Convenient synthesis of N1-substituted orotic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.10.005

A convenient and efficient method for the synthesis of N1-substituted orotic acid derivatives is reported. The synthetic route utilizes substituted maleimide as synthetic intermediate and takes only four simple steps from readily available starting materials. As a result, orotic acid derivatives with various alkyl and aromatic groups at N1 can be readily synthesized.

Full text of DOI:10.1016/j.tetlet.2014.10.005

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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Convenient synthesis of N1-substituted orotic acid derivatives
⇑
Jeannette T. Bowler, Caitlin R. Clausen, Daniel J. Blackburn, Weiming Wu
Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient method for the synthesis of N1-substituted orotic acid derivatives is reported.
The synthetic route utilizes substituted maleimide as synthetic intermediate and takes only four simple
steps from readily available starting materials. As a result, orotic acid derivatives with various alkyl and
aromatic groups at N1 can be readily synthesized.
Received 28 August 2014
Revised 29 September 2014
Accepted 1 October 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Orotic acid
Orotidine
Synthesis
Maleimide
Bromomaleimide
Dibromosuccinimide
Orotic acid and its analogs have been investigated as chemical
models for the reaction catalyzed by orotidine-50-monophosphate
decarboxylase (ODCase).1–12 We are interested in understanding
the effect of hydrogen bonds to the pyrimidine moiety on the rate
of decarboxylation. This investigation requires N1-substituted oro-
tic acid derivatives (structure 1 in Scheme 1) as substrates. Unfortu-
nately N1-substituted orotic acid cannot be prepared from the
alkylation of orotic acid because N-3 is the more reactive site.13
The reported synthesis of N1-substituted orotic acid derivatives is
time-consuming and low-yielding (Scheme 1, the combined yield
for the synthesis of 1-cyclohexylorotic acid is about 15%).11,14–18
Furthermore, we have found that the purification of the final orotic
acids can be difficult sometimes. In this Letter, we report a
convenient and efficient synthesis of N1-substituted orotic acid
derivatives from readily available starting material.
convenient synthetic method for the substituted maleimide 7 from
the commercially available maleimide 8. Bromination of 8 gave
the 2,3-dibromosuccinimide mixed with 2-bromomaleimide.23
Separation of the two products was not necessary because both
products eventually yielded the aminosubstituted maleimide 9
upon treatment with alkylamine or arylamine.23 Although metha-
nol and N-methylpyrrolidinone have been employed for similar
Unsubstituted orotic acid (1, R = H) has been prepared from glu-
tamic acid through the intermediate hydantoin 6 (R = H, Scheme 2),
which is converted to orotic acid 1 (R = H) upon treatment with
hydroxide.19 Unfortunately, N-substituted 6 (prepared from the
aldol condensation of N1-substituted hydantoin with glyoxylic
acid)20 is very stable and has been reported to resist rearrangement
to orotic acid under various conditions.21
On the other hand, N-carboethoxymaleimide
7 has been
reported to rearrange to N1-substituted orotic acid upon treatment
with hydroxide as shown in Scheme 3, although the yields were
low for non-phenyl substituents.22 We have thus designed a
⇑
Corresponding author. Tel.: +1 415 338 1436; fax: +1 415 338 2384.
E-mail address: wuw@sfsu.edu (W. Wu).
Scheme 1.
http://dx.doi.org/10.1016/j.tetlet.2014.10.005
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Please cite this article in press as: Bowler, J. T.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.10.005

