A practical catalytic asymmetric addition of alkyl groups to ketones

Article abstract of DOI:10.1021/ja026568k

Many catalysts will promote the asymmetric addition of alkylzinc reagents to aldehydes. In contrast, there are no reports of additions to ketones that are both general and highly enantioselective. We describe herein a practical catalytic asymmetric additi

Full text of DOI:10.1021/ja026568k

Published on Web 08/21/2002
A Practical Catalytic Asymmetric Addition of Alkyl Groups to Ketones
Celina Garc´ıa, Lynne K. LaRochelle, and Patrick J. Walsh*
P. Roy and Diane T. Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received April 17, 2002
Scheme 1. Synthesis of Ligands 5 and 6
Literally hundreds of catalysts will promote additions of zinc
alkyl groups to aldehydes with high enantioselectivities.1-3 In sharp
contrast, the use of ketones as alkyl and aryl group acceptors under
similar conditions has proven much more challenging. This
discrepancy is due to the greater reactivity of aldehydes over
ketones, which is accentuated by the mild nature of dialkylzinc
reagents.4 As a result, only two catalysts have been shown to
promote the asymmetric addition of aryl or alkyl zinc reagents to
ketones. The addition of phenyl groups to ketones was reported in
1998 by Dosa and Fu5 who employed Noyori’s amino alcohol
ligand DAIB, 1 (15 mol %, Figure 1).6 The success of this addition
can be attributed, in part, to the increased reactivity of diarylzinc
reagents over their dialkylzinc counterparts. In the arylation reaction,
enantioselectivities ranged from 36 to 75% for dialkyl ketones and
72-91% for aryl methyl ketones.5
Reaction of these reagents in the presence of Et3N furnished the
diketone 4. Addition of methyllithium to 4 proceeded to give a
single diastereomer of the diol 5 (Scheme 1).12 Use of 5 in the
asymmetric addition reaction (eq 1) resulted in formation of the
tertiary alcohol addition products in 70-90% ee. Like those in the
Figure 1. Structures of ligands for the asymmetric addition of alkyls to
ketones.
In the same year, Ramo´n and Yus7,8 reported the alkylation of
ketones with dialkylzinc reagents and a titanium-based catalyst.
They employed titanium tetraisopropoxide in combination with a
camphor-based hydroxysulfonamide ligand, 2.7,8 They observed
enantioselectivities from 16 to 89% and obtained good yields in
most cases. However, the resulting catalyst showed low activity;
at 20 mol % catalyst the additions required between 4 and 14 days
for consumption of the substrate.
Our initial experiments in the asymmetric addition of alkyl groups
to ketones involved the use of bis(sulfonamide) ligands9 3 (Figure
1) with titanium tetraisopropoxide and diethylzinc. This is one of
the most efficient and enantioselective catalysts known for the
additions of alkyl groups to aldehydes.9 The catalysts for this
process are believed to be bis(sulfonamido)Ti(OiPr)2.9-11 In some
cases, additions to aldehydes gave >98% ee and were complete in
15 min at -45 °C.11 However, when we used ketones as substrates,
reactions were slow, with 40% conversion after 2 days and 25%
formation of reduction product. Additionally, the ee’s were under
10%. We hypothesized that the reactivity of the catalysts could be
increased by constraining the geometry of the ligand, which would
result in a more open binding site. The first generation ligands were
based on trans-1,2-diaminocyclohexane and camphor sulfonyl
chloride, both of which are commercially available (Scheme 1).
Yus system,7,8 the reactions were very slow; only 5-20% conver-
sion was observed after 24 h. We believed that if the ligand bulk
about the titanium center could be trimmed while maintaining the
constrained geometry, the catalysts might be more active. Diketone
4 was reduced with NaBH4 to form two diastereomers in a 3.5:1
ratio (Scheme 1). The diastereomers were easily separated by
chromatography on silica. The major diastereomer, isolated in 55%
yield, was shown to be the C2-symmetric diol 6 (2D NMR). This
two-step sequence has been used to prepare 6.7 g (12.2 mmol) of
ligand 6. To our delight, ligand 6 formed an efficient and highly
enantioselective catalyst for the addition of alkyl groups to ketones.
The results of our study are shown in Table 1. Catalyst loadings
as low as 2 mol % have been successfully used for the asymmetric
addition reactions. Acetophenone and related derivatives are
excellent substrates for this catalyst. The reactions of acetophenone
and 3-methylacetophenone were complete in less than 30 h, and
the addition products were formed in 96% and 99% ee. Reactions
with 3-methylacetophenone employing 10 and 2 mol % catalyst
gave product with the same ee’s and similar yields (entry 2).
* To whom correspondence should be addressed. E-mail: pwalsh@
sas.upenn.edu.
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J. AM. CHEM. SOC. 2002, 124, 10970-10971
