Total synthesis of two naturally occurring bicyclo[3.2.1]octanoid neolignans.

Article abstract of DOI:10.1021/jo011077o

The first total syntheses of the racemates of naturally occurring macrophyllin-type bicyclo[3.2.1]octanoid neolignans, kadsurenin C 3 and kadsurenin L 4, were accomplished starting from vanillin and resorcinol. The acid-catalyzed rearrangement of hydrobenzofuranoid neolignans into bicyclo[3.2.1]octanoid neolignans was used as the key step.

Full text of DOI:10.1021/jo011077o

Tota l Syn th esis of Tw o Na tu r a lly
Occu r r in g Bicyclo[3.2.1]octa n oid
Neolign a n s
Mingyi Wang,† Anxin Wu,‡ Xinfu Pan,* and
Hongfang Yang†
Department of Chemistry,
National Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, P. R. China
panxf@lzu.edu.cn
Received November 14, 2001
F IGURE 1.
SCHEME 1
Abstr a ct: The first total syntheses of the racemates of
naturally occurring macrophyllin-type bicyclo[3.2.1]octanoid
neolignans, kadsurenin C 3 and kadsurenin L 4, were
accomplished starting from vanillin and resorcinol. The acid-
catalyzed rearrangement of hydrobenzofuranoid neolignans
into bicyclo[3.2.1]octanoid neolignans was used as the key
step.
The bicyclo[3.2.1]octanoid neolignans constitute an
important class of neolignan compounds, which are
further subdivided into the guianin-type 1 and the
macrophyllin-type 2 (Figure 1).1 Among the known
bicyclo[3.2.1]octanoid neolignans, macrophyllin-type neo-
lignans are less common than guianin-type neolignans.2
Most of the isolated macrophyllin-type neolignans, how-
ever, have excellent PAF (platelet-activating factor)3
antagonistic activities, and it was therefore important
to devise an efficient synthetic route to this class of
compounds. Two macrophyllin-type bicyclo[3.2.1]octanoid
neolignans with significant PAF antagonistic activities
are kadsurenin C 3 and kadsurenin L 4, which are
isolated from Piper kadsura (Choisy) Ohwi.4 Their struc-
tures were determined on the basis of spectral analysis
and chemical derivatization. In this paper, the first
total syntheses of the racemates of kadsurenin C 3 and
kadsurenin L 4 starting from vanillin and resorcinol are
described.
report7 afforded macrophyllin-type bicyclooctane prod-
ucts, and their absolute configuration (C-4′) was different
from the desired target molecules. Apparently, the cyclo-
addition strategy could not be used for the syntheses of
kadsurenin C 3 and kadsurenin L 4, and in fact, our
attempt to adopt this strategy also failed.
Gottlieb et al.8 reported the acid-catalyzed rearrange-
ment of mirandin-A 5 into bicyclo[3.2.1]octene 6 through
an intermediate benzylic cation in 76% yield (Scheme 1).
Comparison of 6 with methyl kadsurenin K 10 indicated
that they have identical stereochemistry, and as it
happens, the precursor of methyl kadsurenin K 10 is
kadsurenone 9b,9 which is a hydrobenzofuranoid neolig-
nan with specific antagonistic activity of PAF. Conse-
quently, it was anticipated that the target molecules
could be synthesized according to this strategy, and the
retrosynthetic analysis is presented in Scheme 2.
Recently, we reported an efficient method for the
preparation of cinnamyl aryl ethers.10 The same method
could also be utilized for the synthesis of 3,4-dimethoxy-
cinnamyl 3-(allyloxy)phenyl ether 7 on a large scale and
in good yield (67%, lit.11 23%). The cyclization of 7 in N,N-
diethylaniline was carried out in a sealed tube at 225 °C
for 12 h to stereoselectively afford the trans-dihydroben-
The published approaches for the syntheses of bicy-
clooctanoid neolignans almost always adopt the cycload-
dition strategy pioneered by Bu¨chi et al.,5 which was
further developed by Engler et al.6 In most cases, the
cycloaddition strategy was used for the syntheses of the
guianin-type neolignans and their analogues. Only one
† Present address: Department of Chemistry, Center for Heterocy-
clic Compounds, University of Florida, Gainesville, FL 32611-7200.
‡ Present address: Department of Chemistry and Biochemistry,
University of Maryland, College Park, MD 20742.
(1) Whiting, D. A. Nat. Prod. Rep. 1985, 2, 191.
(2) Ward, R. S. Nat. Prod. Rep. 1995, 12, 183; 1997, 14, 43.
(3) Demopoulos, C. A.; Pinckard, R. N.; Hanahan, D. J . J . Biol.
Chem. 1979, 254, 9355.
