Chiral 1,3,6-trisubstituted 2,4-dioxohexahydropyrimidines: a convenient stereoselective synthesis from aspartic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.03.066

Chiral 1,3,6-trisubstituted 2,4-dioxohexahydropyrimidines were easily synthesized by reaction of homoaspartic acid derivatives with isocyanates, followed by cyclization of the resulting urea, and alkylation at N1 position.

Full text of DOI:10.1016/j.tetlet.2007.03.066

Tetrahedron Letters 48 (2007) 3613–3616
Chiral 1,3,6-trisubstituted 2,4-dioxohexahydropyrimidines:
a convenient stereoselective synthesis from aspartic acid derivatives
a
b
Rosario Patino-Molina,a, Ivan Cubero-Lajo, M. Jesu´s Perez de Vega,
*
´
˜
b
b,
*
´
´
´
M. Teresa Garcıa-Lopez and Rosario Gonzalez-Muniz
˜
aEscuela Te´cnica Superior de Ingenieros Industriales, Universidad de Valladolid, Paseo del Cauce s/n, 4701 Valladolid, Spain
bInstituto de Quı´mica Me´dica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
Received 16 February 2007; revised 9 March 2007; accepted 13 March 2007
Available online 15 March 2007
Abstract—Chiral 1,3,6-trisubstituted 2,4-dioxohexahydropyrimidines were easily synthesized by reaction of homoaspartic acid
derivatives with isocyanates, followed by cyclization of the resulting urea, and alkylation at N1 position.
Ó 2007 Elsevier Ltd. All rights reserved.
The pyrimidine ring, in its different degrees of oxidation,
can often be found embedded on the structure of active
compounds. In this respect, the dihydropyrimidinedione
and the tetrahydropyrimidine-2-one nucleus have
attracted much interest in medicinal chemistry programs
due to the variety of biological activities displayed by
these compounds.1,2 However, the examples of related
2,4-dioxohexahydropyrimidines are much more scarce.
A few examples of bioactive 2,4-dioxohexahydropyr-
imidines include ligands for somatostatin receptors,3
a-glucosidase inhibitors,4antiepileptic agents,5 and HIV-
integrase inhibitors.6 In addition, some 4-oxohexahy-
dropyrimidine derivatives have been used as proline
mimetics,7 and as temporary chiral auxiliaries for asym-
metric synthesis.8
Most common methods for the synthesis of 2,4-dioxo-
hexahydropyrimidines involve the reduction and
photochemical transformations of the corresponding
dihydropyrimidinedione derivatives,9 the three-compo-
nent condensation of primary amines, isocyanates and
b-dielectrophiles,10 and the cyclization of b-amino-
ester-derived ureas.11 We have recently described a sim-
ple four-step procedure for the synthesis of highly
functionalized 1,3,6-trisubstituted 2,4-dioxohexahydro-
pyrimidines I (Chart 1), starting from dipeptide-derived
R1
O
R1
O
R1
O
O
RO2C
N
N
N
N
NH
HN
HN
O
CO2R
O
NHR2
I
O
R1
CO2H
CO2H
N
N
H2N
O
R2
II
Chart 1.
*
Corresponding authors. Tel.: +34 91 562 29 00; fax: +34 91 5644853 (R.G.-M); e-mail: iqmg313@iqm.csic.es
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.066

3614
R. Patin˜o-Molina et al. / Tetrahedron Letters 48 (2007) 3613–3616
Table 1. Synthesis of 2,4-dioxohexahydropyrimidine derivatives
piperazin-2-ones. This procedure consists of the acyl-
ation of the piperazin-2-one with isocyanate, transfor-
mation to the corresponding perhydropyrazino[1,2-f]-
pyrimidine-3,6,8-triones, activation with tert-butylcar-
bonate, and controlled opening of the pyrazine ring
from the bicyclic skeleton.12
Starting
compound
Base
RX
Final
compound
Yielda
(%)
3
3
3
4
4
4
4
5
7
KOtBu
NaH
DBU
KOtBu
KOtBu
KOtBu
—
—
—
—
IMe
BrCH2Ph
BrCH2CO2Me
—
—
—
4
4
70
45
38
73
93
87
80
89
90
4
5
6
Inspired by this process and by the cyclization of b-
aminoester-derived ureas,11 we envisaged a new syn-
thetic pathway to chiral 1,3,6-trisubstituted 2,4-dioxo-
hexahydropyrimidines II from aspartic acid derivatives
(Chart 1). While our first method is restricted to 1-(alk-
oxycarbonyl)alkyl- and 6-aminomethyl-substituted
derivatives, the new procedure should permit a more
flexible pattern of substituents at these two positions.
