Total synthesis of methyl protodioscin: A potent agent with antitumor activity

Article abstract of DOI:10.1021/jo020683w

Methyl protodioscin (1), otherwise known as 3-O-[α-L-rhamnopyranosyl-(1→2)-{α-L-rhamnopyranosyl- (1→4)}-β-D-glucopyranosyl]-26-O-[β-D-glucopyranosyl]-22- methoxy-25(R)-furost-5-ene-3β,26-diol, has been synthesized for the first time from diosgenin through nine steps in an overall yield of 7.8%.

Full text of DOI:10.1021/jo020683w

Tota l Syn th esis of Meth yl P r otod ioscin : A P oten t Agen t w ith
An titu m or Activity
Mao S. Cheng,*,† Qian L. Wang,† Quan Tian,† Hong Y. Song,† Yong X. Liu,† Qiang Li,†
Xin Xu,† Hong D. Miao,† Xin S. Yao,*,† and Zhen Yang*,‡
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road,
Shenhe District, Shenyang, 110016, P. R. China, Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry,
Peking University, Beijing, P. R. China, 100871, and VivoQuest, Inc., 711 Executive Boulevard,
Valley Cottage, New York 10989
zyang@chem.pku.edu.cn
Received November 5, 2002
Methyl protodioscin (1), otherwise known as 3-O-[R-L-rhamnopyranosyl-(1f2)-{R-L-rhamnopyra-
nosyl-(1f4)}-â-D-glucopyranosyl]-26-O-[â-D-glucopyranosyl]-22-methoxy-25(R)-furost-5-ene-3â,26-
diol, has been synthesized for the first time from diosgenin through nine steps in an overall yield
of 7.8%.
In tr od u ction
Although many furostan saponin based natural prod-
ucts have been known for a couple of decades,5 methods
for their syntheses are limited. Herein we would like to
report our efforts to synthesize compound 1.
Methyl protodioscin, 1, a member of the furostan
saponin family with a broad range of biological activities,1
is a furostanol bisglycoside with the chemical name of
3-O-[R-L-rhamnopyranosyl-(1f2)-{R-L-rhamnopyranosyl-
(1f4)}-â-D-glucopyranosyl]-26-O-[â-D-glucopyranosyl]-22-
methoxy-25(R)-furost-5-ene-3â,26-diol. This molecule was
first isolated and identified by Kawasaki and co-workers2
in 1974 from fresh rhizomes of Dioscorea gracillima MiQ.
In continuing efforts to identify active components from
the traditional Chinese herbal medicine,3 we have iso-
lated 14 steroidal saponins with anticancer activities
from Dioscoreaceae by bioactivity-guided isolation for
testing in the panel of 60 human cancer cell lines at NCI.4
Among the tested compounds, methyl protodioscin (1)
showed the most potent activity in vitro. In order to get
a sufficient amount of the compound for further biological
investigations, we therefore initiated a program to syn-
thesize this target molecule.
Resu lts a n d Discu ssion
Retrosynthetically, methyl protodioscin (1) can be
logically disconnected into three distinct fragments (2-
4) (Scheme 1). Trisaccharide 3 may be generated from
the corresponding 2,4-O-â-glucopyranoside 5 and R-L-
rhamnopyranosyl trichloroacetimidate 6,6 respectively.
Inspired by the recent accomplishment of the first
synthesis of furostan saponins by Yu and Hui,7 we
decided to use the same starting material diosgenin (see
Scheme 2) in our synthesis of methyl protodioscin. We
explored a less lengthy, more efficient approach, prefer-
ably more adaptable to a combinatorial format. Such an
approach would allow us to rapidly access a variety of
structural analogues of methyl protodioscin.
We anticipated that the epoxide hemiketal acetate 8,
which has been successfully generated in 92% yield by
Bovicelli and co-workers8 from diosgenin acetate 7 with
DMDO as an oxidant (Scheme 2), could be directly
converted to its corresponding olefin 2 by a suitably
selected method, since many effective methodologies9 are
available for such transformations.
† Shenyang Pharmaceutical University.
‡ Peking University and VivoQuest, Inc.
(1) (a) Hu, K.; Dong, A.-J .; Yao, X.-S.; Kobayashi, H.; Iwasaki, S.
Planta Med. 1997, 63, 161-165. (b) Hostettmann, K.; Marston, A.
