The use of achiral ligands to convey asymmetry: Chiral environment amplification [1]

Full text of DOI:10.1021/ja992892c

1802
J. Am. Chem. Soc. 2000, 122, 1802-1803
Communications to the Editor
Knochel.1
2-16
It was proposed9-11,17 to involve the generation of
complexes, which were subsequently
The Use of Achiral Ligands to Convey Asymmetry:
Chiral Environment Amplification
bis(sulfonamido)Ti(O-i-Pr)
2
synthesized and determined to be competent in the asymmetric
addition reaction (eq 1).18
Jaume Balsells and Patrick J. Walsh*
To better understand the control of asymmetry transfer in this
reaction, a series of experiments were performed using achiral
1) or chiral (2) titanium alkoxide complexes (eq 1, Table 1).
P. Roy and Diane T. Vagelos Laboratories
(
UniVersity of PennsylVania, Department of Chemistry
31 South 34th Street, Philadelphia, PennsylVania 19104-6323
When the chiral ligand (R,R)-3 was used with titanium tetraiso-
propoxide (1) according to eq 1, (S)-1-(4-tolyl)-propanol was
formed in 79% ee (Table 1). The reaction was then performed as
above using (R,R)-3, but with the chiral alkoxide complex (S)-2.
The ee of the (S)-l-(4-tolyl)-propanol was 84%. When the
experiment was performed using the enantiomer of the ligand
{(S,S)-3} and titanium alkoxide complex (S)-2, the (R)-enantiomer
of the alcohol was formed with 81% ee.19 Therefore the chiral
trans-bis(sulfonamide) ligand clearly controls the transfer of
asymmetry and the chiral alkoxides have little influence.
2
ReceiVed August 10, 1999
Several highly enantioselective catalysts contain ligands in
which the chirality is located far from the metal center (e.g.,
1
2
3
BINAP, Chiraphos and TADDOLate ligands). The asymmetry
4
is thus extended toward the metal via the phenyl groups, which
are conformationally biased by the chiral portion of the ligand.
Variation of the achiral groups in such ligands often has a
profound impact on the enantioselectivity of the catalyst. In this
contribution, we decouple the chiral and achiral portions of the
ligand into two separate, yet conformationally dependent, ligands.
This method relies on a chiral ligand and an achiral ligand.
The chiral ligand serves as a source of asymmetry but only
minimally defines the chiral environment of the catalyst. The
chiral ligand interacts with the achiral ligand, causing the latter
to preferentially adopt an asymmetric conformation that is largely
responsible for defining the chiral environment. Such an interac-
tion serves to transmit and amplify the asymmetry of the chiral
ligand. A requirement is that the achiral ligand be conformation-
ally flexible so that degenerate conformations of the free ligand
become diastereomeric in the coordination sphere of the chiral
ligand-metal assembly.
This asymmetric addition reaction is an example of ligand-
accelerated catalysis, which has important ramification in the
following experiments. At -45 °C diethylzinc does not react
with aldehydes at an appreciable rate. However the Lewis acidic
alkoxide complexes 1 and (S)-2 can promote the alkylation, giving
rise to background reactions. Thus, in the absence of bis-
20
Related strategies have been employed with varying degrees
of success. Katsuki used achiral (Salen)Mn(III) complexes and
(
sulfonamide) ligands, addition promoted by titanium tetraiso-
propoxide (1) gives racemic alcohol, while chiral titanium
complex (S)-2 promoted the addition to give (S)-1-(4-tolyl)-1-
propanol in 42% ee. The rate of the background reaction relative
to the ligand accelerated process can have a significant impact
on the ee of the product (Figure 1). After 1 h the background
reaction with 4-methylbenzaldehyde promoted by 1.2 equiv of
S)-2 was 12% complete.
Several achiral bis(sulfonamide) ligands were examined in the
asymmetric alkylation with (S)-2 (Table 1). With R ) 4-tert-
butylbenzene (4a) or R ) 4-methoxybenzene (4b), the (R)-
configuration of 1-(4-tolyl)-1-propanol was generated in 84 and
chiral amines5 or amine N-oxides in the asymmetric epoxidation.
Noyori employed achiral 1,1′-bis(diphenylphosphino)biphenyl
with resolved 1,2-diamino-1,2-diphenylethane bound to ruthe-
nium8 that gave a mixture of diastereomeric catalysts with
different reactivities. Our approach differs from these in that we
optimized the enantioselectivity of the catalyst by varying the
achiral ligands. In doing so, we have observed a change in the
enantioselectivity by over 120%.
,6
7
(
We have applied this strategy, which we term chiral enViron-
ment amplification, to the asymmetric addition of alkyl groups
to aldehydes (eq 1). This process was introduced by Ohno and
Kobayashi9 and was applied to a wide range of substrates by
7
8% ee, respectiVely [as compared to the background which gave
-11
the (S)-alcohol in 42% ee (Table 1)]. Thus, by adding these achiral
bis(sulfonamide) ligands, the change in ee of the alcohol (∆ee)
with respect to the background reaction was greater than 120%.
(
1) Kitamura, M.; Noyori, R. Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley and Sons: New York, 1995, pp
09-513.
2) Whiteker, G. T. Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley and Sons: New York, 1995; Vol. 1, pp
14-515.
