Catalyst control over regio- and enantioselectivity in baeyer-villiger oxidations of functionalized ketones

Article abstract of DOI:10.1021/ja508757g

We report a peptide-based catalyst that can strongly influence the regio- and enantioselectivity of the Baeyer-Villiger (BV) oxidation of cyclic ketones bearing amide, urea, or sulfonamide functional groups. Both types of selectivity are thought to arise from a catalyst-substrate hydrogen-bonding interaction. Furthermore, in selected cases, the reactions exhibit the hallmarks of parallel kinetic resolution. The capacity to use catalysis to select between BV products during an asymmetric process may have broad utility for both the synthesis and diversification of complex molecules, including natural products.

Full text of DOI:10.1021/ja508757g

Communication
pubs.acs.org/JACS
Catalyst Control over Regio- and Enantioselectivity in Baeyer−
Villiger Oxidations of Functionalized Ketones
David K. Romney, Sean M. Colvin, and Scott J. Miller*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: We report a peptide-based catalyst that can
strongly influence the regio- and enantioselectivity of the
Baeyer−Villiger (BV) oxidation of cyclic ketones bearing
amide, urea, or sulfonamide functional groups. Both types
of selectivity are thought to arise from a catalyst−substrate
hydrogen-bonding interaction. Furthermore, in selected
cases, the reactions exhibit the hallmarks of parallel kinetic
resolution. The capacity to use catalysis to select between
BV products during an asymmetric process may have
broad utility for both the synthesis and diversification of
complex molecules, including natural products.
he oxidation of ketones to esters, known as the Baeyer−
1
TVilliger (BV) reaction,
has long been regarded as a
powerful tool for organic synthesis. As such, there have been
Figure 1. (a) Previous electrophilic epoxidation of alkenes. (b)
many attempts to render the process catalytic and enantiose-
lective, which have seen the use of both enzymes2 and small-
Diastereoselective oxidation of an advanced intermediate. (c)
Proposed nucleophilic oxidation of ketones. Cbz = benzyloxycarbonyl.
molecule catalysts.3 However, despite this storied history, the
reaction still presents numerous challenges, such as the issue of
regioselectivity, which can be difficult to predict, let alone
control. For cyclic ketones, the effects of ring strain are an
added complication; if the reaction forms a more strained
lactone from a less strained ketone, then overcoming the energy
barrier to C−C bond migration can be difficult without
substantial activation. Finally, if complex molecule substrates
are to be used, then the catalyst must also be sufficiently
chemoselective to tolerate functionality in addition to the
reacting ketone. Ideal catalysts must therefore be able to oxidize
relatively unstrained ketones to deliver products with both
regio- and enantioselectivity, while also tolerating the presence
of additional functional groups.
We have been studying a catalytic cycle for oxidation in
which the side-chain of a peptide-embedded aspartic acid
shuttles between the carboxylic acid and the corresponding
peracid in situ.4 This system, which has proven particularly
effective for electrophilic oxidation, is well suited to a variety of
substrate and reaction types, such as the oxidation of allylic
carbamate 1 to its epoxide (2, Figure 1a). The selectivity of the
reaction is controlled by the peptide sequence, which may be
tuned for the regio- and enantioselective oxidation of various
substrates.5 Notably, this approach may also be applied to cases
where the reversal of a substrate’s intrinsic reactivity is desired.
For example, indole 3 has a strong proclivity to form
diastereomer 4 when treated with various electrophilic
oxidants; yet, it is converted to 5 in high yield in the presence
of peptide catalyst 6 (Figure 1b).6 In the context of the BV
oxidation, a peracid functions as a nucleophile, not as an
electrophile (Figure 1c). We thus wondered whether the
aspartic acid system might be portable to the BV reaction,
meeting the analogous requirements for selective oxidation in
functional group-rich molecular environments, despite the
fundamentally different role of the peracid intermediate.
