Total Synthesis and Anticancer Activity of (+)-Hypercalin C and Congeners

Article abstract of DOI:10.1002/anie.201812909

The hypercalins are dearomatized acylphloroglucinols with a pendant complex cyclopentane ring that exhibit activity against several cancer cell lines. We report the first total synthesis of (+)-hypercalin C employing a convergent strategy that enabled the

Full text of DOI:10.1002/anie.201812909

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Accepted Article
Title: Total Synthesis and Anticancer Activity of (+)-Hypercalin C and
Congeners
Authors: Daniel Romo, Yongfeng Tao, Keighley Reisenauer, and
Joseph H. Taube
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812909
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10.1002/anie.201812909
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis and Anticancer Activity of (+)-Hypercalin C and
Congeners
Yongfeng Tao, [a] Keighley Reisenauer, [b] Joseph H. Taube, [b]and Daniel Romo*[a]
Abstract: The hypercalins are dearomatized acylphloroglucinols with
a pendant complex cyclopentane ring that exhibit activity against
several cancer cell lines. We report the first total synthesis of (+)-
hypercalin C employing a convergent strategy that enabled dissection
of the essential structural features required for the observed
anticancer activity. A strategic disconnection involving an unusual
Csp3-Csp2 Suzuki-Miyaura coupling with an a-bromo enolether also
revealed an unexpected C-H activation. Our strategy targeted
designed analogs along the synthetic route to address particular
biological questions. Our results support the hypothesis that
hypercalin C may act as a proton shuttle with the dearomatized
acylphloroglucinol moiety being essential for this activity.
congener and designed analogs for synthesis aimed at
interrogating its proposed mode of action as a cellular membrane
proton shuttle.[4]
In
our
retrosynthetic
analysis,
we
considered
disconnections that would allow us to answer biological questions
regarding the cytotoxicity of the hypercalins. Thus, a key
disconnection involved a Csp3-Csp2 Suzuki-Miyaura coupling[5]
between the boronic monoester 4,[6] derived from our previously
described b-lactone 6, and bromoenol ether 5 to provide adduct 3
(Figure 2a). This disconnection enables dissection of the two
principal fragments, the cyclopentyl moiety
A
and the
dearomatized acylphloroglucinol moiety B (Figure 2b), which
would allow us to separately assess their cytotoxicity. A
subsequent site-selective allylic oxidation would deliver bis-
methyl hypercalin C, 2. The requisite cyclopentyl moiety, given its
stereochemical complexity, may play an important role in cellular
target recognition or simply serve as a hydrophobic group and this
could be assessed by coupling with simplified hydrophobic groups
(R = alkyl group; Figure 2b) derived from boronic acid 4 accessible
from our previously described b-lactone 6 in turn derived from
carvone.[7] The coupling partner for the key coupling event, a-
bromo enol ether 5, would be prepared from 1,3-
cyclohexanedione.
The hypercalins and chinensins are members of the
dearomatized, polyprenylated polycyclic acylphloroglucinol
(PPAP) family of natural products isolated by Hostettmann from
Hypericum calycinum L (Figure 1).[1] Several PPAPs undergo
further oxidative cyclizations leading to polycyclic members that
have attracted considerable synthetic interest;[2] however, the
hypercalins and chinensins have not yet been synthesized. The
hypercalins and chinensins display minor structural differences,
namely, substitution at the quaternary carbon center (C4, R1) and
the acyl group (C27, R2). Members of this family possess a range
of biological activities including antibacterial, antiviral and
cytotoxicity.[3] For example, hypercalins A-C showed growth-
inhibitory activity against the Co-115 human colon carcinoma cell
line with ED50 values ranging from 0.60-0.83 µM.
a)
A
Me
HO
Me
HO
H
O
H
site-selective
allylic
oxidation
Demeth-
ylation
O
O
hypercalin C
B
H3C
CH3
H3C
CH3
(1)
O
O
O
O
13
A
9
R2
27
Me
HO
Me
HO
OH
1
OH
H
H
7
O
O
2
3
B
4
O
OH
O
OH
R1
Br
Suzuki-
Miyaura
Coupling
O
O
H
O
H
O
20
+
O
B
OH
+
O
O
hypercalin A : R1 = Me, R2 = i-Bu
hypercalin B : R1 = prenyl, R2 = Ph
chinesin I : R1 = Me, R2 = i-Bu
chinesin II : R1 = Me, R2 = i-Pr
hypercalin C (1)
Me
Me
O
4
5
6
b)
Figure 1. Members of the dearomatized, polyprenylated acylphloroglucinol
family, the hypercalins and chinensins including hypercalin C (1)
essential
moieties
?
