A case of remote asymmetric induction in the peptide-catalyzed desymmetrization of a bis(phenol)

Article abstract of DOI:10.1021/ja807120z

We report a catalytic approach to the synthesis of a key intermediate on the synthetic route to a pharmaceutical drug candidate in single enantiomer form. In particular, we illustrate the discovery process employed to arrive at a powerful, peptide-based asymmetric acylation catalyst. The substrate this catalyst modifies represents a remarkable case of desymmetrization, wherein the enantiotopic groups are separated by nearly a full nanometer, and the distance between the reactive site and the pro-stereogenic element is nearly 6 A. Differentiation of enantiotopic sites within molecules that are removed from the prochiral centers by long distances presents special challenges to the field of asymmetric catalysis. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity of the catalyst. The approach presented herein contrasts enzymatic catalysts and small-molecule catalysts for this challenge. Ultimately, we report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a substantial distance. In addition, studies relevant to mechanism are presented, including (a) the delineation of structure-selectivity relationships through the use of substrate analogs, (b) NMR experiments documenting catalyst-substrate interactions, and (c) the use of isotopically labeled substrates to illustrate unequivocally an asymmetric catalyst-substrate binding event.

Full text of DOI:10.1021/ja807120z

Published on Web 11/12/2008
A Case of Remote Asymmetric Induction in the
Peptide-Catalyzed Desymmetrization of a Bis(phenol)
Chad A. Lewis,† Jeffrey L. Gustafson,† Anna Chiu,‡ Jaume Balsells,‡ David Pollard,‡
Jerry Murry,‡ Robert A. Reamer,‡ Karl B. Hansen,*,‡ and Scott J. Miller*,†
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520, and Merck Research
Laboratories, Rahway, New Jersey 07065
Received September 8, 2008; E-mail: scott.miller@yale.edu
Abstract: We report a catalytic approach to the synthesis of a key intermediate on the synthetic route to
a pharmaceutical drug candidate in single enantiomer form. In particular, we illustrate the discovery process
employed to arrive at a powerful, peptide-based asymmetric acylation catalyst. The substrate this catalyst
modifies represents a remarkable case of desymmetrization, wherein the enantiotopic groups are separated
by nearly a full nanometer, and the distance between the reactive site and the pro-stereogenic element is
nearly 6 Å. Differentiation of enantiotopic sites within molecules that are removed from the prochiral centers
by long distances presents special challenges to the field of asymmetric catalysis. As the distance between
enantiotopic sites increases within a substrate, so too may the requirements for size and complexity of the
catalyst. The approach presented herein contrasts enzymatic catalysts and small-molecule catalysts for
this challenge. Ultimately, we report here a synthetic, miniaturized enzyme mimic that catalyzes a
desymmetrization reaction over a substantial distance. In addition, studies relevant to mechanism are
presented, including (a) the delineation of structure-selectivity relationships through the use of substrate
analogs, (b) NMR experiments documenting catalyst-substrate interactions, and (c) the use of isotopically
labeled substrates to illustrate unequivocally an asymmetric catalyst-substrate binding event.
examples.5,6 Instances of the use of small molecules for remote
catalytic asymmetric induction are rare, and much more typical
Introduction
Situations of remote asymmetric induction present special
challenges to the field of asymmetric catalysis. In particular,
desymmetrization reactions wherein the reactive centers are
substantially removed from pro-stereogenic centers are particu-
larly challenging since the catalyst must simultaneously mediate
bond formation or cleavage, while at the same time affording
some type of meaningful interaction with pro-stereogenic
functionality at a distance. Problems of this type in synthesis
are often addressed through substrate control, with intramo-
lecular relay of chiral information through the covalent frame-
work of the molecule.1,2 When catalytic bond formation is
targeted, across a truly substantial distance, enzymes are often
used.3 Indeed, their macromolecular architecture offers the
potential for simultaneous enantioselective recognition and
functionalization over a considerable vector.4 Historically,
selective C-H bond oxidations distal from functionality and
stereogenic centers provide some of the most dramatic
are situations where the reacting site is removed from a pro-
stereogenic element by just a few bonds.7
We recently confronted the desymmetrization of compound
1, a diphenyl methane bis(phenol), which was required to
deliver, in optically pure form, an unsymmetrical derivative with
distinct para-oxygenated substituents (e.g., 2; Figure 1a). Simple
molecular mechanics calculations underscored the particular
challenge of this desymmetrization; the desired site of func-
tionalization is >5.7 Å from the prochiral stereogenic center
of the substrate (Figure 1b), and nearly a full nanometer spans
the enantiotopic phenol oxygen atoms. We recently reported
our discovery of a small-molecule peptide catalyst (4) that
achieves this challenging desymmetrization with high levels of
enantioselectivity.8 Herein, we describe in detail the process
that led to the discovery of catalyst 4, in addition to experiments
(5) Capdevila, J. H; Wei, S; Helvig, C; Falck, J. R; Belosludtsev, Y; Truan,
G; Graham-Lorence, S. E; Peterson, J. A J. Biol. Chem. 1996, 37,
22663.
