Catalytic Enantioselective Pyridine N-Oxidation

Article abstract of DOI:10.1021/jacs.9b10414

The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine N-oxides further document the utility of this approach. Demonstration of the asymmetric N-oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.

Full text of DOI:10.1021/jacs.9b10414

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Article
Catalytic Enantioselective Pyridine N-Oxidation
Sheng-Ying Hsieh, YU TANG, Simone Crotti, Elizabeth Stone, and Scott J. Miller
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10414 • Publication Date (Web): 26 Oct 2019
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Catalytic Enantioselective Pyridine N-Oxidation
Sheng-Ying Hsieh, Yu Tang, Simone Crotti, Elizabeth A. Stoneand Scott J. Miller*
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Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States
ABSTRACT: The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-
inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic acid-containing peptides as the aspartyl side chain
shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substi-
tuted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine
frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine N-oxides further
document the utility of this approach. Demonstration of the asymmetric N-oxidation in two venerable drug-like scaffolds, Loratadine and Var-
enicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is
applicable to both pyridines and 1,4-pyrazines.
(a) Several bioactive pyridine derivatives
N
N
■
INTRODUCTION
N
OH
HN
N
OMe
OMe
N
Substituted pyridines continue to emerge with high frequency in
disclosures of biologically active scaffolds. Accordingly, methods
H
N
3
CF
H
1
Cl
N
N
N
O
CF
3
N
+
N
O–
Cl
for synthesizing differentially substituted analogs are highly cov-
N
CF
3
2
eted. Strategies for constructing pyridine-containing molecules in
MK-1064
Orexin 2 receptor antagonist
Mefloquine
Treatment for malaria
Seletalisib
PI3Kδ inhibitor
optically enriched form are generally indirect, given the planarity of
the heteroaromatic pyridine N-nucleus. Nonetheless, methodolo-
gies for achieving “asymmetric”, or enantioselective, syntheses of
pyridines are essential given the extant and growing number of pyri-
dine-containing chiral molecules now found in drugs and drug can-
(b) Select methods for constructing “chiral pyridines”
(
i) Assembly with Chiral Building Blocks
(ii) Use of Chiral Auxiliary
CO
2
Et
Me
Me
Me
Me
H
2
N
Me
Ph-MgBr
N
Ph
N
Me
N
O
HN
O
3
130 ºC
Ref 5
Me
OH
N
CO
2
Et
S
S
didates (Fig. 1a).
O
Ref 4
tBu
tBu
Me
3% yield
Enantioselective syntheses of pyridines are often predicated on
(+)-β-hydroxy-
methylenecamphor
70% yield
97% de
7
4
using building blocks containing stereogenic centers (Fig. 1b, i), or
(iii) Asymmetric Photocatalytic Cross-Coupling
(iv) Asymmetric Hydrogenation
appending chiral auxiliaries to the pyridine as a substituent (Fig. 1b,
O
5
PhthN
Me
Me
ii). Using asymmetric catalysts, chiral pyridines can be accessed
Me
N
O
2
H , chiral
catalyst
6
NHAc
R
R
OH
through the coupling of chiral fragments (Fig. 1b, iii) or by perform-
Me
N
Ref 7
N
chiral phosphoric acid
photoredox catalysis
N
O
ing an asymmetric catalytic reaction on a pyridine with a prochiral
NHAc
91% yield, 94% ee
Ref 6
99% yield
up to 99% ee
7
element (Fig. 1b, iv). Particularly inspiring for the present report,
enantioselective N-oxidation of tertiary amines (Fig. 1c) was re-
ported by Sharpless in 1983, wherein chiral Ti-based complexes
were employed in stoichiometric quantities to affect kinetic resolu-
(c) Kinetic resolution of tertiary amines
O
TBHP
N
OH
N
OH
N
OH
i
(R)
(S)
Ti(OPr)4
Ph
Ph
Ph
8
(+)-diisopropyl tartrate
tion of tertiary amines.
