Axial ligand effects: Utilization of chiral sulfoxide additives for the induction of asymmetry in (Salen)ruthenium(II) olefin cyclopropanation catalysts

Article abstract of DOI:10.1002/anie.200460887

An efficient and facile method is used to develop new (salen)ruthenium(II) catalysts for the asymmetric cyclopropanation of olefins, in which a chiral additive induces asymmetry in inexpensive and readily synthesized achiral (salen)ruthenium(II) catalysts

Full text of DOI:10.1002/anie.200460887

Angewandte
Chemie
Asymmetric Catalysis
can not necessarily be extended to all olefin substrates. For
some olefins, multiple catalysts containing different chiral
diamine backbones must be examined before optimal results
can be achieved. The synthesis of a series of chiral salen-based
catalysts with differing backbones is both expensive and time
consuming so an alternative approach is needed to expedite
the screening of new olefins and diazo compounds for the
cyclopropanation reaction.
Previous work in our group has demonstrated a significant
ligand-accelerated catalysis effect for certain substrates
through what is presumed to be axial ligand binding and
further activation of the ruthenium carbene cyclopropanation
intermediate (Scheme 2a).[6] We hypothesized that this could
be used to our advantage and an optically pure Lewis base
Axial Ligand Effects: Utilization of Chiral Sulf-
oxide Additives for the Induction of Asymmetry
in (Salen)ruthenium(ii) Olefin Cyclopropanation
Catalysts**
Jason A. Miller, Bradley A. Gross, Michael A. Zhuravel,
Wiechang Jin, and SonBinh T. Nguyen*
The enantioselective synthesis of compounds containing the
cyclopropyl fragment has recently received considerable
attention, largely because of the frequent occurrence of
cyclopropanes in natural products and their importance as
valuable synthetic intermediates.[1–3] Although many methods
have been developed, transition-metal-catalyzed asymmetric
cyclopropanation has emerged as one of the most efficient
routes for the formation of optically pure cyclopropanes.[1,4]
However, the syntheses of the necessary chiral catalysts for
this important transformation are often rather laborious. A
general and facile method for the asymmetric synthesis of a
cyclopropanation catalyst has yet to be developed.
Recently, we have focused on cultivating efficient meth-
ods for the development of asymmetric catalysts. We began by
improving on our previously reported (salen)ruthenium(ii)
asymmetric cyclopropanation system. This catalyst system has
been shown to be highly effective for the cyclopropanation of
olefins with the carbene precursor ethyl diazoacetate
(EDA).[5] However, although the use of chiral catalyst 1
(Scheme 1) has led to exceptional selectivity and high yields
for the cyclopropanation of olefins with EDA, these results
Scheme 2. a) Ligand-accelerated catalysis in olefin cyclopropanation
catalyzed by a (salen)ruthenium(ii) complex. b) A chiral Lewis base L*
ligated axially to an achiral (salen)ruthenium–carbene cyclopropana-
tion intermediate could induce asymmetry.
could be used to bind axially to an achiral catalyst as an
alternative to using the preformed chiral (salen)ruthenium(ii)
catalyst 1. The Lewis base, if paired correctly with the catalyst
(both electronically and sterically), should force an achiral
salen ligand into an asymmetric conformation, thus trans-
ferring enantioselectivity to the cyclopropanation reaction
occurring on the opposite axial face of the catalyst. This
approach would allow the use of the inexpensive and readily
synthesized achiral catalysts 2–5 and the facile screening of a
nearly endless library of chiral Lewis bases L* that can
function as ligands to the metal carbene intermediate
(Scheme 2b). Related strategies were previously employed
by Katsuki and co-workers with varying degrees of success for
the (salen)manganese(iii)-catalyzed asymmetric epoxidation
of olefins through the application of chiral amines[7,8] and
chiral pyridine N-oxides.[9] Walsh and co-workers also
reported considerable enhancement in selectivity when
chiral additives were used to convey asymmetry into an
achiral titanium precatalyst for the addition of an ethyl
nucleophile to aldehydes.[10–12] A recent review by Walsh et al.
touched on the potential application of this novel and exciting
approach to catalyst screening.[13]
Scheme 1. Asymmetric 1 and achiral (salen)ruthenium(ii) cyclopropa-
nation catalysts 2–5. Py=pyridine.