7
8
—
—
9
10
a Yield of isolated compounds.
(Table 1). To explore the incorporation of molecular
diversity at position N1, compound 4 was reacted with
three different alkylating agents, namely, methyl iodide,
benzyl bromide, and methyl bromoacetate, in the pres-
As shown in Scheme 1, diazoketone 1 was prepared
from commercial Z-L-Asp(OtBu)-OH by activation with
isobutyl chloroformate, in the presence of N-methyl-
morpholine, and reaction of the mixed anhydride
intermediate with diazomethane.13 Compound 1 under-
goes the Arndt–Eistert rearrangement upon treatment
with a catalytic amount of silver benzoate in the pres-
ence of MeOH to yield the orthogonally protected
homoaspartic derivative 2.14 Catalytic hydrogenation
of 2 in the presence of Pd–C as catalyst, followed by
the addition of phenyl isocyanate afforded linear urea
intermediate 3 in good yield. This intermediate cyclized
in a regioselective manner through the methyl ester to
enantioselectively provide the 3,6-disubstituted 2,4-
dioxohexahydropyrimidine 4.15 The best result in this
t
ence of BuOK. The expected chiral 1,3,6-trisubstituted
pyrimidine-2,4-diones 5–7 were obtained in excellent
yield (Table 1).16
Transformation of the substituent at position 6 was also
performed. Thus, compounds 5–7 were easily trans-
formed into carboxamides 8–10, using a two-step proce-
dure that involves acidic hydrolysis of the tert-butyl
ester with TFA, followed by activation of the free car-
boxylic acid with isobutyl chloroformate and reaction
of the mixed anhydride with NH3/THF. An oxidative
Hoffman-type rearrangement, of carboxamide deriva-
tives 9 and 10, promoted by PhI[OC(O)CF3]2 (PIFA),17
afforded the corresponding 6-(amino)methyl substituted
compounds 11 and 12. Finally, these compounds were
coupled to Boc-L-Trp-OH without problems, providing
tryptophyl derivatives 13 and 14 as a single diastereoiso-
t
cyclization was found when BuOK was used as base
t
t
CO2 Bu
CO2 Bu
i
Z
Z
N+
(S)
N
(S)
N
CO2H
N-
H
H
O
O
O
Z-L-Asp(OtBu)-OH
1
R
R
i, ii
N
N
N
N
(S)
(S)
ii
O
O
t
CONH2
CO2 Bu
t
t
CO2 Bu
CO2 Bu
4: R = H
8: R = H
O
iii, iv
5: R = CH3
9: R = CH3
Z
7: R = CH2CO2Me
(S)
N
CO2Me
10: R = CH2CO2Me
(S)
N
N
H
CO2Me
H
H
O
O
3
2
O
R
O
R
v
N
N
N
N
(R)
(R)
iv
iii
O
O
9,10
O
O
R
vi
O
NH
NH2
HN
N
N
N
(S)
(S)
(S)
O
O
O
O
11: R = CH3
12: R = CH2CO2Me
N
t
t
H
CO2 Bu
CO2 Bu
4
6: R = CH3
7: R = CH2Ph
8: R = CH2CO2Me
NH
13: R = CH3
14: R = CH2CO2Me
i
Scheme 1. Reagents and conditions: (i) iBuOCOCl/NMM(THF),
Scheme 2. Reagents and conditions: (i) TFA/CH2Cl2; (ii) 1. BuO-
COCl/NMM; 2. NH3/THF; (iii) PIFA/MeCN/EtOAc/H2O (2:2:1);
(iv) Boc-L-Trp-OH/BOP/TEA/THF.