(±)-1,3-amino alcohol
PhCH
3
, –20 ºC
37% yield, 95% ee
59% yield, 63% ee
Ref 8
c = 60%, s = 15.6
We now report herein an alternative, unprecedented catalytic pyr-
idine N-oxidation reaction, in which chirality is established via re-
mote asymmetric desymmetrization (Fig. 1d). As described below,
the chemistry proceeds with high levels of enantio- and chemoselec-
tivity, and we have also achieved derivatizations of the resulting pyr-
idine N-oxides (Fig. 1d, right) that add to the versatility of the ap-
proach for synthesis. In addition, we have extended this chemistry to
intriguing, now-venerable classes of bioactive heterocyclic scaffolds
(
d) This work
t
NHCO Bu
t
t
NHCO Bu
NHCO Bu
Peptide
BocHN
O
O
N
N
N
N
Nu
N
N
N
O
2
a
3a
H
O
t
NHCO Bu
O
chiral N-oxides of
heterocyclic
pharmaceuticals
or
heterocyclic
pharmaceuticals
enantioselective
pyridine N-oxidation
Nu
N
(
vide infra), which implies generality for this new method.
RESULTS AND DISCUSSION
Our approach required the identification of an appropriate cata-
Figure 1. (a) Representative bioactive pyridine-containing com-
pounds. (b) Several conventional strategies to access optically en-
riched pyridine-containing molecules. (c) Inspiration from enantiose-
lective N-oxidation of tertiary amines. (d) The method reported
herein for enantioselective N-oxidation of pyridines and subsequent
derivatization.
■
lytic cycle for pyridine N-oxidation, and the design of a substrate-
type that would allow us to interrogate enantioselectivity. For the
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The desired pyridine N-oxidation then completes the catalytic cycle
and regenerates . One interesting difference between the presently
disclosed pyridine N-oxidation and our prior epoxidation and BV
catalytic systems is that in this new application, both the substrate
and product can serve as transient co-catalysts for the reaction, pre-
venting deleterious rearrangement of the intermediate O-acyl urea
(
a) Electrophilic Epoxidation
(b) Nucleophilic Baeyer-Villiger Oxidation
Peptide
O
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
BocHN
O
O
Me
2
HO
R
R
OH
OH
H
2
O
2
NHBz
3
DIC
(±)-ketone
DMAP
Peptide
O
O
6
Me
O
O
O
14
96:4 er
(41% conv.)
to the catalytically inactive N-acyl urea
7
, possibly through the for-
+
O
BocHN
O
mation of intermediates like . In our earlier studies, we had deliber-
8
Up to 96.5:3.5 er
75–80% yields)
NHBz
NHBz
(
Peptide favored
m-CPBA favored
ately assigned this function to the additive DMAP or DMAP N-ox-
ide. Notably, we observed no particular advantage or disadvantage
to the incorporation of extra DMAP on the selectivity in the current
studies. In any event, we were pleased to see that with 10 mol% of
Boc-Asp-OMe (1a) as the catalyst, 63% yield of 3a could be
achieved, albeit in racemic form (Fig. 3b, table, entry 1).
H
O
Reversal of Intrinsic
Migratory Aptitude
O
(
c) Catalyst-Dependent Chemoselectivity Based on Outer-Sphere Control
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
OH
Boc-Asp-Pro-Asn(Trt)-
R
O
R
O
D
-Phe-Pro-Asn(Trt)-OMe
H
O
H
Electrophilic
Epoxidation
Site
(10 mol%)
N
N
H
H
3
2 2
0% H O (200 mol%)
HO
Nucleophilic
O
Baeyer-Villiger
Oxidation Site
O
R
O
We then turned our attention to the critical question of enantiose-
lectivity. Given nonexistent analogy in the literature for the explicit
design of chiral catalysts for pyridine N-oxidation, we elected to
compare a combinatorial approach to the discovery of a “hit” catalyst
to a class of b-turn-biased catalysts we have previously employed for
>
99:1 diastereoselectivity
>99:1 chemoselectivity
H
N
Boc-
Pro-
D
-Asp-
-Tyr(tBu)-OMe
(10 mol%)
% aq. H (200 mol%)
D-Pro-Lys(Boc)-
H
D
O
>50:1 regioselectivity
12:1 chemoselectivity
3
2 2
O
O
Figure 2. Asp-containing peptide as catalysts for (a) electrophilic epox-
idation and (b) nucleophilic Baeyer–Villiger (BV) oxidation. (c) Cat-
alyst-dependent reactivity when olefins and ketones are both present in
the molecule.