In earlier work, we demonstrated the viability of the acid/
peracid catalytic cycle for the BV reaction.7 However, despite
exploration of many peptide sequences that had given high
enantioselectivity for epoxidation reactions in the intervening
years, we were unable to achieve comparable levels of selectivity
for the fundamentally different BV reaction. We therefore
turned our attention to combinatorial screening.8
For our initial screen, we synthesized an on-bead library of
catalysts, as depicted in Figure 2a. We evaluated each catalyst in
the kinetic resolution (KR)9 of ketone 7 via oxidation to
lactone 8 (Figure 2b), due to this reaction’s facile analysis. After
screening 245 beads, we identified several “hit” catalysts that
exhibited a modicum of selectivity (e.g., catalyst 9a, krel = 1.7;
see SI). Intriguingly, the “Pro-DXaa-Pro” motif was conserved
in the i + 1 to i + 3 positions, suggesting that this sequence
might be especially suited to the BV reaction manifold.
While the initial threshold of selectivity for these hits was
low, our experience dictated that stronger catalyst control could
Received: August 25, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja508757g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
difference.12 This situation creates the opportunity to track the
degree to which catalyst-controlled reversal of intrinsic
migratory aptitude occurs. Of course, with the achiral oxidant,
each enantiomer of ketone 10a delivers an equivalent ratio of
lactones (11a/12a, 7.9:1; Figure 3b). Yet, with the chiral
catalyst 9b, one sees that the regioselectivity is more
pronounced for (R)-10a (11a/12a, 1:8.1; Figure 3c) than for
(S)-10a, which forms a less selective mixture of lactone isomers
(11a/12a, 2.0:1). Thus, catalyst 9b exhibits the hallmarks of a
stereochemically “matched” case for reaction with (R)-10a;
catalyst 9b may be considered “mismatched” in reactions with
(S)-10a.13
Fascinated by this catalyst-controlled regioselectivity, as well
as the encouraging enantioselectivity, we wished to explore the
role of the peptide sequence, with an eye toward optimization
and identification of mechanistic roles for the different regions
of the catalyst (Chart 1). One hypothesis emerging from the
Figure 2. Combinatorial screening of BV catalysts. (a) Library
composition. (b) Test reaction for on-bead screening. (c) Best
performing catalyst from screen.
be achieved if the substrates possessed additional functional
groups that could engage the peptide through H-bonding.10 We
thus turned our attention to the application of catalyst 9b (the
soluble methyl ester analog of 9a) to the BV oxidation of 10a
(Figure 3a). Ketone 10a presents an excellent test substrate in
Chart 1. Sample Peptides from Sequence Screen
initial on-bead catalyst screen was that the Pro-DXaa-Pro motif
is a crucial sequence element. Indeed, truncated peptide 13,
which lacked the i + 3 Pro, led to a plummet in both conversion
and selectivity, with “normal” lactone 11a being favored (11a/
12a, 1.6:1; residual 10a nearly racemic; Table 1, entry 2).
Conversely, when the two C-terminal residues were replaced
with a simple pyrrolidine (14), the conversion and selectivity
for the “abnormal” lactone were restored to levels comparable
to catalyst 9b (11a/12a, 1:3.7; 12a with 92:8 er; Table 1, entry
3). Given the performance of catalyst 14, the role of the i + 4
position is unclear, but a brief survey revealed DPro-Tyr(t-Bu)-
OCH3 as an optimal C-terminal sequence (15a), leading to
lactone 12a with as high as 94:6 er (11a/12a, 1:3.1; Table 1,
entry 4). The role of the DLys(Boc), where Boc = tert-
butyloxycarbonyl, side-chain in the i + 2 position is not
definitively clear. Replacement of the Boc carbamate with an
acetamide (15b) produces a minimal change in behavior (11a/
12a, 1:2.8; 12a with 94:6 er; Table 1, entry 5). However,
substitution with DAla in this position (15c) leads to a drop in
both conversion and selectivity (11a/12a, 1:1.6; 12a with 90:10
er; Table 1, entry 6). We thus chose 15a as our catalyst for
further study.
A brief survey of reaction solvents showed halogenated
solvents to be superior, with chloroform giving the best results
in terms of both conversion and selectivity (11a/12a, 1:3.7;
12a with 96:4 er; Table 2, entry 1). We next wished to test our
hypothesis that the benzamide was acting mainly as an H-
bonding handle, but that modifications that preserved this
capability should be tolerated. Indeed, we find that when a CH2
is inserted between the phenyl ring and the amide, as in 10b,
the selectivity not only remains but in fact improves, with 12b
forming in as high as 97:3 er at similar conversion (11b/12b,
1:4.5; Table 2, entry 2). Intriguingly, when the CH2 is replaced
with a NH (urea 10c), the reaction shows a pronounced
increase in conversion, seeming to reflect an accelerated
reaction rate for the “mismatched” enantiomer. Importantly,
Figure 3. (a) BV oxidation of 10a. (b) Tracking the regiochemistry of
O atom insertion for each enantiomer of 10a with m-CPBA, and (c)
catalyst 9b. See SI for absolute stereochemical assignment.
