Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective Bromination

Article abstract of DOI:10.1021/jacs.5b07726

We report the development of a tertiary amine-containing β-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope. The structure of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and 2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using density functional theory calculations and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereodetermining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other atropisomerically defined products of interest. For example, (1) a dehalogenation Suzuki-Miyaura cross-coupling sequence delivers ortho-arylated derivatives, and (2) a regioselective Buchwald-Hartwig amination procedure installs para-amine functionality. Stereochemical information was retained during these subsequent transformations.

Full text of DOI:10.1021/jacs.5b07726

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Article
Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-
ones via Peptide-Catalyzed Atroposelective Bromination
Matthew E. Diener, Anthony J. Metrano, Shuhei Kusano, and Scott J. Miller
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07726 • Publication Date (Web): 06 Sep 2015
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Journal of the American Chemical Society
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Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via
Peptide-Catalyzed Atroposelective Bromination
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‡
‡
†
Matthew E. Diener, Anthony J. Metrano, Shuhei Kusano, and Scott J. Miller*
Department of Chemistry, Yale University, New Haven, CT 06520-8107, United States
KEYWORDS: quinazolinone, atropisomerism, bromination, peptide, catalysis
ABSTRACT: We report the development of a tertiary amine-containing β-turn peptide that catalyzes the atroposelective bromina-
tion of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad
substrate scope. The structure of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and
2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using DFT calculations
and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event
is stereo-determining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The
observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other, atropisomeri-
cally-defined products of interest. For example, (1) a dehalogenation-Suzuki-Miyaura cross-coupling sequence delivers ortho-
arylated derivatives, and (2) a regioselective Buchwald-Hartwig amination procedure installs para-amine functionality. Stereochem-
ical information was retained during these subsequent transformations.
(a)
O EtO
Introduction
O
N
Cl
N
N
N
F
Me
O
It is now becoming well appreciated that atropisomer-
ism1 is an issue of significant importance in medicinal
chemistry.2 Chiral compounds that exist as separate atro-
pisomers may present advantages if they have sufficiently
low barriers to racemization, such that dynamic kinetic
resolution3 is possible during selective binding to a target-
ed biological receptor. However, if the opposite atropiso-
mer binds to an off-target receptor, alternative, and even
deleterious, effects may ensue.4 Perhaps these scenarios
are behind an increasing number of reports,5 and even
patents,6 that describe the differential biological functions
of individual atropisomers. Accordingly, synthetic efforts
to prepare individual atropisomers comprise an area of
significant innovation in chemistry.7 Among scaffolds that
present these stereochemical issues, 3-arylquinazolin-
4(3H)-ones8 (1) are an important class of compounds,
whose exploding list of characterized biological properties
enumerates a large swath of biochemical functions (Figure
1a).9 We report herein our recent studies culminating in
catalyst-dependent syntheses of atropisomeric quinazoli-
none bromides (2) with high levels of enantioinduction.
These findings enable efficient access to a range of substi-
tuted quinazolinones available through an atroposelective
tribromination reaction, followed by either dehalogena-
tion-cross-coupling sequences or regioselective amination
reactions.
N
N
O
N
N
N
N
Me
Ph
O
O
Benzomalvin A
(antidepressant)
Et2N
Cl
CP-465022
(anticonvulsant)
Erastin
(antitumor)
1) "Br+" (3.0 equiv)
peptide (cat.)
(b)
Br
OMe
O
N
Br
O
N
(±)
OH
N
2) TMSCHN2
O
Br
N
R
R
1
2
OH
N
Br
N
R
3
stable atropisomer
FIGURE 1: (a) Some 3-arylquinazolin-4(3H)-one-based
bioactive compounds.9 (b) Our strategy for the peptide-
catalyzed atroposelective bromination of quinazolinones 1
to access enantioenriched bromides 2.
We recently demonstrated that peptide-based catalysts
are effective for the atroposelective bromination of both
biaryl10 and tertiary benzamide scaffolds.11 Gratifyingly, a
related approach has also been recently reported to access
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i + 1
O
i + 2
R'
1) NBS (3.0 equiv)
peptide 4 (10 mol%)
PhMe/CHCl3 (9:1 v/v, 0.01 M)
rt, 1 h
1
2
3
4
5
6
R
Br
O
N
N
HN
O Br
N
Me2N
O
OMe
O
(±)
(1)
N
OH
HN
i
2) TMSCHN2, MeOH
Br
Me
2a
NH
R"
Me
N
Boc
O
i + 3
1a
PG
4
7
8
9
Peptide Optimization
4a Boc-Dmaa-DD--PPrroo--AAiibb--PPhhee--OOMMee
4b BBoocc--DDmmaaaa--DD--PPrroo--AAibib--PPhhee--NNHHMMee
4c Boc-Dmaa-DD--PPrroo--AAiibb--PPhhee--NNMMee2
4d BBoocc--DDmmaaaa--DD--PPrroo--AAibib--PPhhee--PPhhee--NNMMee2
2
2
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4e Boc-Dmaa-DD--PPrroo--AAiibb--PPhhee--DD-P-Phhee-N-NMMee2
4f BBoocc--DDmmaaaa--DD-Pro-Aib-DD--PPhhee--PPhhee--NNMMee22
2
4g BBoocc--DDmmaaaa--DD--PPrroo--CClele--PPhhee--NNMMee2
2
4h BBoocc--DDmmaaaa--DD--PPrroo--AAccppcc--PPhhee--NNMMee2
2
4i BBoocc--DDmmaaaa--DD-Pro-Phe-Phe-NMe2
2
4j BBoocc--DDmmaaaa--DD-Pro-Aic-Phe-NMe2
2
4k Boc-Dmaa-DD--PPrroo--AAccppcc--PPhhee--OOMMee
4l BBoocc--DDmmaaaa--DD-Pro-Acpc-Phe-(RR))--aα--MMBBAA
4m BBoocc-D-Dmmaaaa-D-D-P-Proro-A-Acpcpc-cP-Phhee(5(5FF)-)N-NMMee2
2
4n BBoocc--DDmmaaaa--DD--PPrroo--AAccppcc--DD-P-Phhee-N-NMMee2
2
4o BBoocc--DDmmaaaa--DD--PPrroo--AAccppcc--GGlyly--OOMMee
4p BBoocc--DDmmaaaa--DD--PPrroo--AAccppcc--GGlyly--NNMMee2
2
4q BBoocc--DDmmaaaa--DD--PPrroo--AAccppcc--LLeeuu--NNMMee2
2
4r BBoocc--DDmmaaaa--DD-Pro-Acpc-Val-NMe22
4s Boc-Dmaa-DD--PPrroo--AAccppcc--NNllee--NNMMee2
2
4t BBoocc--DDmmaaaa--DD-Pro-Acpc-Npg-NMe2
2
4u Boc-Dmaa-D-Pro-Acpc-Chg-NMe2
Truncation Study
4v Boc-Dmaa-PDy-Prrro-Aib-Phe-OMe
4w BBoocc--DDmmaaaa--DD-P-Proro-O-AMibe-Phe-NHMe
4x Boc-Dmaa-DD--PPrroo--NAMibe-Phe-NMe2
2
4y Boc-Dmaa-DD--PPrroo--NAHibM-Pehe-Phe-NMe2
4z Boc-Dmaa-DD--PPrroo--AAcibp-cP-OheM-De-Phe-NMe2
4α Boc-Dmaa-D-Pro-Acpc-NMe2
4βocB-Docm-Daam-aDa-P-Dro-P-Aroc-pAcc-Cpch-gN-HNMe2
FIGURE 2. Assessment of peptide-based catalysts in the bromination of quinazolinone 1a using the conditions described in
Equation 1. Data shown in blue are the results of peptide optimization studies, and data shown in green are the results of a
truncation study. All results represent the average of two trials. Abbreviations: Boc, tert-butylcarbamate; Dmaa, β-
dimethylaminoalanine; Aib, 2-aminoisobutyric acid; Cle, cycloleucine (1-aminocyclopentane carboxylic acid); Acpc, 1-
aminocyclopropyl carboxylic acid; Aic, 2-aminoindane carboxylic acid; (R)-α-MBA, (R)-α-methyl benzyl amide; Phe(5F),
pentafluorophenylalanine; Nle, norleucine (n-butylglycine); Npg, neopentylglycine; Chg, cyclohexylglycine; Pyrr, pyrrolidinyl.
