Total synthesis and stereochemical confirmation of 2,5-diaryl-3,4- dimethyltetrahydrofuran lignans: (+)-Fragransin A2, (+)-galbelgin, (+)-talaumidin, (-)-saucernetin and (-)-verrucosin

Article abstract of DOI:10.1055/s-2007-968019

A new ring closure to tetrasubstituted tetrahydrofurans from the intramolecular attack of an OMOM ether onto a benzylic mesylate proceeds through a quinonoid intermediate or by direct S_N2 displacement. The synthesis of diastereomeric biological

Full text of DOI:10.1055/s-2007-968019

LETTER
475
Total Synthesis and Stereochemical Confirmation of 2,5-Diaryl-3,4-dimethyl-
tetrahydrofuran Lignans: (+)-Fragransin A2, (+)-Galbelgin, (+)-Talaumidin,
(–)-Saucernetin and (–)-Verrucosin
2
, 5-Diaryl-3,4
t
-dimeth
e
yl Tetrahyd
p
rofuran Lig
h
Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec, H3C 3J7, Canada
E-mail: stephen.hanessian@umontreal.ca
Received 25 October 2006
Lignans are biologically derived from two phenylpro-
Abstract: A new ring closure to tetrasubstituted tetrahydrofurans
panoid units by oxidative dimerization, and they may be
from the intramolecular attack of an OMOM ether onto a benzylic
found in either enantiomeric form in nature. Although
mesylate proceeds through a quinonoid intermediate or by direct
their biological role in plants is not clear, they may be in-
SN2 displacement. The synthesis of diastereomeric biologically ac-
tive natural lignans is described utilizing this general methodology. volved in specific defense mechanisms under hostile
stress. In spite of their relatively modest level of structural
complexity, lignans are endowed with a host of biological
activities. As such they are ideal ‘small molecule’ natural
products for the development of potential chemotherapeu-
tic agents. For example (+)-fragransin A2 and (–)-galbel-
gin are inhibitors of NO production,8 while (–)-talaumidin
exhibits neuroprotective activity in the rat.9
Key words: lignans, tetrahydrofurans, quinonoid intermediate,
cycloetherification, enantioselective synthesis
Among the multitude of natural products produced by
secondary plant metabolites are the lignans.1 The growing
interest in this class of substituted tetrahydrofurans stems
from their potent activities against a variety of therapeuti-
cally relevant areas such as cancer, infection, inflamma-
tion, immunosuppression and their unique antioxidant
properties.2
In most instances only relative configurations have been
determined and further studies have relied on spectro-
scopic and correlation data to assign absolute configura-
tions.3–7,10 Efforts in enantioselective synthesis of these
lignans have been sparse.11 Often, racemic (or meso) mix-
tures resulting from oxidative coupling of diaryl 1,4-ke-
tones have been obtained,12 and separated by chiral
HPLC.13 The first enantioselective synthesis of (–)-talau-
midin (3) was reported only recently.9
MeO
RO
OMe
OR
MeO
HO
OMe
OH
O
O
R = H, (+)-fragransin A2, 1
R = Me, (–)-galbelgin, 2
(+)-verrucosin, 4
We report herein a general strategy for the stereocon-
trolled total synthesis of a series of known lignans or their
enantiomers as illustrated in Figure 2. The strategy capi-
talizes on the utilization of a common intermediate, from
which different stereochemical variants can be obtained
by varying the nature of a directing p-substituent on one
of the aromatic moieties, in conjunction with the stereo-
chemistry of the benzylic ether group.
MeO
HO
MeO
MeO
OMe
OMe
O
O
O
O
(–)-talaumidin, 3
(+)-saucernetin, 5
Figure 1 Structures and proposed absolute configurations of repre-
sentative 2,5-diaryl-3,4-dimethyltetrahydrofurans (lignans).
