Easy and efficient synthesis of enantiomerically enriched 2H-azirines derived from phosphonates

Article abstract of DOI:10.1016/S0040-4039(00)00843-1

An efficient synthesis of 2H-azirines substituted with a phosphonate group is described. The key step is an alkaloid-mediated Neber reaction of β-ketoxime tosylates. Reduction of 2H-azirines with sodium borohydride in ethanol gives 2-phosphorylated cis-aziridines.

Full text of DOI:10.1016/S0040-4039(00)00843-1

Tetrahedron Letters 41 (2000) 5363±5366
Easy and ecient synthesis of enantiomerically enriched
2H-azirines derived from phosphonatesy
Francisco Palacios,* Ana M. Ochoa de Retana and Jose I. Gil
Â
Departamento de Quõmica Organica, Facultad de Farmacia, Universidad del Paõs Vasco, Apartado 450,
Â
Â
01080 Vitoria, Spain
Received 13 April 2000; accepted 23 May 2000
Abstract
An ecient synthesis of 2H-azirines substituted with a phosphonate group is described. The key step is
an alkaloid-mediated Neber reaction of b-ketoxime tosylates. Reduction of 2H-azirines with sodium
borohydride in ethanol gives 2-phosphorylated cis-aziridines. # 2000 Published by Elsevier Science Ltd.
Keywords: azirines; aziridines; asymmetric synthesis; oximes; phosphonates; aminophosphonates.
The highly strained 2H-azirine ring system, the smallest of the nitrogen-unsaturated hetero-
cycles, represents a very important class of compounds, not only for their theoretical interest but
also because of their high reactivity towards nucleophilic and electrophilic reagents,1,2 as well as
in cycloaddition reactions.2b Optically active 2H-azirines, namely azirinomycin,3a (Ia, Scheme 1),
and both (R)-(^)-,3b (S)-(+)-disydazirine,3c (Ib, Scheme 1) and (S)-(+)-antazirine,3c (Ic, Scheme 1),
are naturally occurring antibiotics. Furthermore, it is known that phosphor substituents regulate
important biological functions.4 In particular, fosfomycin (IIIa, XˆO, Scheme 1) is a broad
spectrum antibiotic5a and is used in vitro5b and clinically.5c For these reasons, functionalized
azirines (II, Scheme 1) and aziridines (IIIb, XˆN, Scheme 1) containing a phosphonate group at
the 2-position are expected to play a similar role to that observed in their isosteric analogues I,
Scheme 1. Biologically active three-membered heterocycles
* Corresponding author. E-mail: qoppagaf@vf.ehu.es
y
Dedicated to Professor Dr. Rolf Huisgen on the occasion of his 80th birthday.
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)00843-1