† Yale University.
‡ Merck Research Laboratories.
(1) (a) Linnane, P.; Magnus, N.; Magnus, P. Nature 1997, 385, 799. (b)
Shimizu, M.; Mikami, K. J. Org. Chem. 1992, 57, 6105. (c) Mikami,
K.; Narisawa, S.; Shimizu, M.; Terada, M. J. Am. Chem. Soc. 1992,
114, 6566.
(6) Yang, J.; Breslow, R. Angew. Chem., Int. Ed. 2000, 39, 2692.
(7) (a) Mikami, K.; Narisawa, S.; Shimizu, M.; Terada, M. J. Am. Chem.
Soc. 1992, 114, 6566. (b) Trost, B. M.; Mino, T. J. Am. Chem. Soc.
2003, 125, 2410. (c) Lewis, C. A.; Sculimbrene, B. R.; Xu, Y.; Miller,
S. J. Org. Lett. 2005, 7, 3021. (d) Zhao, Y.; Rodrigo, J.; Hoveyda,
A. H.; Snapper, M. L. Nature 2006, 443, 67.
(2) Clayden, J.; Lund, A.; Vallverdu, L.; Helliwell, M. Nature 2004, 431,
966.
(3) Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. ReV. 2005, 105, 313.
(4) Hughes, D. L.; Bergan, J. J.; Amato, J. S.; Bhupathy, M.; Leazer,
J. L.; McNamara, J. M.; Sidler, D. R.; Reider, P. J.; Grabowski, E. J. J.
J. Org. Chem. 1990, 55, 6252.
(8) 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. Also see: “Research Highlights” Nature
2006, 444, 974.
9
16358 J. AM. CHEM. SOC. 2008, 130, 16358–16365
10.1021/ja807120z CCC: $40.75
2008 American Chemical Society

Peptide-Catalyzed Desymmetrization of a Bis(phenol)
A R T I C L E S
Figure 1. (a) Compound 1 and its desymmetrized analogue 2. (b) Substrate metrics for bis(phenol) 1, defining a 5.75 Å distance between desired site of
functionalization and prochiral stereogenic center (MM calculations). 9.79 Å span the enantiotopic hydroxyl groups. (c) Catalyst 4 effects enantioselective
desymmetrization with high enantiomeric excess.
Scheme 1. Enzymatic Desymmetrization of Bis(acetate)
of optical purity, substantial overhydrolysis to bis(phenol) 1 is
necessary. The requirement for overhydrolysis of 5 to obtain
high optical purity is a result of unremarkable enantiotopic group
discrimination displayed by the enzyme and a reflection of a
secondary kinetic resolution that serves to “correct” the lack of
stereochemical specificity exhibited by the enzyme.10 Indeed,
mono(acetate) 3 is produced with only 50-55% ee at low
conversion. Of course, overconversion of 5 to bis(phenol) 1
substantially reduces the overall yield of the process. Each of
these factors contributed to a low 40% overall yield and 99%
ee after recrystallization of mono(acetate) 3.
