A Concise Enantiodivergent Synthesis of Equol

Article abstract of DOI:10.1055/a-1303-9935

Equol, a nonsteroidal estrogen produced from the metabolism of the isoflavonoid phytoestrogen daidzein, has been synthesized as both enantioenriched forms based on MacMillan's α-Arylation of carbonyl compound mediated by amino acid derived indazolidinones and copper precatalysts. The natural form of (S)-equol and its enantiomer (R)-equol have been synthesized in 8 steps from 2,4-dimethoxybenzaldehyde with good enantiomeric purity (90% ee and 90% ee, respectively).

Full text of DOI:10.1055/a-1303-9935

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, 693–696
letter
693
en
T. Uemura et al.
Letter
Synlett
A Concise Enantiodivergent Synthesis of Equol
Takahito Uemura
Yusuke Saito
O
N
Ph
HO
O
MeO
Motohiro Sonoda
Shinji Tanimori*
N
CHO
·TCA
t-Bu
H
0
0
0
0
-
0
0
0
2
-
7
4
6
8
-
9
8
7
0
MeO
OH
(S)-equol (natural), 90% ee
I+TfO–
MeO
OMe
Department of Applied Life Sciences, Graduate School of Life
and Environmental Sciences, Osaka Prefecture University,
1-1 Gakuencho, Nakaku, Sakai, Osaka 599-8531, Japan
tanimori@bioinfo.osakafu-u.ac.jp
(S)
CHO
MeO
CuBr
2
MeO
HO
O
MeO
CHO
O
SDeMheipnaaijClirotTmararnneinimsmptooornrfiid@AibpnipgoliAneudfothL.oiofseraskSacifeun-uce.asc,.Gjpraduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuencho, Nakaku, Sakai, Osaka 599-8531, Japan
MeO
OH
N
OMe
(R)
Ph
(R)-equol, 90% ee
N
·TCA
t-Bu
H
Received: 14.10.2020
Accepted after revision: 04.11.2020
Published online: 04.11.2020
7-chromanol.6 Since then, a variety of reports dealing with
its biological functions have been documented,1 which in-
clude the treatment of estrogen- or androgen-mediated dis-
eases or disorders,7 skin-health-improving and anti-aging
substance,8 the treatment of menopausal symptoms,9
symptoms of menopausal vaginal atrophy,10 and selective
agonist of ER.11
DOI: 10.1055/a-1303-9935; Art ID: st-2020-u0550-l
Abstract Equol, a nonsteroidal estrogen produced from the metabo-
lism of the isoflavonoid phytoestrogen daidzein, has been synthesized
as both enantioenriched forms based on MacMillan’s -arylation of car-
bonyl compound mediated by amino acid derived indazolidinones and
copper precatalysts. The natural form of (S)-equol and its enantiomer
(R)-equol have been synthesized in 8 steps from 2,4-dimethoxybenzal-
dehyde with good enantiomeric purity (90% ee and 90% ee, respective-
ly).
Therefore, large amount of reports dealing with the
chemical synthesis of equol have been demonstrated which
include both racemic12 and enantioselective syntheses.13
The latter constitutes the methods based on asymmetric
transfer hydrogenation/deoxygenation,13a rhodium-cata-
lyzed asymmetric addition,13b enantioselective allylic al-
kylation,13c organocatalytic annulation of o-quinone
methides and aldehydes,13d a chiral pool approach,13e iridi-
um-catalyzed asymmetric hydrogenation,13f the flavan–iso-
flavan rearrangement,13g deracemization of -aryl hydro-
coumarins via catalytic asymmetric protonation,13h enanti-
oselective iridium-catalyzed hydrogenation,13i allylic
substitution,13j Evans alkylation,13k and catalytic dynamic
kinetic resolution,13l However, few reports for the synthesis
of the both antipodes of equol have been documented13e,f
despite the biological importance of unnatural (R)-equol.14
In this report, we disclose the asymmetric synthesis of
both enantiomers of equol based on enantioselective -ary-
lation of aldehyde 3 with diaryliodonium salt 415 employing
MacMillan’s protocol in a concise and enantiodivergent
manner with acceptable overall yield and good enantiopu-
rity.16
Key words equol, asymmetric synthesis, isoflavan, -arylation,
MacMillan’s catalyst
Equol (1) is an isoflavandiol estrogen metabolized from
daidzein, a type of isoflavone found in soybeans and other
plant sources, by bacterial flora in the intestines (Figure 1).1
A series of congeners for equol have also been elucidated
(Figure 1).2–4
Equol (1) was first isolated from horse urine in 19325
and structurally elucidated to be (3S)-3-(4-hydroxyphenyl)-
HO
O
HO
O
OH
OH
OH
(S)-5-hydroxy-equol2
(S)-equol (1)
effective against
hepatocellular
carcinoma (HCC)
Our synthetic plan for both antipodes of equol is illus-
trated in Scheme 1. -Arylation of aldehyde 3, derived from
commercially available 2,4-dimethoxybenzaldehyde 2, with
diaryliodonium salt 4 in the presence of cuprous bromide
and organocatalyst (2R,5R)-516 should afford aldehyde (S)-6,
presumably.16 Aldehyde (S)-6 would afford natural (S)-
equol (1) by the known transformations.13i,j On the other
HO
O
HO
O
OMe
OH
OMe
OMe
(R)-sativan3
(S)-vestitol4
phytoalexin of Medicago sativa
potential anti-inflammatory activity
Figure 1 Equol and congeners
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 693–696
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

