Total Synthesis of Caesalpinnone A and Caesalpinflavan B: Evolution of a Concise Strategy

Article abstract of DOI:10.1021/jacs.9b04472

The total syntheses of caesalpinnone A (1) and its putative biosynthetic precursor caesalpinflavan B (3) are described. Herein, we describe the evolution of a synthetic strategy toward 1 and 3, which entails a convergent Barluenga coupling that quickly delivers a heavily functionalized benzopyran containing the core carbon framework and exploration of two distinct synthetic routes for forging the flavanoid C-ring by reducing a sterically encumbered embedded alkene: one via a stepwise approach and a second, more direct and atom-economical, enabled by a Shenvi-HAT hydrogenation. The latter strategy allowed access to caesalpinflavan B in 6 steps after Pd-mediated deallylation. A late-stage dearomative phenolic oxidation and deallylation/oxa-Michael cascade was implemented to access caesalpinnone A (1) in 7 steps. We also describe an enantioselective total synthesis and stereochemical revision of (-)-caesalpinflavan B, as well as a formal enantioselective synthesis of (-)-caesalpinnone A, by implementing an enantioselective Pd-catalyzed conjugate addition developed by Stoltz.

Full text of DOI:10.1021/jacs.9b04472

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Article
Total Synthesis of Caesalpinnone A and
Caesalpinflavan B: Evolution of a Concise Strategy
Jacob C. Timmerman, Noah Sims, and John L. Wood
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04472 • Publication Date (Web): 30 May 2019
Downloaded from http://pubs.acs.org on May 30, 2019
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Journal of the American Chemical Society
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Total Synthesis of Caesalpinnone A and Caesalpinflavan B:
Evolution of a Concise Strategy
Jacob C. Timmerman, Noah J. Sims, and John L. Wood*
8
9
Department of Chemistry and Biochemistry, Baylor University, One Bear Place 97248, Waco, Texas, 76798, United States
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Supporting Information Placeholder
would pass through caesalpinflavan B (3, Figure 1, inset)
as well as several structurally related intermediates,
thereby providing numerous interesting compounds for
future biological assays. From a biosynthetic perspective,
3 appeared to be the logical precursor to 1, however,
based on the opposite absolute stereochemistry assigned
to C-2” and -4”, this supposition was unclear. Thus, this
approach, employing 3 as a precursor to 1, would also
potentially address this apparent stereochemical
anomaly. Herein, we describe the realization of this goal
by developing concise syntheses of (±)-1, (±)-3, and (–)-
3. The latter of which enabled the stereochemical
reassignment of (+)-3 and clarified the potential
biosynthetic origin of (+)-1.
ABSTRACT: The total syntheses of caesalpinnone A (1)
and its putative biosynthetic precursor caesalpinflavan B
(3) are described. Herein, we describe the evolution of a
synthetic strategy toward 1 and 3, which entails a
convergent Barluenga coupling that quickly delivers a
heavily-functionalized benzopyran containing the core
carbon framework and exploration of two distinct
synthetic routes for forging the flavanoid C-ring by
reducing a sterically-encumbered embedded alkene: one
via a stepwise approach and a second, more direct and
atom-economical, enabled by
hydrogenation. The latter strategy allowed access to
caesalpinflavan in steps after Pd-mediated
a
Shenvi-HAT
B
6
deallylation. A late-stage dearomative phenolic oxidation
and deallylation/oxa-Michael cascade was implemented
to access caesalpinnone A (1) in 7 steps. We also describe
an enantioselective total synthesis and stereochemical
revision of (–)-caesalpinflavan B as well as a formal
enantioselective synthesis of (–)-caesalpinnone A, by
O
OH
A
[selective
A-ring
oxidation]
HO
O
O
OH
D
C
O
O
implementing
an
enantioselective
Pd-catalyzed
4’’S
2’’R 4’’S
B
conjugate addition chemistry developed by Stoltz.
2’’S
HO
HO
O
(+)-Caesalpinflavan B (3)
(+)-Caesalpinnone A (1)
Introduction
Caesalpinnone A ((+)-1) is a hybrid flavan-chalcone
natural product recently isolated from the twigs and
leaves of caesalpinnea enneaphylla obtained from the
Yannan province in China.1 Accompanying (+)-1 were 3
other flavan-chalcone hybrids, the caesalpinflavans (A–
C, (+)-2–4), all of which possess a trans-2,4-diaryl
substitution pattern on the flavanoid C ring (Figure 1).
However, the trans-2,4-diaryl substituted C ring in 1
(Figure 1, highlighted in red), is embedded within a
unique dioxotricyclo[5.3.3.01,6]tridecane core structure.
Interestingly, as illustrated, the assigned absolute
stereochemistry was not consistent across the four
congeners. From a biological perspective, caesalpinnone
A and the caesalpinflavans A–C were all shown to exhibit
cytotoxic activity against a number of cancer cell lines,
the most potent of which (1) has IC50 values in the sub-
micromolar range (0.54–0.87 M).
OH
A
OH
D
[C–D ring
connection]
+
O
HO
C
O
O
B
5
6
OH
OH
OH
O
O
OH
4’’’’S 2’’’’R
O
OH
4’’R
2’’S
OH
2’’R 4’’S
O
HO
(+)-Caesalpinflavan A (2)
O
(+)-Caesalpinflavan C (4)
Given the relatively potent biological activity of the
caesalpinnone congeners and the fascinating core
architecture of 1, we sought to develop a synthesis that
Figure 1. Isolates from caesalpinnea enneaphylla and
proposed preparation of 1 from 3.
Results and Discussion
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Retrosynthetic
Analysis.