16
chiral isoquinoline N-oxides using a cinchona alkaloid-
derived urea catalyst.12 It is interesting to note that the
enantioselective synthesis of axially chiral quinazolinones
is a subject with a limited literature,13 and most methods
have either involved racemic synthesis followed by resolu-
tion or diastereoselective synthesis using chiral auxiliaries.
Given the growing interest in these compounds in medic-
inal chemistry, we targeted a catalytic asymmetric ap-
proach (Figure 1b). Notably, unlike many biaryl com-
pounds and benzamides, an opportunity also existed for
selective preparation of atropisomerically stable mono-
ortho-substituted quinazolinones (e.g. 3, Figure 1b), given
their established high barriers to enantiomerization.14 At
the same time, these issues could present fundamental
challenges to the development of catalysts that might me-
diate dynamic kinetic resolutions.3 Our assessment of the-
se concepts is presented below.
defined β-turn geometry. In that way, we hoped to capi-
talize on an interaction (e.g., hydrogen bonding or even
proton transfer) between the phenol of 1a and the tertiary
amine moiety of the Dmaa residue, with the potential for
additional interactions provided by the functionality and
11
chirality of the peptide (i.e., catalysts such as 4). Accord-
ingly, dynamic kinetic resolution would be possible via
selective docking and functionalization of one atropisomer
of (±)-1a over the other.
In the absence of any catalyst, bromination of 1a was
sluggish and non-selective under the conditions we exam-
ined. However, using triethylamine (10 mol%) as a cata-
lyst, bromination of 1a proceeded smoothly, providing
88% yield of racemic tribromide 2a. Thus, we began to
assess peptide-based catalysts (4) for this transformation,
and the results of our optimization are summarized in
Figure 2. We were pleased to discover that peptide 4a,
an archetypal β-turn-promoting sequence that we have
17
18
Results and Discussion
11,19
utilized in the past,
provided tribromide 2a in 66:34
Catalyst Identification. Our exploration of this
intriguing system began with a study of peptide-based
catalysts for the bromination of quinazolinone 1a using
er, setting the stage for further optimization. In a number
of previous instances, we have observed a marked effect of
the C-terminal protecting group on the enantioselectivity
15
the conditions described in Equation 1. Our design prin-
16
of peptide-catalyzed reactions. Comparing peptides 4a–
ciple was guided by previous reports from our group,
wherein we were able to embed a tertiary amine-
containing β-dimethylaminoalanine (Dmaa) residue with-
in a peptide sequence that was expected to adopt a well-
f, it is clear that the dimethylamide end cap provides an
advantage over the alternatives, which may be attributed
to the enhanced hydrogen bond acceptor ability of ter-
tiary amides.20
2
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The enantioselectivity of peptide-catalyzed reactions is
Furthermore, we were able to demonstrate the im-
portance of the folded conformation of peptide 4q
through a study of truncated peptide catalysts (Figure 2).
The effect of sequential residue deletions on the outcome
of the bromination reaction was dramatic. For example,
we found that the trimer Boc-Dmaa-D-Pro-Acpc-NHMe
(4β), which is able to access the intramolecular, ten-
membered ring hydrogen bond (NHi+3 to Oi) required for
1
2
3
4
5
6
7
8
often highly sensitive to residue substitutions, especially
those at the i+2 residue, a position that plays an im-
portant role in determining the secondary structural at-
tributes of the peptide. Upon examining the i+2 residue
(as in 4c and 4g–j), we observed a pronounced increase in
enantioselectivity when 1-aminocyclopropyl carboxylic
acid (Acpc) was substituted in this position (as in 4h),
providing 2a in 88:12 er, an increase in 36% ee com-
pared to 4c. The origin of this remarkable effect is not
fully understood, although we have hypothesized that
16
21
21
β-turn formation, provided 2a in 82:18 er, only modest-
9
ly reduced compared to tetramer 4q. On the other hand,
trimers possessing methyl ester (4z) and dimethylamide
(4α) end caps, which cannot form the β-turn hydrogen
bond, were significantly less selective. This provides evi-
dence that the β-turn secondary structure, which is acces-
sible in tetramers and secondary amide-terminated tri-
mers, is important for high levels of enantioinduction.
Dimers 4w–x were significantly less selective than the
corresponding trimers, although we were intrigued to
discover that one dimer, Boc-Dmaa-D-Pro-NHMe (4y),
was equally selective to trimer 4α, delivering 2a in 72:28
er. It is possible that the enhanced selectivity exhibited by
dimer 4y derives from its ability to form a seven-
membered ring hydrogen bonded structure (NHi+2 to
Oi),23 reinforcing the importance of secondary structure to
enantioselectivity. It is also interesting to note that the
inherent selectivity of the Dmaa-monomer itself (4v) actu-
ally favors the opposite enantiomer of 2a, albeit with very
low er.
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changes in the φ and ψ angles of the β-turn conformation
manifest in a more favorable interaction with 1a.
16,21
A
steric effect is also possible, although the degree of en-
hancement associated with the cyclopropyl ring of 4h
relative to the corresponding gem-dimethyl moiety of pep-
tide 4c may be too pronounced to be explained by sterics
alone. Nonetheless, having found a suitable i+2 residue,
we elected to reexamine the C-terminal protecting group
to ensure that the trends upheld with Acpc at the i+2 po-
sition (as in 4h and 4k–l). Indeed, the dimethylamide C-
terminal cap (as in 4h) was again found to outperform the
other functionalities.
Alterations to the i+3 position of β-turn-containing
tetramers allowed for fine-tuning of enantioselectivity.