Saponins; Cambridge University Press: Cambridge, U.K., 1995. (c)
Ori, K.; Mimaki, Y.; Mito, K.; Sashida, Y.; Nikaido, T.; Ohmoto, T.;
Masuko, A. Phytochemistry 1992, 31, 2767-2775. (d) Kamel, M. S.;
Ohtani, K.; Kurokawa, T. Chem. Pharm. Bull. 1991, 39, 1229-
1233. (e) Namba, T.; Huang, X. L.; Shu, Y. Z.; Huang, S. L.; Hattori,
M.; Kakiuchi, N.; Wang, Q.; Xu, G. J . Planta Med. 1989, 55, 501-
505.
After screening a number of known methods to convert
the epoxide into its corresponding olefin in compound 2,9
(2) Kawasaki, T.; Komori, T.; Miyahara, K.; Nohara, T.; Hosokawa,
I.; Mihashi, K. Chem. Pharm. Bull. 1974, 22, 2164-2175.
(3) (a) Sakurai, T.; Nishimura, T.; Otake, N.; Yao, X.-S.; Abe, K.;
Zeida, M.; Nagasawa, H.; Sakuda, S. Bioorg. Med. Chem. 2002, 12,
807-810. (b) Dou, D.-Q.; Zhang, Y.-W.; Zhang, L.; Chen, Y.-J .; Yao,
X.-S. Planta Med. 2001, 67, 19-23. (c) Wang, N.-l.; Yao, X.-S.; Ishii,
R.; Kitanaka, S. Chem. Pharm. Bull. 2001, 49, 938-942. (d) Hu, K.;
Dong, A.-J .; Sun, Q.-S.; Yao, X.-S. Pharm. Biol. 2001, 39, 47-53. (e)
Zhang, Y.-W.; Dou, D.-Q.; Zhang, L.; Chen, Y.-J .; Yao, X.-S. Planta
Med. 2001, 67, 417-422.
(5) Waller, G. R., Yamasaki, K., Eds.; Plenum Press: New York,
1996.
(6) Ziegler, T.; Bien, F.; J urisch, C. Tetrahedron: Asymmetry 1998,
9, 765-780.
(7) Yu, B.; Liao, J .-C.; Zhang, J .-B.; Hui, Y.-Z. Tetrahedron Lett.
2001, 42, 77-79.
(8) Bovicelli, P.; Lupattelli, P.; Fracassi, D.; Mincione, E. Tetrahe-
dron Lett. 1994, 35, 935-938.
(9) (a) Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter 4.4, p 871. (b)
Sonnet, P. E. Tetrahedron 1980, 36, 557-604.
(4) Hu, K.; Dong, A.-J .; Yao, X.-S.; Kobayashi, H.; Iwasaki, S. Planta
Med. 1996, 62, 573-575.
10.1021/jo020683w CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003
3658
J . Org. Chem. 2003, 68, 3658-3662

Total Synthesis of Methyl Protodioscin
SCHEME 1. Retr osyn th etic An a lysis
SCHEME 4. Syn th esis of Com p ou n d 14a
a
(a) K2CO3, THF/MeOH (1:1), rt, 100%; (b) compound 4,
TMSOTf (0.1 equiv), CH2Cl2, rt, 62%; (c) TBAF, THF, rt, 80%.
SCHEME 5. Syn th esis of Tr isa cch a r id e 3a
SCHEME 2. Design of a Con cise Ap p r oa ch
a
(a) Thiophenol, BF3‚Et2O, CH2Cl2, rt, 85%; (b) MeONa, MeOH,
rt, 100%; (c) PivCl, pyridine, CH2Cl2, 0 °C, 70%; (d) BF3‚Et2O,
CH2Cl2, -78 °C, 100%.
CO3/THF/MeOH to afford a mixture of spiroketal 11 and
dione 12 (Scheme 4), which was then glycosylated7,11
directly with 2,3,4,6-tetra-O-benzoyl-R-D-glucopyranosyl
trichloroacetimidate 412 in the presence of a catalytic
amount of TMSOTf (0.1 equiv) to provide the 26-O-
glycosylated product 13. Compound 14 was finally ob-
tained by treatment of compound 13 with tetra-butylam-
monium fluoride.
SCHEME 3. Syn th esis of In ter m ed ia te 2a
The next task was to construct the trisaccharide moiety
3 (Scheme 5). Structurally, the constitution of this
trisaccharide is quite unique. The sequential linkage of
R-L-rhamnopyranosyl-(1f2)-R-L-rhamnopyranosyl-(1f4)-
â-D-glucopyranoside led us to envisage a convergent
approach in which phenyl 3,6-di-O-pivaloyl-1-thio-â-D-
glucopyranoside (5)13 as an acceptor and R-L-rhamnopy-
ranosyl trichloroacetimidate (6)6 was utilized as a donor.