As
illustrated
the equivalents of N-tosylhydrazone 8 showed little
improvement in the yield of 9 (Table 1, entry 2);
1
2
3
4
5
6
7
8
retrosynthetically in Scheme 1, in developing our
synthetic strategy we envisioned that 1 would arise from
dearomative oxidation of the flavanoid A ring in 3,
followed by capture of the resulting p-quinol (A,
Scheme 1) by the most nucleophilic and least sterically
however, while monitoring this reaction by mass
spectrometry, we observed significant formation of side-
product, presumably derived from 8.9 In efforts to
mitigate these side-products, we first chose to increase
the equivalents of 7 (Table 1, entries 3 and 4), which,
gratifyingly, led to isolation of 9 in up to 68% yield on
multi-gram scale. In further attempts to improve the
reaction efficiency, we eventually found that slow
addition of 8 to the reaction mixture provided 9 in up to
91% yield (Table 1, entry 5). Having developed an
efficient method for accessing benzopyran 9, the stage
was set for the key reduction of the C3’’– C4’’ bond.
encumbered
D
ring C4’ phenol.2
In further
consideration of biosynthetic origins, we recognized 3
as a pseudo-dimer of the structurally-related natural
products 7-hydroxyflavanone (5)3 and 2’,4’-
dihydroxychalcone (6, Figure 1, inset),4 thus suggesting
the eventual disconnection at the C,D-ring juncture.5 To
this end, 3 was seen as arising from reduction of
functionalized benzopyran 9, setting the necessary
trans- relationship between the 2'' and 4'' arenes
(caesalpinnone A numbering). Formal construction of
the C,D-ring union would occur in the production of 9
wherein the congested olefin would be produced via a
Pd-catalyzed coupling of N-tosylhydrazone 8 with aryl
iodide 7 (i.e., the Barluenga coupling).6 The latter was
particularly appealing given its demonstrated success in
coupling sterically-demanding arenes to form 1,1’-
diarylalkenes.7
9
10
11
12
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15
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Table 1. Selected optimization trials for the
Barluenga coupling between 7 and 8.
Scheme 1. Overall Retrosynthetic Analysis of 3 and
1.
C-Ring Reduction: Conformational Analysis and
Preliminary Studies. Perhaps the most challenging
aspect of our planned approach to 1 was the development
of conditions for the chemo- and trans-stereo-selective
reduction of 9, as the literature suggested that the
requisite trans relationship of the C2’’ and C4’’ arenes in
the desired product (10a) would likely be disfavored both
thermodynamically and kinetically (Figure 2).10,11 As
illustrated, the kinetically favored path for reduction of
9 would likely involve hydrogen delivery anti- to the 2"
phenyl group, which would provide the undesired cis-
diastereomer 10b (Figure 2, inset A). Additionally, a cis-
substitution pattern between the 2'' and 4'' arenes would
also likely be favored thermodynamically as this allows
both arenes to be positioned pseudo-equatorially about
the C-ring (Figure 2, inset B). Moreover, no examples
were found describing the direct reduction of 2H-
chromenes, such as 9, to synthetically useful amounts of
a corresponding trans-2'',4''-diaryl product.12 In practice,
hydrogenation of the C3"–C4" double bond in 9 was
found to be slow under a variety of both hetero- and
Development of a Barluenga Cross Coupling. Our
synthetic approach began with the synthesis of
benzopyran 9 via Barluenga Coupling. The requisite N-
tosylhydrazone component (8) and aryl iodide (7) were
each prepared in one step from known materials.8 With 7
and 8 in hand, we began exploring conditions for the
planned Barluenga coupling. To this end, we found that
heating a fluorobenzene solution containing 7 (1 equiv),
8 (1.2 equiv), and excess K2CO3 in the presence of a
catalytic amount of both XPhos Pd G3 and XPhos
resulted in full consumption of 7 and provided
benzopyran 9 in 37% yield as a 1:1.8 mixture of
inconsequential atropisomers (Table 1, entry 1).
Selection of these initial coupling conditions were
influenced by preliminary attempts to prepare 1 via
intermediates derived from a similar Barluenga coupling
(see Supporting Information). Unfortunately, increasing
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homogeneous conditions and typically accompanied by 15 was exposed to m-CPBA and sodium bicarbonate to
1
2
3
4
5
6
7
8
more facile benzyl aryl ether hydrogenolysis. Further,
attempts at thermodynamic reduction of 9 by exposure to
a myriad of Birch reduction conditions only led to
deprotection and fragmentation. These initial undesired
outcomes led us to develop a stepwise approach to reduce
the benzopyran double bond and imbed the crucial 2'',4''-
trans- stereochemistry of the flavanoid C-ring (vide
infra).
furnish 14 in 69% yield as a 1:1.9 mixture of
inconsequential of atropisomers,13 presumably through
the intermediacy of epoxide I, wherein oxygen has been
delivered to the less hindered alkene face (Scheme 3).
Direct reduction of 14 by sodium borohydride afforded
alcohol 16 in 76% yield, but disappointingly, with the
incorrect 2",4"-cis C-ring stereochemistry, later verified
by single crystal X-Ray analysis of a downstream
intermediate from a previous synthetic approach to 1 (see
Supporting Information).
9
Figure 2. The 2",4"-cis- stereoisomer 10b is favored
both kinetically (inset A) and thermodynamically (inset
B) in the reduction of 9.
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Given the undesired outcome of the direct reduction
of 14, we sought to instead leverage the trans-
relationship between the 2" phenyl group and 3" hydroxyl
group in p-quinone methide 14 by promoting a Lewis
acid-mediated syn-facial-1,2-hydride shift to form ketone
13 (Scheme 3). After some experimentation, we found
that treatment of 14 with BF3-OEt2 effected the desired
1,2-hydride shift, but isolation led to the corresponding
enol (13-enol). Undeterred, semi-empirical calculations
suggested that a trans- relationship between the 2" and 4"
arenes in ketone 13 would be favored, and thus, we
proceeded to reduce 13 with BH3-tBuNH2, which
furnished 12 possessing the desired 2",4"-trans
diastereomer shown in Scheme 3.14
OAc
OAc
OAc
O
2’’
O
2’’
O
2’’
OBn
OBn
OBn
C
3’’
[Reduction]
C
3’’
C
3’’
or
Ph
Ph
Ph
4’’
4’’
4’’
BnO
BnO
BnO
Me
Me
Me
O
O
O
O
O
O
9
10b, Favored
(kinetic and thermodynamic)
10a, Desired
A
B
BnO
BnO
Me
O
Me
O
O
O
H
O
2’’
O
O
OBn
OBn
H
10b
H
H
Ph–H 1,3-diaxial
interaction
H
C-ring conformation: 10a
C-ring conformation: 10b
Scheme 3. Elaboration of benzopyran 15 to phenol
12.