15
many asymmetric reactions. For the combinatorial approach, we
16
applied the one-bead-one-compound (OBOC) library concept.
t
NHCO Bu
t
NHCO Bu
2 2
30% aq. H O (1.5 equiv)
former, we wondered if a recently explored family of biologically in-
spired oxidation catalysts might suffice. We have shown, for exam-
ple, that aspartic acid-containing catalysts exhibit significant prowess
DIC (1.0 equiv)
Peptide (10 mol%)
CDCl (0.2 M), RT, 12 h
3
N
N
N
N
2a
O
3a
9
as enantioselective epoxidation (Fig. 2a) or asymmetric Baeyer–
(a) Initial Screening of On-bead or Designed Catalysts
10
Villiger (BV) catalysts that also exert control over migratory apti-
i+1
tude in BV reactions (Fig. 2b). Furthermore, the peptide sequence
can control functional group selectivity, selecting olefins (epoxida-
tion) or ketones (BV), even if both are present within the same mol-
O
O
HO
2
C
HN
i+2
O
N
HN
i
HN
O
HO
C
HN
O
2
HO
Ph
2
C
O
HN
O
t
NH
O Bu
O
HN
Boc
HN
O
NH
1
1
NH
O
NHBoc
i+3
Boc
ecule, overcoming the specter of cross-reactivity (Fig. 2c). Moreo-
ver, because these catalysts exhibit high chemoselectivity in the pres-
Boc
HN
O
O
Ph
O
NHBoc
OMe
OMe
1
b, er: 75:25
OMe
1d, er = 74:26
1
2
ence of electron-rich heterocycles, we thought they might have the
mechanistic generality to serve as selective pyridine N-oxidation cat-
alysts, as projected in Fig. 1d. Several other designs of catalytic resi-
dues for enantioselective pyridine N-oxidation were also considered
(on-bead screening:
er: 69.5:30.5)
1c, er: 72:28
(on-bead screening:
er: 70:30)
(b) Tablulated Data for Catalyst and Reaction Optimization
Entry Peptidee
er, 3a
1
3
1
a
Boc-Asp-OMe, 1a
Boc- -Asp- -Pro-Acpc-Phe-OMe, 1d
Boc-Asp- -Pro-Acpc-Phe-OMe, 1e
Boc-Asp-Pro-Acpc-Phe-OMe, 1f
50:50
based on the previous literature.
Shown in Scheme 1 is the catalytic cycle we desired to implement
for asymmetric pyridine N-oxidation of to using Asp-containing
catalysts ( ). Overoxidation to form bis(N-oxide) product is also
2
D
D
74:26
52:48
36:64
48:52
3
4
D
2
3
1
4
5
Boc-
Boc-
Boc-
Boc-
Boc-
D
D
D
D
D
-Asp-Pro-Acpc-Phe-OMe, 1g
possible, as is a general issue with desymmetrizations wherein dou-
ble functionalization can occur. Nevertheless, in analogy to epoxida-
1
tion and BV oxidation, we relied on carbodiimide activation of to
chaperone the Asp-containing catalysts to the Asp-based peracid
6b
7b
8
-Asp-
-Asp-
-Asp-
-Asp-
D
D
D
D
-Pro-Acpc-Phe-OMe, 1d (PhMe)
72.5:27.5
-Pro-Acpc-Phe-OMe, 1d (polar solvents)c < 62:38
-Pro-Acbc-Phe-OMe, 1h
56:44
5
.