[*] Dr. J. A. Miller, B. A. Gross, Dr. M. A. Zhuravel, Dr. W. Jin,
Prof. S. T. Nguyen
Department of Chemistry
Northwestern University
2145 Sheridan Road, Evanston, IL 60208-3113 (USA)
Fax: (+1)847-491-7713
E-mail: stn@northwestern.edu
[**] This work was supported by the National Institute of Health and the
DuPont Company. J.A.M. is an ACS Division of Organic Chemistry
Nelson J. Leonard Fellow sponsored by Organic Synthesis, Inc., and
S.T.N. is an Alfred P. Sloan Research Fellow. We also thank the
Packard Foundation for partial financial support and Prof. M. J.
Hynes for his help with the WinEQNMR program. Salen=N,N’-
bis(salicylidene)ethylenediamine.
Herein, we describe the first example of an asymmetric
cyclopropanation mediated by a combination of achiral
(salen)ruthenium(ii) catalysts 2–5 and a catalytic amount of
chiral sulfoxide additives (6–12; Scheme 3). Sulfoxides were
chosen as a test class of chiral Lewis bases because they have
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460887
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solution (10 mol% relative to EDA), ee values of up to 57%
were noted. These results suggested to us that (R)-(+)-methyl
p-tolyl sulfoxide (R)-7 was the best chiral additive for the
cyclopropanation of styrene. This was somewhat surprising in
light of the small size of the methyl substituent on (R)-7
relative to the larger menthol substituents on additive 6. The
use of additives with amino ((S)-8), ethyl ((R)-9), and benzyl
((R)-10) substituents on the p-tolyl sulfoxide was also
investigated to probe for the optimal steric environment;
however, none of these compounds proved as successful as
(R)-7. (S)-Methyl 2-naphthyl sulfoxide ((S)-11) was used to
determine the effect of adding steric bulk to the other side of
the sulfoxide. Surprisingly, this also yielded lower enantiose-
lectivities than (R)-7. Additive (R)-7 was, however, expected
to produce higher enantioselectivities than the cyclic com-
pound (S)-12, in which the cone angle of the chiral center is
considerably smaller.
As we previously reported, the olefin cyclopropanation
product can be readily separated from a reaction mixture
containing solvent, catalyst, and excess olefin.[17] This same
isolation strategy can also be applied in the current case when
a chiral Lewis base is also present in solution. As a
representative example, the optically enriched styrene cyclo-
propanation product produced in the presence of additive
(R)-7 could be isolated in excellent yield (94%). Further
details on the isolation procedure can be found in the
Experimental Section.
Scheme 3. Sulfoxide Lewis bases used as chiral additives for the cyclo-
propanation of olefins with achiral (salen)ruthenium(ii) complexes.
been recently used as ligands in asymmetric catalysis.[14,15]
Sulfoxide ruthenium(ii) complexes are well known[12,16] and
chiral sulfoxides have centers of asymmetry that are very
close to the ruthenium center during coordination and should
have a high probability of transmitting chirality to a flexible
salen ligand.
We screened several chiral sulfoxides (6–12) individually
as catalytic additives for the cyclopropanation of styrene with
EDA catalyzed by the achiral catalyst 3 [Eq. (1); Table 1]. In
Table 1: The cyclopropanation of styrene and EDA with 3 and chiral
sulfoxides 6–9.[a]
Additive (R)-7 was then subjected to a range of reaction
conditions and catalysts to optimize the enantioselectivity for
the cyclopropanation of styrene (Table 2). The enantioselec-
tivity of the reaction increased to nearly 70% with respect to
the cis isomer when 50 mol% of (R)-7 was used with 3
(Table 2, entry 5). The same increase was noted when the
solvent amount was decreased and the amount of sulfoxide
added was maintained at 10 mol% (Table 2, entries 6 and 7).
Decreasing the temperature of the reaction also positively
affected the ee value of the products; when the reaction
temperature was lowered to À788C and the additive concen-
tration increased, the cis and trans products were obtained in
93 and 87% ee, respectively (Table 2, entry 9). These promis-
ing results are amongst the highest ee values reported for
asymmetric induction resulting from the action of a chiral
additive on an achiral catalyst.