10.1021/ja026568k CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Addition of Ethyl Groups to Ketones with
Ligand 6 in Equation 1
be used when handling the enantiomerically enriched tertiary
alcohols to avoid loss of ee (see Supporting Information).
We have also examined the addition of dimethylzinc to pro-
piophenone using the same enantiomer of the ligand shown in
Scheme 1 and employed in eq 1. Interestingly, the addition to
propiophenone using dimethylzinc gave the (R)-enantiomer of
2-phenyl-2-butanol (2 mol % ligand, 83% yield, 94% ee) while
the addition of diethylzinc to acetophenone gave the (S)-enantiomer
of the same alcohol in 96% ee (Table 1, entry 1). Thus, employing
the same enantiomer of the ligand one can obtain either enantiomer
of 2-phenyl-2-butanol with excellent enantioselectivity.
To test the scalability of this process, the asymmetric addition
reaction of 3-methylacetophenone was examined on a larger scale.
Reaction of 5.0 g (37 mmol) of this ketone was conducted with 2
mol % ligand. After 40 h at room temperature, the reaction was
worked-up with aqueous ammonium chloride, extracted into CH2-
Cl2, and purified on silica to provide 4.5 g (73% yield) of the
addition product with 99% ee. The ligand was recovered in 84%
yield. These results highlight the practicality of this system.
The construction of chiral quarternary centers remains one of
the most challenging frontiers of asymmetric catalysis.13,14 The
catalyst system outlined here generates chiral tertiary alcohols and
allylic alcohols with excellent ee’s. The chiral ligand 6 is easily
synthesized in two steps from commercially available materials and
can be prepared on large scale. Furthermore, we have demonstrated
that the reaction is easily scalable and can be conducted at room
temperature.
We are currently examining the scope and mechanism of this
efficient and enantioselective asymmetric C-C bond-forming
reaction.
a ee’s determined by GC or HPLC. See Supporting Information for
details.
Electron-donating and -withdrawing substituents have little effect
on the ee of the product; 4-methoxy- and 3-(trifluoromethyl)-
acetophenones gave 94 and 98% ee, respectively (entries 3 and 4).
However, the substituent had a significant impact on reaction times
for these substrates. The trifluoromethyl and methoxy derivatives
required 14 and 111 h to complete, respectively. The results from
the reaction of 2-methylacetophenone demonstrated that substitution
of the 2-position does not adversely affect the enantioselectivity
(96%) but does result in reduced reactivity and yield (24%, entry
5). R-Tetralone also gave excellent ee (>99%); however, the yield
was low (35%). Yus also reported a low yield with this compound
(25% yield).7,8 In our case, two aldol products were isolated in 48%
yield.
Acknowledgment. This work was supported by the National
Science Foundation (CHE-9733274) and the National Institutes of
Health (GM58101).
Supporting Information Available: Procedures, characterization
of 6 and chiral alcohols, and ee analyses (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
(2) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York,
1994.
(3) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856.
(4) Knochel, P.; Jones, P. Organozinc Reagents; Oxford University Press:
Oxford, 1999.
(5) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445-446.
(6) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989,
111, 4028-4036.
Other alkyl aryl ketones also proved to be very good substrates
for the asymmetric addition reaction. Valerophenone and 3-chlo-
ropropiophenone underwent additions with enantioselectivities of
88 and 89%, respectively, in good yields (entries 7 and 8).
Reactions of R,â-unsaturated ketones in eq 1 provided tertiary
allylic alcohols. 1-Cyclohexenyl methyl ketone gave product with
96% ee (entry 9). trans-4-Phenyl-3-buten-2-one proved to be an
excellent substrate for the addition reaction, giving 90% ee (entry
10). The related dialkyl ketone, 4-phenyl-2-butanone, was envi-
sioned to be a difficult substrate because the size of the methyl
and the alkyl groups are comparable. Surprisingly, this substrate
gave the addition product in 70% ee (entry 11). Note that care must
(7) Ramo´n, D. J.; Yus, M. Tetrahedron Lett. 1998, 39, 1239-1242.
(8) Ramo´n, D. J.; Yus, M. Tetrahedron 1998, 54, 5651-5666.
(9) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S.
Tetrahedron 1992, 48, 5691-5700.
(10) Ostwald, R.; Chavant, P.-Y.; Stadtmuller, H.; Knochel, P. J. Org. Chem.
1994, 59, 4143-4153.
(11) Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J. J. Am. Chem.
Soc. 1998, 120, 6423-6424.
(12) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 3250-3251.
(13) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388-
401.
(14) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591-4597.
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