Ligand-Assisted Rate Acceleration in Transacylation by a Yttrium - Salen Complex. Demonstration of a Conceptually New Strategy for Metal-Catalyzed Kinetic Resolution of Alcohols

Article abstract of DOI:10.1021/ol025809q

(matrix presented) Yttrium-salen complexes effect transacylation between enolesters and chiral secondary alcohols, resulting in varying degrees of kinetic resolution. Even though the enantioselectivity remains modest (k_fast/k_slow up to 4.81), these results represent the first demonstration of a conceptually new metal-catalyzed acyl transfer process that results in kinetic resolution. On the basis of the solid-state structure of the catalyst, a novel associative mechanistic pathway is proposed for the reaction.

Full text of DOI:10.1021/ol025809q

ORGANIC
LETTERS
2
002
Vol. 4, No. 9
607-1610
Ligand-Assisted Rate Acceleration in
Transacylation by a Yttrium−Salen
Complex. Demonstration of a
Conceptually New Strategy for
Metal-Catalyzed Kinetic Resolution of
Alcohols
1
Mei-Huey Lin and T. V. RajanBabu*
Department of Chemistry, The Ohio State UniVersity, Columbus, Ohio 43210
rajanbabu.1@osu.edu
Received March 4, 2002
ABSTRACT
Yttrium-salen complexes effect transacylation between enolesters and chiral secondary alcohols, resulting in varying degrees of kinetic resolution.
Even though the enantioselectivity remains modest (kfast/kslow up to 4.81), these results represent the first demonstration of a conceptually new
metal-catalyzed acyl transfer process that results in kinetic resolution. On the basis of the solid-state structure of the catalyst, a novel associative
mechanistic pathway is proposed for the reaction.
In this Letter we report the synthesis, characterization, and
application of a class of yttrium complexes that catalyze
enantioselective acyl transfer reactions between enolesters
and secondary alcohols, resulting in kinetic resolution of the
rate of the acyl transfer process vis- a´ -vis the corresponding
Y-alkoxides, enabling this reaction to be carried out at
temperatures as low as -25 °C with 1 mol % of the catalyst.
As a prelude to the present studies, last year we reported
1
alcohols (Scheme 1) In several instances, these Y-salen
complexes have also been found to significantly enhance the
Scheme 1. Kinetic Resolution via Enantiospecific Acyl
Transfer
(1) For leading references for nonenzymatic kinetic resolution of alcohols,
see: (a) Sekar, G.; Nishiyama, H. J. Am. Chem. Soc. 2001, 123, 3603. (b)
Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813. (c) Sano, T.;
Imai, K.; Ohashi, K.; Oriyama, T. J. Chem. Lett. 1999, 265. (d) Yamada,
S.; Katsumata, H. J. Org. Chem. 1999, 64, 9365. (e) Jarvo, E. R.; Copeland,
G. T.; Papaioannou, N.; Bonitatebus, P. J., Jr.; Miller, S. J. J. Am. Chem.
Soc. 1999, 121, 11638. (f) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am.
Chem. Soc. 1997, 119, 1492. (g) Kawabata, T.; Nagato, M.; Takasu, K.;
Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169. Kinetic resolution of a diol:
Iwasaki, F.; Maki, T.; Nakashima, W.; Onomura, O.; Matsumura, Y. Org.
Lett. 1999, 1, 969. For a novel oxidative kinetic resolution, see: Ferreira,
E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725.
1
0.1021/ol025809q CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/28/2002