C-Ring Reduction: A Stepwise Approach. As
illustrated retrosynthetically in Scheme 2, to circumvent
the issues observed in the direct reduction, we envisioned
the key dihydrobenzopyran intermediate 11 arising from
a Barton-McCombie deoxygenation sequence applied to
alcohol 12, which would be derived from the reduction
of ketone 13. Ketone 13 would originate from -hydroxy
p-quinone methide 14 by way of a Lewis acid-mediated
syn-facial 1,2-hydride shift and rearomatization. Alcohol
14 would be accessed from benzopyran 15 via
epoxidation followed by ring-opening to the p-quinone
methide.
Scheme 2. Retrosynthetic Analysis of phenol 11 from
the formal reduction of benzopyran 15.
OH
OH
OH
O
OBn
O
OBn
O
OBn
reduction
Ph
Ph
Ph
H
H
BnO
H
OH
BnO
O
BnO
Barton-McCombie
deoxygentation
Me
Me
O
Me
O
O
O
O
O
11
12
13
O
OH
Lewis acid-mediated
1,2-hydride shift
O
OBn
O
OBn
Ph
Ph
HO
H
BnO
epoxidation/
ring opening
BnO
Me
O
Me
O
O
14
O
15
This approach commenced with formation of the
necessary hydroxy p-quinone methide (14). In the event,
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OH
S
OH
OH
1
2
3
4
5
6
7
8
MeS
O
O
mCPBA (2.5 equiv)
NaHCO3 (20 equiv)
O
OBn
O
OBn
O
OBn
KH, CS2; then MeI
3”
OBn
Ph
Ph
Ph
THF, 4 to 24 °C, 8 h
(66%)
O
CH2Cl2, 4 °C, 1 h
(69%)
(1:1.9 mixture of
atropisomers)
Ph
BnO
OH
BnO
BnO
Me
S
O
O
Me
O
Me
BnO
O
O
15
I
O
SMe
Me
O
O
12
O
17
OH
O
OH
9
NaBH4
(2.9 equiv)
Bu3SnH (10 equiv)
AIBN (0.5 equiv)
10
11
12
13
14
15
16
17
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O
OBn
O
OBn
5 synthetic steps
3 redox manipulations
from 14
O
2”
OBn
3”
Ph
2”
Ph
THF-MeOH (1:1 v/v)
4 to 24 °C, 2 h
(76% 86% BRSM)
(1.7:1 dr)
4”
Ph
PhMe, 100 °C, 1 h
(81%, 5.4:1 dr)
HO
H
BnO
HO
H
BnO
BnO
Me
O
Me
Me
O
O
14
11
O
O
O
16 (major diasteromer)
Direct C-Ring Reduction via Hydrogen Atom
Transfer. In seeking a more direct method for reducing
the C3"–C4" double bond in benzopyran 9, we eventually
turned to Shenvi’s recently developed hydrogen atom
transfer (HAT) chemistry.16 As this method generally
provides a thermodynamic mixture, it was likely to
deliver useful quantities of the trans- isomer in a single
synthetic transformation. In an initial experiment, a
solution of 9 in CH2Cl2/iPrOH (1:1 v/v) was treated with
OH
OH
BF3-OEt2
(1.1 equiv)
THF, 4 to 24 °C
2 h, (94%)
O
OBn
O
OBn
Ph
Ph
H
OH
O
BnO
BnO
Me
Me
O
O
O
O
13 (enol)
13 (keto)
OH
t
a catalytic amount of Mn(dpm)3, butyl hydroperoxide,
and phenylsilane and found to undergo effective
reduction of the C3’’–C4’’ double bond, affording a
separable 1:2.2 mixture of trans and cis-isomers (10a and
10b) in good yield (Table 2, entry 1); we were able to
unambiguously assign the relative stereochemistry of 10a
by single crystal X-ray diffraction (Table 2, inset).
However, given the undesirable product ratio,
considerable effort was expended to increase selectivity
in the HAT hydrogenation of 9 (Table 2, entries 2–15).
Interestingly, employing Shenvi’s more active reductant
iPrO(Ph)SiH2 led to incomplete conversion of 9, and
slightly less desirable 1:2.5 ratio of 10a:10b.17b
Subsequently, a variety of other HAT catalysts (entries
3–5) were also assessed and led to no conversion of 9,
even at extended reaction times. We then turned to
evaluating the effect of solvent on the HAT
hydrogenation. While chlorinated co-solvents (entries 1–
6) afforded an undesirable ratio of 10a:10b, and ethereal
co-solvents led to no reaction (entry 7), we found that
utilization of aromatic solvents led to higher selectivity
for the desired diastereomer 10a (Table 2, entries 8–15).
