substrates with electron-withdrawing groups on the aryl
group were well tolerated as yields of approximately 40%
(out of a theoretical maximum of 50%), >25:1 ratios of
isomers 2 vs 3, and >97% enantiomeric excess were observed
(entries 2, 4, 6, 8, and 14). The increase in steric bulk at the
R2 position caused a decrease in yields presumably due to a
negative interaction with the enzyme catalytic site (entry 14
vs 16, 18, and 2016). A lower solubility substrate such as
2-methyl-2-(naphthalen-2-yl)oxirane gave >25:1 regioselec-
tivity and 98% ee albeit in low yield (entry 23). For epoxides
1h and 1i, Codex HHDH P1H2 was a better match for the
substrate, giving higher enantioselectivities of the corre-
sponding 1-azido-2-arylpropan-2-ols (entries 20 vs 21 and
23 vs 24). Finally, the scope of the reaction was also extended
to 2-methyl-2-phenethyloxirane, a 2,2-dialkyl-disubstituted
epoxide; excellent yields and selectivities were observed
(entry 26).17
reactions (entries 4 and 26). The absolute configuration of
the residual enantiomerically enriched epoxides 4b and 4j
was determined to be (S) by comparing the sign of optical
rotation with the literature data19a and was of high optical
purity 99% ee as determined by SFC (Table 4).20 Therefore,
the azidolysis occurred selectively on the (R) epoxide
providing the (R)-azido alcohol.
The novel regioselective and enantiomerically enriched
2,2-disubstituted azido alcohols reported in this paper are
synthetically valuable chiral building blocks. They can be
converted into enantiomerically enriched 2,2-disubstituted
unprotected aziridines21 through a Staudinger reaction in
>94% ee and regio- and enantioselective 2,2-disubstituted
amino alcohols22 through simple reduction of the azide as
demonstrated by two examples in Scheme 1.
A direct comparison of the biocatalytic azidolysis of 2,2-
disubstituted epoxides was made with a standard uncatalyzed
azidolysis for all substrates tested (Table 1).18 Contrary to
literature precedents that suggest preferential opening at the
terminal position of monosubstituted epoxides,18 the uncata-
lyzed azidolysis of the 2,2-disubstituted epoxides described
in this paper produces a mixture of regioisomers 2 and 3
where the ratios varied between 1.4:1 to 3:1 for most
substrates (entries 1, 3, 5, 7, 9, and 22) and only in strongly
sterically or electronically biased systems such as 1f, 1g, and
1h were the ratios of 2 vs 3 >12:1 (entries 15, 17, and 19).
These results demonstrate that the HHDH P2E2 enzyme
controls both the regioselectivity and enantioselectivities of
the azide opening.
Scheme 1. Novel Enantiomerically Enriched 2,2-Disubstituted
Aziridines and 1,2-Disubstituted Amino Alcohols
Because all of the 1-azido-2-arylpropan-2-ols prepared in
this paper are new compounds not previously reported in
the literature, we determined the stereochemistry of the
residual unreacted enantiomerically enriched epoxide for two
In conclusion, we have developed a method for the
enzymatic resolution of 2-alkyl-2-aryl-disubstituted epoxides
(13) Other azide sources were tested (LiN3, Me3SiN3, Me3SnN3, and
Bu4NN3) which had no influence on the azidolysis: see ref 5a.
(14) The enzyme loading was optimized to 50 wt % or ∼2.5 × 10-3
mol % of enzyme.
(15) Representative Procedure: (R)-1-Azido-2-phenylpropan-2-ol [(R)-
2a]. To a solution of the enzyme (HHDH P2E2, 250 mg) in 0.1 M K2HPO4
(buffered at pH ) 7) (70 mL) at room temperature was added a solution of
sodium azide (133 mg, 2.05 mmol) in 0.1 M K2HPO4 (25 mL) followed by
a solution of the epoxide 1a (500 mg, 3.73 mmol) in DMSO (5 mL) and
the mixture stirred overnight. The reaction mixture was diluted with EtOAc
and water, and the layers were separated by centrifugation. The organic
layer was dried over Na2SO4. The solvent was removed under reduced
pressure and the crude mixture purified by column chromatography on silica
gel using hexane/EtOAc (gradient: 0-100% EtOAc) to provide 300 mg
(45%) of (R)-2a. [R]D ) -27.50 (c 1.04, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.52-7.47 (m, 2H), 7.45-7.38 (m, 2H), 7.37-7.31 (m, 1H),
3.65 (d, J ) 12.1 Hz, 1H), 3.49 (d, J ) 12.3 Hz, 1H), 2.33 (s, 1H), 1.64 (s,
3H). The enantiomeric excess was determined by SFC (Chiralcel-OJ, 2 mL/
min, 5-40% MeOH at 4%MeOH/min, tR (major) 6.64min, tR(minor) 6.37
min (98% ee). SFC (supercritical fluid chromatography) where mobile
phases are carbon dioxide and a polar modifier, methanol.