Comparing peptides 4h and 4m–u, a number of trends
emerged. First, it is clear that none of these changes pro-
duced as dramatic an effect as substitutions to the i+2
residue. Yet, it was also apparent that alkyl-substituted
residues (4q–u) provide higher enantioenrichment of 2a
than benzyl- (4h, 4m–n) and unsubstituted (4o–p) resi-
dues. There was also very little difference among the al-
kyl-substituted i+3 residues of peptides 4q–u, so we opted
to move forward using leucine-containing 4q as the lead
catalyst, which provided tribromide 2a in 92:8 er under
the conditions of Equation 1. Compared to peptide 4t,
which contained a slightly bulkier neopentylglycine (Npg)
residue at the i+3 position and provided 2a in 93:7 er,
peptide 4q had the added benefit of containing a protein-
ogenic, inexpensive, and readily available residue at the
i+3 position.
O
N
N
HN
Me2N
O
O
O
H
N
i-Pr
≡
H
O
O
NMe2
4q
FIGURE 3. X-ray crystal structure of Boc-Dmaa-D-Pro-
Acpc-Leu-NMe2 (4q).24 Two different conformations of
4q are present in the unit cell, both of which show intra-
molecular hydrogen bonds characteristic of type II' β-
turns.21
Br
Br
O
O
O
Br
N
O
Catalyst Structure. Catalyst 4q proved amenable
to study with X-ray diffraction (Figure 3). Interestingly,
two different conformations of 4q are present in the unit
cell, one of which has an extended backbone (as drawn)
while the other exhibits a backbone bend of nearly 110°
out-of-plane. We have observed this sort of backbone
OH
OH
OH
N
N
OH
N
Br
Me
Br
Me
N
Me
1a
N
N
Me
N
3a
ΔG‡ = 35.5 kcalmol–1
5a
ΔG‡ = 18.1 kcalmol–1
2a'
ΔG‡ > 50 kcalmol–1
TSs did not converge.
ΔG‡ = 18.8 kcalmol–1
Br
F
O
N
O
O
Br
N
O
OH
OH
OH
N
N
OH
Br
H
Br
H
N
H
N
N
Me
1n
N
22
bending previously, although it remains unclear if this
1g
ΔG‡ = 7.6 kcalmol–1
3g
ΔG‡ = 22.6 kcalmol–1
2g'
ΔG‡ = 36.7 kcalmol–1
ΔG‡ = 26.6 kcalmol–1
geometry is representative of active catalytic species.
Nonetheless, both structures exhibit intramolecular hy-
drogen-bonding patterns and φ and ψ dihedral angles
consistent with a type II’ β-turn. We also studied the
structure of 4q in solution using H-1H NOESY, and we
were able to observe 50 non-sequential nOes consistent
with a rigid β-turn geometry (see Supporting Infor-
mation).
FIGURE 4. Computed barriers to rotation about the N–
CAr bond in a series of relevant quinazolinones. Barriers
were derived from optimization of the stationary points
along torsional potential energy profiles using M06-2X/6-
311++G(2d,3p)//B3LYP/6-31+G(d,p).25–26
21
1
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Optimization of reaction conditions. Having
lated that, if the barrier to enantiomerization27 of 1a is
1
2
3
4
5
6
7
8
identified catalyst 4q that is able to deliver tribromide 2a
in 92:8 er under the conditions of Equation 1, in which N-
bromosuccinimide (NBS) was added in one portion at the
outset of the reaction, we wondered if we might be able to
boost the enantioselectivity by changing the mode of NBS
delivery. This speculation was borne of the hypothesis
that full and rapid racemization of the starting material is
required in order to achieve the best possible results in a
sufficiently high, the starting material may not be able to
re-racemize on the time scale of a very rapid and ste-
reodetermining bromination event. Indeed, DFT calcula-
tions25 showed that the barrier to enantiomerization in 1a
is 18.8 kcalmol-1 corresponding to a first-order half-life of
6.9 s (Figure 4), which may be slow with respect to the
time scale of bromination. After optimization of the rele-
vant parameters, we discovered that slow addition of NBS
over 2.5 h at 0 °C, as described in Equation 2 (R = Me),
resolution.3
2-Substituted-3-
9
dynamic
kinetic
28
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arylquinazolinones, such as 1a, have been reported to
have intrinsic barriers to rotation about the N–CAr bond,
even in the absence of ortho-substituents on the phenol
ring, that could impede rapid re-racemization as a dy-
namic kinetic resolution proceeds.13 Therefore, we specu-
provided 2a in a notably improved 97:3 er. It is im-
portant to note that this increase in selectivity was ob-
served even in the presence of 5% (by volume) acetone,10a
which was added to the delivery solution to facilitate dis-
solution of the NBS.
1) NBS (3.0 equiv, slow addition over 2.5 h)
4q (10 mol%)
PhMe/CHCl3 (9:1 v/v, 0.01 M) with 5% acetone
0 ºC, 3 h total
m
o
R"
o'
R"
Br
p
O
N
O Br
N
6
7
OMe
(±)
(2)
N
2
OH
2) TMSCHN2, MeOH, 15 min
R'
R'
Br
R
N
R
1
2
a,b
Table 1. Substrate Scope
e.r.d
e.r.d
Entry
Quinazolinone
Product
Yieldc
Entry
Quinazolinone
Product
Yieldc
Br
Br
O
N
O
N
O
O
Br
N
Br
N
MeO
OMe
OMe
MeO
OH
OH
OH
OH
OH
1
86%
97:3
8
85%
95:5
Br
Me
2a
Br
N
Me
1a
N
Me
N
O
N
Me
1h
2h
Br
Br
O
O
O
Br
Br
N
OMe
OMe
N
OH
N
N
2
3
4
79%
78%
79%
97:3
96:4
96:4
9
85%
93%
92%
93:7
96:4
99:1
Br
Br
Et
2b
F3C
N
Me
N
O
Et
F3C
N
Me
N
O
1b
1i
2i
Br
Cl
Cl
O
O
Br
N
Br
N
OMe
OMe
N
10e
N
OH
Br
Br
Me
2j
N
O
i-Pr
N
O
i-Pr
N
O
Me
N
O
1c
2c
1j
Br
Me
OH
Me
Br
N
Br
N
OMe
OMe
N
11e
N
Br
Br
Me
2k
N
i-Bu
N
i-Bu
N
Me
N
1d
2d
1k
Cl
Cl
Br
Br
O
N
O
N
Br
N
O
N
Br
N
O
N
OMe
OMe
N
OH
5
75%
93:7
12
89%
96:4
Br
N
OH
Br
Me
Bn
Bn
Me
1l
1e
2e
2l
Me
Me
Br
Br
O
N
O
N
Br
N
O
Br
N
O
OMe
OMe
N
OH
OH
6
63%
80%
63:37
65:35
13
77%
84%
98:2
Br
N
OH
OH
Br
Me
2m
CF3
1f
CF3
N
O
N
O
Me
1m
2f
Br
F
Br
O
N
O
N
Br
N
F
OMe
OMe
N
N
N
7
14e
56:44
Br
H
Br
Me
2n
H
1g
N
Me
N
2g
1n
a Reaction Conditions: quinazolinone 1 (0.10 mmol, 1 equiv), peptide 4q (0.01 mmol, 10 mol% w.r.t. 1), NBS (0.30 mmol, 3 equiv w.r.t.
b
1), PhMe/CHCl3 (9:1 v/v) with 5% acetone additive (by volume), slow addition of NBS over 2.5 h. Data represent the average of two
c
d
trials. Isolated yields after chromatography are presented. Enantiomer ratios were determined by chiral HPLC using OJ-H or AD-H
columns. e 2.0 equiv NBS was used in the bromination.
