Asymmetric total synthesis of (+)-ovafolinins A and B

Article abstract of DOI:10.1039/c8cc03456g

(+)-Ovafolinins A and B are two homologous lignans containing unique polycyclic skeletons. Benefiting from a highly diastereoselective alkylation of (S)-Taniguchi lactone, a double Friedel-Crafts reaction, a global debenzylation and a Cu(OAc)₂-

Full text of DOI:10.1039/c8cc03456g

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DOI: 10.1039/C8CC03456G
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Asymmetric Total Synthesis of (+)-Ovafolinins A and B
Xianhe Fang,a Lei Shen, a Xiangdong Hu* a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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6
MeOH) for ovafolinin A, +52.0 (c = 0.26, MeOH) and +43.3 (c
= 0.12, MeOH)7 for ovafolinin B), the exploration convincingly
suggested that natural ovafolinins A and B were both isolated
in scalemic mixtures. Attracted by their architectural
complexity, we started our synthesis with the purpose to
devise a new, efficient, and asymmetric route to these lignans.
(+)-Ovafolinins A and B are two homologous lignans containing
unique polycyclic skeletons. Benefiting from
a
high
diastereoselective alkylation of (S)-Taniguchi lactone, a double
Friedel-Crafts reaction, a global debenzylation and a Cu(OAc)2-
enabled benzylic oxidative cyclization, we present herein an
efficient synthetic approach to (+)-ovafolinins A and B.
Based on our retrosynthetic analysis (Figure 1), (+)-
ovafolinin A (
from three building blocks: phenol
Taniguchi lactone ). The diastereoselective alkylation
between and will be a feasible strategy to set up initially
two stereogenic centers of and . For introduction of the
1
) and (+)-ovafolinin B (
2
5
) could be constructed
Lignans are a large family of natural products widely existing in
plants and our food sources, such as wheat, soybeans, broccoli
and strawberry.1 Many important biological properties
including anticancer,2 antiviral,3 antioxidant activities4 and
alleviating menopausal symptoms, reducing the risk of
cardiovascular disease5 have been disclosed from biological
evaluations of this family. In 2010, ovafolinin A, ovafolinin B
and other three lignans were discovered during Yun and
coworkers’ explorations on Lyonia ovalifolia var. elliptica, a
deciduous tree growing in China and Japan.6 Ovafolinin B was
also found in Sinocalamus affinis (Rendle) McClure (Poaceae),7
a widely cultivated traditional Chinese medicine named “Ci Zhu
Li” and applied in treatments for various diseases including
cough and phlegm in China.8 Structurally, ovafolinin A has a
particular polycyclic skeleton containing an aryl tetralin unit
, bromide and (S)-
8
(
9
9
8
1
2
top-right aromatic ring and formation of the central six-
membered ring, a double Friedel-Crafts reaction process
between
Friedel-Crafts hydroxyalkylation of
six-membered ring first. Subsequently, intermediate
formed from a diastereoselectively intermolecular Friedel-
Crafts alkylation with . As a related precedent, Takayama and
5
and
6
was originally proposed. An intramolecular
could furnish the central
could be
6
4
5
coworkers reported a gentle construction of complex bridged
ring frames through a double Friedel-Crafts reaction between
acetal and two different aromatic rings.11 Regarding the
construction of the seven-membered benzoxepin bridged-ring
with
a tetrahydrofuran motif and a seven-membered
unit, we imagined that a dehydration cyclization in
a reasonable solution. Three benzyl protecting groups were
designed in for the convenience of synthesis. In light of the
close structural relationship of and and their simultaneous
generation in synthesis of Barker and coworkers, we envisaged
that could be reached through benzylic oxidative
cyclization of
Our synthesis started with the preparation of bromide
4 could be
benzoxepin bridged-ring. Ovafolinin B possesses very similar
framework except the opening of the tetrahydrofuran ring.
The first asymmetric synthesis of (+)-ovafolinins A and B was
achieved by Barker and co-workers9 employing an acyl-Claisen
rearrangement developed in their laboratory.10 The unique
polycyclic skeleton was achieved through an interesting
cascade cyclization enabled by a bulky protecting group. As the
pioneering work, Barker and coworkers’ synthesis
demonstrated an expedient pathway to the unique skeleton of
(+)-ovafolinins A and B. Furthermore, based on optical rotation
comparisons between the synthetic compounds ( +154.8 (c =
0.16, MeOH) for (+)-ovafolinin A, +150.0 (c = 0.26, MeOH) for
3
1
2
1
a
2
.