694
T. Uemura et al.
Letter
Synlett
I+TfO–
MeO
N
2
MeO
MeO
MeO
CHO
4
CHO
(S)-equol (1)
O
CHO
CuBr
MeO
3
MeO
MeO
OMe
2
Ph
(S)-6
O
N
·TCA
t-Bu
H
N
4
Ph
·TCA
(2R,5R)-5
CuBr
N
t-Bu
H
(2S,5S)-5
MeO
CHO
(R)-equol (1)
MeO
OMe
(R)-6
Scheme 1 Synthetic strategy for (R)- and (S)-equols
hand, by switching the chiral catalyst from (2R,5R)-5 to its
enantiomer (2S,5S)-5, (R)-equol (1) would be synthesized
along the same sequences.
Substrate 3 for the asymmetric -arylation reaction was
synthesized from 2,4-dimethoxybenzaldehyde (2) through
the Doebner modification of the Knoevenagel reaction fol-
lowed by reduction of both carboxyl group and double
bond, and then oxidation by PCC in 63% (3 steps) via car-
boxylic acid 7 and primary alcohol 8 (Scheme 2).17
Then, aldehyde 3 was subjected to -arylation reaction
with the use of MacMillan’s catalyst (2R,5R)-516 (20 mol%)
and diaryliodonium salt 415 in the presence of copper(I)
bromide (20 mol%) to afford product (S)-6. The aldehyde
(S)-6 was directly converted into bromide (S)-10 through
the reduction of aldehyde (S)-6 to primary alcohol (S)-9
(not shown) followed by bromination with CBr4/PPh3 sys-
tem.13i Then, the bromide (S)-10 was transformed to (S)-
equol (1) by the literature procedure with degradation of
methyl ether using boron tribromide followed by base-me-
diated intramolecular alkylation via triol (S)-11 (not
shown).13i,j The optical purity of (S)-equol (1) have been de-
termined by chiral HPLC column to be 90% ee (see the Sup-
porting Information).
As the natural enantiomer of equol has been successful-
ly synthesized with an acceptable enantioselectivity and
yield, we next focused on the synthesis of (R)-equol due to
its potential biological activity.14 First, catalyst (2S,5S)-5, re-
quired for the access to antipode of natural (S)-equol (1),
was newly prepared starting from D-phenylglycine as
shown in Scheme 3.16b,17
Along the same reaction sequences for the synthesis of
(S)-equol (1), (R)-equol (1) was synthesized through -ary-
lation protocol with the use of enantiomeric (2S,5S)-5 cata-
lyst in a similar manner (Scheme 4). The optical purity of
obtained (R)-equol (1) was 90% ee (see the Supporting In-
formation).
CH2(CO2H)2
piperidine
MeO
MeO
MeO
R
1. LiAlH4, 78%
2. PCC, CH2Cl2
CHO
CO2H
98%
MeO
MeO
MeO
8: R = CH2OH
3: R = CHO
2
7
–OTf
I+
MeO
MeO
N
OMe
MeO
Br
CHO
4
1. NaBH4
(1.1 equiv)
3
O
2. CBr4, PPh3
15% (from 8)
CuBr (20 mol%)
NaHCO3 (4.5 equiv)
PhMe/Et2O (2:1)
rt, 44 h
MeO
MeO
OMe
OMe
Ph
(S)-6
(S)-10
N
·TCA
t-Bu
H
(2R,5R)-5 (20 mol%)
HO
O
1. BBr3, CH2Cl2
2. K2CO3, acetone
76% (2 steps)
OH
(S)-equol (1)
90% ee
Scheme 2 Synthesis of (S)-equol (1)
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 693–696