CH2N2/Et2O; (ii) C6H5CO2Ag/TEA/MeOH; (iii) H2/Pd–C/MeOH.
t
(iv) PhNCO/THF; (v) BuOK/THF; (vi) RX/tBuOK/THF.

R. Patin˜o-Molina et al. / Tetrahedron Letters 48 (2007) 3613–3616
3615
2. To illustrate some tetrahydropyrimidine-2-ones with inter-
esting biological activities, see: (a) De Lucca, G. V.; Liang,
J.; De Lucca, I. J. Med. Chem. 1999, 42, 135–152; (b)
Adams, J. L.; Meek, T. D.; Mong, S.-M.; Johnson, R. K.;
Wetcalf, B. W. J. Med. Chem. 1988, 31, 1355–1359; (c)
Cohan, V. L.; Pettipher, E. R. Eur. Pat. Appl. E.P.
636369, 1995; Chem. Abstr. 1995, 122, 178386.
3. Poitout, L.; Thurieau, C.; Brault, V. Pat. Appl. WO
2001009090, 2001; Chem. Abstr. 2001, 134, 163050.
4. Tewari, N.; Tiwari, V. K.; Mishra, R. C.; Tripathi, R. P.;
Srivastava, A. K.; Ahmad, R.; Srivastava, R.; Srivastava,
B. S. Bioorg. Med. Chem. Lett. 2003, 11, 2911–2922.
5. Jones, Kathryn A.; Weaver, Donald F.; Tiedje, Kathryn
E. Pat. Appl. WO 2004009559, 2004; Chem. Abstr. 2004,
140, 146155.
6. Embrey, M. W.; Wai, J. S.; Funk, T. W.; Homnick, C. F.;
Perlow, D. S.; Young, S. D.; Vacca, J. P.; Hazuda, D. J.;
Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.;
Schleif, W. A.; Gabryelski, L. J.; Jin, L.; Chen, I.-W.; Ellis,
J. D.; Wong, B. K.; Lin, J. H.; Leonard, Y. M.; Tsou, N. N.;
Zhuang, L. Bioorg. Med. Chem. Lett. 2005, 15, 4550–4554.
7. Konopelski, J. P.; Filonova, L. K.; Olmstead, M. M. J.
Am. Chem. Soc. 1997, 119, 4305–4306.
mer in each case. This confirms the lack of racemization
during the synthesis of precursor 1. As demonstrated
with the synthesis of 13 and 14, the 6-(amino)methyl
substituent, as well as the 6-(carboxy)methyl counter-
part, could serve to extend the variety of groups at the
C6 substituent level. The synthesis of 14 also allowed
us to unequivocally assign the C6 configuration of a pair
of diastereoisomers of 14 prepared by an alternative
method12,18 (Scheme 2).
In summary, we have developed a short, simple, and
highly enantioselective synthetic procedure for the prep-
aration of 1,3,6-trisubstituted 2,4-dioxohexahydro-
pyrimidines. The key steps of this process are the
formation of urea-substituted homoaspartic acid deriva-
tives, the base-promoted cyclization to the tetrahydro-
pyrimidinedione ring, and the alkylation at position
N1. The application of this heterocyclic scaffold in the
generation of molecular diversity, by using different iso-
cyanates (providing the substituents at N3), diverse
alkylating agents (at N1), and by the incorporation of
amines or acyl groups at the C6 substituents, may be
anticipated.
8. Hopkins, S. A.; Ritsema, T. A.; Konopelski, J. P. J. Org.
Chem. 1999, 64, 7885–7889.
9. (a) Agami, C.; Dechoux, L.; Melaimi, M. Tetrahedron
Lett. 2001, 42, 8629; (b) Scannell, M. P.; Prakash, G.;
Falvey, D. E. J. Phys. Chem. A 1997, 101, 4332–4337.
10. Hakkou, H.; Vanden Eynde, J. J.; Hamelin, J.; Bazureau,
J. P. Tetrahedron 2004, 60, 3745–3753.
Acknowledgment
11. Martins, M. A. P.; Teixeira, M. V. M.; Cunico, W.;
Scapin, E.; Mayer, R.; Pereira, C. M. P.; Zanatta, N.;
Bonacorso, H. G.; Peppe, C.; Yuan, Y.-F. Tetrahedron
Lett. 2004, 45, 8991–8994.