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interesting data. The p-Cl-substituted dibromide 2j was
1
2
3
4
5
6
7
8
9
isolated in excellent yield (93%) and with 96:4 er (entry
10). We also found that tribromide 2l, which was derived
from the m-Cl-substituted quinazolinone 1l, was isolated
in high yield (89%) and with 96:4 er (entry 12). These
results show that peptide 4q is able to process substrates
possessing electron withdrawing substituents on the arene
with negligible erosion of enantioselectivity relative to 2a.
In addition, electron donating Me substituents at the p-
(1k) and m-positions (1m) provide excellent substrates, as
dibromide 2k was isolated in 92% yield with 99:1 er (en-
try 11) and tribromide 2m was isolated in 88% yield and
Substrate scope. With optimal conditions in hand,
we turned our attention to the substrate scope. Catalyst
4q is able to address a wide range of quinazolinones 1
(Table 1). As noted, the bromination of 1a affords tri-
bromide 2a with 97:3 er, and 86% isolated yield (entry 1).
In order to establish the absolute configuration of the
product, we subjected 2a to standard demethylation con-
29
ditions using BBr3 to obtain free phenol 2a’, which we
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
were able to crystallize and analyze by X-ray diffraction
(Equation 3). The crystal structure of 2a’ reveals the (S)-
absolute stereochemistry of 2a.
31
98:2 er (entry 13).
Br
Lastly, we examined a compound that was pre-
functionalized at the o’-position of the phenol moiety. In
this case, we anticipated a reduced er value by virtue of a
high barrier to racemization in the starting material. In-
deed, o’-F-substituted 1n was found to deliver dibromide
2n in only 55:45 er (entry 14). DFT calculations25
showed that 1n has a 26.6 kcalmol-1 barrier to rotation
about the chiral axis (Figure 4), corresponding to a half-
life to rotation of 3.6 x 106 s. Thus, racemization is pre-
sumed to be slow on the time scale of bromination. In
this scenario, compound 1n was projected to be a suitable
substrate for a traditional kinetic resolution.32 According-
ly, running the bromination of 1n to low conversion using
only 0.5 equivalents of NBS under otherwise identical
conditions, delivered 2n in 93:7 er (14% isolated yield),
showing that quinazolinones with high barriers to racemi-
zation may indeed be synthesized enantioselectively em-
ploying a classical kinetic resolution.
O
N
Br
N
BBr3 (2.0 equiv)
OMe
(3)
CH2Cl2, –78 ºC, 3 h
Br
Me
2a
(S)-2a'
Quinazolinones possessing alkyl substituents at the 2-
position (1b–e) were processed by 4q with good yields
(75–86%) and high levels of enantioinduction (93:7 to
97:3 er, entries 2–5). However, 2-CF3-substituted 1f did
not follow this same trend, as bromination delivered only
63% yield of modestly enriched 2f (63:37 er, entry 6). The
result was initially surprising given the high levels of enan-
tioselectivity observed in tribromide 2c (95:5 er, entry 3),
as the steric size of a CF3 group is comparable to an i-Pr
30
group on some scales. It appears that the electron with-
drawing CF3 group of 1f influences the catalyst-substrate
complex in a manner we do not understand. Yet, we also
observed low levels of enantioenrichment in tribromide
2g (65:35 er, entry 7), in which the 2-position is unsubsti-
tuted. The origin of this phenomenon may derive from a
low barrier to rotation about the chiral axis in the corre-
sponding ortho-monobromide 3g, which we presume is the
immediate product of stereodetermining bromination.
Indeed, using DFT calculations,25 we were able to com-
pute a barrier to rotation of 22.6 kcalmol-1 in monobro-
mide 3g, which may be sufficiently low so as to permit
racemization on the time scale of the slow addition. By
way of comparison, the computed rotational barriers for
quinazolinone 1g and tribromide 2g’ were found to be
7.6 and 36.7 kcalmol-1, respectively, using DFT computa-
tions (Figure 4).25
SCHEME 1. Study of the major monobromides in
the catalyzed and uncatalyzed bromination of 1a
Br
O
No Catalyst
OH
N
N
O
Me
5a
Br
O
N
NBS (1.0 equiv)
2.5 h slow addn.
Et3N (10 mol%)
OH
N
OH
N
PhMe/CHCl3
(9:1 v/v, 0.01 M)
5% acetone
0 ºC, 3 h
Me
1a
N
O
Me
5a
4r (10 mol%)
OH
N
Br
N
Me
Many other substrates were brominated by 4q with
high levels of enantioselectivity. For example, we found
that substitution on the benzo moiety of the quinazoli-
none scaffold is often tolerated (entries 8–9). Tribromide
2h, having an electron donating methoxy group at the 6-
position, was isolated in 85% yield and 95:5 er, only
slightly lower than the parent compound (entry 8). Like-
wise, 7-CF3-susbtituted tribromide 2i was isolated in 85%
yield and 93:7 er (entry 9). These results suggest a weak
effect of distal-substitution on enantioselectivity, though
both electron donating and electron withdrawing groups
are still largely tolerated by 4q. Substitution on the phe-
nol moiety of the quinazolinone scaffold also revealed
3a
98:2 er
Mechanism-Driven Experiments. Examination
of the substrate scope inspired us to investigate certain
mechanistic aspects of this enantioselective bromination
reaction. We began with an LC/MS-enabled study of the
background and catalyzed bromination of 1a under con-
ditions of reagent-controlled low conversion (Scheme 1).