If successful, such a strategy would allow convergent
generation of trisaccharide 3 in one step.
For this purpose, commercially available 1,2,3,4,6-
penta-O-acetyl-â-D-glucopyranose (15) was chosen as a
starting material for the preparation of 5, as its anomeric
acetate was quite easily exchanged with thiophenol under
acidic conditions14 to give 2,3,4,6-tetra-O-acetyl-1-thio-â-
D-glucopyranoside (16) in 85% yield. Hydrolysis of the
remaining acetates in compound 16 was achieved by
a
(a) TBDPSiCl, imid., DMF, rt, 90%; (b) oxone, NaHCO3, H2O,
acetone, CH2Cl2, rt; (c) Zn, KI, AcOH, Ac2O, rt (58% for two steps).
we finally chose the Cornforth procedure10 for our pur-
pose, since the real chemistry for this conversion turned
out to be extremely effective as shown in Scheme 3. After
protection of the C-3 hydroxyl group in diosgenin with
TBDPS, compound 9 was then oxidized with DMDO at
the double bond and spiroketal to afford compound 10,
which, without purification, directly underwent reductive
cleavage of the epoxide to regenerate the double bond.
Thus, the diketone acetate 2 was obtained in 58% yield
in a one-pot operation under very mild conditions.
We then focused our attention on the synthesis of
glycosylated intermediate 14. To this end, the 26-O-acetyl
group in compound 2 was removed by treatment with K2-
(11) (a) Deng, S.; Yu, B.; Xie, J .; Hui, Y. J . Org. Chem. 1999, 64,
7265-7266. (b) J iang Z.-H.; Schmidt, R. R. Liebigs Ann. Chem. 1992,
975-982. (c) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503-
1531.
(12) Fukase, K.; Winarno, H.; Kusumoto, S. Chem. Express 1993,
8, 409.
(13) J iang, L.; Chan, T.-H. J . Org. Chem. 1998, 63, 6035-6038.
(14) (a) Rosa, L.; Alfonso, F.-M. J . Org. Chem. 1994, 59, 737-745.
(b) Erbing, B.; Lindberg, B. Acta Chem. Scand., Ser. B 1976, 30, 611-
612.
(10) Cornforth, J . W.; Cornforth, R. H.; Mathew, K. K. J . Chem. Soc.
1959, 2539-2547.
J . Org. Chem, Vol. 68, No. 9, 2003 3659

Cheng et al.
SCHEME 6. Com p letion of Syn th esisa
obtained in 83% yield by deprotection of benzoyl and
pivaloyl groups, and in situ methoxylation at C22 positon
in a basic MeOH solution (Scheme 6).
The analytical data for the synthesized furostan sa-
ponin 1 were identical in all respects to those of the
natural product (isolated by our laboratories),4 including
1H and 13C NMR, DEPT, ESI-MS, optical rotation, and
IR.
In conclusion, a highly convergent approach for the
synthesis of methyl protodioscin 1 has been developed,
which paves the way to easily access methyl protodioscin
and its diversified analogues.
Exp er im en ta l Section
Analytical thin-layer chromatography (TLC) was performed
on precoated plates of silica gel HF254 (0.5 mm, Qingdao,
China). Flash column chromatography was performed on silica
gel H (60 µm, Qingdao, China). Dried solvents used as reaction
media were purified in the usual way, and solvents for
extraction and chromatography were reagent grade and used
as received. The boiling range of the petroleum ether used was
60-90 °C.
Syn th esis of 3 â-TBDP S Diosgen in 9. tert-Butylchlo-
rodiphenylsilane (TBDPSCl, 8 mL, 31.4 mmol) was added to
a stirred mixture of diosgenin (10.0 g, 24.1 mmol) (Northeast
General Pharmaceutical Factory, Shenyang, China) and imid-
azole (3.3 g, 48.2 mmol) in dried DMF (150 mL) at room
temperature, and the mixture was then stirred at the same
temperature for 12 h. The reaction was worked up with
saturated NH4Cl solution (50 mL), the mixture was extracted
with petroleum ether (150 mL × 3), and the combined organic
layer was washed sequentially with a saturated NaHCO3
aqueous solution (100 mL × 2) and then water (200 mL × 2)
and dried over anhydrous Na2SO4. The solvent was removed
under vacuum, and the residue was purified by flash column
chromatography (silica gel, petroleum ether/ethyl acetate )
30/1) to afford compound 9 as a white solid (14.1 g, 90%
yield): mp 156.5-158.5 °C; Rf ) 0.5 (petroleum ether/ethyl
acetate, 20:1); [R]30 D -86.8° (c 0.65, CH2Cl2); 1H NMR (CDCl3,
300 MHz) δ 7.68-7.66 (m, 4H), 7.43-7.32 (m, 6H), 5.11 (d,
1H, J ) 4.9 Hz), 4.41-4.34 (m, 1H), 3.55-3.43 (m, 2H), 3.39-
3.32 (t, 1H, J ) 10.7 Hz), 2.36-2.29 (m, 1H), 2.16-2.10 (dd,
1H, J 1 ) 13.0, J 2 ) 3.5 Hz), 1.98-1.80 (m, 3H), 1.76-1.51 (m,
11H), 1.46-1.42 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 141.3,
135.8, 134.8, 129.4, 127.4, 120.8, 109.2, 80.8, 73.2, 66.8, 62.1,
56.5, 50.0, 42.5, 41.6, 40.2, 39.8, 37.2, 36.6, 32.0, 31.8, 31.4,
30.3, 28.8, 27.0, 20.8, 19.4, 19.1, 17.1, 16.2, 14.5; ESI-MS m/z
653.
