Generation of highly enantioselective catalysts from the pseudoenatiomeric assembly of BINOL, F8BINOL, and Ti(OiPr)4 [17]

Full text of DOI:10.1021/ja0039942

3850
J. Am. Chem. Soc. 2001, 123, 3850-3851
Generation of Highly Enantioselective Catalysts from
the Pseudoenatiomeric Assembly of BINOL,
F8BINOL, and Ti(OiPr)4
Subramanian Pandiaraju, Gang Chen, Alan Lough,† and
Andrei K. Yudin*
Department of Chemistry, UniVersity of Toronto
80 St. George St., Toronto, Ontario M5S 3H6
ReceiVed NoVember 17, 2000
The quest for new asymmetric catalysts continues to depend
both on accidental discovery and on mechanistic understanding
of the uncovered processes.1 The development of new and
improved chiral ligands is one of the most important research
activities in this area. The derivatives of 2,2′-binaphthol (BINOL,
1) are among the most widely used chiral ligands in asymmetric
catalysis.2-4 A number of modifications of the BINOL scaffold
aimed at improving its catalytic performance have been docu-
mented.5-14 We recently reported the synthesis and catalytic
applications of F8BINOL (2), an isostere of BINOL with
modulated coordination preferences and stability toward racem-
ization under a wide range of reaction conditions.15,16 In this
communication, we report on the “pseudoenantiomeric” relation-
ship between the enantiomers of 1 and 2 (Figure 1) and its
potential applications to asymmetric catalysis using the glyoxy-
late-ene reaction17 as a model.
Many well-known asymmetric catalysts rely on the active
species produced in equilibrating metal/ligand mixtures. Titanium
is known to exhibit particularly convoluted behavior when several
ligands are capable of entering its coordination sphere.18,19 Some
important breakthroughs in titanium chemistry are attributed to
ligand-accelerated catalysis (LAC) which involves in situ selection
of the active catalyst from many thermodynamically accessible
complexes.20 This powerful approach provides a means to direct
a reaction toward the enantioselective pathway even though the
catalytically active species may be present only in small amount
Figure 1. (S)-BINOL and (R)-F8BINOL as pseudoenantiomers (AM1
electrostatic potential surfaces).
relative to the more abundant, but less selective, species. Another
important consequence of the agglomerate formation is nonlinear
effect which enables one to use nonenantiopure ligands in
asymmetric catalysis. When the minor ligand is converted into
the less active, but generally more stable meso species, asymmetric
amplification may take place.21,22
M + rac-L f MLRLR + MLSLS + MLRLS
(1)
A
B
C
M ) Ti(IV); L ) BINOL
Both asymmetric amplification and enantiomer-selective acti-
vation of racemic catalysts were recently demonstrated for the
glyoxylate-ene process.23-25 A remarkable nonlinear effect in
this system was attributed to the increase in activity of the
homochiral BINOL/Ti adducts A an B (equation 1) compared to
the more stable meso-adduct C.23 It was established that the meso
adduct, rather than a mixture of homochiral adducts, is prefer-
entially formed between racemic BINOL and Ti. We reasoned
that if one of the enantiomers of BINOL is replaced by its
fluorinated analogue, a “pseudo-meso” aggregate may be formed
for similar geometrical reasons that are responsible for the
formation of the meso aggregate in the BINOL case.
We started by investigating the more acidic F8BINOL ligand
(F8BINOL pKa′ 9.29; BINOL pKa′ 10.28) in titanium-catalyzed
asymmetric glyoxylate-ene process using the literature condi-
tions. With Ti(OiPr)4 as the source of Ti(IV), high levels of
enantioselectivity were obtained. For example, the reaction
between ethyl glyoxylate and R-methyl styrene in the presence
of 10 mol % (S)-2/Ti(OiPr)4 (2:1 ratio) catalyst afforded ethyl
(S)-2-hydroxy-4-phenylpent-3-enoate with 92% ee in 53% yield
(Table 1, entry 1). Thus, the same sense of asymmetric induction
is observed for both Ti/(S)-F8BINOL and Ti/(S)-BINOL catalysts.
