Biomimetic Desymmetrization of a Carboxylic Acid

Article abstract of DOI:10.1021/jacs.7b12185

The enantioselective desymmetrization of carboxylic acids by chiral Br?nsted base catalysis is reported, leading to bridged bicyclic lactones with up to 94% ee. Crystallographic analysis of a substrate-catalyst complex suggests an origin of stereocontrol, reminiscent of functional Br?nsted bases in biological settings, and enabled reaction optimization. The products contain an all-carbon quaternary stereocenter and can be derivatized to functionalized cyclopentanes.

Full text of DOI:10.1021/jacs.7b12185

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Biomimetic Desymmetrization of a Carboxylic Acid
Matthew T. Knowe,† Michael W. Danneman,† Sarah Sun,† Maren Pink,‡ and Jeffrey N. Johnston*,†
†Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235-1822,
United States
‡Indiana University Molecular Structure Center, Bloomington, Indiana 47405, United States
S
* Supporting Information
ABSTRACT: The enantioselective desymmetrization of
carboxylic acids by chiral Brønsted base catalysis is
reported, leading to bridged bicyclic lactones with up to
94% ee. Crystallographic analysis of a substrate−catalyst
complex suggests an origin of stereocontrol, reminiscent of
functional Brønsted bases in biological settings, and
enabled reaction optimization. The products contain an
all-carbon quaternary stereocenter and can be derivatized
to functionalized cyclopentanes.
arboxylic acids are robust substrates widely valued for
their availability and utility in substitutions (e.g.,
C
Mitsunobu reactions) and addition reactions to activated
alkenes. As a reagent, the carboxylic acid can function as a
catalyst,1 although successful chiral carboxylic acid organo-
catalysts2 remain relatively limited. Likewise, development of
asymmetric activation strategies for reactions of carboxylic acid
substrates have evolved slowly.3,4 Cases of enzyme-mediated
base activation of carboxylates are known, but a similar
demonstration in small molecule catalysis is absent. Advances
in chemistry have blurred the distinction between enzymatic
and organic catalysis,5,6 and the latter has been categorized by
mechanism (covalent vs noncovalent catalysis) and function-
ality (hydrogen bonding). A detailed understanding of those
features necessary for catalysis involving carboxylic acids,
however, is still developing and catalyst designs trend toward
confined cavities for catalysis and stereocontrol.3,4,7
Figure 1. Hydrogen bond-driven activation: (A) double hydrogen
bond donation to one oxygen, and Brønsted base activation of the
other, leading to enhancement of an oxygen’s nucleophilicity in
dethiobiotin synthetase; (B) model for simultaneous electrophile and
carboxylic acid activation by a chiral phosphoric acid (proposed); (C)
carboxyl oxygen desymmetrization using an array of three hydrogen
bonds (proposed). *For Etter graph set nomenclature, see ref 14.
A variety of strategies have been employed for alkene
halofunctionalization,8,9 yet activation of carboxylic acids by a
simple Brønsted base has little precedent,10−12 preventing
development of a clear picture for activation and stereocontrol.
A remarkable example of carboxyl control is found in the
carbamic acid nucleophile in the enzyme dethiobiotin synthetase,
for which crystallographic evidence supports a hydrogen-bond-
mediated oxygen differentiation (Figure 1A).13 The hydrogen
bond-accepting feature of chiral phosphoric acids was used
recently to activate a carboxylic acid, with simultaneous
activation of an electrophile by hydrogen-bond donation3,4
(Figure 1B, Etter graph sets14). Similarly, bifunctional Brønsted
acid−base catalysis in the coactivation of a carboxylic acid and a
halogen donor has been firmly established for enantioselective
alkene haloesterification.15
conformationally unrestricted substrates (I) for which dual
Brønsted base/Brønsted acid activation can be envisioned, the
conformational restrictions of cyclic acids II/III require
halonium delivery anti to the carboxyl, such that a catalyst
hydrogen bond donor/acceptor can bind only the nucleophile
or electrophile. Symmetric diene II requires only π-carbon
selectivity, while unsaturated acid III additionally demands
carboxylic acid oxygen-selectivity. Framed by this mechanistic
question and existing evidence for bifunctional catalysis of π-
face selective halocyclizations,16 we sought to apply BisAMidine
We reasoned that prochiral cyclic unsaturated acids III/1
(Figure 2) might further challenge a catalyst by decoupling
Brønsted base and Brønsted acid activation of a carboxylic acid
and a halonium source, respectively. In contrast to more
Received: November 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b12185
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Discovery and Development of an Enantioselective
Synthesis of a Bridged Lactone
I+
source
temp
(°C)
time
(h)
yield
c
ee
(%)
a
b
d
entry
catalyst
(%)
1
2
3
4
5
6
3a·HNTf2
NIS
NIS
NIS
NIS
NIS
NIP
NIP
NIP
−20
−20
−20
−20
−50
−50
−50
−20
48
48
24
24
48
48
24
24
<5
50
64
79
74
86
83
36
−
3a
3b
3c
3c
3c
3d
3e
62
61
73
85
89
94
69
e
7
8
a
b
All reactions were performed on a 0.05 mmol scale. NIS = N-
iodosuccinimide, NIP = N-iodophthalimide. Yield determined by H
NMR analysis relative to an internal standard (CH2Br2). Enantio-
c
1
d
meric ratios were measured using HPLC with a chiral stationary phase.
