Stereoselective synthesis of tetrahydrofuran lignans via BF 3·OEt2-promoted reductive deoxygenation/ epimerization of cyclic hemiketal: Synthesis of (-)-odoratisol C, (-)-futokadsurin A, (-)-veraguensin, (+)-fragransin A2, (+)-galbel

Article abstract of DOI:10.1021/ol7016388

A versatile route to the synthesis of 2,5-diaryl-3,4- dimethyltetrahydrofuran lignans, (-)-odoratisol C. (1), (-)-futokadsurin A (2), (-)-veraguensln (3), (+)-fragransin A₂ (4), (+)-galbelgin (5), and (+)-talaumidin (6), is described. Central t

Full text of DOI:10.1021/ol7016388

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3965-3968
Stereoselective Synthesis of
Tetrahydrofuran Lignans via
BF3
Deoxygenation/Epimerization of Cyclic
Hemiketal: Synthesis of ( )-Odoratisol
C, ( )-Futokadsurin A, ( )-Veraguensin,
)-Galbelgin, and
‚OEt2-Promoted Reductive
−
−
−
(
(
+
+
)-Fragransin A2, (
)-Talaumidin
+
Hyoungsu Kim, Ceshea M. Wooten, Yongho Park, and Jiyong Hong*
Department of Chemistry, Duke UniVersity, Durham, North Carolina 27708
jiyong.hong@duke.edu
Received July 12, 2007
ABSTRACT
A versatile route to the synthesis of 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans, (
(3), ( )-fragransin A2 (4), ( )-galbelgin (5), and ( )-talaumidin (6), is described. Central to the synthesis of the lignans is BF3
deoxygenation/epimerization of the hemiketal 9a followed by stereoselective reduction of the oxocarbenium ion intermediates 8a,b.
−)-odoratisol C (1), (−)-futokadsurin A (2), (−)-veraguensin
+
+
+
‚OEt2-promoted
Lignans and neolignans are a class of secondary plant
metabolites produced by oxidative dimerization of two
phenylpropane (C6-C3) units, which are formed biogeneti-
cally through the shikimate pathway.1 Although their mo-
lecular backbone consists of only two phenylpropane units,
lignans show an enormous structural diversity. Lignans
possess significant pharmacological activities, including
antitumor, anti-inflammatory, immunosuppressive, cardio-
vascular, neuroprotective, neurotrophic, antioxidant, and
antiviral actions.2 There is a growing interest in lignans and
their synthetic derivatives due to applications in cancer
chemotherapy and a variety of other pharmacological effects.
Among lignans and neolignans, 2,5-diaryl-3,4-dimethyltet-
rahydrofuran lignans have stimulated substantial synthetic
efforts due to their structural diversity and biological activity.3
Herein, we report a versatile route to the synthesis of (-)-
odoratisol C (1),4 (-)-futokadsurin A (2),5 (-)-veraguensin
(3),6 (+)-fragransin A2 (4),7 (+)-galbelgin (5),8 and (+)-
(2) Saleem, M.; Kim, H. J.; Ali, M. S.; Lee, Y. S. Nat. Prod. Rep. 2005,
22, 696.
(3) (a) Hanessian, S.; Reddy, G. J. Synlett. 2007, 475. (b) Hanessian, S.;
Reddy, G. J.; Chahal, N. Org. Lett. 2006, 8, 5477. (c) Esumi, T.; Hojyo,
D.; Zhai, H.; Fukuyama, Y. Tetrahedron Lett. 2006, 47, 3979. (d) Jahn,
U.; Rudakov, D. Org. Lett. 2006, 8, 4481 and references cited therein.
(4) Giang, P. M.; Son, P. T.; Matsunami, K.; Otsuka, H. Chem. Pharm.
Bull. 2006, 54, 380.
(1) (a) Whiting, D. A. Nat. Prod. Rep. 1990, 7, 349. (b) Ward, R. S.
Nat. Prod. Rep. 1999, 16, 75 and references cited therein.
(5) Konishi, T.; Konoshima, T.; Daikonya, A.; Kitanaka, S. Chem. Pharm.
Bull. 2005, 53, 121.
10.1021/ol7016388 CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/01/2007