Initial rate studies indicate that the catalyst derived from F8BINOL
(k ) 0.6 × 10-3, see Supporting Information) is approximately 4
times slower than the catalyst derived from BINOL (k ) 2.7 ×
10-3, see Supporting Information). From these data, we expected
† To whom correspondence about the crystallographic data should be
addressed.
(1) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH: New York, 1993.
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10.1021/ja0039942 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/28/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 16, 2001 3851
Table 1. Use of F8BINOL and Mixed F8BINOL/BINOL Catalysts
in the Glyoxylate-Ene Reaction
entry
1
R
catalyst
yield (%)* ee (%)
phenyl
(S)-2 (10 mol %),
Ti(OiPr)4 (5 mol %)
(R)-2 (5 mol %), (S)-1 (5 mol %),
Ti(OiPr)4 (5 mol %)
(R)-2 (5 mol %), (S)-1 (5 mol %),
Ti(OiPr)4 (5 mol %)
(R)-2 (5 mol %), (S)-1 (5 mol %),
Ti(OiPr)4 (5 mol %)
53
95
57
71
47
59
65
92 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
78 (R)
2
3
4
5
6
7
phenyl
methyl
ethyl
cyclohexyl (R)-2 (5 mol %), (S)-1 (5 mol %),
Ti(OiPr)4 (5 mol %)
cyclopentyl (R)-2 (5 mol %), (S)-1 (5 mol %),
Ti(OiPr)4 (5 mol %)
(R)-2 (5 mol %), rac-1 (5 mol %),
Ti(OiPr)4 (5 mol %)
Figure 2. Molecular structure of the pseudoracemic Ti/(R)-F8BINOL/
(S)-BINOL adduct 4 and its schematic representation (LH ) BINOL; LF
) F8BINOL).
phenyl
*Isolated yield based on olefin.
asymmetric ene process. We designed additional experiments to
further prove that BINOL and F8BINOL are linked within the
catalyst. An important insight was obtained when (R)-2 was
combined with rac-1 at the catalyst preparation stage (Table 1,
entry 7). The conversion/time study (see Supporting Information)
indicates that the rac-1/Ti is more active than the (R)-2/Ti catalyst.
Therefore, the racemic product would have been dominant had 1
and 2 acted independently. However, this process afforded the
(R)-R-hydroxyester in good enantioselectivity (78% ee) indicating
apparent competition between the mixed diastereomeric catalysts.
It is possible that fluorine atoms break the meso symmetry of the
catalytically active ligand/Ti(IV) assembly resulting in the
observed enantioselective outcome of the catalytic process. The
structurally characterized higher order aggregate 4 is significant
as it captures the complimentarity between 1 and 2 and confirms
the driving force to form the meso-aggregate in the mixture of
pseudoenantiomers. Mikami and co-workers established that the
oxygen-bridged cluster acts as an asymmetric catalyst in the
glyoxylate ene reaction.27 We have observed almost no catalytic
activity for the mixed cluster 4, which is not surprising. As
opposed to Mikami’s example, all titanium centers in the
thermodynamically controlled aggregate 4 are octahedral which
prevents 4 from acting as the Lewis acid.28 We are currently trying
to “intercept” mixed complexes that contain more reactive
titanium centers.
In summary, highly enantioselective catalysts of increased
activity are generated in the mixture of opposite enantiomers of
BINOL and its electron-poor isostere, F8BINOL. An important
point is that the pseudoracemic system not only gives higher
enantioselectivity but also affords much better yield indicating
high stability of the catalyst. Structural evidence for the ligand
synergy has been obtained. Investigations are currently underway
to define the scope and limitations of the pseudoenantiomeric
metal complexes in asymmetric catalysis. The key goal now is
to identify other cases where better catalysts are produced in the
“pseudo-meso” mixtures. In this regard, finding ligand-accelerated
versions of the corresponding catalytic reactions will be most
rewarding.
only moderate enantioselectivity (around 60%ee) for the catalyst
produced in the (R)-F8BINOL/(S)-BINOL/Ti(OiPr)4 mixture (1:
1:1 ratio). However, the reaction between ethyl glyoxylate and
R-methyl styrene proceeded with excellent enantioselectivity
(Table 1, entry 2). Most intriguing was a significant yield
improvement in the “mixed” case compared to either 1 or 2 alone.
