A practical oligomeric [(salen)Co] catalyst for asymmetric epoxide ring-opening reactions

Article abstract of DOI:10.1002/1521-3773(20020415)41:8<1374::AID-ANIE1374>3.0.CO;2-8

Prepared by a high yield, chromatography-free route, "oligosalen" exists as a mixture of dimer, trimer, and tetramer (see picture). Derived catalyst systems display remarkable activity and selectivity in the asymmetric ring-opening of epoxides, with turnover numbers exceeding 100000 in some cases.

Full text of DOI:10.1002/1521-3773(20020415)41:8<1374::AID-ANIE1374>3.0.CO;2-8

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1H NMR (400 MHz, trace TFA/CDCl
À2.37(1H, br s), À1.16 (2H, br s), 1.65 (6H, t, J ˆ 7Hz), 3.14 (6H, s), 3.72
, monocation): d ˆ À3.68 (1H, br s),
3
A Practical Oligomeric [(salen)Co] Catalyst for
Asymmetric Epoxide Ring-Opening
Reactions**
(
9
4H, br q), 7.51 ± 7.55 (2H, br m), 8.25 (5H, br m), 8.87 (2H, s), 9.44 (2H, s),
.75 (2H, br d, J ˆ 7.5 Hz); H NMR (400 MHz, TFA/CDCl
1
3
, dication): d ˆ
À0.90 (2H, br s), 1.49 (1H, s), 1.58 (6H, t, J ˆ 7.4 Hz), 3.04 (6H, s), 3.59
Joseph M. Ready and Eric N. Jacobsen*
(
(
1
1
1
4H, br q), 4.33 (2H, br s), 8.40 (2H, m), 8.51 (3H, m), 9.26 (2H, m), 9.42
1
3
2H, s), 9.73 (2H, m), 9.79 (2H, s); C NMR (100 MHz, TFA/CDCl
3
): d ˆ
), 106.84, 118.18, 124.40, 127.49,
31.56, 134.01, 134.49, 139.48, 140.27, 140.67, 144.46, 146.71, 151.92, 152.02,
0.60, 16.10, 19.69, 35.82 (internal CH
2
The development of catalysts that are not only enantiose-
lective and high yielding but also useful from a practical
standpoint persists as a challenging goal in asymmetric
synthesis. In the ideal case, a catalyst should be readily
available or easily synthesized on any scale and should display
both high reactivity (turnover frequency) and durability
52.04, 154.99; HRMS (FAB): calculated for C37
H
32
N
2
‡ H: m/z 505.2642;
1
found: 505.2644; elemental analysis (%) calcd for C37
6.51, H 6.47, N 5.45; found: C 86.26, H 6.24, N 5.66.
H
32
N
2
¥ ³
2
H
2
O: C
8
Received: January 8, 2002 [Z18495]
(
turnover number). In this context, substantial progress has
been made over the past several years in the discovery of
chiral salen-metal-based catalysts (H salen ˆ bis(salicylid-
2
[
[
1] D. T. Richter, T. D. Lash, Tetrahedron 2001, 57, 3659.
2] a) T. D. Lash, Chem. Eur. J. 1996, 2, 1197; b) T. D. Lash, J. Porphyrins
Phthalocyanines 1997, 1, 29.
3] T. D. Lash, Synlett 2000, 279.
4] T. D. Lash in The Porphyrin Handbook, Vol. 2 (Eds.: K. M. Kadish,
K. M. Smith, R. Guilard, Academic Press, San Diego, 2000, pp. 125 ±
ene)ethylenediamine) for the asymmetric ring-opening of
epoxides, and attention has focused recently on the develop-
ment of these catalysts from a practical perspective.[ We
describe herein a significant advance in this regard, with the
development of easily synthesized and highly active oligo-
meric [(salen)Co] catalysts for the asymmetric hydrolysis of
meso-epoxides and kinetic resolution of terminal epoxides.
We reported recently the preparation of mixtures of cyclic
oligomeric [(salen)Co] complexes (1), which were designed to
enforce the cooperative bimetallic mechanism common to
many epoxide ring-opening reactions.[ Catalyst system 1
displayed substantial improvements in reactivity and enan-
tioselectivity relative to monomeric analogues, with kinetic
behavior consistent with cooperative reactivity within the
1]
[
[
1
99; L. Latos-Grazynski in The Porphyrin Handbook, Vol. 2 (Eds.:
K. M. Kadish, K. M. Smith, R. Guilard, Academic Press, San Diego,
000, pp. 361 ± 416.
