Total syntheses of (+)-sesamin and (+)-sesaminol

Article abstract of DOI:10.1246/cl.140613

Total syntheses of (+)-sesamin (1a ) and (+)-sesaminol (1b), which are major components of sesame lignans derived from Sesamum indicum, were accomplished in a highly stereo-controlled manner. Key steps include an L-proline-catalyzed cross-a ldol reaction, which was accelerated with the aid of bifunctional urea 7, and the construction of a furofuran lignan skeleton through a quinomethide intermediate.

Full text of DOI:10.1246/cl.140613

CL-140613
Received: June 20, 2014 | Accepted: July 8, 2014 | Web Released: July 17, 2014
Total Syntheses of (+)-Sesamin and (+)-Sesaminol
Ryo Ishikawa, Naoto Yoshida, Yusuke Akao, Yusuke Kawabe, Makoto Inai,
Tomohiro Asakawa, Yoshitaka Hamashima,* and Toshiyuki Kan*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526
(E-mail: hamashima@u-shizuoka-ken.ac.jp, kant@u-shizuoka-ken.ac.jp)
Total syntheses of (+)-sesamin (1a) and (+)-sesaminol (1b),
provide the desired furofuran skeleton of 1a and 1b. Incorpo-
ration of the two different aromatic rings into the core skeleton
of 2a and 2b could be performed by stepwise aldol reactions:
these compounds could be derived from diastereoselective aldol
reaction of 3 with benzaldehyde derivatives 4a and 4b, obtained
by catalytic asymmetric aldol reaction of aldehyde 5 with
benzaldehyde derivative 6.
which are major components of sesame lignans derived from
Sesamum indicum, were accomplished in a highly stereo-
controlled manner. Key steps include an L-proline-catalyzed
cross-aldol reaction, which was accelerated with the aid of
bifunctional urea 7, and the construction of a furofuran lignan
skeleton through a quinomethide intermediate.
As shown in Scheme 2, the total syntheses of 1a and 1b
were commenced with a proline-catalyzed cross-aldol reaction9
between aliphatic aldehyde 510 and 3,4-dihydroxybenzaldehyde
The biologically active furofuran lignans (+)-sesamin (1a)
and (+)-sesaminol (1b) (Figure 1), isolated from sesame seeds,
have been reported to exhibit various biological activities,
including antitumor, antioxidant, antiviral, and antihypertensive
activity as well as inhibition of low-density lipoprotein
oxidation.1,2 Therefore, 1a and 1b and their derivatives are
expected to be useful as lead compounds for drug development.
Furthermore, there is a need for synthesis of probe molecules to
identify their target proteins, as well for analysis of the in vivo
kinetics of 1a and 1b.3 There are a few reports on the synthetic
study,4 and total syntheses of symmetric 1a.5 However, there is
no report on the synthesis of 1b, which possesses a hydroxy
group. Herein, we report an efficient and flexible total synthesis
of (+)-sesamin (1a) and (+)-sesaminol (1b).
During the course of our synthetic investigations of
polyphenols,6 we found that the electronic properties of the
phenol-protecting group can tune the reactivity at the benzylic
position. For example, an electron-rich protecting group stabil-
izes the benzylic cation,6c,6d while an electron-deficient func-
tionality enhances the reactivity of the carbonyl group and the
stability to oxidation.6d,6e Recently, we accomplished the total
synthesis of a hybrid neolignan natural product, hedyotol A,7
by using our original diastereoselective C-H insertion reaction
as a key step.8 Furthermore, in the course of the total synthesis,
we found that the stereoselective construction of an exo-exo-
type furofuran can be accomplished through the quinomethide
intermediate by acidic treatment of the benzyl alcohol. We
envisioned that this background would provide the basis for the
concise asymmetric total synthesis of 1a and 1b.
O
O
O
O
O
O
HO
HO
7
8
H
H
H
H
8'
7'
O
O
O
O
OH
OH
R
R = H: 2a
R
R = OPG: 2b
R = H: (+)-Sesamin (1a)
R = OH: (+)-Sesaminol (1b)
OPG
H
ONs
O
O
ONs
O
H
3
O
H
ONs
ONs
+
+
MeO
H
O
O
O
5
6
O
R
R = H: 4a
R = OPG: 4b
Scheme 1. Retrosyntheses of sesamin (1a) and sesaminol (1b).
