Dynamic Kinetic Resolution of Secondary Alcohols
SCHEME 1
tion that proceeds through transfer-hydrogenation reac-
tions.18 Without adding ketones as hydrogen mediators,
the racemization can proceed, but the yield of DKR
decreases significantly due to the formation of ketones
through the dehydrogenation of alcohols.14l The use of 1
with alkenyl acetates as acyl donors also decreases the
yield of DKR. Ba¨ckvall et al. solved this problem by using
p-chlorophenyl acetate as the acyl donor.14l Unreacted
p-chlorophenyl acetate, however, frequently makes the
separation of the DKR product difficult in the purification
step. The indenyl ruthenium complex 2 and the η6-arene
ruthenium complexes 3 do not catalyze the dehydroge-
nation of alcohols to produce molecular hydrogen in
significant amount;14h,j only catalytic amounts of ketones
are produced. However, 2 and 3 need weak bases as
additives.
To develop new processes to circumvent the formation
of ketones as side products in the DKR with 1, we used,
instead of racemic alcohols, ketones and enol acetates as
substrates with hydrogen donors under the conditions for
the DKR with 1.19 Ketones were hydrogenated with 2,6-
dimethylheptan-4-ol or molecular hydrogen and then the
resulting alcohols successfully transformed into chiral
esters. Meanwhile, enol acetates acted as acyl donors and
as the precursors of ketones; thus, the separation problem
caused by p-chlorophenyl acetate was solved.
complexes has increased the potential of DKR.13 Enzy-
matic acylation or hydrolysis has been successfully
combined with the metal-catalyzed racemization for the
DKR of alcohols,14 allylic acetates,15 and amines.16 In the
first example of the metal-enzyme combinations for DKR
of alcohols, Williams et al. used a rhodium complex to
transform racemic 1-phenylethanol into (R)-1-phenyl-
ethyl acetate in a moderate yield.14n Subsequently, Ba¨ck-
vall et al. reported the use of a diruthenium complex
(1),14l which greatly increased the yield and the optical
purity of the product (Scheme 1). Soon after, we found
that other ruthenium complexes,14h,j 2 and 3, are also
effective in the DKR of secondary alcohols.
Although the DKR with metal-enzyme combinations
has shown attractive potentials for asymmetric synthesis,
it is desirable to develop racemization catalysts that are
active at the temperature low enough for the DKR with
thermally labile enzymes.20 Recently in a preliminary
communication,21 we have reported the synthesis of a
new ruthenium complex (4) and its catalytic activity in
the racemization of secondary alcohols at room temper-
ature. The catalytic activity is compatible with isopro-
penyl acetate and the enzymatic acylation of alcohols to
make possible the room-temperature DKR of secondary
alcohols. Herein, we present a full account of this work,
including the synthesis of the derivatives of 4, the scope
of our catalyst system, and mechanistic studies for the
catalytic racemization.
The racemization catalysts have pros and cons. The
complex 1 is commercially available and easy to handle.17
However, it needs hydrogen mediators for the racemiza-
(8) (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. J pn.
1995, 68, 36. (b) Kitamura, M.; Tokunaga, M.; Noyori, R. J . Am. Chem.
Soc. 1993, 115, 144. (c) Kitamura, M.; Tokunaga, M.; Noyori, R.
Tetrahedron 1993, 49, 1853.
(9) (a) Kawashima, M.; Hirata, R. Bull. Chem. Soc. J pn. 1993, 66,
2002. (b) Paquette, L. A.; Wang, T. J . Am. Chem. Soc. 1988, 110, 8192.
(10) (a) Dijksman, A.; Elzinga, J . M.; Li, Y.-X.; Arends, I. W. C. E.;
Sheldon, R. A. Tetrahedron: Asymmetry 2002, 13, 879. (b) Koh, J . H.;
J ung, H. M.; Kim, M.-J .; Park, J . Tetrahedron Lett. 1998, 39, 5545. (c)
Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397.
(11) Li, R.; Powers, V. M.; Kozarica, J . W.; Kenyon, G. L. J . Org.
Chem. 1995, 60, 3347.
(12) (a) Cuiper, A. D.; Kouwijzer, M. L. C. E.; Grootenhuis, P. D. J .;
Kellog, R. M.; Feringa, B. L. J . Org. Chem. 1999, 64, 9529. (b) Van
der Heuve, M.; Cuiper, A. D.; Van der Deen, H.; Kellog, R. M.; Feringa,
B. L. Tetrahedron Lett. 1997, 38, 1655.
(13) Reviews: (a) Pa`mies, O.; Ba¨ckvall, J .-E. Chem. Rev. 2003, 103,
3247. (b) Kim, M.-J .; Ahn, Y.; Park, J . Curr. Opin. Biotechnol. 2002,
13, 578. (c) Panke, S.; Wubbolts, M. Curr. Opin. Biotechnol. 2002, 13,
111. (d) Huerta, F. F.; Minidis, A. B. E.; Ba¨ckvall, J .-E. Chem. Soc.
Rev. 2001, 30, 321. (e) Azerad, R.; Buisson, D. Curr. Opin. Biotechnol.
2000, 11, 565. (f) Gihani, M. T. E.; Williams, J . M. T. Curr. Opin. Chem.
Biol. 1999, 3, 11. (g) Strauss, U. T.; Felter, U.; Faber, K. Tetrahedron:
Asymmetry 1999, 10, 107.