2
[
[
[
[
[
5] T. D. Lash, Angew. Chem. 1995, 107, 2703; Angew. Chem. Int. Ed.
Engl. 1995, 34, 2533.
6] J. L. Sessler, M. R. Johnson, V. Lynch, J. Org. Chem. 1987, 52,
4
394.
7] T. D. Lash, S. T. Chaney, D. T. Richter, J. Org. Chem. 1998, 63,
076.
2]
9
8] T. D. Lash, M. J. Hayes, Angew. Chem. 1997, 109, 868; Angew. Chem.
Int. Ed. Engl. 1997, 36, 840.
9] T. D. Lash, S. T. Chaney, Angew. Chem. 1997, 109, 867; Angew. Chem.
Int. Ed. Engl. 1997, 36, 839.
[
10] a) T. D. Lash, S. T. Chaney, Chem. Eur. J. 1996, 2, 944;
b) T. D. Lash, S. T. Chaney, Tetrahedron Lett. 1996, 37, 8825;
c) M. J. Hayes, T. D. Lash, Chem. Eur. J. 1998, 4, 508; d) T. D.
Lash, D. T. Richter, J. Am. Chem. Soc. 1998, 120, 9965;
e) T. D. Lash, D. T. Richter, C. M. Shiner, J. Org. Chem.
R
R
O
O
O
1
999, 64, 7973.
O
[
[
[
11] T. D. Lash, J. L. Romanic, M. J. Hayes, J. D. Spence, Chem.
Commun. 1999, 819.
12] H. Furuta, H. Maeda, A. Osuka, J. Am. Chem. Soc. 2000,
tBu
tBu
tBu
tBu
1
22, 803.
O
O
N
N
N
N
O
O
13] T. D. Lash, Chem. Commun. 1998, 1683.
M
M
N
O
N
O
M
R
R
tBu
tBu
O
O
5
: R = tBu
O
O
6: R = OC(O) tBu
7: R = OC(O)CH(Cl)CH3
: R = OC(O)C(Cl)2CH3
R
R
8
n
1
: M = Co(OTs), R = Cl, n =1 - 5
a: M = Co(OTs)
b: M = Co(csa)
2
3
4
: M = Co, R = H, n = 1 - 3
: M = Co(csa), R = H, n = 1 - 3
: M = Co(nbs), R = H, n = 1 - 3
[
*] Prof. E. N. Jacobsen, J. M. Ready
Department of Chemistry and Chemical Biology
Harvard University
Cambridge, MA 02138 (USA)
Fax : (‡1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[
**] This work was supported by the NIH (GM 43214). H
licylidene)ethylenediamine.
2
salen ˆ bis(sa-
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
1374
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Angew. Chem. Int. Ed. 2002, 41, No. 8

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cyclic framework. In addition, the local C symmetry in the
individual salen units allowed oligomerization to be effected
simply by condensation of dialdehyde and 1,2-diamine in a
Table 1. Asymmetric hydrolysis of cyclohexene oxide catalyzed by [(salen)-
Co] complexes.[
2
a]
OH
[
(salen)Co] catalyst
CH3CN/CH2Cl2
1
:1 molar ratio. However, problems tied to the structure and
O
+
H2O
synthesis of 1 detract from the utility of this catalyst system.
Specifically, installation of the chlorine substituents in the a
and a' positions of the linker units requires harsh conditions
and proceeds in only moderate yield, with the requisite
purification limiting mass throughput. Once installed, the
chlorine substituents activate the adjacent carbonyl groups
and render the oligomer sensitive to decomposition under the
conditions of epoxide ring-opening. Finally, a statistical
mixture of diastereomeric linker units was generated and
introduced into the oligomer; the synthesis of 1 could there-
by produce in excess of 1000 discrete compounds consider-
ing all possible diastereomers of the observed ring sizes.[
This presents an obvious barrier to understanding how the
cyclic oligomeric salen framework imparts both high reac-
tivity and enantioselectivity in epoxide ring-opening reac-
tions.