See Supporting Information for complete details. Reaction stirred in a
2−5 mL round bottomed microwave vial.
Figure 2. Prior approaches to alkene functionalization (I, II) and this
approach (III) requiring simultaneous control of nucleophilic carboxyl
oxygen and carbon-CO2H bond conformation by a chiral base (*B:).
e
(BAM) catalysis to the desymmetrization of constrained Z-
alkenes (1).17 A map of stereocontrol (Figure 2) illustrates that
carboxyl oxygen selectivity during nucleophilic attack, as well as
orientation about the C−CO2H bond, are equally necessary to
achieve enantioselection. This report details the first
enantioselective iodolactonizations of cyclopentenes 1, evi-
dence for Brønsted base activation of the carboxylic acid, and
the X-ray crystal structure of a substrate−BAM complex. The
latter suggests the role of an array of three hydrogen bonds,
which we hypothesize to be the origin of enantiocontrol
(Figure 1C). The overall picture is reminiscent of enzymatic
hydrogen bonding where substrate conformational control and
carboxyl activation play a key role in catalysis.
Our initial studies with 1a indicated that the free base of
organocatalyst 3a was moderately active and selective while the
1:1 Brønsted acid salt (Table 1, entries 1−2) was essentially
inactive.18 This result stood in striking contrast to all other
alkene iodofunctionalizations with BAMs16 and was interpreted
as evidence for monofunctional activation. At this point, a
single crystal of catalyst 3a with 1a was successfully prepared
and analyzed by X-ray diffractometry (Figure 3). Two features
were evident: (1) the amidinium-carboxylate salt effectively
bound the substrate close to the catalyst’s chiral cavity, assisted
by a third hydrogen bond donor, and (2) the second quinoline
ring is oriented such that its 4-substituent (pyrrolidine) is
positioned near the substrate binding pocket.
We undertook a broader investigation of catalysts, resulting
in the discovery that N-aryl BAM 3b provided competitive
levels of selectivity and significantly improved reactivity (Table
1, entry 3). We hypothesized that a substituent at the quinoline
6-position might buttress the aniline in 3b, deterring a
conformation that places the aromatic ring away from the
binding site.19 The effect of a 6-tert-butyl was explored with 3c
providing selectivity to 73% ee at −20 °C (Table 1, entry 4)
and 85% ee at −50 °C (Table 1, entry 5).
Figure 3. Key features of the X-ray cocrystal structure of 1a·(R,R)-3a.
with optimal selectivity and reactivity (Table 1, entry 7). The
influence of the 6-tert-butyl substituent does not translate to the
original findings with 3a (cf. Table 1, entries 2, 8). Several
commercially available chiral phosphoric acids and thioureas
were evaluated, but provided only racemic bridged lactones.19
The structure in Figure 3 provides a reasonable basis to
further refine our hypothesis for stereocontrol (vide supra),
proposing that the three hydrogen bond contacts between the
catalyst and carboxylic acid may be responsible for
enantioselection.20 Two hydrogen bonds from one amidine
and a third hydrogen bond from the ancillary amidine
effectively desymmetrize the carboxylate by diminishing the
nucleophilicity of the doubly bonded oxygen relative to the
Investigation of iodonium sources found N-iodophthalimide
increased enantioselectivity to 89% ee (Table 1, entry 6). Other
halogen sources provided lower selectivity and reactivity.
Investigation of aniline derivatives identified 3d as a catalyst
B
DOI: 10.1021/jacs.7b12185
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
singly bonded carboxylate oxygen. Catalyst−substrate binding
in solution was investigated by isothermal titration calorim-
etry21 and found to be driven by strong hydrogen bonding (KA
= 2.52 × 105 M−1).19 The role of the quinoline 4-substituent
(pyrrolidine (3a) → p-toluidine (3d)) may be critical to
achieve the second criterion for selectivityrestricted rotation
about the cyclopentene−CO2H bondby a steric interac-
tion.19 Importantly, this hypothesis suggests that this second
quinoline may not be important for binding and activation (i.e.,
to NIP).