695
T. Uemura et al.
Letter
Synlett
O
O
1. TFAA, 87%
2. LDA; K2CO3, 39%
1. SOCl2
2. 40% MeNH2 aq.
N
HOOC
NH2
Ph
N
Ph
·TCA
Ph
N
3. TCA, 96%
t-Bu
3. t-BuCHO
4. HCl/EtOAc
N
t-Bu
H
H
(2S,5S)-5
Scheme 3 Synthesis of organocatalyst (2S,5S)-5
The mechanism for the reaction pathway and enantio-
discrimination step for the -arylation reaction is assumed
as shown in Scheme 5.16 The re-face attack of copper spe-
cies 12 formed from diaryliodonium salt 4 and copper(I)
bromide to -carbon of enamine 13 would be preferable
due to the steric effect to afford the desired enantiomer 6,
selectively.
In conclusion, we have developed a simple protocol for
the enantioselective synthesis of equol through MacMillan’s
-arylation method. The (S)- and (R)-equols have been syn-
thesized by simply applying the enantiomeric organocata-
lysts (2R,5R)-5 and (2S,5S)-5, respectively. This method
would serve as the synthesis of isoflvan and related com-
pounds with chiral center at C-3 position. Synthesis of other
isoflavans related to equol (Figure 1) by applying the pres-
ent protocol is now in progress.
Funding Information
This work was supported by the Japan Society for the Promotion of
Science (JSPS KAKENHI, Grant Number JP17K07776) to S.T.
J
a
pa
n
S
oc
i
e
t
y
for
t
hePro
m
oti
o
n
o
f
Sc
i
e
nce(J
P
1
7
K
0
7
7
7
6
)
O
N
4,
Ph
N
MeO
HO
O
·TCA
t-Bu
H
CHO
(2S,5S)-5
CuBr
3
MeO
OMe
OH
(R)-6
(R)-equol (1)
90% ee
Scheme 4 Synthesis of (R)-equol 1
O
O
N
N
MeO
H+
CHO
O
– H+
H+
t-Bu
t-Bu
Ph
N+
Ph
N
H
MeO
3
Ar1
13
Ar1
H2O
N
Ph
5
–OTf
I+
N
H
t-Bu
Br
CuIII
TfO
O
Ar2
MeO
OMe
CuBr
Ar2I
12
MeO
4
CHO
MeO
O
OMe
N
6
N
H
N
H2O
Ar1
t-Bu
H
t-Bu
N+
Ph
N+
Ph
Br
Br
Ar2
Cu
Ar2
Cu
Ar2
TfO
re-face attack
Ar1
Ar1
Formation of aryl-Cu(III) 12 from iodonium salt 4 and CuBr
Br
Cu
‡
–OTf
I+
–OTf
I+
TfO–
CuBr
CuBr
I+
12
Ar2
Ar2
– Ar2I
OMe
MeO
OMe
OMe
4
π-complex
Scheme 5 Proposed mechanism for the formation aldehyde 6
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 693–696