9
-Pro-Cle-Phe-OMe, 1i
-Pro-Acpc-Phe-OMe, 1j
-Pro-Acpc-Phe-OMe, 1k
-Pro-Acpc-Phe-OMe, 1l
54:46
79.5:20.5
78: 22
tBuNHCO-
Boc-Gly- -Asp-
Boc-Phe- -Asp-
D-Asp-D
1
0
O-to-N acyl transfer
11
D
D
DIC
1
2
D
D
76.5:23.5
83.5:16.5
84:16
Catalyst (1)
O
N
O
N
O
O
N
13
Boc-
Boc-
Boc-
D
D
D
-Phe-
-Phg-
-Phg-
D
D
D
-Asp-
-Asp-
-Asp-
D-Pro-Acpc-Phe-OMe, 1m
D-Pro-Acpc-Phe-OMe, 1n
D-Pro-Acpc-Phe-OMe, 1n
NHBoc
NHBoc
1
4
t
DMAP
or
2, 3 or 4
NHBoc
NHCO Bu
O
OH
O
H
O
15d
16
iPr
86:14
iPr
O
N
N
N
Boc-Pro-
D
-Asp-
D
-Pro-Acpc-Phe-OMe, 1o
-Pro-Acpc-Phe-OMe, 1p
74:26
6
iPr
i
NHPr
N
N
1
7
Boc- -Pro-
D
D-Asp-
D
71:29
O
7
O
N
Product (3a) +
2 2
H O
bis-(N-oxide) (4a)
O
H
N
Figure 3. Screening of peptide catalysts from (a) the one-bead-one-
NHBoc
t
NHCO Bu
NHBoc
Nuc
compound (OBOC) library and (b) proline-type β-turn peptides.
O
a
b
O
O
8
Nuc = DMAP, DMAP N-oxide,
or 2, 3, or 4
The mono-N-oxide 3a was produced in 63% yield. Instead of
N
N
O
2 2
H O
CDCl
3
, the solvent listed in parentheses was used in this reaction.
Substrate (2a)
5
c
d
Polar solvents included: EtOAc, Et O, and THF. The reaction was
2
performed at 4 °C. Ers were measured according to the eluent order.
Scheme 1. Hypothesis of the catalytic cycle for enantioselective N-
oxidation of pyridine substrates.
e
Abbreviatiations are specified in the Supporting Information.
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Journal of the American Chemical Society
Application of this approach (described in the Supporting Infor-
(
1j, entry 10) resulted in observation of nearly 80:20 er. Addition of
1
2
3
4
5
6
7
8
9
mation) to the desymmetrization of 2a led to the identification of a
number of “hit” catalysts, including 1b and 1c (Fig. 3a). These cata-
lysts delivered 3a with appreciable enantioselectivity under the con-
ditions of the assay (resin-bound 1b, 69.5:30.5 enantiomeric ratio
(er); resin-bound 1c, 70:30 er); synthesis and evaluation under ho-
a fifth amino acid residue to the N-terminal side gave further en-
hancement of er (entries 11–17). Of these catalysts, peptide 1n with
a Boc-D-phenylglycine (Boc-D-Phg, entry 15) N-terminal residue
delivered 3a with an 86:14 er. Accordingly, we elected to examine
this catalyst further with reaction conditions and for studies of sub-
strate scope.
mogeneous conditions gave validating results (1b, 75:25 er; 1c
,
72:28 er). In parallel, our assessment of b-turn-biased catalysts in-
Table 1. Optimization of reaction conditions for pyridine N-
oxidation with peptide 1n performed on 0.05 mmol scale.
cluded a survey of the diastereomers of canonical Boc-Asp-Pro-type
15b, 17
tetramers (Fig. 3b, table, entries 2–5),
and of these catalysts, 1d
t
NHCO Bu
delivered 3a with 74:26 er. Thus, we elected to pursue catalysts re-
lated to 1d further. Parenthetically, we suspect that any of the three
scaffolds in Fig. 3a could in principle be optimized for the selective
NHCOtBu
2 2
30% aq. H O (1.5 equiv)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
DIC (X equiv)
1n (10 mol%)
CDCl (0.2 M), 4 °C, 12 h
3
Me
N
N
Me
Me
N
N
Me
O
2
b
3b
oxidation of 2a to 3a
.