Syn th esis of Com p ou n d 2. To the stirred mixture of
compound 9 (30 g, 0.046 mol), NaHCO3 (73 g, 0.869 mol), H2O
(500 mL), CH2Cl2 (400 mL), and acetone (100 mL) was added
oxone (2KHSO5‚KHSO4‚K2SO4) (160 g, 0.258 mol) at room
temperature in portions. The reaction was then monitored by
TLC to follow the reaction to completion. The precipitated solid
was then filtered off, and the filtrate was extracted with CH2-
Cl2 (200 mL × 2). The combined organic layer was then washed
with water (50 mL × 2) and dried over anhydrous Na2SO4.
The solvent was removed under vacuum, and the residue was
dissolved in a mixture of acetic acid (100 mL) and acetic
anhydride (100 mL), followed by addition of zinc powder (14.9
g, 0.230 mol) and KI (19 g, 0.115 mol) at room temperature.
After the reaction mixture was stirred at the same tempera-
ture for 15 h, the solid was removed by filtration, and the
filtrate was extracted with CHCl3 (150 mL × 3). The combined
organic layer was first washed with water (200 mL × 2), then
with a saturated sodium bicarbonate solution (200 mL × 3),
and finally with a saturated NH4Cl water solution (200 mL ×
2) and dried over anhydrous MgSO4. The solvent was removed
under vacuum, and the yellowish oil was purified by flash
column chromatography (silica gel, petroleum ether/ethyl
a
(a) NIS, TfOH, CH2Cl2, rt, 52%; (b) NaBH4, i-propanol, CH2Cl2,
rt, 70%; (c) MeONa, MeOH, reflux, 83%.
treatment with a catalytic amount of sodium methoxide
in methanol to give a quantitative yield of tetraol 17,
which was then regioselectively acylated with pivaloyl
chloride in pyridine to afford 5 in 70% yield.13 A success-
ful glycosylation of compound 5 (acceptor) was eventually
conducted in the presence of BF3‚Et2O with rhamose-
derived trichloroacetmidate 6 (donor) at -78 °C15 to
provide the key intermediate trisaccharide 3 in quantita-
tive yield.
With efficient synthetic access to intermediates 3 and
14, we then examined their union via an iodonium ion
promoted coupling reaction16 between thioglycoside 3 and
the secondary alcohol in compound 14. Gratifyingly, this
glycosidation gave us a 52% yield of desired product 18
after treatment of 14 and 3 with N-iodosuccinimide (NIS)
and a catalytic amount of trifluoromethanesulfonic acid
(TfOH) at room temperature (Scheme 6). Preferential
reduction of the C16-ketone in compound 18 with NaBH4
in i-PrOH was achieved by following the known proce-
dure,17 and the newly generated secondary alcohol con-
currently cyclized to give the hemiketal 19 in 70% yield.
The final target furostan saponin 1 was eventually
(15) Li, B.; Yu, B.; Hui, Y. Z.; Li, M.; Han, X. W.; Fung, K. P.
Carbohydr. Res. 2001, 331, 1-7.
(16) (a) Ley, S. V.; Priepke, H. W. M. Angew. Chem., Int. Ed. Engl.
1994, 33, 2292-2294. (b) Veeneman, G. H.; Leeuwen, S. H. van; Boom,
J . H. van. Tetrahedron Lett. 1990, 31, 1331-1334.
(17) (a) Uhle, F. C. J . Am. Chem. Soc. 1961, 83, 1460-1472. (b)
Nohara, T.; Miyahara, K.; Kawasaki, T. Chem. Pharm. Bull. 1975, 23,
872-885. (c) Uhle, F. C. J . Org. Chem. 1966, 31, 4193-4201.
