The synthesis of enantiomerically pure disubstituted aziridines and N- alkoxy aziridines

Article abstract of DOI:10.1016/S0040-4039(99)02211-X

The addition of a chloroallyl phosphonamide anion to oximes has allowed the preparation of a variety of cis-disubstituted N-alkoxy aziridines in enantiomerically pure form. Oxidative cleavage of the chiral auxiliary followed by derivatization of the products has allowed the preparation of enantiopure N-alkoxy aziridines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02211-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 787–790
The synthesis of enantiomerically pure disubstituted aziridines
and N-alkoxy aziridines
Stephen Hanessian ∗ and Louis-David Cantin
Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec, H3C 3J7 Canada
Received 25 October 1999; accepted 22 November 1999
Abstract
The addition of a chloroallyl phosphonamide anion to oximes has allowed the preparation of a variety of cis-
disubstituted N-alkoxy aziridines in enantiomerically pure form. Oxidative cleavage of the chiral auxiliary followed
by derivatization of the products has allowed the preparation of enantiopure N-alkoxy aziridines. © 2000 Elsevier
Science Ltd. All rights reserved.
The synthesis of enantiomerically pure aziridines has been of interest in synthetic organic and
medicinal chemistry,1 because of their biological properties,2 their utilization as precursors to non-natural
amino acids,1,3 and as intermediates in the total synthesis of natural products.4 Especially interesting are
aziridines bearing a carboxylic acid functionality because of their structural similarity to α-amino acids,
and for the products obtained from nucleophilic ring opening reactions.5 On the other hand, N-hydroxy
and N-alkoxy aziridines have received little attention despite early reports of their preparation,6 and their
possible uses as N-hydroxy amino acids. The usual method for the preparation of N-alkoxy aziridines
involves the dipolar cycloaddition of diazomethane to activated oximes to yield mixtures of isomers,7 or
the electrophilic addition of O-methylhydroxylamine to olefins,8 although other classical methods have
also been reported.9 Enantiomerically pure N-hydroxy aziridines have been prepared by the resolution
of racemic mixtures10 and by the use of chiral non-racemic oximes,11 in connection with studies of the
effects of substituents on the inversion barrier of the nitrogen atom.12 N-Alkoxy aziridines are reported
to stimulate the production of leukocytes.9
We report herein on the formation of enantiopure N-alkoxy aziridines from the reaction of the
anion of chloroallyl phosphonamide 113 with different oximes. Our initial attempts led to mixtures of
diastereoisomers or to the recovery of starting material. However, the reaction of the anion of 1, generated
from NaHMDS, with an iso-propyl glyoxylate O-benzyl oxime 2 led to aziridine 3 in 46% yield (recovery
of 15% of 1) as a single isomer (Scheme 1).
Since variation of the reaction conditions did not improve the yield, we varied the ester group in 2.
However, the reaction of the anion of 1 with 2 (R1=Me, Bn) afforded only traces of the corresponding
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02211-X
tetl 16139

788
Scheme 1.
aziridine. Reaction of the anion of 1 with t-butyl glyoxylate O-benzyl oxime, O-p-methoxybenzyl and O-
trityl oximes proved much more rewarding. In each case, we isolated the corresponding aziridine deriva-
tives 4, 5, and 6, respectively, in good yields. Cleavage of the vinyl phosphonamide moiety in compounds
4–6 by ozonolysis,13 and reduction of the resulting ozonide, afforded the corresponding aziridines 7–9 in
good to excellent yields (Scheme 1). A single crystal X-ray analysis of the camphorsulfonate derivative
12, obtained from 7, allowed a definitive structural and stereochemical assignment (Scheme 2).
Scheme 2. Reagents: (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0°C, 95%; (b) DIBAL-H, CH2Cl2, −78 to 0°C, 84%; (c)
(+)-(1S)-camphorsulfonyl chloride, CH2Cl2, Et3N, 0°C, 83%; (d) Ac2O, Et3N, DMAP, CH2Cl2, 0°C, 15 min; (e) 5% Pd/BaSO4,
H2 (1 atm.), EtOH; (f) TFA, CH2Cl2, H2O, 45–55%
With a reliable method to generate enantiomerically pure N-alkoxy aziridines, we turned our attention
to the deprotection of the nitrogen to afford the corresponding N-hydroxy and N-H aziridines. Using
catalytic hydrogenation conditions with the O-benzyl aziridines bearing an α-carboxyl substituent
resulted only in the recovery of the starting material. On the other hand, reduction proceeded smoothly
with 10 and 11 to give the 2,3-disubstituted aziridines 12 and 13, respectively (Scheme 2). Oxidative
cleavage of the N-OPMB derivative with DDQ or CAN, gave a product that decomposed under the
reaction conditions. Access to the N-hydroxy aziridine derivative 15 was possible via deprotection of the
N-trityloxy group by treatment of 14 with TFA in CH2Cl2 (Scheme 2). Compound 15 slowly decomposed
above −20°C.
The stereochemistry of the aziridination product can be explained by an approach of the oxime from
the less hindered left cleft of the phosphonamide anion 113 in a Darzens-like reaction14 (Scheme 3). The
requirement of a bulky ester moiety such as t-butyl, may reflect a preferred reactive conformation, that
results in an irreversible C–C bond formation.
The fact that the iso-propyl ester of 2 gave a modest yield, and the methyl ester was recovered