(4) (a) Han, G. Q.; Dai, P.; Xu, L.; Wang, S. C.; Zheng, Q. T. Chin.
Chem. Lett. 1992, 3, 521. (b) Ma, Y.; Han, G. Q.; Liu, Z. J . Yaoxue
Xuebao 1993, 28, 307.
(7) Mortlock, S. V.; Seckington, J . K.; Thomas, E. J . J . Chem. Soc.,
Perkin Trans. 1 1988, 2305.
(8) De Alvarenga, M. A.; Brocksom, B U.; Gottlieb, O. R.; Toshida,
M.; Filho, R. B.; Figliuolo, R. J . Chem. Soc., Chem. Commun. 1978,
831.
(5) (a) Bu¨chi, G.; Mak, C. P. J . Am. Chem. Soc. 1977, 99, 8073. (b)
Bu¨chi, G.; Chu, P. S. J . Org. Chem. 1978, 43, 3717.
(6) Engler, T. A.; Wei, D.; Letavic, M. A. Tetrahedron Lett. 1993,
34, 1429.
(9) Chang, M. N.; Han, G. Q.; Arison, B. H.; Springer, J . P.; Hwang,
S. B.; Shen, T. Y. Phytochemistry 1985, 24, 2079.
(10) Wang, M. Y.; Wu, A. X.; Pan, X. F. J . Chem. Res., Synop. 1998,
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10.1021/jo011077o CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/26/2002
J . Org. Chem. 2002, 67, 5405-5407
5405

SCHEME 2
SCHEME 3
zofuran 8 in 40% yield. The thermal reaction apparently
involved two Claisen rearrangements, followed by an
abnormal Claisen rearrangement (1,5-homosigmatropic
hydrogen shift).12 Following a literature method,11 oxida-
tion of dihydrobenzofuran 8 in methanol gave the oxida-
tive methoxylation products 9a and 9b. Using lead
tetraacetate as an oxidant was unsatisfactory, since the
major products were not 9a and 9b (15% and 9%,
respectively) but were the epimeric acetates 9c and 9d
(40%). With phenyliodonium diacetate (PIDA)13 as an
oxidant, however, it was found that the yields of 9a and
9b were substantially increased to 50% and 20%, respec-
tively, whereas the yields of 9c and 9d dropped sharply
to less than 5%. The acid-catalyzed rearrangement of a
mixture of 9a and 9b in methanol afforded the desired
bicyclo[3.2.1]octane skeleton 10 (73%) from 9b. However,
the same procedure employing pure 9a did not give any
rearrangement products, and the starting material was
recovered. This suggests that the rearrangement might
be controlled by the relative configuration of the tetra-
substituted sp3 carbon atom. Selective reduction of 10
with sodium borohydride in ethanol at -15 °C provided
3 in 85% yield, which was reacted with acetic anhydride
in pyridine at room temperature to give 4 in 90% yield
(Scheme 3). The structures of 10, 3, and 4 were supported
by 1H NMR and 13C NMR spectroscopic comparisons with
literature data,4b and the stereochemistry at C-4′ was
assigned by analogy with the work of Gottlieb.8 The
spectral data of 3 and 4 are consistent with those
reported.4
eluent. Compounds 7 and 8 were prepared according to literature
methods.10,11b
r a c-Den u d a tin B (9a ) a n d r a c-Ka d su r en on e (9b). To a
solution of dihydrobenzofuran 8 (500 mg, 1.5 mmol) in dry MeOH
(10 mL) was dropwise added a solution of PIDA (1.0 g, 3.1 mmol)
in dry MeOH (15 mL) at room temperature. After the addition,
the reaction mixture was stirred for 2 h and then evaporated to
dryness. The residue was purified by flash column chromatog-
raphy on silica gel H (200 mesh; petroleum ether-ethyl acetate,
4:1 to 2:1, v/v) to afford a yellow oil (420 mg). The crude product
was purified by column chromatography on silica gel H (400
mesh; petroleum ether-ethyl acetate-acetone, 8:1.5:0.5, v/v).
The first eluted compound was 9a ,11b obtained as a colorless oil
(270 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 1.13 (3H, d, J )
6.7 Hz, CH3), 2.18-2.22 (1H, m, H-3), 3.13 (3H, s, OCH3), 3.09-
3.24 (2H, m, CH2CHdCH2), 3.89 (6H, s, 2 × Ar-OCH3), 5.12-
5.17 (2H, m, CH2CHdCH2), 5.36 (1H, d, J ) 9.5 Hz, H-2), 5.82
(1H, s, H-7), 5.88 (1H, m, CH2CHdCH2), 6.27 (1H, s, H-4), 6.78-
6.90 (3H, m, ArH). EIMS (m/z): 356 (M+).