that primary and secondary alcohols react with enolesters at
room temperature in the presence of catalytic amounts
was concentrated to obtain the complexes, which were
directly used for transesterification reactions in a hydrocarbon
medium. Recrystallization from pentane of the resulting
i
i
6
(
0.05-1 mol %) of Y
5
(O Pr)13O or Y(thd)
2
( PrO) [thd )
2
,2,6,6-tetramethyl-3,5-heptanedionato] to give the corre-
product 1 (L
gave crystals suitable for X-ray analysis.
1 2 2 1 2
Y[N(SiMe H) ][THF]) from the ligand L -H
2
7
sponding esters in nearly quantitative yields (eq 1). On the
The salen complexes of yttrium are excellent catalysts for
the synthesis of esters via acyl transfer reactions from
isopropenyl acetate as shown in eq 3 and Table 1. Several
basis of the observation that a phenolic hydroxyl group is
not acylated under these reaction conditions, we reasoned
that salen-type ligands might be a rational first choice if we
were to develop an enantiospecific version of this reaction.
Accordingly, we prepared a variety of enantiopure salen and
related ligands and their corresponding monomeric Y-
complexes. Several of these complexes are efficient catalysts
for acyl transfer reactions, some effecting the reaction with
significant kinetic resolution when a racemic secondary
alcohol is the substrate. Even though the degree of asym-
metric induction remains modest, these results represent the
first demonstration of a conceptually new metal-catalyzed
process for the kinetic resolution of secondary alcohols. Our
initial studies that validate the concept are reported here.
Prototypical examples of the ligands used in this study
are shown in Figure 1.3,4 The corresponding yttrium com-
alcohols are converted into the corresponding acetates in
excellent yields with catalytic amounts (1-5 mol %) of the
Table 1. Y-Catalyzed Acyl Transfer Reactions (eq 3)
no.
conditions
mol % Y conv
1-Phenylethanol
1
2
3
4
5
6
11 mol % HN(dms)2, rt, 16 h
0
0
5
1
5
1
0
0
62
65
100
100
5 mol % L1-H2, rt, 22 h
i
1 mol % Y5(O Pr)13O, -3 °C, 5.5 h
1 mol % Y(L1)(N(dms)2(THF), -3 °C, 5.5 h
i
1 mol % Y(O Pr)13O + 5L1, -20 °C, 13 h
1 mol % Y(L1)(N(dms)2(THF), 22 °C, 1 h
1
-Indanol
i
7
8
9
1 mol % Y5(O Pr)13O, -27 °C, 12 h
5
1
1
38
77
95
1 mol % Y(L1)(N(dms)2(THF), -25 °C, 12 h
1 mol % Y(L1)(N(dms)2(THF), -22 °C, 4 h
R-Tetralol
1 mol % Y5(O Pr)13O, -22 °C, 24.5 h
1 mol % Y5(O Pr)13O + 5 L1, 22 °C, 0.5 h
i
1
1
1
0
1
2
5
1
1
35
97
51
i
1 mol % Y(L1)(N(dms)2(THF), 22 °C, 4 h
Y-salen complexes at or below room temperature (entries
, 6, 9, and 11). For the three alcohols shown in Table 1,
5
the Y-salen complexes are more efficient catalysts compared
to the commercially available yttrium isopropoxide,
i
Y
5
(O Pr)13O. Thus 1-phenylethanol is converted into the
(2) Lin, M.-H.; RajanBabu, T. V. Org. Lett. 2000, 2, 997. For an example
of a lanthanide-catalyzed transesterification, see: Okano, T.; Miyamoto,
K.; Kiji, J. Chem. Lett. 1995, 246.
(3) See Supporting Information for a more complete list of ligands, their
preparation and characterization, and experimental details of their utility in
various acyl transfer reactions.
Figure 1. Selected ligands for yttrium in acyl transfer.
(4) For a review of metal-salen complexes in asymmetric synthesis,
see: Canali, L.; Sherrington, D. C. Chem. Soc. ReV. 1999, 28, 85. For some
recent notable applications of these ligands, see (L1): (a) Jacobsen, E. N.;
Wu, M. H. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; p 649. Jacobsen,
E. N. Acc. Chem. Res. 2000, 33, 421. (b) Mascarenhas, C. M.; Miller, S.
P.; White, P. S.; Morken, J. P. Angew. Chem., Int. Ed. 2001, 40, 601. (L3):
(c) Balsells, J.; Walsh, P. J. J. Org. Chem. 2000, 65, 5005. (L4): (d) Spassky,
N.; Wisniewski, M.; Pluta, C.; Le Borgne, A. Macromol. Chem. Phys. 1996,
plexes were prepared by the extended silylamide route (eq
5
2
). A stoichiometric mixture of analytically pure ligand
+
Ligand: (L-H2)
Y[N(SiHMe ) ] ‚2THF 2HN(SiHMe2)28
2
2 3
-
1
97, 2627. (f) Evans, D. A. Janey, J. M.; Magomedov, N.; Tedrow, J. S.
Angew. Chem., Int. Ed. 2001, 40, 1884.
5) (a) Herrmann, W. A.; Anwander, R.; Munck, F. C.; Scherer, W.;
Dufaud, V.; Huber, N. W.; Artus, G. R. J. Z. Naturforsch., B: Chem. Sci.
994, 49, 1789. (b) Runte, O.; Priermeier, T.; Anwander, R. J. Chem. Soc.,
LY[N(SiHMe ) ][THF] (2)
2
2
(
1
2 2 2 3
(L-H ) and Y[N(SiMe H) ] ‚2THF was stirred at room
Chem. Commun. 1996, 1385. (c) Evans, W. J.; Fujimoto, C. H.; Ziller, J.
W. J. Chem. Soc., Chem. Commun. 1999, 311.
temperature in 1:1 hexane and THF (0.1 M) for 5 days and
1608
Org. Lett., Vol. 4, No. 9, 2002