+
bis(N-oxide) 4b
Accordingly, we then turned to the optimization of catalyst 1d, ex-
ploring simple variations of side chains and stereochemical configu-
rations at each position of the catalyst. Several illustrative and heu-
ristic substitutions are shown in the table of Fig. 3b. First, the mono-
meric Asp-derived catalyst 1a noted above delivered the product in
racemic form, indicating that some higher-order structure would be
necessary for enantioselectivity (Fig. 3b, table, entry 1). Further-
more, the survey of the stereochemical disposition of each residue in
the b-turn-biased sequence (entries 2–5) revealed that Boc-D-Asp-
D-Pro-Acpc-Phe-OMe (1d) was indeed optimal, delivering the
Entry
DIC Equiv
Yield 3b [%]
er, 3b
Yield 4b [%]
1
2
3
4
1.0
1.2
1.4
1.6
71%
73%
68%
55%
92:8
93.5:6.5
96:4
12
18
30
45
98.5:1.5
Variations of the reaction parameters impacted the enantioselec-
tivity, but none more profound than the nature of the 6- and 6′-posi-
tions of
2. Thus, when 2b was employed, with a methyl group at the
6- and 6′-positions, we observed an increase in the er such that 3b
was produced with 92:8 er, and in 71% isolated yield (Table 1, entry
1). Moreover, we discovered that there was a degree of secondary
kinetic resolution in the overoxidation of 3b (to give 4b) that led to
further er enhancement (entries 2–4). Indeed, 3b was generated
with >98:2 er when 1.6 equiv of DIC was employed, albeit with a
small sacrifice in yield (55% yield). With this level of
7
4:26 er, while other diastereomers gave lower selectivity. Chloro-
form also emerged as the preferred solvent with catalyst 1d in a pre-
18
liminary survey (entries 6–7). Variation of the i+2 residue gener-
ally led to catalysts with lower selectivity (entries 8–9); yet, variation
of substituents to the N-terminal side of the peptide sequence led to
promising improvements. An N-terminal tert-butyl urea substituent
O
R
3
N
HN
R3
2
HO C
30% aq. H
2
O
2
(1.5 equiv)
R2
R1
R2
R1
O
O
R2
4
R2
DIC (1.4 equiv)
(S)
HN
3
5
6
1
n (10 mol%)
NH
N
N
O
2
O
Ph
R1
N
N
R1
CDCl
3
(0.2 M), 4 °C, 12 h
O
NH
Boc
Peptide 1n
OMe
3
Ph
2
+
bis(N-oxide) 4
(a)
t
t
t
t
t
NHCO
t
Bu
t
NHCO Bu
NHCO Bu
NHCO Bu
NHCO Bu
NHCO Bu
NHCO Bu
N
N
Me
N
N
Me
i
Pr
N
N
i
Pr
t
Bu
N
N
t
Bu
N
N
Ph
N
N
Ph
N
N
O
O
O
O
O
O
O
F
F
3
a (18 h)
3b
76% yield
97:3 er
3c
71% yield
99:1 er
3d (48 h)
70% yield
98.5:1.5 er
3e
3f (24 h)
3g (24 h)
75% yield
8
69% yield
99:1 er
78% yield
98:2 er
78% yield
99:1 er
7:13 er
t
t
NHCO Bu
NHCO Bu
t
NHCOtBu
t
NHCO Bu
NHCO Bu
X-ray
Me
Me
structure
absolute
config.