Intermediate 6 is readily available in enantiomerically
pure form as recently reported in the total synthesis of
manassantin A, B and B1 (Scheme 1).14 Treatment with 4-
benzyloxy-3-methoxyphenylmagnesium bromide in the
presence of CeCl3 as an additive15 gave an epimeric mix-
ture of alcohols, which could be separated into major (8)
and minor (9) compounds as MOM ethers, after removal
of the TBS and allyl groups. Oxidation of the mixture of
alcohols 7a and 7b under Dess–Martin conditions to the
ketone, followed by reduction with NaBH4 in the presence
2,5-Diaryl-3,4-dimethyl-substituted tetrahydrofurans are
an important subclass of lignans, with several configura-
tionally distinct members, often varying in the nature of
the aromatic ether substituents. They are particularly dif-
ferent with regard to the relative orientations of substitu-
ents as illustrated in the proposed structures of fragransin
A2,3 galbelgin4 and talaumidin5 for one group (anti/anti/
anti), saucernetin6 (syn/anti/syn), and verrucosin3a,7 (anti/
anti/syn) for another group (Figure 1).
16
of CeCl3 gave the R-alcohol 7b as the major product
(90:10, Scheme 2). Protection of 7b as the MOM ether,
followed by de-O-silylation gave 10. Mesylation, resulted
in cyclization to the protected lignan 11 in 90% yield,
most likely proceeding through a quinonoid intermediate.
Deprotection of the allyl and benzyl ethers afforded (+)-
fragransin A2 (1),17 which upon O-methylation led to (+)-
SYNLETT 2007, No. 3, pp 0475–0479
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-968019; Art ID: S18006ST
© Georg Thieme Verlag Stuttgart · New York
1
5.
0
2.
2
0
0
7

476
S. Hanessian, G. J. Reddy
LETTER
OR
OR
OH
MeO
RO
MeO
OR
OR
O
OMOM
RO
2,3- and 4,5-anti/syn combinations
cycloetherification
enolate alkylation
CO2Me
OH
OH
O
MeO
CHO
MeO
RO
MeO
RO
H
RO
extension
conjugate addition
asymmetric cyano addition
Figure 2 Disconnective analysis.
CeCl3,
MeO
BnO
MgBr
MeO
OBn
OMe
OTBS
OTBS
MeO
CHO
*
OH
7a, S-OH
7b, R-OH
THF, 76%
dr 2.5:1
AllylO
6
AllylO
OBn
OH
MeO
major isomer (8)
OMe
1. MOMCl,
Hünig's base
2. TBAF, THF
55%
OMOM
HO
+
OBn
OMe
3. Pd(PPh3)4,
NaBH4, THF
OH
minor isomer (9)
21%
MeO
HO
OMOM
Scheme 1 Synthesis of compound 8 and 9.
galbelgin (2).18 The assigned structures and configura- to (+)-galbelgin (2; rather than to its enantiomer as origi-
tions were confirmed by a single crystal X-ray analysis of nally assumed,3 Scheme 1).
synthetic (+)-fragransin A2 (1). Although the optical rota-
tion of 1 is in accord with the reported value, the absolute
configuration should be revised. Thus, our synthetic se-
quence establishes the correct absolute configuration of
The synthesis of (+)-talaumidin was completed in the
same manner from the 3,4-methylenedioxyaryl intermedi-
ate 12, obtained from 6 as described in Scheme 1 and
Scheme 2. Intramolecular displacement of the mesylate
(+)-fragransin A2 (1) as shown in Scheme 2 and relates it
also took place in a highly face selective attack on a
OBn
OBn
OMe
OH
OTBS
1. MOMCl,
Hünig's base
OBn
OMe
MeO
OTBS
1. DMP oxidation
MeO
OMe
MeO
2. CeCl3, NaBH4
MeOH, CH2Cl2
*
OMOM
2. TBAF, THF
OH
AllylO
AllylO
10
OH
7b
80% (over two steps)
AllylO
67% (over two steps)
7a,b
dr 90:10
OBn
OBn
OMe
OMs
MeO
OMe
OBn
MeO
MeO
O
MsCl, Et3N
OMe
90%
OMOM
OMOM
11
AllylO
O
O
1. Pd (PPh3)4, NaBH4
THF, 81%
MeO
HO
OMe
MeO
MeO
OMe
OMe
O
K2CO3, Me2SO4
O
2. Pd(OH)2/C, H2
EtOAc, 87%
1
OH
acetone, reflux
80%
2
Ortep diagram of
(+)-fragransin A2
(+)-fragransin A2
(+)-galbelgin
Scheme 2 Total synthesis of (+)-fragransin A2 (1) and (+)-galbelgin (2). Revised absolute configuration of (+)-fragransin A2.