As noted above, in the absence of catalyst, the bromina-
tion proceeds slowly, and in fact the major species in the
crude reaction mixture is the p-monobromide 5a, alt-
hough all mono-, di-, and tribromides were observed in
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Page 6 of 11
(a) 1a (0.01 M in C6D6 at 25 ºC)
(d)
1
2
H
O
3
4
5
6
7
8
N
HN
p
o'
Me2N
O
O
N
O
o
O
5
OH
HN
Me
i-Pr
N
o
H
NH
H
O
Me
(b) 1a + 4q (1:1, 0.01 M in C6D6 at 25 ºC)
O
N
Me
1a
4q
Scale
2.50–2.74 Å
2.75–2.99 Å
3.00–3.24 Å
3.25–3.49 Å
3.50–4.00 Å
9
(e)
O
N
o
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
1
2
4
7
6
O
H
5
N
Me
Me
Br+
H6
H3
N
(c) 4q (0.01 M in C6D6 at 25 ºC)
Me
N
H7
Me
Me
O
N
H1
O
N
O
H5
1
3
5
4
6
2
N
7
H4
O
Boc
H2
N
Me
Me
1
1
1
FIGURE 5. (a) H-NMR spectrum of quinazolinone 1a. (b) H-NMR spectrum of 1a-4q complex (1:1 molar ratio). (c) H-
NMR spectrum of peptide 4q. (d) NOESY correlation diagram showing the intermolecular nOes observed in the 1a-4q
complex. (e) Possible binding model based on NMR data. The model explains the (S)-absolute configuration of the products
and also predicts the first site of bromination at the ortho-position of 1a.
minor quantities. When triethylamine is used as a catalyst,
the reaction proceeds more efficiently and with significant
regioselectivity, also favoring the p-monobromide 5a with
no evidence of the other monobromides. The o,p-
dibromide was also formed in approximately equal quan-
tities under the triethylamine conditions, and the tribro-
mide was observed as a minor product. Using peptide 4r,
which provides enantioselectivity similar to 4q (vide supra),
the reaction constrained to reach low conversion exhibits
a strikingly different result: the major monobromide is the
alternative regioisomer 3a, while only a very small quan-
tity of the p-monobromide 5a is detected, while the o,p-
dibromide and tribromide 2a’ are also detected. These
results indicate that the peptide-based catalyst is able to
overturn the inherent site-selectivity of the bromination
reaction, which also implies that the stereodetermining
bromination event is the first bromination to give 3a (See
Supporting Information for LC/MS data). Furthermore,
when the crude reaction mixture of the 4r-catalyzed reac-
tion was subjected to methylation and analyzed by chiral
HPLC, it was discovered that monobromide 3a was en-
antioenriched to 98:2 er. To the best of our knowledge,
this is a rare example of an atroposelective reaction in
which the chiral axis is set after the first functionalization
constituents under identical conditions.34 Notably, while
the other amide signals shift downfield upon complexa-
tion, the NHLeu signal barely shifts at all, providing evi-
dence for a strong hydrogen bond between NHLeu and
ODmaa. In contrast, the NHAcpc shifts downfield by nearly
1.0 ppm upon complexation, which implicates this proton
in an important intermolecular hydrogen bond with 1a.
The NHDmaa signal also shifts downfield by about 0.3
ppm, which may suggest a change in the β-hairpin con-
formation as a result of complexation. It may also impli-
cate the carbamate NH proton in an interaction with the
substrate.
Furthermore, we observed a global upfield shifting of
all of the i+3 leucine signals, especially the γLeu signal.
This suggests that the i+3 residue might be situated be-
neath an arene, such that electron density in the π-system
leads to this anisotropic effect. The αD-Pro signal also shifts
upfield, presumably for similar reasons. Similarly, the all
of the Dmaa signals tend to shift downfield, in keeping
with a decrease in electron density around the side-chain
N-atom as would be expected in a Me2NDmaa to HO1a
hydrogen bond. It is also evident that the βDmaa signals of
4q become significantly more differentiated in the com-
plex than in the free peptide. With respect to the sub-
33
of an atropisomerically dynamic starting material.
1
strate, all of the H-NMR signals of 1a shift downfield in
To further our understanding of the basis of stereose-
lectivity, we studied the peptide-substrate complex using
NMR techniques. The results of our findings are summa-
rized in Figure 5. Compared to the H-NMR spectra of
1a (Figure 5a) and 4q (Figure 5c), the spectrum of the 1:1
the complex. However, only the ortho-position (Figure 2d)
shifts downfield to a significant degree (> 0.30 ppm),
which may be consistent with this position disposed most
proximally to the peptide. In light of these results, as well
as our mechanistic studies that identified this position as
1
complex (Figure 5b) differs significantly from its isolated
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1
2
SCHEME 2. Cross-coupling of quinazolinone bromides.
3
(a) Suzuki-Miyaura cross-coupling
(b) Buchwald-Hartwig amination
4
5
6
7
R'R"NH (2.0 equiv)
Pd2(dba)3 (10 mol%)
rac-BINAP (20 mol%)
Ar–B(OH)2 (2.0 equiv)
Pd2(dba)3 (10 mol%)
P(t-Bu)(Cy)2•HBF4 (20 mol%)
Br
NR'R"
OMe
O
O
N
O
N
O
N
Br
N
Br
N
OMe
OMe
OMe
N
N
NaOt-Bu (1.4 equiv)
PhMe, 80 ºC
18 h
K3PO4 (4.0 equiv)
THF/H2O (3:1 v/v)
45 ºC, 24 h
Br
Me
Ar
Me
Br
Me
Br
Me
N
Me-3a
97:3 e.r.
6
2a
97:3 e.r.
7
8
9
O
N
O
O
O
NHPh
OMe
NHBn
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
N
O
N
Br
N
Br
N
OMe
OMe
OMe
O
Br
OMe
N
N
N
N
OMe
N
Br
Br
Me
N
Me
N
Me
N
N
N
Me
Br
N
Me
Me
O
N
Me
6a
95% yield
97:3 e.r.
6b
96% yield
97:3 e.r.
6c
85% yield
97:3 e.r.
6d
83% yield
97:3 e.r.
7a
72% yield
96:4 e.r.
7b
75% yield
96:4 e.r.
7c
60% yield
96:4 e.r.
ciently and without loss of enantioenrichment. As shown
in Equation 4, palladium-catalyzed hydrogenation under
well-established conditions achieved this goal,38 affording
monobrominated compound Me-3a in 80% yield with
high levels of regioselectivity presumably governed by
sterics. Despite the lack of a second heavy atom ortho’-
substituent on the phenol ring, this compound exhibited
good atropostablity at ambient temperature. The barrier
to rotation about the chiral axis in 3a was calculated to be
35.5 kcalmol-1 using DFT calculations,25 which corre-
sponds to a half-life of 1.13 x 1013 s (Figure 4).
the site of the first bromination event, it seems plausible
that the peptide delivers Br+ to this position via one of the
proximal, Lewis basic carbonyls.35 It should also be noted
1
that many of the H-NMR signals corresponding to com-
plexed 1a possess minor shoulder peaks, while this is not
evident in any of the signals derived from 4q. This per-
haps suggests that 1a might be fluxional in the bound
state. We also studied the binding interaction between 1a
and 4q using H-1H-NOESY, and we were able to ob-
1
serve several intermolecular nOes that supported this
model. A summary of these interactions is presented in
Figure 5d, where the color-coded distances are derived
from integration of the relevant NOESY cross-peaks.36
This experiment highlighted a number of interactions that
Br
O
H2 (balloon)
Pd/C (10 mass%)
O
Br
N
OMe
OMe
(4)
N
Br
Me
MeOH, 12 h, rt
Br
Me
N
1
N
were not observed in the simple H-NMR complexation
2a
97:3 e.r.