We thank the Plan Nacional de Biomedicina (SAF 2003-
07207-C02) for financial support.
´
´
12. Patino-Molina, R.; Garcıa-Lopez, M. T.; Cenarruzabeitia,
˜
´
´
E.; Del Rıo, J.; Gonzalez-Muniz, R. Synthesis 2007, 1047–
1053.
˜
References and notes
13. This transformation was described to proceed without
appreciable racemization: Plucinska, K.; Liberek, B.
Tetrahedron 1987, 43, 3509–3517.
14. Misiti, D.; Santaniello, M.; Zappia, G. Bioorg. Med.
Chem. Lett. 1992, 2, 1029–1032.
1. Representative examples of bioactive dihydropyrimidi-
nones include: antivirals (a) Botta, M.; Occhionero, F.;
Nicoletti, R.; Mastromarino, P.; Conti, C.; Magrini, M.;
Saladino, R. Bioorg. Med. Chem. Lett. 1999, 9, 1925–1931;
(b) Botta, M.; Corelli, F.; Maga, G.; Manetti, F.; Renzulli,
M.; Spadari, S. Tetrahedron 2001, 57, 8357–8367; (c)
Balzarini, J.; McGuigan, C. J. Antimicrob. Chemother.
2002, 50, 5–9; (d) McGuigan, C.; Pathirana, R. N.;
Snoeck, R.; Andrei, G.; De Clercq, E.; Balzarini, J. J.
Med. Chem. 2004, 47, 1847–1851; (e) Stray, S. J.; Bourne,
C. R.; Punna, S.; Lewis, W. G.; Finn, M. G.; Zlotnick, A.
Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 8138–8143; (f)
Semaine, W.; Johar, M.; Lorne, D.; Tyrrell, J.; Kumar, R.;
Agrawal, B. J. Med. Chem. 2006, 49, 2049–2054; Calcium
channel blockers (g) Atwal, K. S.; Rovnyak, G. C.;
Schwartz, J.; Moreland, S.; Hedberg, A.; Gougoutas, J. Z.;
Malley, M. F.; Floyd, D. M. J. Med. Chem. 1990, 33,
1510–1515; a 1a-Antagonists (h) Barrow, J. C.; Nanter-
met, P. G.; Selnick, H. G.; Glass, K. L.; Rittle, K. E.;
Gilbert, K. F.; Steele, T. G.; Homnick, C. F.; Freidinger,
R. M.; Ransom, R. W.; Kling, P.; Reiss, D.; Broten, T. P.;
Schorn, T. W.; Chang, R. S. L.; O’Malley, S. S.; Olah, T.
V.; Ellis, J. D.; Barrish, A.; Kassahun, K.; Leppert, P.;
Nagarathnam, D.; Forray, C. J. Med. Chem. 2000, 43,
15. Representative analytical and spectroscopic data of com-
pound 4: [a]D À41.9 (c 0.99, CHCl3). 1H NMR (300 MHz,
CDCl3): d 7.45–7.15 (m, 5H, C6H5), 6.33 (br s, 1H, H-1),
4.05 (m, 1H, H-6), 2.95 (ddd, 1H, J = 16.3, 5.1, 0.8, H-5),
2.66 (dd, 1H, J = 16.3, 8.6, H-5), 2.55 (m, 2H, 6-CH2),
t
1.49 (s, 9H, Bu). 13C NMR (75 MHz, CDCl3): d 169.4,
168.5, 153.7 (CO), 134.7, 129.1, 128.6, 128.5 (Ar), 82.4 (C,
tBu), 43.5 (C-6), 40.2 (C-5), 36.9 (6-CH2), 28.0 (CH3, tBu).
Anal. Calcd for C16H20N2O4: C, 63.14; H, 6.62; N, 9.20.
Found: C, 63.05; H, 6.65; N, 9.24.