789
Scheme 3.
unchanged, may lend credence to this hypothesis. The necessity of using NaHMDS rather than the less
effective Li or K bases is also of interest.
While trying to broaden the scope of the reaction to other C_N systems, the addition of the anion
of 1 onto hydrazones gave a dimeric compound 18 whose structure was ascertained by single crystal
X-ray analysis. The same compound could also be obtained in 70% yield by reacting 1 with NaHMDS at
−78°C for 2 h (Scheme 4). A plausible mechanism involves the formation of the isomeric phosphonamide
17, by internal quenching of 16 by HMDS.15 Conjugate addition of an anion 16 onto 17, followed by
intramolecular elimination of chloride from the resulting intermediate, could explain the formation of 18.
Scheme 4.
Unlike N-activated aziridine carboxylic esters,5 treatment of derivatives of 7 with soft nucleophiles
such as cuprates, thiolates and azide did not provide the desired ring opened products, even in the
presence of Lewis acids. However, treatment of 7 with 4N HCl in dioxane16 gave the α-chloro ester
19 which was subsequently lactonized to give 20 (Scheme 5).
Scheme 5. Reagents: (a) 4N, HCl/dioxane, dioxane, rt, 1 h, 89%; (b) TFA, CH2Cl2, rt, 46%; (c) NaH, THF, 0°C, 70%; (d) 30%
HBr/AcOH, CH2Cl2, 89%; (e) 30% HBr/AcOH, CH2Cl2, 81%; (f) Bu3SnH, VASO®, CH2Cl2, hν, −78°C, 30 min, 62%; (g)
TrocCl, pyr., DMAP, CH2Cl2, 0°C, 73%; (h) H2, 10% Pd/C, EtOAc, 86%