L*
Yield [%][b]
cis/trans
cis ee [%][c]
trans ee [%][c]
none
(S)-6
(R)-6
(S)-7
(R)-7
(S)-8
(R)-9
(R)-10
(S)-11
(S)-12
92
86
87
84
86
85
96
90
90
87
1:7.5
1:7.3
1:7.2
1:7.5
1:7.6
1:7.2
1:7.4
1:7.3
1:7.3
1:7.4
–
–
5 (S,S)
5 (R,R)
42 (S,S)
46 (R,R)
10 (R,R)
29 (R,R)
45 (R,R)
45 (S,S)
16 (R,R)
23 (S,R)
23 (R,S)
50 (S,R)
57 (R,S)
40 (R,S)
51 (R,S)
56 (R,S)
41 (S,R)
33 (R,S)
[a] Reaction conditions: EDA (0.5 mmol), styrene (2.5 mmol),
3
(1 mol%), L* (10 mol%), CH2Cl2 (5 mL), RT, 12 h. [b] Yield determined
by GC analysis based on EDA with undecane as an internal standard.
[c] Absolute configuration determined from chiral GC analysis versus
known standards.
Table 2: Optimization of reaction conditions for the cyclopropanation of styrene and EDA with sulfoxide
(R)-7.[a]
general, the addition of these chiral
additives does not affect either the
yield or diastereoselectivity of the
reaction. Furthermore, reversing
the chirality of the sulfoxide (that
is, (S)-6 versus (R)-6 and (S)-7
versus (R)-7) leads to opposite
enantioselectivities, thus lending
support to the supposition that
the chirality of the product is a
direct result of the Lewis base
additive.
Entry Cat. (R)-7 [mol%] CH2Cl2 [mL] T [8C] Yield [%][b] cis/trans cis ee [%][c] trans ee [%][d]
1
2
3
4
5
6
7
8
9
2
3
4
5
3
3
3
3
3
10
10
10
10
50
10
10
10
10
5.0
5.0
5.0
5.0
5.0
3.5
2.5
2.5
0.0[e]
25
25
25
25
25
25
25
0
87
86
90
89
88
88
85
90
1:7.6
1:7.6
1:5.7
1:7.8
1:7.3
1:7.0
1:6.9
1:7.4
1:6.7
41
57
27
0
67
65
72
85
93
19
46
13
0
57
57
64
81
87
À78[f] 92
[a] Reaction conditions: EDA (0.5 mmol), styrene (2.5 mmol), cat. (1 mol%), 12 h. [b] Yield determined
by GC analysis based on EDA with undecane as an internal standard. [c] R,S configuration in all cases.
[d] R,R configuration in all cases. [e] Reaction was carried out in neat styrene. [f] Original temperature
followed by slow warming to RT over 6 h.
These preliminary results were
quite promising. Even with a very
low concentration of additive in
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We propose that the mechanism of asymmetric induction
for Equation (1) involves the axial coordination of the chiral
sulfoxide to the ruthenium center as a key induction step in
the reaction stereoselectivity (Scheme 4). Initial reaction of
the product cyclopropanes compared to when 3, which loses
both PPh3 moieties at the beginning of the catalytic cycle, was
employed (see entries 1 and 2). This effect is most likely
because of competition between the pyridine and the additive
for the axial position of the catalyst.
Pyridine binds strongly to the rutheniu-
m(ii) center,[5] so coordination of the
chiral additive is hindered. Titration
data suggest that this is indeed the case,
as addition of increasing amounts of
pyridine to a mixture of (R)-7 and 3
leads to linearly decreasing enantiomeric
excess.
Control experiments with either a
chiral sulfoxide/EDA system or pre-
formed sulfoxide ylides,[19] both with
and without the (salen)ruthenium(ii) cat-
alyst 3, confirm that the metal center is
necessary for catalytic activity and that
the reaction does not occur through a
pathway that requires the formation of a
sulfoxide ylide. These results are consis-
Scheme 4. Proposed mechanism of asymmetric induction through a chiral additive.
