Enantioselective synthesis of atropisomeric benzamides through peptide-catalyzed bromination

Article abstract of DOI:10.1021/ja400082x

We report the enantioselective synthesis of atropisomeric benzamides employing catalytic electrophilic aromatic substitution reactions involving bromination. The catalyst is a simple tetrapeptide bearing a tertiary amine that may function as a Br?nsted base. A series of tri- and dibrominations were accomplished for a range of compounds bearing differential substitution patterns. Tertiary benzamides represent appropriate substrates for the reaction since they exhibit sufficiently high barriers to racemization after ortho functionalization. Mechanism-driven experiments provided some insight into the basis for selectivity. Examination of the observed products at low conversion suggested that the initial catalytic bromination may be regioselective and stereochemistry-determining. A complex between the catalyst and substrate was observed by NMR spectroscopy, revealing a specific association. Finally, the products of these reactions may be subjected to regioselective metal-halogen exchange and trapping with I₂, setting the stage for utility.

Full text of DOI:10.1021/ja400082x

Communication
pubs.acs.org/JACS
Enantioselective Synthesis of Atropisomeric Benzamides through
Peptide-Catalyzed Bromination
Kimberly T. Barrett and Scott J. Miller*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
great frequency in the medicinal chemistry literature.3 Structures
ABSTRACT: We report the enantioselective synthesis of
atropisomeric benzamides employing catalytic electrophilic
aromatic substitution reactions involving bromination. The
catalyst is a simple tetrapeptide bearing a tertiary amine
that may function as a Brønsted base. A series of tri- and
dibrominations were accomplished for a range of
compounds bearing differential substitution patterns.
Tertiary benzamides represent appropriate substrates for
the reaction since they exhibit sufficiently high barriers to
racemization after ortho functionalization. Mechanism-
driven experiments provided some insight into the basis
for selectivity. Examination of the observed products at
low conversion suggested that the initial catalytic
bromination may be regioselective and stereochemistry-
determining. A complex between the catalyst and substrate
was observed by NMR spectroscopy, revealing a specific
association. Finally, the products of these reactions may be
subjected to regioselective metal−halogen exchange and
trapping with I2, setting the stage for utility.
such as 2 (Figure 1b), unless resolved, may exist and function as
independent diastereomers.4 Bioactive compounds like 3,5 which
cannot be resolved at physiological temperatures because of the
low barrier to amide atropisomerization, may function in one
conformation but might also exhibit deleterious off-target effects
in the other rotameric form. As a result, methods for
atropisomer-selective synthesis are a current objective. Ap-
proaches involving asymmetric ortho-functionalization reactions
are described in the literature,6 as are applications of chiral
auxiliaries.7 Catalytic asymmetric approaches are less well known
but are now emerging, as exemplified by recent studies of [2 + 2 +
2] cycloadditions8 and dynamic kinetic resolutions.9 We report
herein an addition to the catalytic, enantioselective approaches to
the synthesis of this important class of chiral compounds.
We previously demonstrated that peptide-based catalysts
could be effective for the atropisomer-selective bromination of
biaryl compounds to establish axial chirality in a series of
biphenyls.10 Given the analogy between the axial chirality
implicit in biphenyls and the axis of chirality intrinsic to
benzamides, we wondered whether it might be possible to
achieve enantioselective reactions of the type shown in eq 1.
ertiary aromatic amides with appropriate substitution may
T
exhibit axial chirality about the carbonyl carbon−aryl
carbon bond axis (Figure 1a).1 With a sufficiently high barrier to
Some keys for effective catalysts in our prior studies appear to
include functional groups that can form contacts (perhaps
through hydrogen bonding11) between the catalyst and the
substrate.12 In addition, putative bromine-directing groups (e.g.,
Lewis base catalysis of bromine transfer involving an amide
carbonyl13) are likely key for bromine−arene bond formation.