OH
Catalyst[b]
[mol%]
Yield[c]
[%]
ee [d]
[%]
Entry
1
2
3
4
5
6
7
8
t
[h]
1 (1.5)
1 (1.5)
3 (1.5)
3 (0.5)
4 (1.5)
4 (0.5)
6b (1.5)
6b (0.5)
3
11
4
12
4
12
36
96
95
98
9793
90
91
92
72
16
86
94
[e]
93
93
93
71
51
[
a] Reactions carrired out with [epoxide]
room temperature unless indicated otherwise. See Supporting Information
for details. [b] mol% Co relative to epoxide. [c] Yield of isolated product.
0
ˆ 2.5m in 1:1 CH
3 2 2
CN/CH Cl at
3]
[
d] Determined by chiral GC analysis. [e] Reaction carried out at 48C.
The issues outlined above are all tied to the presence of the
chlorine substituents in the linker unit of 1 and would be
circumvented if a simpler pimelate-linked system derived
from 2 were employed instead.[ The impetus for introducing
the chlorine substituents in the first place arose from an
empirical screen of monomeric model systems. This study
revealed that electronic tuning of carboxylate-substituted
ligands as in 6 ± 8 was impor-
Catalysts 3 and 4 were prepared on large scale under
chromatography-free conditions from inexpensive compo-
nents (Scheme 2).[ Coupling of phenol 9 with pimelic acid
in the presence of 1,3-diisopropylcarbodiimide (DIC) and a
catalytic amount of dimethylaminopyridine (DMAP) provid-
ed 10 in 99% purity following extraction and filtration. The
free base of (R,R)-1,2-diaminocyclohexane was generated in
situ from the commercially available tartrate salt and
condensed with dialdehyde 10 in quantitative yield. Metal
insertion followed by air oxidation in the presence of one
equivalent of a sulfonic acid derivative provided the oligo-
meric catalysts 3 and 4.[ Mass spectral and NMR data
indicated the exclusive formation of cyclic oligomers contain-
ing 2 ± 4 metal ± salen units.
8]
[2]
4]
tant to achieve reactivity com-
parable to that observed with
5
, the benchmark salen cata-
N
O
N
O
9]
Co
Y
lyst for asymmetric ring-open-
ing reactions. However, there
is an alternative site for elec-
tronic tuning on the [(salen)-
Co] catalysts: the ancillary
ligand(s) that do not partici-
pate directly in catalysis
X
X
tBu
tBu
Complexes 3 and 4 were found to display remarkable
activity in the hydrolytic kinetic resolution (HKR) of terminal
epoxides. Styrene oxide and styrenediol were obtained in high
yield and enantiomeric excess after 2.5 h using 0.08 mol% Co
[Eq. (1)]. In contrast, under otherwise identical conditions,
24 h were required to obtain epoxide in 99% ee using 1. The
results with propylene oxide highlight the practical aspects of
reactions using 4: 1.5 mol epoxide were resolved in 24 h at
238C using only 5 mg catalyst to provide 39 g recovered
epoxide in >99% ee and 59 g diol in 97% ee [Eq. (2)].
While complexes 3 and 4 displayed similar activity in the
HKR, complex 4 proved superior for the kinetic resolution of
terminal epoxides with alcohols and phenols. As demonstrat-
ed by the data in Equations (3) ± (5), monoprotected 1,2-diols
and 1-aryloxy alcohols were synthesized regioselectively in
high yield and optical purity. It is noteworthy that the results
in Equation (3) were obtained with an eightfold decrease in
catalyst loading and a fourfold decrease in reaction time
relative to the results obtained previously with 1.[
Scheme 1. Sites for electronic
tuning of the [(salen)Co] cata-
lysts. X: ligand tuning; Y: coun-
terion tuning.
(
Scheme 1). Only recently
has it become apparent that this might be a viable option
for optimization of salen-based catalysts for epoxide ring-
opening.[ Clearly, it suggests a more straightforward strategy
for tuning the electronic environment of the metal center in
the oligomeric complexes.
