Asymmetric Synthesis of Griffipavixanthone Employing a Chiral Phosphoric Acid-Catalyzed Cycloaddition

Article abstract of DOI:10.1021/jacs.8b12520

Asymmetric synthesis of the biologically active xanthone dimer griffipavixanthone is reported along with its absolute stereochemistry determination. Synthesis of the natural product is accomplished via dimerization of a p-quinone methide using a chiral ph

Full text of DOI:10.1021/jacs.8b12520

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Communication
Asymmetric Synthesis of Griffipavixanthone Employing
a Chiral Phosphoric Acid-Catalyzed Cycloaddition
Michael J Smith, Kyle D Reichl, Randolph A Escobar, Thomas
Heavey, David F. Coker, Scott E. Schaus, and John A. Porco
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12520 • Publication Date (Web): 19 Dec 2018
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Asymmetric Synthesis of Griffipavixanthone Employing a Chiral
Phosphoric Acid-Catalyzed Cycloaddition
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Michael J. Smith, Kyle D. Reichl, Randolph A. Escobar, Thomas J. Heavey, David F. Coker, Scott E.
Schaus,* and John A. Porco, Jr.*
Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue,
Boston, Massachusetts 02215, United States
Supporting Information Placeholder
Scheme 1. Brønsted acid-catalyzed dimerization cascade
ABSTRACT: Asymmetric synthesis of the biologically active
xanthone dimer griffipavixanthone (GPX) is reported along with its
absolute stereochemistry determination. Synthesis of the natural
product is accomplished via dimerization of a p-quinone methide
(p-QM) using a chiral phosphoric acid (CPA) catalyst to afford a
protected precursor in excellent diastereo- and enantioselectivity.
Mechanistic studies, including an unbiased computational
investigation of chiral ion-pairs using parallel tempering (PT), were
performed in order to probe the mode of asymmetric induction.
The dimeric natural product (+)-griffipavixanthone (1)1 has
become a desirable synthetic target due to its interesting framework
and anti-cancer properties. Compound (+)-(1) has been shown to
increase intracellular reactive oxygen species (ROS) and cleave
caspase-3, thereby inducing apoptosis in lung cancer cells.2 Recent
studies have shown that (+)-(1) is a B-Raf and C-Raf inhibitor in
esophageal cancer cell lines with comparable effects to FDA-
approved drugs.3
We have previously reported the biomimetic synthesis of (±)-
1 wherein treatment of p-QM precursor 2 with Lewis or Brønsted
acids triggered an isomerization-cycloaddition-cyclization cascade
affording the polycyclic core (Scheme 1). The reaction sequence
began with acid-mediated isomerization of the vinyl p-QM 2 to 1,3-
diene 3. Cationic, stepwise [4+2] cycloaddition of 2 and 3 afforded
the anti-cycloadduct 4 and syn-cycloadduct 5, the latter which
underwent intramolecular arylation to afford griffipavixanthone
tetramethyl ether 6.4
Scheme 2. Representative CPA-catalyzed asymmetric
reactions of p-quinone methides
The complexity and unique nature of this cationic cascade
prompted our interest to undertake an asymmetric synthesis. In this
regard, we considered that enantioselectivity could be introduced
via chiral ion-pairing catalysis.5–7 Asymmetric [4+2]
cycloadditions are mediated by both Brønsted and Lewis acids.8,9
Scheme 2 depicts select literature reports of chiral Brønsted acid-
mediated asymmetric reactions involving p-QMs. Sun and
coworkers have reported CPA-mediated, enantioselective 1,6-
arylations of p-QMs (Scheme 2a).10,11 In addition, Li and
coworkers have demonstrated asymmetric α-alkylations to p-QMs
generating two contiguous stereocenters (Scheme 2b).12 There is a
single report of a diastereoselective, CPA-mediated intramolecular
[4+2] cycloaddition.13 These studies further prompted our interest
to develop an intermolecular, asymmetric [4+2] cycloaddition of a
p-QM (Scheme 2c). Herein, we (1) describe a CPA-catalyzed
asymmetric synthesis of (+)-1, (2) demonstrate catalyst-dependent
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diastereoselectivity, (3) assign absolute stereochemical
a.
configuration to (+)-1, and (4) provide computational insight for
the asymmetric induction observed using parallel-tempering (PT)
simulation methods.