Catalyst 6 embodies these elements. Peptide 6 contains the
dimethylaminoalanine residue (Dmaa), which we felt might
target the acidic m-hydroxyl of the benzamide,14 possibly
activating the arene. We elected to embed Dmaa within peptide
frameworks we have examined extensively over the years. Among
these, the D-Pro-Aib-Phe-OMe fragment (Aib = α-amino-
isobutyric acid) has found utility for a wide variety of
Figure 1. (a) Chiral benzamides, which have barriers to isomerization
that are dependent on the nature of A and B. (b) Examples of bioactive
compounds that may exist as benzamide atropisomers with either a high
(2) or low (3) barrier to isomerization.
interconversion, 1 and ent-1 thus may be isolated and studied as
independent entities. These phenomena have been known from
the chemical perspective for many years, and more recently,
differential biological activity has been noted for isolated
enantiomers of chiral benzamide drugs and drug candidates.2
In fact, the property of amide atropisomerism is emerging with
Received: January 4, 2013
Published: February 14, 2013
© 2013 American Chemical Society
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Communication
enantioselective processes.15 Peptide 6 was projected to possess
the capacity to exhibit a β-hairpin structure that could provide
conformational constraints favoring bifunctional synergy be-
tween the Dmaa side chain and a distal Lewis basic functional
group.16
Table 1. Substrate Scope for Enantioselective Bromination of
Substituted Benzamides Employing Catalyst 6
Notably, as shown in eq 2, evaluation of catalyst 6 for the
tribromination of substrate 7 yielded an encouraging initial
result.17 When the reaction was conducted with 10 mol % 6 [−40
°C, dibromodimethylhydantoin (DBDMH) as the brominating
agent, CHCl3, 20 h], product 8 was isolated in 86% yield,
exhibiting a 75:25 enantiomeric ratio (er). Moreover, when the
piperizyl moiety of 7 was replaced with a piperidyl group (i.e., 9;
eq 3), the reaction selectivity improved. In this case, tribromide
10 was isolated in 92% yield with a 90:10 er. Importantly,
evaluation of the same sample after 40 days revealed no erosion
of the er, reflecting a high barrier to racemization. Evaluation of
diisopropylbenzamide 11 led to further enhancement of the
selectivity, as 12 was now isolated in 89% yield with a 94:6 er (eq
4). In this case, the product could also be recrystallized to give a
98:2 er (59% recovered after a single recrystallization). Our
rationale in evaluating compound 11 involved speculation that
the amide of substrate 7 or 9 itself might be a Lewis base mediator
of autocatalytic (and nonselective) bromination. Compound 11
was selected to probe steric inhibition of such nonselective
catalysis, although this hypothesis remains rigorously unpro-
ven.18
We therefore wished to evaluate the substrate scope for this
process. As shown in Table 1, in addition to the parent
compound 11 (entry 1), a variety of differentially substituted
benzamides were explored under standardized conditions.
Substituents ortho to the phenol were well-tolerated, with
cyclopropyl-substituted amide 13 undergoing conversion to
dibromide 14 with a 96:4 er (79% isolated yield; entry 2).
Sterically demanding aryl substitution was also tolerated, as 15
was converted to 16 in 86% yield with a 93:7 er (entry 3). When a
pre-existing bromide was present (as in 17; entry 4), the reaction
proceeded similarly, and 12 was produced in 89% yield with a
92:8 er. (The mechanistic ramifications of this observation are
discussed in greater detail below). The o-methyl-bearing
substrate 18 was converted to 19 in 69% yield with a 93:7 er
(entry 5). Meta substitution also provided suitable substrates.
For example, the cyclopropyl group of 20 was tolerated, allowing
21 to be isolated in 90% yield with a 92:8 er (entry 6). A phenyl
group was also accommodated in this position, as 22 was
converted to 23 in 89% yield with a 93:7 er (entry 7).
a
Reactions were conducted at −40 °C for 4−48 h, employing 10 mol
% 6 and 0.02 M substrate in CHCl3; 1.0 equiv of DBDMH was used,
except for entries 1, 5, and 6 (1.5 equiv). See the Supporting
Information for details. All of the experiments were performed in
b
c
triplicate. Yields of the products after phenol methylation.
d
e
Determined by chiral HPLC within 1 day of synthesis. After 40
days of storage, this sample exhibited an 81:19 er (see the text).
However, p-bromine substitution (as in 26; entry 9) led to a
significant drop in selectivity, as 12 was isolated in 90% yield but
in near-racemic form (52:48 er). Moreover, a methyl group ortho
to both the phenol and the amide (as in 27) also led to reduced
selectivity, as 28 was isolated with a 63:37 er, albeit in 76% yield
(entry 10). Compound 29, with bromine in the same position,
afforded a nearly racemic product (51:49 er; entry 11).