EDA with the axial triphenylphosphane ligands of 3–5 causes
the rapid formation of phosphorus ylides, which do not bind
significantly to the metal center.[18] This leaves the axial
positions of the catalyst open to coordination by the chiral
sulfoxide. The chiral additive can then bind preferentially to
one of the two chiral conformers of the achiral (salen)ruthe-
nium complex,[7–9] thus effectively forcing the larger achiral
salen ligand to adopt a preferred chiral conformation. There-
fore, the asymmetry of the additive is transmitted/amplified to
the opposite axial position where a ruthenium carbene can
interact stereoselectively with an olefin to complete the
cyclopropanation cycle. Balsells and Walsh termed this
phenomenon chiral environment amplification.[12] The cata-
lytic formation of cyclopropanes through this induced chiral
environment, especially when coupled with ligand-acceler-
ated catalysis (Scheme 2a), would afford an excess of one
enantiomer, as expected from our work with preformed chiral
(salen)ruthenium(ii) complexes.[5] Catalyst 5, with the rigid
phenylene diamine backbone, yielded no enantioselectivity
when chiral sulfoxide (R)-7 was used as an additive (entry 4),
which is consistent with our proposed mechanism.
tent with our proposed mechanism and fully support the idea
of chiral induction by an axial ligand.
Further support for our proposed mechanism was
obtained by examining the binding mode of the sulfoxide to
A by NMR spectroscopy.[20] The changes in the chemical shift
of the resonances for the a-methyl protons in 7 when it was
alone in solution and when it was in solution with the carbene
complex A were compared (d = 2.07 versus d = 2.14 ppm,
respectively), thus indicating that 7 binds through the
sulfoxide oxygen atom. This small change in chemical shift
(< 0.1 ppm) is diagnostic of the oxygen-atom binding mode;
binding through the sulfur atom produces a much larger
change (> 1 ppm).[15] Furthermore, analysis of the carbene
proton of the (salen)ruthenium carbene cyclopropanation
intermediate allowed us to calculate the binding constant for
the formation of the bound complex 13 [Eq. (2); salen tBu
Catalyst 4, which contains the propylenediamine back-
bone, yields the same sense of chiral induction as the
ethylenediamine analogue 3 in the presence of (R)-7
(Table 2, entries 3 and 2), as could be predicted from the
proposed mechanism in Scheme 4. It is also reassuring that
the cis/trans ratio is very close to that when the reaction is
carried out in the absence of a chiral additive (1:6.2).
The addition of either (R)-7 or (S)-7 to the cyclopropa-
nation reaction of styrene with EDA using the chiral
preformed catalyst 1 (R,R or S,S) results in no increase or
decrease in the enantiomeric excess of the cyclopropane
product compared to use of the chiral catalyst alone. These
match/mismatch experiments suggest that the backbone of a
chiral catalyst overrides the chirality of an additive and,
therefore, plays a larger role in asymmetric induction.
groups omitted for clarity]. Figure 1 shows that increasing
concentrations of sulfoxide in solution leads to a downfield
shift of the carbene proton. These data were used to calculate
a binding constant of Keq = 129 Æ 6mÀ1 using WinEQNMR
software.[21]
Although binding at the ruthenium center to the oxygen
atom of the sulfoxide group is inferred by our spectroscopic
observations (see above), it is possible that a Curtin–
Hammett situation may occur in which the oxygen-bound
complex is not necessarily the active species responsible for
the excellent cyclopropanation enantioselectivities. That is,
The use of (R)-7 and catalyst 2, which contains pyridine
axial ligands, together with led to lower optical enrichment of
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chiral additives. These exciting results prove that styrene is
not a unique case and that this method is, in fact, applicable to
other olefins. Interestingly, although additive (R)-7 induces
the greatest enantioselectivities for styrene and its para-
substituted derivatives, it is not the best chiral Lewis base for
all other substrates: methyl methacrylate gave the best results
when (R)-benzyl p-tolyl sulfoxide (R)-10 was utilized,
whereas (a-methyl)styrene required the use of (R)-6.
Table 3 shows representative results for these two substrates
with some of the optimally performing sulfoxides. These
results show that a combinatorial approach can be used to
simultaneously screen the substrate and chiral additives for
optimum selectivity and reaction conditions. As with styrene,
the cyclopropanation products of the substrates listed in
Table 3 can be readily isolated in yields closely matching
those calculated by GC-calibration techniques.