OH
H
Me
HO
H
O
H
R
O
Me
HO
O
1
O
O
B
In terms of anticancer activity, hypercalin C is one of the
most potent members of this family.[1a] We therefore targeted this
O
CH3
A
6
OH
H3C
Me
HO
O
O
H
O
5
OH
proton
shuttle
?
R
[a]
Y. Tao, Prof. Dr. D. Romo
Department of Chemistry and Biochemistry
K. Reisenauer, Prof. Dr. J. Taube
Department of Biology
Figure 2. a) Retrosynthetic analysis of hypercalin C and b) targeted derivatives,
including the cyclopentyl moiety A and the dearomatized acylphloroglucinol
moiety B, guided by biological questions to be answered in the course of the
total synthesis.
Baylor University
101 Bagby Ave.
Waco, TX 76798, USA
E-mail: Daniel_Romo@baylor.edu
A proton shuttle, or protonophore, disrupts the pH gradient
across a cell membrane by transporting protons from outside the
cell to the higher pH environment inside the cell.[4, 8] We planned
to test the hypothesis that hypercalin C exerts its bioactivity
through this mechanism (Figure 3), which is enabled by the
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201812909
Angewandte Chemie International Edition
COMMUNICATION
highlighted, intramolecularly hydrogen bonded and relatively
acidic C1 and C5 enol hydroxyls (yellow boxes, Figure 2b) and
the resulting highly delocalized, anionic species that would be
expected to readily traverse the cell membrane (Figure 3). We
therefore targeted the bis-enol ether 2, which is also a convenient
synthetic precursor to the targeted bis-enol, and removes the
ability of these molecules to transport protons across the cell
membrane while also minimizing steric perturbations.
(Scheme 2). Use of less substituted halogenated arenes would
also provide simplified ring A hypercalin C derivatives to inform
structure-activity relationships (SAR). Screening of >50 different
reaction conditions with tris-methoxy aryl bromide 10, failed to
provide the desired adduct 11, a species containing most of the
structural features of the natural product. The steric hindrance
caused by the bis-ortho substitution of the aromatic substrate is
known to dramatically impede the reductive elimination step,[14]
leading to a competing b-hydride elimination as evidenced
through isolation of the exocylic alkene resulting from
dehydroboronation of boronic monoester 4, and the reduced
arene derived from bromoarene 10. We anticipated that removal
of one of the ortho-substituents would facilitate the reductive
elimination step by minimizing b-hydride elimination to enable
subsequent cross-coupling. Indeed, boronic monoester 4 coupled
efficiently under conditions reported by Buchwald and
coworkers[15] with the less substituted aromatic bromides 12 and
14, with at least one open ortho position.
