Linear free-energy relationship analysis of a catalytic desymmetrization reaction of a diarylmethane-bis(phenol)

Article abstract of DOI:10.1021/ol100927m

(Figure presented) Linear free-energy relationships have been found for enantioselectivity and various steric parameters in an enantioselective desymmetrization of symmetrical bis(phenol) substrates. The potential origin of this observation and the role of different steric parameters are discussed.

Full text of DOI:10.1021/ol100927m

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2794-2797
Linear Free-Energy Relationship
Analysis of a Catalytic
Desymmetrization Reaction of a
Diarylmethane-bis(phenol)
Jeffrey L. Gustafson,† Matthew S. Sigman,*,‡ and Scott J. Miller*,†
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen,
Connecticut 06520-8107, and Department of Chemistry, UniVersity of Utah,
315 South 1400 East, Salt Lake City, Utah 84112
sigman@chem.utah.edu; scott.miller@yale.edu
Received April 22, 2010
ABSTRACT
Linear free-energy relationships have been found for enantioselectivity and various steric parameters in an enantioselective desymmetrization
of symmetrical bis(phenol) substrates. The potential origin of this observation and the role of different steric parameters are discussed.
The analysis of enantioselectivity in catalytic reactions is a
highly challenging endeavor due to the small differences in
absolute energies of competing transition states that lead to
useful levels of selectivity. In the case of enantioselective
reactions, a mere 2.7 kcal/mol of partitioning between
competing transition states can lead to the gold standard of
success in the field, >98% ee. As a result, catalyst design
from first principles remains a daunting task, leading to a
substantial reliance on empiricism.1 Moreover, after-the-fact
analysis of the basis of observed selectivities remains highly
challenging in and of itself. As a result, tools that assist in
quantitative analysis of reaction outcomes are of great value.
In fact, correlation techniques, perhaps best exemplified by
the venerable Hammett analysis,2 are now entrenched
methods that ground organic chemistry as a quantitative
science.3 The development of quantitative tools for the
analysis of catalytic enantioselective reactions has evolved
more slowly than for other types of reaction analysis. In part,
this may be due to the often mechanistically complicated
reaction coordinates that characterize catalytic enantioselec-
(2) (a) Hammett, L. P. Chem. ReV. 1935, 17, 125–136. (b) Anslyn, E. V.;
Dougherty, D. A. Modern Physical Organic Chemistry; University Science
Books: Mill Valley, CA, 2006. (c) Hansch, C.; Leo, A.; Taft, R. W. Chem.
ReV. 1991, 91, 165–195.
† Yale University.
‡ University of Utah.
(3) (a) Anders, E.; Ruch, E.; Ugi, I. Angew. Chem., Int. Ed. 1973, 12,
25–29. (b) Inoue, Y.; Wada, T.; Asaoka, S.; Sato, H.; Pete, J.-P. Chem.
Commun. 2000, 251–259. (c) Rekharsky, M. V.; Inoue, Y. Chem. ReV. 1998,
98, 1875–1917. (d) Buschmann, H.; Scharf, H.-D.; Hoffman, N.; Esser, P.
Angew. Chem., Int. Ed. 1991, 30, 477–515. (e) Buschman, H.; Hoffman,
N.; Scharf, H.-D. Tetrahedron: Asymmetry 1991, 2, 1429–1444. (f) Cainelli,
G.; Galletti, P.; Giacommi, D. Chem. Soc. ReV. 2009, 38, 990–1001.
(1) (a) Jandeleit, B.; Schaefer, D. J.; Powers, T. S.; Turner, H. W.;
Weinberg, W. H. Angew. Chem. Int. Ed. 1999, 38, 2494–2532. (b) Reetz,
M. T. Angew. Chem., Int. Ed. 2001, 40, 284–310. (c) Crabtree, R. H. Chem.
Commun. 1999, 17, 1611–1616. (d) Kuntz, K. W.; Snapper, M. L.; Hoveyda,
A. H. Curr. Opin. Chem. Biol. 1999, 3, 313–319. (e) Francis, M. B.;
Jamison, T. F.; Jacobsen, E. N. Curr. Opin. Chem. Biol. 1999, 2, 422–428.
10.1021/ol100927m  2010 American Chemical Society
Published on Web 05/20/2010