(19) (a) Sone, T.; Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2008, 130, 10078. (b) Matsumoto, K.; Kubo, T.; Katsuki, T.
Chem.sEur. J. 2009, 15, 6573.
(20) See the experimental details in the Supporting Information.
(21) For studies on catalytic asymmetric aziridination reactions, see: (a)
Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M.
J. Am. Chem. Soc. 1993, 115, 5328. (b) Li, Z.; Conser, K. R.; Jacobsen,
E. N. J. Am. Chem. Soc. 1993, 115, 5326. (c) Tanner, D.; Andersson, P. G.;
Harden, A.; Somfai, P. Tetrahedron Lett. 1994, 35, 4631. (d) Omura, K.;
Murakami, M.; Uchida, T.; Irie, R.; Katsuki, T. Chem. Lett. 2003, 32, 354.
(e) Liang, J.-L.; Yuan, S.-X.; Chan, P. W. C.; Che, C.-M. Tetrahedron Lett.
2003, 44, 5917. (f) Xu, J.; Ma, L.; Jiao, P. Chem. Commun. 2004, 1616.
(g) Fioravanti, S.; Mascia, M. G.; Pellacani, L.; Tardella, P. A. Tetrahedron
2004, 60, 8073. (h) Kwong, H.-L.; Liu, D.; Chan, K.-Y.; Lee, C.-S.; Huang,
K.-H.; Che, C.-M. Tetrahedron Lett. 2004, 45, 3965. (i) Redlich, M.;
Hossain, M. M. Tetrahedron Lett. 2004, 45, 8987. (j) Fruit, C.; Mu¨ller, P.
Tetrahedron: Asymmetry 2004, 15, 1019. (k) Ma, L.; Du, D.-M.; Xu, J. J.
Org. Chem. 2005, 70, 10155. (l) Murugan, E.; Siva, A. Synthesis 2005,
2022. (m) Ma, L.; Jiao, P.; Zhang, Q.; Xu, J. Tetrahedron: Asymmetry 2005,
16, 3718. (n) Kawabata, H.; Omura, K.; Katsuki, T. Tetrahedron Lett. 2006,
47, 1571. (o) Shen, Y.-M.; Zhao, M.-X.; Shi, Y. Angew. Chem., Int. Ed.
2006, 45, 8005. (p) Aziridines and Epoxides in Organic Synthesis; Yudin,
A. K., Eds.; WILEY-VCH Verlag: Weinheim, 2006. (q) Armstrong, A.;
Baxter, C. A.; Lamont, S. G.; Pape, A. R.; Wincewicz, R. Org. Lett. 2007,
9, 351. (r) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129,
7185. (s) Musio, B.; Clarkson, G. J.; Shipman, M.; Florio, S.; Luisi, R.
Org. Lett. 2009, 11, 325–328.
(16) Where R2 ) CF3, a major byproduct for this particular substrate
was hydolysis of the epoxide providing the corresponding diol.
(17) In ref 6b, 90% ee was observed for this substrate.
(18) (a) Mosher, C. W.; Acton, E. M.; Crews, O. P.; Goodman, L. J.
Org. Chem. 1967, 32, 1452. (b) Audier, H. E.; Dupin, J. F.; Jullien, J. Bull.
Soc. Chim. Fr. 1968, 3844. (c) Boaz, N. W. Tetrahedron: Asymmetry 1995,
6, 15. (d) Boruwa, J.; Borah, J. C.; Kalita, B.; Barva, N. C. Tetrahedron
Lett. 2004, 45, 7355. (e) Haak, R. M.; Tarabiono, C.; Janssen, D. B.;
Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. Org. Biomol. Chem. 2007,
5, 318. (f) Hopmann, K. H.; Himo, F. Biochemistry 2008, 47, 4973. (g)
Hopmann, K.; Himo, F. J. Chem. Theor. Comput. 2008, 4, 1129.
3774
Org. Lett., Vol. 12, No. 17, 2010