It is likely that further and intensive study of enzymatic
processes could well lead to an effective biocatalytic solution
to the desymmetrization of 5.11 Yet, the inherently low
stereospecificity exhibited by the enzymes, in combination with
the low volumetric throughput encountered in the enzymatic
studies,12 stimulated the pursuit of an alternative strategy. In
that shed some light on the mechanistic basis of this intriguing
particular, we elected to pursue a small-molecule asymmetric
asymmetric reaction.
acylation approach,13 with peptide-based catalysts as the
Results and Discussion
cornerstone of the strategy.14
Directed Library Design. The presence of the phenol func-
tionality in the substrate, as well as the large span between the
Enzymatic Desymmetrization of Bis(phenol) 1. The initial
approach to the desymmetrization of 1 examined enzymatic
desymmetrization of bis(acetate) 5 (Scheme 1). After examina-
tion of a large lipase collection (>450 enzymes), the hydrolysis
route was able to offer reasonable access to mono(acetate) 3
using Mucor miehei, a lipase composed of hundreds of amino
acids.9 However, two main liabilities conspired to motivate an
alternative strategy. First, high levels of throughput of bis(ac-
etate) 5 to mono(acetate) 3 are difficult to achieve during
individual batch runs, in part due to the substrate’s minimal
solubility in the aqueous buffered media that allows maximum
enzymatic efficiency. Furthermore, to obtain 3 with high levels
(10) Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc.
1987, 109, 1525.
(11) Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114.
(12) Jacobsen, E. N.; Finney, N. S. Chem. Biol. 1994, 1, 85.
(13) (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809–1810.
(b) Ruble, J. C.; Latham, H. A.; Hu, G. C. J. Am. Chem. Soc. 1997,
119, 1492–1493. (c) Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams,
H. J. Org. Chem. 1999, 64, 9430–9443. (d) Spivey, A. C.; Maddaford,
A.; Redgrave, A. J. Org. Prep. Proced. Int. 2000, 32, 333. (e) France,
S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003, 103, 2985.
(f) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc. 2004,
126, 12212. (g) Connon, S. J. Lett. Org. Chem. 2006, 3, 333. (h)
MacKay, J. A.; Vedejs, E. J. Org. Chem. 2006, 71, 498. (i) Wurz,
R. P. Chem. ReV. 2007, 107, 5570.
(9) (a) Tonouchi, N.; Shoun, H.; Uozumi, T.; Beppu, T. Nucleic Acids
Res. 1986, 14, 7557. (b) Fatima, S.; Ahmad, B.; Khan, R. H. Life
2007, 59, 179–186.
(14) (a) Colby Davie, E.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. ReV
2007, 107, 5759. (b) Miller, S. J. Acc. Chem. Res. 2004, 37, 601.
9
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A R T I C L E S
Lewis et al.
enantiomeric excesses was observed with this catalyst set (21%
ee to 40% ee), and yields of 3 were modest (12% to 46%), due
primarily to overacylation of the product. We note that our early
analysis of the results assumed that there was only minimal
modulation of product enantioselectivity as a function of
secondary kinetic resolution. While we did not verify this
assertion in all instances, we did show in selected cases that
the results were a good indicator of raw enantiotopic group
discrimination in the catalysis. Subsequent experiments with the
best catalyst confirmed that kinetic resolution of (()-3 occurs
to only a minimal extent with many of these catalysts (Vide
infra).
The most promising catalyst of the first peptide library
possessed the aromatic-aliphatic-aromatic motif with the
sequence Boc-Pmh-Asn(Trt)-Leu-Val-D-Phe-Phe-OMe (catalyst
6; 40% ee, entry 1, Table 1). Although the amount of bis(acetate)
5 that was produced is high (73%), the 40% enantiomeric excess
represented a reasonable starting place for further catalyst
optimization. A second library was synthesized (entries 8-14,
24 members) to optimize the i + 2 and i + 3 residues within
the catalyst. Residues were selected at random and included
some stereochemical perturbations to assess any variation in
selectivity as a function of diastereomeric catalyst structures.
Indeed, some improvements over the first library were observed,
with enantioselectivities of up to 49% documented (25% yield,
entry 8, Table 1). Most notably, alteration of the valine residue
(i + 3) within catalyst 6 to protected serine or threonine led to
enhanced selectivity (47% ee, entry 9; 49% ee, entry 8, Table
1). The third library (entries 16-20, 24 members) examined
variation of the i + 1 site (occupied by tritylated asparagine in
catalyst 6). Most perturbations at this position were deleterious
to the selectivity (e.g., 32-42% ee, entries 15, 16, 17, and 20).
