Asymmetric Induction via a Helically Chiral Anion: Enantioselective Pentacarboxycyclopentadiene Br?nsted Acid-Catalyzed Inverse-Electron-Demand Diels-Alder Cycloaddition of Oxocarbenium Ions

Article abstract of DOI:10.1021/jacs.8b00260

An enantioselective catalytic inverse-electron-demand Diels-Alder reaction of salicylaldehyde acetal-derived oxocarbenium ions and vinyl ethers to generate 2,4-dioxychromanes is described. Chiral pentacarboxycyclopentadiene (PCCP) acids are found to be effective for a variety of substrates. Computational and X-ray crystallographic analyses support the unique hypothesis that an anion with point-chirality-induced helical chirality dictates the absolute sense of stereochemistry in this reaction.

Full text of DOI:10.1021/jacs.8b00260

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Communication
Asymmetric Induction via a Helically Chiral Anion:
Enantioselective PCCP Brønsted Acid-Catalyzed Inverse Electron-
Demand Diels-Alder Cycloaddition of Oxocarbenium Ions
Chirag Gheewala, Jennifer S. Hirschi, Wai-Hang Lee, Daniel
W. Paley, Mathew J. Vetticatt, and Tristan H. Lambert
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00260 • Publication Date (Web): 27 Feb 2018
Downloaded from http://pubs.acs.org on February 27, 2018
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Asymmetric Induction via a Helically Chiral Anion: Enantioselective PCCP Brønsted
Acid-Catalyzed Inverse Electron-Demand Diels-Alder Cycloaddition of Oxocarbenium
Ions.
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Chirag D. Gheewala1, Jennifer S. Hirschi2, Wai-Hang Lee1, Daniel W. Paley1, Mathew Vetticatt2*, and
Tristan H. Lambert1,3*
1Department of Chemistry, Columbia University, New York, New York 10027; 2Department of Chemistry, Binghamton
University, Binghamton, New York 13902; 3Department of Chemistry and Chemical Biology, Cornell University,
Ithaca, New York 14853
RECEIVED DATE (automatically inserted by publisher); tristan.lambert@cornell.edu
temperature in benzene. Cycloadduct diastereoselectivity
was found to be >20:1 in all cases. The use of the previously
ABSTRACT:
An enantioselective catalytic inverse
electronꢀdemand DielsꢀAlder reaction of salicylaldehyde
acetalꢀderived oxocarbenium ions and vinyl ethers to
generate 2,4ꢀdioxychromanes is described. Chiral PCCP
acids are found to be effective for a variety of substrates.
Computational and Xꢀray crystallographic analyses
support the unique hypothesis that a point chiralityꢀ
induced, helically chiral anion dictates the absolute sense
of stereochemistry in this reaction.
(a)
acid
OR2
O
OR2
R3
OH
OR1
OR1
catalyst
+
R3
OH
OR1
2,4-dioxychromanes
+
O
R1
Me
Me
CO2H
O
H
OH
O
O
HO
O
H
Me
Me
O
O
O
Me
MeO2C Me
Me
C3H7
H
C7H15
O
O
OH
OH
Oxygenated chromanes form the core architecture of a
number of natural products, including the antitumor agent
berkelic acid,1 the antibiotic paecilospirone,2 and the antiꢀ
HIV agent calanolide A3 (Figure 1a). A particularly
attractive strategy to access such structures would be to fuse
readily available salicylaldehyde acetals and vinyl ethers via
an inverse electron demand DielsꢀAlder reaction. In theory,
a chiral Brønsted acid catalyst4 could ionize the acetal
substrate to form an activated oxocarbenium ion, and
subsequently exert control over absolute stereochemistry in
the cycloaddition step, thereby generating enantioenriched
2,4ꢀdioxychromanes. Indeed, related reactions of oꢀquinone
methide intermediates generated by the ionization of diaryl
methanols or similar species can be achieved with high
enantioselectivity.5 The production of 2,4ꢀdioxychromanes,
on the other hand, requires the generation and absolute
stereocontrol of oxocarbenium ion intermediates, which
represents a substantial challenge at the forefront of the field
of asymmetric catalysis.6 Additionally, a viable catalyst for
this process must be sufficiently mild to avoid ionizing the
chromane products, which in our design also incorporate
acetal functionality.
