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Helvetica Chimica Acta ± Vol. 82 (1999)
recrystallized from EtOH. The colorless solid was stirred with conc. aq. NaOH (aq), extracted with Et2O, dried
(MgSO4), and evaporated: 3 was isolated in 59% yield (175.2 g) as yellow oil.
Synthesis of 1,3-Dibenzyl-1,2,3,4,5,6-hexahydro-5-hydroxypyrimidin-2-one (4). Bis(4-nitrophenyl) carbo-
nate (10; 10 g, 32.87 mmol, 1 equiv.) and 3 (15 g, 55.56 mmol, 1.7 equiv.) were refluxed in CH2Cl2 (2.5 l) for 24 h.
The mixture was extracted once with citric acid and five times with aq. NaOH. After evaporation, the product
was recrystallized from Et2O and CH2Cl2: 4 was isolated in 85% yield (8.3 g) as a colorless solid. M.p. 1158.
Synthesis of 1,3-Dibenzyl-1,2,3,4,5,6-hexahydropyrimidine-2,5-dione (5). The hydroxy ketone 4 (11.5 g,
38.85 mmol, 1 equiv.) and the freshly prepared Dess-Martin reagent (58.28 mmol, 1.5 equiv.) were stirred
overnight in CH2Cl2 (100 ml) saturated with H2O (TLC control). The reaction was quenched by addition of sat.
aq. NaHCO3 and aq. Na2S2O3, and stirred until the precipitate completely dissolved. After extraction with
CH2Cl2, drying (MgSO4), and evaporation, the crude product was filtered through a short column of silica
(Et2O/pentane 1:1): 5 was isolated as a yellow oil in 79% (9.0 g), which crystallized after some time. M.p. 738.
Synthesis of 1,3-Dibenzyl-1,2,3,4,5,6-hexahydro-5-{[2-(methoxymethyl)pyrrolidin-1-yl]imino}pyrimidine-
2,5-dione (6). The dione 5 (9 g, 30.61 mmol, 1 equiv.) and SAMP or RAMP (4.48 ml, 33.67 mmol, 1.1 equiv.)
were dissolved in CH2Cl2, and the mixture was stirred for 5 h at r.t. with molecular sieves (3 ). After filtration
and evaporation of the solvent, the crude product was filtered through a short column of silica gel (Et2O): 6 was
isolated in 93% yield (11.6 g) as a yellow oil.
Synthesis of the 4-Alkyl-1,3-dibenzyl-1,2,3,4,5,6-hexahydro-5-{[2-(methoxymethyl)pyrrolidin-1-yl]imino}-
pyrimidine-2,5-diones 7a ± e (1 ± 3 mmol-scale). 2,2,6,6-tetramethylpiperidine (1.3 equiv.) was dissolved in dry
THF (20 ml) in a pre-dried Schlenk flask under Ar, and a BuLi soln. (1.2 equiv. of a 1.6m soln. in hexane) was
added. The pale-yellow soln. was stirred for 10 min at r.t. and then cooled to 788. A soln. of 6 (1 equiv., 788)
in THF (20 ml) was added slowly via a double-ended needle. After stirring for 10 min at 788, a soln. of the
electrophile in THF (5 ml) was added with a syringe pump (5 ml/h), and the mixture was stirred for a further 2 h
at 788, and then quenched with aq. NH4Cl. After extraction with Et2O and drying (MgSO4), the solvent was
removed. The crude products were used directly in the following cleavage reactions.
Synthesis of the 4-Alkyl-1,3-dibenzyl-1,2,3,4,5,6-hexahydropyrimidine-2,5-diones 8a ± e. Method A: Com-
pounds 7a ± e were dissolved in acetone (20 ml) and H2O (5 ml). A 0.1m soln. of dimethyldioxirane (5 equiv.) in
acetone was added, and the mixture was stirred overnight (TLC control). After addition of H2O, the mixture
was extracted wtih Et2O and dried (MgSO4), and the solvent was removed. The product was purified by
chromatography on silica gel (Et2O/pentane 1:3) to afford 8a ± e in 44 ± 59% yield.
Method B: The compounds 7a ± e were dissolved in THF (5 ml) and H2O (1 ml). CuCl2 (5 equiv.) was
added, and the mixture was stirred overnight (TLC control). After addition of H2O, the mixture was extracted
with Et2O, dried (MgSO4), and the solvent was removed. The product was purified by chromatography on silica
gel (Et2O/pentane 1:3).
Synthesis of the 4-Alkyl-1,3-dibenzyl-1,2,3,4,5,6-hexahydro-5-hydroxypyrimidine-2,5-diones 9a ± e. A soln.
of 8a ± e in THF (10 ml) was added to a suspension of LiAlH4 (3 equiv.) in dry Et2O (10 ml) at 08. The mixture
was stirred for 1 h (TLC control) at 08, and the reaction was then quenched with aq. NH4Cl, and the mixture was
filtered and washed with CH2Cl2, dried (MgSO4), and the solvent was removed. The pure hydroxy ketones 9a ± e
were obtained after column chromatography on silica gel (Et2O/pentane 1:1) in 76 ± 84% yield. The de value of
the reduction products was in all cases > 96% (1H-NMR). The enantioselectivities were determined by
1H-NMR shift experiments with ( )-Pirkle alcohol (ee 76 ± > 96%).
REFERENCES
Â
[1] a) F. Barre-Sinoussi, J. C. Chermann, F. Rey, M. T. Nugeyre, S. Chamaret, J. Gruest, C. Dauguet, C. Axler-
Â
Blin, F. Vezinet-Brun, C. Rouzioux, W. Rozenbaum, L. Montagnier, Science 1983, 220, 868; b) R. C. Gallo,
P. S. Sarin, E. P. Gelman, M. Robert-Guroff, E. Richardson, V. S. Kalyanaraman, D. Mann, G. D. Sidhu,
R. E. Stahl, S. Zoller-Pazner, J. Leibowich, M. Popovic, ibid. 1983, 220, 865; c) F. Clavel, D. Guetard, F.
Â
Brun-Vezinet, S. Chamaret, M.-A. Rey, M. O. Santos-Ferreira, A. G. Laurent, C. Dauguet, C. Katlama, C.
Rouzioux, D. Klatzmann, J. L. Champalimaud, L. Montagnier, ibid. 1986, 233, 343.
[2] R. A. Katz, A. M. Skalka, Annu. Rev. Biochem. 1994, 63, 133.
[3] a) N. E. Kohl, E. A. Emini, W. A. Schleif, L. J. Davis, J. C. Heimbach, R. A. F. Dixon, E. M. Scolnick, I. S.
Sigal, Proc. Nat. Acad. Sci. U.S.A. 1988, 85, 4686; b) C. Peng, B. K. Ho, T. W. Chang, N. T. Chang, J. Virol.
1989, 63, 2550.
[4] C. Debouck, AIDS Res. Hum. Retroviruses 1992, 8, 153.