A rapid total synthesis of (±)-sylvone

Article abstract of DOI:10.1055/s-2007-990926

We report a convergent and diastereoselective synthesis of (±)-sylvone that utilizes a diastereoselective [1,3] ring contraction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990926

126
LETTER
A Rapid Total Synthesis of ( )-Sylvone
Total
Synthesis
o
h
f
Sylvone ristopher G. Nasveschuk, Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Fax +1(970)4911801; E-mail: rovis@lamar.colostate.edu.
Received 31 August 2007
Sylvone (1) is a furofuran lignan isolated by Banerji and
co-workers from the petrol extracts of seeds derived from
piper sylvaticum.7 Although the bioactivity profile of 1 is
not known, other members of its class display a range of
activity including antitumor, antimitotic, and antiviral
characteristics.8 Interestingly, of this subclass of furofuran
lignans, only sesaminone has been synthesized. Gordon
and co-workers used a diastereoselective syn aldol to set
the relative stereochemistry of the tetrahydrofuran core
while Yoda and co-workers employed a diastereoselec-
tive Grignard aldehyde alkylation.9 We envisioned the
formation of the 2,3,4-trisubstituted tetrahydrofuran core
of sylvone by a ring contraction of a 1,3-dioxepin. This
strategy revolves around the use of cis-1,4-butene diol as
a lynchpin (Figure 1). The diol is functionalized with an
aldehyde to provide a symmetrical 1,3-dioxepin. The ole-
fin is subsequently desymmetrized by a Heck reaction,
which simultaneously adds a necessary aryl substituent
and activates the system towards [1,3] rearrangement
(Scheme 1).
Abstract: We report a convergent and diastereoselective synthesis
of ( )-sylvone that utilizes a diastereoselective [1,3] ring contrac-
tion.
Key words: ring contraction, [1,3] rearrangement, 1,3-dioxepin,
tetrahydrofuran, sylvone
Furofuran lignans are a large and diverse class of mole-
cules that possess a tetrahydrofuran core and ornamental
aromatic substitution. Typically isolated from plant mate-
rial, many of which are used in indigenous and traditional
herbal medicines, furofurans display broad biological ac-
tivity.1 New lignans continue to be isolated and have thus
compelled the community to develop new synthetic meth-
odology that provides access to the variety of different
substitution patterns possessed by these molecules.1,2 Of
currently existing strategies, there are few that provide di-
rect and efficient construction of 2,3,4-trisubstituted tet-
rahydrofurans.3 Perhaps the most elegant of these
approaches was reported by Marsden and co-workers in
which substituted tetrahydrofurans may be constructed by
condensation of an aldehyde and a [1,2]oxasilepine.4 As
part of a program to study [1,3] rearrangements,5 we have
developed a complementary approach to the 2,3,4-trisub-
stituted tetrahydrofuran framework via a diastereoselective
[1,3] ring contraction of 1,3-dioxepins.6 Herein we de-
scribe the successful implementation of this strategy in the
synthesis of furofuran lignan ( )-sylvone (1) (Figure 1).
The synthetic sequence commences with condensation of
cis-1,4-butenediol and veratraldehyde. An intermolecular
Heck reaction between 510 and 1,1-disubstituted alkene
611 proceeds in excellent diastereoselectivity and moder-
ate yield (Scheme 2). It was found that increasing the cat-
alyst loading or extending the reaction time does not
improve the yield.12
OMe
O
OMe
O
HO
HO
OMe
OMe
OMe
O
OMe
O
MeO
MeO
MeO
MeO
sylvone (1)
hernone (2)
OMe
OMe
OMe
O
O
HO
HO
O
O
O
O
O
O
O
O
nymphone (3)
sesaminone (4)
Figure 1 Furofuran lignans
SYNLETT 2008, No. 1, pp 0126–0128
x
x.
x
x.
2
0
0
7
Advanced online publication: 03.12.2007
DOI: 10.1055/s-2007-990926; Art ID: S06307ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Sylvone
127
R2
condensation
Heck coupling
HO
OH
+
O
O
O
O
O
R1
R1
R1
R2
ring contraction
O
O
R1
Scheme 1 Strategy
Ring contraction of key dioxepin 713 under our previously
reported conditions leads to complex mixtures of uniden-
tifiable products (Table 1, entry 1). It was hypothesized
that exposure to aqueous acid during workup facilitated
product decomposition. This pitfall was overcome by low
temperature quench of the Lewis acid with Et3N followed
by an aqueous NaHCO3 workup. Unfortunately, the TM-
SOTf–MeCN conditions produce the desired tetrahydro-
furan with modest diastereomeric ratio. Only two of the
four possible diastereomers are formed, where the major
diastereomer is the 2,3-cis/3,4-trans product and the mi-
nor diastereomer contains the 2,3-trans/3,4-cis relative
configuration (entry 2). Diastereoselectivity may be re-
stored by changing the solvent to EtCN, which allows ac-
cess to lower reaction temperatures (entry 3).14
Table 1 Optimization of Ring Contraction
O
TMSOTf (10 mol%)
solvent, temp
O
OMe
OMe
MeO
7
OMe
MeO
O
OMe
MeO
OMe
O
8
MeO
OMe
Entry
Solvent
MeCN
MeCN
EtCN
Temp (°C)
–40
dr
1
2
3
NDa
The remainder of the synthesis proceeded without inci-
dent (Scheme 3). Reduction of the aldehyde with NaBH4
is followed by dihydroxylation of the 1,1-disubstituted
olefin. Finally, oxidative cleavage with NaIO4 produces
( )-sylvone15 in 85% from 7. Due to the acid-sensitive na-
ture of tetrahydrofuran 8 and the complex diastereomeric
mixture derived from facially unselective dihydroxyla-
tion, this four-reaction sequence was performed without
intermediate purification. Upon workup, ( )-sylvone was
isolated as a white solid whose physical data matched the
reported literature values.7 The synthesis was completed
in 33% overall yield for six linear steps from commercial-
ly available materials.