The second component eluted was obtained as a light yellow
oil and identified as 9b11b (110 mg, 20%). 1H NMR (400 MHz,
CDCl3) δ 1.13 (3H, d, J ) 7.6 Hz, CH3), 2.65-2.71 (1H, m, H-3),
3.04 (3H, s, OCH3), 3.10-3.15 (2H, m, CH2CHdCH2), 3.89 and
3.90 (6H, 2s, 2 × Ar-OCH3), 5.12 (2H, d t, J ) 2.0, 17.0 Hz,
CH2CHdCH2), 5.23 (1H, s, H-2), 5.85 (1H, m, CH2CHdCH2),
5.89 (1H, s, H-7), 6.21 (1H, s, H-4), 6.84-6.89 (2H, m, ArH), 7.02
(1H, d, J ) 0.5 Hz, ArH). HRMS (FAB) calcd for C21H24O5 [M +
1] 357.1702. Found 357.1700.
The successful syntheses of kadsurenin C 3 and kad-
surenin L 4 through rearrangement of the hydrobenzo-
furan to bicyclooctane neolignans indicates that this route
may have general utility in the convenient syntheses of
many members of the neolignan group.
r a c-Meth yl Ka d su r en in K (10). A solution of 9b (50 mg,
0.14 mmol) in dry MeOH (5 mL) containing a catalytic amount
of p-toluenesulfonic acid was refluxed vigorously for 1.5 h. The
residue obtained on removal of MeOH was purified by column
chromatography on silica gel H (400 mesh; petroleum ether-
ethyl acetate, 4:1, v/v) to afford pure 104b as a colorless oil (36.5
mg, 73%). IR (film): νmax 2931, 2846, 1671, 1623, 1516, 1259,
Exp er im en ta l Section
1138 cm-1 1H NMR (400 MHz, CDCl3) δ 1.08 (3H, d, J ) 6.0
;
Melting points were determined on a micro-melting point
apparatus and are uncorrected. 1H and 13C NMR were recorded
with CDCl3 as the solvent and tetramethylsilane as the internal
standard. Column chromatography was conducted on silica gel
H (200-400 mesh) and with 60-90 °C petroleum ether in the
Hz, H-9), 2.44-2.50 (2H, m, H-7, H-8), 3.10-3.13 (2H, m, H-7′),
3.53 (1H, s, H-3′), 3.64 (3H, s, OCH3-5′), 3.86 (6H, s, 2 × Ar-
OCH3), 5.16-5.20 (2H, m, H-9′), 5.83-5.90 (1H, m, H-8′), 6.58
(1H, d, J ) 1.8 Hz, H-2), 6.66 (1H, dd, J ) 2.0, 8.1 Hz, H-6),
6.79 (1H, d, J ) 8.2 Hz, H-5), 7.06 (1H, s, H-6′); 13C NMR (125
MHz, CDCl3) δ 133.8 (C-1), 110.0 (C-2), 147.1 (C-3), 149.3 (C-4),
111.4 (C-5), 119.3 (C-6), 45.3 (C-7), 48.8 (C-8), 13.7 (C-9), 140.4
(C-1′), 194.4 (C-2′), 69.9 (C-3′), 202.2 (C-4′), 89.3 (C-5′), 148.4
(C-6′), 32.7 (C-7′), 133.7 (C-8′), 118.2 (C-9′), 54.0 (OCH3-5′), 55.9
(OCH3-3), 55.9 (OCH3-4). EIMS (m/z): 356 (M+). HRMS (FAB)
calcd for C21H24O5 [M + 1] 357.1702. Found 357.1728.
(11) Ponpipom, M. M.; Yue, B. Z.; Bugianesi, R. L.; Brooker, D. R.;
Chang, M. N.; Shen, T. Y. Tetrahedron Lett. 1986, 27, 309. (b)
Ponpipom, M. M.; Bugianesi, R. L.; Brooker, D. R.; Yue, B. Z.; Hwang,
S. B.; Shen, T. Y. J . Med. Chem. 1987, 30, 136.
(12) Schmid, E.; Frater, G.; Hansen, H.-J .; Schmid, H. Helv. Chim.
Acta 1972, 55, 1625.
r a c-Ka d su r en in C (3). To a solution of 10 (18 mg, 0.05 mmol)
in dry EtOH (15 mL) was dropwise added a solution of NaBH4
(13) Pelter, A.; Elgendy, S. M. A. J . Chem. Soc., Perkin Trans. 1
1993, 1891.