Synlett 2007, No. 3, 475–479 © Thieme Stuttgart · New York

LETTER
2,5-Diaryl-3,4-dimethyl Tetrahydrofuran Lignans
477
O
O
1. MsCl, NEt3
OH
MeO
HO
90%
O
O
MeO
O
2. Pd (PPh3)4,
NaBH4
THF, 84%
OMOM
3
AllylO
(+)-talaumidin
12
Scheme 3 Total synthesis of (+)-talaumidin (3).
quinonid intermediate to give, after allyl deprotection, mer in the original Grignard addition (Scheme 4). Again
(+)-talaumidin (3) in excellent overall yield (16 steps, mesylation led directly to the tetrahydrofuran 14 which
12.7% overall yield, Scheme 3).19
upon deprotection gave (–)-verrucosin (4).21 The intra-
molecular cyclization of 13 to 14 was less efficient (51%
yield compared to 90% for 10 to 11), although only one
diastereomer was formed. Presumably, the trajectory of
attack on the quinonoid oxonium ion intermediate in the
case of 11 (oxonium ion A), is more favorable compared
to that leading to 14 (oxonium ion B) as illustrated in
Figure 3.
The authors of the recent paper,9 describing the synthesis
of natural (–)-talaumidin, utilize Evans aldol chemistry20
to set up an anti-aldol intermediate, which is followed by
a series of functional group adjustments and extensions
that comprise three oxidations, a Tebbe olefination, and a
Brown hydroboration leading to a lactone intermediate,
before the second aryl group is introduced. Nevertheless,
(–)-talaumidin was obtained in 16 steps and 10.7% overall Applying the same strategy to a p-nitrobenzoyl sub-
yield.9
stituent, readily available from 8, resulted in the direct
formation of the syn/anti/syn-tetrahydrofuran 16 through
an SN2-type reaction (Scheme 4).
The synthesis of (–)-verrucosin (4) was initiated with the
epimeric benzylic alcohol 13, available as the major iso-
OBn
OH
Br
p-NBCl, Et3N
MeO
HO
K2CO3,
OMe
CH2Cl2, 94%
acetone, 75%
OMOM
OBn
8
OBn
OMe
OH
OH
MeO
MeO
O
O
OMe
OMOM
OMOM
OMOM
O
15
13
MsCl, Et3N
O2N
MsCl, Et3N
CH2Cl2
OBn
OMe
OMs
MeO
O
OBn
OMe
OMs
MeO
O
O
OMOM
O2N
41%
OBn
OMe
MeO
OMe
OBn
O
O
MeO
O
16
O
OMOM
1. LiOH, MeOH–THF–H2O
2. Pd(OH)2/C, H2, EtOAc
O2N
51%
77% (over two steps)
MeO
OMe
OBn
O
MeO
HO
OMe
O
17
AllylO
14
OH
1. Pd (PPh3)4, NaBH4, THF
2. Pd(OH)2/C, H2, EtOAc
72% (over two steps)
K2CO3, Me2SO4
acetone, reflux
80%
MeO
HO
OMe
MeO
MeO
OMe
OMe
O
O
4
OH
5
(–)-verrucosin
(–)-saucernetin
Scheme 4 Total synthesis of (–)-verrucosin (4) and (–)-saucernetin (5).
Synlett 2007, No. 3, 475–479 © Thieme Stuttgart · New York

478
S. Hanessian, G. J. Reddy
LETTER
(4) (a) Takaoka, D.; Watanabe, K.; Hiroi, M. Bull. Chem. Soc.
Jpn. 1976, 49, 3564. (b) Lopes, N. P.; Blumenthal, E. E. A.;
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Deprotection of the ester and benzyl ether groups gave 17
which was O-methylated to (–)-saucernetin (5).22 Our
synthesis confirms the proposed structure (Figure 1),
however, the reported6c sign of optical rotation should be
reversed.
O
O
(6) (a) Rao, K. V.; Alvarez, F. M. Tetrahedron Lett. 1983, 24,
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H
Me
Me
Ar
H
H
H
H
Me
Me
Ar
MOMO
MOMO
B
A
less favored (14)
favored (11)
Figure 3 Favored (A) and less favored (B) transition states of
quinonoid oxonium ions.
(8) Konishi, T.; Konoshima, T.; Daikonya, A.; Kitanaka, S.