C8H17
O
Me
O
paecilospirone
calanolide A
berkelic acid
anticancer
antibiotic
anti-HIV
(b)
O
OR
RO
O
OR
RO
O
OH
OR
O
O
H+
+
–
RO
OR
RO
O
O
OR
O
O
OR
PCCPs
Figure 1. (a) Inverse electronꢀdemand DielsꢀAlder reaction of
salicylaldehyde acetals and vinyl ethers to yield 2,4ꢀ
dioxychromanes, and several biologically active natural products
that incorporate this architecture. (b) PCCP Brønsted acids.
reported catalyst 4, derived from Lꢀmenthol, resulted in the
production of chromane 3 in 54% yield with an 85:15 er
(entry 1). Catalysts 5 and 6, derived from acyclic alcohols
(entries 2 and 3), and catalyst 7, derived from a fiveꢀ
membered cyclic alcohol (entry 4), also showed promise but
could not be sufficiently optimized in terms of
enantioselectivity and so were not further pursued.
We recently reported a platform for chiral Brønsted acid
catalysis based on pentacarboxycyclopentadienes (PCCPs),7
which are strongly acidic and simple to prepare from chiral
alcohol precursors (Figure 1b).8 In this Communication, we
report the development of an enantioselective PCCPꢀ
catalyzed inverse electron demand DielsꢀAlder reaction.
We selected the reaction of salicylaldehyde diethyl acetal
(1) and ethyl vinyl ether (2) to identify a viable catalyst for
Remarkably, catalyst
8, derived
from transꢀ2ꢀ
methylcyclohexanol, generated product with a 91:9 er (entry
5), a significant improvement over the structurally related
catalyst 4. In fact, we observed a clear trend of decreasing
enantioselectivity with increasing size of the 2ꢀsubstituent,
with iꢀPr, iꢀBu, and cꢀhexyl resulting in enantiomeric ratios
of 89:11, 82:18, and 59:41 respectively (catalysts 9ꢀ11,
entries 6ꢀ8). On the other hand, catalyst 12, derived from
transꢀ2ꢀphenylcyclohexanol, furnished the product in 63%
yield with 92:8 er (entry 9), which is an essentially identical
the DielsꢀAlder reaction (Table 1).
conducted with mol% catalyst loading at ambient
Reactions were
5
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outcome to catalyst 8. Once again, however, attempts to
in producing 21 (entry 3). Methyl substitution on the
aromatic ring was well tolerated as long as it was not ortho
to the phenol group (entries 4ꢀ6). A significant effect of
halide substitution was also observed. Thus, while a fluoro
substituent was innocuous relative to hydrogen (entry 7), a
switch to chloro (entry 8) and especially bromo (entry 9)
resulted in dramatic decreases in enantioselectivity.
With regard to the vinyl ether, we found that βꢀ
substitution was possible, leading to the production of 28 or
29 bearing three stereogenic centers (entries 10 and 11).
Notably, αꢀsubstitution on the vinyl ether reduced both the
yield and the enantioselectivity (entry 12). Alteration of the
ether substituent to an iꢀbutyl group was also feasible (entry
13). With the current catalyst, a cyclic vinyl ether
participated with only poor enantiocontrol (entry 14).
However, there is cause for optimism in the fact that the use
of a different catalyst (i.e. 4) had a noticeable impact on the
stereoselectivity of the reaction (entry 15).
1
2
3
4
5
6
7
8
increase selectivity with further alkyl substitution led to a
major decrease in reactivity (catalysts 13 and 14, entries 10
and 11), and in the case of 14, of enantioselectivity as well.
In the extreme, catalyst 15, containing an oꢀmethylphenyl
substituent, was completely unreactive (entry 12). We next
explored the effects of modulating the electronic nature of
the phenyl ring. We found that, while a pꢀCF3 substituent
was detrimental to selectivity (16, entry 13), pꢀmethoxy and
pꢀmethylthioxy substituents resulted in appreciable increases
in both yield and enantioselectivity (17 and 18, entries 14
and 15). Catalyst 19, incorporating a phenylacetylene
substituent, was reactive but generated racemic product
(entry 16). Based on the combination of performance and
accessibility, we selected PCCP 17 as our optimal catalyst.
The findings of these catalyst optimization studies were
initially perplexing because the catalysts seem to be
relatively insensitive to electronic perturbation and to
generally follow an inverse steric trend. However, we
believe these data can be rationalized via the stereochemical
model that we have subsequently developed (vide infra).
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Table 2. Scope studies for inverse electron demand DielsꢀAlder
reaction.a
Table 1. Catalyst optimization studies for inverse electron demand
DielsꢀAlder reaction.a,b
a Yields were determined on purified product. Enantiomeric ratios were
determined by HPLC analysis. b The catalysts depicted in entries 2, 4, 5,
11ꢀ13, and 15 are the opposite enantiomer to the ones used, but are
drawn as the same series to minimize confusion. The major product
obtained in these cases was thus also the opposite enantiomer (entꢀ3).
a Yields were determined on purified product. Enantiomeric ratios were
determined by HPLC analysis.
