A green chemistry approach to a more efficient asymmetric catalyst: Solvent-free and highly concentrated alkyl additions to ketones

Article abstract of DOI:10.1021/ja052200m

There is a great demand for development of catalyst systems that are not only efficient and highly enantioselective but are also environmentally benign. Herein we report investigations into the catalytic asymmetric addition of alkyl and functionalized alk

Full text of DOI:10.1021/ja052200m

Published on Web 11/04/2005
A Green Chemistry Approach to a More Efficient Asymmetric
Catalyst: Solvent-Free and Highly Concentrated Alkyl
Additions to Ketones
Sang-Jin Jeon, Hongmei Li, and Patrick J. Walsh*
Contribution from the Department of Chemistry, P. Roy and Diana T. Vagelos Laboratories,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received April 6, 2005; E-mail: pwalsh@sas.upenn.edu
Abstract: There is a great demand for development of catalyst systems that are not only efficient and
highly enantioselective but are also environmentally benign. Herein we report investigations into the catalytic
asymmetric addition of alkyl and functionalized alkyl groups to ketones under highly concentrated and
solvent-free conditions. In comparison with standard reaction conditions employing toluene and hexanes,
the solvent-free and highly concentrated conditions permit reduction in catalyst loading by a factor of 2- to
40-fold. These new conditions are general and applicable to a variety of ketones and dialkylzinc reagents
to provide diverse tertiary alcohols with high enantioselectivities. Using cyclic conjugated enones, we have
performed a tandem asymmetric addition/diastereoselective epoxidation using the solvent-free addition
conditions followed by introduction of a 5.5 M decane solution of tert-butyl hydroperoxide (TBHP) to generate
epoxy alcohols. This one-pot procedure allows access to syn epoxy alcohols with three contiguous
stereocenters with excellent enantio- and diastereoselectivities and high yields. Both the solvent-free
asymmetric additions and asymmetric addition/diastereoselective epoxidation reactions have been conducted
on larger scale (5 g substrate) with 0.5 mol % catalyst loadings. In these procedures, enantioselectivities
equal to or better than 92% were obtained with isolated yields of 90%. The solvent-free and highly
concentrated conditions are a significant improvement over previous solvent-based protocols. Further, this
chemistry represents a rare example of a catalytic asymmetric reaction that is highly enantioselective under
more environmentally friendly solvent-free conditions.
Introduction
the “greenness” of a reaction, such as its E factor and the volume
productivity, are now considered. The E factor9 is defined as
In an era when synthetic chemists have demonstrated that
even the most complex natural products can be prepared,1-3
the focus of organic synthesis is shifting to the development of
truly practical methods for their construction.4-6 One of the
challenges facing chemists this century, therefore, is to develop
new transformations that are not only efficient, selective, and
high yielding but that are also environmentally benign.7,8
Historically, the most common measure for success of reactions
has been the product yield. While reaction yields will always
be important, alternative measures of success with respect to
the ratio of weight waste to weight product, while the volume
productivity10 is defined as the grams product per liter of
reaction medium. The E factor for many pharmaceuticals has
been estimated to exceed 100.11 The largest contribution to the
magnitude of E factors comes from organic solvents, many of
which are ecologically harmful and require costly remediation.
In industry, solvents are recycled whenever possible; however,
recycling is rarely accomplished with complete efficiency.
One approach to reducing the environmental impact of a
reaction is to conduct them under solvent-free conditions.11-14
Advantages of solvent-free reactions include cost savings,
reduced energy consumption, decreased reaction times, and a
considerable reduction in reactor size and, therefore, capital
investment. These attributes have inspired a substantial research
effort directed toward the development of solvent-free reac-
tions.11-14
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Despite recent progress in solvent-free polymerizations,12,15
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J. AM. CHEM. SOC. 2005, 127, 16416-16425
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A More Efficient Asymmetric Catalyst
A R T I C L E S
photochemical reactions,13 there have been a limited number
of catalytic enantioselective solvent-free reactions,17-34 exclud-
ing those that employ a large excess of one reagent.35-37 Of
these few solvent-free processes, some have not yet been shown
to exhibit substrate generality24,27,29,31,33,34 while others are
plagued with enantioselectivities that are either low26,28,31,32,38
or generally below the useful range (g90% ee).23 Examples of
highly enantioselective catalysts that exhibit good substrate
generality under solvent-free conditions include Jacobsen’s
kinetic resolution of racemic epoxides, desymmetrization of
meso epoxides,18,20-22 and hetero-Diels-Alder reaction,39 Ding’s
hetero-Diels-Alder25 and carbonyl-ene40 reactions, and the
Hoveyda/Schrock enantioselective ring-closing metathesis route
to cyclic amines.30
The scarcity of highly enantioselective solvent-free reactions
is not surprising. In solution, catalyst enantioselectivity and
efficiency can be highly sensitive to the nature of the solvent.41
For example, instances where a catalyst can generate opposite
enantiomers of the product with high levels of enantioselectivity
in different solvents are known.42 Further, asymmetric catalysts
can exhibit concentration dependent enantioselectivities. Thus,
in solvent-free reactions, two of the most important variables
for catalyst optimization, solvent type and concentration, are
not available. Further complicating development of solvent-free
reactions is that the reaction medium changes significantly as
reagents and substrates are converted to products. We believe
that these limitations have dissuaded many investigators from
considering solvent-free catalytic asymmetric reactions. Al-
though the challenges of solvent-free asymmetric catalysis are
significant, the potential environmental and economical benefits
have created high demand for such processes. With these
considerations in mind, we decided to evaluate our enantiose-
lective catalysts for asymmetric C-C bond formation under
solvent-free conditions.