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J. T. Bowler et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Acknowledgments
This investigation was supported by the National Institutes of
Health, Grant SC1 GM095419 (W.W.), Beckman Scholarship
(J.T.B.), CSUPERB Presidents’ Commission Scholarship (D.J.B.), and
Summer Research Fellowship from the Department of Chemistry
and Biochemistry at SFSU (C.R.C.). We thank Rania Ikhouane for
technical assistance. The NMR facility was funded by the National
Science Foundation (DUE-9451624 and DBI 0521342). We thank
Professor Ihsan Erden (SFSU) for helpful discussion.
Scheme 2.
References and notes
1. Beak, P.; Siegel, B. J. Am. Chem. Soc. 1976, 98, 3601–3606.
2. Radzicka, A.; Wolfenden, R. Science 1995, 267, 90–93.
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4. Nakanishi, M. P.; Wu, W. Tetrahedron Lett. 1998, 39, 6271–6272.
5. Feng, W. Y.; Austin, T. J.; Chew, F.; Gronert, S.; Wu, W. Biochemistry 2000, 39,
1778–1783.
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Chem. Soc. 2000, 122, 3296–3300.
7. Wong, F. M.; Wu, W. Bioorg. Chem. 2006, 34, 99–104.
8. Yeoh, F. Y.; Cuasito, R. R.; Capule, C. C.; Wong, F. M.; Wu, W. Bioorg. Chem. 2007,
35, 338–343.
9. Wong, F. W.; Capule, C. C.; Wu, W. Org. Lett. 2006, 8, 6019–6022.
10. Wong, F. M.; Capule, C. C.; Chen, D. X.; Gronert, S.; Wu, W. Org. Lett. 2008, 10,
2757–2760.
Scheme 3.
11. Lewis, C. A., Jr.; Wolfenden, R. Biochemistry 2009, 48, 8738–8745.
12. Senger, N. A.; Bliss, C. E.; Keeffe, J. R.; Gronert, S.; Wu, W. Tetrahedron 2013, 69,
5287–5292.
13. Curran, W. V.; Angier, R. B. J. Org. Chem. 1966, 31, 201–205.
14. Landesman, P. W. Ph.D. Dissertation, State University of New York, Buffalo,
1982.
15. Inoue, H.; Ueda, T. Chem. Pharm. Bull. 1971, 19, 1743–1744.
16. Inoue, H.; Ueda, T. Chem. Pharm. Bull. 1978, 26, 2657–2663.
17. Okano, T.; Goya, S.; Takahashi, T. Yakugaku Zasshi 1968, 88, 1112–1117.
18. Senger, N. A.; Bowler, J. T.; Mercado, R. S.; Lin, S.; Wu, W. Tetrahedron Lett. 2013,
54, 4245–4246.
19. Nyc, J. F.; Mitchell, H. K. J. Am. Chem. Soc. 1947, 69, 1382–1384.
20. Ivin, B. A.; D’yachkov, A. I.; Rutkovakil, G. V.; Sochilin, E. G. Russ. J. Org. Chem.
1976, 12, 1802–1803.
Table 1
Yields for the synthesis of orotic acid 1 from maleimide 8
Entry
Substituents (R=)
Yielda (8–9) (%)
Yielda (9–1) (%)
a
b
c
d
e
f
Cyclohexyl
n-Butyl
Phenyl
Neopentyl
Allyl
83
78
78
79
100
90
71
68
90
51
70
69
Benzyl
a
Isolated yield.
21. Ralph, R. K.; Shaw, G.; Naylor, R. N. J. Chem. Soc. 1959, 1169–1178.
22. Seres, J.; Náray-Szabó, G.; Simon, K.; Dakóczi-Csuka, K.; Szilágyi, I.; Párkányi, L.
Tetrahedron 1981, 37, 1565–1569.
23. Davis, S. J.; Rondestvedt, C. S. Chem. Indus. 1956, 845–846.
24. Wiley, R. H.; Slaymaker, S. C. J. Am. Chem. Soc. 1958, 80, 1385–1388.
25. Smith, D. G.; Buffet, M.; Fenwick, A. E.; Haigh, D.; Ife, R. J.; Saunders, M.; Slingsby,
B. P.; Stacey, R.; Ward, R. W. Bioorg. Med. Chem. Lett. 2001, 11, 635–639.
26. Experimental details: All reagents were obtained from commercial sources and
used without further purification. Typical experimental procedures are
described below using 1-cyclohexylorotic acid (1a) as an example.
reactions,24,25 acetonitrile was found to be the best solvent. The
reactions were conveniently carried out at room temperature over-
night. Treatment of 9 with ethyl chloroformate gave the desired
synthetic intermediate 7, which did not require further purification
and was readily converted to N1-substituted orotic acid 1 via an
improved procedure.22,26
The reaction has been successfully carried out with various
alkylamine or arylamine substrates. This method thus allows the
successful synthesis of orotic acid derivatives with various substit-
uents at N1 in good yield as reported in Table 1. The previously
reported synthetic route as seen in Scheme 1 is not only lengthy
but also limited to non-allylic and non-benzylic alkyl groups. In
the third step in Scheme 1 (the bromination of dihydrouracil 3
with Br2/HOAc), bromination occurred readily at unwanted posi-
tions when substrates substituted with allylic, benzylic, or aro-
matic groups were utilized. The conversion from dihydrouracil 3
to bromouracil 4 was thus unsuccessful for substrates with these
groups. The current method, however, tolerates a diverse group
of substituents.
In summary, the new method allows the convenient synthesis
of N1-substituted orotic acid derivatives from readily available
starting material in good yield. The method works well for sub-
strates with a variety of substituents such as aromatic or alkyl
(including allylic or benzylic) groups. It should be pointed out that
this synthetic route also involves sequential incorporation of nitro-
gen atoms to the pyrimidine structure and thus should allow the
incorporation of a single 15N label at N-1. The method represents
a significant improvement from the previously reported synthetic
route.
Synthesis of 3-cyclohexylmaleimide (9a): To a solution of maleimide (2.0 g) in
15 mL of chloroform was added a solution of bromine (2.5 mL) in 15 mL of
chloroform dropwise. Upon refluxing for 2 h, the reaction mixture was
evaporated to dryness. The off-white solid (5.3 g) obtained was identified by
NMR to be a mixture of cis- and trans-2,3-dibromosuccinimide as well as 3-
bromomaleimide. The crude product mixture was used directly in the next
step without further purification.
To a solution of the crude mixture (1.0 g, 4 mmol) in 2 mL of acetonitrile was
added a solution of cyclohexylamine (1.0 g, 12 mmol) in 12 mL of acetonitrile
and the solution was stirred at room temperature overnight. The precipitate
was filtered and washed with methylene chloride. The mother liquor was
concentrated to dryness and purified by column chromatography to yield 3-
cyclohexylaminomaleimide (9a) as a yellow solid (0.6 g, 83% combined yield).
Synthesis of 1-cyclohexylorotic acid (1a): Maleimide 9a (0.30 g, 1.5 mmol) was
dissolved in 15 ml anhydrous acetone. Ethyl chloroformate (0.26 g, 2.4 mmol)
and triethylamine (0.24 g, 2.4 mmol) were added dropwise simultaneously
with stirring. After completion of the addition, the mixture was stirred for
45 min and then refluxed for 45 min. Upon standing overnight the reaction
mixture was filtered to remove the precipitated triethylammonium salt and
washed with methylene chloride. The mother liquor was evaporated to
dryness to give the crude 1-ethoxycarbonyl-3-cyclohexylaminomaleimide 7a,
which was suspended in 8.0 ml 1 M aqueous KOH and heated at 65 °C for 2 h.
The reaction mixture was acidified with 6 N HCl and concentrated to about a
third of the original volume. The resulting off-white precipitate was filtered,
washed with cold water and ether, and recrystallized from water or water/
ethanol to give 1-cyclohexylorotic acid 1a as a white solid (0.26 g, 71%).
Please cite this article in press as: Bowler, J. T.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.10.005