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Yamamoto and coworkers have demonstrated that chiral
Brønsted acid-mediated cycloadditions require specific pKa’s as
dictated by the substrate.14 With this in mind, our investigation
began by surveying chiral Brønsted acids with varying pKa’s
including CPAs, imidodiphosphoric acids (IDPs), and N-triflyl
phosphorimides.14–17 While the latter two catalyst classes chiefly
led to isomerization of p-QM 2 to diene 3, use of CPAs led to
production of cycloadducts 4-6. A study of electronically-variable
CPAs was performed (Table 1). We found that treatment of 2 with
CPA A18 (entry 1) generated dimer 6 in high enantioselectivity
along with products 3-5. Electron rich CPAs B and C19 lowered the
reactivity for cycloadducts (entries 2 and 3). With the most
promising result observed using –CF3 catalyst (A), we expanded
our assessment of electron-deficient, aryl-substituted CPAs and
found that the highly electron-deficient Yamamoto catalyst (CPA
D)20 favored the anti-cycloadduct 4 (entry 4). However, the
moderately electron deficient CPA E21 afforded several products,
while still maintaining high enantioselectivity for dimer 6 (entry 5).
Interestingly, use of CPA F19 bearing the strongly electron-
withdrawing nitro (NO2) substituent provided high diastereo- and
enantioselectivity (entry 6). At elevated temperatures (entry 7), the
reaction was driven to completion affording (+)-6 in 72% yield and
99% ee.
b.
20
15
10
5
(8R,8aR,12S)–1 (Calculated)
(+)–1 (Experimental)
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0
-5
-10
-15
-20
200
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wavelength (nm)
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Figure 1. Absolute stereochemical determination of (+)-1. (a)
Synthesis of (+)-GPX. (b) Comparison of experimental and
computational ECD spectra for (+)-griffipavixanthone.
At this juncture, we were also interested to determine the
enantioselectivity of the anti-cycloadduct, the only dimeric product
formed upon treatment of 2 with CPA D. Upon isolation of the
dimeric p-QM cycloadduct 4, heterogeneous reduction with
H2/Pd/C afforded cycloadduct 7 in 33 % yield (2 steps) and 71% ee
(Scheme 3). The absolute stereochemistry of (+)-7 was determined
using ECD analysis.22
Table 1. Assessment of BINOL-derived CPAs
Scheme 3. Reductive trapping of anti-cycloadduct 4 to
determine enantioselectivity
entry
1
CPA
A
3 (%)
4 (%)
5 (%)
6a (%) (% ee)
7
30
9
34 (96)
2
3
B
C
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11
8
3
-
-
1
We also used in situ H-NMR analysis to monitor reactions
4
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6
7b
D
E
F
F
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5
-
comparing both TFA and CPA F as catalysts. Using TFA as a
catalyst, production of the anti-cycloadduct 4 appears to be more
favorable than the syn-cycloadduct 5 (Figure 2a). Remarkably,
CPA F shows reversal of the TFA-catalyzed preference for anti-
cycloadduct 4, instead showing initial formation of the syn-
cycloadduct 5 (Figure 2b). Presumably, CPA catalyst F reduces
the energetic barrier to the syn-cycloadduct 5 (vide infra). 1H-NMR
data (Figure 2) also indicated formation of diene 3 in situ. To probe
the potential for decomposition or dimerization, diene 3 was
subjected to the standard conditions; in the event, 6 was isolated in
69% yield and 96% ee.22
36 (95)
61 (99)
72c (99)
-
-
1H-NMR yields determined using 1,2,4,5-tetramethylbenzene as
a
internal standard. b Reaction temperature is 40 °C. c Isolated yield.