696
T. Uemura et al.
Letter
Synlett
Supporting Information
Zhao, J.-J.; Yu, S. J. Am. Chem. Soc. 2018, 140, 16914. (d) Zhang, J.;
Zhang, S.; Yang, H.; Zhou, D.; Yu, X.; Wang, W.; Xie, H. Tetrahe-
dron Lett. 2018, 59, 2407. (e) Yalamanchili, C.; Chittiboyina, A.
G.; Rotte, S. C. K.; Katzenellenbogen, J. A.; Helferich, W. G.; Khan,
I. A. Tetrahedron 2018, 74, 2020. (f) Xia, J.; Nie, Y.; Yang, G.; Liu,
Y.; Zhang, W. Org. Lett. 2017, 19, 4884. (g) Nakamura, K.;
Ohmori, K.; Suzuki, K. Chem. Commun. 2015, 51, 7012. (h) Lee,
J.-W.; List, B. J. Am. Chem. Soc. 2012, 134, 18245. (i) Yang, S.; Zhu,
S.-F.; Zhang, C.-M.; Song, S.; Yu, Y.-B.; Li, S.; Zhou, Q.-L. Tetrahe-
dron 2012, 68, 5172. (j) Takashima, Y.; Kaneko, Y.; Kobayashi, Y.
Tetrahedron 2010, 66, 197. (k) Heemstra, J. M.; Kerrigan, S. A.;
Doerge, D. R.; Helferich, W. G.; Boulanger, W. A. Org. Lett. 2006,
8, 5441. (l) Qin, T.; Metz, P. Org. Lett. 2017, 19, 2981.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1303-9935.
S
u
p
p
orti
n
gI
n
f
orm
a
ti
o
nS
u
p
p
orti
n
gInform
a
ti
o
n
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(17) General Procedure for the Synthesis of (S)-3-(2,4-Dime-
thoxyphenyl)-2-(4-methoxyphenyl)propan-1-ol (9)16a
To an oven-dried round-bottom flask was added crude dia-
ryliodonium salt 4 (65–70% purity determined by 1H NMR; 3.24
g, 4.34 mmol) and CuBr (122 mg, 0.85 mmol), and then toluene
(6.4 mL) and Et2O (3.2 mL) were added. Afterwards, (2R,5R)-5
(334 mg, 0.844 mmol) and NaHCO3 (1.62 g, 19.3 mmol) were
added to the suspension. Under argon atmosphere, a solution of
aldehyde 3 (823 mg) in toluene/Et2O (2:1, 4.8 mL) was added.
The reaction mixture was stirred at room temperature for 44 h.
The resulting mixture was diluted with CH2Cl2 (10 mL) and
cooled to –23 °C. After adding NaBH4 (1.64 g, 43.3 mmol), cold
MeOH (8 mL) was gradually added to the solution, and the
mixture was stirred for 1 h at –23 °C. The reaction mixture was
quenched with water (8 mL) and extracted with EtOAc (3 × 30
mL). The combined organic layer was washed with sat. NH4Cl
aq. (2 × 30 mL), dried over Na2SO4, and the solvent was removed
in vacuo. The resulting yellow oil was purified by silica gel
column chromatography using hexane/EtOAc (7:3) as an eluent
to give (S)-3-(2,4-dimethoxyphenyl)-2-(4-methoxyphenyl)pro-
pan-1-ol (9) including inseparable 3-(2,4-dimethoxyphe-
nyl)propyl alcohol (8) as a pale yellow oil (630 mg, (S)-9/8 =
71:29 estimated by 1H NMR analysis).
© 2020. Thieme. All rights reserved. Synlett 2021, 32, 693–696