Figure 2. Initial peptide design influenced by target structure.
hydroxyls, made it necessary to generate some lead catalysts
by preparing a library of peptides. This peptide library was
biased to mimic the functional group array presented by the
substrate. Figure 2 illustrates our initial thinking, wherein
incorporation of a “linear” aromatic-aliphatic-aromatic motif
was targeted to mimic the substrate architecture of bis(phenol)
1. Hexapeptides were initially chosen with the hypothesis that
the bis(phenol) could be a bifunctional substrate, one that would
present one hydroxyl group for derivatization, while another
might form a noncovalent contact with the catalyst in the
transition state.15 We speculated, on the basis of hand-held
models, that a six-residue peptide could easily interact with both
termini of the substrate. If such a bifunctional catalyst-substrate
complex could form, then we speculated that the twists and turns
of a peptide secondary structure in these transition states could
lead to substantial energetic differentiation of diastereomeric
transition states that would result from interaction of each
phenolic group as either a nucleophile or anchor for hydrogen
bond contact to catalyst.
The first 42 hexapeptides were produced using solid-phase
peptide synthesis and contained both directed aromatic-aliphatic-
aromatic as well as random sequences. The initial conditions
employed were 2.5 mol % peptide catalyst in toluene at 4 °C
with 2 equiv of acetic anhydride. Nonpolar solvents (e.g.,
PhCH3) were found to be optimal, although in the initial studies
small aliquots of EtOH were included in the reaction mixture.
This modification was identified as beneficial in terms of
maintaining homogeneous solutions throughout the course of
the reaction. In later studies, EtOH was omitted in favor of a
small quantity of THF, which had the same effect (Vide infra).
The addition of tertiary amine bases to scavenge the acetic acid
was found to catalyze the reaction and produce racemic product
and was not pursued any further.16 The most selective peptide
catalysts are shown in Table 1 (entries 1-7).17 A range in
The fourth library altered and optimized the aliphatic and
aromatic portion (i + 3, 4, 5, 6) of the peptide while maintaining
the i + 1 position as either a tritylated histidine or asparagine
(Table 2). We also explored variations in the reaction conditions.
For example, the optimal solvent system was found to be a blend
of toluene and chloroform (1/1 v/v). At this stage, the inclusion
of 1% THF (by volume) was also identified as beneficial for
complete solubilization of materials and homogeneous condi-
tions throughout the course of the reaction. Modulation of
temperature also resulted in a dramatic effect. Performing
reactions at -20 °C led to an improved yield of the monoacy-
lated material 3, with substantial diminution of bis(acetate) 5.
At the same time, enantioselectivity was markedly improved.
The results of the studies of the fourth library are shown in
Table 2 and culminated in lead catalyst 7 (72% yield, 79% ee,
entry 7, Table 2).
At this stage, further variation in peptide sequence did not
lead to dramatic changes in catalyst performance. As shown in
Table 3, additional variations at the i + 1, 5 or i + 1, 4 residues
did not lead to improvements (75-78% yield, 81% ee, entries
1 and 2, Table 3). Strikingly, changes at the i + 4, 5 positions
(73-78% yield, 72-80% ee, entries 3-6, Table 3) also had
little effect. As a result, we wondered if the residues were
necessary at all, and they were thus targeted for deletion.
(15) Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J. Angew. Chem., Int. Ed.
2001, 40, 2824.
(16) Zhu, J.; Chastanet, J.; Beugelmans, R. Synth. Commun. 1996, 26, 2479.
(17) HPLC product ratios.