To determine the absolute stereochemistry of 1 prepared using
CPA F, global demethylation of (+)-6 using our previously
reported conditions4 was performed. By measuring the optical
rotation of 1, we found that (R)-CPA F provided the natural (+)-
enantiomer of
6 (Figure 1a). To elucidate the absolute
As we identified catalyst diastereoselectivity, we were also
interested to probe the point at which enantioselectivity was
introduced. Treatment of (±)-5 with CPA F resulted in the
formation of (+)-6 in 78% ee (Scheme 4a). In a control experiment,
(±)-4 was subjected to the same conditions, affording (+)-6 in 99%
ee. These results indicate that reorganization to the syn-cycloadduct
stereochemistry of (+)-1, an electronic circular dichroism (ECD)
spectrum was obtained. Comparison with the theoretical ECD
spectrum (CAM-B3LYP/def2-TZVP/PCM (MeOH) // CAM-
B3LYP/def2-SVP/PCM (MeOH) indicates that (+)-1 has
8R,8aR,12S stereochemistry (Figure 1b).22
5
is the enantiodetermining step. To further understand
enantioinduction, the reaction was stopped after three minutes and
the syn-cycloadduct 5 was purified and isolated in 53% yield and
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calculations, multiple independent simulations are run in parallel at
a range of temperatures; this enables frequent crossing of energetic
barriers, thereby fully sampling the thermal equilibrium
distribution. Applications of PT methodology primarily include
biomolecular dynamics to further understand protein structure.31–35
A representative video from a simulation involving the preferred
enantiomeric TS and CPA F is provided.36
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The ensembles of configurations of the transition-states (TS-
1 = major, ent-TS-1 = minor) and CPA F generated by these PT
simulations contain many structures exhibiting simultaneous
double hydrogen-bonds (DHBs), where the catalyst acts as a
Brønsted acid and a Lewis base. Representative structures of TS-
1—CPA F and ent-TS-1—CPA F complexes sampled during these
simulations are presented in Figures 3a and b, respectively.
Hydrogen bonding interactions between two phenols on both
xanthone fragments37 with the phosphate moiety of the CPA
provide a template for long-range chirality transfer.
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Consequently, histograms of the probability distributions
were used to compute free energy surfaces of hydrogen bonding
distances for both TS-1 and ent-TS-1 (Figures 3c and d,
respectively). As expected, the lowest free energy structures are
observed when CPA F is doubly hydrogen bound. The simulation
of the TS-1—CPA F reveals evidence of significantly more
complexes in which TS-1 hydrogen bonds to a single phosphate
oxygen22 (Figure 3c) compared to ent-TS-1 (Figure 3d). The
increased frequency of these intermediate SHB structures results
Figure 2. In-situ 1H-NMR analysis over time upon treatment
of 2 with TFA (a) and CPA F (b).
99% ee (Scheme 4b). This reaffirmed that the formation of the syn-
cyclohexene moiety is the enantiodetermining step (cf. 5, Scheme
1). In addition, we performed kinetics studies using React IR
analysis. The data obtained is consistent with a first-order reaction
with respect to catalyst.22
Previous literature has shown that CPAs promote reactivity
Scheme 4. Enantioenrichment of (±)-p-quinone methide
dimers
a.
b.
through the Brønsted acidic site, the Lewis basic site, or both. This
interaction generates transient diastereomeric ion-pairs, one of
which is more favorable.23 Notably, density functional theory
(DFT) calculations have been used to elucidate the primary
phosphate interaction and the secondary stereoelectronic
interactions imparting enantioselectivity.24–27
Figure 3. Representative configurations of TS-1 (pink) doubly-
hydrogen bonding with CPA F (green). DFT-optimized (a) TS-1—
CPA F (0 kcal/mol) and (b) ent-TS-1—CPA F (7 kcal/mol). Free
energy surface cuts at T = 298 K for (c) TS-1—CPA F simulation
shows free energy minima with single hydrogen bonds (SHB) and
DHB. (d) ent-TS-1—CPA F simulation reveals a single DHB
minimum only.
To investigate the mode of enantioinduction, we used a
computational methodology that has not been employed as a tool
in organic synthesis. As we were unsure of the mode of asymmetric
induction leading to 5,4 we used an enhanced-sampling28
computational method to explore configurations with CPA F in an
unbiased manner. Parallel tempering (PT) simulations29 were
conducted using a molecular-mechanics force field.30 In these
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from the enhanced flexibility of TS-1—CPA F compared to the
Based on this model, we were interested in developing a
catalyst that may perturb enantioinduction by steric interactions
(Scheme 5). Use of the sterically modified CPA G permitted the
formation of dimer 6, albeit in lower yield and ee (23% and 42%,
ent-TS-1—CPA F. The intermolecular dihedral distribution in
Figure 4a shows that the conformational space for TS-1 relative to
CPA F permits free rotation of the bis-xanthone transition state (cf.
Figure 4c for atoms involved). In Figure 4b, insurmountable
barriers hinder relative rotation of ent-TS-1—CPA F, dramatically
reducing conformational space (cf. Figure 3b) in the presence of
CPA F. Figure 4c depicts the rotational freedom of TS-1 around
the catalyst while maintaining long-range chirality transfer. These
findings suggest that enantioinduction is derived, in part
entropically, by reducing the configuration space available to ent-
TS-1. Thus, TS-1—CPA F can interact by a SHB or DHB while
the minor can only bind to the transition state in a DHB
configuration.
