Table 2 Effect of concentration of b-CD on enantioselectivity as shown by
of freedom of the guest molecule possibly through hydrogen
bonding, favorable control of geometry in the approach of the
substrate to the ‘active site’ etc. A balance of these interactions
determines the enantioface selectivity.
2e
Entry
Ratio (b-CD–1e)
Ee(%)
These CD mediated water solvent reactions are very useful
both from economical and environmental points of view and
also for the practical convenience of not having to handle
flammable anhydrous organic solvents or toxic and expensive
reagents. b-Cyclodextrin, apart from being non-toxic, is also
considered as metabolically safe.12 Thus, the present method-
ology for the synthesis of chiral 2-azido-1-arylethanols of great
significance in asymmetric synthesis and medicinal chemistry
involving water as solvent may be considered as simple from
the practical point of view with great potential for future
applications.
1
2
3
4
5
1.5+1
1+1
0.75+1
0.50+1
0.25+1
80
80
37
14
0
optimum at 1+1 since a lower ratio of b-CD led to a decrease in
ee whereas a higher ratio has not shown any improvement in
enantioselectivity (Table 2). The enantiomeric excesses (ee) of
the products were determined by chiral HPLC analysis. These
compounds have been shown to have S configuration by
comparison of the sign of rotation with those of the known
MAR thanks CSIR, New Delhi, India for the award of a
fellowship.
6
compounds. An interesting feature of this reaction is that the
substrates having electron donating substituents on the aromatic
ring have shown higher enantioselectivity compared with the
electron withdrawing substituents (Table 1). This may be
ascribed to additional stabilization of the transition state of
carbonyl–borohydride complex by electron donating sub-
stituents which can result in better enantioselectivity. However,
this will be complimentary to other factors.
Notes and references
1 K. I. Sutawardoyo, M. Emziane, P. Lhoste and D. Sinou, Tetrahedron,
1
1
991, 47, 1437; M. Chini, P. Crotti and F. Macchia, Tetrahedron Lett.,
990, 31, 5641.
2
The Chemistry of the Azido Group, ed. S. Patai, Wiley, New York,
1
971
Among the compounds studied, compound 2i with an
3
4
5
E. F. V. Scriven and K. Turnbull, Chem. Rev., 1988, 88, 297.
isopropoxy group has shown the highest enantioselectivity
E. J. Corey and J. O. Link, J. Org. Chem., 1991, 56, 442.
(81% ee) followed by 2e (80% ee), 2f (73% ee), 2g (66% ee), 2h
(53% ee) and 2a (52% ee) whereas lower enantioselectivities
M. Meguro, N. Asao and Y. Yamamoto, J. Chem. Soc., Chem.
Commun., 1995, 1021; L. E. Martinez, J. L. Leighton, D. H. Carsten and
E. N. Jacobsen, J. Am. Chem. Soc., 1995, 117, 5897; H. Lebel and E. N.
Jacobsen, Tetrahedron Lett., 1999, 40, 1703.
were observed with the rest of the compounds (0–12% ee). To
study the effect of substitution on enantioselectivity, the azido
group was replaced by H, OH and OTBDMS with increasing
bulkiness. Though increase in bulkiness in this series (2k–q) has
led to enhancement in enantioselectivity (Table 1) with 2p
showing a maximum of 61% ee, the ketones with azide group
6
7
8
E. J. Corey and C. J. Helal, Angew. Chem., Int. Ed., 1998, 37, 1986; J.
S. Yadav, P. T. Reddy and S. Riaz Hashim, Synlett, 2000, 1049; B. T.
Cho and Y. S. Chun, J. Org. Chem., 1998, 63, 5280.
N. Baba, Y. Matsumura and T. Sugimoto, Tetrahedron Lett., 1978, 44,
4
281; R. Fornasier, F. Reniero, P. Scrimin and U. Tonellato, J. Org.
(
2a–j) appeared to fit best in the CD cavity for reduction with
Chem., 1985, 50, 3209.
sodium borohydride giving an ee up to 81% (Table 1).
(a) L. R. Reddy, N. Bhanumathi and K. R. Rao, Chem. Commun., 2000,
2321; (b) L. R. Reddy, M. A. Reddy, N. Bhanumathi and K. R. Rao,
Synlett, 2000, 339; (c) M. A. Reddy, L. R. Reddy, N. B. Hanumathi and
K. R. Rao, New J. Chem., 2001, 25, 359; (d) M. A. Reddy, L. R. Reddy,
N. Bhanumathi and K. R. Rao, Chem. Lett., 2001, 246; (e) K. R. Rao and
H. M. S. Kumar, Synth. Commun., 1993, 23, 1877; (f) K. R. Rao and P.
B. Sattur, J. Chem. Soc., Chem. Commun., 1989, 342.
1
The inclusion complex formation was observed from H
NMR spectra10 and powder X-ray spectra of the solid CD
complexes. Hydrogen bonding of substrates with CD hydroxy
groups was seen from IR by a shift of the CNO stretch to lower
11
2
1
frequency in CD complexes (in the range of 2–53 cm
)
compared with the uncomplexed substrates. Stronger shifts
were observed for the substrate–CD complexes which yielded
products with higher ee. Thus, the CD induced asymmetric
reductions by supramolecular catalysis may involve various
factors such as hydrophobic binding, carbonyl exposure to the
CD rim of secondary hydroxy groups, a decrease in the degrees
9
A. W. Czarnik, J. Org. Chem., 1984, 49, 924; V. T. Dsouza and K. B.
Lipkowitz, Chem. Rev., 1998, 98, 1741.
1
1
0 P. V. Demarco and A. L. Thakkar, Chem. Commun., 1970, 2.
1 J. Szejtli and T. Osa, Comprehensive Supramolecular Chemistry,
Pergamon, UK, 1996, vol. 3, p. 253
12 K. Uekama, F. Hirayama and T. Irie, Chem. Rev., 1998, 98, 2045.
Chem. Commun., 2001, 1974–1975
1975