–40
78:22b
90:10b
–78
a The reaction was quenched with aq NH4Cl; ND = not determined.
b The reaction was quenched with Et3N.
In conclusion, we have developed a rapid total synthesis
of ( )-sylvone. The salient features of this sequence are
the sequential installation of each aryl group followed by
a diastereoselective [1,3] ring contraction. This allows us
to systematically vary the substitution around the furofu-
O
HO
OH
+
O
PTSA (5 mol%)
O
OMe
PhH
5
Dean–Stark
OMe
85%
OMe
OMe
MeO
MeO
I
O
6
OMe
O
OMe
Pd(OAc)2, BnEt3NCl
i-Pr2NEt, DMF, 80 °C
OMe
MeO
MeO
OMe
7
>95:5 dr, 45%
Scheme 2 Synthesis of key 1,3-dioxepin
Synlett 2008, No. 1, 126–128 © Thieme Stuttgart · New York

128
C. G. Nasveschuk, T. Rovis
LETTER
HO
1) TMSOTf, EtCN, –78 °C
2) NaBH4, MeOH
O
O
O
OMe
OMe
3) OsO4, NMO
acetone–t-BuOH–H2O (4:1:1)
4) NaIO4, THF–H2O (5:1)
MeO
OMe
( )-sylvone (1)
O
OMe
7
MeO
MeO
OMe
MeO
OMe
4 steps, 85%
6 steps LLS, 33% overall
Scheme 3 Completion of ( )-sylvone
(10) 2-(3,4-Dimethoxyphenyl)-4,7-dihydro[1,3]dioxepine (5):
1H NMR (400 MHz, CDCl3): d = 7.08–7.02 (2 H, m), 6.84
(1 H, d, J = 8.1 Hz), 5.79 (1 H, s), 5.75 (2 H, s), 4.41–4.19 (4
H, m), 3.88 (3 H, s), 3.86 (3 H, s). 13C NMR (100 MHz,
CDCl3): d = 149.2, 148.9, 131.8, 130.2, 118.9, 110.8, 109.7,
102.3, 64.7, 56.1. IR (NaCl dep. from CHCl3): 2942, 2837,
1516, 1259, 1160, 777 cm–1.
ran core as a route to any member of this family of natural
products.
Acknowledgment
We thank Merck, Eli Lilly, Johnson and Johnson and Boehringer-
Ingelheim for support. T.R. is a fellow of the Alfred P. Sloan Foun-
dation. T.R. thanks the Monfort Family Foundation for a Monfort
Professorship.
(11) For a procedure to prepare 6, see: Scannell, R. T.; Stevenson,
R. J. Heterocycl. Chem. 1980, 17, 1727.
(12) Vinyl iodide 6 is consumed in these reactions. Small
amounts of dioxepin 5 could be re-isolated (ca. 20%).
(13) 2-(3,4-Dimethoxyphenyl)-5-[1-(3,4,5-trimethoxy-
phenyl)vinyl]-4,5-dihydro[1,3]dioxepine (7): 1H NMR
(400 MHz, CDCl3): d = 7.08–7.02 (2 H, m), 6.84 (1 H, d,
J = 8.3 Hz), 6.62 (2 H, s), 6.53 (1 H, dd, J = 7.5, 3.0 Hz),
5.49 (1 H, s), 5.38 (1 H, s), 5.19 (1 H, s), 5.01 (1 H, d, J = 7.3
Hz), 4.23 (1 H, d, J = 11.5, 4.5 Hz), 3.94–3.82 (16 H, m),
3.38 (1 H, dd, J = 11.1, 11.1 Hz). 13C NMR (100 MHz,
CDCl3): d = 153.3, 149.6, 149.1, 148.4, 145.3, 138.2, 136.9,
131.6, 118.7, 114.2, 113.3, 110.9, 109.0, 106.4, 103.9, 74.4,
61.1, 56.4, 56.2, 56.1, 46.9. IR (NaCl dep. from CHCl3):
2937, 2836, 1645, 1411, 1128, 732 cm–1. HRMS (+TOF
MS): m/z calcd for C24H29O7 [M + H]+: 429.1908; found:
429.1893.
