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The 1-methyl(iso-propyl)-2-benzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones 8 and 9 could be regio- and diastereoselectively alkylated at C(4) with retention of configuration at both stereocentres.

The substitution of the 4-methyl group by a 4-isopropyl group in the 2-benzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione system allows a notable improvement in the stereoselective alkylation at C-1. The configuration of the newly introduced stereogenic centre has been assigned on the basis of 1H NMR data and NOE measurements.

Alkyl halides behave differently to benzyl halides in C-1 alkylation of the title compounds. The syn and anti 1,4-disubstituted diastereomers thus obtained show different regioselectivity by further alkylation leading to the 1,4,4- and 1,1,4-trisubstituted compounds, respectively. Alkylation is always directed anti with respect to the bulkier substituent at C-1 or C-4. Debenzylation attempts on 2-benzyl-derivatives 1b by treatment with HCOOH and C/Pd or H2/C–Pd/MeOH/H+ led to C-1 oxidised or 7,8,9,10-tetrahydro-derivatives. Deprotection of 2-p-methoxybenzyl- and 2-(2,4-dimethoxybenzyl)-derivatives with CAN and with TFA/anisole, respectively, was successful, but in the latter case epimerization at C-1 occurred.

Acylation of 1 leads to the syn derivatives 2 . Traces of the anti isomers equilibrate to the syn isomers when stored in CHCl 3 . Aldol condensation showed great diastereoselectivity, but racemization could not be avoided. The configuration of the new introduced stereogenic centres has been assigned on the basis of 1 H-NMR data and NOE measurements.

1-Alkylation of O (3)-lactim, N (11)-azaenolate dilithium species derived from N (2)–H compounds 1a and 1b and the lithium azaenolates derived from the N (2)-phenyl and N (2)-(1-arylethyl) substituted compounds 2 , 3 and 4 is studied. In 1 the trans -diastereoselectivity of 1-alkylation is controlled by 1,4-asymmetric induction, with some of these products precursors of the ent -ardeemin framework. By contrast in compounds 2 – 4 , the stabilization of the lithium azaenolate imposed by the phenyl substituent in 2 , and the repulsive steric 1,2-interactions present in the initially formed 1,4- trans derivatives of 3 and 4 , favour a C(1)-epimerization to the 1,4- cis isomers.