We recently reported a practical and highly enantioselective
catalyst for the addition of alkyl groups to ketones (eq 1).43-45
Unlike the addition of alkyl groups to aldehydes, a reaction that
can be catalyzed by a wide variety of highly enantioselective
catalysts,46,47 to date only our catalyst exhibits high enantiose-
lectivity and efficiency for alkyl additions to ketones. This
catalyst will also promote the asymmetric addition of phenyl,48-50
vinyl,51,52 and dienyl52 groups to ketones with high enantiose-
lectivities. The enantioenriched tertiary alcohols generated in
these reactions are useful chiral building blocks and have been
used in natural product synthesis.53,54
(15) Komiya, K., Fukuoka, S., Aminaka, M., Hasegawa, K., Hachiya, H.,
Okamoto, H., Watanabe, T., Yoneda, H., Fukawa, J., Dozono, T. In Green
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Chem. Soc. 1995, 117, 5897-5898.
As outlined in eq 1, the asymmetric addition of alkyl groups
to ketones using a solvent mixture of toluene and hexanes
required 2-10 mol % of the chiral bis(sulfonamide) diol ligand
1 to achieve the highest levels of enantioselectivity. While 2
mol % ligand loading is low for early transition-metal catalysts,
many substrates required 10 mol % 1 to maintain high
enantioselectivities and reasonable reaction times. We hypoth-
esized that reducing the amount of solvent employed in the
asymmetric addition would have several benefits. First, the
corresponding increase in the concentration of the catalyst and
reagents could result in greater catalyst turnover frequency,
possibly allowing a reduction in catalyst loadings. Second,
decreasing the quantity of solvent would make scale-up more
attractive by cutting waste generation and reducing costs. Given
that titanium tetraisopropoxide and most dialkylzinc reagents
are liquids at room temperature, we were optimistic that the
asymmetric addition would proceed under solvent-free condi-
tions. We were not able to predict, however, how this dramatic
(18) Tokunaga, M.; Larrow, J. F.; Kakuichi, F.; Jacobsen, E. N. Science 1997,
277, 936-938.
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10970-10971.
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A R T I C L E S
Jeon et al.
Table 1. Diethylzinc Additions to 3′-Methylacetophenone under
Solvent-Free and Highly Concentrated Reaction Conditions
a high degree of ligand acceleration over the uncatalyzed
background reaction of diethylzinc with ketone substrates.55
Table 2 shows the scope and limitations in solvent-free and
concentrated diethylzinc additions to ketones (eq 2). Like 3′-
methylacetophenone, acetophenone and 3′-trifluoromethylaceto-
phenone underwent addition with high enantioselectivities and
yields with 0.5 mol % catalyst loading. Using our standard
conditions, ethyl addition to 4′-methoxyacetophenone required
111 h at 10 mol % catalyst loading. Under the solvent-free
conditions, the reaction was significantly faster, reaching
completion in 12 h at 1 mol % catalyst loading. Unfortunately,
both the yield and ee of the tertiary alcohol decreased to 50%
and 81%, respectively (Table 2, entry 3). By conducting the
addition with 2 equiv of toluene, the enantioselectivity increased
to 89%. In this case, the methoxy group may be causing a
significant change in the polarity of the reaction medium or
possibly coordinating to titanium or zinc species. 2′-Acetonaph-
thone gave high enantioselectivities (98%) with solvent-free and
highly concentrated conditions (Table 2, entry 4). Valerophenone
exhibited a decrease in reaction times from over 4 days at 2
mol % 1 under standard conditions to 1 day at 1 mol % 1 under
solvent-free and highly concentrated conditions. The enanti-
oselectivity dropped, however, to 80% (Table 2, entry 5). These
initial results highlight an important difference between our
standard conditions and highly concentrated and solvent-free
conditions: in the latter cases, the enantioselectivities are more
sensitive to substrate structure.
entry
1 (mol %)
time (h)
yield (%)
ee (%)
1
2
3
4
5
1
1
0.5
0.25
0.1
4
7
20
21
24
79
78
80
62
58
99a
99b
98a
97a
96a
a Solvent-free conditions. b Two equiv of toluene were added to the
reaction.
change in reaction medium would impact the catalytic process
or the catalyst enantioselectivity.
In this report, we present our study of highly concentrated
and solvent-free asymmetric addition of alkyl and functionalized
groups to ketones to afford a variety of tertiary alcohols with
excellent ee’s. Importantly, under these conditions, catalyst
loadings can be reduced by up to 40-fold while maintaining
enantioselectivity over 90%. We also demonstrate that cyclic
enones can be converted to syn epoxy alcohols with three
contiguous stereocenters in a one-pot procedure employing the
solvent-free asymmetric alkyl addition followed by in-situ
epoxidation initiated upon adding tert-butyl hydroperoxide
(TBHP). The resulting epoxy alcohols can be isolated in >87%
yield, >95% ee, and as a single diastereomer, providing access
to complex chiral building blocks for enantioselective synthesis.
Finally, we have developed a protocol for the reaction workup
that uses a minimum amount of environmentally benign solvent.