N
N
N
N
MeO
N
N
OMe
N
N
N
O
N
O
O
O
O
MeO
OMe
(S)
3
h (72 h)
74% yield
8:2 er
3i (24 h)
79% yield
96:4 er
3j
3k (96 h)
3l
79% yield
97:3 er
67% yield
88:12 er
65% yield
87:13 er
9
(b)
tBu
Ph
Me
Ot-Bu
Me
Me
NHCO Bu
t
NHCO Bu
t
HN
O
N
HN
O
HN
O
N
O
N
O
N
N
N
Me
N
O
Me
N
Me
Me
N
N
Me
Me
N
N
Me
Me
N
Me
O
O
O
O
3
m
3n (18 h)
54% yield
52:48 er
3o
71% yield
54:46 er
3p
3q
3r
5
5
6% yield
0:50 er
67% yield
84:16 er
69% yield
72:28 er
64% yield
60:40 er
Figure 4. Substrate scope of the desymmetrization of bis(pyridine)s with peptide catalyst 1n, with (a) substrates reacting well to excellently and (b)
those that reacted with low to no selectivity. Different reaction times are noted in parentheses. For reaction details, see Supplementary Information.
Absolute configuration of 3a
as uncertain.
–
3k and 3p
–
–
3r were determined by analogy to the single-crystal X-ray diffraction of 3l, and the ones of 3m 3o were listed
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
enantioselectivity, we turned our attention to the scope and limita-
tions for this new asymmetric process.
Our explorations of substrates led to the identification of a num-
ber of excellent substrates, as well as some that did not work as well.
Under optimized conditions (1.5 equiv oxidant, 0.2 M in substrate,
with the substrate in a manner that is consistent with the identity of
the major enantiomer in the (S)-configuration that we observe. This
model is predicated on well-precedented conformational analyses
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
15b, 19
for Pro-Acpc peptides,
and accommodates the SAR derivable
from Fig. 3b and Fig. 4. In this speculative transition state, the pep-
tide adopts a type II′ b-turn conformation in the reactive complex.
Hydrogen bonding interactions are envisioned to contribute to cat-
alyst-substrate organization.
The optically enriched pyridine N-oxides emerging from this
study also provide a platform for the synthesis of chiral pyridine-con-
taining scaffolds, as demonstrated in Fig. 6. For example, Ph-substi-
4
°C), 3a was isolated in 75% yield with 87:13 er (Fig. 4a). In addi-
tion, quite a few excellent substrates emerged with 6,6’-di-substitu-
tion. For example, 3b was isolated in 76% yield with 97:3 er. iso-Pro-
pyl-bearing product 3c was also obtained with high er (71% yield,
99:1 er), as was the tert-butyl substituted compound 3d (70% yield,
98.5:1.5 er), albeit requiring a 48 h reaction time in this case. Simi-
larly, the cyclohexyl-bearing substrate 2e was converted to 3e with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tuted pyridine N-oxide 3f was permuted to aminopyridine
9
, arylox-
9
9:1 er (69% isolated yield). Aryl-substituted pyridines were also
well-tolerated by catalyst 1n, as illustrated by the isolations of 3f
78% yield, 98:2 er), 3g (78% yield, 99:1 er), 3h (74 % yield, 98:2
ypyridine 10, and thioether variant 11 under established PyBroP®-
2
0
based substitution conditions (Fig. 6). Parenthetically, the desym-
metrized unsubstituted pyridine N-oxide 3a may also be regioselec-
tively diversified. For example, using recrystallized material of 3a
(91:9 er), amination delivered 12 in a 15:1 ratio of 2/6 positional
regioisomers, while sulfonamidation (13) occurred in a >19:1 ratio
of 6/2 positional regioisomers (Fig. 6).