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In conclusion, we have described a general method for the
intramolecular cyclization of suitably disposed and func-
tionally differentiated 1,4-benzylic alcohols as a 1,4-diar-
yl-2,4-dimethyl acyclic framework, to the corresponding
tetrasubstituted tetrahydrofurans. A p-O-allyl ether group
assists in the facile departure of a benzylic mesylate
through the formation of quinonoid oxonium ion interme-
diate which in turn is attacked in an intramolecular face
selective fashion by the ether oxygen of a MOM ether.
When an ester group (p-NB) replaces the allyl group, tet-
rahydrofuran formation proceeds in an SN2-type manner.
Thus, by selecting the aromatic substituents, and the con-
figuration of the OMOM-substituted benzylic carbon, it is
possible to access a diverse set of configurationally dis-
tinct 2,5-diaryl-3,4-dimethyl-substituted tetrahydrofuran
lignans of natural origins, as well as their enantiomers.
(11) (a) Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G. J.
Am. Chem. Soc. 2005, 127, 12808. (b) Jahn, U.; Rudakov,
D. Org. Lett. 2006, 8, 4481; and references cited therein.
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B.; Lewis, N. G. Org. Biomol. Chem. 2003, 1, 2307.
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1997, 38, 6573.
Acknowledgment
(17) Data of (+)-Fragransin A2 (1).
Mp 198–200 °C (Lit.3a 200–202 °C); [a]D +77.7 (c 1.0,
CHCl3) [Lit.3a +79.0 (c 0.84, CHCl3)]. IR (thin film): 3428,
2957, 2926, 1515, 1272, 1034 cm–1. 1H NMR (400 MHz,
CDCl3): d = 6.85–6.98 (m, 6 H), 5.58 (s, 2 H), 4.65 (d, 2 H,
J = 9.2 Hz), 3.94 (s, 6 H), 1.76–1.82 (m, 2 H), 1.06 (d, 6 H,
J = 6.0 Hz) ppm. 13C NMR (400 MHz, CDCl3): d = 146.2,
144.7, 134.0, 119.0, 113.6, 108.0, 88.0, 55.6, 50.6, 13.47
ppm. HRMS: m/z calcd for C20H25O5 [M + H]+: 345.1698;
found: 345.1696.
We thank NSERC for financial assistance, and Navjot Chahal for
assisting in the preparation of some intermediate compounds. We
also thank Michel Simard for X-ray crystal structure analysis.
References and Notes
(1) Ward, R. S. Nat. Prod. Rep. 1995, 12, 183; and earlier
reviews in this series.
(2) (a) Saleem, M.; Kim, H. J.; Ali, M. S.; Lee, Y. S. Nat. Prod.
Rep. 2005, 22, 696. See also: (b) Li, G.; Ju, H. K.; Chang, H.
W.; Jahng, Y.; Lee, S.-H.; Son, J.-K. Biol. Pharm. Bull.
2003, 26, 1039. (c) Lopes, N. P.; Kato, M. J.; Yoshida, M.
Phytochemistry 1999, 51, 29. (d) Kraft, C.; Jenett-Siems,
K.; Kohler, I.; Tofern-Reblin, B.; Siems, K.; Bienzle, U.;
Eich, E. Phytochemistry 2002, 60, 167. (e) Zhai, H.; Inoue,
T.; Moriyama, M.; Esumi, T.; Mitsumoto, Y.; Fukuyama, Y.
Biol. Pharm. Bull. 2005, 28, 289. (f) Zhai, H.; Nakatsukasa,
M.; Mitsumoto, Y.; Fukuyama, Y. Planta Med. 2004, 70,
598.
(18) Data of (+)-Galbelgin (2).
Mp 140–142 °C (Lit.4c 141–142 °C); [a]D +83.4 (c 0.47,
CHCl3) [Lit.4c –85.1 (c 0.047, CHCl3) for (–)-galbelgin]. IR
(thin film): 2957, 2929, 1515, 1263, 1028 cm–1. 1H NMR
(400 MHz, CDCl3): d = 6.84–7.01 (m, 6 H), 4.68 (d, 2 H,
J = 9.2 Hz), 3.93 (s, 6 H), 3.90 (s, 6 H), 1.78–1.87 (m, 2 H),
1.07 (d, 6 H, J = 5.6 Hz) ppm. 13C NMR (400 MHz, CDCl3):
d = 148.6, 148.0, 134.5, 118.2, 110.4, 108.7, 88.0, 55.54,
55.52, 50.6, 13.5 ppm. HRMS: m/z calcd for C22H29O5 [M +
H]+: 373.2009; found: 373.2014.