One important class of substrates for these asymmetric
addition reactions is enones, because the addition products are
tertiary allylic alcohols that can be functionalized at the double
bond through hydroxyl directed reactions.56 As illustrated in
Table 2, enantioselectivities >90% were observed with a variety
of enones at 1 mol % catalyst loading with 2 equiv of toluene.
We were surprised to find that 2,4,4-trimethylcyclohexenone
gave only 36% yield of the addition product, with the remainder
of the material isolated as byproducts. This is in contrast to the
standard conditions, where the product was isolated with 76%
yield (Table 2, entry 8). The increased quantity of byproducts
under the highly concentrated reaction conditions appears to
be substrate dependent.
Certain substrates gave low yields under the standard condi-
tions and, therefore, were evaluated under the concentrated
conditions. Unfortunately, both R-tetralone and 2-benzylidene
cyclohexanone gave similar yields as compared to the standard
conditions, although the enantioselectivities remained very high
(Table 2, entries 9 and 10).
Results and Discussion
Diethylzinc Additions to Ketones Under Solvent-Free
Conditions. In our initial examination of highly concentrated
and solvent-free reactions, we employed diethylzinc in the
asymmetric addition to 3′-methylacetophenone (Table 1). Under
the conditions we originally reported for this addition using
toluene and hexane solvents, referred to herein as our “standard
conditions”, we employed 2 mol % catalyst, and the reaction
required 24 h providing 78% isolated yield of the tertiary alcohol
with 99% ee.44 We were pleased to find that the solvent-free
reactions exhibited a substantial decrease in reaction time. In
the absence of solvent, the same addition reaction was complete
in much less time (4 h) at lower catalyst loading (1 mol %)
with essentially the same enantioselectivity and yield (Table 1,
entry 1). Similar results were obtained under what we will refer
to as “highly concentrated conditions”, when 2 equiv of toluene
(relative to ketone) were added (Table 1, entry 2). In the case
of a 1 mmol reaction, this translates to 0.11 mL of toluene added.
Given these observations, we investigated the possibility of
further decreasing the catalyst loading to as low as 0.1 mol %.
In these cases, the addition product was obtained in slightly
lower yields and with a small decrease in enantioselectivity (up
to 3%). As anticipated, the reactions also required longer times
at the lower catalyst loadings (Table 1, entries 3-5). The results
in Table 1 indicate that low catalyst loadings can be successfully
employed, in part because the catalyst derived from 1 exhibits
We also investigated ketone substrates containing heteroaro-
matic groups in the asymmetric addition reaction. Thus, using
our standard conditions, thiophene derivatives generate corre-
sponding products with good to excellent enantioselectivities
and high yields (Table 2, entries 11-13). Under solvent-free
reaction conditions, similar yields and enantioselectivities could
(55) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1995, 34, 1059-1070.
(56) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-
1370.
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A More Efficient Asymmetric Catalyst
A R T I C L E S
Table 2. Diethylzinc Additions to Ketones under Solvent-Free, Highly Concentrated, and Standard Conditions
a Solvent-free conditions. b Two equiv of toluene were added to the reaction. c Reaction at -10 °C. d Two equiv of toluene were added and 0.6 equiv
Ti(OiPr)4 was used.
be obtained with reduction of catalyst loadings by up to 20-
fold. Higher enantioselectivity was realized at lower temperature
(-10 °C) under solvent-free conditions than standard conditions
in case of 2-acetylthiophene (Table 2, entry 11). Acetylferrocene
was an excellent substrate and underwent addition with 90%
enantioselectivity using standard conditions. Our initial attempt
with acetylferrocene under solvent-free conditions showed a
significant drop in enantioselectivity to 61%. By conducting
the addition with 2 equiv of toluene and 0.6 equiv of Ti(OiPr)4,
the enantioselectivity increased to 89% (entry 14). The ketone
substrates in entries 4, 6, 9, 12, and 14 of Table 2 are solids.
Solids did not present a problem in the asymmetric reactions.
No noticeable increase in viscosity was observed, and all
reactions were stirred with standard magnetic stir bars and
magnetic stir plates.
Solvent-Free Additions of Dimethylzinc to Ketones. The
solvent-free asymmetric addition of dimethylzinc to ketones was
explored for several reasons. First, it is well-known that
dimethylzinc adds to aldehydes around 20 times slower than
diethylzinc with amino alcohol-based catalysts.57 We wanted
to determine the difference in turnover frequency under solvent-
free conditions with our catalyst. Second, methyl groups are
the most common substituents in natural products. Finally, we
believed that dimethylzinc would be a superior reagent for
(57) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989,
111, 4028-4036.
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A R T I C L E S
Jeon et al.
Table 3. Dimethylzinc Additions under Solvent-Free and Standard Reaction Conditions
a 0.4 equiv Ti(OiPr)4 was used.
solvent-free reactions, because reduction byproducts occasion-
ally encountered with diethylzinc would not be observed with
dimethylzinc because of the absence of â-hydrogens. We were
pleased to find that excellent results were obtained in the solvent-
free dimethylzinc addition reactions (Table 3).
reaction with dimethylzinc reached completion in about twice
the time compared to the reaction with diethylzinc (Table 3,
entry 3 vs Table 2, entry 5).