3) Seebach, D.; Pichota, A.; Beck, A. K.; Pinkerton, A. B.; Litz, T.;
5
(
(12) Rozema, M. J.; Eisenberg, C.; Lutjens, H.; Ostwald, R.; Belyk, K.;
Knochel, P. Tetrahedron Lett. 1993, 34, 3115.
5
(13) Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57,
1956-1958.
(
Karjalainen, J.; Gramlich, V. Org. Lett. 1999, 1, 55-58.
(14) Rozema, M. J.; Eisenberg, C.; L u¨ tjens, H.; Ostwald, R.; Belyk, K.;
Knochel, P. Tetrahedron Lett. 1993, 34, 3115-3118.
(15) Brieden, W.; Ostwald, R.; Knochel, P. Angew. Chem. Int. Ed. Engl.
1993, 32, 582-584.
(
(
(
4) Braun, M. Angew. Chem. Int. Ed. 1998, 35, 519-522.
5) Hashihayata, T.; Ito, Y.; Katsuki, T. Synlett 1996, 1079-1081.
6) Hashihayata, T.; Ito, Y.; Katsuki, T. Tetrahedron 1997, 53, 9541-
9
552.
(16) Reddy, C. K.; Knochel, P. Angew. Chem. Int. Ed. Engl. 1996, 35,
1700-1701.
(
7) Miura, K.; Katsuki, T. Synlett 1999, 783-785.
(
8) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.; Noyori,
(17) Ostwald, R.; Chavant, P.-Y.; Stadtmuller, H.; Knochel, P. J. Org.
Chem. 1994, 59, 4143-4153.
R. Angew. Chem., Int. Ed. 1999, 495-497.
(
9) Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M.
Tetrahedron Lett. 1989, 30, 7095-7098.
10) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S.
Tetrahedron 1992, 48, 5691-5700.
11) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989, 30,
657-1660.
(18) Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J. J. Am.
Chem. Soc. 1998, 120, 6423-6424.
(
(19) Initial ee’s were used due to small variations in the ee’s with time.
Balsells, J.; Walsh, P. J., work in progress.
(
(20) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem. Int. Ed.
Engl. 1995, 34, 1059-1070.
1
1
0.1021/ja992892c CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/11/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 8, 2000 1803
Table 1a
Figure 1. Conversion (%) vs time (min) for 4a-d and 7.
Scheme 1a
a
(A) The enantiomers of cis-1,2-diaminocyclohexane interconvert
through ring inversion. (B) Likewise, when L is achiral, the two
enantiomers interconvert in a similar fashion. However, if L is chiral,
the two structures are diastereomeric and have different energies. (Sulfonyl
coordination not shown.)
a
4
mol % ligand was used unless noted. Ee’s were determined by
GC (30m Supelco â-DEX).
1). Second, coordination of the ligand to the chiral alkoxide-
metal assembly results in desymmetrization of the ligand.
Furthermore, we have shown that coordination of the sulfonyl-
oxygens to titanium is important in the solid-state structures of
Ligands 4c-e, which contained larger aryl groups, resulted in
smaller ∆ee values (Table 1). Addition of bis(sulfonamide) ligands
derived from 1,2-diaminoethane (5), 1,3-diaminopropane (6), and
2
the bis(sulfonamido)Ti(O-i-Pr) complexes derived from trans-
2,2′-diaminobiphenyl (7) resulted in ee’s of 22, 2, and 19% with
1
,2-diaminocyclohexane and may be important in the transition
the (R)-enantiomer predominating in each case (Table 1). The
product alkoxide is incorporated into the catalyst, resulting in ee’s
that change over time. For this reason, the ee’s in Table 1 are
reported at low conversion.
18
state of the addition. Once the ligand is bound to the Ti(OR*)
2
fragment, the sulfonyl oxygens are rendered inequivalent. Upon
coordination of the sulfonyl oxygens to titanium, the sulfurs
become stereogenic centers, thus extending the chiral environment.
These features make ligands derived from meso-1,2-diamino-
cyclohexane particularly adept at amplifying the chiral environ-
ment.
Chiral environment amplification is a modular approach to
asymmetric catalysis. It involves catalyst modification using
combinations of chiral ligands and achiral amplifying ligands and
is amenable to facile high throughput screening. We are currently
applying this technique to other systems.
The ee’s of products in reactions which exhibit ligand acceler-
ated catalysis20 reflect not only the enantioselectivity of the
catalyst but also the turnover frequency (TOF). The background
reaction can be competitive with the ligand-accelerated pathway
if the ligand acceleration is low. Under these conditions the
background reaction can make a substantial contribution to the
ee of the product (Figure 1). However, 4a and 4b gave the same
ee at 4 and 10 mol % ligand, indicating that the reaction catalyzed
by the ligated titanium complex was much faster than the
background reaction. In contrast, 4c gave 4% ee (S) at 4 mol%
and 32% ee (R) at 10 mol%. Thus low ee’s may reflect catalysts
that exhibit only modest degrees of ligand acceleration or low
inherent enantioselectivities.
Acknowledgment. This work was supported by the National Science
Foundation (CHE-9733274) and the National Institute of Health
(GM58101).
Supporting Information Available: Characterization of 2-7 and the
details of the asymmetric additions are outlined (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
We believe the meso-diaminocyclohexane is particularly good
at amplifying the chirality of the alkoxides for several reasons.
First, the two static chair conformations of the free ligand are
enantiomers which interconvert by cyclohexane ring flip (Scheme
JA992892C