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Peptide-Catalyzed Desymmetrization of a Bis(phenol)
A R T I C L E S
Table 1. Peptide Results for First Three Libraries
entry
i
i + 1
i + 2
i + 3
i + 4
i + 5
1 (%)
3 (%)
5 (%)
ee (%)
Library 1
DPhe
1
2
3
4
5
6
7
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Asn(Trt)
Phe
Dbg
Tyr(t-Bu)
Leu
Phe
Leu
Gly
DPhe
DPhe
Aib
Val
Leu
DPro
DHis(Trt)
Phe
Phe
Phe
Leu
Phe
Phe
Phe
Phe
0.2
0.3
4.7
0.2
0.2
0.4
0.5
27.2
19.5
46.3
16.2
12.1
18.4
30.4
72.6
80.2
49.0
83.6
87.7
81.2
69.1
40
29
28
25
23
21
21
Phe
Val
Tyr(t-Bu)
DVal
Phe
Gly
DPro
Pro
Ser(t-Bu)
Thr(t-Bu)
Phe
Library 2
8
9
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Leu
Leu
Leu
Aib
Dbg
Leu
Ala
Thr(t-Bu)
Ser(t-Bu)
Ala
Val
Val
DPhe
DPhe
DPhe
DPhe
DPhe
DPhe
DPhe
Phe
Phe
Phe
Phe
Phe
DPhe
Phe
0.1
0.2
0.2
0.2
0.2
0.2
0.2
25.4
27.3
14.7
20.2
17.8
15.6
70.6
74.5
72.5
85.1
79.6
82.0
84.2
29.2
49
47
43
41
39
38
32
10
11
12
13
14
Val
Val
Library 3
15
16
17
18
19
20
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
DAsp(Ot-Bu)
DAsp(Ot-Bu)
Asp(OBzl)
Asn(Trt)
Asn(Trt)
DAsp(Ot-Bu)
Leu
Leu
Leu
Leu
Leu
Leu
Thr(t-Bu)
Ser(t-Bu)
Val
Tle
Val
DPhe
DPhe
DPhe
DPhe
DVal
DPhe
Phe
Phe
Phe
Phe
Phe
Phe
1.3
0.2
0.2
0.1
0.4
0.3
25.0
16.6
9.4
25.4
40.0
16.6
73.7
83.2
90.4
74.5
59.6
83.1
42
42
40
36
34
32
Val
Table 2. Fourth Peptide Library with Varying Temperature
entry
i
i + 1
i + 2
i + 3
i + 4
i + 5
1 (%)
3 (%)
5 (%)
ee (%)
4 °C Reactions
1
2
3
4
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Asn(Trt)
Asn(Trt)
His(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Aib
Aib
Aib
Leu
Leu
Leu
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
Thr(t-Bu)
Ser(t-Bu)
DTyr(t-Bu)
DPhe
DPhe
DTyr(t-Bu)
DTyr(t-Bu)
DPhe
Phe
Phe
Phe
Phe
Phe
Phe
0.2
0.2
0.2
0.1
0.2
0.1
24.8
24.1
21.9
26.4
23.3
11.7
75.0
75.7
77.9
73.5
76.5
88.2
56
52
51
51
51
51
5
6a
-20 °C Reactions
7
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Asn(Trt)
His(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Aib
Aib
Aib
Aib
Leu
Leu
Ser(t-Bu)
Ser(t-Bu)
Thr(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
DTyr(t-Bu)
DPhe
DPhe
DPhe
DPhe
Phe
Phe
Phe
Phe
Phe
Phe
3.2
2.4
0.2
3.5
0.6
71.9
73.5
53.5
74.8
62.8
73.2
24.9
24.1
46.3
21.7
36.6
14.2
79
78
78
77
70
68
8
9
10
11a
12
DTyr(t-Bu)
12.6
a Entry 9, Table 1.
Truncation of the most selective hexapeptide catalyst (7; Table
2, entries 1 and 7) was examined to determine the number of
residues required for enantioselectivity. Indeed, we found that
the first four residues were most critical (i.e., catalyst 8: Boc-
Pmh-Asn(Trt)-Aib-Ser(t-Bu), entry 9, Table 3), and the last two
residues are nearly superfluous (66-68% yield, 68-72% ee,
entries 7 and 8, Table 3).
We then undertook studies of optimization of the C-terminal
substituent of tetrameric peptide catalyst 8. In particular, we
explored changing the C-terminus group from a methyl ester
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A R T I C L E S
Lewis et al.
Table 3. Final Library and Truncation Studies
5
(%)
entry
i
i + 1
i + 2
i + 3
i + 4
i + 5
1 (%)
3 (%)
ee (%)
1
2
3
4
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
Pmh
His(Trt)
His(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Asn(Trt)
Aib
Aib
Aib
Aib
Aib
Aib
Aib
Aib
Aib
Aib
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
Ser(t-Bu)
DTyr(t-Bu)
DLeu
DLeu
DTyr(t-Bu)
DTyr(t-Bu)
DTyr(t-Bu)
DTyr(t-Bu)
DTyr(t-Bu)
Phg
Phe
Phe
Phg
Ala
Ile
5.1
15.5
3.4
8.2
18.2
6.1
13.9
8.5
3.3
10.4
20.4
77.8
75.2
77.7
76.9
74.4
73.4
66.0
68.0
68.8
64.2
52.1
17.1
9.3
18.9
14.9
7.4
20.5
20.1
23.5
27.9
25.4
27.5
81
81
80
80
78
72
68
72
71
54
11
5
6
7a
8
Phe
9
10
11
a Entry 7, Table 2.