O
N
N
N
H
H
O
O
O
O
OH
O
7 (5 mol%)
H
ONs
ONs
L-proline (20 mol%)
H
ONs
ONs
H
H
+
MeO
MeO
DMF
4 °C, 6 h
5
8
6
OH
OH
H
H
ONs
ONs
ONs
NaBH4
MeOH
AcOH
The heart of our synthetic plan for 1a and 1b is illustrated in
Scheme 1. According to our recent total synthesis of furofuran
lignin,7 acid treatment of tetraol 2a and 2b would readily
HO
O
MeO
toluene
ONs
70 °C
O
O
67% (3 steps)
dr = 10:1 (97% ee)
9
10
without 7 [63%, 74% ee (3 steps)]
Ar =
O
O
1) PhSH, Cs2CO3
CH3CN, 0 °C
(+)-Sesamin (1a)
OTBS
OTBS
TBSCl
H
H
O
O
O
ONs
ONs
O
imidazole
85%
O
O
O
O
H
H
DMF
90%
2) BrCH2Cl
Cs2CO3
O
O
(+)-Sesaminol (1b)
Ar
O
O
11
DMF, 110 °C
68%
12
Furofuran core
OH
Figure 1. Structures of sesamin (1a) and sesaminol (1b).
Scheme 2. Synthesis of lactone 12.
1572 | Chem. Lett. 2014, 43, 1572–1574 | doi:10.1246/cl.140613
© 2014 The Chemical Society of Japan

O
O
O
O
O
O
H
OTBS
OH
H
OTBS
OH
H
H
H
H
O
O
BnO
O
O
OTBS
OTBS
4a
LiHMDS
O
H
O
16
LiHMDS
H
Ca(BH4)2
EtOH
O
O
Ca(BH4)2
EtOH
O
O
O
O
O
O
BnO
THF, -78 °C
62% (dr =1.3:1)
THF, -78 °C
(dr = 1:1)
O
O
17
12
O
12
O
13
O
O
OTBS
OTBS
H
O
O
H
H
O
O
O
AcCl
AcCl
MeOH
O
O
HO
HO
HO
HO
O
MeOH
H2
OH
HC(OMe)3
Pd/C
O
HC(OMe)3
1b
H
H
H
OH
1a
OH
H
H
BnO
CH2Cl2
THF/MeOH
31% (4 steps)
CH2Cl2
69% (2 steps)
O
O
O
O
O
HO
O
OBn
O
14
O
O
18
15
19
Scheme 3. Completion of total synthesis of (+)-sesamin (1a).
Scheme 4. Completion of total synthesis of (+)-sesaminol (1b).
derivative 6.7 In this reaction, a significant enhancement of the
reactivity of benzaldehyde 6 was produced by the incorporation
of nitrobenzenesulfonate (-ONs) at the phenol group11 as an
electron-withdrawing group.12 Addition of bifunctional urea 713
greatly accelerated the aldol reaction. When 5 and 6 were reacted
in the presence of L-proline and 7, the desired aldol reaction
proceeded smoothly to provide 8, and the reaction was complete
within 6 h, while the reaction in the absence of 7 required 26 h to
achieve a similar chemical yield. Reducing the reaction time was
advantageous for maintaining the high enantiomeric excess.
Without isolation of the less-stable 8, chemoselective reduction
of the aldehyde by NaBH4 and treatment with AcOH provided
lactone 10 in 67% yield (three steps) in a highly enantioselective
manner (dr = 10:1, 97% ee). After protection of the secondary
alcohol of 10 with a TBS group and subsequent removal of
the Ns groups of 11, a key intermediate 12 was synthesized by
treatment of the resultant catechol with bromochloromethane
and Cs2CO3.