In an initial finding, we found that HAT hydrogenation
BH3-tBuNH2 (4.7 equiv)
O
OBn
3”
Ph
CH2Cl2, 4 °C, 6 h
(42%)
HO
H
BnO
Me
O
O
12
With 12 in hand, deoxygenation of the unnecessary 3"
hydroxy group was undertaken. Treatment of 12 with KH
and CS2, followed by methylation, furnished bis-xanthate
17 (Scheme 4). While a number of conditions were
investigated for xanthylation of the sterically-hindered 3"
alcohol, those illustrated in Scheme 4 were by far the
most efficacious. Exposure of 17 to standard Barton-
McCombie conditions furnished phenol 11 in good yield
and as a 5.4:1 mixture of trans- and cis- isomers.15 While
the overall sequence from benzopyran 14 to
dihydrobenzopyran 11 afforded our desired C-ring
stereochemistry with good overall stereoselectivity, it
was unacceptably inefficient, requiring five-steps and
three redox manipulations for the formal trans-
hydrogenation of 15. In light of this inefficiency, we
turned toward identifying a more direct method for
accessing 11.
i
of 9 in the presence of a 1:1 mixture of PhH and PrOH
led to a 1.1:1 ratio of 10a and 10b, favoring, for the first
time, 10a, albeit with incomplete conversion (entry 8).17
Using toluene as the co-solvent sluggishly led to a 1.5:1
ratio of 10a:10b, but with reduced yield relative to
chlorinated solvents. Further solvent screening identified
fluorinated aromatic hydrocarbons as being particularly
enabling for this transformation (entries 9–15) with
trifluorotoluene (PhCF3) leading to a 1.5:1 ratio of
Scheme 4. Barton-McCombie deoxygenation of 12.
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Journal of the American Chemical Society
10a:10b in just 2.5 hours (Table 2, entry 12). Increasing (MeOH/HCl) and benzyl ether hydrogenolysis with
Pearlman’s catalyst to furnish bisphenol 18a.19 Allylation
of 18a followed by methanolysis and Claisen-Schmidt
condensation with benzaldehyde furnished 19a,20,21
which upon deallylation22 delivered caesalpinflavan B
(3) in 40% yield over the three steps.
1
2
3
4
5
6
7
8
the ratio of PhCF3 in the solvent system led to increased
reaction rates and concomitant increase in chemical yield
while maintaining a 1.5:1 dr of 10a/10b (entry 13). Using
this solvent mixture, we also found that performing the
reaction at –25 ºC led to no change in the product ratio
(entry 14), and likewise, substitution of 2-propanol with
hexafluoroisopropanol (HFIP) led to no reaction (entry
15). In addition, a number of protecting groups were
investigated for the A-ring phenol (Piv, MOM, 2-Ns), but
none had a positive effect in increasing selectivity for
10a. Although we attempted to advance 10a and 10b to 1
and C2”-epi-1, respectively, only the former proved
amenable to delivering the caesalpinnone ring-system
(vide infra).
Scheme 5. HAT hydrogenation of the C3”–C4” bond
and completion of caesalpinflavan B (3).
OAc
9
OAc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
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59
60
Mn(dpm)3 (10 mol %)
PhSiH3 (2 equiv)
tBuO2H (2 equiv)
HCl/MeOH
then Pd(OH)2/C
H2 (balloon)
O
OBn
O
OBn
Ph
4’’
Ph
4’’
3’’
PhCF3/iPrOH (3:1)
24 °C, 1.5 h
3’’
MeOH/THF
24 °C, 1 h
BnO
BnO
Me
O
O
(85%)
Me
9
O
10a
(1.5:1 trans (10a)/cis (10b))
O
Table 2. Selected optimization trials for the HAT
hydrogenation of 9.
OH
OAc
OAc
OAc
OAc
i) Allyl bromide, K2CO3
acetone, 75 °C, 4 h
O
OAllyl
O
OH
[cat.] (10 mol %)
silane (2 equiv)
tBuO2H (2 equiv)
Ph
Ph
ii) MeOH
O
O
OBn
OBn
O
OBn
iii) PhCHO, LiOH
MeOH, 24 to 50 °C
(56% over two steps)
AllylO
19a
HO
18a
Ph
Ph
Ph
O
Ph
solvent, 24 °C
O
Me
BnO
BnO
BnO
Me
Me
O
O
Me
O
O
OH
O
O
O
MeN
NMe
O
10a
solvent
10b
9
O
time
(h)
O
OH
10a:10bb
entry
[cat.]
yielda
silane
(2.3 equiv)
Pd(PPh3)4 (10 mol %)
CH2Cl2/iPrOH (1:1)
CH2Cl2/iPrOH (1:1)
CH2Cl2/iPrOH (1:1)
CH2Cl2/iPrOH (1:1)
CH2Cl2/iPrOH (1:1)
DCE/iPrOH (1:1)
THF/iPrOH (1:1)
1:2.2
1:2.5
–
1
2
3
Mn(dpm)3
Mn(dpm)3
Fe(acac)3
PhSiH3
iPrO(Ph)SiH2
PhSiH3
84
(68)
≤5
2
4
HO
THF, 24 °C, 15 min
(40% from 10a)
18
18
18
8
O
(R,R)-Mn(Salent-Bu,t-Bu)Cl PhSiH3
4
–
≤5
Caesalpinflavan B (3)
(R,R)-Co(Salent-Bu,t-Bu
)
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
5
–
≤5
6c
7
Mn(dpm)3
1:2.2
–
(45)
≤5
Completion of Caesalpinnone
A
(1) and
Mn(dpm)3
24
22
5
Unexpected formation of Tricycle 21. With 3 in hand,
we attempted to access 1 by way of phenolic oxidation of
the more electron-rich A-ring, and subsequent oxa-
Michael addition of the C4' D-ring phenol onto the
vinylogous ester moiety of the resulting p-quinol (Figure
3). Unfortunately, all attempts to access 1 through this
sequence proved futile.23
PhH/iPrOH (1:1)
1:1.1
1:5:1
1.3:1
1:1.1
1.5:1
1.5:1
1.5:1
–
8
Mn(dpm)3
(74)
67
PhMe/iPrOH (1:1)
PhF/iPrOH (1:1)
9
Mn(dpm)3
10
11
12
13
14d
15
Mn(dpm)3
82
4
C6F6/iPrOH (1:1)
PhCF3/iPrOH (1:1)
PhCF3/iPrOH (3:1)
PhCF3/iPrOH (1:1)
PhCF3/HFIP (1:1)
Mn(dpm)3
62
4.5
2.5
1.5
16
24
Mn(dpm)3
75
Mn(dpm)3
Mn(dpm)3
85
66
Mn(dpm)3
≤5
aIsolated yields. Yields in parentheses refer to conversion as judged by 1H NMR.
bRatios were obtained by 1H NMR analysis. cReaction run at 60 °C. dReaction
conducted at –25 °C.
