A short synthesis of (+)-bakuchiol

Article abstract of DOI:10.1055/s-0033-1338968

The concise enantioselective total synthesis of (+)-bakuchiol has been achieved using an asymmetric 1,4-addition to construct its all-carbon chiral quaternary center based on the induction of chirality by the (2′S)-2′-phenyloxazolidinone auxiliary, followed by a one-pot transformation under aldol reaction conditions. The synthesis was completed in four steps from (E)-geranic acid in an overall yield of 53%. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338968

LETTER
▌1845
lAetteSr hort Synthesis of (+)-Bakuchiol
A Short Synthesis of (+)-Bakuchiol
Tomoyuki Esumi,* Chihiro Yamamoto, Yoshiyasu Fukuyama
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 7708514, Japan
Fax +81(88)6553051; E-mail: esumi@ph.bunri-u.ac.jp
Received: 10.05.2013; Accepted after revision: 11.06.2013
antioselective total synthesis of 1 because of the difficul-
ties associated with constructing its chiral tetraalkylated
quaternary center in a stereoselective manner. Takano et
al.10 reported the first enantiocontrolled total synthesis of
Abstract: The concise enantioselective total synthesis of (+)-baku-
chiol has been achieved using an asymmetric 1,4-addition to con-
struct its all-carbon chiral quaternary center based on the induction
of chirality by the (2′S)-2′-phenyloxazolidinone auxiliary, followed
by a one-pot transformation under aldol reaction conditions. The (+)-bakuchiol (1) in 1990 in 11 steps from (S)-O-benzyl-
glycidol. Following on from this work, Asaoka et al.11 (16
synthesis was completed in four steps from (E)-geranic acid in an
overall yield of 53%.
steps, in 1999), Li et al.12 (10 steps, in 2008), Novikov et
al.13 (10 steps, in 2009) and Hoveyda et al.14 (3 steps, in
Key words: bakuchiol, asymmetric 1,4-addition reaction, asym-
metric aldol reaction, removal of oxazolidinone, decarboxylation,
all-carbon quaternary center
2010) have all succeeded in developing elegant enantiose-
lective total syntheses of (+)-1. In our previous paper,15
we reported the successful total synthesis of (+)-bakuchiol
(1) in 14 steps from but-3-yn-1-ol based on the asymmet-
(+)-Bakuchiol (1) is a phenolic isoprenoid with a chiral
tetraalkylated (all-carbon) quaternary center that was iso-
lated from the seeds of Psoralea corylifolia Linn. (San-
skrit: Bakuchi, Sungandha kantak; Hindi: Babchi) by Dev
et al.1,2 Its plane structure was elucidated in 19661,2 and
the absolute configuration of its quaternary center was de-
termined to be S in 19733 (Figure 1).
ric 1,4-addition reaction of (H2C=CH)2Cu(CN)Li2 to an
α,β-unsaturated carboxylic acid derivative equipped with
a chiral oxazolidinone auxiliary 2 for constructing the all-
carbon chiral quaternary center15 (Scheme 1).