tive reactions. In any case, Sigman et al. recently demon-
strated a series of quantitative studies of enantioselective
processes employing linear free energy analysis.4 This
analysis is aimed at both gaining further insight into the
origin of steric effects and at helping develop predictive
power in the design of new catalysts.
Recently, Lewis et al. demonstrated that peptide catalyst
1 is able to efficiently catalyze the desymmetrization of
symmetrical bis(phenol) 2 (Scheme 1), which bears a bulky
Scheme 1
.
Empirical Effect of Sterics on the Enantioselective
Desymmetrization of Bis(phenols)
Figure 1. Origin of common steric parameters.
paramaters (Figure 1a)9 with modifications to take inductive
and resonance factors into account, are perhaps the most
studied and well-developed steric parameter.10 With this in
mind we wished to expand upon the initial set of bis(phenols)
to include a diverse array of substrates containing substituents
for which reported υ values were available.
t-Bu group at the prostereogenic center (80% yield, 97.5:
2.5 er).5 Given the unusual nature of this reaction, and the
curious role of the remote prostereogenic center, we sought
to study this reaction further. Indeed, we set out to probe
the role of steric bulk at the key position through the
synthesis of a series of bis(phenols) with a varying degree
of steric bulk at the prostereogenic center.6 Whereas the t-Bu-
bearing compound 2 was converted to the monoacetate with
97.5:2.5 er, the i-Pr-bearing compound 3 was converted to
its monoacetate with 86.5:13.5 er. The Et-substituted com-
pound 4 delivered its derived product with 78.5:21.5 er, and
finally the Me-bearing compound 5 gave the product with a
lower, but perhaps still remarkable, 76.0:24.0 er. In fact, we
were quite surprised by the seemingly well-behaved trend
for this remote steric effect, and we wished to understand it
in a quantitative way. For this goal, we turned to the linear
free-energy analysis of catalytic enantioselective reactions
of Sigman,7 and the striking results are presented herein.
One of the challenges associated with this study was the
identification of appropriate reference parameters for the
linear free-energy relationship analysis. As shown in Figure
1, one might imagine exploitation of Charton values (Figure
1a), Winstein-Holness values (“A-values”, Figure 1b), or
Interference values (Figure 1c), inter alia, to the analysis.
Charton values (υ),8 which are based on the Taft steric
As shown in Table 1, we found that the substrates in which
the steric bulk was located at the carbon R to the prostereo-
Table 1. Evaluation of Various Bis(phenols) with Catalyst 1 and
Corresponding Common Steric Parameters
Charton A-value
IX-H
(kcal/
mol)e
%
yielda
er
(R/S)b
value
(kcal/
mol)d
entry
R
(ν)c
1
2
3
4
5
6
7
8
tBu
iPr
Et
Me
Ph
80
62
60
42
40
55
97.5:2.5
1.24
0.76
0.56
0.52
0.57
0.87
1.33
1.28
1.34
0.98
0.70
1.25
4.5
18.29
12.56
---
9.60
7.90
---
---
---
---
---
86.5:13.5
78.5:21.5
76.0:24.0
75.0:25.0
82.5:17.5
98.5:1.5
2.21
1.79
1.74
2.80, 2.20
2.20
---
cC6H11
1-adamantyl 55
CHEt2
CH2tBu
CH2iPr
CH2Ph
CHPh2
80
45
53
46
49
91.0:9.0
---
9
77.5:22.5
67.5:32.5
71.5:28.5
85.0:15.0
2.00
---
1.68
---
10
11
12
---
---
a Isolated yields. b Determined by chiral HPLC analysis. c See refs 8c
(4) Miller, J. J.; Sigman, M. S. Angew. Chem., Int. Ed. 2008, 47, 771–
774.
and d. d See ref 11. e See ref 14.
(5) Lewis, C. A.; Chiu, A.; Kubryk, M.; Balsells, J.; Pollard, D.; Esser,
C. K.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J. J. Am. Chem.
Soc. 2006, 128, 16454–16455.
genic center (entries 1-7) exhibited a strong correlation
between enantioselectivity (plotted as ∆∆Gq which is dervied
from enantiomeric ratio) and υ (Figure 2). The large slope
(Ψ) for this plot (Ψ ) 1.39) indicates a strong sensitivity to
(6) Lewis, C. A.; Gustafson, J. L.; Chiu, A.; Balsells, J.; Pollard, D.;
Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J. J. Am. Chem. Soc.
2008, 130, 16358–16365.
(7) (a) Ref 4. (b) Sigman, M. S.; Miller, J. J. J. Org. Chem. 2009, 74,
7633–7643.
Org. Lett., Vol. 12, No. 12, 2010
2795