8
(Scheme 1). The starting material was the commercially
available syringaldehyde (10). After the benzyl protection,
reduction and bromination,
yield. The diastereoselective alkylation of (S)-Taniguchi lactone
) is a reliable strategy to introduce two adjacent stereogenic
8 can be obtained in 66% overall
9
(+)-ovafolinin B) and the natural samples (-37.3 (c = 0.36,
(
9
centers with defined absolute and relative configurations in
synthesis of natural products.12 According to Kieseritzky’s
approach,13
9
can be prepared in enantiomerically pure form
over three steps. The alkylation process between and
successfully afforded in excellent stereoselectivity. The
a.Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of
Ministry of Education, College of Chemistry & Materials Science, Northwest
University, Xi’an 710127, China. Xiangdonghu@nwu.edu.cn
8
9
7
†
Electronic Supplementary Information (ESI) available: [details of any
treatment of 7 with excess amount of benzyl bromide under
basic conditions opened the lactone unit smoothly,14
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Figure 1. Our original retrosynthetic analysis of (+)-ovafolinins A and B
OMe
OH
OMe
OMe
OBn
OMe
OBn
dehydration
cyclization
O
H
O
H
OH
HO
H
O
global
debenzylation
HO
H
OMe
OMe
OMe
OMe
OMe
OMe
double Friedelꢀ
Crafts reaction
OMe
OMe
H
H
H
H
H
H
H
H
benzylic
oxidative
cyclization
OH
OH
OBn
OMe
O
OBn
HO
BnO
BnO
OMe
OMe
OMe
3
(+)ꢀovafolinin A (1)
4
(+)ꢀovafolinin B (2)
stereoselective
alkylation
O
O
OMe
OBn
OMe
MeO
BnO
MeO
BnO
MeO
BnO
Br
+
OH
OBn
O
+
HO
O
OHC
OMe
OMe
OMe
8
5
6
(S)ꢀTaniguchi lactone (9)
7
generating ester 12 in 78% yield. After the subsequent observed in all cases.16 As a result, intermolecular Friedel-
reduction, product 13 was subjected to the vinyl oxidation. Crafts reaction seems not a feasible method to couple the
The product was hemiacetal 14 generated from the addition of fragment 5 with 14.
hydroxy to the aldehyde group. The originally proposed double
Friedel-Crafts reaction between 515 and 14 was then examined
Therefore, we moved our attention to introduce motif
the molecule before the construction of the carbon skeleton.
Starting again from 13, motif was readily connected with 13
through a Mitsunobu transformation (Scheme 2). Following
vinyl oxidation treatments established the aldehyde group in
16. Notably, during the construction of the unique polycyclic
5 into
with various Lewis acids. However, no consumption of
Scheme 1. Attempt on synthesis of
5 was
5
4
MeO
CHO
BnBr, K2CO3
MeO
BnO
CHO
1. NaBH4, MeOH, 0
skeletons of
1 and 2, Barker and coworkers explored cascade
HO
cyclization of compounds similar to 16. The bulky tert-
butyldiphenylsiyl protecting group on the bottom-left hydroxy
was found pivotal to enable the expected cyclization.
However, methoxymethyl protection will lead to
2.PBr3, CH2Cl2, 0
72% in 2 steps)
DMF, r.t.
(92%)
OMe
OMe
11
(
10
O
O
Br
O
Scheme 2. Total synthesis of (+)-ovafolinin B (2)
MeO
BnO
MeO
BnO
9
O
OMe
OBn
MeO
LiHMDS, THF
ꢀ78 (71%)
d.r. >95:5
O
H
BnO
MeO
OH
OMe
OMe
MeO
BnO
OH
OBn
8
7
OMe
OMe
5
H
O
DEAD, PPh3
PhMe/Et2O, r.t.
OBn
OMe
OMe
MeO
BnO
BnO
OBn
OBn
LiAlH4
THF, 0 (quant.)
