Stereocontrolled assembly of tetrasubstituted tetrahydrofurans: A concise synthesis of virgatusin

Article abstract of DOI:10.1021/ol051292h

(Chemical Equation Presented) The condensation of substituted allylsiloxanes with aldehydes leads to the highly stereoselective construction of 2,3,4,5-tetrasubstituted tetrahydrofurans. With electron-rich aryl and α,β-unsaturated aldehydes as substrates,

Full text of DOI:10.1021/ol051292h

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3685-3688
Stereocontrolled Assembly of
Tetrasubstituted Tetrahydrofurans: A
Concise Synthesis of Virgatusin
Tito Akindele,† Stephen P. Marsden,*,† and John G. Cumming‡
School of Chemistry, UniVersity of Leeds, Leeds LS2 9JT, U.K., and AstraZeneca,
Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
s.p.marsden@leeds.ac.uk
Received June 2, 2005
ABSTRACT
The condensation of substituted allylsiloxanes with aldehydes leads to the highly stereoselective construction of 2,3,4,5-tetrasubstituted
tetrahydrofurans. With electron-rich aryl and -unsaturated aldehydes as substrates, the stereochemical outcome at C5 can be dictated by
appropriate choice of Lewis acid. The reaction has been applied to a concise (nine step) synthesis of ( )-virgatusin (ent-1).
r,â
+
Among the diverse skeleta of the lignan family of natural
products, the 2,5-diaryl-3,4-di(alkoxymethyl)tetrahydrofuran
skeleton has been observed to occur in several natural
products. These have been isolated from a range of plant
sources, many of which are used in traditional herbal
medicines to treat a range of ailments. Representatives of
four of the six possible diastereoisomeric classes of these
compounds have been isolated. The cis,trans,trans and all-
trans isomers are the most populous, exemplified by virga-
tusin 11 and urinaligran 22 in the former class and icariol A2
3,3 neo-olivil 4,4 and taxumairin 55 in the latter (Figure 1).
Members of the cis,trans,cis6 and trans,cis,trans7 classes
are also known. Further, glycosylated derivatives of the
parent lignans have been isolated, either as O-arylglycosides8
or with the sugars appended to the hydroxymethyl substit-
uents.7,9
Given the diversity of these structures and the enormous
breadth of biological activity associated with lignan natural
products in general,10 these compounds are desirable targets
for synthesis. To our knowledge, synthetic approaches to just
one member of this class have been reported. Yoda synthe-
sized (-)-virgatusin 1 in 17 steps from dihydroxyacetone
† University of Leeds.
‡ AstraZeneca.
(1) Huang, Y. L.; Chen, C. C.; Hsu, F. L.; Chen, C. F. J. Nat. Prod.
1996, 59, 520.
(2) Chang, C. C.; Lien, Y. C.; Chen Liu, K. C. S.; Lee, S. S.
Phytochemistry 2003, 63, 825.
(3) Matsushita, H.; Miyase, T.; Ueno, A. Phytochemistry 1991, 30, 2025.
(4) Scho¨ttner, M.; Reiner, J.; Tayman, F. S. K. Phytochemistry 1997,
46, 1107.
(5) Shen, Y. C.; Chen, Y. C.; Lin, Y. M.; Kuo, Y. H. Phytochemistry
1997, 46, 1111.
Figure 1. Representative tetrasubstituted lignan natural products.
10.1021/ol051292h CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/22/2005