3
O
O
steps
HO
TBSO
N
O
3
S
Ph
but-3-yn-1-ol
2
S
OH
O
O
10
steps
Cu(CN)Li2
2
(+)-bakuchiol (1)
TBSO
R
N
1
O
3
Et2O, –50 °C
Figure 1 Structure of (+)-bakuchiol (1)
Ph
3 92%, 3R/3S = 95:5
(+)-Bakuchiol (1), which was initially used as an antibiot-
ic against Staphylococcus aureus,2 has shown a broad
range of biological activities against a variety of different
targets, such as protein tyrosine phosphatase 1B (PTB1B)
inhibition,4 a caspase-3-dependent apoptosis-inducing ef-
fect,5 prevention of mitochondrial lipid peroxidation,6 in-
hibition of inducible nitric oxide synthase (i.e., iNOS and
NOS II) expression,7 and DNA polymerase and topoisom-
erase II inhibition.8 Thus, 1 has been recognized as an im-
portant lead compound for the development of new
medicines. Compound 1 has also become an attractive tar-
get for many synthetic chemists because of its biological
profile and simple intriguing structure. The first total syn-
thesis of (±)-1 was achieved by Carnduff and Miller9 with
a Claisen rearrangement being used as a key step in the
synthesis. In the 20 years following its isolation, however,
there were no reports in the literature concerning the en-
Scheme 1 Previous total synthesis of (+)-bakuchiol by our group
We recently found that the reaction of 3′ with an electron-
rich aromatic aldehyde such as p-methoxybenzaldehyde
led to the occurrence of a series of reactions, including an
aldol reaction followed by the removal of the oxazolidi-
none moiety through a lactonization/decarboxylation se-
O
O
SHMDS, THF
–78 °C, 30 min
TBDPSO
N
O
2
then
OHC
Ph
3'
OMe
TBDPSO
2
OMe
SYNLETT 2013, 24, 1845–1847
4
Advanced online publication: 26.07.2013
DOI: 10.1055/s-0033-1338968; Art ID: ST-2013-U0439-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 2 Sequential one-pot transformation (aldol/β-lactoniza-
tion/decarboxylation)

1846
T. Esumi et al.
LETTER
PivCl, Et3N, THF
–25 to –20 °C
O
Cu(CN)Li2
2
O
CO2H
O
N
then LiCl
O
Et2O, –50 °C
overnight
(E)-geranic acid
HN
Ph
O
S
5 100%
Ph
SHMDS, THF
–78 °C
O
O
MeMgI
1
87%
R
N
then
OHC
O
160 °C
10 min
Ph
6 78%, 3R/3S = 92:8
OMe
7 94%
OMe
overnight
Scheme 3 Total synthesis of (+)-bakuchiol
quence to afford (E)-arylalkene 4 in good yield16 (Scheme the synthesis of the various compounds including the chi-
2). This result prompted us to synthesize (+)-bakuchiol (1) ral tetraalkylated quaternary center adjacent to arylated
according to a more efficient route than those previously (E)-olefin.
reported in the literature. Herein, we report a short enan-
tioselective total synthesis of (+)-bakuchiol (1) using an
asymmetric 1,4-addition to an α,β-unsaturated carboxylic
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan (grant no. 23590035).
acid derivative equipped with a chiral oxazolidinone aux-
iliary followed by a sequential one-pot transformation (al-
dol/β-lactonization/decarboxylation) as the key steps.
Our current synthesis of (+)-bakuchiol (1) started from
(E)-geranic acid (Scheme 3). Thus, (E)-geranic acid was
treated with a mixture of pivaloyl chloride and triethyl-
amine in THF, followed by a mixture of (2′R)-2′-phenyl-
oxazolidinone in the presence of LiCl to give the 1,4-
addition precursor 5 in quantitative yield. Compound 5
was then subjected to an asymmetric 1,4-addition reaction
with (H2C=CH)2Cu(CN)Li2 in Et2O, according to the
method described in our previous report.15 The reaction
proceeded smoothly to afford the (R)-1,4-adduct 6 in good
yield with a diastereoselectivity of 92:8.17 The one-pot
transformation of 6 into O-methylbakuchiol (7) was then
investigated. Thus, the treatment of 6 with SHMDS in
THF at –78 °C followed by the addition of p-methoxy-
benzaldehyde led to the occurrence of a domino reaction
to give the desired O-methylbakuchiol (7) in excellent
yield. In addition, the (2′S)-2′-phenyloxazolidinone gen-
erated during this stage was readily recovered in a quanti-
tative manner by silica gel column chromatography.
Compound 7 was then demethylated by heating at 160 °C
in the presence of MeMgI9 to give (+)-bakuchiol (1) in
good yield. The spectral data (1H NMR, 13C NMR, IR, EI–
MS, [α]D)18 collected for the synthetic 1 were identical to
those of the natural product.
References and Notes
(1) Mehta, G.; Nayak, U. R.; Dev, S. Tetrahedron Lett. 1966,
4561.
(2) Mehta, G.; Nayak, U. R.; Dev, S. Tetrahedron 1973, 29,
1119.