5364
and may even be used as key intermediates in the enantioselective synthesis of a- and b-amino-
phosphorus derivatives. Aminophosphonates can be considered as surrogates for amino acids6a
and have been used as haptens for catalytic antibodies,6b as enzyme inhibitors,6c and as pharma-
ceuticals.6d
Many procedures for the synthesis of 2H-azirines have been reported,1 and enantiomerically
enriched 2H-azirines, containing a carboxylic ester on the ring system, have been previously pre-
pared either from chiral N-substituted aziridine 2-carboxylic esters,7a c or by using the Neber
reaction.7d,e However, 2H-azirines directly substituted with a phosphorus containing functional
group have received scarce attention. To the best of our knowledge, only the 2-phosphino-, 2-
phosphonio, and the thioxo-phosphoranyl-2-silyl-2H-azirines obtained by reaction of carbenes
and aromatic nitriles,8a,b and regioisomeric mixtures of 2H- and 3H-azirinyl-phosphonates with a
phenyl group at the 2-position, obtained by Swern oxidation of enantiopure substituted aziridines,
have been recently reported.8c Continuing with our interest in the synthesis of new phosphorus
substituted heterocycles,9 we are involved in the design of new 2H-azirines bearing a phosphonate
moiety. Here we report a simple asymmetric synthesis of 2H-azirinyl phosphonates from easily
available tosyloximes, given that the modi®ed Neber reaction10 using tosylketoximes derived
from phosphonates 2 seems to be an interesting method for the preparation of azirines.
The preparation of the required functionalized b-tosyloximes 2,{ can be easily accomplished by
simple reaction of b-oximes 1 derived from phosphonates11 with tosyl chloride in pyridine
(Scheme 2, Table 1, entries 1±3). Alkyl and phenyl substituted 2H-azirines 3x were prepared from
b-ketoximes 2 by treatment with triethylamine at room temperature for 8 h in benzene (Table 1,
entries 4±6). This process can also be extended to the asymmetric synthesis of 2H-azirine 3 when
stoichiometric amounts of chiral bases are used. Alkaloids such as quinidine (QN), hydro-
quinidine (HQ), sparteine (SP) or quinine (Q) were used and the best results were obtained with
quinidine in benzene (Scheme 3, Table 1, entries 7, 9 and 12). The enantiopurity of azirines
derived from phosphonate 3{ (ee 2±52%) was determined by 31P NMR measurements in CDCl3
using a chiral shift reagent (Yb(tfc)3).
Scheme 2. 2H-Azirines formation through modi®ed Neber reaction of tosyl ketoximes 2
{
All new compounds reported here gave satisfactory elemental analysis. Spectral data for 2a: ꢀH (300 MHz, CDCl3):
7.79 (d, 3JHH=7.5 Hz, 4H), 7.27 (d, 3JHH=7.5 Hz, 4H), 3.98 (m, 8H), 2.97 (d, 2JPH=23.7 Hz, 2H), 2.73 (d, 2JPH=21.9
3
3
Hz, 2H), 2.38 (s, 6H), 2.05 (s, 3H), 2.06 (s, 3H), 1.12 (t, JHH=7.2 Hz, 6H), 1.22 (t, JHH=7.2 Hz, 6H) ppm; ꢀP (120
MHz, CDCl3): 19.8 and 21.4 ppm; ꢀC (75.4 MHz, CDCl3): 160.9 (d, 2JPC=8.1 Hz), 158.9 (d, JPC=8.1 Hz), 144.9 (s),
2
132.4±129.0 (m), 62.5 (s), 62.4 (s), 33.4 (d, 1JPC=135.8 Hz), 29.2 (d, 1JPC=133.9 Hz), 21.5 (s), 21.4 (s), 20.9 (s), 16.3 (s),
16.1 (s) ppm; m/z 364 ([M+1]+, 18).
x
2
Spectral data for 3a : ꢀH (300 MHz, CDCl3): 4.10 (m, 4H), 2.54 (s, 3H), 1.72 (d, JPH=39.3 Hz, 1H), 1.32 (m, 6H)
3
1
ppm; ꢀP (120 MHz, CDCl3): 23.1 ppm; ꢀC (75.4 MHz, CDCl3): 161.4 (d, JPC=3.5 Hz), 62.1 (s), 22.5 (d, JPC=214.5
Hz), 16.2 (s), 13.2 (d, 3JPC=2.0 Hz) ppm; m/z 192 ([M+1]+, 3).
Optical rotation of compounds 3a ‰ꢁŠ2D0=^19 from quinidine, ‰ꢁŠD20=^2 from (^)-sparteine, 3b ‰ꢁŠ2D0=^27 from qui-
{
nidine, ‰ꢁŠ2D0=^24 from hydroquinidine, ‰ꢁŠD20=+8 from quinine, 3c ‰ꢁŠD20=^104 from quinidine, determined using a
concentration c=0.75 in CH2Cl2.