that both isomeric lactones 11a and 12a are formed upon
exposure to 3-chloroperoxybenzoic acid (m-CPBA). When this
stoichiometric oxidant is used, lactone 11a dominates, in a ratio
of 7.9 to 1. However, with catalyst 9b (10 mol %), we observed
notable catalyst control, including reversal of intrinsic migratory
aptitude, with lactone 12a being favored 3.4 to 1 at 36%
conversion. Moreover, all three species (unreacted substrate
and both lactones) were enantioenriched (Table 1, entry 1),
with 12a being formed in 91:9 enantiomeric ratio (er).
This reaction exhibits characteristics of a parallel kinetic
resolution (PKR),11 in that each enantiomer of substrate is
converted preferentially to a different product. However, unlike
an archetypical PKR, the enantiomers exhibit an ∼5-fold rate
a
Table 1. Effect of Peptide Sequence on Selectivity
c
er
b
c
entry catalyst conv. (%)
ratio of 11:12
10a
11a
12a
1
2
3
4
5
6
9b
13
36
12
31
32
27
19
1:3.4
1.6:1
1:3.7
1:3.1
1:2.8
1:1.6
66:34
51:49
64:36
64:36
61:39
55:45
62:38
58:42
61:39
67:33
64:36
61:39
91:9
72:28
92:8
14
15a
15b
15c
94:6
94:6
90:10
a
b
Reaction conditions depicted in Figure 3, conditions B. Conversion
= ee10/(ee10 + eepdt), where eepdt is the aggregate enantiomeric excess
c
(ee) of both lactone products. Determined by HPLC.
B
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Communication
a
Table 2. Effect of Substituents and Ring Size on Selectivity
b
e
b
reversal of regioselectivity: regioisomer ratio (11:12)
er
c
d
entry
substrate
conv. (%)
m-CPBA
(15a, total)
15a, matched
10
11
12
1
2
3
4
5
6
10a
10b
10c
10d
10e
10f
41
45
64
7.9:1
2.5:1
1.4:1
3.0:1
(1:3.7)
(1:4.5)
(1:1.8)
(1:3.1)
(1:1.8)
(1:7.3)
(1:38)
(5.2:1)
(1.2:1)
1:12
1:28
73:27
76:24
71:29
70:30
85:15
93:7
96:4
97:3
92:8
95:5
91:9
93:7
85:15
99:1
88:12
1:24
f
g
20
1:8.2
1:4.4
1:23
ND
64:36
64:36
71:29
78:22
56:44
83:17
h
20
44
51
6.1:1
56:44
80:20
85:15
54:46
53:47
5.2:1
1:2.3
i
7
10g
10h
10i
<1:100
2.3:1
1:4.3
f
8
9
52
>100:1
3.3:1
f
44
a
Conditions: 15a (10 mol %), 4-dimethylaminopyridine (DMAP, 10 mol %), N,N′-diisopropylcarbodiimide (DIC, 3.0 equiv), H2O2 (3.8 equiv),
b
c
d
e
CHCl3 (0.1 M), 21 °C, 24 h. Determined by HPLC. See Table 1, footnote b. m-CPBA (1.1 equiv), CHCl3 (0.1 M), 21 °C, 12 h. Product ratio
for the enantiomer that reacts more rapidly with the catalyst. Conversion approximated from comparison of HPLC peak integrations of the products
to the substrate. ND = not determined. m-CPBA (2.0 equiv) used. DIC (1.5 equiv), H2O2 (1.9 equiv) used.
f
g
h
i
the rate acceleration in the mismatched series does not come at
the expense of enantioselectivity. Instead, this reaction is more
similar to an ideal PKR, with 11c and 12c forming in 93:7 and
92:8 er, respectively (11c/12c, 1:1.8; Table 2, entry 3). On the
other hand, the reaction performs poorly with substrate 10d,
wherein the directing group is a carbamate. Decreases in both
conversion and selectivity (11d/12d, 1:3.1; 12d with 95:5 er;
Table 2, entry 4) are observed in this case, possibly indicating
that, in contrast to 10c, the introduction of an oxygen, which is
a nominal H-bond acceptor, creates Coulombic repulsion that
weakens the catalyst−substrate interaction. Finally, tosylamide
10e is also a competent substrate, exhibiting similar trends in
both enantio- and regioselectivity (11e/12e, 1:1.8; 12e with
91:9 er; Table 2, entry 5). Taken together, these data suggest
an H-bonding interaction between the NH of the substrate and
an as yet unidentified H-bond acceptor on the catalyst.
enantioenrichment (11i/12i, 1.2:1; 12i with 88:12 er, Table
2, entry 9).
