The synthesis of N-acyl-2-hydroxymethyl aziridines of biological interest

Article abstract of DOI:10.1016/j.tetlet.2003.11.136

A practical synthesis of the title compounds from protected amino acylazides is described. All the compounds might be considered as a novel class of dipeptide isostere precursors; they all induce lymphocyte proliferation and protein production as observed from preliminary biological tests.

Full text of DOI:10.1016/j.tetlet.2003.11.136

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1211–1213
The synthesis of N-acyl-2-hydroxymethyl aziridines
of biological interest
W. Medjahed, A. Tabet Zatla, J. Kajima Mulengi,* F. Z. Baba Ahmed and H. Merzouk
Laboratoire de Chimie Organique, Substances Naturelles et Analyses (COSNA), Facultꢀe des Sciences, Universitꢀe de Tlemcen,
PO Box 119, 13000 Tlemcen, Algeria
Received 27 August 2003; revised 19 November 2003; accepted 28 November 2003
Abstract—A practical synthesis of the title compounds from protected amino acylazides is described. All the compounds might be
considered as a novel class of dipeptide isostere precursors; they all induce lymphocyte proliferation and protein production as
observed from preliminary biological tests.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
starting materials. Phthalimido amino acids were pre-
pared according to modified literature procedures21 and
were recrystallized. They were further converted into
azides according to Palomo and co-workers.22 The
azides were used without further purification in the next
step to yield the target iminophosphoranes according to
mechanism displayed in Scheme 1.
In recent years, several papers and reviews have been
published regarding a number of aspects of aziridines
chemistry.1–13 It is well known that natural or synthetic
compounds that contain the aziridine moiety generally
exhibit interesting biological activity such as antitumour14
or protease inhibitor properties.15 Of special interest for
us was the assumption that N-alkoxy aziridines stimulate
the production of leukocytes.16 On the syntheticback-
ground, it is well known that vicinal azido alcohols and
triphenylphosphine (Ph3P) give five-membered interme-
diates that may afford aziridines spontaneously.17
The iminophosphoranes were submitted to a dropwise
addition of the glycidol oxyanion generated by treat-
ment of the epoxy alcohol with NaH in dry ether.23 The
oxyanion might initiate attack on the phosphorus atom
of 1 generating a nitrogen nucleophile that opens the
epoxide ring, thus leading either to a five-membered (a)
or a six-membered ring intermediate (b). However, we
believe that the five-membered oxazaphospholidine
would be more favoured.
We therefore assumed that under the same conditions
an iminophosphorane derived from an amino acyl azide
would react with an epoxide to yield an aziridine.
Glycidol was considered to be the best epoxide since its
alkoxide would react with an iminophosphorane to give
a nitrogen nucleophile that would open the epoxide,
thus leading to hydroxylated compounds that might be
considered as analogues or precursors of hydroxy
dipeptides isosteres.18–20
After quenching the reaction mixture with an aqueous
solution of NH4Cl and removal of triphenylphosphine
oxide, all compounds were purified on a silica gel col-
umn using petroleum ether–dichloromethane as the
eluent. Satisfactory IR, 1H NMR, 13C NMR and
microanalyses were obtained for all compounds and an
example is detailed in the experimental (Table 1).
2. Results and discussion
During NMR analysis, it was observed that signals were
not pure multiplets, thus indicating the presence of a
mixture of diastereoisomers. Of special interest were the
doublet at 1.75 and the quartet at 4.92 ppm. Actually
they were superimposed doublets and quartets of almost
the same magnitude and could not be separated by
NMR analysis.
In an initial attempt to check our hypothesis, racemates
of phthalimido amino acids and glycidol were used as
Keywords: Aziridines; Peptide isosteres; Amino acids.
* Corresponding author. Tel./fax: +213-43-21-5886; e-mail:
k_mulengi@yahoo.com
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.136