Table 4. C-Terminus Optimizationa
Scheme 2. Final Optimized Peptide
of catalyst 4, led to isolation of 3 in 80% yield, with an optical
purity of 95% ee (Scheme 2). Overall, 138 peptides were
synthesized in various sublibraries to deliver a lead peptide-
based hexameric catalyst (7; Table 2, entries 1 and 7). The
peptide was then truncated to a tetrapeptide catalyst (8; Table
3, entry 9). Optimization of the C-terminal substituent afforded
the final catalyst 4, which provides excellent results for the
desymmetrization.
Substrate Analogue Studies - Variation of the Prochiral
Center Substituent. The role of the prochiral center of bis(phe-
nol) 1 in this unique desymmetrization is intriguing to consider.
On the one hand, it could impart steric demands on bond
rotations that dictate the relative disposition of the aryl rings
(e.g., note arrows in structure 15). On the other hand, there is
the possibility that the substituent actually is involved in
catalyst-substrate contacts. Varying the nature of this substitu-
entwouldallowexaminationofthesubtleeffectsofsubstrate-catalyst
interactions. A series of bis(phenol) analogues were generated,
and the peptide catalyst was applied under the standard
conditions (Table 5). The systematic reduction of the steric bulk
of the t-Bu group (1) to isopropyl decreased the selectivity
(substrate 15a, 73% ee, entry 1). Further decreasing the size of
a All reactions were run at -30 °C in CHCl3 with 2.5 mol % catalyst
loading.
(8) to a number of amides (9-14, 4, Table 4). The simple
exchange of the ester for benzyl amide 9 increased the selectivity
marginally (61% yield, 68% ee, entry 2, Table 4). The use of
chiral methylated benzyl amide 10 and 11 maintained similar
results (60-68% yield, 69-70% ee, entries 3 and 4, Table 4).
Extension of the aromatic system to chiral naphthyl amide 13
increased the ee to 79%, and it was found that tosyldiamine 4
(Table 4, entry 8) was even more beneficial, delivering catalyst
4 that afforded the product with 84% ee and 89% isolated yield.
At this stage, we endeavored to further optimize the reaction
conditions for the best catalyst. Indeed, we found that performing
the reaction at -30 °C in chloroform, with a mere 2.5 mol %
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16362 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Peptide-Catalyzed Desymmetrization of a Bis(phenol)
A R T I C L E S
Table 5. Variation of Prochiral Center
Table 6. Kinetic Resolution
entry
R
recovered 15 (%)
16 (%)
ee 16 (%)
17 (%)
1
2
3
4
i-Pr a
Et b
Me c
Ph d
22
22
50
32
62
60
42
40
73
63
52
50
7
10
7
entry
R
recovered 18 (%)
ee 18 (%)
krel 18
19 (%)
ee 19 (%)
1a
2a
3b
4b
OAc, 3
H, a
OMe, b
OTBS, c
52c
52
55
62
11c
16
5
1.4
1.7
1.2
1.2
48d
46
44
38
s
22
13
5
11
5
the R group to ethyl (15b), methyl (15c) led to lower
enantioselectivities (63% and 52% ee, entries 2 and 3). Quite
notably, phenyl-bearing substrate 15d, which is nearly C3-
symmetric, still leads to an observed enantiomeric excess of
50% (entry 4). Thus, the absolute steric size of the substituent
(as defined by A-values, or Charton values, for example)18
correlates only loosely with the magnitude of the enantioselec-
tivities. These observations may suggest that an explicit contact
between the prochiral center substituent and the catalyst may
not be stereochemistry determining. Rather, these observations
suggest that the role of the substituent may be more critical in
creating a propeller-like twist between the aryl rings of 1 and
that the barrier to interconversion between propeller twists may
be significant for enantioselective catalysis.
a 2 equiv of Ac2O. b 4 equiv of Ac2O. c Mono(acetate) 3. d Bis(acetate) 5.
Kinetic Resolution Studies. Effective desymmetrization of 1
could derive from (a) enantiotopic group selection and/or (b)
secondary kinetic resolution of a monofunctionalized product.19
Each catalyst could rely on varying contributions from these
two situations, which influence product ratios as well as
enantioselectivity. In an optimally efficient desymmetrization,
the selective catalyst will afford high enantiotopic group
selection and rely less on the secondary kinetic resolution.20 In
this limit, the recovery of the monofunctionalized product
approaches 100%. However, for less selective catalysts, such
as the enzymes initially studied above, the enantiotopic group
selection may be poor, but the secondary kinetic resolution may
provide good enantioselectivity. In this scenario, yield suffers.