(
er) and 3i (79% yield, 96:4 er). Some other more exotic substituents
were also promising, as bis(quinoline) 3j was isolated in 79% yield
with 97:3 er under these conditions. 6,6′-Bismethoxy-substitution
was less tolerated, although 3k was still isolated with 88:12 er and in
6
7% yield. Altering the position of the pyridyl substituent to 5,5′-di-
H
2
N
Ph
NHCO Bu
t
methylation led to a product with somewhat lower selectivity, as 3l
was isolated with 87:13 er and 65% yield. The absolute configuration
of N-oxide 3l was determined by single crystal X-ray diffraction,
which enabled the assignment of the remaining substrates by anal-
ogy.
(1.25 equiv)
Amination
Ph
N
NH
N
Ph
Ph
9
(a)
t
58% yield, 96:4 er
NHCO Bu
Me
HO
On the other hand, Fig. 4b depicts several substrates that do not
work as well with peptide 1n, including substitution at the 2-position
of the pyridine (3m) or when the pyridyl moieties are bridged at the
t
NHCO Bu
Ph
N
N
Ph
Me
O
(+)-3f
96:4 er
(1.25 equiv)
Ph
N
O
N
Ph
Etherification
Me
Me
4
-positions (3n). These two cases afforded products that were
PyBroP® (1.3 equiv)
NEt (3.75 equiv)
iPr
2
nearly racemic with catalyst 1n. In addition, compounds related to
3
CH
2
Cl
2
, RT, overnight
10
74% yield, 96:4 er
generally exhibited higher selectivity when the bridging amide group
was a secondary pivaloyl amide. When the free N-H group was re-
placed with N-Me (3o), selectivity was greatly diminished (54:46
er), suggesting that the secondary amide may play a mechanistic role
as a hydrogen bond donor. When the pivaloyl group was converted
to benzoyl (3p) or acetyl (3q), selectivity was partially restored
HS
t
NHCO Bu
tBu
N
PF
Br
6
–
+
N
P
(1.25 equiv)
N
Ph
N
S
N
Ph
Thioetherification
PyBroP®
tBu
11
55% yield, 96:4 er
(
84:16 er and 72:28 er, respectively). The Boc-protected substrate
was also examined, but delivered the product with a reduced er
60:40 er). It is certainly possible that re-optimization with another
t
3
r
NHCO Bu
NH (1.2 equiv)
(
PyBrop (1.3 equiv)
iPr
CH
NEt (3.75 equiv)
Cl , RT, overnight
N
N
N
catalyst from our library might address these classes in a more selec-
tive manner.
2
(b)
NHCO Bu
t
2
2
Amination
12
2% yield
8
regioselectivity =15:1
91:9 er
While we do not yet know the basis of asymmetric induction in
the highly selective variants of these reactions, we are in a position to
offer some speculation in analogy to previous studies. In this spirit,
the ensemble shown in Fig. 5 presents a schematic drawing in which
the activated aspartic peracid catalytic intermediate may interact
6
2
N
N
O
O
(+)-3a
1:9 er
Ph
S
NH
2
t
NHCO Bu
9
O
(1.75 equiv)
PyBrop (1.3 equiv)
iPr
NEt (3.75 equiv)
CH Cl , RT, 15 h
N
NH
S
N
2
O
O
2
2
Ph
O
t
Bu
Sulfonamidation
13
7
5% yield
regioselectivity > 19:1
0:10 er
H
N
9
H
H
N
Figure 6. Derivatization of (a) enantioenriched 3f via amina-
tion, etherification, and thioetherification and (b) 3a through
regioselective amination and sulfonamidation.
N
N
N
O
O
O
O
H
N
H
O
O
H
H
O
H
N
Ph
OMe
R
Substrate 2a + Peptide Catalyst
(Posed in type II’ β-hairpin
conformation)
Figure 5. A speculative and heuristic model for the enantiomeric
outcome.
ACS Paragon Plus Environment

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Journal of the American Chemical Society
fundamental and applied studies in both process-oriented and dis-
Cl
1
2
3
4
5
6
7
8
9
covery-oriented synthetic chemistry settings.