In order to gain insight into the structure of this catalyst,
we subjected the conjugate base of 17 (as the +NMe4 salt) to
single crystal Xꢀray analysis (Figure 2a). Notably, the five
carboxyl groups appear strongly geared to one another,
existing in an (M) helically chiral arrangement. Each
carboxyl exists at an angle of between 28 and 57 degrees
relative to the plane of the cyclopentadienyl ring, with the
Using catalyst 17, we next probed the impact of structural
changes to the substrates (Table 2). In terms of the
salicylaldehyde acetal moiety, we found that ethyl and
isopropyl acetals led to products 3 and 20 with essentially
equal enantioselectivities (entries 1 and 2), while the reaction
with the methyl acetal substrate was somewhat less selective
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carbonyl oxygens on one face and the 2ꢀarylcyclohexyl
substituents on the other.
structures suggest that the helical conformation has an
inherently strong energetic bias, which we attribute to
conformational A(1,3)ꢀminimization of each chiral ester
group along with gearing of all five carboxyls to
accommodate the steric demands of the chiral substituents.
It thus appears that the point chirality of the ester
substituents induces helical chirality of the PCCP anion as a
whole, which in turn leads to biasing of the
enantiodetermining transition state.
This view offers a rationale for the results obtained in the
catalyst SAR study (Table 1). Specifically, chiral
substituents (e.g. 17, entry 14) that reinforce the helical
organization result in high enantioselectivities, while those
that destabilize the helix, either due to excessive steric
volume (e.g. 11, 14, and 15, entries 8, 11, and 12) or length
(e.g. 19, entry 16) are less effective.
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8
(a) Molecular structure of 17·NMe4 (X-ray)
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(b) Transition states of 1 + 2 + 17 (calculated)
To investigate how this helically chiral anion achieves
asymmetric induction, we modeled the cycloaddition
transition state involving the putative oxocarbenium ion
+
O
H
–
CH3
H3C
O
O
H
H
H
H
1.58
2.90
intermediate and vinyl ether (2) catalyzed by the PCCP
O
2.34
10
O
2.73
O
O
catalyst 17 using B3LYP /6ꢀ31G* calculations as
11
O
O
implemented in Gaussian 09 (Figure 2b).
We chose
O
O
O
catalyst 8 for our initial computational study since it had 55
atoms fewer than the optimal catalyst 17, thus allowing for a
more rigorous conformational analysis. The lowest energy
structures for each enantiomer that emerged from these
initial calculations were recalculated using catalyst 17. A
detailed description of the computational methodology along
with cartesian coordinates for all relevant structures located
using both catalyst 8 and 17 are in the Supporting
Information. The energies reported in Figure 2b are
extrapolated relative Gibbs free energies obtained from
single point energy calculations performed using the
B3LYPꢀGD3 method12 with a 6ꢀ31+G* basis set and the
PCM solvent model13 for benzene. This dispersionꢀcorrected
DFT method provides a reasonable description of the
energetics of nonꢀcovalent interactions present at the
transition state.
The lowest energy transition state TS(S,S) leading to the
major (S,S)ꢀenantiomer of the cycloaddition product is
described as a concerted but highly asynchronous [4+2]
transition structure with C–C bond formation being more
advanced (2.42 Å) than C–O bond formation (3.11 Å). Three
key nonꢀcovalent interactions that stabilize this transition
state are: (a) a strong Hꢀbonding interaction (1.58 Å)
between the phenolic hydrogen and a carbonyl oxygen atom
of 17; (b) a weak C–H…O interaction (2.34 Å) between the
oxocarbenium C–H and second carbonyl oxygen atom of 17;
O
TS(S,S)
Erel = 0.0 kcal/mol
+
O
O
H3C
O
H
1.62
H
CH3
H
2.12
H
O
H
O
O
2.44
3.05
O
O
O
–
O
O
O
O
TS(R,R)
Erel = 2.8 kcal/mol
Figure 2. (a) Xꢀray structure of 17•NMe4. Only a portion of the
crystal unit is shown. There are four independent PCCP anions and
ammonium cations in the crystal unit, along with two molecules of
chloroform. The anions and cations pack alternately in columnar
arrays, meaning that each anion is closely associated with two
cations; only one cation is shown. In addition, there was disorder in
the cations, but only one orientation is shown for clarity. (b)
Lowest energy transition structures leading to the major (S,S) and
minor (R,R) enantiomer of the [4+2] cycloaddition product of the
reaction of 1 and 2 catalyzed by 17 computed using B3LYP/6ꢀ
31G*. The two forming bonds are highlight in pink and the aromatic
ring of the catalyst is highlighted in green. All distances are in
angstroms.
and (c) a strong C–Hꢀπ interaction between the polarized
14
internal vinylic C–H of 2 and the cyclopentadienyl anion.