nucleophilic addition of an aryllithium reagent to 10 followed
by stereoselective reduction of the oxocarbenium ion inter-
mediate 8a formed from BF3‚OEt2-promoted deoxygenation
of the cyclic hemiketal 9a. We anticipated a hydride to be
added to 8a from the inside face of the envelope conformer
to stereoselectively provide the 2,3-cis-3,4-trans-4,5-trans-
tetrahydrofuran 7a for the synthesis of (-)-odoratisol C (1),
(-)-futokadsurin A (2), and (-)-veraguensin (3). In addition,
we expected that BF3‚OEt2-promoted epimerization of the
hemiketal 9a followed by reductive deoxygenation to produce
7b would complete the synthesis of (+)-fragransin A2 (4)
and (+)-galbelgin (5).
Scheme 2. Synthesis of
3,4-Dimethyl-5-aryldihydrofuran-2(3H)-one (10)
Figure 1. 2,5-Diaryl-3,4-dimethyltetrahydrofuran lignans.
talaumidin (6)9 (Figure 1) via BF3‚OEt2-promoted deoxy-
genation/epimerization of the hemiketal 9a followed by
stereoselective reduction of the oxocarbenium ion intermedi-
ates 8a,b.
Scheme 1. Retrosynthetic Analysis
As outlined in Scheme 2, the synthesis of 3,4-dimethyl-
5-aryldihydrofuran-2(3H)-one (10) began with the highly
stereoselective Evans asymmetric syn-adol reaction.10 Com-
mercially available 4-benzyloxy-3-methoxybenzaldehyde was
reacted with (4S)-4-(1-methylethyl)-3-(1-oxopropyl)-2-ox-
azolidinone (11) in the presence of n-Bu2BOTf and Et3N to
provide the desired syn-adol adduct 12 in 88% yield as a
single diastereomer. Protection of 12 with TBSCl (91%)
followed by reduction of 13 with NaBH4 provided the
corresponding alcohol 14 (88%). Protection of 14 with MsCl
and subsequent treatment with NaCN accomplished one-
carbon homologation to give 15 (89% for two steps). Single-
step conversion of 15 to the γ-lactone 16 was achieved by
treatment with NaOH in refluxing THF/MeOH/H2O followed
by acidic workup with HCl in Et2O (70%). Stereocontrolled
R-methylation of the γ-lactone 16 under conventional
conditions (LHMDS, MeI) exclusively produced 3,4-di-
methyl-5-aryldihydrofuran-2(3H)-one (10) in 92% yield.
Scheme 1 describes our approach to the synthesis of
tetrahydrofuran lignans (1-5) via 3,4-dimethyl-5-aryldihy-
drofuran-2(3H)-one (10), which could be constructed by
employing the highly stereoselective Evans asymmetric syn-
aldol reaction of (4S)-4-(1-methylethyl)-3-(1-oxopropyl)-2-
oxazolidinone (11) with 4-benzyloxy-3-methoxybenzalde-
hyde. The strategy underlying our synthetic plan was to apply
(6) Crossley, N. S.; Djerassi, C. J. Chem. Soc. 1962, 1459.
(7) (a) Hattori, M.; Hada, S.; Kawata, Y.; Tezuka, Y.; Kikuchi, T.;
Namba, T. Chem. Pharm. Bull. 1987, 35, 3315. (b) Hanessian et al.
established the correct absolute configuration of (+)-fragransin A2; see ref
3a.
(9) Zhai, H.; Nakatsukasa, M.; Mitsumoto, Y.; Fukuyama, Y. Planta Med.
2004, 70, 598.
(8) (a) Takaoka, D.; Watanabe, K.; Hiroi, M. Bull. Chem. Soc. Jpn. 1976,
49, 3564. (b) Hanessian et al. confirmed the stereochemical assignment of
(+)-galbelgin; see ref 3a.
(10) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) For a similar Evans aldol strategy for the synthesis of a
stereoisomer of 14, see ref 3c.
3966
Org. Lett., Vol. 9, No. 20, 2007