Derivatization of the bicyclic lactone products (Scheme 1)
was readily achieved, each with conservation of enantiomeric
Scheme 1. Conversions of Lactone 2a
The reaction scope was evaluated using catalyst 3d, and
exploratory substrate 1a (Table 2, entry 1) was completed on 1
Table 2. Enantioselective Iodolactonizations Catalyzed by
a
BAM 3d: Scope and Limitations
b
c
entry
R
1/2 time (h) yield (%)
ee (%)
1
C6H5
a
a
b
c
d
e
f
24
48
72
72
24
24
48
120
72
24
24
48
72
72
72
72
87
66
78
72
69
74
65
78
55
69
74
66
66
64
66
<5
93
94
90
67
89
89
91
86
94
92
87
87
86
64
74
−
excess. Reduction of 2a with lithium aluminum hydride at low
temperature leads to iododiol 4 in 42% yield and at higher
temperature facilitates reduction followed by etherification to
bicyclic alcohol 5 in 59% yield. Reductive deiodination and
allylation proceeded in good yield, providing 6 and 7 (5:1 dr)
respectively. Finally, aminolysis of lactone 6 afforded syn-γ-
hydroxy amide 8 in good yield (70%), to give a functionalized
cyclopentane core common to carbocyclic nucleosides,22
providing novel approaches toward accessing this type of
therapeutic.23
In conclusion, monofunctional Brønsted base catalysis of a
unique iodolactonization has been discovered using a substrate
that deconstructs the normal bifunctional activation mode of
chiral hydrogen bond catalysts. Structural studies reveal a
network of three hydrogen bonds that desymmetrizes the
bound carboxylate, while a distant N-aryl substituent influences
the cyclopentene ring’s conformation. Both of these effects are
necessary for enantioselection and are achieved using a C2-
symmetric Brønsted basic catalyst. Broader use of this strategy
for carboxylic acid activation may lead to an expansion of their
utility in enantioselective transformations, and an improved
understanding of the essential characteristics of enzymatic
reactions using carboxyl nucleophiles.
2
C6H5 (1.0 mmol scale)
2Np
1Np
3
4
5
mClC6H4
pBrC6H4
p(MeO)C6H4
p(O2N)C6H4
pPhC6H4
2-thiophene
iPr
6
7
8
g
h
i
9
10
11
12
13
14
15
16
j
Bn
k
l
Me
t
CO2 Bu
C(O)StBu
m
n
o
H
a
All reactions were performed on a 0.10 mmol scale using 1 equiv of
the carboxylic acid, 10 mol % catalyst, and 1.04 equiv NIP in toluene
(0.05 M). Isolated yield. Enantiomeric ratios were measured using
HPLC and a chiral stationary phase. See Supporting Information for
details.
b
c
mmol scale with good yield (66%) and 94% ee (Table 2, entry
2). 2-Naphthyl derivative 1b reacted well and with good
selectivity (Table 2, entry 3), while the sterically demanding 1-
naphthyl 1c provided good yield and moderate enantioselection
(Table 2, entry 4). Halophenyl substrates were also tolerated
(Table 2, entries 5−6). The electronic nature of the aromatic
ring exhibited some generality, with 1f−1h converting to
product in moderate to good yields and with high
enantioselectivity (Table 2, entries 7−10), although 1g required
an extended reaction time. Isopropyl-, benzyl-, and methyl-
substituents are well tolerated, reacting with slightly lower
selectivity relative to aryl substrates (Table 2, entries 11−13).
Malonate half-ester 1m and thioester 1n provide additional
versatility for applications of the lactone products, albeit with
some depression of enantioselection. α-Unsubstituted carbox-
ylic acid 1o failed to convert under these conditions (Table 2,
entry 16), suggesting ground state destabilization, provided by
compression of the carboxylic acid−alkene distance, may be
needed.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b12185.
■
S
Complete experimental details (PDF)
NMR and HPLC trace data (PDF)
Crystallographic data for 1a·3a (CIF)
Crystallographic data for 2a (CIF)
AUTHOR INFORMATION
Corresponding Author
*jeffrey.n.johnston@vanderbilt.edu
ORCID
Jeffrey N. Johnston: 0000-0002-0885-636X
Notes
The authors declare no competing financial interest.
■
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DOI: 10.1021/jacs.7b12185
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Johnston, J. N. J. Am. Chem. Soc. 2015, 137, 7302. (c) Toda, Y.; Pink,
M.; Johnston, J. N. J. Am. Chem. Soc. 2014, 136, 14734.
(17) (a) Ikeuchi, K.; Ido, S.; Yoshimura, S.; Asakawa, T.; Inai, M.;
ACKNOWLEDGMENTS
■
S.S. was supported by the Vanderbilt University Summer
Research Program. We are grateful to the National Institute of
General Medical Sciences (NIH GM 084333) for financial
support.
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DOI: 10.1021/jacs.7b12185
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