16. Analytical and spectroscopic data of selected compounds:
Compound 7: [a]D À17.9 (c 0.92, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.47–7.17 (m, 5H, C6H5), 4.54 (d,
1H, J = 17.7, 1-CH2) 4.09 (d, 1H, J = 17.7, 1-CH2), 4.06
(m, 1H, H-6), 3.76 (s, 3H, OMe), 3.35 (dd, 1H, J = 16.3,
6.3, H-5), 2.86 (dd, 1H, J = 16.7, 7.3, 6-CH2), 2.77 (dd,
1H, J = 16.3, 1.9, H-5), 2.59 (dd, 1H, J = 16.7, 6.3, 6-
t
CH2), 1.45 (s, 9H, Bu). 13C NMR (75 MHz, CDCl3): d
169.7, 169.6, 168.4, 152.8 (CO), 134.9, 129.0, 128.5, 128.4
t
(Ar), 82.1 (C, Bu), 52.3 (OMe), 48.9 (C-6), 49.2 (1-CH2),
`
`
2703–2718; (i) Patane, E.; Pittala, V.; Guerrera, F.;
Salerno, L.; Romeo, G.; Siracusa, M. A.; Russo, F.;
Manetti, F.; Botta, M.; Mereghetti, I.; Cagnotto, A.;
Mennini, T. J. Med. Chem. 2005, 48, 2420–2431; Angio-
tensin II receptor antagonists (j) Atwal, K. S.; Ahmed, S.
Z.; Bird, J. E.; Delaney, C. L.; Dickinson, K. E.; Ferrara,
F. N.; Hedberg, A.; Miller, A. V.; Moreland, S.; O’Reilly,
B. C. J. Med. Chem. 1992, 35, 4751–4763.
38.9 (C-5), 37.2 (6-CH2), 27.9 (CH3, tBu). Anal. Calcd for
C19H24N2O6: C, 60.63; H, 6.43; N, 7.44. Found: C, 60.74;
H, 6.40; N, 7.47.
Compound 10: [a]D +6.20 (c 0.55, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.44–7.13 (m, 5H, C6H5), 6.38 and
5.78 (br s, 2H, CONH2), 4.32 (d, 1H, J = 17.7, 1-CH2)
4.11 (d, 1H, J = 17.7, 1-CH2), 4.00 (m, 1H, H-6), 3.72 (s,

3616
R. Patin˜o-Molina et al. / Tetrahedron Letters 48 (2007) 3613–3616
3H, OMe), 3.25 (dd, 1H, J = 16.4, 6.4, H-5), 2.74 (dd, 1H,
2H, NH2), 3.73 (m, 1H, H-6), 3.53 (m, 1H, 6-CH2), 3.36
(m, 1H, 6-CH2), 3.17 (s, 3H, 1-CH3), 3.11 (dd, 1H,
J = 16.8, 7.1, H-5), 2.85 (dd, 1H, J = 16.8, 1.5, H-5). Anal.
Calcd for C12H15N3O2: C, 61.79; H, 6.48; N, 18.01.
Found: C, 61.54; H, 6.72; N, 17.88.
J = 16.4, 1.5, H-5), 2.60 (dd, 1H, J = 15.2, 6.4, 6-CH2),
2.44 (dd, 1H, J = 16.4, 6.5, 6-CH2). 13C NMR (75 MHz,
CDCl3): d 171.4, 169.9, 168.7, 152.8 (CO), 135.1, 129.0,
128.6, 128.4 (Ar), 52.3 (OMe), 50.3 (C-6), 49.4 (1-CH2),
38.6 (C-5), 36.7 (6-CH2). Anal. Calcd for C15H17N3O5: C,
56.42; H, 5.37; N, 13.16. Found: C, 56.52; H, 5.36; N,
13.07.
17. Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.;
Blodgett, J. K.; Boutin, R. H. J. Org. Chem. 1984, 49,
4272–4276.
Compound 11: [a]D +2.71 (c 0.52, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.47–7.14 (m, 5H, C6H5), 5.12 (br t,
18. Compound 14: White foam. [a]D À17.5 (c 0.41, CHCl3),
described in Ref. 12: [a]D À17.3 (c 0.12, CHCl3).