H
O
H
O
O
R
O
R
O
O
H
O
OH
pH ~6.6
extracellular
H
O
-H
R
O
O
O
O
R
O
MeO
H
O
Br
OH
O
OMe
OMe
H
Me
MeO
Br
OH
O
10
pH ~7.7
MeO
OMe
11
H
O
OMe
Figure 3. Proton shuttle hypothesis for the cytotoxicity of the hypercalins
MeO
Me
HO
H
H
H
O
12
O
10% Pd(OAc)2, 20% SPhos,
Cs2CO3, toluene (0.1 M), 110 o
(73%)
B
We first targeted the synthesis of a versatile Csp3-Csp2
Suzuki-Miyaura, cyclopentyl coupling partner and chose the
bicyclic boronic monoester 4 building on prior successful
application of this type of coupling partner (Scheme 1).[9] The
synthesis commenced with our previously described diol 8,
OH
C
MeO
OMe
4
13
H
Br
O
H
Me
HO
H
H
14
available in four steps from (R)-carvone, through
a
“
(70%)
O
diastereoselective nucleophile catalyzed aldol-b-lactonization
(NCAL) process which proceeds with high diastereoselectivity (dr
>19:1) to deliver an intermediate b-lactone 6 setting the two
additional stereocenters required for the cyclopentyl moiety of the
hypercalins.[10] Selective mesylation of the primary alcohol
followed by a Finkelstein reaction[11] provided iodide 9 readied for
alkylithium generation. Since lithium-halogen exchange is known
to be faster than deprotonation,[12] iodide 9 was pre-treated with
PhLi to deprotonate the tertiary alcohol and avoid intramolecular
quenching. Subsequent addition of t-BuLi and quenching with
B(OMe)3 delivered the desired cyclopentyl cyclic boronic
monoester 4.
H
15
Scheme 2. Model studies for the cross-coupling with cyclopentyl boronic
monoester 4 leading to simplified, aromatic variants of the cyclohexyl trione core
Having identified successful cross-coupling conditions, we
targeted the synthesis of an appropriately substituted coupling
partner (i.e. vinyl bromide 5), cognizant of steric issues identified
during model studies (Scheme 3). Alkylative bis-prenylation of
1,3-cyclohexanedione provided dialkylated dione 16.[16]
Subsequent conversion to the highly unstable dibromo diketone
17 was achieved through bromination (freshly recrystallized NBS)
of the derived bis-silyl enol ether (freshly distilled TMSCl) and
immediate conversion to the bis-enolether 18 through a bis-a-
deprotonation, bis-O-methylation sequence. This process
required extensive optimization since the light sensitive dibromide
17 upon deprotonation was, not surprisingly, highly susceptible to
side reactions likely stemming from a-elimination leading to
carbene generation. Following extensive experimentation, slow,
inverse addition of a THF solution of dibromide 17 to a mixture of
high quality KHMDS (a relatively new/recently opened bottle) and
MeOTf in DMPU/THF (1:20) at -78oC was found to be key for
reproducible production of bis-enolether 18. Finally, a mono
lithium-halogen exchange was achieved by careful control of n-
BuLi stoichiometry at low temperature to deliver a vinyllithium
O
H
O
H
OH
3 steps
O
Me
OH
Me
H
(R)-carvone
6
8
H
I
1) MsCl, Et3N, DMAP,
0 oC, CH2Cl2
PhLi, t-BuLi, B(OMe)3
Et2O, -78 o
C
B
OH
OH
Me
2) NaI, acetone, reflux
(86%, 2 steps)
(67%)
O
Me
9
4
Scheme 1. Synthesis of the cyclopentyl, cyclic boronic monoester 4
Since transition metal-couplings with ortho-disubstituted
arenes can be challenging,[13] model studies utilizing boronic
monoester 4 and various aryl bromides were undertaken
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10.1002/anie.201812909
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COMMUNICATION
species which was reacted with the Weinreb amide derived from
2-methyl propionic acid to afford the desired keto vinyl bromide 5.
frequently used as substrates for cross-coupling reactions.
However, insertion into C-H bonds adjacent to oxygen atoms are
well-precedented.[15b]
Br
Br
1) LDA, DMPU/THF
-78 oC,then TMSCl
Br
O
O
O
O
2) NBS, THF
K2CO3,acetone, reflux
(56%)
O
O
Building on literature precedent for insertions into C-H
(75%, 2 steps)
bonds adjacent to oxygen atoms,[15b] we propose that a Pd(II)
16
17
[17]
intermediate II is formed following oxidative addition
and due
Br
Br
to sterics induced by the adjacent quaternary center and the bulky
nature of the SPhos ligand, the methoxy group is forced closer to
the Pd-center facilitating an agostic interaction with the C-H bonds
of the methyl group which at elevated temperatures can lead to
C-H insertion, generating a Pd (IV) species III. The Csp3 nature of
the boronic monoester 4, may also retard the rate of
transmetalation, enabling C-H insertion to be competitive with
transmetalation. Reductive elimination would presumably be
facilitated by release of severe steric compression through
insertion leading to the Pd(II)-metallocycle III. Since b-hydride
elimination is not possible at this stage, the longevity and relative
stability of intermediate III enables subsequent transmetalation
with boronic monoester 4 which following reductive elimination
delivers the observed CH-insertion adduct 20.