The acylation utilizing successful catalyst 4 provided 80% yield
and 95% ee in the desymmetrization of 1, which suggest a low
level of reliance on secondary kinetic resolution. The peptide was
tested against racemic mono(acetate) material (3), and indeed, it
was found to produce only 11% ee material with 52% recovery of
the mono(acetate) (krel ) 1.4,21 entry 1, Table 6).
Figure 3. Possible mechanistic roles of phenols during 4-catalyzed
desymmetrization of 1.
perhaps by H-bonding, during the stereodefining transition state.
Similarly, neither methyl ether nor silyl protected substrates
exhibit significant kinetic resolution (18b and 18c; krel ) 1.2
and 1.2, entries 3 and 4, Table 6). Taken together, these data
may imply a bifunctional transition state with a role for each
substrate phenol, a situation in which one undergoes bond
formation,whiletheotherservesasananchorforacatalyst-substrate
interaction nearly a full nanometer removed from the reacting
center.
Spectroscopic Studies Related to Mechanism. If indeed there
is a bifunctional mechanism at play during the desymmetrization
of 1, it could be possible to observe a catalyst-substrate
complex that reflects key interactions. Such a complex could
also have implications for the mechanism of bond formation in
the reaction. The basis of N-methylimidazole catalyzed acylation
of alcohols with anhydrides is something of a matter of debate,
with studies supporting both nucleophilic and general base
catalysis mechanisms described in the literature.22 In fact, certain
Nevertheless, further studies of kinetic resolution of substrate
analogues provided additional mechanistic insight. For example,
monodeoxy substrate (18a, entry 2, Table 6) also proves a poor
substrate for kinetic resolution (22% ee at 46% conversion, krel
) 1.7). One possible implication is that the “nonreacting” free
phenol of 1 may be involved in a catalyst-substrate contact,
(18) (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley & Sons: New York, 1994; p 696. (b) Miller, J. J.;
Sigman, M. S. Angew. Chem. Int. Ed. 2008, 47, 771–774.
(19) (a) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal.
2001, 343, 5. (b) Robinson, D. E. J. E.; Bull, S. D. Tetrahedron:
Asymmetry 2003, 14, 1407. (c) Vedejs, E.; Jure, M. Angew. Chem.,
Int. Ed. 2005, 44, 3974.
(20) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765.
(21) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
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J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16363

A R T I C L E S
Lewis et al.
Figure 5. 13C Spectra for catalysts and labeled bis(phenol). (a) NMI, 0%
ee; (b) Table 3, entry 10, 54% ee; (c) Table 3, entry 8, 72% ee; (d) Table
3, entry 9, 71% ee; (e) Peptide catalyst 4, 95% ee.
complex should be possible.23 Indeed, comixing substrate 1 and
catalyst 4 in a 1:1 ratio in CDCl3 resulted in a 1H NMR spectrum
(500 MHz) consistent with nondegenerate aromatic rings in the
bis(phenol) region (Ha ≈ 6.67 and Hb ≈ 7.16 ppm; Figure 4).
This lack of degeneracy suggests the formation of a catalyst-
substrate complex that is in slow exchange on the NMR time
scale. Such differentiation of the two rings could then be
manifested in the catalytic reactions through ground-state
destabilization, or alternatively the loss of degeneracy could also
be manifested in a transition state involving the participation
of acetic anhydride as well.
To further understand these catalyst-substrate complexes,
we also performed related experiments with 13C-labeled sub-
strates. Simulating the reaction conditions, a 13C-labeled sub-
strate 1 was produced and mixed with the different catalysts at
-30 °C in CDCl3 and their 13C NMR spectra were recorded
(500 MHz). Strikingly, when the most effective catalyst 4 is
employed in this experiment, an unambiguous loss of aryl ring
degeneracy is observed (Figure 5e). However, when less
selective catalysts were comixed with 1, the effect is much less
striking and even undetectable with catalysts that are quite
unselective in the catalytic reaction. For example, when N-
methylimidazole (NMI) is mixed with 1, a unique and sharp
singlet is observed (Figure 5a). Of course, when NMI catalyzes
acylation of 1, a racemic (0% ee) product is formed. Less
selective peptide-based catalysts provided an intermediate result,
with catalysts that afford moderate ee (Figure 5b-d, 54%-72%)
producing 13C NMR spectra that exhibit line broadening,
reflecting weak interactions between catalyst and substrate.