Me-3a
80% yield
97:3 e.r.
experiment (vide supra). For instance, strong nOes were
observed between (1) Me2NDmaa and the ortho-position of
1a and (2) βAcpc and the 5-position of 1a, suggesting that
these groups are very close to one another in space in the
complex. Moderate nOes were also observed between
βDmaa and the 2-Me group of 1a, as well as between the i-
Pr group of leucine and the ortho-position of 1a. Weak
nOes were also observed, allowing us to fine-tune our
proposed binding orientation.
Monobromide Me-3a was then examined as a tem-
plate for diversification. After initial studies of Suzuki-
Miyaura cross-coupling39 reactions revealed that some
racemization could occur at high temperatures (> 60 °C),
we discovered that excellent results could be achieved at
lower temperatures (45 °C) when a highly active catalyst
was employed. Under the optimized conditions, Pd2(dba)3
and (t-Bu)(Cy)2P•HBF4 enabled the Suzuki coupling of
3a with various arene and heterocycle boronic acids un-
der atropstable conditions, providing good yields of struc-
turally complex products (6) with no loss of enantioen-
richment, as shown in Scheme 2a.
The culmination of these mechanistically driven stud-
ies is a self-consistent binding model from which we were
able to rationalize the first site of bromination, as well as
the (S)-absolute configuration of products 2 and ortho-
mono-bromides 3 (Figure 5e). Our model suggests two
intermolecular hydrogen bonds in the catalyst-substrate
complex, one between OH1a and Me2NDmaa and the other
between NHAcpc and C=O1a.
Upon the success of atropstable Suzuki coupling of
Me-3a, we sought to expand the scope of our product
derivatization beyond the formation of C–C bonds using
Buchwald-Hartwig O- and N-arylation.40 Unfortunately,
under the conditions we had examined thus far, which
required high temperatures of ~80 °C for product for-
mation, products were observed with reduced levels of
enantioenrichment, suggesting racemization during the
reaction.41 However, the more atropisomerically stable
tribromide 2a, having a computed barrier to enanti-
Cross Coupling. With the atroposelective bromina-
tion of quinazolinones established, we turned to the
demonstration of further synthetic utility through derivat-
ization of the brominated products.37 Recognizing the
prevalence of monosubstituted quinazolinones in the me-
dicinal chemistry literature (Figure 1a),9 we sought to es-
tablish that tribromide 2a could be converted to 3a effi-
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omerization of over 50 kcalmol-1 (2a’, Figure 4),42 proved
Page 8 of 11
ACKNOWLEDGMENTS
1
2
3
4
5
6
7
8
a good substrate, wherein regioselective amination could
be achieved to form compounds such as 7a–c in good
yields and with very little erosion of er (Scheme 2b). The
site selectivity of the amination is presumably due to steric
differentiation.
A.J.M. would like to extend his sincerest thanks to the NSF
Graduate Research Fellowship Program for financial support.
We would like to thank Dr. Eric Paulson for his assistance with
our NMR studies and Dr. Brandon Mercado for solving our X-
ray crystal structures. We would also like to thank Nadia Abas-
cal, Dr. Guillaume Pelletier, and Dr. Byoungmoo Kim for help-
ful discussions. All computational work was supported by the
facilities and staff of the Yale University Faculty of Arts and
Sciences High Performance Computing Center, and by the
National Science Foundation under grant #CNS 08-21132 that
partially funded acquisition of the facilities.
Conclusions
9
Peptide-catalyzed atroposelective bromination has
been extended to a highly significant scaffold in medicinal
chemistry. Critical to the achievement of this advance
were the discovery of an optimized catalyst and an appre-
ciation of the physical organic principles that govern the
barriers to rotation in the starting materials and products
for these unique reactions. Catalyst 4q was found to be
effective for a broad substrate scope, and moreover the
unique conformational properties (i.e., barriers to atro-
pisomerization) of the products enable site-selective
debromination and cross-coupling reactions of several
types to deliver multiple drug-like chemotypes. Mecha-
nism-driven experiments have also revealed a number of
interesting features of these asymmetric reactions, includ-
ing the likely site of the initial and stereo- determining
bromination. NMR spectroscopic experiments have un-
veiled critical features of the catalyst-substrate complex
that are consistent with the observation of the absolute
configuration of the products that emerge from these re-
actions. It is our hope that these concepts set the stage for
synthetic applications in the context of this biologically
relevant scaffold.
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34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
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REFERENCES
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ASSOCIATED CONTENT
Additional experimental details, characterization data for all
catalysts, substrates, and products, crystallographic information,
and computational data are provided in the Supporting Infor-
mation. This material is available free of charge on the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: scott.miller@yale.edu
(6) Evarts, J. B.; Ulrich, R. G. (Gilead Galistoga LLC, USA). At-
ropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and meth-
ods of use. US 8,440,677 B2, May 14, 2013.
(7) For reviews on atroposelective synthesis, please see: (a)
Bencivenni, G. Synlett 2015, 26, 1915–1922. (b) Wencel-Delord, J.;
Panossian, A.; Leroux, F. R.; Colobert, F. Chem. Soc. Rev. 2015, 44,
3418–3430. (c) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.;
Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005,
44, 5384–5427.
Present Addresses
† Department of Chemistry, Faculty of Science, Fukuoka Uni-
versity, Fukuoka, 814-0180, Japan.
Author Contributions
‡ M.E.D. and A.J.M. contributed equally to the project.
(8) From this point forward, we will refer to 3-arylquinazolin-
4(3H)-ones (1) as quinazolinones for simplicity.
Funding Sources
(9) CP-465022: (a) Lazzaro, J. T.; Paternain, A. V.; Lerma, J.;
Chenard, B. L.; Ewing, F. E.; Huang, J.; Welch, W. M.; Ganong, A.
H.; Menniti, F. S. Neuropharmacology 2002, 42, 143–153. Benzoma-
livin A: (b) Sun. H. H.; Barrow, C. J.; Sedlock, D. M.; Gillum, A.
M.; Cooper, R. J. Antibiotics 1994, 47, 515–522. (c) Sun. H. H.;
Barrow, C. J.; Cooper, R. J. Nat. Prod. 1995, 58, 1575–1580. Eras-
tin: (d) Gangadhar, N. M.; Stockwell, B. R. Curr. Opin. Chem. Biol.
2007, 11, 83–87. (e) Yagoda, N.; von Rechenberg, M.; Zaganjor,
E.; Bauer, A. J.; Yang, W. S.; Fridman, D. J.; Wolpaw, A. J.; Smuk-
ste, I.; Peltier, J. M.; Boniface, J. J.; Smith, R.; Lessnick, S. L.; Sa-
hasrabudhe, S.; Stockwell, B. R. Nature 2007, 447, 864–868.
We are grateful to the National Institute of General Medical
Sciences of the NIH (GM-068649) for support.