5365
Table 1
Tosyloximes 2, 2H-azirines 3, aziridines 4, 5 and b-aminophosphonates 6 obtained
Scheme 3. Formation of aziridines 4, 5 and b-aminophosphonates 6
The absolute con®guration of alkyl substituted azirines 3a,b (R=Me, Et) was established by
correlation with optically active b-aminophosphonates 6,12k and in the case of azirine 3c the
absolute con®guration was established by correlation with the optical rotation of optically active
3-phenyl-2H-azirine,8c (‰ꢁŠD20=^202, c=0.32, CHCl3). Reduction of azirines derived from phos-
phonates 3 with sodium borohydride in ethanol gave exclusively cis-aziridines 4 (Table 1, entries
13 and 14). The stereochemical assignment was based on the large ring proton coupling constant
observed for 4a (3JHH=6.8 Hz).8c,13 Furthermore, no loss of chirality was observed. Enantio-
merically enriched N-p-toluenesulfonyl-cis-aziridines 5 were prepared by treatment of aziridines
4 with p-toluenesulfonyl chloride in dichloromethane at room temperature in the presence of
triethylamine (Scheme 3). The products were isolated by ¯ash chromatography and the new
aziridines 5 were obtained in excellent yields (Table 1, entries 15 and 16). Hydrogenolysis of N-
substituted aziridines 5 was accomplished with HCO2NH4 and palladium on carbon in re¯uxing
ethanol for 2 h (Table 1, entries 17 and 18), to give b-aminophosphonates 6 in good yields and
retention of the con®guration, in a similar way to that previously reported for aziridines derived
from carboxylates.2a,14
In conclusion, we have devised a simple, mild, and convenient strategy for the synthesis, from
readily available starting materials, of enantiomerically enriched 2H-azirines 3, as well as cis-
aziridines 4 and 5 substituted with a phosphonate group. These heterocycles may be very useful
intermediates in organic synthesis1,2 and for the preparation of a large variety of molecules that
Optical rotation of compounds 4a ‰ꢁŠD20=+1, c=0.30 in CH2Cl2, 4b ‰ꢁŠ2D0=+1, c=0.75 in CH2Cl2, 5a ‰ꢁŠ2D0=+2,
k
c=0.45 in CH2Cl2, 5b ‰ꢁŠ2D0=+2, c=1.00 in CH2Cl2, 6a ‰ꢁŠD20=+6, c=0.24 in MeOH, 6b ‰ꢁŠ2D0=+4, c=0.38 in MeOH.