Unlike diethylzinc addition to 2,4,4-trimethylcyclohexenone,
which generated mostly byproducts, dimethylzinc addition
proceeded smoothly in 75-83% yield with >95% enantiose-
lectivity. Other cyclic enones also proved to be excellent
substrates for the solvent-free dimethylzinc additions (Table 3,
entries 5-7). Of particular note are the results of addition to
2-pentyl-2-cyclopenten-1-one (entry 5) and the TBS protected
enone (entry 6). For these substrates, the catalyst loading could
be lowered 20-fold with similar or better enantioselectivity,
yield, and reaction time as compared to the standard conditions.
Additionally, although the yield of addition to the 2-benzylidene
cyclohexanone remained low in the solvent-free reactions, it
was double that of the standard solution phase reaction (Table
3, entry 8). Solid substrates also underwent asymmetric dim-
ethylzinc addition smoothly exhibiting high yields and enanti-
oselectivities under solvent-free condition (Table 3, entries 2,
7, and 8).
In the dimethylzinc addition reactions, 2 equiv of the
dimethylzinc and 1.2 equiv of Ti(OiPr)4 were generally em-
ployed. Propiophenone and 3′-chloropropiophenone gave excel-
lent yields (83-95%) and enantioselectivities (92-94%) using
1.0 or 0.5 mol % 1 (Table 3, entries 1 and 2). The enantiose-
lectivity in the methyl addition to propiophenone decreased to
80% at 0.25 mol % catalyst loading, however. We hypothesized
that the background reaction promoted by titanium tetraisopro-
poxide could be playing a role in the erosion of enantioselec-
tivity at 0.25 mol % catalyst. With this in mind, we employed
a substoichiometric amount of titanium tetraisopropoxide under
otherwise identical conditions. When the titanium tetraisopro-
poxide was reduced from 1.2 equiv to 0.4 equiv at 0.25 mol %
catalyst loading, the enantioselectivity was restored to 92%
(Table 3, entry 1).
Valerophenone provided an opportunity to directly compare
the rates of addition of diethyl- and dimethylzinc with our
catalyst in the absence of solvent. Under solvent-free conditions,
Addition of Functionalized Dialkylzinc Reagents To
Ketones Under Highly Concentrated Conditions. We recently
examined the addition of a series of functionalized dialkylzinc
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A More Efficient Asymmetric Catalyst
A R T I C L E S
Table 4. Comparison of Solvent-Free, Highly Concentrated, and Standard Reaction Conditions for the Asymmetric Addition of
Functionalized Organozinc Reagents to Ketones
a Solvent-free conditions. b 2 equiv toluene were added to the reaction. c 0.6 equiv Ti(OiPr)4 was used.
reagents to ketones to generate tertiary alcohols bearing
functional groups with high levels of enantioselectivity.45 In this
study, we found that under our standard conditions, 10 mol %
loading of ligand 1 resulted in high enantioselectivities but long
reaction times (48-120 h). With the goal of reducing the catalyst
loading and reaction times, we examined the addition of
functionalized diorganozinc reagents to ketones under solvent-
free and highly concentrated reaction conditions.
Using the method of Knochel for the preparation of func-
tionalized organozinc reagents,58-64 we initially employed a
dialkylzinc reagent bearing a TBS-protected alcohol in the
asymmetric addition to 3′-methylacetophenone under solvent-
free conditions. Although we were able to lower the catalyst
loadings to 1 mol % and were able to reduce the reaction times,
the enantioselectivities were 80% or less under the solvent-
free conditions, significantly below the 98% enantioselectiv-
ity recorded for the standard conditions at 10 mol % catalyst
(Table 4, entry 1). Addition of 2 equiv of toluene, however,
restored the enantioselectivity to 97%. Similarly, addition of
the bromoalkyl to this substrate exhibited higher yields and
enantioselectivity under highly concentrated conditions than
with the solvent-free conditions (Table 4, entry 2). Higher
enantioselectivities under the concentrated reaction condi-
tions relative to the solvent-free conditions were found to
be general for the additions of functionalized organozinc
reagents (Table 4, entries 1-3). Surprisingly, with 2′-aceto-
naphthone, the enantioselectivities with the functionalized
organozinc reagents were higher under the concentrated condi-
tions than under the standard conditions with both functionalized
organozinc reagents employed. In Table 4, entry 3, reduction
of the amount of titanium tetraisopropoxide from 1.2 to 0.6 equiv
at 0.25 mol % catalyst resulted in an increase in the enantiose-
lectivity from 76 to 90%. Additions to trans-4-phenyl-3-buten-
2-one at 1 mol % catalyst loading under concentrated conditions
exhibited similar enantioselectivities compared to the standard
conditions with significantly reduced reaction times (Table 4,
(58) Knochel, P.; Rosema, M. J.; Tucker, C. E.; Retherford, C.; Furlong, M.;
AchyuthaRou, S. Pure Appl. Chem. 1992, 64, 361-369.
(59) Knochel, P. Chemtracts: Org. Chem. 1995, 8, 205-221.
(60) Knochel, P.; Jones, P. Organozinc Reagents; Oxford University Press:
Oxford, U.K., 1999.
(61) Langer, F.; Waas, J.; Knochel, P. Tetrahedron Lett. 1993, 34, 5261-5264.
(62) Langer, F.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. Synlett 1994,
410-412.
(63) Lutz, C.; Knochel, P. J. Org. Chem. 1997, 62, 7895-7898.
(64) Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57, 1956-
1958.
9
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A R T I C L E S
Jeon et al.