Notes
Crystallographic data are deposited with the Cambridge Crys-
tallographic Data Centre under the accession number CCDC
1412919 (2a’) and CCDC 1412920 (4q).
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Journal of the American Chemical Society
(10) (a) Gustafson, J. L.; Lim, D.; Miller, S. J. Science 2010, 328,
Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.;
Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.,
Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers,
E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; To-
masi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli,
C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V.
G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Dan-
iels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.;
Fox, D. J. Gaussian, Inc., Wallingford CT, 2009. (b) In general,
rotational barriers were derived from optimization of the stationary
points of a relaxed torsional potential energy scan of the N–CAr
anilide axis at the M06-2X/6-311++G(2d,3p)//B3LYP/6-
31+G(d,p) level.26 Frequency calculations were performed at the
B3LYP/6-31+G(d,p) level, and all transition states were found to
have one, single imaginary frequency corresponding to a vibration
along the N–CAr torsional reaction coordinate.
(26) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215–
241. See also ref 11b.
(27) Reist, M.; Testa, B.; Carrupt, P.-A.; Jung, M.; Schurig, V.
Chirality 1995, 7, 396–400.
(28) Slow addition was accomplished using a syringe pump. We
found that using an 18 G needle avoided clogging via NBS precipita-
tion over the 2.5 h slow addition. The rate of addition (1.60 mLmin-
1), length of addition (2.5 h), and composition/volumes of delivery
(3.5 mL of 9:1 v/v PhMe/CHCl3 with 0.5 mL acetone additive, 4
mL total) and source (6 mL of 9:1 v/v PhMe/CHCl3) solutions were
rigorously optimized for the 0.10 mmol-scale reaction. Additional
details on the optimization of the reaction conditions may be found
in the Supporting Information.
(29) (a) McOmie, J. F. W.; Watts, M. L.; West, D. E. Tetrahedron
1968, 24, 2289–2292. (ꢀ b) This reaction was performed on small-
scale, and isolated yield was not obtained following crystallization.
(30) Hirsch, J. A. Table of Conformational Energies. In Topics in
Stereochemistry; Allinger, N. L.; Eliel, E. L., Eds.; Wiley: Hoboken, NJ,
1967; Vol. 1, pp. 199–222.
(31) In the case of 2k, we hypothesized that the marked increase
in enantioselectivity to 99:1 er (relative to 97:3 er in 2a, correspond-
ing to ΔΔG‡ = 0.61 kcalmol-1 at 0 ºC) may be due to (1) the Me-
group being electron-releasing and thereby ring activating and (2)
the Me-group blocking the position of first bromination in the un-
catalyzed background reaction (see Mechanism-Driven Experiments
section). In that way, the catalyzed reaction outcompetes the back-
ground reaction significantly. In the case of 2m, ring activation of
the meta-Me-substituent provides an increase to 98:2 er relative to
the parent, but the background pathway is still possible via bromina-
tion at the para-position. The results obtained for Cl-substituted 2j
and 2l (both 96:4 er) might suggest that ring activation is important
to the er of the reaction. Steric effects may also be at play in these
instances.
1251–1255. (b) Garand, E.; Kamrath, M. Z.; Jordan, P. A.; Wolk,
A. B.; McCoy, A. B.; Miller, S. J.; Johnson, M. A. Science 2012, 335,
694–698.
(11) (a) Barrett, K. T.; Miller, S. J. J. Am. Chem. Soc. 2013, 135,
2963–2966. (b) Barrett, K. T.; Metrano, A. J.; Rablen, P. R.; Miller,
S. J. Nature 2014, 509, 71–75.
1
2
3
4
5
6
7
8
(12) Miyaji, R.; Asano, K.; Matsubara, S. J. Am. Chem. Soc. 2015,
137, 6766–6769.
(13) For examples of methods providing access to enantioen-
riched 3-arylquinazolin-4(3H)-ones, please see: (a) Tokitoh, T.; Ko-
bayashi, T.; Nakada, E.; Inoue, T.; Yokoshima, S.; Takahashi, H.;
Natsugari, H. Heterocycles 2006, 70, 93–99. (b) Penhoat, M.; Bohn,
P.; Dupas, G.; Papamicaël, C.; Marsais, F.; Levacher, V. Tetrahedron:
Asymmetry 2006, 17, 281–286. (c) Dai, X.; Wong, A.; Virgil, S. C. J.
Org. Chem. 1998, 63, 2597–2600.
(14) (a) Azanli, E.; Rothchild, R.; Sapse, A.-M. Spectrosc. Lett.
2002, 35, 257–274. (b) Colebrook, L. D.; Giles, H. G. Can. J. Chem.
1975, 53, 3431–3434. (c) Mannschreck, A.; Kaller, H.; Stühler, G.;
Davies, M. A.; Traber, J. Eur. J. Med. Chem. Chim. Ther. 1984, 19,
381.
(15) The reaction solvent was rigorously optimized in the early
stages of this project. We found that 9:1 v/v PhMe/CHCl3 deliv-
ered higher enantioselectivities than pure PhMe, pure CHCl3, 9:1
v/v CHCl3/PhMe, and 9:1 v/v CHCl3/C6F6. Furthermore, the
concentration of the reaction (0.01 M) was also optimized at an
early stage. Dilution beyond 0.01 M served to decrease yield with no
effect on enantioselectivity. Concentrations greater than 0.01 M
provided lower er values, presumably due to an acceleration of the
background rate.
(16) For relevant reviews, see: (a) Miller, S. J. Acc. Chem. Res.
2004, 37, 601-610. (b) Jarvo, E. R.: Miller, S. J. Tetrahedron 2002,
58, 2481–2495. For recent examples of β-turn peptides in enantiose-
lective reactions, see: (c) Metrano, A. J.; Miller, S. J. J. Org. Chem.
2014, 79, 1542–1554. (d) Mbofana, C. T.; Miller, S. J. J Am. Chem.
Soc. 2014 136, 3285–3292. (e) Romney, D. K.; Miller, S. J. Org. Lett.
2012, 14, 1138–1141. (f) Peris, G.; Jakobsche, C. E.; Miller, S. J. J.
Am. Chem. Soc. 2007, 129, 8710–8711.
(17) The bromination of 1a in the absence of catalysts provides <
5% yield of tribromide 2a. The majority of 1a is converted to a
complex mixture of monobromides and dibromides, with the mon-
obromides being favored. Please consult the “Mechanism-Driven
Experiments” section and the Supporting Information for more
details. Dissolution of the starting materials is also poor when no
catalyst is present.
(18) Only enantioselectivities were measured in the peptide-
optimization studies summarized in Figure 2. Isolated yields were
not assessed on small scale. Conversion of 1a was always near quan-
titative by crude 1H-NMR.
(19) For examples of peptides taking advantage of a D-Pro-Aib β-
turn sequence, see: (a) Fowler, B. S.; Mikochik, P. J.; Miller, S. J. J.