causing the bulky substituent to behave more like a smaller
ethyl group than a t-Bu group, similar to what is seen in
cyclohexanes (Figure 3a). In the context of hydrolysis of an
Figure 3. Comparison of A-values and Charton values for R )
CH2tBu.
ester, steric bulk at the ꢀ position will still significantly hinder
the π* orbital (Figure 3b) of the carbonyl resulting in a large
υ. Thus, for these substitutions, Charton values may indicate
a steric effect greater than what may actually be present.
With that in mind, we decided to investigate whether other
steric parameters may provide a more appropriate correlation.
Winstein-Holness values (A-values)11 may well be the most
commonly quoted steric paramater. They are derived from
the energy difference between the equatorial and axial
conformers of monosubstituted cyclohexanes.12 A-values are
commonly used as a teaching tool to first introduce confor-
mational analysis and the concept of steric bulk (Figure 1b).
We thus wondered if A-values might be better suited to our
system due to the sensitivity of A-values to gauche-type
torsional strain (Figure 4a). For example, the A-values of
Figure 2. (a) Charton plot of selected substituents with bulk R to
the prostereogenic center. (b) Charton plot of all substituents
evaluated.
changes in sterics at the prostereogenic center. This may
suggest that the substitution at the R carbon leads to a
propeller-like twist between the aryl rings of 2, where
decreased steric bulk causes a less rigid system with a lower
barrier to interconversion between the two possible propeller
twists. This in turn could make diastereotopic recognition
by the catalyst more difficult. Another possible explanation
is that since peptide 1 was optimized specifically for
bis(phenol) 2 through several directed libraries the alkyl
group steric bulk at that position might be needed for some
sort of substrate-catalyst interaction.
Figure 4.
Plot of ∆∆Gq derived from enantiomeric ratio versus
the corresponding A-value.
Interestingly, this correlation seems to break down for
substrates in which the steric bulk is further removed from
the prostereogenic center (Figure 2). This may be related to
entropic effects, associated with the ability of the bonds in
the substrate to rotate in such a way as to minimize steric
contacts between the alkyl substitution and the phenol rings,
t-Bu and CH2t-Bu are 4.5 and 2.0 kcal/mol, compared to
Charton values where υ ) 1.24 and 1.34, respectively.
Indeed, a strong correlation between ∆∆Gq and A-values
was observed (Figure 4). Unfortunately, to our knowledge,
the breadth of A-values available in the literature is not near
(8) (a) Charton, M. J. Am. Chem. Soc. 1969, 91, 615–618. (b) Charton,
M. J. Am. Chem. Soc. 1975, 97, 3691–3693. (c) Charton, M. J. Am. Chem.
Soc. 1975, 97, 1552–1556. (d) Charton, M. J. Org. Chem. 1976, 41, 2217–
2220.
(11) (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N., Ed Stereochemistry
of Organic Compounds; Wiley: New York, 1994. (b) Hirsch, J. A. Top.
Stereochem. 1967, 1, 199–217.
(9) (a) Taft, R. W., Jr. J. Am. Chem. Soc. 1952, 74, 2729–2732. (b)
Taft, R. W., Jr. J. Am. Chem. Soc. 1953, 75, 4538–4539.
(10) Forster, H.; Vogtle, F. Angew. Chem., Int. Ed. 1977, 16, 429–441.
(12) (a) Winstein, S.; Holness, N. J. J. Am. Chem. Soc. 1955, 77, 5562–
5578. (b) Eliel, E. L. Angew. Chem., Int. Ed. 1965, 4, 761–774.
2796
Org. Lett., Vol. 12, No. 12, 2010