Since the catalyst mediates a range of substrate-dependent
reaction paradigms, from classical KR to PKR, we selected three
substrates that exemplify distinct modes of reactivity and
subjected them to minimally optimized BV conditions in order
to demonstrate the isolation of enantioenriched products in
each of these scenarios. Ketone 10g, which undergoes a KR
with catalyst 15a, can be oxidized at −8 °C, to give 38% yield of
12g in 93:7 er and 50% recovery of 10g with 86:14 er (krel of
27, Scheme 1a). The oxidation of 10b, which represents an “in
a
Scheme 1
Having evaluated the catalyst’s performance with a variety of
H-bonding handles, we next wished to investigate the effect of
modification to the ring. The catalyst tolerates substitution
adjacent to the directing group, with 4,4-dimethyl substrate 10f
giving selectivity comparable to parent benzamide 10a (11f/
12f, 1:7.3; 12f with 93:7 er; Table 2, entry 6). The introduction
of a 2-methyl group adjacent to the amide (10g) creates a slight
preference for the formation of lactone 12g when m-CPBA is
used (11g/12g, 1:2.3; Table 2, entry 7). This is strongly
amplified by catalyst 15a, leading to an almost undetectable
level of 11g (11g/12g, 1:38; Table 2, entry 7). This reaction,
which is now similar to a classical KR, proceeds with good
enantioselectivity, corresponding to a krel of 11. Conversely,
isomeric substrate 10h exhibits a strong preference for lactone
11h (11h/12h, >100:1 with m-CPBA; Table 2, entry 8). Even
so, catalyst 15a forms an appreciable quantity of 12h in almost
enantiopure form (11h/12h, 5.2:1; 12h with 99:1 er). Finally,
we find that cyclopentanone 10i also undergoes clean oxidation
with “PKR-like” behavior, in which products 11i and 12i are
formed in near equal quantities, with similar levels of
a
Conditions: 15a (10 mol %), DMAP (10 mol %), CHCl3. A: DIC
(1.5 equiv over 8 h), H2O2 (1.9 equiv), −8 °C, 58 h. B: DIC (4 equiv
over 12 h), H2O2 (5 equiv), 21 °C, 32 h.
between” form of KR/PKR since each substrate enantiomer
leads to a different regioisomer but at different rates, allows for
the isolation of “m-CPBA-disfavored” lactone 12b in 24% yield
(>58:1, 12b/11b) with 97:3 er (Scheme 1b). Finally, ketone
10c, which leads to a more “PKR-like” reaction, may be
converted to lactones 11c and 12c in 56% combined yield, with
96:4 and 92:8 er respectively (Scheme 1c).
In summary, we have described catalysts that influence both
the regio- and enantioselectivity of BV reactions involving
functionalized ketones. The catalysts show the capacity to
overturn the regioselectivity exhibited by m-CPBA, suggesting
C
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Journal of the American Chemical Society
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(13) The situation is reminiscent of double diastereoselection, as
codified previously, but pertains to regio- and enantioselectivity in
these cases. See: Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R.
Angew. Chem., Int. Ed. 1985, 24, 1.
more generally that intrinsically disfavored BV products may be
accessed with peptide catalysis. Furthermore, the mechanism
underlying the selectivity, which likely stems from interactions
between the peptide and H-bonding functionality of the
substrate, constitutes a distinct approach to selective BV
oxidation, relative to known small molecule catalysts. Further
interrogation of this mechanism as well as applications to both
enantioselective synthesis and natural product modification are
ongoing objectives in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional figures, experimental details and characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
scott.miller@yale.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Institutes of Health
(NIH R01-GM096403). We also thank Dr. Brandon Q.
Mercado for X-ray crystallographic analyses.
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D
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