Br
O
i) n-BuLi, THF, -78 o
C
KHMDS, MeOTf
O
O
O
O
DMPU/THF, -78 o
(90%)
C
ii)
O
OMe
N
(63%)
18
5
Scheme 3. Synthesis of the Suzuki-Miyaura coupling partner, bis-a-bromo enol
ether 5
Table 1. Optimization of the key Suzuki-Miyaura coupling of vinyl bromide 5
and boronic monoester 4.a
Me
HO
Me
HO
H
H
Br
O
coupling
conditions
O
O
Me
H
O
O
+
O
+
O
O
O
O
B
HO
Br
4
5
19
20
C-H insertion
product
R2
R1
=
O
O
R1
R1
R1
PPh2
PPh2
R1
Me
oxidative
addition
Ph2P
PPh2
O
O
P
4
O
Me
reductive
elimination
P
20
N
BDPP
L
Br
Suzuki-Miyaura
cross coupling
Pd(0)L2
R2
O
SPhos
iPr
APhos
Pd
I
Xantphos
H
tBu
R2
L
O
H
R1
P
R1
19
Pd
tBu
R1
C-H insertion
PPh2
PPh2
R1
II
O
O
Fe
Ph2P
PPh2
iPr
Fe
P
P
tBu
O
dppp
R1
R1
tBu
(di-tBu)ferrocene
dppf
RuPhos
V
H
L
Br
Pd
transmetalation
entry
Ligand
(0.2 equiv)
Base
(3 equiv)
Suzuki-
C-H
insertionb
O
Miyaura
couplingb
trace
trace
trace
trace
trace
trace
47%
34%
10%
40%
74%
R1
Me
R1
L
Br
H
H
Me
O
Pd
III
R2
=
SPhosc
SPhosd
PPh3
Xantphos
dppp
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
K2CO3
K3PO4
Cs2CO3
Cs2CO3
30%
51%
2%
B
H
HO
1
2
3
4
5
6
7
8
9
reductive
elimination
HO
O
4
R1
R1
IV
Scheme 4. Proposed catalytic cycle leading to typical Suzuki-Miyaura and an
21%
trace
17%
trace
22%
17%
12%
trace
unexpected C-H insertion into an enol ether
dppf
To find optimal conditions for both the desired Suzuki cross
coupling and unexpected C-H insertion, we considered the factors
likely impacting these reaction pathways. Most importantly, since
C-H activation of the methoxy group is likely driven by the extreme
steric environment caused by both the quaternary center in the
substrate and the ligand, we anticipated that replacement of
SPhos with a smaller ligand would drive the reaction to the
desired Csp3 Suzuki coupling. On the other hand, to promote
oxidative addition of palladium to the rather electron rich bromo
enol ether, the ligand employed should be electron rich and bulky,
which in turn also promotes the final reductive elimination. At the
same time, a considerable energy barrier is present for C-H
insertion, thus the high temperature favors this side reaction.
Indeed, when the temperature was lowered from 110 to 65 ºC, the
desired Suzuki-Miyaura coupled product 19 was obtained in 20-
30% yield, while the C-H insertion product, ether 20, was still
obtained in 30% yield (Table1, entry 2). Furthermore, the
intramolecular nature of the C-H insertion process makes reaction
RuPhos
SPhos
SPhos
APhos
APhose,f
10
11
aStandard conditions: 10% Pd(OAc)2, ligand (0.2 equiv), base (3
equiv), PhMe (0.1M), 65 ºC. bYields refer to purified, isolated products.
cReaction temperature was 110 ºC. dConcentration: 0.01M. eSlow
addition of the catalyst (0.1 mL/h, over 3 h) as a toluene solution.
fConcentration: 0.2 M.