Scheme 1
Figure 2. Planned synthetic approach to tetrasubstituted lignans.
dimer,11 while more recently Yamauchi reported the synthesis
of both enantiomers of virgatusin in 15 steps from (R)-
benzyloxazolidinone.12 Both syntheses feature as a key step
a diastereoselective reduction of a cyclic hemiacetal to access
the fully substituted tetrahydrofuran. Stevenson has reported
stereoselective racemic routes to cis,trans,trans and all-trans-
2,5-diaryl-3,4-dimethyltetrahydrofuran natural products which
employ the corresponding hydroxymethyl derivatives as
precursors.13,14 The key transformation is an FeCl3-mediated
dimerization of substituted cinnamates and could in principle
be used to access racemic compounds of type 1-5. Pohma-
kotr described the synthesis of all-cis-2,5-diaryl-3,4-di-
(hydroxymethyl)tetrahydrofurans by reaction of dilithiated
R-aroylsuccinates with aldehydes,15 although this stereo-
chemical motif has not yet been found in natural materials.
We16 and others17 have reported the stereocontrolled
synthesis of tetrahydrofurans by condensation of metathesis-
derived cyclic allylsiloxanes with aldehydes or acetals. The
substitution patterns accessed so far have primarily been
2,3,5-16a,17 and 2,3,4-trisubstituted,16b but Cossy reported two
examples of the synthesis of 2,3,4,5-tetrasubstituted products,
utilizing an allylsiloxane derived from crotonylation of an
aldehyde.17 We felt that the method could provide rapid
access to target structures of type 1-5 if more highly
functionalized, enantiomerically enriched precursor allylsil-
oxanes of type 6 were utilized (Figure 2). The C3 carboxyl
substituent and C4 ethenyl group of the resulting tetrahy-
drofuran 7 serve as latent hydroxyalkyl groups, which can
be unmasked simultaneously or sequentially as required,
allowing access to the nonsymmetrically substituted natural
products such as 5. We now report the attainment of these
goals, including the ability to tune the C5-stereochemistry
by judicious choice of Lewis acid and the application of the
method in the shortest synthesis to date of virgatusin 1.
The requisite allylsiloxanes of type 6 have previously been
prepared by Taylor and co-workers,18 using a deconjugative
aldol reaction of a crotonyl oxazolidinone, followed by
silylation of the aldol adduct with allylchlorodimethylsilane
and ring-closing olefin metathesis. Application of this
procedure to benzyloxazolidinone 8 with dihydrocinnamal-
dehyde and veratraldehyde gave the allylsiloxanes 9 and 10,
respectively, in excellent yield over the three steps (Scheme
1). These building blocks contain two of the asymmetric
centers present in the tetrahydrofuran targets, and the relative
stereochemistry corresponds to the establishment of a 2,3-
trans relationship in the tetrahydrofuran.
With these materials in hand, we then commenced an
examination of their condensation reactions with a range of
aldehydes. Initially, our efforts focused on the alkyl-
substituted siloxane 9 under the standard conditions we had
previously developed, namely the use of boron trifluoride
etherate as Lewis acid, commencing the reaction at -78 °C
and allowing the mixture to warm to room temperature.
Under these conditions, we were delighted to find that the
reaction worked with a range of aldehyde substrates, and
the results are outlined in Table 1.
Condensation with aliphatic aldehydes gave good to
excellent yields of the corresponding adducts 11a/12a as a
single diastereoisomer (entries 1 and 2). This was assigned
the given stereochemistry on the basis of NOE studies on
11a. Reaction with benzaldehyde for 23 h gave a 65% yield
of a mixture of two diastereoisomers 13a and 13b. Attempts
to achieve higher yields by prolonged reaction times at room
temperature (entry 4) or at reflux (entry 5) did indeed lead
to slightly higher yields but at the expense of diastereose-
lectivity: reduced selectivity in favor of 13a was seen, and
a third diastereoisomer 13c could now be detected in the 1H
NMR spectrum. Reaction with piperonal (entry 6) gave a
91:9 mixture of products, with the all-trans isomer 14b now
dominating over 14a. This stereochemical assignment was
made on the basis of the observed upfield chemical shift of
(6) Yesilada, E.; Taninaka, H.; Takaishi, Y.; Honda, G.; Sezik, E.;
Momota, H.; Ohmoto, Y.; Taki, T. Cytokine 2001, 13, 359.
(7) Kanchanapoom, T.; Salah Kamel, M.; Kasai, R.; Yamasaki, K.;
Picheansoonthon, C.; Hiraga, Y. Phytochemistry 2001, 56, 369.
(8) Gongo´ra, L.; Ma´n˜ez, S.; Giner, R. M.; Recio, M. C.; Gray, A. I.;
R´ıos, J. L. Phytochemistry 2002, 59, 857.
(9) Sugiyama, M.; Nagayama, E.; Kikuchi, M. Phytochemistry 1993, 33,
1215.
(10) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75.
(11) (a) Yoda, H.; Mizutani, M.; Takabe, K. Tetrahedron Lett. 1999,
40, 4701. (b) Yoda, H.; Mizutani, M.; Takabe, K. Synlett 1998, 855.
(12) Yamauchi, S.; Okazaki, M.; Akiyama, K.; Sugahara, T.; Kishida,
T.; Kashiwagi, T. Org. Biomol. Chem. 2005, 3, 1670.
(13) Ahmed, R.; Schreiber, F. G.; Stevenson, R.; Williams, J. R.; Yeo,
H. M. Tetrahedron 1976, 32, 1339.
(14) Stevenson, R.; Williams, J. R. Tetrahedron 1977, 33, 285.
(15) Pohmakotr, M.; Issaree, A.; Sampaongoen, L.; Tuchinda, P.;
Reutrakul, V. Tetrahedron Lett. 2003, 44, 7937.
(16) (a) Cassidy, J. H.; Marsden, S. P.; Stemp, G. Synlett 1997, 1411.
(b) Miles, S. M.; Marsden, S. P.; Leatherbarrow, R. J.; Coates, W. J. J.
Org. Chem. 2004, 69, 6874. (c) Miles, S. M. Ph.D. Thesis, University of
London, 2004.
(18) Taylor, R. E.; Engelhardt, F. C.; Schmitt, M. J.; Yuan, H. J. Am.
Chem. Soc. 2001, 123, 2964.
(17) Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38, 7861.
3686
Org. Lett., Vol. 7, No. 17, 2005