(14) Procedure for the Stereoselective Ring Contraction of 7
A flame-dried round-bottomed flask was purged with argon
then charged with propionitrile (0.1 M with respect to 1,3-
dioxepin) and 0.1 equiv of TMSOTf. The solution was
cooled to –78 °C. A separate flame-dried round-bottomed
flask was purged with argon and charged with propionitirile
(0.1 M with respect to 1,3-dioxepin) and 1 equiv of 7. The
solution was then cooled to –78 °C. The solution containing
7 was transferred via cannula to the solution containing
Lewis acid at an approximate rate of 1 mL/min. The solution
was allowed to mix for 1 h at –78 °C. When the reaction was
complete the Lewis acid was quenched with 1 equiv of Et3N
and subsequently poured into sat. aq NaHCO3. The aqueous
layer was extracted with Et2O (3 ×), then the organic layer
was dried with MgSO4. After filtration the solvent removed
in vacuo and the crude product was carried through the
remainder of the synthetic steps to afford ( )-sylvone 1.
(15) ( )-Sylvone (1)
References and Notes
(1) For reviews concerning lignans, see: (a) MacRae, W. D.;
Towers, G. H. N. Phytochemistry 1984, 23, 1207.
(b) Whiting, D. A. Nat. Prod. Rep. 1987, 4, 499. (c) Ward,
R. S. Nat. Prod. Rep. 1993, 10, 1. (d) Ward, R. S. Nat. Prod.
Rep. 1995, 12, 183. (e) Ward, R. S. Nat. Prod. Rep. 1997,
14, 43. (f) Ward, R. S. Nat. Prod. Rep. 1997, 16, 75.
(2) For reviews on the strategies of oxacycle synthesis, see:
(a) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407.
(b) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301.
(3) For methods resulting in a total synthesis of a furofuran
lignan, see: (a) Takano, S.; Samizu, K.; Ogasawara, K.
Synlett 1993, 785. (b) Akindele, T.; Marsden, S. P.;
Cumming, J. G. Org. Lett. 2005, 7, 3685. (c) Wardrop, D.
J.; Fritz, J. Org. Lett. 2006, 8, 3659. (d) Review: Brown,
R.; Swain, N. A. Synthesis 2004, 811.
(4) (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.
(5) (a) Zhang, Y.; Reynolds, N. T.; Manju, K.; Rovis, T. J. Am.
Chem. Soc. 2002, 124, 9720. (b) Zhang, Y.; Rovis, T.
Tetrahedron Lett. 2003, 59, 8979. (c) Nasveschuk, C. G.;
Rovis, T. Org. Lett. 2005, 7, 2173. (d) Nasveschuk, C. G.;
Rovis, T. Angew. Chem. Int. Ed. 2005, 44, 3264. (e) Frein,
J. D.; Rovis, T. Tetrahedron 2006, 62, 4573.
(6) Nasveschuk, C. G.; Jui, N. T.; Rovis, T. Chem. Commun.
2006, 3119.
(7) (a) Banerji, A.; Sarkar, M.; Ghosal, T.; Pal, S. C.; Shoolery,
J. N. Tetrahedron 1984, 40, 5047. (b) Banerji, A.; Basu, S.
J. Indian Chem. Soc. 1992, 69, 321.
1H NMR (400 MHz, CDCl3): d = 7.41 (2 H, s), 6.84 (3 H, m),
5.03, (1 H, d, J = 6.0 Hz), 4.43 (1 H, dd, J = 7.9, 7.9 Hz),
4.31 (1 H, ddd, J = 7.7, 5.8, 2.8 Hz), 4.24 (1 H, dd, J = 8.1,
5.8 Hz), 3.96–3.77 (15 H, m), 3.41 (2 H, d, J = 6.4 Hz), 2.89
(1 H, ddd, J = 6.2, 6.0, 2.8 Hz), 1.40 (1 H, br s). 13C NMR
(100 MHz, CDCl3): d = 198.7, 153.3, 149.1, 148.4, 142.9,
131.5, 130.6, 117.9, 111.2, 108.9, 106.4, 81.5, 69.1, 62.1,
61.1, 56.4, 56.0, 56.0, 49.9, 48.9. IR (NaCl dep. from
CHCl3): 3516, 2941, 1673, 1516, 1127, 731 cm–1. MS (EI+):
m/z calcd for C23H28O8 [M + H]+: 433.2; found: 433.3.
(8) For reports that discuss the bioactivity of lignans, see:
(a) Chen, I.-S.; Chen, J.-J.; Duh, C.-Y.; Tsai, I.-L.
Phytochemistry 1997, 45, 991. (b) Parmar, V. S.; Jain, S. C.;
Bisht, K. S.; Jain, R.; Taneja, P.; Jha, A.; Tyagi, O. D.;
Prasad, A. K.; Wengel, J.; Olsen, C. E.; Boll, P. M.
Phytochemistry 1997, 46, 597.
(9) (a) Maioli, A. T.; Civiello, R. L.; Foxman, B. M.; Gordon, D.
M. J. Org. Chem. 1997, 62, 7413. (b) Yoda, H.; Kimura, K.;
Takabe, K. Synlett 2001, 400.
Synlett 2008, No. 1, 126–128 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.