Our initial studies of the key Suzuki-Miyaura coupling with
vinyl bromide 5 and boronic monoester 4 employing the
conditions previously optimized for arene 12 did not deliver the
expected adduct 19 but rather the Csp3-Csp3 cross-coupled product
20 (30% yield) via a presumed C-H insertion into the adjacent
methoxy group (Table 1, entry 1). The observed C-H activation
of an enol ether is unprecedented, to the best of our knowledge,
and this may be due to the fact that a-bromo enol ethers are not
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10.1002/anie.201812909
Angewandte Chemie International Edition
COMMUNICATION
concentration a key factor and it was surmised that lower
concentration would favor the C-H insertion pathway. With the
above considerations and extensive screening including variation
of ligands and base (Table1, entries 3-11; for other conditions
examined, see SI, Table S1), we ultimately found reaction
conditions that favored the desired Suzuki-Miyaura coupling using
APhos as ligand (74%, Table 1, entry 11) while alternative
conditions employing SPhos at low concentration gave primarily
the C-H insertion product 20 (51% yield, Table 1, entry 2).
The final steps to the targeted dimethyl hypercalin C and
hypercalin C required a selective allylic oxidation followed by
demethylation for the latter product. This oxidation required site-
selectivity given the presence of two prenyl groups and an
isobutenyl moiety presenting nine potential oxidizable allylic
positions with most positions being less hindered than the
targeted allylic position. However, electronic effects of the
targeted bis-allylic position were expected to favor a site-selective
oxidation. This led us to oxidative methods that involved initial
hydrogen atom abstraction since the resulting bis-allylic radical
would be stabilized.[18] We were gratified to find that conditions
reported by Shair in their synthesis of hyperforin[19], involving
generation of a peroxide radical for hydrogen atom abstraction at
the most reactive allylic site (weakest C-H bond) and subsequent
oxidation, provided a 43% yield of the desired ketone 2 (Scheme
5). Demethylation of dimethyl hypercalin C (2) was achieved with
LiCl in DMSO at elevated temperature providing clean conversion
to hypercalin C (1) in 90% yield.
the mode of action of the hypercalins. On the other hand, the
hydrogenated derivative 22 showed similar activity as the natural
product, indicating that unsaturation of the prenyl side chains has
minimal effect on cytotoxicity.
In conclusion, the first total synthesis of hypercalin C was
achieved in 10 steps (longest linear sequence from carvone) with
an overall yield of 8%. The synthetic sequence featured a key
Csp3-Csp2 Suzuki coupling with an uncommon a-bromo enol ether
coupling partner and a boronic monoester derived from carvone.
This disconnection represents a formal a-alkylation of a ketone
via transition metal coupling, offering a unique perspective for
ketone a-functionalization. In addition, we discovered an
unexpected and conceptually novel C-H insertion/Suzuki coupling
process employing the a-bromo enol ether substrate. Guided by
the desire to answer particular biological questions regarding
SAR enabled by the designed synthetic strategy, several
hypercalin C analogs were accessed and tested against two
cancer cell lines for cytotoxicity. Some support for the proton
shuttle hypothesis for hypercalin C was garnered through these
studies however the modest decrease in cytotoxicity when the
acidic enol protons are substituted for methyl groups suggests
that other cellular mechanisms for the observed cytotoxicity of the
hypercalins are likely operative.
Table 2. Cytotoxicity of hypercalin C and derivatives against HCT-116 (in black)
and MDA-MB-231 (in red) cell lines (IC50, µM).