corresponding acetate upon reaction with isopropenyl acetate
study of the solvent effect revealed that aromatic hydrocar-
bons such as toluene and benzene were optimum. Dichlo-
romethane was marginally useful, while solvents containing
i
in the presence of 1 mol % of the aggregate Y
mol % in Y) in 62% yield at -3 °C in 5.5 h (entry 3),
whereas the salen complex 1 (Y[L ][THF][N(SiHMe ])
5
(O Pr)13O (5
1
2
)
2
3
heteroatoms, (e.g, THF or CH CN) retarded the reaction,
effects the same conversion with 1 mol % Y (entry 4) during
even when they were used as cosolvents.
the same reaction time. A catalyst prepared by addition of
In initial scouting experiments various alcohols 2-6 were
i
stoichiometric amount of the ligand L
1
to Y
5
(O Pr)13
O
subjected to kinetic resolution using the [L
1 2 2
]Y[N(SiMe H) ]-
6
followed by removal of the volatile side products also
provides enough enhancement of the rate of acylation of the
alcohols to allow a quantitative reaction to be carried out at
[THF] as catalyst, and the results are shown in Table 2. As
-
20 °C (entry 5). The Y-salen complex is also a relatively
superior catalyst for the acylation of 1-indanol (entries 7 and
). Entries 10-12 document a similar effect on the acylation
(THF)-Catalyzed Kinetic Resolutiona
1 2
Table 2. Y(L )N(dms)
8
of R-tetralol. Control experiments show that in the absence
of Y, there is no reaction between an enolester and an alcohol
3
(entries 1 and 2).
2
In earlier investigations we had recognized the unique
entry alcohol Y (mol %)
°C
h
conv % eeb
kf/ks
ability of yttrium alkoxides to effect the transacylation
reaction. Since the Lewis acidity of the metal is likely to be
an important consideration in any mechanistic scenario (vide
infra), we also examined complexes of a number of other
1
2
3
4
5
2
3
4
5
6
1
2
1
1
2
-3
-10
-25 12
-3
5.6
8
65
39
76
61
42
23 (S) 1.50
14 (R) 1.78
91 (R) 4.81
36 (S) 2.18
13 (S) 1.60
7.5
9
metals including the well-known salen complexes L
Cl), L Cr(Cl), and L Al(OMe). None showed any activity
in the acyl transfer reactions. A scandium complex, L Sc-
N(SiMe H) ) (prepared from Sc[N(SiMe H) ‚THF and L
was found to be less active compared to the corresponding
Y complex. In sharp contrast to Y[(NSiMe H) ‚nTHF, the
corresponding scandium complex, Sc[N(SiMe H) ‚THF, is
not catalytically competent. A chloride-bridged Y-dimer,
1
Mn-
-10
(
1
4
a
For procedure, see text. b Percent ee (HPLC) of unconverted alcohol.
1
(
2
2
2
]
2 3
1
)
with other methods of kinetic resolutions based on the
2
2 3
]
1
acylation reaction, the kinetic selectivity as measured by
2
2 3
]
10
the s factor (kfast/kslow) varies considerably with the structure
of the alcohol, with 1-indanol providing the highest ee for
the unreacted alcohol (entry 3). A number of enol esters
derived from other ketones and aldehydes were tested in the
reaction. Even though we noticed considerable difference
in the reactivities of these enolesters, none gave selectivity
3,8
[
(L
1
)Y(µ-Cl)THF]
2
,
also showed no catalytic activity, even
in the presence of added silver salts such as AgOTf or AgOTf
9
and Ph
them bis(oxazoline) (BOX) and bisoxazolinylpyridine
PYBOX) complexes of Cu and Sn with various counter-
3
P. A carefully chosen set of Lewis acids, among
(
1
1
higher than isopropenyl acetate.
Next the effect of the structure of the salen ligand on the
kinetic resolution of 1-indanol (4) and 1-(1-naphthyl)ethanol
anions, were also examined as potential catalysts for the
transacylation reaction. None offered any advantages over
the yttrium complexes. In most instances, the reactions were
complicated by the formation of unwanted side products. A
(5) using 2-propenyl acetate as the acyl transfer agent was
examined; the results are shown in Table 3. As can be seen
(6) Typical Experimental Procedure for Transacylation. A mixture
of alcohol (1 mmol) and the Y-catalyst in toluene (1.5 mL) was cooled to
the indicated temperature under nitrogen, and the enol acetate (1.27 mmol)
was added. At the end of the prescribed time, the cold solution was poured
into water, and the products were extracted with ether. The ether solution
was washed with saturated NaCl and dried, and the products were isolated
by column chromatography. The ee’s of unreacted alcohols were determined
by chiral HPLC. See Supporting Information for details.
Table 3. Ligand Effects in Y-Catalyzed Kinetic Resolution
entry alcohol L (mol % Y) conditions/conv (%) % ee kf/ks
1
2
3
4
5
6
4
4
4
5
5
5
L1 (1)
L2 (1)
L3 (1)
L1 (1)
L2 (1.5)
L3 (1.5)
-25 °C, 12 h/77
-25 °C, 12 h/40
-12 °C, 18 h/80
-3 °C, 7.5 h/61
-3 °C, 9 h/69
91
26
85
36
61
15
4.81
2.83
3.50
2.18
2.97
2.54
(7) Crystallographic data (excluding structure factors) for the structure
of 1 have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication nos. CCDC-181773. Copies of the data
can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB12EZ, UK (fax: (+44) 1223-336-033; e-mail: deposit@
ccdc.cam.ac.uk. See Supporting Information for details.
-3 °C, 11 h/29
(8) For a related complex, see ref 5c.
(
9) For a leading reference, see: Evans, D. A.; Johnson, J. S. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer-Verlag: Berlin, 1999; p 1177.
from the Table, the two alcohols have widely different
reactivities, 1-indanol being more reactive. Indanol also
shows much better selectivity in the kinetic resolution under
these reaction conditions with L and L , whereas L gives
1 3 2
better selectivity in the acylation of 5. The sulfonamide
complex (entries 3 and 6) is less active.
(
(
10) Kagan, H. B.; Fiaud, J. C. Topics Stereochem. 1988, 18, 249.
11) The following ketones (with their s values shown in the bracket)
were tested the for acylation of 1-indanol: tert-butyl methyl ketone (1.33,
2 °C), 4-methylacetophenone (1.30, 22 °C), isobutyraladehyde (2.60, -3
C), cyclohexanone (1.67, -15 °C), (-)-menthone (1.5, -15 °C), and
camphor (1.00, -15 °C). Most remarkably, the enolacetate derived from
2
°
(
+)-menthone showed no reactivity at -15 °C (0% conversion!) under
conditions where the corresponding (-)-menthone enolacetate gave 59%
conversion. We saw the same behavior in the acylation of R-tetralol but
not in the acyclic alcohols. See Supporting Information for details.
While the mechanism of this remarkable reaction remains
to be elucidated, the solid-state structure of the catalyst,
Org. Lett., Vol. 4, No. 9, 2002
1609