that of Charton values, making it difficult to make a complete
comparison. For example, in Figure 4, if one were to exclude
the tert-butyl group, the quality of the correlation would
suffer. Yet, the inclusion of R groups such as adamantyl
would likely improve the correlation, were the additional and
appropriate parameters available. Nonetheless, the correlation
between ∆∆Gq and A-values is encouraging, and we believe,
based on analysis of hand-held models, this trend would hold
for the substrates in which there are no reported A-values.
Since the early part of the 20th century, chemists have
been qualitatively describing steric bulk from data derived
by observing the t1/2 of racemization of ortho, ortho′
substituted biaryls.13 Since the bis(phenol) structure 1 bears
both aryl moieties as well as substituents residing on an sp3-
carbon center, we wondered if interference values might also
provide an insightful correlation parameter. This question
was facilitated by the explicit studies of Sternhell and co-
workers, who applied modern NMR techniques and a well-
designed molecular system (Figure 1c) to quantify these
trends in the form of interference values (IX-H).14 Though
interference values are very limited in number in the
literature, we made a preliminary plot which demonstrates
an excellent correlation between enantioselectivity and IX-H
(Figure 5).
In summary, we have successfully constructed linear free-
energy relationships for a unique enantioselective desym-
metrization of bis(phenol) substrates containing a remote
stereocenter. To accomplish this, three distinct steric param-
eters including Charton values, A-values, and interference
values were correlated to the enantiomeric ratio of the
desymmetrization reaction. While precise catalyst/substrate
information must be interpreted carefully, an important
conclusion is that one must understand the origin of the
parameter being investigated. Specifically, we found success
using Charton values for substrates with the steric bulk
Figure 5.
Plot of ∆∆Gq derived from enantiomeric ratio versus
the corresponding interference values.
directly adjacent to the chiral center; however, when the steric
bulk was distal to the chiral center, a poor correlation
resulted. In contrast, better correlations with A-values and
interference values were found although only a limited set
of values are currently available. This work clearly illustrates
the usefulness of steric parameters in asymmetric catalyst
analysis but also highlights the caution one must use in
evaluating steric effects as well as the need to develop new
or more complete sets of steric parameters.
Acknowledgment. M.S.S. thanks the National Science
Foundation (CHE-0749506) for support. S.J.M. is grateful
to National Institutes of Health Foundation (GM-068649)
for financial support. We are grateful to Dr. Chad Lewis and
Merck Research Laboratories for their support in the initial
phases of this work, noted in references 5 and 6.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Adams, R.; Yuan, H. C. Chem. ReV. 1933, 12, 261–338. (b)
Stoughton, R. W.; Adams, R. J. Am. Chem. Soc. 1932, 54, 4426–4434. (c)
Kenner, J.; Stubbings, W. V. A. J. Chem. Soc. 1921, 119, 593–602.
(14) Bott, G.; Field, L. D.; Sternhell, S. J. Am. Chem. Soc. 1980, 102,
5618–5626.
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