3660 J . Org. Chem., Vol. 68, No. 9, 2003

Total Synthesis of Methyl Protodioscin
acetate ) 10:1) to give 18.9 g of compound 2 as a white solid
(58% yield): mp 48-50 °C; Rf ) 0.35 (petroleum ether/ethyl
31.7, 31.5, 30.9, 26.7, 20.5, 19.4, 17.0, 15.3, 12.9; ESI-MS m/z
1026 (M + H2O), 1031(M + Na).
acetate ) 10:1); [R]30 -132.4°(c 1.17, CH2Cl2); 1H NMR
Syn th esis of Com p ou n d 16.15 To a solution of penta-O-
acetyl-â-D-glucopyranose (15) (12.3 g, 31.5 mmol) in dried CH2-
Cl2 (50 mL) was sequentially added thiophenol (3.9 mL, 37.8
mmol) and BF3‚Et2O (47%-47.7%, 12 mL, 94.5 mmol) at 0 °C
under N2 atmosphere. After the mixture was stirred at room
temperature for 3 h, the reaction mixture was diluted with
CH2Cl2 (200 mL). This organic phase was washed sequentially
with saturated sodium bicarbonate solution (50 mL × 3) and
water (50 mL × 2) and dried over anhydrous MgSO4. The
solvent was removed under vacuum, and the residue was
purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate ) 5:1) to give compound 16 (11.8 g, 85%
D
(CDCl3, 300 MHz) δ 7.68-7.66 (m, 4H), 7.44-7.34 (m, 6H),
5.11 (d, 1H, J ) 4.3 Hz), 3.93 (dd, 2H, J ) 6.1, 1.4 Hz), 3.57-
3.50 (m, 1H), 2.85-2.71 (m, 1H), 2.65-2.53 (m, 3H), 2.40-
2.30 (m, 1H), 2.21-2.12 (m, 2H), 2.05 (s, 3H), 1.99-1.97 (m,
1H), 1.91-1.62 (m, 7H), 1.62-1.43 (m, 8H); 13C NMR (CDCl3,
75 MHz) δ 217.9, 213.2, 171.2, 141.4, 135.7, 134.7, 129.4, 127.4,
120.3, 73.1, 69.0, 66.1, 51.2, 49.6, 43.3, 42.4, 41.6, 39.6, 38.6,
37.1, 36.9, 36.5, 32.1, 31.8, 31.7, 30.9, 27.0, 26.7, 20.9, 20.5,
19.4, 19.1, 16.8, 15.3, 12.9; ESI-MS m/z 711(M + 1).
Syn th esis of Com p ou n d 13. Compound 2 (6.0 g, 8.4 mmol)
and K2CO3 (1.4 g, 10.1 mmol) were dissolved in a mixed solvent
of THF/MeOH (1:1, 100 mL) and then stirred at room tem-
perature for 3 h to remove the acetate. The reaction mixture
was first extracted with CHCl3 (150 mL × 3), and then, the
combined organic layer was washed with water (50 mL × 3)
and finally dried over anhydrous MgSO4. The solvent was
removed, and the residue was a white solid as a mixture of
compounds 11 and 12 (5.9 g), which was used in the next step
without further purification.
yield) as a white solid: mp 107.5-109.5 °C; Rf 0.3 (petroleum
1
ether/ethyl acetate ) 4:1); [R]30 -11.0° (c 0.47, CH2Cl2); H
D
NMR (CDCl3, 300 MHz) δ 7.51-7.48 (m, 2H), 7.33-7.31 (m,
3H), 5.23 (t, 1H, J ) 9.3 Hz), 5.07-4.94 (m, 2H), 4.71 (d, 1H,
J ) 10.0 Hz), 4.22-4.19 (m, 2H), 3.76-3.70 (m, 1H), 2.09 (s,
3H), 2.08 (s, 3H), 2.02 (s, 3H), 1.99 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 170.4, 170.1, 169.3, 169.1, 133.1, 131.6, 128.9, 128.3,
85.7, 75.8, 73.9, 69.9, 68.2, 62.1, 20.6, 20.5; ESI-MS m/z 463
(M + Na).
A slurry solution of the prepared compounds 11 and 12 (4.1
g, 6.1 mmol), 2,3,4,6-tetra-O-benzoyl-R-D-glucopyranosyl trichlo-
roacetimidate (4) (5.2 g, 7.1 mmol), and anhydrous powdered
molecular sieves (4 Å) in dried CH2Cl2 (50 mL) was stirred at
room temperature under N2 for about 30 min. Then, TMS-
OTf (0.1 mL, 0.6 mmol) was added, and the reaction mixture
was continuously stirred for another 5 h. The solid was
removed by filtration and was washed with CH2Cl2 (200 mL).