5]
II
Pimelate-linked oligomeric [(salen)Co ] complex (2) was
prepared and oxidized with air in the presence of a variety of
Br˘nsted acids (HX) to provide the corresponding [(salen)-
III
Co (X)] oligomers. These complexes were evaluated for
their ability to catalyze the asymmetric hydrolysis of cyclo-
hexene oxide. Whereas oxidation with air/p-toluenesulfonic
acid led to a catalyst that was less effective than 1, catalysts
generated by oxidation with camphorsulfonic acid (3, CSA ˆ
2]
10-camphorsulfonate) and 3-nitrobenzenesulfonic acid (4,
NBS ˆ 3-nitrobenzenesulfonate) displayed comparable reac-
Catalyst 1 exists as a complicated mixture of diastereoisom-
ers and ring sizes,[ whereas 3 and 4 were synthesized as
mixtures of only three compounds (dimer, trimer, and
tetramer). It was anticipated that this simplification would
aid our efforts to understand the differences in enantioselec-
tivity between oligomeric and monomeric [(salen)Co] com-
2]
tivity and slightly improved selectivity relative to 1 (Table 1,
entries 1 versus 3 and 5).[
6, 7]
Longer reaction times and
decreased reaction temperature were required to obtain
highly enantioenriched diol product using catalyst 1 (Table 1,
entry 2).
Angew. Chem. Int. Ed. 2002, 41, No. 8
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reactive than either 3a or 3c. As expect-
ed, the activity and selectivity of the
mixture reflects an average of the mix-
ture×s components. Whereas 3b is clearly
the superior catalyst, it is nonetheless
remarkable that all three components of
3
provide substantially higher enantio-
meric excesses than the monomeric ana-
logue 6b (Table 1, entries 7and 8).
In reactions catalyzed by monomeric
metal ± salen complexes, decreases in
product ee were observed when catalyst
loading was decreased (Table 1, entries 7
and 8). These observations are consistent
with a competition between a second-
order, bimetallic pathway and a less
selective monometallic pathway.[
11]
In
contrast, the enantioselectivity displayed
by 3 and 4 was independent of catalyst
loading (Table 1, entries 3 and 4, entries 5
and 6) indicating that a highly selective
intramolecular, cooperative process dom-
inates over a range of oligomer concen-
trations.[ Even under optimal condi-
12]
tions, however, monomeric catalysts dis-
play lower enantioselectivity than 3 or 4.
Scheme 2. Chromatography-free synthesis of 3 and 4.
The intervention of a monometallic path-
way therefore does not account solely for the
observed enhancement in selectivity.
A second factor that may be responsible for
the improved enantioselectivity displayed by 3
and 4 involves the range of reactive conforma-
tions available to oligomeric versus monomeric
complexes. Incorporation of salen units into a
cyclic framework may enforce conformations
in which the salen units are in the appropriate
relative orientation for optimal stereochemical
communication. The chirality of both the nucleophile and
electrophile components plays an important role in defining
the asymmetric environment in the reaction, as indicated by
the fact that nonlinear effects have been observed in both the
HKR[ and the [(salen)Cr]-catalyzed addition
13]
[14]
of HN to meso-epoxides. We propose that
3
the structures of 3 and 4 enforce a selective
head-to-tail arrangement of the reacting
salen units (Figure 2).[15] The subtle differences
in selectivity observed between 3a ± 3c likely
reflect differences in available reactive con-
formations. The data suggest that the trimer
combines sufficient rigidity to minimize non-
selective pathways while maintaining enough
flexibility to access the optimal transition
state.
plexes. The discrete components of the catalyst mixture were
Catalysts 3 and 4 appear to hold significant promise from
both a fundamental and a practical perspective. The sterically
diverse range of reacting partners accommodated by these
catalysts within the confines of a rigidified cyclic architecture
is, to the best of our knowledge, unprecedented in asymmetric
catalysis. As a result of the ease of their synthesis, we hope
prepared independently following the strategy shown in
Scheme 3.[
9, 10]
Catalysts 3a ± c were evaluated in the asym-
metric hydrolysis of cyclohexene oxide to determine the effect
of ring size on reactivity and selectivity. As revealed by the
data in Figure 1, the trimer 3b is more enantioselective and
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1433-7851/02/4108-1376 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 8

COMMUNICATIONS
Springer, New York, 1999,
pp. 1309 ± 1326; b) E. N. Jacobsen,
Acc. Chem. Res. 2000, 33, 421 ± 431.
[
2] J. M. Ready, E. N. Jacobsen, J. Am.
Chem. Soc. 2001, 123, 2687± 2688.
3] Calculated by using the formula
[
i
S3 (i ˆ 2 ± 6), where i corresponds
to the different oligomers present.