(3) Rao, A. S. C. P.; Bhalla, V. K.; NaYak, U. K.; Dev, S.
Tetrahedron 1973, 29, 1127.
(4) Kim, Y.-C.; Oh, H.; Kim, B. S.; Kang, T.-H.; Ko, E.-K.;
Han, Y. M.; Kim, B. Y.; Ahn, J. S. Planta Med. 2005, 71, 87.
(5) Park, E.-J.; Zhao, Y.-Z.; Kim, Y.-C.; Sohn, D. H. Eur. J.
Pharmacol. 2007, 559, 115.
(6) Haraguchi, H.; Inoue, J.; Tamura, Y.; Mizutani, K. Planta
Med. 2000, 66, 569.
(7) Pae, L. C.; Sanceau, J.; Drapier, J.-C.; Wietzerbin, J. Int.
Immunopharmacol. 2001, 1, 1849.
(8) Sun, N. J.; Woo, S. H.; Cassady, J. M.; Snapka, R. M. J. Nat.
Prod. 1998, 61, 362.
(9) Carnduff, J.; Miller, J. A. Chem. Commun. 1967, 606.
(10) Takano, S.; Shimazaki, Y.; Ogasawara, K. Tetrahedron Lett.
1990, 31, 3325.
(11) Sakakiyama, S.; Yamamoto, K.; Asaoka, M. Nat. Prod. Lett.
1999, 14, 1.
(12) Du, X.-L.; Chen, H.-L.; Feng, H.-J.; Li, Y.-C. Helv. Chim.
Acta 2008, 91, 371.
(13) Bequette, J. P.; Jungong, C. S.; Novikov, A. V. Tetrahedron
Lett. 2009, 50, 6963.
(14) Gao, F.; McGrath, K. P.; Lee, Y.; Hoveyda, A. H. J. Am.
Chem. Soc. 2010, 132, 14315.
In conclusion, we have successfully achieved a short and
efficient enantioselective total synthesis of (+)-bakuchiol
(1) in four steps from (E)-geranic acid in an overall yield
of 64%. This achievement demonstrates that asymmetric
1,4-addition reaction followed by the domino reaction un-
der aldol reaction conditions is effectively applicable to
(15) Esumi, T.; Shimizu, H.; Kashiyama, A.; Sasaki, C.; Toyota,
M.; Fukuyama, Y. Tetrahedron Lett. 2008, 49, 6846.
(16) Esumi, T.; Yamamoto, C.; Tsugawa, Y.; Toyota, M.;
Asakawa, Y.; Fukuyama, Y. Org. Lett. 2013, 15, 1898.
(17) The ratio was determined by 1H NMR (600 MHz).
Synlett 2013, 24, 1845–1847
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Short Synthesis of (+)-Bakuchiol
1847
(18) Data for Synthetic (+)-Bakuchiol: [α]D20 +26.0 (c 0.45,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.4 Hz,
2 H), 6.77 (d, J = 8.4 Hz, 2 H), 6.25 (d, J = 16.4 Hz, 1 H),
6.10 (d, J = 16.4 Hz, 1 H), 5.88 (dd, J = 10.8, 17.2 Hz, 1 H),
5.10 (quint t, J = 1.6, 7.2 Hz, 1 H), 5.03 (dd, J = 1.6, 10.8 Hz,
1 H), 5.01 (dd, J = 1.6, 17.2 Hz, 1 H), 4.78 (br s, 1 H), 1.95
(dt, J = 7.2, 9.2 Hz, 2 H), 1.67 (d, J = 1.2 Hz, 3 H), 1.58 (d,
J = 0.8 Hz, 3 H), 1.49 (m, 2 H), 1.19 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 155.2, 146.5, 136.5, 131.9, 131.5, 127.9,
127.0, 125.4, 115.9, 112.5, 43.1, 41.9, 26.3, 23.9, 23.8, 18.2.
HRMS (EI): m/z [M]+ calcd for C18H24O: 256.1821; found:
256.1827.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1845–1847