OH
A
O
A
O
HO
O
Phenolic oxidation
of A-ring
Oxa-Michael
addition
O
OH
D
O
OH
4’
HO
O
4’
Ph
Ph
D
Ph
O
HO
HO
HO 2’
2’
R
O
O
Ph
BnO
OAc
≡
Ph
A (R = C(O)C2H2Ph)
O
Caesalpinflavan B (3)
Caesalpinnone A (1)
OBn
O
Me
Figure 3. Attempted direct conversion of 3 to 1
10a
Undeterred, we decided to attempt phenolic oxidation
prior to allyl deprotection of the D-ring phenols. Previous
investigations in our laboratories revealed Doyle's
dearomative phenolic oxidation method as effective for
the dearomative phenolic oxidation of sterically-
encumbered substrates.24,25 Given this, we treated 19a
with catalytic Rh2(cap)4 in the presence of TBHP and,
after reductive cleavage of the internal peroxide with
Pb/Cd couple, received 15% yield of the desired p-quinol
Having established reliable access to the trans
stereochemistry of the flavanoid C-ring, we turned our
attention to accessing caesalpinflavan B (3) en route to
completing the synthesis of 1. At this juncture, all that
remained to complete 3 was global deprotection of 10a
and installation of the enone moiety. To be completed
effectively, this conversion required three steps18
beginning with concomitant acetal hydrolysis
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Page 6 of 10
20a (Scheme 6, inset). Efforts to develop more efficient
Scheme 7. Synthesis of 20b and surprising formation
of tricycle 21.
1
2
3
4
5
6
7
8
conditions for this conversion ultimately led to the
treatment of 19a with phenyliodide(III) diaceate (PIDA)
in a mixture of acetonitrile and water (8:1 MeCN–H2O
v/v) at –5 ºC. Under these conditions we obtained a 3.3:1
mixture of p-quinols 20a and 20b in 29% yield. (Scheme
6, inset).26,27
Enantioselective Total Synthesis of (–)-3 and Formal
Total Synthesis of (–)-1. Having completed syntheses
of 1 and 3 in racemic form, we began exploring means
to render the synthesis enantioselective. To this end we
opted to pursue the unnatural enantiomer of
caesalpinnone A, (–)-1, and thus began exploring
Scheme 6. Phenolic oxidation of 12a and completion
of the total synthesis of caesalpinnone A (1).
9
methods
for
accessing
N-tosylhydrazone
8
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
enantioselectively. To this end, we turned to a
palladium-catalyzed conjugate addition method
developed by Stoltz and co-workers,28 which had been
used to generate (R)-5 in one step from 7-chromenone
(22, Scheme 8). Subsequent conversion of (R)-5 to (R)-
8 would then set the stage for Barluenga coupling. As
illustrated in Scheme 8, this method was found to work
exactly as reported and allowed for preparation of (R)-5
in 77% yield and in 96.5:3.5 er, which was further
manipulated to (R)-8 in 95:5 er (Scheme 8) in the same
manner as the racemic material.29
O
OAllyl
O
OAllyl
O
OAllyl
HO
HO
Ph 2’’
see inset
+
Ph
4’’
Ph
2’’
4’’
AllylO
AllylO
AllylO
O
Ph
O
Ph
O
Ph
20a
conditions
1) Rh2(cap)4, TBHP, DCE, 4 °C
19a
20b
entry
yield
20a:20b
≥20:1
1
15%
29%
2) Pb/Cd couple, NH4OAc (aq.)/THF, 24 °C
2
PIDA, MeCN/H2O (8:1 v/v), –5 °C
3.3:1
O
O
O
Scheme 8. Enantioselective conjugate addition of 22
and elaboration to (R)-8
MeN
O
NMe
HO
O
9”
(3.4 equiv)
O
HO
OH
4’
O
O
O
Pd(PPh3)4 (13 mol %)
O
Ph
HO
THF, 24 °C, 10 min
(56%)
N
N
(S)-tBuPyOX (6 mol %)
HO
2’
tBu
1) Ac2O, pyr,
DMAP
2) NH2NHTs
MeOH
OH
OH
O
A
Ph
(±)-Caesalpinnone A (1)
Pd(TFA)2 (5 mol %)
PhB(OH)2 (2 equiv)
(R)-8
(95:5 er)
O
O
Having implemented the phenolic oxidation, we
turned toward allyl deprotection and completion of the
synthesis. To this end, exposure of the mixture of 20a
and 20b to catalytic Pd(PPh3)4 and 3.4 equivalents of 1,3-
dimethylbarbituric acid resulted in rapid consumption of
both with the former producing (±)-1 in 56% yield, likely
through the intermediacy of A (Scheme 3). Monitoring
of this reaction by UPLC/MS revealed the presence of a
minor isomeric product, presumably derived from 20b.
To further explore this latter event, a sample of pure 20b
was prepared and subjected to the deallylation
conditions. Interestingly, this reaction was found to
produce the regiomeric tricycle 21 as the only isolable
product (34% yield) and not epi-1 as initially expected
NH4PF6 (30 mol %)
H2O (5 equiv)
DCE, 60 ºC, 28 h
(77%, 96.5:3.5 er)
(65% over
two steps)
O
Ph
O
(R)-5
22
With (R)-8 in hand, the stage was set for the synthesis
of enantioenriched benzopyran 9. Employing the
optimized conditions for the synthesis of racemic 9
(Table 3, entry 1) afforded optically enriched 9 in 91%
yield, but with significant erosion of enantiopurity
(72:28 er). To probe the cause of this unexpected
racemization, we subjected 9 (72:28 er) to the reaction
conditions (equation 1) and observed nearly complete
racemization after 13 hours (t1/2 = 238 min).