A. Chem. Soc. 2010, 132, 2870–2871. (b) Cowen, B. J.; Saunders, L.
B.; Miller, S. J. J. Am. Chem. Soc. 2009, 131, 6105–6107. See also ref.
11.
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20
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24
25
26
27
28
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45
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47
48
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55
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(20) Gilli, P.; Pretto, L.; Bertolasi, V.; Gilli, G. Acc. Chem. Res.
(32) (a) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth.
Catal. 2001, 343, 5–26. (b) Kagan, H. B.; Fiaud, J. C. Kinetic Reso-
lution. In Topics in Stereochemistry; Eliel, E. L.; Wilen, S. H., Eds.;
Wiley: Hoboken, NJ, 1988; Vol. 18, pp. 249–340.
(33) Based purely on rotational barriers, many previously studied
systems, including biaryls and benzamides, require two functionali-
zation events (one at each ortho-position) to lock the asymmetric axis.
See refs. 10–11.
2009, 42, 33–44.
(21) (a) Haque, T. S.; Little, J. C.; Gellman, S. H. J. Am. Chem.
Soc. 1996, 118, 6975–6985. (b) Wilmot, C. M.; Thornton, J. M. J.
Mol. Biol. 1988, 203, 221–232.
(22) Blank, J. T.; Miller, S. J. Biopolymers 2006, 84, 38–47.
(23) (a) Gellman, S. H.; Dado, G. P.; Liang, G.-B.; Adams, B. R.
J. Am. Chem. Soc. 1991, 113, 1164–1173. (b) Yang, D.; Zhang, D.-
W.; Hao, Y.; Wu, Y.-D.; Luo, S.-W.; Zhu, N.-Y. Angew. Chem. Int.
Ed. 2004, 116, 6887–6890. (c) Trabocchi, A.; Potenza, D.; Guarna,
A. Eur. J. Org. Chem. 2004, 4621–4627.
(24) CYLview was used to render the X-ray crystal data: CYL-
view, 1.0b; Legault, C. Y., Université de Sherbrooke, 2009
(http://www.cylview.org).
(25) DFT computations were performed using the Gaussian 09
suite: (a) Gaussian 09, Revision C.01, Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
(34) The NMR studies were performed in C6D6 to simulate the
bulk PhMe of the reaction conditions (Equation 2) without having
two residual solvent lines in the spectrum. Even though the catalytic
reaction is run at 0.001 M with respect to peptide 4q, we opted to
perform our NMR studies at 0.01 M to obtain better signal-to-noise.
We verified that 4q does not aggregate at 0.01 M solution by com-
1
paring H-NMR spectra of 4q at 0.001 M and 0.01 M under oth-
erwise identical conditions. No change was observed in the proton
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signals at the higher concentration relative to the more dilute sam-
ple.
(35) For a related example, please see: Denmark, S. E.; Burk, M.
T. Proc. Nat. Acad. Sci. U.S.A. 2010, 107, 20655–20660.
(36) (a) Cavanagh, J.; Fairbrother, W. J.; Palmer, A. G.; Rance,
1
2
3
4
M; Skelton, N. G. Protein NMR Spectroscopy: Principles and Prac-
tice, 3rd Ed. Elsevier Academic Press: Boston, 2007.ꢀ (b) Abascal, N.
5
C.; Lichtor, P. A.; Giuliano, M. W.; Miller, S. J. Chem. Sci. 2014, 5,
4504–4511. (c) Lichtor, P. A.; Miller, S. J. J. Am. Chem. Soc. 2014,
136, 5301–5308.
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7
8
9
(37) For related examples, please see: (a) Barrett, K. T.; Miller, S.
J. Org. Lett. 2015, 17, 580–583. (b) Gustafson, J. L.; Lim, D.; Barrett,
K. T.; Miller, S. J. Angew. Chem. Int. Ed. 2011, 50, 5125–5129.
(38) For an example of reductive dehalogenation of aryl bromides
using Pd/C, please see: (a) Ramanathan, A.; Jiminez, L. S. Synthesis
2010, 217–220. For an example of a regioselective dehalogenation
of aryl bromides, please see: (b) Chae, J.; Buchwald, S. L. J. Org.
Chem. 2004, 69, 3336–3339.
(39) For examples of Suzuki-Miyaura cross-coupling of aryl hal-
ides in the context of quinazolinone scaffolds, please see: (a) Gar-
lapati, R.; Pottabathini, N.; Gurram, V.; Kasani, K. S.; Gundla, R.;
Thulluri, C.; Machiraju, P. K.; Chaudhary, A. B.; Addepally, U.;
Dayam, R.; Chunduri, V. R.; Patro, B. Org. Biomol. Chem. 2013, 11,
4778–4791. (b) Fang, X.; Chen, Y. T.; Sessions, E. H.; Chowdhur-
ym S.; Vojkovsky, T.; Yin, Y.; Pocas, J. R.; Grant, W.; Schröter, T.;
Lin, L.; Ruiz, C.; Cameron, M. D.; LoGrasso, P.; Bannister, T. D.;
Feng, Y. Bioorg. Med. Chem. Lett. 2011, 21, 1844–1848. (c) Li, H.-y.;
Wang, Y.; McMillen, W. T.; Chaterjee, A.; Toth, J. E.; Mundla, S.
R.; Voss, M.; Boyer, R. D.; Sawyer, J. S. Tetrahedron 2007, 63,
11763–11770.
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48
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(40) For examples of Buchwald-Hartwig amination reactions of
aryl bromides, please see: (a) Driver, M. S.; Hartwig, J. F. J. Am.
Chem. Soc. 1996, 118, 7217–7218. (b) Wolfe, J. P.; Wagaw, S.;
Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215–7216.
(41) The computed half-life to enantiomerization in monobro-
mide 3a is 27 y at 80 ºC,25 which perhaps suggests that the species
that undergoes racemization under the attempted amination condi-
tions is not monobromide Me-3a. It is possible that the aryl-
palladium species formed upon oxidative addition has a lower barri-
er to enantiomerization by way of a significantly lengthened bond.
(42) The transitions states to enantiomerization of 2a’ were nev-
er found explicitly using the computational methods described in
ref. 25. The reported barrier of > 50 kcalmol-1 is derived from the
torsional scan computation (see Supporting Information for details).
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TOC Graphic
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Br
Br
N
O
N
O
N
1) NBS, peptide (10 mol%)
2) TMSCHN2
OMe
(±)
N
OH
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Br
Me
Me
1) Dehalogenation
2) Suzuki-Miyaura
cross-coupling
Buchwald-Hartwig
cross-coupling
14 Examples
Up to 93% yield
Up to 98:2 er
O
R
N
O
Br
N
HN
O
N
R
Me2N
O
OMe
O
OMe
N
N
HN
i-Pr
stable
atropisomer
Ar
Br
Me
NH
N
Me
Boc
O
4 Examples
Up to 95% yield
No erosion of er
3 Examples
Up to 75% yield
Regioselective
NMe2
peptide
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