Table 5. One-Pot Epoxidation of Cyclic Enones with TBHP
Scheme 1. One-Pot Asymmetric Addition/Diastereoselective
Epoxidation Reaction with Dioxygen
entries 5-7). In general, addition of 2 equiv toluene allows a
10-fold reduction in catalyst loading and reduced reaction times
while maintaining high enantioselectivities. At this time, the
origin of the beneficial effect of toluene is not understood. The
results in Table 4 lead us to hypothesize that the highly
concentrated nature of these reactions makes them particularly
sensitive to the small changes in the composition of the reaction
mixture.
Investigation of the Scalability of the Solvent-Free Asym-
metric Additions to Ketones. To test the scalability of our
solvent-free procedure for the enantioselective addition of alkyl
groups to ketones, the addition of dimethylzinc to propiophenone
was examined on larger scale. The reaction of 5 g propiophenone
was conducted with 0.5 mol % catalyst loading employing
(R,R)-1 under solvent-free conditions (eq 3). After 48 h at room
temperature, the reaction was diluted with ethyl acetate,
quenched with aqueous NH4Cl, extracted into ethyl acetate, and
purified on silica gel to provide 5 g (90% yield) of the addition
product with 92% ee. The ligand 1 was recovered in 84% yield.
These results highlight the potential scalability of this solvent-
free process.
Given our experience with these tandem reactions and the
fact that epoxy alcohols are very useful chiral building blocks
for enantioselective synthesis,66-69 we turned our attention to
development of a one-pot asymmetric addition/diastereoselective
epoxidation protocol employing our solvent-free reaction condi-
tions. We chose to employ the addition of dimethylzinc to
enones as outlined in Table 3 for the initial asymmetric step.
After conducting the addition under the solvent-free reaction
conditions, the reaction mixture was cooled to -10 °C, and
commercially available 5.5 M TBHP in decane was cautiously
added (Table 5). The reaction mixture was then allowed to warm
to room temperature, and the progress of the epoxidation was
followed by thin layer chromatography (TLC). After 4 h, the
reaction was complete, and the epoxy alcohols were isolated in
high yields (87-95%) after standard workup and purification
(Table 5). These yields are significantly higher than those
obtained under standard conditions.53 Inspired by these results,
we examined the one-pot asymmetric addition/diastereoselective
epoxidation on a larger scale.
Investigation of the Scalability of the Solvent-Free Asym-
metric Addition/Diastereoselective Epoxidation Reactions.
To examine the scalability of the solvent-free asymmetric
addition/diastereoselective epoxidation reaction, we tested the
addition of dimethylzinc to 2-pentyl-2-cyclopenten-1-one using
5 g of the enone, 2 equiv dimethylzinc, and 0.5 mol % ligand
1 as outlined in eq 4. Upon completion of the asymmetric
addition, the reaction was cooled to -10 °C, and 24 mL of 5.5
M TBHP (4 equiv) was carefully added. Once evolution of
methane ceased, the reaction was warmed to room temperature
and was stirred for 4 h. After quenching the reaction mixture,
extraction and purification by chromatography resulted in
isolation of the epoxy alcohol in 90% yield (5.45 g). Addition-
ally, the ligand 1 was recovered in 90% yield. The 90% yield
of the syn epoxy alcohol obtained in this large scale reaction
represents a significant improvement over the 67% yield
originally reported for the asymmetric addition/diastereoselective
epoxidation under standard conditions. Although we have not
One-Pot Asymmetric Addition/Diastereoselective Epoxi-
dation. We recently reported a one-pot procedure whereby the
asymmetric addition to enones could be followed by a directed
epoxidation to afford syn epoxy alcohols with three contiguous
stereocenters.53 In this chemistry, the asymmetric addition was
conducted under standard conditions, and the resulting tertiary
allylic alkoxide product was exposed to dioxygen to initiate the
directed epoxidation. As shown in Scheme 1, we propose that
the mechanism of this reaction involves insertion of dioxygen
into the Zn-C bond to generate a zinc peroxy species.
Transmetalation of the peroxide to the titanium allylic alkoxide
followed by oxygen atom transfer and workup affords the epoxy
alcohol product. In support of this proposal, we have also found
that TBHP can be substituted for dioxygen in the directed
epoxidation step.65 Presumably, the TBHP protonates the
dialkylzinc to generate a similar zinc peroxide. An advantage
of TBHP over dioxygen in the epoxidation is that it is easier to
control the rate of addition of the TBHP.
(65) Rowley Kelly, A.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005,
127, 14668-14674.
(66) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5776.
(67) Katsuki, T. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, pp 621-648.
(68) Katsuki, T.; Martin, V. S. Org. React. 1996, 1.
(69) Bonini, C.; Righib, G. Tetrahedron 2002, 58, 4981-5021.
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A More Efficient Asymmetric Catalyst
A R T I C L E S
Table 6. Yields Obtained Using 1.5 g Ketone Substrate and 15
mL EtOAc for Workup Followed by Distillation
ing reaction mixtures with saturated ammonium chloride, 10
mL of ethyl acetate was added and the heterogeneous solution
was filtered. The solid was then washed with 5 mL ethyl acetate.
TLC of this filtrate indicated that it contained substantial
amounts of tertiary alcohol. The combined filtrates were dried,
the solvent was removed under reduced pressure, and the
resulting tertiary alcohol was distilled under reduced pressure
to yield the product in 75-86%. This protocol allowed isolation
of the product with high levels of purity without loss of ee (Table
6, entries 1-3). An identical workup procedure was applied to
the asymmetric addition/diastereoselective epoxidation as out-
lined in Table 6, entries 4-6, with good yields (78-83% yields).