Table 3. Optimization trials of (R)-8 and 7 to produce
enantioenriched 9.
(Scheme 7).
O
OAc
O
MeN
O
NMe
O
(3.5 equiv)
O
OBn
O
HO
OAllyl
Pd(PPh3)4 (11 mol %)
See Schemes 5 and 6
(27% over 3 steps)
Ph
Ph
MeOH, 24 °C, 3 h
(34%)
BnO
AllylO
Me
O
O
Ph
O
10b
20b
(derived from HAT
hydrogenation)
O
O
O
H
HO
O
O
O
HO
O
O
O
OH
HO
Ph
HO
HO
HO
O
epi-(1)
not observed
O
Ph
A’
21
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Journal of the American Chemical Society
this, we found that increasing the loading of Mn(dpm)3
1
2
3
4
5
6
to 50 mol % and lowering the equivalents of TBHP
allowed for isolation of 10a with only small amounts of
epimerization (89:11 er, Scheme 9). Gratifyingly, the
enantiopurity of 10a could easily be upgraded to 99:1 er
with a single recrystallization from hexanes/iPrOH.
OAc
OAc
7
8
9
Mn(dpm)3 (50 mol %)
PhSiH3 (2.5 equiv)
tBuO2H (2.1 equiv)
O
O
2”
OBn
OBn
1) HCl/MeOH;
Pd(OH)2/C, H2
Ph
Ph
4”
PhCF3/iPrOH (3:1 v/v)
24 °C, 40 min
2) allyl bromide, K2CO3
acetone, 75 ºC; then
PhCHO, LiOH, MeOH
BnO
BnO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
Me
(58%, 1.5:1 10a:10b)
O
O
O
O
(R)-9
(R,S)-10a
89:11 er
(99:1 er after recrystallization)
O
OH
OH
OH
MeN
O
NMe
O
O
OH
O
OH
(3.5 equiv)
Pd(PPh3)4
O
OAllyl
Ph
Ph
(R)
(R)
(S)
(S)
Ph
MeOH, 24 °C
(41% over three steps)
(>99:1 er)
HO
HO
AllylO
(R,S)-19a
O
Ph
O
Ph
O
Ph
(–)-Caesalpinflavan B (3)
(+)-Caesalpinflavan B (3)
(stereochemical
See Scheme 6
reassignment)
(–)-Caesalpinnone A (1)
Scheme 9. Conversion of (R)-9 to (–)-3 and formal
enantioselective synthesis of (–)-1.
Establishing the viability of (+)-3 as the
biosynthetic precursor to (+)-1: Stereochemical
Revision of (+)-3. The absolute stereochemistry of
natural (+)-1 was unambiguously assigned during its
initial isolation by high quality single crystal X-ray
diffraction. In contrast, the absolute stereochemistry of
natural (+)-3 was assigned only by analysis of its CD
spectrum.1 Based on analyses of these data, Wang and
co-workers assigned the carbon atoms at C2” and C4”
in natural (+)-1 and (+)-3 as being opposite in absolute
Given this outcome, we set out to further optimize the
Barluenga coupling between (R)-8 and 7 to limit
racemization of 9. To this end, we reasoned that slow
addition of (R)-8 to the reaction mixture was detrimental
as it required long reaction times. Indeed, a Barluenga
coupling employing (R)-8 and 2.5 equivalents 7
afforded 9 in a modest 35% yield after 30 minutes, albeit
with minimal loss of stereochemistry (Table 3, entry 2).
We envisaged that the racemization of 9 may be
configuration.
Given potential biosynthetic
considerations, this was puzzling and, if indeed correct,
anticipates that (C2”R, C4”S)-10a (Scheme 9) would
produce the natural enantiomer of caesalpinflavan B
(i.e., (+)-3). However, as illustrated in Scheme 9,
elaboration of (C2”R, C4”S)-10a was found to furnish
(–)-3, wherein the optical rotation is opposite in sign to
natural (+)-3. Based on this analysis, natural (+)-3 was
determined to possess the same absolute configuration
at C2” and C4” as naturally occurring (+)-1, thus
arguing strongly for their biosynthetic relationship. In
addition to the synthesis of unnatural (–)-3, the
enantioselective synthesis of (R,S)-19a constitutes a
formal total synthesis of unnatural (–)-1.
occurring
through
reversible
Pd--allyl
formation/intramolecular phenoxide addition of 9 and
decided to change reaction conditions to increase the
rate of our desired, intermolecular coupling process.30
To accomplish this, we found that increasing the
concentration of the reaction, as well as increasing the
equivalents of 7, led to higher conversion without
significant racemization, affording 9 in 58% yield and
91.5:8.5 er after 60 minutes (Table 3, entry 3). We
subsequently found that heating this reaction mixture
for longer time periods (Table 3, entry 4) failed to
significantly increase the chemical yield and only led to
lower enantiomeric ratios of 9.
Having optimized the Barluenga coupling for the
enantioenriched substrate we next turned our attention
to the HAT hydrogenation of enantioenriched 9. While
seemingly innocuous, the reduction of the C–C double
bond in 9 required a HAT reaction in the presence of an
exceedingly weak benzylic, allylic ether C–H bond. In
practice, applying our previous optimized HAT
reduction procedure (Table 2, entry 13) to
enantioenriched 9 led to isolation of 10a with significant
erosion of enantiopurity (84.5:15.5 er). To circumvent
Conclusions
In conclusion, we have developed the first total
syntheses of caesalpinflavan B (3) and caesalpinnone A
(1), in 6 and 7 steps, respectively. In addition to
providing expedient access to these bioactive natural
products and several structural analogs, our synthetic
efforts have further expanded the scope of the venerable
Barluenga coupling reaction by highlighting its utility
for sterically-demanding couplings and, to our
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Page 8 of 10
[5.3.3.01,6]Tridecane-Bridged System and Caesalpinflavans A–C
from Caesalpinia enneaphylla. Org. Lett. 2017, 19, 4315.
knowledge, providing the first example of its use in the
context of
natural product total synthesis.31
1
2
3
4
5
6
7
8
a
2. a) Chen, X.; Brauman, J. I. Hydogen Bonding Lowers Intrinsic
Nucleophilicity of Solvated Nucleophiles. J. Am. Chem. Soc. 2008,
130, 15038. b) Kanamori, D.; Furukawa, A.; Okamura, T.;
Yamamoto, H.; Ueyama, N. Contribution of the intramolecular
hydrogen bond to the shift of the pKa value and the oxidation
potential of phenols and phenolate anions. Org. Biomol. Chem. 2005,
3, 1453.