Given the unprecedented nature of this type of catalytic
enantioselective approach to atropisomeric amides, we wished to
understand the basis for the enantioselectivity. These experi-
ments were in large part stimulated by the fact that the parent
compound 11 and the monobromides 17, 26, and 29 each gave
slightly (entry 1 vs 4) or significantly (entry 1 vs 9 and 11)
different results in their respective pathways to 12. A particularly
Substitution para to the phenol provided more variation in the
results. For example, the p-methyl-substituted compound 24
gave 25 with a slightly reduced er of 90:10 (80% yield; entry 8).
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revealing experiment involved subjecting substrate 11 to
tribromination conditions in the presence or absence of catalyst
6 (Scheme 1). When these reactions were quenched at low
(Figure 2). When the spectrum of a 1:1 mixture of 6 and 11 is
contrasted with the independent spectra, significant alterations in
Scheme 1
conversion,19 different monobrominated species were apparent
20
1
in the LCMS and H NMR data. In the reaction without
catalyst 6, the dominant species in the reaction mixture, other
than the starting material, was monobromide 26, with bromine
installed para to the phenol. In addition, monobromide 17 was
also observed. Monobromides 26 and 17 were also the dominant
monofunctionalized products when the reaction was conducted
in the presence of a simple tertiary amine (e.g., triethylamine)
under analogous conditions. On the other hand, in the variant
where catalyst 6 was employed, the dominant species was instead
monobromide 29, with bromine installed in the most sterically
demanding position, ortho to both the phenol and the amide.
These monobromides proceeded to different dibromides: in the
uncatalyzed case, 30 was primarily detected; in the catalyzed case,
31a could be detected prior to completion of the reaction, along
with 31b. Our results suggest that the initial bromination in the
6-catalyzed reaction, leading to the formation of 29, may be
stereochemistry-determining. This interpretation is consistent
with our other observations. As noted, when racemic 26 was used
as the starting material under catalytic conditions (Table 1, entry
9), the substrate was not processed enantioselectively. Perhaps
monobromide 26 does not undergo racemization at the low
temperature at which the reaction was conducted, en route to
dibromides and eventually 12. Interestingly, when the p-bromide
of 26 was replaced with a methyl group (as in 24; Table 1, entry
8), significant enantioselectivity was still observed, consistent
with the smaller steric demand of the methyl group relative to
bromide on most scales of steric effects relevant to
atropisomers.21 Racemization of substrate 24 thus remained
possible under these catalytic conditions. Compound 29, with
the 2-bromo substituent, is a particularly poor substrate for the
reaction since the putative stereochemistry-determining site is
blocked, and the substrate may also exhibit a sluggish rate of
isomerization under the reaction conditions. Finally, it is also
interesting to note that compound 27 (Table 1, entry 10), in
which the site that may be stereochemistry-determining is
blocked with a methyl group, was processed with substantially
diminished er. It may be that for this case, the site para to the
phenol is functionalized in the stereochemistry-determining
event, albeit with a less differentiated set of competing transition
states. Thus, it is consistent with our observations that a single,
initial monobromination ortho to both the phenol and the amide
carbonyl is stereochemistry-determining, setting the fate of the
atropisomer-selective reaction at that stage.
Figure 2. Independent NMR spectra of substrate 11 and catalyst 6 and
the spectrum of their 1:1 comixture (0.02 M, CDCl3, 0 °C).
the chemical shifts are evident. In particular, changes consistent
with the formation of complex 32 are observed. For example,
whereas the Dmaa β-proton signals (a, a′) appear nearly
coincident for the free catalyst, they become distinct in the
complex, with one of the resonances exhibiting a Δδ of 0.29 ppm.
Notably, there is also a loss of degeneracy of the methyl groups
associated with the isopropyl groups of the substrate. Critically,
we also observe a significant change in the chemical shift of the
proton associated with the Aib NH (d). In this case, the observed
Δδ is 0.24 ppm downfield, consistent with a possible hydrogen
bond between the substrate and this locus of the catalyst.22
Finally, the prolyl Cα proton (c) may be particularly diagnostic.