Summary
The development of truly efficient, practical, and more
environmentally friendly catalyst systems is one of the central
goals in catalysis and green chemistry. These goals can be
approached by drastically reducing or eliminating solvents,
which represent the largest contribution to the quantity of waste
generated in nearly all chemical reactions. Further, the art of
conducting reactions without solvent was described as one of
the “grand challenges” facing chemists in the 21st century.70
There are several benefits to running solvent-free reactions in
addition to the decreased environmental impact. As outlined in
this study, we have been able to reduce catalyst loading by 4-
to 40-fold while maintaining similar yields and levels of
enantioselectivity compared to reactions conducted with sol-
vents. In the asymmetric addition of functionalized organozinc
reagents to ketones, catalyst loadings have been reduced by a
factor of 10 under the highly concentrated reaction conditions.
encountered problems in the reactions outlined in this report,
we recommend taking appropriate safety considerations (Ex-
perimental Section) when conducting reactions involving con-
centrated dialkylzinc reagents and either oxygen or TBHP.
There is also a significant cost reduction with solvent-free
and concentrated reaction conditions. Under our standard
asymmetric addition conditions, the catalyst system required the
use of high purity toluene and hexanes. Traces of oxygen and
water in these solvents were detrimental to the reaction and
needed to be removed. Further, both toluene and hexanes pose
health risks. Under solvent-free conditions, relatively benign
ethyl acetate was used directly out of the bottle in reaction
workup. By minimizing the amount of ethyl acetate employed
in workup and distillation of the enantioenriched tertiary alcohol,
we have substantially reduced the amount of solvent with respect
to the standard conditions.
We have also demonstrated that the solvent-free asymmetric
additions to ketones can be used in tandem with a diastereo-
selective epoxidation reaction to provide syn epoxy alcohols
with high levels of enantio- and diastereoselectivity. Further,
the results outlined here suggest that both the asymmetric
alkylation of ketones and the asymmetric addition/diastereose-
lective epoxidation are amenable to scale-up.
Minimization of Solvent Use in the Workup and Purifica-
tion Steps. The results of Tables 1-5 indicate that use of
solvent-free and highly concentrated reaction conditions are
advantageous with respect to the standard conditions. The
solvent-free and highly concentrated reactions discussed to this
point were subjected to traditional workup procedures involving
quenching, extraction with ethyl acetate, and purification of the
tertiary alcohols by standard chromatographic procedures. In
pursuit of a more environmentally friendly asymmetric addition
protocol, we focused our attention on minimizing the amount
of solvent employed in the workup and purification procedure.
For these experiments, the asymmetric addition was conducted
with 1.50 g ketone substrate. Attempts to quench reaction
mixtures and directly distill the tertiary alcohols were low
yielding, most likely because of the nature of solid metal-
containing byproducts generated on workup. Thus, after quench-
Although the reduced tunability of the catalyst and increased
difficulty in controlling heat transfer represent real challenges
for the future development of other solvent-free asymmetric
reactions, the significant benefits of a successful solvent-free
catalytic asymmetric process should inspire additional investiga-
tions in this area. The potential utility and scalability of our
asymmetric addition of alkyl groups to ketones have been greatly
improved under the highly concentrated and solvent-free condi-
tions reported here.
(70) Lippard, S. L. Chem. Eng. News 2000, 78, 64-65.
9
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A R T I C L E S
Jeon et al.
1
oil: [R]20 ) +30 (c 1.55, CH2Cl2); H NMR (CDCl3, 500 MHz) δ
Experimental Section
D
1.03-1.08 (br, 9H), 1.38 (s, 3H), 1.55-1.61 (m, 2H), 1.74-1.85 (m,
2H), 1.86-1.96 (m, 1H), 2.05-2.12 (m, 1H), 3.34 (br, 1H), 4.06 (d, J
) 11.9 Hz, 1H), 4.47-4.52 (m, 1H), 5.62 (t, J ) 3.9 Hz, 1H), 7.39-
7.52 (m, 6H), 7.68-7.82 (m, 4H) ppm; 13C{1H} NMR (CDCl3, 125
MHz) δ 19.5, 19.6, 26.0, 27.0, 27.3, 28.5, 39.1, 67.3, 70.1, 127.5, 128.1,
128.15, 128.22, 130.0, 130.2, 130.3, 133.3, 133.4, 135.3, 136.1, 139.6
ppm; IR (neat) 3444, 3070, 3049, 2931, 2858, 1959, 1891, 1823, 1470,
1388, 1364 cm-1; HRMS calcd for C24H30OSi (M-H2O)+: 362.2066,
found 362.2088.
Cautionary Note. Caution must be used in handling dialkylzinc
reagents, adding TBHP or oxygen to reaction mixtures containing
dialkylzinc reagents, and quenching reaction mixtures.