The filtrate was first washed with water (100 mL × 2), then
dried over anhydrous Na2SO4, and concentrated under vacuum
to give the residue, which was purified by flash column
chromatography (silica gel, petroleum ether/ethyl acetate )
8:1) to give the product as a white solid (4.7 g, 62% yield): mp
Syn th esis of Com p ou n d 17. Compound 16 (2.4 g, 5.4
mmol) was suspended in a basic solution of methanol (10 mL)
and NaOMe (0.11 g, 2 mmol), the mixture was stirred at room
temperature for 15 min, and the solid was dissolved. This
solution was then treated with ion-exchange resin (H+) for
about 20 min. The resin was filtered off, and the solvent was
removed under vacuum to quantitatively give compound 17
as a white solid (1.4 g).
Syn th esis of Com p ou n d 5.14 To a stirred solution of
compound 17 (7.1 g, 26 mmol) in pyridine (40 mL) was added
a solution of pivaloyl chloride (12.9 mL, 104 mmol) in CH2Cl2
(15 mL) dropwise at 0 °C. The reaction was stirred at the same
temperature for 6 h. The reaction mixture was then diluted
with ethyl acetate (250 mL) and sequentially washed with an
aqueous solution of 1 N HCl (100 mL × 4), a saturated
NaHCO3 solution (50 mL × 3), and then water (50 mL × 2).
The organic layer was dried over anhydrous MgSO4, the
solvent was removed under vacuum, and the residue was
subject to flash column chromatography (silica gel) (petroleum
ether/ethyl acetate ) 3:1) to give the pure compound 5 (8.0 g,
yield 70%) as a white solid: mp 68.5-70 °C; TLC Rf 0.5
72.5-75 °C; Rf 0.4 (petroleum ether/ethyl acetate ) 4:1); [R]30
D
1
-55.8°(c 0.24, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 8.0 (d,
2H, J ) 7.2 Hz), 7.94 (d, 2H, J ) 7.2 Hz), 7.89 (d, 2H, J ) 7.3
Hz), 7.83 (d, 2H, J ) 7.2 Hz), 7.70-7.66 (m, 4H), 7.55-7.24
(m, 18H), 5.88 (t, 1H, J ) 9.6 Hz), 5.66 (t, 1H, J ) 9.7 Hz),
5.52 (dd, 1H, J ) 9.6, 7.9 Hz), 5.10 (d, 1H, J ) 4.3 Hz), 4.88
(d, 1H, J ) 7.8 Hz), 4.66-4.61 (m, 1H), 4.52-4.46 (m, 1H),
4.21-4.08 (m, 1H), 3.74-3.68 (m, 1H), 3.57-3.48 (m, 2H); 13
C
NMR (CDCl3, 75 MHz) δ 218.0, 213.3, 166.1, 165.8, 165.2,
165.1, 141.5, 135.7, 134.7, 133.4, 133.1, 129.7, 129.5, 128.9,
128.3, 127.5, 120.3, 101.0, 74.6, 73.1, 72.1, 72.0, 70.1, 66.2, 63.3,
51.2, 49.6, 43.3, 42.4, 41.6, 39.6, 38.6, 37.1, 36.9, 36.5, 32.3,
31.8, 31.7, 30.9, 27.0, 26.7, 20.5, 19.4, 19.1, 17.0, 15.3, 12.9;
ESI-MS m/z 1364 (M + H2O).
(petroleum ether/ethyl acetate, 2:1); [R]30 -112.9° (c 0.12,
D
CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.57-7.54 (m, 2H),
7.31-7.29 (m, 3H), 4.94 (t, 1H, J ) 9.1 Hz), 4.62 (d, 1H, J )
9.7 Hz), 4.45 (dd, 1H, J ) 12.1, 2.1 Hz), 4.31 (dd, 1H, J 1
)
12.0, J 2 ) 5.7 Hz), 3.62-3.60 (m, 1H), 3.48-3.42 (m, 2H), 3.21
(br s, 1H), 2.72 (br s, 1H), 1.22 (s, 18H); 13C NMR (CDCl3, 75
MHz) δ 180.1, 178.8, 132.6, 131.8, 128.9, 128.1, 88.3, 78.9, 78.4,
70.5, 69.2, 63.5, 39.0, 38.8, 27.1, 27.0; ESI-MS m/z 442 (M +
1), 903 (2 × M + Na).