5366
could be useful in the synthesis of biologically active compounds of interest to medicinal
chemistry.3 6 Further studies on phosphonyl-2H-azirines 3 and -aziridines 4, 5 are now in pro-
gress in our laboratory.
Acknowledgements
The present work has been supported by the Direccion General de Ensenanza Superior e
Investigacion Cientõ®ca (Madrid. DGESIC, PB96-0252) and by the Departamento de Educacion,
Universidades e Investigacion del Gobierno Vasco (Vitoria, PI 98-53). J. I. Gil thanks the Uni-
versidad del Paõs Vasco for a predoctoral fellowship.
References
1. For reviews on azirines, see: (a) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 1, pp. 1±
60. (b) Backes, J. In Methoden der Organische Chemie (Houben-Weyl); Thieme, G., Eds.; Stuttgart, 1992; Vol.
E16c; pp. 317±369.
2. (a) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T. V.; Reddy, G. V.; Zhang, Y. L. J. Org. Chem. 1999, 64, 7559±7567.
(b) Albrecht, E.; Mattay, J.; Steenken, S. J. Am. Chem. Soc. 1997, 119, 11605±11610.
3. (a) Miller, T. M.; Tristram, E. W.; Wolf, F. J. J. Antibiot. 1971, 24, 48±50. (b) Molinski, T. F.; Ireland, C. M.
J. Org. Chem. 1988, 53, 2103±2105. (c) Salomon, C. E.; William, D. H.; Faulkner, D. J. J. Nat. Prod. 1995, 58,
1463±1466.
4. For reviews, see: (a) Engel, R. In Handbook of Organophosphorus Chemistry; Dekker, M. Inc.: New York, 1992.
(b) Kafarski, P.; Lejezak, B. Phosphorus & Sulfur 1991, 63, 193±215.
5. (a) Allenberger, F.; Klare, Y. J. Antimicrob. Chemother. 1999, 43, 211±217. (b) Kawakami, Y.; Furuwatari, C.;
Akahane, T.; Okimura, Y.; Fusihata, K.; Katsuyama, T.; Matsumoto, H. J. Antibiot. 1994, 47, 507±510. (c)
Tsuboi, T.; Ida, H.; Yoshikawa, E.; Hiyoshi, S.; Yamagi, E.; Nakayama, Y.; O'Hara, K.; Nonomiya, T.;
Shigenobu, F.; Toniguchi, K.; Shimizu, M.; Sawai, T.; Mizuokowa, K. Clin. Chim. Acta 1999, 279, 175±179.
6. (a) Smith, A. B.; Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc. 1995, 117, 10879±10888. (b) Hirschmann, R.;
Smith, A. B.; Taylor, C. M.; Benkovic, P. A.; Taylor, S. D.; Yager, K. M.; Spengler, P. A.; Benkovic, S. J. Science
1994, 265, 234±237. (c) Meyer, J. H.; Bartlett, P. A. J. Am. Chem. Soc. 1998, 120, 4600±4609. (d) Smith, A. B.;
Yager, K. M.; Taylor, C. M. PCT Int. Appl. WO 95 25,11, 1995; Chem. Abstr. 1996, 124, 87370.
7. (a) Davis, F. A.; Liu, H.; Liang, C.; Reddy, G. V.; Zhang, Y.; Fang, T.; Titus, D. D. J. Org. Chem. 1999, 64, 8929±
8935. (b) Davis, F. A.; Reddy, G. V.; Liu, H. J. Am. Chem. Soc. 1995, 117, 3651±3652. (c) Gentillucci, L.; Grijzen,
Y.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1995, 36, 4665±4668. (d) Verstappen, M. M. H.; Arians, G. J. A.;
Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491±8492. (e) Piskunova, I. P.; Eremeev, A. V.; Mishnev, A. F.;
Vosekalna, I. A. Tetrahedron 1993, 49, 4671±4676.
8. (a) Alcaraz, G.; Wecker, U.; Baceiredo, A.; Dahan, F.; Bertrand, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1246±
1248. (b) Piquet, V.; Baceiredo, A.; Gornitzka, H.; Dahan, F.; Bertrand, G. Chem. Eur. J. 1997, 3, 1757±1264. (c)
Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249±252.
9. (a) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron 1999, 55, 13767±13778. (b) Palacios, F.; Ochoa de
Retana, A.; Oyarzabal, J. Tetrahedron 1999, 55, 5947±5964. (c) Palacios, F.; Gil, M. J.; Martõnez, E.; Rodrõguez,
M. Tetrahedron Lett. 1999, 40, 2411±2414.
10. (a) Neber, P. W.; Burghard, A. Justus Liebigs Ann. Chem. 1932, 493, 281±294. (b) McCarthy, C. G. In The
Chemistry of the Carbon±Nitrogen Bond; Patai, S., Ed.; Interscience: New York, 1973; pp. 447±452.
11. Palacios, F.; Aparicio, D.; de los Santos, J. M.; Rodrõguez, E. Tetrahedron 1998, 54, 599±614.
12. Duggan, M. E.; Karanewsky, D. S. Tetrahedron. Lett. 1983, 24, 2935±2938.
13. (a) Thomas, A. A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379±8385. (b) Hori, K.; Sugihara, H.; Ito, Y. N.;
Katsubi, T. Tetrahedron Lett. 1999, 40, 5207±5210.
14. (a) Chandrasekhar, S.; Ahmed, M. Tetrahedron Lett. 1999, 40, 9325±9327. (c) Davis, F. A.; Zhou, P.; Reddy, G. V.
J. Org. Chem. 1994, 59, 3243±3245.