(14) (a) Kim, M.-J .; Choi, M. Y.; Han, M. Y.; Choi, Y. K.; Lee, J . K.;
Park, J . J . Org. Chem. 2002, 67, 9481. (b) Runmo, A.-B. L.; Pa`mies,
O.; Faber, K.; Ba¨ckvall, J .-E. Tetrahedron Lett. 2002, 43, 2983. (c)
Pa`mies, O.; Ba¨ckvall, J .-E. J . Org. Chem. 2002, 67, 1261. (d) Kim, M.-
J .; Choi, Y. K.; Choi, M. Y.; Park, J . J . Org. Chem. 2001, 66, 4736. (e)
Pa`mies, O.; Ba¨ckvall, J .-E. J . Org. Chem. 2001, 66, 4022. (f) Pa`mies,
O.; Ba¨ckvall, J .-E. Adv. Synth. Catal. 2001, 343, 726. (g) Huerta, F.
F.; Ba¨ckvall, J .-E. Org. Lett. 2001, 3, 1209. (h) Lee, D.; Huh, E. A.;
Kim, M.-J .; J ung, H. M.; Koh, J . H.; Park, J . Org. Lett. 2000, 2, 2377.
(i) Huerta, F. F.; Santosh Laxmi, Y. R.; Ba¨ckvall, J .-E. Org. Lett. 2000,
2, 1037. (j) Koh, J . H.; J ung, H. M.; Kim, M.-J .; Park, J . Tetrahedron
Lett. 1999, 40, 6281. (k) Person, B. A.; Huerta, F. F.; Ba¨ckvall, J .-E. J .
Org. Chem. 1999, 64, 5237. (l) Persson, B. A.; Larsson, A. L. E.; Ray,
M.-L.; Ba¨ckvall, J .-E. J . Am. Chem. Soc. 1999, 121, 1645. (m) Larsson,
A. L. E.; Persson, B. A.; Ba¨ckvall, J .-E. Angew. Chem., Int. Ed. Engl.
1997, 36, 1211. (n) Dinh, P. M.; Howarth, J . A.; Hudnott, A. R.;
Williams, J . M. J . Tetrahedron Lett. 1996, 37, 7623.
(17) (a) Schneider, B.; Goldberg, I.; Reshef, D.; Stein, Z.; Shvo, Y. J .
Organomet. Chem. 1999, 588, 92. (b) Shvo, Y.; Goldberg, I.; Czerkie,
D.; Reshet, D.; Stein, Z. Organometallics 1997, 16, 133. (c) Menashe,
N.; Salant, E.; Shvo, Y. J . Organomet. Chem. 1996, 514, 97. (d)
Menashe, N.; Shvo, Y. Organometallics 1991, 10, 3885. (e) Mays, M.
J .; Morris, M. J .; Raithby, P. R.; Shvo, Y. Organometallics 1989, 8,
1162. (f) Abed, M.; Goldberg, I.; Stein, Z.; Shvo, Y. Organometallics
1988, 7, 2055. (g) Shvo, Y.; Czarkie, D.; Rahamin, Y. J . Am. Chem.
Soc. 1986, 108, 7400. (h) Blum, Y.; Czarkie, D.; Rahamin, Y.; Shvo, Y.
Organometallics 1985, 4, 1459.
(18) (a) Almeida, M. L. S.; Beller, M.; Wang, G.-Z.; Ba¨ckvall, J .-E.
Chem. Eur. J . 1996, 2, 1533. (b) Almeida, M. L. S.; Kocˇovsky´, P.;
Ba¨ckvall, J .-E. J . Org. Chem. 1996, 61, 6587. (c) Wang, G.-Z.;
Andreasson, U.; Ba¨ckvall, J .-E. J . Chem. Soc., Chem. Commun. 1994,
1037. (d) Ba¨ckvall, J .-E.; Andreasson, U. Tetrahedron Lett. 1993, 34,
5459. (e) Wang, G.-Z.; Ba¨ckvall, J .-E. J . Chem. Soc., Chem. Commun.
1992, 337. (f) Chowdhury, R. L.; Ba¨ckvall, J .-E. J . Chem. Soc., Chem.
Commun. 1991, 1063.
(19) (a) J ung, H. M.; Koh, J . H.; Kim, M.-J .; Park, J .Org. Lett. 2000,
2, 2487. (b) J ung, H. M.; Koh, J . H.; Kim, M.-J .; Park, J . Org. Lett.
2000, 2, 409.
(20) Usually, the complex 1 is heated over 60 °C to provide a
reasonable activity. The high activity of 4 at room temperature has
been applied to the DKR of secondary alcohols with subtilisin, which
is a thermally labile lipase, to produce (S)-acetates: Kim, M-.J .; Chung,
Y.; Choi, Y. K.; Lee, H. K.; Kim, D.; Park, J . J . Am. Chem. Soc. 2003,
125, 11494.
(15) (a) Choi, Y. K.; Suh, J . H.; Lee, D.; Lim, I. T.; J ung, J . Y.; Kim,
M.-J . J . Org. Chem. 1999, 64, 8423. (b) Allen, J . V.; Williams, J . M. J .
Tetrahedron Lett. 1996, 37, 1859.
(21) Choi, J . H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.-J .;
Park, J . Angew. Chem., Int. Ed. 2002, 41, 2373.
(16) Reetz, M. T.; Schimossek, K. Chimia 1996, 50, 668.
J . Org. Chem, Vol. 69, No. 6, 2004 1973