N
Cl
Cl
N
N
R′
H
H
rapid
N
N
interconversion
N
R
R
O
R
ASSOCIATED CONTENT
Supporting Information
R = OEt, R′ = H, Loratadine
i
R = Pr, R′ = Br, 14
3
R = NH(p-CF Ph), R′ = H, 15
The Supporting Information is available free of charge on the ACS Pub-
lications website.
Cl
N
30% aq. H O
(1.5 equiv)
DIC (1.0 equiv)
2
2
Experimental details, characterization, and X-ray crystallographic data
O
H
N
(PDF)
NH
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1d (10 mol%)
CDCl
4 °C, 20 h
O
3
(0.2 M)
AUTHOR INFORMATION
CF
3
1
6
Corresponding Author
X-ray structure
45% yield, 95:5 er
* scott.miller@yale.edu
Figure 7. Dynamic kinetic resolution of Loratadine derivative 15.
Funding Sources
To address the question of whether our approach might be appli-
cable generally, and in genuinely different classes of substrates, we
conclude with two exotic and demanding applications in unambigu-
This work is supported by the National Institute of General Medical Sci-
ences of the National Institutes of Health for support (R35
GM132092). S.Y.H. is very grateful to the Swiss National Science Foun-
dation for a postdoctoral fellowship. E.A.S. acknowledges the support of
the NSF Graduate Research Fellowship Program.
21
ously drug-like scaffolds. Loratadine, the active ingredient in the al-
lergy medicine Claritin®, exhibits unusual stereochemical properties.
For example, while Loratadine itself does not exhibit stable enantio-
mers due to rapid conformational interconversion, compounds like
14 can be isolated with optically purity due to high barriers to race-
Notes
X-Ray crystallographic data for compounds 3l (CCDC 1950272), 16
(CCDC 1950546), and 18 (CCDC 1950273) are available free of
charge from the Cambridge Crystallographic Data Center.
2
2
mization of the helically chiral enantiomers (Fig. 7). Thus, we won-
dered whether or not catalytic, enantioselective pyridine N-oxida-
tion of Loratadine derivative 15 could be subjected to dynamic ki-
netic resolution. Notably, catalyst 1d afforded 16 in 45% yield with
ACKNOWLEDGMENT
We thank Dr. Margaret J. Hilton for critical suggestions. We also would
like to thank Dr. Brandon Q. Mercado for solving our X-ray crystal struc-
tures.
9
5:5 er (Fig. 7). Pyridine N-oxidation is preferred, although we also
observed 30% conversion to the corresponding putative epoxide un-
der these conditions, as assayed by LC/MS (See Supporting Infor-
mation for details). This result highlights the applicability of this
chemistry beyond desymmetrizations. Moreover, we demonstrated
ABBREVIATIONS
See Supporting Information for details.
2
3
that a scaffold related to Varenicline may undergo desymmetriza-
tion, such that 17 was converted to 18 with catalyst 1d in 61% yield
and with 95.5:4.5 er (Fig. 8). This last result suggests the present ap-
proach may have generality with respect to other, enantio- and site-
selective heteroarene N-oxidations.
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■
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13) (a) Limnios, D.; Kokotos, C. G. “2,2,2-Trifluoroacetophenone as an
Organocatalyst for the Oxidation of Tertiary Amines and Azines to N-
(
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Enantioselective Access to Chiral N-Heterocyclic Scaffolds
Peptide
t-Bu
BocHN
O
X
N
R’
Cl
+
O
HN
O
N
R
*
–
O
H
R
R
N
+
HO
N
N
R
–
Claritin® analog, 95:5 er
H
2
O
2
O
DIC
DMAP
R
N
Remote
Desymmetrization
Peptide
O
BocHN
O
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
Various substrates;
Best cases,
N
up to 99:1 er
H
O
Chantix® analog, 95.5:4.5 er
O
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ACS Paragon Plus Environment