Syn th esis of Com p ou n d 14. Compound 13 (3.6 g, 2.88
mmol) and anhydrous 4 Å powder molecular sieves (2 g) were
mixed in THF (40 mL), and the generated mixture was treated
with TBAF (tetrabutylammonium fluoride) (TBAF‚3H2O, 3.6
g, 11.5 mmol). The reaction mixture was stirred at room
temperature for 8 h. The solid was removed by filtration and
washed with CHCl3 (200 mL), and the organic phase was then
washed with water (50 mL × 3) and dried over MgSO4. The
solvent was removed under vacuum, and the residue was
purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate ) 2:1) to give compound 14 (2.3 g, 80%
yield) as a white solid: mp 90-92 °C; Rf 0.5 (petroleum ether/
Syn th esis of Com p ou n d 3. To a mixture of compounds 5
(1.0 g, 2.3 mmol) and 6 (3.5 g, 5.6 mmol) and 4 Å powdered
molecular sieves (0.5 g) in dried CH2Cl2 (40 mL) at -78 °C
was added BF3‚Et2O (0.3 mL, 2.3 mmol). After being stirred
for 4 h (at -78 °C), the reaction was quenched with Et3N (5
mL). The solid was then filtered off, and the filtrate was
concentrated under vacuum to give a yellow oil, which was
purified by flash column chromatography (petroleum ether/
ethyl acetate ) 5:1) to quantitatively give compound 3 (3.1 g)
as a white solid: mp 82.5-85 °C; Rf 0.4 (petroleum ether/ethyl
ethyl acetate, 1:1); [R]30 -120°(c 0.13, CH2Cl2); 1H NMR
D
(CDCl3, 300 MHz) δ 8.01 (d, 2H, J ) 7.2 Hz), 7.94 (d, 2H, J )
7.2 Hz), 7.89 (d, 2H, J ) 7.2 Hz), 7.83 (d, 2H, J ) 7.2 Hz),
7.55-7.24 (m, 12H), 5.89 (t, 1H, J ) 9.6 Hz), 5.66 (t, 1H, J )
9.7 Hz), 5.53 (dd, 1H, J ) 9.6, 7.9 Hz), 5.34 (d, 1H, J ) 4.6
Hz), 4.88 (d, 1H, J ) 7.8 Hz), 4.66-4.61 (m, 1H), 4.52-4.47
(m, 1H), 4.21-4.08 (m, 1H), 3.72 (dd, 1H, J ) 9.7, 6.8 Hz),
3.58-3.49 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 218.0, 213.3,
166.1, 165.8, 165.2, 165.1, 141.0, 133.4, 133.1, 129.7, 129.5,
128.9, 128.3, 120.8, 101.0, 74.7, 73.1, 72.1, 72.0, 70.1, 66.2, 63.3,
51.3, 49.7, 43.3, 42.2, 41.6, 39.6, 38.6, 37.2, 36.9, 36.6, 32.4,
acetate, 4:1); [R]30 +90.2° (c 0.35, CH2Cl2); 1H NMR (CDCl3,
D
300 MHz) δ 8.07 (dd, 4H, J 1 ) 7.3, J 2 ) 1.9 Hz), 7.98 (d, 2H,
J ) 7.4 Hz), 7.94 (d, 2H, J ) 7.4 Hz), 7.74 (d, 2H, J ) 7.4 Hz),
7.63 (dd, 2H, J 1 ) 8.0, J 2 ) 1.7 Hz), 7.56 (t, 4H, J ) 8.7 Hz),
7.50-7.45 (m, 5H), 7.40-7.23 (m, 8H), 7.16 (t, 4H, J ) 6.9
Hz), 7.05 (t, 2H, J ) 7.7 Hz), 5.85-5.76 (m, 3H), 5.69 (td, 3H,
J ) 9.5 Hz, J 2 ) 2.0 Hz), 5.44 (t, 1H, J ) 5.3 Hz), 5.35 (s, 1H),
5.23 (s, 1H), 5.08 (d, 1H, J ) 8.2 Hz), 4.75-4.69 (m, 1H), 4.56
(dd, 1H, J 1 ) 11.8 Hz, J 2 ) 3.5 Hz), 4.43-4.35 (m, 2H), 4.19-
J . Org. Chem, Vol. 68, No. 9, 2003 3661

Cheng et al.
