Enantioselective ring opening of epoxides with trimethylsilyl azide (TMSN3) in the presence of β-cyclodextrin: An efficient route to 1,2-azido alcohols

Article abstract of DOI:10.1016/S0957-4166(99)00464-4

The ring opening of epoxides with nucleophiles such as TMSN₃ and isopropylamine takes place enantioselectively in the presence of β- cyclodextrin under extremely mild conditions and the azido alcohols and amino alcohols are formed as (S)-isomers. (C) 1999 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00464-4

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4261–4264
Enantioselective ring opening of epoxides with trimethylsilyl
azide (TMSN3) in the presence of β-cyclodextrin: an efficient
route to 1,2-azido alcohols †
Ahmed Kamal,∗ M. Arifuddin and Maddamsetty V. Rao
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 30 August 1999; accepted 18 October 1999
Abstract
The ring opening of epoxides with nucleophiles such as TMSN3 and isopropylamine takes place enantioselec-
tively in the presence of β-cyclodextrin under extremely mild conditions and the azido alcohols and amino alcohols
are formed as (S)-isomers. © 1999 Published by Elsevier Science Ltd. All rights reserved.
Epoxides are versatile intermediates in organic synthesis as their ring can be easily opened by a variety
of nucleophiles, yielding a broad range of valuable products.1 Enantioselective ring opening of meso
or racemic epoxides by nucleophilic reagents is one of the most powerful methods in the asymmetric
synthesis of 1,2-disubstituted compounds.2 Among the vast number of nucleophiles that have been
employed in the ring opening, azides (which afford the corresponding vicinal azidohydrins) have received
considerable attention. The classical reagents for azidohydrin synthesis are the combined use of TMSN3
or sodium azide and a Lewis acid or a transition-metal complex.3 Further, the vicinal azidohydrins are
precursors of β-amino alcohols, which are present in numerous natural products. Recently, Jacobsen
reported the asymmetric ring opening of epoxides by using TMSN3 in the presence of a chiral Cr
complex.4 Similarly, the asymmetric ring opening of meso epoxides with anilines has been accomplished
in the presence of chiral BINOL–Yb triflate complexes and amines.5
In the context of our recent studies,6 it has been shown that liver microsomes can be used in the
stereoselective ring opening of epoxides with amines and they have also been opened selectively by
various amines in the presence of lipases. The selective ring opening reaction of epoxides with sodium
borohydride in the presence of cyclodextrin in aqueous media has also been reported.7 In the literature,
cyclodextrins and macrocyclic compounds consisting of α-1,4-linked D-glucopyranose have attracted
much attention, because of their ability to form inclusion complexes.8,9
∗
†
Corresponding author. Tel: +91 40 7173874; fax: +91 40 7173387; e-mail: ahmedkamal@iict.ap.nic.in
Part of the work presented at the First National Symposium on ‘Green Chemistry’, January 1999, New Delhi, India.
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00464-4

4262
A. Kamal et al. / Tetrahedron: Asymmetry 10 (1999) 4261–4264
Based on the above findings, it was considered of interest to investigate the effect of β-cyclodextrin on
the ring opening reaction of epoxides with nucleophiles. Herein, we wish to report the stereoselective ring
opening reaction with TMSN3 in the presence of β-cyclodextrin in aqueous media to afford 1,2-azido
alcohols.
Some of the earlier studies on azidolysis with TMSN3 require high temperature and alkaline conditions
in the absence of catalysts, whereas, in some of the recent reports, metal complexes such as Ti(O-i-
Pr)4,10a–c Al(O-i-Pr)3,10b Yb(O-i-Pr)3,10d and [Hf(OTf)4, Zr(OTf)4, Yb(OTf)3]10e have been employed
as catalysts for the regio- and chemoselective azidolysis with TMSN3 to afford the corresponding azido
alcohols or azido silyl ethers. In the case of azido silyl ethers, they have been hydrolyzed under acidic
conditions to yield the desired azido alcohols.
In the present study, the reaction of an epoxide with TMSN3 in the presence of β-cyclodextrin
gives a mixture of the ring-opened azido alcohol and the epoxide which has been monitored by HPLC
employing a chiral column. The unreacted epoxide and azido alcohol have been separated by column
chromatography.
In a typical procedure, 3-phenoxy-1,2-epoxypropane (100 mg, 0.66 mmol) was dissolved in 1 ml
of ethanol and to this β-cyclodextrin (1.13 g, in 20 ml water) was added. After stirring for 30 min at
room temperature, trimethylsilyl azide (100 mg, 0.86 mmol) was added and incubated at 37°C in an
orbital shaker for 5 h. The reaction mixture was then extracted with ethyl acetate and dried over MgSO4.
The residue was purified by silica gel column chromatography to give corresponding unreacted epoxide
followed by the 1,2-azido alcohol. This method has been found to be applicable to a series of terminal
epoxides and the results are illustrated in Table 1.
Table 1
Ring opening of racemic epoxides with TMSN3 in the presence of β-cyclodextrin
In all cases studied, the conversion was detected by HPLC, and after about 50% conversion, the
reaction mixture was extracted with ethyl acetate. The conversion of these substrates 1a–f to the
corresponding azido alcohols 2a–f takes place in one-pot as azido silyl ethers are not formed (Scheme 1).
It is observed from the results that the (S)-isomer is formed predominantly. Interestingly, when these
epoxide ring opening reactions have been performed using NaN3, significant enantioselectivity has not
been observed.
Scheme 1.