KOH, BnBr
13
(94%)
15
PhMe, 65
(78%)
OMe
12
OMe
O
OBn
1. K2OsO4—2H2O, NMO
OMe
OMe
H
CHO
H
THF/H2O/tꢀBuOH, 35
TFA, CH2Cl2
r.t. (87%)
1. K2OsO4—2H2O, NMO
MeO
BnO
OH
2. NaIO4, acetone/H2O, r.t.
(77% in 2 steps)
THF/H2O/tꢀBuOH, 35
OBn
OBn
OMe
BnO
2. NaIO4, acetone/H2O, r.t.
(93% in 2 steps)
OMe
16
13
OMe
OMe
OBn
MeO
BnO
MeO
Lewis acids
OMe
O
H
OH
OH
HO
H
MeO
BnO
O
H
OBn
OMe
OMe
OBn
OMe
HO
H
OMe
OMe
Pd/C, H2
OMe
OMe
O
5
H
H
H
EtOH/EtOAc, r.t.
(quant.)
H
OH
OH
OMe OBn
OBn
OMe
HO
BnO
BnO
OMe
(+)ꢀovafolinin B (2)
14
4
3
2 | J. Name., 2012, 00, 1-3
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Scheme 3. Synthesis of (+)-ovafolinin A
global debenzylation and
a
Cu(OAc)2-enabled benzylic
oxidative cyclization. As the result, the synthesis (+)-ovafolinin
B has been completed in 11 linear steps and 23% total yield.
And the synthesis of (+)-ovafolinin A has been achieved in 12
linear steps and 21% total yield.
OMe
OH
OMe
O
H
O
H
OH
OMe
OMe
OMe
OMe
conditions
H
We are grateful for financial support from the National
Natural Science Foundation of China (21772153, 21642006 and
21372184), the Key Science and Technology Innovation Team
of Shaanxi Province (2017KCT-37) and the China Postdoctoral
Science Foundation (334100041).
H
H
H
OH
OH
O
HO
OMe
OMe
(+)ꢀovafolinin B (2)
(+)ꢀovafolinin A (1)
conditions
yields of 1
OMe
PhI(OAc)2, DCM, r.t.
28%
Conflicts of interest
O
H
OH
Ag2O, DCM, r.t.
DDQ, 1,4ꢀdioxane, r.t.
Cu(OAc)2, MeCN, 65
TBAF, air, THF, r.t.
air, neat, r.t.
55%
76%
91%
52%
< 5%
OMe
OMe
There are no conflicts to declare.
H
O
HO
OMe
Notes and references
17
1
(a) J. Chang, J. Reiner, J. Xie, Chem. Rev. 2005, 105, 4581-
4609. (b) R. B. Teponno, S. Kusari, M. Spiteller, Nat. Prod.
Rep. 2016, 33, 1044-1092.
decomposition products.9 In our case, protections of three
hydroxy groups in 16 are all benzyl groups. To our delight,
treatment of 16 with trifluoroacetic acid established
successfully the expected polycyclic skeleton through basically
2
3
4
T. F. Imbert, Biochimie 1998, 80, 207-222.
J. L. Charlton, J. Nat. Prod. 1998, 61, 1447-1451.
M. Fauré, E. Lissi, R. Torres, L. A. Videla, Phytochemistry
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P. C. Li, D. H. F. Mark, M. K. T. Poon, S. P. Ip, K. M. Ko,
Phytomedicine 1996, 3, 217-221.
a double Friedel-Crafts reaction process, affording
yield. The subsequent hydrogenation removed all three benzyl
protections and gave (+)-ovafolinin B ( ) in quantitative yield.
Noteworthy, the final de-protection process in Barker’s
synthesis led to formation of not only but also , both in
poor yields. In our synthesis, there was no formation of
observed during the debenzylation process of
3 in 87%
5
6
7
2
K. Kashima, K. Sano, Y. S. Yun, H. Ina, A. Kunugi, H. Inoue,
Chem. Pharm. Bull. 2010, 58, 191-194.
2
1
L. Xiong, C. Zhu, Y. Li, Y. Tian, S. Lin, S. Yuan, J. Hu, Q. Hou, N.
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H. H. Jia, X. D. Wu, Zhong Yao Cai. 1992, 15, 35-36.