In this case, we observe a Δδ of 0.34 ppm upfield.22 If the catalyst
and substrate associate in a manner similar to that drawn for
complex 32, we would expect the ring current of the aromatic
ring of the substrate to perturb the prolyl Cα proton in this
fashion. It is of further interest to note that if complex 32 is
reactive and relevant, one could envision the stereochemistry-
determining bromine atom to be introduced as shown in
complex 33. This particular enantiomer would then go on to
form the observed major enantiomer of 12, as demonstrated by
heavy-atom X-ray crystallography (12-X-ray).23 At this stage, we
are unable to pinpoint which of the catalyst carbonyl groups, if
any, might be responsible for delivering the electrophilic
bromine. It is nonetheless interesting to note that several seem
appropriately disposed. One could also readily imagine, for
example, dynamics associated with the system in which amide
carbonyls participate in hydrogen bonds at one point along the
reaction coordinate but then change roles to deliver bromine at
another point.
In pursuit of observable catalyst−substrate interactions, we
The intriguing nature of this atropisomer-selective benzamide
synthesis has also stimulated our interest in this approach as a
examined 1H NMR spectra of potentially relevant species
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C.; Watkins, C.; Davis, J.; Stubberfield, C. Bioorg. Med. Chem. Lett. 2009,
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functionalization of the various aryl bromide positions could
heighten utility.24 To demonstrate the viability of this goal, we
subjected 19-(Me) to metal−halogen exchange conditions at low
temperature.25 In this experiment, we observed efficient,
regioselective lithiation26 followed by trapping with I2 to give
compound 34. Notably, 34 was isolated without loss of er (eq 5)
(5) (a) Deng, X.; Dzamko, N.; Prescott, A.; Davies, P.; Liu, Q.; Yang,
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(12) Garand, E.; Kamrath, M. Z.; Jordan, P. A.; Wolk, A. B.; McCoy, A.
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as the illustrated regioisomer.20 Trapping with alternative
electrophiles or selective manipulation of scaffolds like 34
could prove to be a fruitful path for preparing other
atropisomerically enriched benzamides.
In summary, we have discovered an enantioselective
bromination process that leads to enantioenriched benzamides.
The reaction mechanism is complex but appears to follow a
pathway that involves a clear mechanistic dichotomy between
peptide-catalyzed and uncatalyzed variants. Given the increasing
attention to atropisomeric compounds in medicinal chemistry,3
we are hopeful that this catalytic process will increase access to
this family of structures, which along with mechanistic pursuits,
will be the continuing focus of this project.
(15) (a) Copeland, G. T.; Jarvo, E. R.; Miller, S. J. J. Org. Chem. 1998,
63, 6784. (b) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.;
Bonitatebus, P. J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638.
(c) Cowen, B. J.; Saunders, L. B.; Miller, S. J. J. Am. Chem. Soc. 2009, 131,
6105. (d) Fowler, B. S.; Mikochik, P. J.; Miller, S. J. J. Am. Chem. Soc.
2010, 132, 2870.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures for all experiments, characterization
data, and crystallographic data (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
(16) Haque, T. S.; Little, J. C.; Gellman, S. H. J. Am. Chem. Soc. 1996,
118, 6975.
AUTHOR INFORMATION
Corresponding Author
scott.miller@yale.edu
Notes
■
(17) A variety of peptide-based scaffolds were evaluated. It is notable
that 6 proved to be among the best at an early stage in this project. In
reactions employing peptides lacking the Dmaa residue, no
enantioselectivity was observed. The lead catalyst described in ref 10
delivered 5 in good yield with a 36:64 er under similar conditions, with a
preference for the enantiomer opposite to that obtained using 6.
(18) The results were consistent when reactions were performed on
scales ranging from 0.2 through 1.0 mmol of substrate. See the
Supporting Information for details.
(19) The reactions were efficiently quenched by the addition of butyl
vinyl ether to the reaction mixture at −40 °C.
(20) See the Supporting Information for details.
(21) Bott, G.; Field, L. D.; Sternhall, S. J. Am. Chem. Soc. 1980, 102,
5618.
(22) (a) Williams, D. H.; Fleming, I. Spectroscopic Methods in Organic
Chemistry, 3rd ed.; McGraw-Hill: Maidenhead, U.K., 1980. (b) Gomes,
J. A. N. F.; Mallion, R. B. Chem. Rev. 2001, 101, 1349.
(23) The absolute sense of the chirality for the other compounds in
Table 1 is not known and has been drawn as shown by analogy to 12.
(24) Gustafson, J. L.; Lim, D.; Barrett, K. T.; Miller, S. J. Angew. Chem.,
Int. Ed. 2011, 50, 5125.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Institute of General Medical
Sciences of the NIH (GM-068649) for support and to Timothy
Schmeier for X-ray crystallography.
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