo]quinazoline core, N-Boc protected amino acid 76 was employed instead of carboxylic acid 72 (Scheme 49) in the synthesis of the corresponding intermediate benzoxazinones 77. The subsequent reaction with an amine moiety of another amino acid ester 78 was accompanied by concomitant cleavage of the N-Boc protecting group and diketopiperazine-like cyclization (for the one-pot deprotection-cyclization reaction of N-Boc dipeptide esters to afford 2,5-piperazinedione under microwave dielectric heating, see [128]) to afford the target heterocycle 79. Hence, the total... 

An alternative protocol towards pyrazino 2,l-b]quinazolines 79 relied on cyclocondensation of diketopiperazine-derived lactim ethers with anthranilic acid. Microwave dielectric heating in a domestic oven (600 W irradiation power) furnished heterocycles 79 within 3-5 min, while the corresponding reaction in an oil-bath required 2 hours heating at 120-140 °C [129]. The use of N-protected co-amino acids 83 in the microwave-assisted reaction with anthranilic acid 71 furnished pyrrolo 2, -b]quinazolines 85 via transannu-lar cyclization of the intermediate cyclic diamide 84 [126]. Subsequent in situ condensation with a variety of aldehydes furnished isaindigotone 86 and analogues, possessing cytotoxic activity (Scheme 51). 

Pyrimidines fused to other six-membered rings, most frequently in the form of bicyclic structures, can be degraded to corresponding substituted monocyclic pyrimidines. Fused pyrimidine structures described are benzo- (quinazolines), pyrano[2,3-tf]-, pyrazino[2,3-i/j- (pteridines), pyrimido[l,2-u]-, pyrimido[4,5-i/]pyrimidines, and pyrimido[5,4-e]-a -triazines, pyrimido[5,4- f]-v-triazine, pyrim-ido[4,5-i/][l,3]oxazines, pyrimido[5,4-i/][l,3]oxazine, pyrimido[4,5- ][l,4]thiazines, pyrimido[5,4- ][l,4]thiazines, and pyrimido[4,5-e][l,2,4]thiadiazines. References to these reactions can be found in . 

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