There are three stereoisomers of
each linker unit (d, l, and meso).
4] We have also evaluated both short-
er (e.g. adipate) and longer (e.g.
subarate) linkers. In general, pi-
melate-based oligosalen systems
have proven more reactive and
stereoselective.
[
[
5] Recent studies on the hydrolytic
kinetic resolution (HKR) of termi-
nal epoxides catalyzed by mono-
Scheme 3. Synthesis of cyclic oligomeric [(salen)Co] complexes 3a ± c.
2
meric [(salen)Co(O CR)] com-
plexes have demonstrated a critical role for the carboxylate counter-
ion with respect both to catalyst reactivity and stability (J. Hong, D. G.
Blackmond, E. N. Jacobsen, work in progress). These results suggest
that the carboxylate is in fact retained within the coordination sphere
of at least some portion of the catalytically active complex.
[
[
6] Interestingly, the CSA analogue of 1 displayed similar reactivity but
diminished selectivity compared to 3.
7] A slight cooperative effect is observed between the stereochemistry of
the salen unit and that of the camphorsulfonate derivative, with the
1
S-10-camphorsulfonate proving slightly more effective than its
enantiomer in association with the catalyst derived from (R,R)-
diaminocyclohexane. For example, in the hydrolysis of cyclohexene
oxide at room temperature, complex 3 bearing mismatched CSA
afforded diol in 92% ee (versus 93% ee with matched CSA) and 2%
lower conversion after 24 h.
[
[
8] Complex 3 has been prepared in our laboratories on a 16 g scale.
9] See Supporting Information for experimental details and character-
ization of new compounds.
Figure 1. Asymmetric hydrolysis of cyclohexene oxide catalyzed by
oligomeric [(salen)Co] complexes. Reactions were carried out with
[
10] Attempted synthesis of the macrocycle prior to metal insertion
provided a mixture of ring sizes, suggesting that under the conditions
of Scheme 2 the formation of 11 is reversible.
11] The relative rates of a monometallic pathway (umono) versus a
bimetallic pathway (ubi) catalyzed by monomeric complexes are
[
epoxide]
0
ˆ 2.5m and 2.5 mol% Co catalyst ([Co]total ˆ 0.0625m) in 1:1
CH CN/CH
3
2
Cl at 238C. Conversion determined by GC analysis relative to
2
an internal standard.
[
inversely proportional to catalyst concentrations ([cat]) according to
2
tBu
u
mono/ubi ˆ (kmono[cat])/(kbi[cat] ) ˆ (kmono)/(kbi[cat]).
N
[
12] The relative rates of a monometallic pathway (umono) versus a
bimetallic pathway (ubi) catalyzed by 3 and 4 would be independent
of catalyst concentration ([cat]) according to umono/ubi ˆ (kmono[cat])/
N M
O
O
tBu
tBu
O
O
M
N
N
tBu
(
k
bi[cat]) ˆ (kmono)/(kbi). For preliminary kinetic analysis of reactions
R
R
Nu
Nu
of 1, see ref. [2].
[
13] a) D. W. Johnson, Jr., D. A. Singleton, J. Am. Chem. Soc. 1999, 121,
O
O
M
O
9
307± 9312; b) D. G. Blackmond, J. Am. Chem. Soc. 2001, 123, 545 ±
553.
[14] K. B. Hansen, J. L. Leighton, E. N. Jacobsen, J. Am. Chem. Soc. 1996,
18, 10924 ± 10925.
15] R. G. Konsler, J. Karl, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120,
0780 ± 10781.
O
tBu
tBu
O
N
O
M
N
N
N
1
[
"
Head-to-Tail"
"Head-to-Head"
low selectivity
1
high selectivty
Figure 2. Limiting geometries for the transition state in epoxide ring-
opening reaction catalyzed by [(salen)Co] complexes. Some substituents on
the aromatic rings are omitted for clarity.
that these oligomeric catalysts will be of immediate utility to
the organic chemistry community.
Received: August 30, 2001
Revised: January 31, 2002 [Z17821]
[
1] For reviews, see: E. N. Jacobsen, M. H. Wu in Comprehensive
AsymmetricCatalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Angew. Chem. Int. Ed. 2002, 41, No. 8
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4108-1377 $ 20.00+.50/0
1377