-
which incorporates one anionic ligand [ N(SiHMe
2 2
) ] and
12
one neutral ligand (THF), suggests an attractive possibility.
Scheme 2. Possible Mechanism for the Acyl Transfer Process
Note that it has a distorted trigonal prismatic structure rather
than the familiar octahedral geometry seen in most transition
metal salen complexes. The large yttrium atom is placed 0.95
2 2
Å above the N O plane. Replacement of the two ligands
by an alkoxide (anionic) and an enol ester (neutral) could
lead to activation of both these reactants within the coordina-
tion sphere of yttrium.
nary kinetic studies suggest that the reaction is first order in
the catalyst. Further studies to elucidate the mechanism of
the reaction and expand its scope through the use of other
ligands are in progress.
In summary, the first example of a transition-metal-
catalyzed asymmetric acyl transfer reaction is reported. Mild
reaction conditions, high turnover frequency of the catalyst,
and prospects of ligand tuning to improve the kinetic
selectivity provide ample incentives for further research in
the area.
Acknowledgment. We acknowledge the financial as-
sistance by the Petroleum Research Fund (ACS) and U.S.
National Science Foundation (CHE 0079948). We thank Dr.
Judith C. Gallucci for the X-ray structure determination.
If the intermediate retains the distorted trigonal prismatic
structure of the starting complex, the two reacting partners
will be held closer in a “cis” orientation. An internal
nucleophilic attack by the alkoxide on the carbonyl group
could initiate a chain of events leading to the final products
Supporting Information Available: Experimental details
on the synthesis and utility of the complete set of ligands
showing conversions and enantiomeric excesses and crystal-
lographic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(Scheme 2). In accordance with such a mechanism, prelimi-
(12) The structure also reveals an unusual agostic interaction between
one of the Si atoms and Y, presumably brought about by the chiral backbone.
In a related salen complex prepared from 1,2-ethylenediamine, this
interaction is absent.5b These structural aspects will be addressed separately.
OL025809Q
1610
Org. Lett., Vol. 4, No. 9, 2002