(19) Data of (+)-Talaumidin (3).
(3) (a) Hattori, M.; Hada, S.; Kawata, Y.; Tezuka, Y.; Kikuchi,
T.; Namba, T. Chem. Pharm. Bull. 1987, 35, 3315.
(b) Kasahara, H.; Miyazawa, M.; Kameoka, H.
Phytochemistry 1996, 43, 111.
Colorless oil; [a]D +76.0 (c 0.5, CHCl3) [Lit.9 –81.8 (c 0.43,
CHCl3) for (–)-talaumidin]. 1H NMR (400 MHz, CDCl3):
d = 6.77–6.97 (m, 6 H), 5.96 (s, 2 H), 5.57 (br s, 1 H), 4.63
(d, 2 H, J = 8.8 Hz), 3.93 (s, 6 H), 1.74–1.82 (m, 2 H), 1.05
Synlett 2007, No. 3, 475–479 © Thieme Stuttgart · New York

LETTER
(d, 3 H, J = 5.6 Hz), 1.04 (d, 3 H, J = 6.0 Hz) ppm. 13C NMR
(400 MHz, CDCl3): d = 147.4, 146.6, 146.2, 144.7, 136.2,
133.7, 119.3, 119.0, 113.6, 108.1, 107.6, 106.2, 100.6, 88.1,
87.8, 55.6, 50.8, 50.5, 13.45, 13.43 ppm. HRMS: m/z calcd
for C20H23O5 [M + H]+: 343.1540; found: 343.1553.
(20) Evans, D. A.; Rieger, D. L.; Biodeau, M. T.; Urpi, F. J. Am.
Chem. Soc. 1991, 113, 1047.
2,5-Diaryl-3,4-dimethyl Tetrahydrofuran Lignans
479
H, J = 6.5 Hz), 0.68 (d, 3 H, J = 7.0 Hz) ppm. 13C NMR (100
MHz, CDCl3): d = 146.1, 145.8, 144.8, 144.2, 132.9, 132.4,
119.5, 118.9, 113.8, 113.5, 109.4, 109.3, 87.0, 82.8, 55.50,
55.46, 47.3, 45.6, 14.6, 14.5 ppm. HRMS: m/z calcd for
C20H25O5 [M + H]+: 345.1698; found: 345.1693.
(22) Data of (–)-Saucernetin (5).
Mp 77–79 °C (Lit.6c 78–80 °C); [a]D –44.2 (c 0.5, CHCl3)
[lit.6c +48.1 (c 0.5, CHCl3)]. IR (thin film): 2957, 2926,
1515, 1272, 1033 cm–1. 1H NMR (400 MHz, CDCl3): d =
6.85–6.90 (m, 6 H), 5.47 (d, 2 H, J = 6.0 Hz), 3.92 (s, 6 H),
3.90 (s, 6 H), 2.25–2.32 (m, 2 H), 0.71 (d, 6 H, J = 6.4 Hz).
13C NMR (400 MHz, CDCl3): d = 148.2, 147.5, 133.6, 118.0,
110.3, 109.1, 83.1, 55.5, 43.7, 14.4 ppm. HRMS: m/z calcd
for C22H29O5 [M + H]+: 373.2009; found: 373.2014.
(21) Data of (–)-Verrucosin (4).
Colorless oil; [a]D –16.14 (c 0.96, CHCl3) [Lit.3a +14.8 (c
1.38, CHCl3) for (+)-verrucosin]. IR (thin film): 3435, 2937,
2963, 1510, 1266, 1033 cm–1. 1H NMR (400 MHz, CDCl3):
d = 6.81–7.07 (m, 6 H), 5.62 (s, 1 H), 5.56 (s, 1 H), 5.14 (d,
1 H, J = 8.6 Hz), 4.42 (d, 1 H, J = 9.3 Hz), 3.94 (s, 3 H), 3.88
(s, 3 H), 2.19–2.31 (m, 1 H), 1.76–1.86 (m, 1 H), 1.08 (d, 3
Synlett 2007, No. 3, 475–479 © Thieme Stuttgart · New York