Analysis of the conversion/time characteristics confirmed the
unexpected higher activity of the catalyst produced in the
pseudoracemic mixture (see Supporting Material). In addition,
the reaction between ethyl glyoxylate and aliphatic olefins in the
presence of the mixed catalyst led to the desired R-hydroxy esters
with >99% ee (Table 1, entries 3-6). In our hands, neither 1/Ti
nor 2/Ti alone gave any conversion with aliphatic olefins.
To clarify this synergistic behavior, we carried out structural
work. Upon mixing (R)-2 and (S)-1 with Ti(OiPr)4 in toluene,
we were able to isolate crystals of a new species 426 incorporating
both 1 and 2, rather than an equimolar mixture of 2/Ti and 1/Ti
complexes. The molecule of 4 (Figure 2) contains a pseudocrys-
tallographic inversion symmetry which is broken by fluorine
substitution. The stabilizing stacking interactions between the
proximal aromatic planes in 4 were identified through the
corresponding intraplanar distances in the region of 3.5 Å. The
central core in this structure is composed of six titanium centers
surrounded by the BINOL- and F8BINOL halves. The source of
the oxo bridges, which serve as links between the initially formed
Ti/F8BINOL dimers, is under investigation.
The outlined experiments strongly suggest a synergystic
relationship between the opposite enantiomers of 1 and 2 in the
(26) Crystal structure analysis: The data were collected on a Nonius Kappa-
CCD diffractometer with Mo KR using φ scans and ω scans with κ offsets.
Data were integrated and scaled using the Denzo-SMN package. The structure
was solved and refined using the SHELXTL V5.1 package. 3: C138H90F24O22-
Ti6‚6(C7H8), Mr ) 3396.3, triclinic, space group P1, a ) 14.3920(4) Å, b )
15.8740(3) Å, c ) 18.2460(6) Å, R ) 87.342(2)°, â ) 73.951(1)°, γ ) 75.966-
(1)°, V ) 3885.47(18) Å3, Z ) 1, Fcalcd ) 1.451 Mg m-3, F(000) ) 1742, λ
) 0.71073 Å, µ(Mo KR) ) 0.393 mm-1, T ) -123 °C, crystal size 0.35 ×
0.32 × 0.13 mm. Of the 49717 reflections collected (5.18 < 2θ < 50.16°),
Acknowledgment. This paper is dedicated to Professor K. Barry
Sharpless on the occasion of his 60th birthday. We thank the National
Science and Engineering Research Council (NSERC), Canada Foundation
for Innovation, the Research Corporation, and the University of Toronto
for financial support. We are grateful to Mr. Tung Siu for many helpful
discussions.
22937 were independent; max/min residual electron density 0.37/-0.38 eÅ-3
,
R1 ) 0.0493 (I >2σ(I)) and wR2 ) 0.1218(all data). Crystallographic data
(excluding structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as Supplementary Publication no. CCDC-146925.
Copies of the data can be obtained free of charge on application to CCDC,
12 union Road, Cambridge CB2 1EZ, UK (Fax: (+44) 1223-336-033;
e-mail: deposit@ccdc.cam.ac.uk).
Supporting Information Available: Experimental procedures and
characterization data for compounds 3a-e, 4, conversion/time diagrams,
and kinetic plots are available (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(27) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg. Chim.
Acta 1999, 296, 267-272.
(28) Corey, E. J.; BarnesSeeman, D.; Lee, T. W.; Goodman, S. N.
Tetrahedron Lett. 1997, 38, 6513-6516.
JA0039942