1212
W. Medjahed et al. / Tetrahedron Letters 45 (2004) 1211–1213
R
R
Ph3P
- N2
O
O
PhthN
PhthN
N
N3
1
PPh3
O
O
R
O
R
Ph3P
N
O
O
R
Ph3P
PhthN
b
a
PhthN
N
N
b
PhthN
O
PPh3
O
O
a
O
O
b
O
a
NH4Cl, H2O
- OPPh3
O
R
OH
N
N
O
O
2
Scheme 1. Plausible mechanism for the conversion of the starting azides into aziridines.
Table 1. N-protected hydroxymethylaziridines
3. Conclusion
2
R
Yield (%)
We have developed a straightforward synthesis leading
to disubstituted aziridines of biological interest. The
synthesis requires simple reagents and the overall pro-
cedure provides good to excellent yields of product 2. In
vitro preliminary biological studies performed with
racemates have shown promising activity on the prolif-
eration of lymphocytes. However, work with natural
amino acids and both (R)- and (S)-glycidol is under
investigation in order to obtain more accurate data on
the biological activity dependence on stereochemistry as
well as chemical and spectroscopic analytical data of
pure stereoisomers.
a
b
c
H
Me
51
60
98
PhCH2
d
96
N
H
e
f
(H)PhthN(CH2)4
Me2CH
60
52
45
50
g
h
(H)PhthNC6H4CONH
Me2CHCH2
In vitro biological tests were performed on isolated
human lymphocytes and each aziridine was used at
successive concentrations of 100, 50 and 25 lM. Glycyl-
aziridine (2a) was the most potent in inducing cell pro-
liferation when used at any of the above-mentioned
concentrations. Aminohippuryl aziridine (2g) was
the only one to inhibit cell proliferation when a con-
centration of 100 lM was used. However, the same
compound induced cell proliferation in the presence of
concavalin-A at a concentration of 25 lM, whereas
other aziridines induced lymphocyte proliferation along
with protein synthesis to a lower extent than glycyl
aziridine.
Acknowledgements
We are indebted to Laboratoire de Pharmacochimie et
ꢁ
ꢀ
Systemes Membranaires, Universite Denis Diderot Paris
1
7/France for H and 13C NMR spectra.
References and notes
1. Atkinson, R. S. Tetrahedron 1999, 55, 1519–1559.
2. McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365.