The second aromatic ring was incorporated by means of a
strong base-mediated aldol reaction of lactone 12 with aldehyde
4a (Scheme 3). Upon treatment of 12 and 4a with LiHMDS, the
alkylation reaction occurred from the less-hindered β-face of the
lactone ring to afford 13 in 62% yield. Although the stereo-
chemistry of the newly formed benzylic alcohol was in a 1.3:1
ratio, both diastereomers were converted to the same exo-exo
furofuran ring. After reduction of lactone 13 with Ca(BH4)2,14
treatment of 14 with anhydrous HCl, generated in situ from
AcCl and MeOH, promoted smooth construction of the
furofuran ring to provide (+)-sesamin (1a). Since a single
diastereomer was obtained, it is likely that this cyclization
reaction occurred through the biomimetic quinomethide inter-
mediate 15 to furnish 1a as a thermodynamically stable exo-exo
furofuran ring. Furthermore, trimethoxy orthoformate played an
important role in pushing this reaction forward by trapping the
H2O generated in the cyclization. All spectral data (1H NMR,
13C NMR, IR, and HRMS) of the synthetic 1a were in full
agreement with reported values.5
provided triol 18. Acidic cyclization of 18 proceeded smoothly
to give furofuran 19. Finally, removal of the benzyl group under
hydrogenolysis condition furnished (+)-sesaminol (1b). All
spectral data (1H NMR, 13C NMR, IR, and HRMS) of synthetic
1b were in full agreement with reported values.15
In conclusion, we have established an efficient and flexible
synthetic method for furofuran lignans such as 1a and 1b.
Our stereocontrolled synthesis features an L-proline-catalyzed
cross-aldol reaction of an aliphatic and aromatic aldehyde and
biomimetic construction of the exo-exo furofuran skeleton
through the quinomethide intermediate. Considering the mild-
ness of all the reaction conditions and the convergent nature
of the synthetic route, our synthetic strategy is, in principle,
suitable for the easy preparation of a furofuran library.17
Furthermore, an electron-rich aromatic ring would be beneficial
for the incorporation of a halogen atom, which can act as a
handle for the installation of a linker group by cross-coupling
reaction. Thus, the concise preparation of various probe
molecules should be possible.3a-3d Further synthetic studies
and biological investigations of other furofuran lignans, as well
as development of probe molecules are in progress.
This work was financially supported by the Uehara
Memorial Foundation (Y.H.), MEXT/JSPS KAKENHI Grant
Numbers 23390007 and 26860013, Grants-in-Aid for Scientific
Research on Priority Areas 12045232 and 24105530 from the
Ministry of Education, Culture, Sports, Science and Technology
(MEXT) of Japan, and a grant for Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology.
Supporting Information is available electronically on J-STAGE.
References and Notes
1
2
a) D. Prabhuraj, T. Shekshavali, I. J. Kuppast, T.
Veerashekar, Int. J. Innovations Pharm. Sci. 2013, 2,
PD/1. b) M. Sugano, J.-Y. Gu, K. Yamada, in Food Factors
for Cancer Prevention, ed. by H. Ohigashi, T. Osawa, J.
Terao, S. Watanabe, T. Yoshikawa, Springer, Tokyo, 1997,
pp. 245-248. doi:10.1007/978-4-431-67017-9_49.
a) M.-H. Kang, M. Naito, K. Sakai, K. Uchida, T. Osawa,
Life Sci. 1999, 66, 161. b) M.-H. Kang, H. Katsuzaki, T.
Osawa, Lipids 1998, 33, 1031. c) Y.-M. Chiung, H. Hayashi,
Having established the synthetic route to 1a, we thought that
this methodology should be applicable to the preparation of
numerous asymmetric furofuran derivatives. As an example, the
enantioselective synthesis of (+)-sesaminol (1b)15 was demon-
strated, as shown in Scheme 4. The LiHMDS-mediated addition
reaction of 12 and 1616 and subsequent reduction with Ca(BH4)2
Chem. Lett. 2014, 43, 1572–1574 | doi:10.1246/cl.140613
© 2014 The Chemical Society of Japan | 1573

H. Matsumoto, T. Otani, K.-I. Yoshida, M.-Y. Huang, R.-X.
Chen, J.-R. Liu, M. Nakayama, J. Antibiot. 1994, 47, 487.
d) S. Iwakami, J.-B. Wu, Y. Ebizuka, U. Sankawa, Chem.
Pharm. Bull. 1992, 40, 1196. e) S. Iwakami, Y. Ebizuka, U.