3. 7-hydroxyflavanone (5) has been isolated from a wide variety of
plants, for examples see: a) Zampini, I. C.; Vilena, J.; Salva, S.;
Herrera, M.; Isla, M. I.; Alvarex, S. Potentiality of standardized
extract and isolated flavonoids from Zuccagnia punctata for the
treatment of respiratory infections by Streptococcus pneumoniae: In
vitro and in vivo studies. J. Ethnopharmacol. 2012, 140, 287. b)
Shirota, O.; Pathak, V.; Sekita, S.; Satake, M.; Nagashima, Y.;
Hirayama, Y.; Hakamata, Y.; Hayashi, T. Phenolic Constituents from
Dalbergia conchinchinensis. J. Nat. Prod. 2003, 66, 1128. c)
Tanrisever, N.; Fronczek, F. R.; Fischer, N. H.; Williamson, G. B.
Ceratiolin and other flavonoids from Ceratiola ericoides.
Phytochemistry 1986, 26, 175.
4. 2',4'-dihydroxychalcone (6) has been isolated from a wide variety
of plants, for examples see: a) Li, H.; Jean, S.; Webster, D.;
Robichaud, G. A.; Calhoun, L. A.; Johnson, J. A.; Gray, C. A.
Dibenz[b,f]oxepin and Antimycobacterial Chalcone Constituents of
Empetrum nigrum. J. Nat. Prod. 2015, 78, 2837. b) Mativandela, S.
P. N. Muthidhi, T.; Kikuchi, H.; Oshima, Y.; Hamilton, C.; Hussein,
A. A.; van der Walt, M. L.; Houghton, P. J.; Lall, N.
Antimycobacterial Flavonoids from the Leaf Extract of Galenia
Africana. J. Nat. Prod. 2009, 72, 2169. c) Wollenweber, E.; Dörr, M.;
Stelzer, R.; Arriaga-Giner, F. J. Lipophilic Phenolics from the Leaves
Additionally, these efforts have further demonstrated
the utility of Shenvi’s HAT hydrogenation protocol,
which in the current context, provided stereo-divergent
access to two distinct molecular scaffolds. We have
likewise described the enantioselective total synthesis
of (–)-3, the stereochemical reassignment of naturally-
derived 3, and a formal enantioselective total synthesis
of (–)-1, which were all enabled by the use of
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
enantioselective
palladium-catalyzed
conjugate
addition to provide (R)-5. We anticipate the synthetic
strategy described in this article will serve as inspiration
for the stereoselective synthesis other structurally-
related flavan-chalcone hybrids, along with related
flavanoid natural products.
Future efforts will be directed towards biological
investigation of 1, with particular regard to applications
as a selective cytotoxic agent and mode-of-action studies.
Furthermore, owing to both the brevity and potential
modularity of this synthetic sequence, analogs of 1 and
21, along with synthetic intermediates, will likewise be
investigated and the results of these investigations
reported in due course.
ASSOCIATED CONTENT
of Empetrum nigrum
— Chemical Structures and Exudate
Localization. J. Bot. Acta. 1992, 105, 300.
5. Flavan-chalcone and flavan-flavanone hybrid natural products
bearing structures similar to 3 have been previously proposed to arise
biosynthetically directly from C–D ring bond formation, see: a)
Meesakul, P.; Pudhom, K.; Pyne, S. G.; Laphookhieno, S. Hybrid
flavan-flavanones from Friesodielsia desmoides and their inhibitory
activities against nitric oxide production. RSC Adv., 2017, 7, 17545.
b) Attwood, M. R.; Brown, B. R.; Lisseter, S. G.; Torrero, C. L.;
Weaver, P. M. Spectra Evidence for the Formation of Quinone
Methide Intermediates from 5- and 7-hydroxyflavanoids. J. Chem.
Soc., Chem. Comun., 1984, 177.
6. a) Barluenga, J.; Valdés, C. Tosylhydrazones: New Uses for
Classic Reagents in Palladium-Catalyzed Cross-Coupling and Metal-
Free Reactions. Angew. Chem. Int. Ed. 2011, 50, 7486. b) Barluenga,
J.; Moriel, P.; Valdés, C.; Anzar, F. N-Tosylhydrazones as Reagents
for Cross-Coupling Reactions: A Route to Polysubstituted Olefins.
Angew. Chem. Int. Ed. 2007, 46, 5587.
7. Roche, M.; Hamze, A.; Provot, O.; Brion, J-. D.; Alami, M.
Synthesis of Ortho/Ortho′-Substituted 1,1-Diarylethylenes through
Cross-Coupling Reactions of Sterically Encumbered Hydrazones and
Aryl Halides. J. Org. Chem. 2013, 78, 445.
8. See Supporting Information for the synthesis of 7 and 8.
9. Mass spectroscopic analysis of the Barluenga coupling between 7
and 8 suggested significant formation of diazine-derived side-
products. However, we were unable to isolate and unambiguously
characterize these side-products.