A. Kamal et al. / Tetrahedron: Asymmetry 10 (1999) 4261–4264
4263
This method is applicable to various epoxides having different substituents on the aryl ring of the
phenoxy group. The absolute configuration has been assigned based on earlier literature studies,11 by
employing a Chiralcel OD column and unambiguous synthesis to the corresponding known β-blockers.
Further, this study has been extended to the ring opening of racemic epoxides with isopropylamine in the
presence of β-cyclodextrin. Also, in this reaction the (S)-isomer of the product is observed predominantly
and the results of this investigation are described in Table 2.
Table 2
Ring opening of racemic epoxides with isopropylamine in the presence of β-cyclodextrin
In summary, we have developed a synthetically useful and practical approach for the preparation of
enantiomerically enriched azido alcohols in one-pot by the opening of racemic epoxides with TMSN3 in
the presence of β-cyclodextrin in aqueous medium. This method has potential for the preparation of non-
racemic 1,2-amino alcohols of biological interest. In addition, the enantioselective opening of epoxide
with TMSN3 takes place under extremely mild conditions and is expected to have wide applicability.
Acknowledgements
One of the authors (MA) is grateful to CSIR, New Delhi for the award of a Senior Research Fellowship.
References
1. (a) Erden, I. In Comprehensive Heterocyclic Chemistry; Padwa, A., Ed.; Pergamon Press: Oxford, 1996; Vol. IA, Chapter
1.03. (b) Bartok, M.; Lang, K. L. In Chemistry of Heterocyclic Compounds; Weissberger, A.; Taylor, E. C., Eds.; Wiley:
New York, 1985; Vol. 42, part 3, p. 1.
2. Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361 and references cited therein.
3. (a) Birkofer, I.; Kaiser, W. Liebigs Ann. Chem. 1975, 266. (b) Blandy, C.; Choukroun, R.; Gervais, D. Tetrahedron Lett.
1983, 24, 4189. (c) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1560. (d) Maruoka, K.; Sano, H.; Yamamoto, H.
Chem. Lett. 1985, 599. (e) Sinou, D.; Emziane. M. Tetrahedron Lett. 1986, 27, 4423. (f) Caron, M.; Carlier, P. R.; Sharpless,
K. B. J. Org. Chem. 1988, 53, 5185. (g) Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768. (h) For a recent review, see:
Paterson, I.; Berrisford, D. J. In Organic Synthesis Highlights III; Mulzer, J.; Waldmann, H., Eds.; Wiley-VCH, 1998.

4264
A. Kamal et al. / Tetrahedron: Asymmetry 10 (1999) 4261–4264
4. (a) Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897. (b) Leighton, J.
L.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 389. (c) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996,
118, 7420. (d) Annis, D. A.; Helluim, O.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl. 1998, 37, 1907.
5. Hou, X.-L.; Wu, J.; Dai, L.-X.; Xia, L.-J.; Tang, M.-H. Tetrahedron: Asymmetry 1998, 9, 1747.
6. (a) Kamal, A.; Rao, A. B.; Rao, M. V. Tetrahedron Lett. 1992, 33, 4077. (b) Kamal, A.; Damayanthi, Y.; Rao, M. V.
Tetrahedron: Asymmetry 1992, 3, 1361. (c) Kamal, A.; Rao, M. V. Tetrahedron: Asymmetry 1994, 5, 1881.
7. Hu, Y.; Uno, M.; Harada, A.; Takahashi, S. Chem. Lett. 1990, 797 and references cited therein.
8. (a) Tabushi, I. Acc. Chem. Res. 1982, 15, 66. (b) Breslow, R.; Campbell, P. Bioorg. Chem. 1971, 1, 140. (c) Komiyama,
M.; Hirai, H. J. Am. Chem. Soc. 1984, 106, 74. (d) Sakuraba, H.; Inomata, N.; Tanaka, Y. J. Org. Chem. 1989, 54, 3482.
(e) Hu, Y.; Harada, A.; Takahashi, S. Synth. Commun. 1988, 18, 1607. (f) Banfi, S.; Colonna, S.; Julia, S. Synth. Commun.
1983, 13, 1049.
9. For recent reviews on cyclodextrin, see: (a) Breslow, R.; Dong, S. D. Chem. Rev. 1998, 98, 1997. (b) Takahashi, K. Chem.
Rev. 1998, 98, 2013.
10. (a) Yamashita, H. Bull. Chem. Soc. Jpn. 1988, 61, 1213. (b) Sutowardoyo, K. I.; Emziane, M.; Lhoste, P.; Sinou, D.
Tetrahedron 1991, 47, 1435. (c) Hayashi, M.; Kohmura, K.; Oguni, N. Synlett 1991, 774. (d) Meguro, M.; Asao, N.;
Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1995, 1021. (e) Crotti, P.; Bussolo, V. D.; Favero, L.; Macchia, F.; Pineschi,
M. Tetrahedron Lett. 1996, 37, 1675.
11. Ader, U.; Muschalek, V.; Schneider, M. P. Chirality 1993, 5, 554.