Sankawa, Heterocycles 1990, 30, 795. f) K. Ichikawa, T.
Kinoshita, S. Nishibe, U. Sankawa, Chem. Pharm. Bull.
1986, 34, 3514.
Chem. Commun. 1988, 189. m) A. Pelter, R. S. Ward, D. J.
Watson, I. R. Jack, J. Chem. Soc., Perkin Trans. 1 1982, 183.
n) A. Pelter, R. S. Ward, D. J. Watson, P. Collins, I. T. Kay,
J. Chem. Soc., Perkin Trans. 1 1982, 175. o) M. Beroza,
M. S. Schechter, J. Am. Chem. Soc. 1956, 78, 1242.
For a short review: a) T. Asakawa, Y. Hamashima, T. Kan,
Curr. Pharm. Des. 2013, 19, 6207. See also: b) T. Furuta, Y.
Hirooka, A. Abe, Y. Sugata, M. Ueda, K. Murakami, T.
Suzuki, K. Tanaka, T. Kan, Bioorg. Med. Chem. Lett. 2007,
17, 3095. c) Y. Hirooka, M. Nitta, T. Furuta, T. Kan, Synlett
2008, 3234. d) Y. Aihara, A. Yoshida, T. Furuta, T.
Wakimoto, T. Akizawa, M. Konishi, T. Kan, Bioorg. Med.
Chem. Lett. 2009, 19, 4171. e) Y. Kawabe, Y. Aihara, Y.
Hirose, A. Sakurada, A. Yoshida, M. Inai, T. Asakawa, Y.
Hamashima, T. Kan, Synlett 2013, 24, 479.
6
3
For our investigations in chemical biology, based on probe
synthesis: a) K. Ikeuchi, R. Fujii, S. Sugiyama, T. Asakawa,
M. Inai, Y. Hamashima, J.-H. Choi, T. Suzuki, H.
Kawagishi, T. Kan, Org. Biomol. Chem. 2014, 12, 3813.
b) A. Hiza, Y. Tsukaguchi, T. Ogawa, M. Inai, T. Asakawa,
Y. Hamashima, T. Kan, Heterocycles 2014, 88, 1371. c) S.
Sasaki, H. Suzuki, H. Ouchi, T. Asakawa, M. Inai, R. Sakai,
K. Shimamoto, Y. Hamashima, T. Kan, Org. Lett. 2014, 16,
564. d) A. Yoshida, Y. Hirooka, Y. Sugata, M. Nitta, T.
Manabe, S. Ido, K. Murakami, R. K. Saha, T. Suzuki, M.
Ohshima, A. Yoshida, K. Itoh, K. Shimizu, N. Oku, T.
Furuta, T. Asakawa, T. Wakimoto, T. Kan, Chem. Commun.
2011, 47, 1794. e) H. Fuwa, Y. Takahashi, Y. Konno, N.
Watanabe, H. Miyashita, M. Sasaki, H. Natsugari, T. Kan, T.
Fukuyama, T. Tomita, T. Iwatsubo, ACS Chem. Biol. 2007,
2, 408. f) T. Kan, Y. Kita, Y. Morohashi, Y. Tominari, S.
Hosoda, T. Tomita, H. Natsugari, T. Iwatsubo, T. Fukuyama,
Org. Lett. 2007, 9, 2055. g) Y. Morohashi, T. Kan, Y.
Tominari, H. Fuwa, Y. Okamura, N. Watanabe, C. Sato, H.
Natsugari, T. Fukuyama, T. Iwatsubo, T. Tomita, J. Biol.
Chem. 2006, 281, 14670. h) T. Kan, Y. Tominari, Y.
Morohashi, H. Natsugari, T. Tomita, T. Iwatsubo, T.
Fukuyama, Chem. Commun. 2003, 2244.
7
8
Y. Kawabe, R. Ishikawa, Y. Akao, A. Yoshida, M. Inai, T.
Asakawa, Y. Hamashima, T. Kan, Org. Lett. 2014, 16, 1976.
For the recent review of our C-H insertion: a) T. Kan,
J. Synth. Org. Chem., Jpn. 2014, 72, 171. See also recent
example: b) S. Matsumoto, T. Asakawa, Y. Hamashima, T.