5406 J . Org. Chem., Vol. 67, No. 15, 2002

(25 mg, 0.06 mmol) in dry EtOH (5 mL) at -15 °C. After the
addition, the reaction mixture was stirred at -15 °C for 15 min
and then water was added to quench the reaction. The products
were extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with water, sat. NaHCO3, and sat. NaCl
and dried over Na2SO4. The crude oily product obtained on
removal of the solvent was purified by preparative TLC (hex-
anes-ethyl acetate, 2:1, v/v) to give 34b as a light yellow oil (15.3
mg, 85%). IR (film): νmax 3455 (br), 2950, 2931, 1681, 1590, 1515,
colorless crystals (10.1 mg, 90%), mp 136-137 °C. IR (KBr): νmax
2961, 2933, 1736, 1681, 1599, 1515, 1460, 1412, 1370, 1321,
1300, 1252, 1233, 1160, 1073 cm-1; 1H NMR (500 MHz, CDCl3)
δ 1.01 (3H, d, J ) 6.5 Hz, H-9), 2.18 (3H, s, -OCOCH3), 2.43
(1H, d, J ) 8.0 Hz, H-7), 2.74-2.80 (1H, m, H-8), 3.00 (1H, s,
H-3′), 3.03-3.05 (2H, m, H-7′), 3.38 (3H, s, OCH3-5′), 3.87 and
3.88 (6H, 2s, 2 × Ar-OCH3), 5.14-5.18 (2H, m, H-9′), 5.32 (1H,
s, H-4′), 5.80-5.90 (1H, m, H-8′), 6.80 (1H, d, J ) 5.1 Hz, H-5),
6.85-6.87 (3H, m, H-2, H-6, H-6′); 13C NMR (125 MHz, CDCl3)
δ 134.3 (C-1), 111.1 (C-2), 147.9 (C-3), 148.7 (C-4), 111.3 (C-5),
120.1 (C-6), 51.3 (C-7), 46.3 (C-8), 13.2 (C-9), 140.0 (C-1′), 197.6
(C-2′), 54.1 (C-3′), 75.1 (C-4′), 88.4 (C-5′), 148.9 (C-6′), 32.4 (C-
7′), 133.7 (C-8′), 117.7 (C-9′), 60.7 (OCH3-5′), 55.9 (OCH3-3), 55.9
(OCH3-4), 21.2 and 169.1 (-OCOCH3). EIMS (m/z): 400 (M+).
HRMS (FAB) calcd for C23H28O6 [M] 400.1886. Found 400.1830.
1461, 1363, 1264, 1236, 1128, 1101, 1027 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.00 (3H, d, J ) 6.9 Hz, H-9), 2.38 (1H, d, J )
8.1 Hz, H-7), 2.64-2.69 (1H, m, H-8), 3.01-3.05 (2H, m, H-7′),
3.09 (1H, s, H-3′), 3.46 (3H, s, OCH3-5′), 3.87 (6H, s, 2 × Ar-
OCH3), 4.22 (1H, s, H-4′), 5.13-5.17 (2H, m, H-9′), 5.80-5.88
(1H, m, H-8′), 6.76 (1H, d, J ) 8.2 Hz, H-5), 6.85 (1H, s, H-6′),
6.88 (1H, d, J ) 8.2 Hz, H-6), 7.13 (1H, s, H-2); 13C NMR (100
MHz, CDCl3) δ 134.6 (C-1), 110.8 (C-2), 147.8 (C-3), 149.0 (C-4),
111.8 (C-5), 120.7 (C-6), 51.8 (C-7), 46.7 (C-8), 13.1 (C-9), 139.8
(C-1′), 198.8 (C-2′), 53.6 (C-3′), 75.5 (C-4′), 89.8 (C-5′), 148.4 (C-
6′), 32.5 (C-7′), 134.5 (C-8′), 117.4 (C-9′), 62.0 (OCH3-5′), 55.8
(OCH3-3), 55.8 (OCH3-4). EIMS (m/z): 358 (M+). HRMS (FAB)
calcd for C21H26O5 [M + 1] 359.1858. Found 359.1868.
r a c-Ka d su r en in L (4). To a solution of 3 (10 mg, 0.028 mmol)
in dry pyridine (1 mL) was added freshly distilled Ac2O (0.1 mL)
at 0 °C. After the addition, the reaction mixture was stirred at
0 °C to room temperature overnight. The excess solvents were
removed in vacuo, and the residue was dissolved in EtOAc (10
mL), washed with 2 N HCl and water, and dried over anhydrous
Na2SO4. Purification through preparative TLC gave pure 4,4b
which was recrystallized from ethyl ether-hexane to give
Ack n ow led gm en t. We thank Dr. Yuxin Cui for
obtaining the NMR spectra of compounds 3 and 4. Many
thanks are also due to Dr. Suoming Zhang for discus-
sions. Financial support was provided by the National
Science Foundation of China (No. 20172023) and is
highly appreciated.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of 3,
4, 9b, and 10. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O011077O
J . Org. Chem, Vol. 67, No. 15, 2002 5407