HCT-116
MDA-MB-231
Me
HO
R =
H
O
R
O
Me
HO
OH
Me
HO
Me
HO
H
O
H
H
PhI(OCOCF3)2,
TBHP, Cs2CO3
H3C
CH3
LiCl, DMSO
O
O
O
R
O
O
25.4±0.95
18.8±5.97
̠ C
0 âˆ
OH
120 o
(90%)
C
>100
>100
EtOAc, -78
(43%)
O
OH
O
O
O
O
8
R
2
(dimethyl hypercalin C)
>100
>100
O
19
2
hypercalin C (1)
Me
HO
OH
H
15
O
Scheme 5. Completion of the total synthesis of hypercalin C (1)
1.02±0.13
1.69±0.17
R
O
OH
44.5±2.36
63.6±6.05
O
We measured the cytotoxicity of synthetic hypercalin C and
derivatives against HCT-116 colon cancer and MDA-MB-231
breast cancer cell lines (Table 2). The bare cyclopentyl moiety
bearing an additional alcohol 8 or aromatic moieties in place of
the cyclohexanetrione, namely arene derivatives 15 and 13, were
not cytotoxic up to 100 µM. These results suggest that the
cyclopentyl moiety alone, though rich in stereochemical
information, does not contribute significantly to the observed
cytotoxicity. This is further supported by derivative 21,[20] which
retains some of the original cytotoxicity (6.5-7.7X decrease) while
only possessing a simple isopentyl chain in place of the complex
cyclopentane found in hypercalin C. Interestingly, the presence of
oxygen in the arene ring, cf. derivative 13, but devoid of acidic
protons led to the initial observed cytotoxicity (at <100 µM). The
cytotoxicity of synthetic hypercalin C was found to be in the 3-4
μM range, consistent with previous reports[1a] however dimethyl
hypercalin C (2) showed a measurable decrease in cytotoxicity
(~5-7X). While this lends some credence to the proposed
requirement of acidic enols for cytotoxicity, the difference is not
significant enough to exclude alternative hypotheses regarding
O
O
22 (hexahydro hypercalin C)
13
OH
OH
R
O
OH
O
3.76±0.71
3.92±1.75
24.6±5.27
30.2±9.42
O
O
OH
21
1 (hypercalin C)
IC50 values were determined for the indicated compounds with MDA-MB-231
and HCT-116 cells in vitro. Standard error of the mean represents the variation
of three biological replicates, each with at least three technical replicates
Acknowledgements
Support from the Welch Foundation (AA-1280) and partial
support from NIH (R37 GM052964) is gratefully acknowledged.
We acknowledge Dr. Morgan A. Shirley for early synthetic
studies toward hypercalin C in the Romo Group and Tim Philip
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10.1002/anie.201812909
Angewandte Chemie International Edition
COMMUNICATION
for technical support in the Taube Group. HCT-116 and MDA-
MB-231 cells were generous gifts from Dr. Ajay Goel and Dr.
Sendurai Mani, respectively.
[14]
[15]
G. Maestri, E. Motti, N. Della Ca’, M. Malacria, E.
Derat, M. Catellani, J. Am. Chem. Soc. 2011, 133,
8574-8585.
a) S. D. Walker, T. E. Barder, J. R. Martinelli, S. L.
Buchwald, Angew. Chem. 2004, 116, 1907-1912; b)
T. E. Barder, S. D. Walker, J. R. Martinelli, S. L.
Buchwald, J. Am. Chem. Soc. 2005, 127, 4685-
4696; c) R. Martin, S. L. Buchwald, Acc. Chem.
Res. 2008, 41, 1461-1473.
Keywords: C-H insertion • b-lactone • chiral pool• Suzuki-
Miyaura coupling• protonophore
[16]
[17]
S. Kotha, R. Ali, V. Srinivas, N. G. Krishna,
Tetrahedron 2015, 71, 129-138.
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This article is protected by copyright. All rights reserved.

10.1002/anie.201812909
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Yongfeng Tao, Keighley Reisenauer,
Joe Taube* and Daniel Romo*
H
Me
HO
Me
OH
Suzuki-Miyaura
Coupling
Br
H
Me
O
(+)-hypercalin C:
a protonophore?
OH
H
O
O
O
+
O
O
B
Page No. – Page No.
O
OH
O
O
HO
Title
The first total synthesis of (+)-hypercalin C was achieved through a key sp3-C
Suzuki coupling and a highly regioselective allylic oxidation. Several designed
derivatives were targeted in the course of the synthesis to address the hypothesis
that hypercalin C and congeners are cytotoxic due to their potential as
protonophores. An unexpected insertion into an ether C-H bond during Pd-
mediated coupling of an a-bromo, methyl enol ether was discovered.
This article is protected by copyright. All rights reserved.