Kan, Synlett 2012, 1082.
9
A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc.
2002, 124, 6798.
10 S. Hajra, A. K. Giri, J. Org. Chem. 2008, 73, 3935.
11 For reviews on Ns-chemistry: a) T. Kan, T. Fukuyama,
J. Synth. Org. Chem., Jpn. 2001, 59, 779. b) T. Kan, T.
Fukuyama, Chem. Commun. 2004, 353. See also employ-
ment for protecting group of phenol: refs 6d and 6e.
12 Although aldol reaction of benzaldehyde 4a and 5 would be
ideal, the aldol reaction itself did not proceed under the same
reaction conditions.
13 S. L. Poe, A. R. Bogdan, B. P. Mason, J. L. Steinbacher,
S. M. Opalka, D. T. McQuade, J. Org. Chem. 2009, 74, 1574.
14 a) N. Mori, H. Watanabe, T. Kitahara, Synthesis 2006, 400.
b) M. Matsui, M. Miyano, K. Tomita, Bull. Agric. Chem.
Soc. Jpn. 1956, 20, 139. c) J. Kollonitsch, O. Fuchs, V.
Gábor, Nature 1954, 173, 125.
15 a) K.-C. Jan, L. S. Hwang, C.-T. Ho, J. Agric. Food Chem.
2009, 57, 6101. b) K.-C. Jan, K.-L. Ku, Y.-H. Chu, L. S.
Hwang, C.-T. Ho, J. Agric. Food Chem. 2011, 59, 3078.
16 The aldol reaction with 16 was not affected by in the
presence of o-substitution of the benzaldehyde derivatives.
17 Our synthetic strategy was also applicable for readily
syntheses of (+)-demethoxyaschantin (1c) and (+)-5¤-hy-
droxymethylpiperitol (1d).
4
5
For reviews on the synthetic study of furofuran lignans:
a) J.-Y. Pan, S.-L. Chen, M.-H. Yang, J. Wu, J. Sinkkonen,
K. Zou, Nat. Prod. Rep. 2009, 26, 1251. b) H. Ohmizu, T.
Ogiku, T. Iwasaki, Heterocycles 2000, 52, 1399. c) R. S.
Ward, Nat. Prod. Rep. 1999, 16, 75.
a) B. Banerjee, S. C. Roy, Synthesis 2005, 2913. b) J.-C.
Kim, K.-H. Kim, J.-C. Jung, O.-S. Park, Tetrahedron:
Asymmetry 2006, 17, 3. c) D. J. Aldous, A. S. Batsanov,
D. S. Yufit, A. J. Dalençon, W. M. Dutton, P. G. Steel, Org.
Biomol. Chem. 2006, 4, 2912. d) N. Kise, A. Fujimoto, N.
Moriyama, N. Ueda, Tetrahedron: Asymmetry 2003, 14,
2495. e) S. C. Roy, K. K. Rana, C. Guin, J. Org. Chem.
2002, 67, 3242. f) R. C. D. Brown, C. J. R. Bataille, G.
Bruton, J. D. Hinks, N. A. Swain, J. Org. Chem. 2001, 66,
6719. g) K. K. Rana, C. Guin, S. C. Roy, Tetrahedron Lett.
2000, 41, 9337. h) H. M. Hull, R. G. Jones, D. W. Knight,
J. Chem. Soc., Perkin Trans. 1 1998, 1779. i) K. Samizu, K.
Ogasawara, Chem. Lett. 1995, 543. j) H. Suginome, K.
Orito, K. Yorita, M. Ishikawa, N. Shimoyama, T. Sasaki,
J. Org. Chem. 1995, 60, 3052. k) K. Orito, K. Yorita, H.
Suginome, Tetrahedron Lett. 1991, 32, 5999. l) S. Takano, T.
Ohkawa, S. Tamori, S. Satoh, K. Ogasawara, J. Chem. Soc.,
Ar =
MeO
O
(+)-demethoxyaschantin (1c)
O
O
MeO
MeO
O
H
H
(+)-5'-hydroxymethylpiperitol (1d)
Ar
MeO
OH
1574 | Chem. Lett. 2014, 43, 1572–1574 | doi:10.1246/cl.140613
© 2014 The Chemical Society of Japan