Table 1. Condensation of Allylsiloxane 9 with Aldehydes
Table 2. Condensation of Allylsiloxanes 9 and 10 with
Aldehydes
R1
R2
product
yield
dr
entry
R2
product
yield (%)
dr (a/b/c)
entry
1
2
3
4a
5b
6
7
8c
9
BnCH2
BnOCH2
Ph
Ph
Ph
piperonyl
(E)-styryl
(E)-styryl
EtO2C
11a
12a
91
65
65
78
74
37
39
25
0
100:0:0
100:0:0
93:7:0
80:12:8
73:15:12
9:91:0
1
2
3
4
5
6
7
8
9
BnCH2
BnCH2
BnCH2
BnCH2
BnCH2
veratryl
veratryl
veratryl
veratryl
BnCH2
BnOCH2
Ph
piperonyl
(E)-styryl
BnCH2
Ph
11a
12a
13a
14a
15a,b
16a
17a
86
76
81
72
95
41
34
63
0
100:0
100:0
100:0
100:0
97:3
100:0
100:0
91:9
13a,b
13a-c
13a-c
14a,b
15a-c
15a,b
11:78:11
78:12:0
piperonyl
(E)-styryl
18a,b
a Extended reaction time at room temperature. b Reaction from -78 °C
to reflux. c Reaction held at -78 °C.
or at C2 by a â-elimination/Michael addition pathway. Again,
exposure of diastereomerically pure 13a to boron trifluoride
etherate leads to the appearance of minor signals in the H
NMR due to 13c, supporting the notion that the latter is an
isomer of the former.
1
the C5-proton in 14b (4.75 ppm, cf. 5.22 ppm in 14a), which
correlates with trends seen in our previous studies16b and
presumably arises from anisotropic shielding by the C4-vinyl
group in 14b. A similar outcome was seen with cinnamal-
dehyde (entry 7) where isomer 15b was the dominant of three
isomeric products. Attempted reactions with the electron-
deficient aldehyde ethyl glyoxylate gave no product (entry
9), and likewise, the dimethyl acetals of methyl glyoxylate
and pyruvaldehyde failed to yield any tetrahydrofuran.
The stereochemical outcome of the reaction follows from
our previously proposed model,16 whereby cyclization through
a chairlike transition state leads to the formation of isomers
11-15a (Figure 3). With electron-donating unsaturated
aldehydes, subsequent Lewis acid mediated epimerization19
through a stabilized allylic or benzylic cation leads to the
more stable all-trans isomer 11-15b. In support of this
proposition, exposure of diastereomerically pure 14a (vide
infra) to boron trifluoride etherate returns predominantly 14b.
At this stage, we do not know the identity of the third
isomeric component 13/15c, but suspect that epimerisation
may be occurring at C3 by enolization of the carboxyl group,
We had previously shown that the epimerisation pathway
operates only at higher temperatures,16b and indeed carrying
out the reaction with cinnamaldehyde for a prolonged period
at -78 °C returned a 78:12 mixture of isomers 15a to 15b,
albeit in a reduced yield (entry 8). Using trimethylsilyl
trifluoromethanesulfonate as the activating agent16b,17 the
reactions proceed smoothly at -78 °C, allowing high
conversions under conditions where the isomerization is
minimized. The application of these conditions to the
reactions of siloxanes 9 and 10 was investigated, and the
results are outlined in Table 2.
We were pleased to find that the condensation reactions
of siloxane 9 were uniformly high yielding under these
conditions and further that a single isomer corresponding to
the kinetic product was formed in all cases except for reaction
with cinnamaldehyde, where 3% of the isomeric product was
observed. We then turned our attention to the more exacting
case of the veratraldehyde-derived siloxane 10. The reactions
here are complicated both by the potential for cleavage of
the labile benzylic C-O bond in the siloxane (or intermedi-
ates therefrom) during the reaction, and by the presence of
a second labilizing group which may cause fragmentation/
isomerization in the product tetrahydrofurans.
In the event, reaction of 10 with dihydrocinnamaldehyde
and benzaldehyde gave modest yields of single diastereo-
meric products 16/17a. More interestingly still, reaction with
piperonal gave the tetrahydrofuran skeleton with electron-
rich aryl groups at both the C2 and C5 positions in good
yield and as an inseparable 91:9 mixture of diastereomers
18a/b.
(19) For an example of Lewis acid-mediated isomerisation of lignan
skeleta, see: Aldous, D. J.; Dalencon, A. J.; Steel, P. G. J. Org. Chem.
2003, 68, 9159.
Figure 3. Rationale of stereochemical outcome.
Org. Lett., Vol. 7, No. 17, 2005
3687