The lowest energy transition state leading to the minor
(R,R)ꢀenantiomer of the cycloaddition product TS(R,R) differs
from TS(S,S) in terms of the mode of stabilization of the three
acidic hydrogen atoms. While the phenolic hydrogen is
stabilized by a strong Hꢀbonding interaction (1.62 Å) similar
to TS(S,S), the mode of stabilization of the oxocarbenium C–
H and the polarized internal vinyl C–H is switched compared
to TS(S,S) – the oxocarbenium C–H is now stabilized by a
moderate C–Hꢀπ interaction with the aromatic ring and the
internal vinylic C–H is engaged in a strong Hꢀbonding
interaction (2.12 Å) with a carbonyl oxygen atom of 17.
The C–C and C–O bondꢀforming distances in TS(R,R) are
2.24 Å and 2.81 Å respectively; a significantly ‘later’
This type of helical arrangement might be presumed to be
a result of crystal packing energetics. However, when we
calculated the corresponding transition structures using
9
catalyst 17, the lowest energy transition structures had
precisely the same helicallyꢀgeared conformation of the
carboxyl groups (Figure 2b). These closely matching
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transition structure compared to TS(S,S) (vide supra). The
catalysts with weakly interacting intermediates and will
inform further catalyst development studies.
1
2
3
4
5
6
7
8
difference in the Gibbs free energy barrier for these two
‡
transition structures (∆∆G ) is 2.8 kcal/mol in favor of
Acknowledgement: Financial support was provided by NIGMS
(R01 GM120205). CDG is grateful for an NSF graduate fellowship.
TS
; this corresponds to a predicted enantioselectivity of
(S,S)
99% ee at room temperature. Considering the size of the
model system (220 atoms) and the limitations of the DFT
methods used, this value is in reasonable agreement with the
experimental 87% ee observed for catalyst 17 (Table 1, entry
14). The steric portion of the PCCP catalyst does not directly
interact with the organization of either of the transition
structures shown in Figure 2b. In the absence of any notable
steric bias, the energetic preference for TS(S,S) over TS(R,R) is
likely a result of superior transition state stabilization
achieved by the nonꢀcovalent interactions present in TS(S,S)
Supporting Information Available:
Experimental
procedures and product characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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.
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oxocarbenium–PCCP salt 33.
Cycloaddition of this
oxocarbenium with ethyl vinyl ether (2) then proceeds
through transition state 34, in which the absolute
stereochemistry of the product is dictated by the helical
chirality of the anion transmitted via a collection of Hꢀ
bonding, C–H…O interactions and CꢀHꢀaryl interactions.
Finally, deprotonation of the resulting intermediate 35 by the
PCCP anion furnishes the chromane product
3 and
regenerates the catalyst. As an alternative to this final
“proton return” step, we note that it may be that intermediate
35 serves as the acid to directly ionize another molecule of
substrate in a “proton propagation” pathway.
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961.
Figure 3. Mechanistic rationale for PCCPꢀcatalyzed inverse
electronꢀdemand DielsꢀAlder reaction.
In conclusion, we have developed an enantioselective
Brønsted
acidꢀcatalyzed
DielsꢀAlder
reaction
of
(8) Gheewala, C. G.; Radtke, A. M.; Hui, J.; Hon, A. B.; Lambert, T. H
salicylaldehyde acetals and vinyl ethers. This protocol
enables enantioenriched 2,4ꢀdioxychromanes to be prepared
in straightforward fashion. Through a combined effort of
SAR investigation, Xꢀray analysis, and computational study,
we have developed a unique stereochemical rationale for this
process involving a pointꢀchirality induced, helically chiral
anion. This model offers insight into the operation of PCCP
Org. Lett. 2017, 19, 4227.
(9) This structure was computed based on the lowest energy transition
structures for 17 (Figure 2). The coordinates and pdb files for the two
transition structures located for catalyst 17 are in the Supporting
Information.
(10) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(11) Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H.
B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.;
Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato,
M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
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Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman,
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Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
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(13) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105,
2999−3093.
(14) This interaction is characterized by a 2.69 Å and 2.73 Å distance
between the internal vinylic CH of 2 and two of the aromatic carbon
atoms of 17.
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OH
O
OEt
PCCP–H+
OEt
OEt
OEt
OEt
major
enantiomer
helically chiral
PCCP anion
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