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental procedures, analytical data for new
compounds (1H and 13C NMR, HRMS, IR), optimization
tables, and HPLC traces for enantioenriched materials
(PDF)
AUTHOR INFORMATION
Corresponding Author
*John_L_Wood@Baylor.edu
ACKNOWLEDGMENT
Financial support for this work was provided by The
Welch foundation (Chair, AA-006), the Cancer Prevention
Research Institute of Texas (CPRIT, R1309), and NSF
(CHE-1764240). The authors graciously thank Dr. Yu-
Wen Huang for assistance in high-throughput screening in
the early stages of the Barluenga coupling development.
Collin Mondrik, Kristen Bluer, Dr. Mina Nahkla and Dr.
Kevin Klausmeyer are acknowledged for their assistance
in X-Ray crystallographic analysis. The authors also thank
Eric Alexy and Professor Brian Stoltz (Caltech) for their
generous gift of (S)-tBuPyOX ligand.
10. For examples of catalytic hydrogenation of 2-substituted-(2H)-
chromes
giving
predominantly
cis-2,4-substituted
dihydrobenzopyrans, see: Pawar, G. G.; Tiwari, V. K.; Jena, H. S.;
Kapur, M. Hetereoatom-Guided, Palladium-Catalyzed, Site-
Selective C–H Arylation of 4H-Chromenes: Diastereoselective
Assembly of the Core Structure of Myristinin B through Dual C–H
Functionalization. Chem. Eur. J. 2015, 21, 9905. b) Rueping, M.;
Uria, U.; Lin, M-.Y.; Atodiresei, I. Chiral Organic Contact Ion Pairs
in Metal-Free Catalytic Asymmetric Allylic Substitutions. J. Am.
Chem. Soc. 2011, 133, 3732.
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13. The atropisomers of 14 were separable by preparative HPLC.
Analysis of the isolated compounds indicated that both possessed the
same C2”, C3” stereochemistry. The axial chirality was not assigned
and thus illustrations here reflect an arbitrary atropisomeric choice.
See Supporting Information for more details.
14. We also attempted to deoxygenate ketone 13 directly using
classical Wolff-Kishner conditions, which only led to decomposition.
15. Hecht and co-workers also saw small amounts of epimerization
of the 2" stereocenter during a deoxygenation step in their synthesis
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27. It is not currently understood how 20b is formed in the PIDA-
mediated dearomative oxidation of 19a but, as suggested by one
reviewer,
a possible manifold is benzylic deprotonation/re-
protonation, which is driven by the thermodynamic stability of the
cis-configuration in 20b.
28. Holder, J. C.; Marziale, A. N.; Gatti, M.; Mao, B.; Stoltz, B. M.
Palladium-Catalyzed Asymmetric Conjugate Addition of
Arylboronic Acids to Hetereocyclic Acceptors. Chem. Eur. J. 2013,
19, 74.
29. The slight enantioerosion from (R)-5 to (R)-8 occurred during the
N-tosylhydrazone forming step.
30. Heating a solution of enantioenriched 9 in PhF and K2CO3 at 85
ºC for 18 hours led to no detectible racemization. As such, alternative
reaction pathways, such as retro 6- photoracemization of 2H-
chromenes, were discounted; for a seminal reference in this area, see:
Wipf, P.; Weiner, W. S. Enantioselective Synthesis and
Photoracemization Studies of (+)-2-Cyclopropyl-7,8-dimethoxy-2H-
chromene-5-carboxylic Acid Methyl Ester, an Advanced
Intermediate of a Dihydrofolate Reductase Inhibitor J. Org. Chem.
1999, 64, 5321.
31. Shenvi and co-workers recently reported a coupling between a
quinone diazide and an alkyl boronic acid in their synthesis of
azamerone: Landry, M. L.; McKenna, G. M.; Burns, N. Z.
Enantioselective Synthesis of Azamerone. J. Am. Chem. Soc. 2019,
141, 2867.
17. We found it imperative that 9 be completely consumed in the
HAT hydrogenation due to our inability to efficiently separate 9 and
10a/b on silica gel chromatography.
18. We define a chemical step as the conversion of one material to
another in a single reaction flask, without isolation or removal from
the flask, and regardless of the number of reagent additions or
manipulations. This step count convention is based on the definition
given by Baran, see: Kawamura, S.; Chu, H.; Felding, J. Baran P. S.
Nineteen-step total synthesis of (+)-phorbol. Nature, 2016, 532, 90.
19. The benzyl groups were replaced with allyl groups at this point
for two reasons: 1) We found that installation of the chalcone moiety
needed to be performed with the D-ring phenols protected and 2)
hydrogenolysis of the benzyl ethers in the presence of the chalcone
moiety would likely prove troublesome.
20. Bhagat, S.; Sharma, R.; Sawant, D. M.; Sharma, L.; Chakraborti,
A. K. LiOH·H2O as a novel dual activation catalyst for highly
efficient and easy synthesis of 1,3-diaryl-2-propenones by Claisen–
Schmidt condensation under mild conditions. J. Mol. Catal. A: Chem
2005, 244, 20.
21. Initially, we attempted the Claisen-Schmidt on an unprotected
substrate (i.e., i). However, we were unable to isolate appreciable
amounts of 3. Instead, this reaction delivered an inseparable mixture
containing 3 accompanied by at least one other cyclized flavanone
product tentatively assigned as ii.
OH
OH
OH
PhCHO
LiOH-H2O
O
O
OH
OH
O
OH
+
Ph
MeOH
24 to 50 °C
O
HO
HO
O
O
Me
O
i
ii
Caesalpinflavan B (3)
22. a) Tsukamoto, H.; Suzuki, T.; Kondo, Y. Remarkable Solvent
Effect on Pd(0)-Catalyzed Deprotection of Allyl Ethers Using
Barbituric Acid Derivatives: Application to Selective and Successive
Removal of Allyl, Methallyl, and Prenyl Ethers. Synlett, 2007, 20,
3131. b) Tsukamoto, H.; Kondo, Y. Facile and Selective Cleavage of
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