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Scheme 5. Disruption of Enantioselectivity using a Modified
CPA
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respectively). Erosion of enantioselectivity may be explained by
steric interference between the substrate and the methyl groups of
CPA G. To rationalize this outcome, PT simulations were also
conducted. Interestingly, the major enantiomeric transition state
(TS-1—CPA G) deviated from that of CPA F. In the TS-1—CPA
F system, the nitro aryl groups are stacking with the xanthone
moieties (Figure 5a). However, the added sterics of CPA G
prevent π-stacking, resulting in the nitro aryl groups being forced
out of plane with the xanthone (Figure 5b). DFT assessment
revealed only a 1.5 kcal/mol energy difference between transition
states, providing computational support for the erosion of
enantioselectivity. The calculated free energy surfaces and energy
distributions for the TS-1—CPA G system are provided in the SI.22
In addition, π-stacking interactions with the catalyst were also
found to be prominent.22 Previous studies have observed
electrostatic donor—acceptor aromatic stacking effects wherein
nitrophenyl substituents are amongst the strongest acceptors.38
These strong π-interactions play an important role in stabilizing the
TS-1—CPA F complex, driving enantioselectivity.
In summary, we have reported asymmetric syntheses and
absolute stereochemistry assignment of (+)- and (-)-
griffipavixanthone, a biologically active xanthone dimer. The key
cascade reaction utilizes a chiral phosphoric acid (CPA)-catalyzed
cycloaddition of a para-quinone methide (p-QM) monomer in
which a specific aryl nitro-substituted CPA catalyst provides high
diastereo- and enantioselectivity. In addition, we have interrogated
the mechanism and mode of enantioinduction through catalyst
electronic effects, in situ 1H-NMR reaction profiles, kinetic studies,
and computational studies using parallel tempering (PT)
simulations to broadly sample chiral ion pair complexes. Further
studies on the synthesis of xanthone dimers as well as applications
of parallel tempering (PT) to address problems in organic synthesis
are currently in progress and will be reported in due course.
a.
b.
Figure 4. Panels (a) and (b) show free energy surfaces as a function
of intermolecular dihedral angle, D, for TS-1 and ent-TS-1 with
CPA F, respectively. Areas with a barrier of >20 kcal/mol were not
sampled. Greater rotation and flexibility is observed in TS-1 (c) as
assessed by the free energy obtained from the intermolecular
dihedral angle than in ent-TS-1, where free rotation relative to CPA
F is inaccessible at the reaction temperature.
The CPA F catalyst also promotes enthalpic stabilization of
the major TS-1 enantiomer. A random selection of complexes from
PT simulations were DFT-optimized (B3LYP/6-31G(d)/IEF-PCM
[CH2Cl2]to obtain energies for the catalyst–transition state
complexes in the presence of a polarizable continuum model
(PCM) solvent. On average, the major TS-1—CPA F complex is
energetically more favorable than its minor enantiomeric
counterpart by nearly 7 kcal/mol.22
Figure 5. Structural comparison of DFT-optimized (a) TS-1—
CPA F and (b) TS-1—CPA G highlighting the altered
complexation resulting from the sterically modified catalyst.
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Experimental procedures, computational data, and
characterization data for new compounds (PDF)
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Video clip from the parallel tempering (PT) simulation of
TS-1 and CPA F (.avi)
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AUTHOR INFORMATION
Corresponding Author
porco@bu.edu
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Notes
We declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Institutes of Health (NIH) (R35 GM-
118173 to JAP) and Boston University (BU) for financial support.
SES and RAE acknowledge the NIH for support (R01 GM-
078240). KDR is supported by a postdoctoral fellowship (PF-16-
235-01-CDD) from the American Cancer Society. NMR (CHE-
0619339) and MS (CHE-0443618) facilities at BU are supported
by the National Science Foundation (NSF). We also thank the NSF
(CHE-1665367 to DFC) for funding. Work at the BU-CMD is
supported by the NIH (R24 GM-111625). We acknowledge Prof.
Richard Johnson and Dr. Sharon Song (UNH) for their
computational investigations in the synthesis of (±)–1. We also
thank Prof. Benjamin List (MPI) for kindly providing catalysts for
our initial screen.
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