Williamson etherification with iodomethane returned (+)-
1, as an inseparable ca. 3:1 mixture with its C5 epimer. The
1H NMR and 13C NMR data for the major component
matched that reported for (-)-1,1 and the optical rotation of
the mixture displayed an opposite sign and similar magnitude
to that for the natural compound. It should be noted that the
synthesis compares extremely favorably in terms of length
(9 steps from (S)-benzyloxazolidinone) with those reported
by Yoda11 and Yamauchi.12
Scheme 2
In summary, a concise route to the synthesis of enantio-
merically pure tetrasubstituted tetrahydrofurans has been
outlined. With electron-rich conjugated aldehydes, control
of the C5-stereochemistry is possible through appropriate
choice of Lewis acid. The potential of the chemistry has been
demonstrated through the shortest synthesis of virgatusin to
date, and further applications of the method are in hand.
Compound 18a contains the necessary aryl groups and
relative stereochemistry for a synthesis of the unnatural
antipode of the natural product virgatusin 1. We were able
to complete this synthesis according to the final steps in
Scheme 2.
Acknowledgment. We thank the EPSRC and Astra-
Zeneca for an Industrial CASE award (T.A.).
Chemoselective oxidative cleavage of the C4-olefin in the
presence of the electron-rich aromatics was achieved by
dihydroxylation/periodate cleavage to give a C4-aldehyde.
This was subsequently reduced with sodium borohydride,
with concomitant reductive cleavage of the oxazolidinone
auxiliary, to give diol 19 as a ca. 3:1 mixture of diastereo-
mers, the enrichment in the minor isomer possibly being a
result of partial chromatographic resolution. Finally a double
Supporting Information Available: Experimental details
for the cyclocondensation reactions and the synthesis of
1
virgatusin are provided, along with H NMR spectra of all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL051292H
3688
Org. Lett., Vol. 7, No. 17, 2005