Next, we converted 10 into the 2,3-cis-3,4-trans-4,5-trans-
tetrahydrofuran 7a (Scheme 3). Treatment of 10 with 4-tert-
Table 1. Stereoselectivity of the Reductive Deoxygenation
Reaction
Scheme 3. Reductive Deoxygenation of Cyclic Hemiketal 9a
ratio
(I:II:III)
entry substrate
conditions
1
2
3
9a
17
9a
BF3·OEt2, NaBH3CN, -78 °C, 30 min 10:1:0
BF3·OEt2, Et3SiH, -78 to -20 °C, 3 h 25:1:0
BF3·OEt2, -78 to -20 °C, 2 h
1:0.1:4
then NaBH3CN, -78 °C, 30 min
butyldimethylsilyloxy-3-methoxyphenyllithium gave a 4:1
anomeric mixture of the cyclic hemiketal 9a in 70% yield
(86% based on recovered starting material). We expected
that treatment of 9a with Et3SiH in the presence of BF3‚
OEt211 would preferentially provide the 2,3-cis-3,4-trans-4,5-
trans-tetrahydrofuran 7a through the addition of hydride from
the inside face of the envelope conformer (vide infra).
However, the reaction conditions for reductive deoxygenation
(BF3‚OEt2, Et3SiH, -78 to -20 °C, 9 h) gave a 1.3:1
diastereomeric mixture of 2,5-diaryl-3,4-dimethyltetrahy-
drofurans in poor yield (<20%). To our surprise, careful
the reaction proceeded to give a 10:1 diastereomeric mixture
of 9a-I and 9a-II (99%) without epimerization of the C2-
aryl group (entry 1). In the case of the electron-withdrawing
Bz protecting group on the C2-aryl substituent, the reductive
deoxygenation reaction of 1715 (BF3‚OEt2, Et3SiH, -78 to
-20 °C, 3 h) also proceeded without epimerization of the
C2-aryl group to give 17-I in excellent diastereoselectivity
(17-I:17-II ) 25:1, 62%) (entry 2). However, epimerization
of 9a, afforded by treatment with BF3‚OEt2 (-78 to -20
°C, 2 h), followed by reduction with NaBH3CN provided a
1:0.1:4 mixture of 9a-I, 9a-II, and 9a-III (96%) (entry 3).
Treatment of 9a with BF3‚OEt2 (-78 to -20 °C, 2 h) in
the absence of a reducing agent resulted in an equilibrium
between 9a and 9b (1:4 ratio) proving the observed BF3‚
OEt2-promoted epimerization of 9a (Scheme 4). The epimer-
ization of 9a might occur through a quinonoid oxonium ion
intermediate facilitated by an inductive effect of the electron-
donating Bn group on the C2-aryl substituent.3a,b,13 Further
study is required to prove the putative mechanism. The
preference for 9b in equilibrium can be explained by
unfavorable steric interaction between cis substituents in 9a.
To determine the stereochemical outcome of hydride reduc-
tion, we isolated and independently subjected 9a and 9b to
reductive deoxygenation conditions (BF3‚OEt2, NaBH3CN,
-78 °C, 30 min). Under the reaction conditions, 9a and 9b
provided 7a (7a:7c ) 10:1, 99%) and 7b (single diastere-
omer, 92%), respectively.16 The stereochemical outcome can
be explained by Woerpel’s recent studies.17 Due to unfavor-
able steric interactions of the incoming hydride with axially
oriented 3,4-dimethyl groups in conformation A, the hydride
adds to the sterically more favorable conformation B from
1
analysis of H NMR spectral data revealed that the major
diastereomer had the 2,3-trans-3,4-trans-4,5-trans-configu-
ration 7b and the minor diastereomer had the desired 2,3-
cis-3,4-trans-4,5-trans-configuration 7a, indicating that epimer-
ization of the C2-aryl group occurred under the reaction
conditions.12
The observed epimerization of 9a was rationalized on the
basis that Lewis acid activation of the hemiketal 9a by BF3‚
OEt2 combined with an inductive effect of the electron-
donating Bn group on the C2-aryl substituent effectively
competed with slow reduction of the oxocarbenium ion
intermediate 8a by Et3SiH.13 On the basis of this rationale,
we expected that either fast reduction of 8a or a change of
the electron-donating Bn group on the aryl substituent to an
electron-withdrawing group would prevent the epimerization
of the C2-aryl group.14
Table 1 summarizes the stereoselectivity of the reductive
deoxygenation reaction of 9a. When 9a was treated with BF3‚
OEt2 combined with NaBH3CN (a strong reducing agent),
(11) Yoda, H.; Mizutani, M.; Takabe, K. Heterocycles 1998, 48, 679.
(12) It is known that 2,5-diaryl-3,4-trans-dimethyltetrahydrofurans have
1
unique chemical shifts for H2, H3, H4, and H5 in H NMR depending on
their relative stereochemistry. Thus, we determined the relative stereo-
(15) 17 was prepared from 10 by Bn-deprotection, Bz-protection, and
ArLi-addition; see the Supporting Information for details.
chemistry of tetrahydrofurans 7a and 7b by comparison of chemical shifts
1
in H NMR with literature values; see refs 3-9.
(16) It is important to note that the cis,trans-hemiketal 9a and trans,trans-
hemiketal 9b are both configurationally stable under the reaction condition.
(17) (a) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc.
2003, 125, 14149. (b) Bear, T. J.; Shaw, J. T.; Woerpel, K. A. J. Org.
Chem. 2002, 67, 2056. (c) Larsen, C. H.; Riggway, B. H.; Shaw, J. T.;
Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 12208. (d) Shaw, J. T.;
Woerpel, K. A. Tetrahedron 1999, 55, 8747. (e) Shaw, J. T.; Woerpel, K.
A. J. Org. Chem. 1997, 62, 6706.
(13) For an example of Lewis acid-mediated fragmentation/isomerization
of furofurans, see: Aldous, D. J.; Dalencon, A. J.; Steel, P. G. J. Org.
Chem. 2003, 68, 9159.
(14) Hanessian et al. reported a method for the stereocontrolled synthesis
of 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans by modulating the nature
of a directing para substituent on one of the aryl groups; see refs 3a and
3b.
Org. Lett., Vol. 9, No. 20, 2007
3967