In conclusion, we have found an efficient and facile
method for the development of new (salen)ruthenium(ii)
catalysts for the asymmetric cyclopropanation of olefins. This
exciting modular approach is amenable to parallel-screening
optimization and has great potential advantages over tradi-
tional catalyst development and synthetic methods. We feel
that this approach may also be extended to other types of
catalysis where one metal coordination site is free during a
reaction. The initial selectivities with this achiral catalyst/
chiral Lewis base system are very promising and provide a
solid proof-of-concept that chirality can be
Figure 1. Changes in the chemical shift of the ruthenium carbene
proton on addition of sulfoxide 7.
the sulfur-bound carbene complex could be present in a
minute quantity that cannot be observed by NMR spectros-
copy but is primarily responsible for the asymmetric induc-
tion. Further mechanistic experiments are in progress to help
elucidate this possibility and the results will be published at a
later date.
We have also extended this sulfoxide-induced chiral
amplification strategy to the cyclopropanation of other olefins
(Table 3). Quite promising enantioselectivities were observed
for these substrates despite having a limited library of chiral
sulfoxides, such as 6–12. As observed with styrene, diaster-
eoselectivities remained similar both with and without the
introduced into a complex cyclopropana-
Table 3: Optimized results for the cyclopropanation of various olefins with EDA by using chiral
sulfoxides to induce asymmetry into achiral catalyst 3.[a]
tion system through the addition of a simple
optically active additive. Screening experi-
ments with other classes of chiral additives
is underway and optimization data will be
reported in due course.
Substrate
Product
Additive
Yield [%][b]
cis/trans
cis ee
trans ee
(R)-6
(R)-7
(R)-10
86
1:45.7
1:40.2
1:45.8
–
–
–
47
68
80
98
98 (84[c])
(R)-6
(R)-7
(R)-10
97 (89[c])
97
97
1:1.1
1:1.4
1:1.3
43
10
0
53
3
0
Experimental Section
General procedure for the asymmetric cyclopro-
panation of olefins with EDA using (salen)ruthe-
nium(ii) complexes 1–5 and chiral sulfoxide addi-
tives 6–12:[22] A mixture of achiral ruthenium
catalyst (0.005 mmol), olefin (2.5 mmol), and
sulfoxide (0.05 mmol for 10 mol% and
0.25 mmol for 50 mol%) in CH2Cl2 (2.5 mL)
(R)-7
(R)-7
(R)-7
(R)-7
97 (97[c])
95 (88[c])
86 (92[c])
98 (98[c])
1:5.9
1:4.8
1:5.8
1:7.8
89
93
80
79
87
87
83
86
was placed in
a 25-mL round-bottom flask
under N2 in a drybox. A three-times degassed
CH2Cl2 (2.5 mL) solution of EDA (0.50 mmol)
and undecane internal standard (0.50 mmol) was
slowly added by a gas-tight syringe over a period
of 20 min under N2. After the addition was
complete, the reaction mixture was allowed to
stir for 12 h at room temperature. A sample of the
solution was then passed through a short plug of
silica gel (0.3 ꢀ 3 cm) to remove the catalyst and
the plug was washed with CH2Cl2 (15 mL). The
combined organic solutions were analyzed by
using standard-phase GC for diasteroselectivity
and either chiral-phase GC or HPLC for enan-
tioselectivity.
[a] Reaction conditions: EDA (0.5 mmol), olefin (2.5 mmol), 3 (1 mol%), additive (10 mol%), 12 h.
[b] Yield determined by GC analsis relative to styrene cyclopropane based on EDA with undecane as an
internal standard. [c] Yield of isolated cyclopropane (see the Supporting Information for details).
Received: June 7, 2004
Revised: February 9, 2005
Published online: May 18, 2005
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Keywords: cyclopropanation · ligand-accelerated catalysis ·
.
ruthenium · salen · sulfoxides
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[22] Detailed procedures for the catalytic screening, product isola-
tion, pyridine addition, and control experiments as well as details
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synthesis of sulfoxides 9–11, and GC and HPLC analytical
methods are available in the Supporting Information.
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