W. Medjahed et al. / Tetrahedron Letters 45 (2004) 1211–1213
1213
3. Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry
1997, 11, 1693–1715.
4. Among recent references see: (a) Boukhris, S.; Souizi, A.;
Sun, W.; Xia, C.-G. Tetrahedron Lett. 2003, 44, 3259–
3261; (b) Wang, H.-W. Tetrahedron Lett. 2003, 44, 2409–
2411.
acids were recrystallized as follows: glycine, leucine
(ethanol–water 1:1), phenylalanine, tryptophan (ethanol–
water 4:1), 6-amino caproic acid (water–ethanol 2:1),
valine (water–ethanol 3:1), amino hippuricacid (ethanol).
22. Arrieta, A.; Aizpurua, J. M.; Palomo, C. Tetrahedron Lett.
1984, 25, 3365–3368, Example of an acyl azide: Phthalim-
ido alanylazide: yield: 78%; mp 79 ꢁC (dec); IR (KBr):
5. Choi, S.-K.; Lee, J.-S.; Kim, J.-H.; Lee, W. K. J. Org.
Chem. 1997, 62, 743–745.
2145, 1730, 1718 cmꢀ1
.
1H NMR (CDCl3): 1.68 (d,
6. Meguro, M.; Asao, N.; Yamamoto, Y. Tetrahedron Lett.
1994, 35, 7395–7398.
7. Piro, J.; Forns, P.; Blanchet, J.; Bonin, M.; Micouin, L.;
Diez, A. Tetrahedron: Asymmetry 2002, 13, 995–1004.
8. Bhanu Prasad, B. A.; Sanghi, R.; Singh, V. K. Tetrahedron
2002, 58, 7355–7363.
9. Davis, F. A.; Deng, J.; Zhang, Y.; Haltiwanger, R. C.
Tetrahedron 2002, 58, 7135–7143.
10. Park, C. S.; Choi, H. G.; Lee, H.; Lee, W. K.; Ha, H.-J.
Tetrahedron: Asymmetry 2000, 11, 3283–3292.
11. Vicario, J. L.; Badia, D.; Carrillo, L. J. Org. Chem. 2001,
66, 5801–5807.
J ¼ 8 Hz, 3H, CH3), 3.02 (q, J ¼ 8 Hz, 1H, CH), 7.83 (s,
4H, PhthN).
23. Synthesis of aziridines. Typical procedure: 2-hydroxy-
methyl-1-(N-phtaloylalanyl) aziridine 2b.
Solution A: N-acylazide (25 mmol) was introduced under
nitrogen to a dry flask containing dry dichloromethane
(100 mL). The solution was cooled to 0 ꢁC and triphenyl-
phosphine (25 mmol) was added in small portions and the
solution was stirred for 2 h.
Solution B: In a separate flask, sodium hydride (27 mmol)
previously washed with ether was introduced in ether
(50 mL) and the suspension stirred under nitrogen. To the
cooled suspension was added a solution of (ꢁ)-glycidol
(25 mmol) dropwise in dry ether (50 mL) over 20 min.
After the addition was complete, the mixture was stirred
for an additional 30 min.
12. Chandrasekhar, M.; Sekar, G.; Singh, V. K. Tetrahedron
Lett. 2000, 41, 10079–10083.
13. Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 2537–
2539.
14. Papaioannu, N.; Evans, C. A.; Blank, J. T.; Miller, S. J.
Org. Lett. 2001, 3, 2879–2882, and references cited therein.
15. Schirmeier, T.; Peric, M. Bioorg. Med. Chem. 2000, 8,
1281–1291.
16. Hanessian, S.; Cantin, L.-D. Tetrahedron Lett. 2000, 41,
787–790, and references cited therein.
17. Ariza, X.; Pineda, O.; Urpi, F.; Vilarrasa, J. Tetrahedron
Lett. 2001, 42, 4995–4999.
18. Dolle, R. E.; Herpin, T. F.; Shimshock, Y. C. Tetrahedron
Lett. 2001, 42, 1855–1858.
19. Benedetti, F.; Maman, P.; Norbedo, S. Tetrahedron Lett.
2000, 41, 10075–10078.
20. Huff, J. R. J. Med. Chem. 1991, 34, 2305–2315.
21. (a) Applegate, H. E.; Cimarusti, C. M.; Dolfini, J. E.;
Funke, P. T.; Koster, W. H.; Puar, M. S.; Slusarchyk, W.
A.; Young, M. G. J. Org. Chem. 1979, 44, 811–818; (b)
Solution B was then siphoned off under nitrogen into a
constant-pressure dropping funnel mounted on the flask
containing solution A; this solution was added dropwise to
solution A cooled in an ice bath. Following addition, the
mixture was warmed to 50 ꢁC for 1.5 h and cooled to room
temperature. A solution of 10% ammonium chloride was
added and the mixture was extracted with dichloro-
methane (3 · 25 mL). The organic extracts were combined
and dried over anhydrous CaSO4.
After removal of the solvent, the residue was dissolved in
cold anhydrous ether (100 mL) and triphenylphosphine
oxide was filtered off under suction. This operation was
repeated until no solid separated from the ethereal
solution. After removal of the solvent, the residue was
purified on a silica gel column using petroleum ether (bp
40–60 ꢁC) and dichloromethane (4:1).
The resulting compound was stored in the cold under dry
nitrogen. Yield: 70%; mp 60 ꢁC; IR (KBr): 3457, 1711, 741.
1H NMR (CDCl3, 200 MHz): 1.15 (d, J ¼ 7:2, 2H, CH2),
1.5 (dd, J ¼ 6:6, 2 Hz, 1H, CH), 1.75 (d, J ¼ 7:4, 3H,
CH3), 3.0 (m, 2H, CH2–OH), 4.92 (q, J ¼ 7:4, 1H, CH),
7.35 (s, 4H, Phth). 13C NMR (CDCl3, 50 Hz): 15.98 (CH3),
27 (CH2), 29.56 (CH), 52.09 (CH2–OH), 52.5 (Phth–CH–
CO), 131, 132 (CHar), 137 (Car), 168 (CH–CO–N), 179
(CO–N–CO). Calcd for C14H14N2O4: C, 61.34; H, 5.11; N,
10.22. Found: C, 61.40; H, 5.18; N, 10.10.
ꢀ
ꢁ
Duguay, G.; Guemas, J.-P.; Meslin, J.-C.; Pradere, J.-P.;
Reliquet, F.; Reliquet, A.; Tea-Gokou, C.; Quiniou, H.;
Rabiller, C. J. Heterocyclic Chem. 1980, 17, 767–770.
Modified procedure for protection of amino acids: ( )-
alanine (0.13 mol) was suspended in glacial acetic acid
(40 mL) and phthalicanhydride (0.13 mol) was added. The
mixture was refluxed for 2 h until all the solids dissolved
and then cooled to room temperature and then in an ice
bath. The solid was filtered under suction and recrystal-
lized from water and ethanol (4:1). Other protected amino