Figure 4. 1H NMR of peptide-bis(phenol) complex.
alcohols such as aliphatic alcohols may proceed by a nucleo-
philic catalysis mechanism (Scenario 1, Figure 3) due to the
high pKa of the hydroxyl. Phenolic analogues such as 1 may
proceed by general base catalysis (Scenario 2, Figure 3) since
the pKa of the hydroxyl is substantially lower. Peptide catalyst
4 possesses a modified histidine amino acid, which may act as
a nucleophilic catalyst or a general base type catalyst (Figure
3). Thus, any observation of a catalyst-substrate complex does
not definitively establish the role of an individual phenolic site
either as a locus of general base-catalyzed bond formation or
alternatively as an anchor for H-bonding contemporaneous with
bond formation at a remote site. Nonetheless, the observation
of a catalyst-substrate complex could provide evidence for
differentiation of the two phenols on the time scale of an NMR
experiment, supporting the notion that each phenol fulfills a
different role in the transition state.
If substrate 1 and catalyst 4 form a preacylation complex on
the NMR time scale, observation of a catalyst-substrate
(22) (a) Guibe-Jampel, E.; Bram, G.; Vilkas, M. Bull. Soc. Chim. Fr. 1973,
1021. (b) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int.
Ed. Engl. 1978, 17, 569. (c) Pandit, N. K.; Connors, K. A. J. Pharm.
Sci. 1982, 71, 485. (d) Hiratake, J.; Inagaki, M.; Yamamoto, Y.; Oda,
J. J. Chem. Soc., Chem. Commun. 1985, 1717. (e) Hiratake, J.; Inagaki,
M.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Perkin Trans. 1 1987, 1053.
(f) Savelova, V. A.; Belousova, I. A.; Simanenko, Y. S. Zh. Org. Khim.
1994, 30, 246. (g) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int.
Ed. 2008, 47, 2.
(23) Although we have not established the kinetic order of these reactions
explicitly, in related studies a first-order dependence on substrate and
catalyst was found. It is, of course, possible that an alternative kinetic
order ensues in the present cases. See: (a) Jarvo, E. R.; Copeland,
G. T.; Papaioannou, N.; Bonitatebus, P. J., Jr.; Miller, S. J. J. Am.
Chem. Soc. 1999, 121, 11638–11643.
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16364 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Peptide-Catalyzed Desymmetrization of a Bis(phenol)
A R T I C L E S
Strikingly, only the best catalyst (4, 95% ee for desymmetri-
zation of 1) reveals a doubling of signals upon exposure to the
carbon-labeled analogue of 1. These observations suggest a
correlation between significant catalyst-substrate binding and
ultimate catalyst performance. Indeed, the specific interaction
of 1 with 4 suggests that this unique catalyst is able to associate
with unique substrate 1, breaking the symmetry of the phenolic
rings, and that this capacity is also manifested kinetically in
this remarkable desymmetrization.
extremes of remote asymmetric induction. Furthermore, the
collection of evidence supporting specific catalyst-substrate
interactions suggests that the determination of a three-
dimensional solution structure of a complex might be possible
and that such a structure could be correlated to the outcome of
the catalytic reaction.
Finally, since target-oriented natural products syntheses and
process-oriented pharmaceutical syntheses often present tantaliz-
ing and unique structures that have not been previously
encountered in synthetic methodology development, the rapid,
protocol-based approach to the discovery of effective specific
catalysts may be of particular value in these arenas.
Conclusions
The catalyst discovery protocol employed for this study
culminated, after the synthesis of fewer than 150 simple
peptides, in tetrameric catalyst 4 that is highly effective for a
desymmetrization reaction involving a substrate with substantial
enantiotopic group separation. It is also notable that substrate
1 bears no resemblance to any class of alcohol substrate that
had been previously studied with simple peptide-based catalysts.
Since peptide 4 is simpler than a macromolecular enzyme, its
performance establishes that small molecules may supplement
enzymes as potential catalysts for reactions involving the
Acknowledgment. This work was supported by the NIH (GM-
068649) and Merck Research Laboratories.
Supporting Information Available: Experimental procedures
and data. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA807120Z
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