S. J. Davidson, D. Barker, Angew. Chem. Int. Ed. 2017, 56,
9483-9486.
1
2.
8
9
With the successful development of an asymmetric route to
, we focused on the synthesis of . We envisaged that the
benzylic oxidation cyclization of could lead to the formation
of p-benzoquinone methide intermediate 17 And the
following conjugated addition from the vicinal hydroxy group
will furnish in the end. Therefore, was submitted to various
2
1
10 (a) C. E. Rye, D. Barker, J. Org. Chem. 2011, 76, 6636-6648.
(b) S. J. Davidson, D. Barker, Tetrahedron Lett. 2015, 56,
4549-4553. (c) C. E. Rye, D. Barker, Synlett 2009, 3315-3319.
11 T. Suzuki, M. Takamoto, T. Okamoto, H. Takayama, Chem.
Pharm. Bull. 1986, 34, 1888-1900.
12 (a) F. Ishibashi, E. Taniguchi, Chem. Lett. 1986, 15, 1771-
1774. (b) F. Ishibashi, E. Taniguchi, Bull. Chem. Soc. Jpn.
1988, 61, 4361-4366. (c) F. Ishibashi, E. Taniguchi,
2
.
1
2
conditions reported for formation of benzoquinone methide
intermediates. The employment of PhI(OAc)2 resulted in the
17
generation of
and DDQ19 could significantly improve the formation of
respectively. The best result was obtained from the treatment
with Cu(OAc)2,20 affording
in 91% yield. Barker’s condition
was also checked, which lead to the formation of in
moderate yield after the complete consumption of . Due to
our curiosity, the aerial oxidation of was checked under neat
can be formed after three
1
but in poor yield. The oxidation with Ag2O18
1,
Phytochemistry 1998, 49, 613-622. (d) G. Stork, D. Niu, A.
Fujimoto, E. R. Koft, J. M. Balkovec, J. R. Tata, G. R. J. Dake, J.
Am. Chem. Soc. 2001, 123, 3239-3242. (e) H. Miyaoka, Y.
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Ohshiro, E. Kawashima, H. Miyaoka, Chem. Eur. J. 2012, 18,
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1
1
2
2
condition. Only trace amount of
days.
1
13 F. Kieseritzky, Y. Wang, M. Axelson, Org. Process Res. Dev.
2014, 18, 643-645.
14 (a) J. Rath, S. Kinast, M. E. Maier, Org. Lett. 2005, 7, 3089-
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Lavielle, P. Karoyan, J. Org. Chem. 2004, 69, 7940-7948.
After the synthesis of
rotation properties of our synthetic (+)-ovafolinins A and B
were checked. The data (+159.5, (c = 0.36, MeOH) for and
+166.0 (c = 0.16, MeOH) for ) are close to those observed by
1 and 2 completed, the optical
1
2
Baker and coworkers, which supports Barker’s conclusion that
natural ovafolinins A and B were both isolated in scalemic
mixtures.
15 Compound
5
was prepared in three steps from
syringaldehyde. Please see the Supporting Information file
for experimental details.
16 For attempts on the originally proposed double Friedel-
Crafts reaction between
Supporting Information for detail.
17 B. Fang, X. Xie, C. Zhao, P. Jing, H. Li, Z. Wang, J. Gu, X. She, J.
Org. Chem. 2013, 78, 6338-6343.
18 (a) F. D. Ramdayal, D. J. Kiemle, R. T. LaLonde, J. Org. Chem.
1999, 64, 4607-4609. (b) K. C. Rice, W. C. Ripka, J. Reden, A.
Brossi, J. Org. Chem. 1980, 45, 601-607.
5 and 14, please see the
Conclusions
In summary, an asymmetric synthetic approach to (+)-
ovafolinins A and B has been developed. The entire synthetic
route features with a high stereoselective alkylation of (S)-
Taniguchi lactone, a double Friedel-Crafts reaction process, a
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19 T. Sengoku, S. Xu, K. Ogura, Y. Emori, K. Kitada, D. Uemura,
H. Arimoto, Angew. Chem. Int. Ed. 2014, 53, 4213-4216.
20 J.-A. Jiang, C. Chen, J.-G. Huang, H.-W. Liu, S. Cao, Y.-F. Ji,
Green Chem. 2014, 16, 1248-1254.
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