General Methods. All reactions were carried out under a nitrogen
atmosphere with oven-dried glassware. The progress of all reactions
was monitored by thin-layer chromatography. All manipulations
involving dialkylzinc and titanium(IV) isopropoxide were carried out
under a dinitrogen atmosphere using standard Schlenk or vacuum line
techniques. Toluene was dried through alumina columns. Titanium-
(IV) isopropoxide and all liquid ketone substrates were distilled prior
to use. Dimethyl- and diethylzinc were used neat and were a gift of
Akzo Chemical. All other dialkylzinc reagents were prepared by
literature methods and were used without isolation.45,62,71 The 1H NMR
and 13C{1H} NMR spectra were obtained at 500 and 125 MHz,
respectively. Silica gel (230-400 mesh, Silicycle) was used for air-
flashed chromatography. Analysis of enantiomeric excess was per-
formed using chiral GC and HPLC. Chiral tertiary alcohols not reported
in the Experimental Section have previously been reported.44,45,53,72,73
Enantioselective Addition of Dialkylzinc Reagents to Ketones
Under Highly Concentrated and Solvent-Free Conditions. General
Procedure A (Solvent-Free Conditions). The bis(sulfonamide) ligand
1 was weighed into the reaction vessel under a nitrogen atmosphere,
and the neat dialkylzinc and the titanium(IV) isopropoxide were added
at room temperature. After 5 min, the substrate ketone was added neat.
The reaction mixture was stirred at room temperature. After completion,
as determined by TLC analysis, it was diluted with EtOAc, quenched
with a small amount of water (0.5-1 mL) at 0 °C, dried over MgSO4,
concentrated under reduced pressure, and purified by column chroma-
tography on silica gel.
Enantioselective Methyl Addition/Diastereoselective Epoxidation
with TBHP. 2-(tert-Butyl-dimethyl-silanyloxymethyl)-1-methyl-cy-
clohex-2-enol (Table 5, Entry 2). The (R,R)-bissulfonamide ligand 1
(1.1 mg, 0.5 mol %) was weighted into the flame-dried Schlenk flask,
and dimethylzinc (56 µL, 0.8 mmol) and titanium(IV) isopropoxide
(124 µL, 0.42 mmol) were added neat. After 5 min, 2-(tert-butyl-
dimethyl-silanyloxymethyl)-cyclohex-2-enone (100 µL, 0.4 mmol) was
added. The reaction mixture was stirred for 44 h at room temperature.
After completion, the reaction vessel was cooled to -10 °C. TBHP
(292 µL, 5.5 M in decane, 4 equiv) was carefully added at that
temperature, and the reaction was stirred for 4 h while warming to
room temperature. The reaction mixture was diluted with EtOAc (8
mL), quenched with a small amount of water (0.5 mL) at 0 °C, dried
over MgSO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel (hexanes/
EtOAc:90/10) to give the product (103.5 mg, 95% yield) as an oil:
[R]20D ) -13.9 (c 1.04, CH2Cl2); 1H NMR (CDCl3, 500 MHz) δ 0.04
(s, 3H), 0.05 (s, 3H), 0.87 (s, 9H), 1.23-1.33 (m, 2H), 1.39 (s, 3H),
1.42-1.51 (m, 1H), 1.57-1.65 (m, 1H), 1.73-1.81 (m, 1H), 1.82-
1.92 (m, 1H), 3.17 (br, 1H), 3.33 (s, 1H), 3.56 (d, J ) 11.5 Hz, 1H),
4.10 (d, J ) 11.5 Hz, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ
-5.21, -5.13, 18.3, 18.5, 23.2, 25.3, 26.2, 36.3, 58.8, 64.0, 65.7, 71.7
ppm; IR (neat) 2932, 2856, 1468, 1387, 1366, 1254, 1142 cm-1; HRMS
calcd for C14H29O3Si (MH)+: 273.1886, found 273.1893.
General Procedure B (Highly Concentrated Conditions). To a
Schlenk flask under nitrogen was added 2 equiv of toluene before
addition of the substrate ketones. The remainder of the procedure is
identical to general procedure A.
Large-Scale One-Pot Epoxidation with TBHP: 2-Methyl-1-
pentyl-6-oxa-bicyclo[3.1.0]hexan-2-ol (Eq 4). The (R,R)-bissulfona-
mide ligand 1 (90 mg, 0.5 mol %) was weighted into the flame-dried
Schlenk flask, and dimethylzinc (4.62 mL, 66 mmol) and titanium(IV)
isopropoxide (11.7 mL, 39.4 mmol) were added neat. After 5 min,
2-pentylcyclopent-2-enone (5 g, 32.8 mmol) was added. The reaction
mixture was stirred for 45 h at room temperature. After completion,
the reaction vessel was cooled to -10 °C. TBHP (24 mL, 5.5 M in
decane, 4 equiv) was carefully added over 30 min at that temperature
and was stirred for 4 h while slowly warming to room temperature.
The reaction mixture was diluted with EtOAc (100 mL) and was
quenched by careful addition of water to the solution at 0 °C; the
organics were extracted into EtOAc (3 × 50 mL), were dried over
MgSO4, and were concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel (hexanes/
EtOAc: 80/20) to give the product (5.45 g, 90% yield, 97% ee) as an
oil. Eighty-one milligrams (90% yield) of ligand 1 was recovered by
subsequent column chromatography using more polar eluting conditions
(hexanes/EtOAc: 65/35).
2-(2,5-Dimethyl-thiophen-3-yl)-butan-2-ol (Table 2, Entry 13).