790
Similarly, treatment of 7 or 21 with HBr gave the bromo lactone 22 (NOESY NMR). Radical-mediated
debromination of 22 gave the corresponding 3-amino lactone 23 which was in turn debenzylated to the
N-hydroxy lactone 24 which was isolated as the N-Troc derivative. Hydroxylamines and their N-acylated
derivatives are biologically interesting,17 as exemplified by hadacidin (N-hydroxy-N-formyl glycine),
which has herbicidal properties,18 as well as related structures.19
Acknowledgements
We thank NSERCC for generous financial assistance through the Medicinal Chemistry Chair Program,
and Dr. Michel Simard for the X-ray analyses. L.-D.C. thanks Servier Canada for financial support
through a pre-doctoral scholarship.
References
1. Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599; Osborn, H. M.; Sweeny, J. Tetrahedron: Asymmetry 1997, 8, 1693;
Padwa, A.; Woodhouse, A. D. In Comprehensive Heterocyclic Chemistry; Lwowski, W., Ed.; Pergamon: Oxford, 1984; Vol.
7, p. 47.
2. See, for example: Schirmeister, T. J. Med. Chem. 1999, 42, 560; Kasai, M.; Kono, M. Synlett 1992, 778; Gerhart, F.; Higgins,
W.; Tardif, C.; Ducep, J.-B. J. Med. Chem. 1990, 33, 2157.
3. Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517.
4. For recent examples, see: Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64, 3237; Wipf, P.; Venkatraman, S. Synlett 1997,
1; Hudlickly, T.; Tian, X.; Königsberger, K.; Mauryan, R.; Rouden, J.; Fan, B. J. Am. Chem. Soc. 1996, 118, 10752. See also
Ref. 1.
5. Toda, A.; Aoyama, H.; Mimura, N.; Ohno, H.; Fujii, N.; Ibuka, T. J. Org. Chem. 1998, 63, 7053; Antolini, L.; Bucciarelli,
M.; Caselli, E.; Davoli, P.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. J. Org. Chem. 1997, 62, 8784; Zwanenburg, B.; Thijs,
L. Pure Appl. Chem. 1996, 68, 735; Dauban, P.; Dubois, L.; Tran Huu Dau, M. E.; Dodd, R. J. Org. Chem. 1995, 60, 2035.
6. Backer, H. J. Rec. Trav. Chim. Pays-Bas 1950, 69, 1223; for intramolecular aziridination to N-methoxy aziridines, see:
Wright, D. L.; McMills, M. C. Org. Lett. 1999, 1, 667.
7. Perrocheau, J.; Carrié, R.; Fleury, J.-P. Can. J. Chem. 1994, 72, 2458.
8. Vedejs, E.; Sano, H. Tetrahedron Lett. 1992, 33, 3261; Rudchenko, V. F.; Ignatov, S. M.; Kostyanovsky, G. J. Chem. Soc.,
Chem. Commun. 1990, 261.
9. Bosies, E.; Kampe, W.; Thiel, M.; Bicker, U.; Boerner, D. US 4,517,183, 1985.
10. Rudchenko, V. F.; D’Yachenko, O. A.; Zolotoi, A. B.; Atovmyan, L. V.; Chervin, I. I.; Kostyanovsky, R. G. Tetrahedron
1982, 38, 961.
11. Prosnyanik, A. V.; Mishchenko, A. I.; Zaichenko, N. L.; Shustov, G. V.; Nelov, P. N.; Kostyanovsky, R. G. Bull. Acad. Sci.
USSR. Div. Chem. Sci. (Engl. Trans.) 1984, 33, 546.
12. Prosnyanik, A. V.; Bondarenko, S. V.; Markov, V. I.; Chervin, I. I.; Isobaev, M. D.; Kushch, S. D.; Kostyanovsky, R. G.
Chem. Heterocycl. Compd. (Engl. Transl.) 1980, 16, 154; Pierre, J.-L.; Baret, P.; Arnaud, P. Bull. Soc. Chem. Fr. 1971, 3619;
Brois, S. J. J. Am. Chem. Soc. 1970, 92, 1079.
13. Hanessian, S.; Andreotti, D.; Gomtsyan, A. J. Am. Chem. Soc. 1995, 117, 10393.
14. Cantrill, A. A.; Hall, L. D.; Jarvis, A. N.; Osborn, H. M. I.; Raphy, J.; Sweeney, J.-B. Chem. Comm. 1996, 2631; Florio, S.;
Troisi, L.; Capriati, V. J. Org. Chem. 1995, 60, 2279.
15. Bunz, U.; Herpich, W.; Podlech, J.; Polborn, K.; Pratzel, A.; Stephenson, D. S.; Szeimies, G. J. Am. Chem. Soc. 1994, 116,
7637; Vedejs, E.; Lee, N. J. Am. Chem. Soc. 1995, 117, 891; Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 162.
16. Ambrosi, H.-D.; Duczek, W.; Ramm, M.; Jähnisch, K. Tetrahedron Lett. 1994, 35, 7613.
17. For reviews and leading references, see: Romine, J. L.; Org. Prep. Proc. Int. 1996, 251; Sandler, S. R.; Karo, W. In Organic
Functional Group Preparations; Wasserman, H. H., Ed.; Academic Press: San Diego, 1989; Vol. 3, pp. 482; Ottenheijm, H.
C. J.; Heirscheid, J. D. M. Chem. Rev. 1986, 86, 697.
18. Jahngen Jr., E. G. E.; Rossomando, E. F. Syn. Commun. 1982, 12, 601.
19. Hanessian, S.; Lu, P.-P., Sancéau, J.-Y.; Chemla, P.; Gohda, K.; Fonne-Pfister, R.; Prade, L.; Cowan-Jacob, S. Angew. Chem.,
Int. Ed. 1999, 38, 3159.