and Bn protecting groups in 7b gave (+)-fragransin A2 (4)
(88% for two steps) and methylation of 4 completed the
synthesis of (+)-galbelgin (5) (86%).
Scheme 4. BF3‚OEt2-Promoted Epimerization and Reductive
Deoxygenation
The epimerization of the C2-aryl group was also utilized
in the synthesis of (+)-talaumidin (6) (Scheme 6). The
Scheme 6. Synthesis of (+)-Talaumidin (6)
lactone 10 was converted to the methyl acetal 19 through
one-pot reduction (DIBALH) and acetalization in 93% yield.
As we expected, Friedel-Crafts-type arylation conditions
(BF3‚OEt2, CH2Cl2, -78 to -20 °C, 2 h)3c proceeded with
the epimerization at the C2 position of 19 to provide 2,3-
trans-3,4-trans-4,5-trans-tetrahydrofuran 20 as a single di-
astereomer (89%). Final deprotection of the Bn protecting
group in 20 completed the synthesis of (+)-talaumidin (6)
(93%).
the inside face of the envelope conformer (“inside attack”
model) to provide the desired 2,3-cis-3,4-trans-4,5-trans-
tetrahydrofuran 7a. Also, in the case of 9b, 2,3-trans-3,4-
trans-4,5-trans-tetrahydrofuran 7b was formed from com-
formation D via “inside attack” of the hydride.
With both 7a and 7b in hand, we proceeded to complete
the synthesis of tetrahydrofuran lignans 1-5 (Scheme 5).
In summary, we applied BF3‚OEt2-promoted deoxygen-
ation/epimerization of the cyclic hemiketal 9a and stereo-
selective reduction of the oxocarbenium ion intermediates
8a,b to the synthesis of 2,5-diaryl-3,4-dimethyltetrahydro-
furan lignans. Combination of BF3‚OEt2 with a strong
reducing agent (e.g., NaBH3CN) enabled the synthesis of
(-)-odoratisol C (1), (-)-futokadsurin A (2), and (-)-
veraguensin (3) without epimerization of the C2-aryl group,
whereas BF3‚OEt2-promoted epimerization of 9a or methyl
acetal 19 under the conditions of slow reduction (e.g., Et3-
SiH) combined with an electron-donating protecting group
(e.g., Bn) was explored for the synthesis of (+)-fragransin
A2 (4), (+)-galbelgin (5), and (+)-talaumidin (6). This
versatile synthetic strategy should be broadly applicable to
the efficient synthesis of a diverse set of bioactive 2,5-diaryl-
3,4-dimethyltetrahydrofuran lignans.
Scheme 5. Synthesis of Tetrahydrofuran Lignans 1-5
Acknowledgment. This work was supported by Duke
University, and H.K. gratefully acknowledges the Korea
Research Foundation Grant funded by the Korean Govern-
ment (MOEHRD) (KRF-2006-352-E00028) for a postdoc-
toral fellowship.
Deprotection of TBS and Bn groups under conventional
conditions converted 7a to (-)-odoratisol C (1) (88% for
two steps). One-pot TBS-deprotection/methylation of 7a
provided 18 (93%), and subsequent removal of the Bn
protecting group in 18 with H2/Pd-C afforded (-)-futokad-
surin A (2) (94%). Synthesis of (-)-veraguensin (3) was
achieved by methylation of 2 in 92% yield. Removal of TBS
Supporting Information Available: General experimen-
tal procedures including spectroscopic and analytical data
for compounds 1-7, 9, 10, and 12-20 along with copies of
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL7016388
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Org. Lett., Vol. 9, No. 20, 2007