The (R,R)-bissulfonamide ligand 1 (2.74 mg, 1.0 mol %), dimethylzinc
(62 µL, 0.6 mmol), titanium(IV) isopropoxide (178 µL, 0.6 mmol),
and 3-acetyl-2,5-dimethylthiophene (72 µL, 0.5 mmol) were added to
the Schlenk flask by general procedure A. The reaction mixture was
stirred at room temperature for 72 h. After completion, it was diluted
with EtOAc (5 mL), quenched with a small amount of water (0.5 mL)
at 0 °C, dried over MgSO4, and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica
gel (hexanes/EtOAc:90/10) to give the product (64.5 mg, 70% yield,
96% ee) as an oil: [R]20D ) -14.1 (c 1.66, CHCl3); 1H NMR (CDCl3,
500 MHz) δ 0.86 (t, J ) 7.5 Hz, 3H), 1.52 (s, 3H), 1.69 (br, 1H),
1.74-1.86 (m, 2H), 2.36 (s, 3H), 2.49 (s, 3H), 6.53 (s, 1H) ppm; 13C-
{1H} NMR (CDCl3, 125 MHz) δ 8.95, 15.4, 29.7, 29.8, 36.4, 75.5,
126.4, 131.7, 134.5, 142.7 ppm; IR (neat) 3420, 2967, 2920, 2877,
1452, 1371, 1224 cm-1; HRMS calcd for C10H16OS (M+): 184.0922,
found 184.0931.
2-(tert-Butyl-diphenyl-silanyloxymethyl)-1-methyl-cyclohex-2-
enol (Table 3, Entry 7). The (R,R)-bissulfonamide ligand 1 (1.1 mg,
1.0 mol %), dimethylzinc (28 µL, 0.4 mmol), titanium(IV) isopropoxide
(71 µL, 0.24 mmol), and 2-(tert-butyl-diphenyl-silanyloxymethyl)-
cyclohex-2-enone (73 mg, 0.2 mmol) were added to the Schlenk flask
by general procedure A. The reaction mixture was stirred at room
temperature for 60 h. After completion, it was diluted with EtOAc (5
mL), quenched with a small amount of water (0.5 mL) at 0 °C, dried
over MgSO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel (hexanes/
EtOAc:95/5) to give the product (70 mg, 90% yield, 96% ee) as an
Minimization of Solvent Use in the Workup and Purification
Steps. Asymmetric Addition: 2-Phenyl-butan-2-ol (Table 6, Entry
1). The (R,R)-bissulfonamide ligand 1 (31 mg, 0.5 mol %), dimethylzinc
(1.54 mL, 22.4 mmol), and titanium(IV) isopropoxide (3.97 mL, 13.5
mmol) were added to the Schlenk flask by general procedure A. After
5 min, propiophenone (1.5 g, 11.2 mmol) was added. The reaction
mixture was stirred for 48 h at room temperature. After completion,
the reaction vessel was cooled to -10 °C. Aqueous NH4Cl (1.2 mL)
was carefully added over 30 min at that temperature followed by
dilution with 10 mL of EtOAc. The resulting heterogeneous solution
was vigorously stirred for 4 h while slowly warming to room
temperature, and MgSO4 (0.3 g) was added. The reaction mixture was
then filtered, and the solid was washed with EtOAc (5 mL). Solvent
(71) Schwink, L.; Knochel, P. Tetrahedron Lett. 1994, 35, 9007-9010.
(72) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 6117-6128.
(73) Misterkiewicz, B. J. Organomet. Chem. 1982, 224, 43-47.
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16424 J. AM. CHEM. SOC. VOL. 127, NO. 47, 2005

A More Efficient Asymmetric Catalyst
A R T I C L E S
was removed under reduced pressure, and vacuum distillation of the
resulting liquid afforded the desired product (1.45 g, 86% yield) as an
oil (30 °C, 0.9 mmHg).
(0.3 g) was added. The reaction mixture was then filtered, and the solid
was washed with EtOAc (5 mL). Solvent was removed under reduced
pressure, and vacuum distillation of the resulting liquid afforded the
desired product (1.54 g, 83% yield) as an oil (37-38 °C, 0.7 mmHg).
Addition/Epoxidation: 1,2,5,5-Tetramethyl-7-oxa-bicyclo[4,1,0]-
heptan-2-ol (Table 6, Entry 4). The (R,R)-bissulfonamide ligand 1
(29.8 mg, 0.5 mol %), dimethylzinc (1.50 mL, 21.8 mmol), and
titanium(IV) isopropoxide (3.85 mL, 13.1 mmol) were added to the
Schlenk flask by general procedure A. After 5 min, 2,4,4-trimethyl-
2-cyclohexen-1-one (1.5 g, 10.9 mmol) was added. The reaction mixture
was stirred for 44 h at room temperature. After completion, the reaction
vessel was cooled to -10 °C. TBHP (7.93 mL, 5.5 M in decane, 4
equiv) was carefully added over 30 min at that temperature and was
stirred for 4 h while slowly warming to room temperature. Aqueous
NH4Cl (1.2 mL) was carefully added at 0 °C followed by dilution with
10 mL of EtOAc. The resulting heterogeneous solution was vigorously
stirred for 4 h while slowly warming to room temperature, and MgSO4
Acknowledgment. This work was supported by the NIH,
National Institute of General Medical Sciences (GM58101). We
thank Akzo Nobel for a generous gift of dimethyl- and
diethylzinc reagents.
Supporting Information Available: Procedures and full
characterization of new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA052200M
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J. AM. CHEM. SOC. VOL. 127, NO. 47, 2005 16425