4.12 (m, 1H), 4.08 (t, 1H, J ) 6.4 Hz), 3.96 (dd, 1H, J 1 ) 8.2
Hz, J 2 ) 4.8 Hz), 1.41 (d, 3H, J ) 6.2 Hz), 1.37 (d, 3H, J ) 6.1
Hz), 1.23 (s, 9H), 1.16 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
177.9, 176.8, 165.9, 165.8, 165.4, 165.3, 165.2, 133.4, 132.4,
129.9, 129.7, 129.5, 128.5, 128.4, 127.9, 97.6, 97.2, 85.1, 77.0,
76.2, 75.2, 75.0, 71.7, 71.3, 71.0, 70.0, 68.3, 67.8, 63.2, 38.9,
27.2, 26.9, 17.6, 17.5; ESI-MS m/z 1374 (M + NH3), 1380 (M
+ Na).
19 (1.2 g, 70%) as a white solid: mp 132-134 °C; TLC Rf 0.5
(petroleum ether/ethyl acetate, 1:1); [R]30 +81.3° (c 0.1, CH2-
D
1
Cl2); H NMR (d6-DMSO, 300 MHz) 5.99 (t, 1H, J ) 9.5 Hz),
5.75-5.36 (m, 9H), 5.27-5.17 (m, 3H), 5.02 (s, 1H), 4.52-4.20
(m, 8H), 4.08-3.89 (m, 3H), 3.59 (m, 2H), 3.47 (m, 1H), 2.57
(br s, 1H), 2.07 (br s, 1H), 1.99 (s, 1H), 1.93-1.75 (m, 3H); 13
C
NMR (d6-DMSO, 100 MHz) 177.1, 176.3, 165.3, 165.1, 164.8,
164.7, 164.6, 164.4, 140.0, 134.0, 133.6, 133.4, 129.3, 129.2,
129.1, 129.0, 128.9, 128.8, 128.7, 128.5, 128.4, 121.7, 109.4,
99.8, 98.8, 97.3, 95.4, 79.7, 78.3, 77.7, 76.5, 74.1, 73.2, 71.9,
71.7, 71.3, 71.0, 70.8, 70.3, 69.7, 69.5, 67.7, 67.2, 66.4, 63.3,
62.8, 62.5, 55.7, 49.6, 39.7, 39.1, 38.9, 38.5, 38.3, 36.8, 36.3,
35.6, 32.9, 31.6, 30.9, 27.7, 27.0, 26.9, 26.8, 26.7, 26.4, 20.7,
18.9, 17.4, 17.2, 16.5, 15.9, 15.7, 14.0; ESI-MS m/z 2241 (M +
1 - H2O), 1120.
Syn th esis of Com p ou n d 18. A mixture of 14 (2.2 g, 2.2
mmol), 3 (5.9 g, 4.4 mmol), and 4 Å powdered molecular sieves
in dried CH2Cl2 (90 mL) was stirred at room temperature
under N2 for about 30 min, and then, NIS (2.0 g, 8.7 mmol)
and TfOH (76 µL, 0.87 mmol) were added and the coupling
reaction was carried out at room temperature for about 15 min.
After being quenched with Et3N (5 mL) and filtered, the filtrate
was diluted with CH2Cl2 (150 mL), washed sequentially with
saturated aqueous of Na2S2O3 (50 mL × 3) and water (100 mL
× 2), and dried over anhydrous MgSO4. The solvent was
removed under vacuum, and residue was purified by flash
column chromatography (petroleum ether/ethyl acetate ) 2:1)
to give compound 18 (2.6 g, 52.8% yield) as a white solid: mp
138-139.5 °C; Rf 0.5 (petroleum ether/ethyl acetate ) 3:2);
Meth yl P r otod ioscin 1. Sodium (50 mg, 2 mmol) was
dissolved in CH3OH (15 mL), and then, compound 19 (0.1 g,
0.044 mmol) was added. After refluxing for about 35 h, the
solution was neutralized with ion-exchange resin (H+), filtered,
and concentrated to give a yellow oil, which was purified by
flash column chromatography (CHCl3/MeOH/H2O, 60:20:1) to
afford the compound as a white solid (39 mg, yield 83%): mp
[R]30 +65.7° (c 0.14, CH2Cl2); 1H NMR(CDCl3, 300 MHz) δ
175-177 °C; TLC Rf 0.25 (CHCl3/MeOH/H2O, 60:20:1); [R]30
D
D
8.10-7.78 (m, 20H), 7.63-7.20 (m, 30H), 5.89 (t, 1H, J ) 9.6
Hz), 5.85-5.76 (m, 3H), 5.76-5.58 (m, 4H), 5.57-5.44 (m, 3H),
5.21 (s, 2H), 5.06(s, 1H), 4.90 (d, 1H, J ) 7.8 Hz), 4.64 (d, 2H,
J ) 11.7 Hz), 4.57-4.43 (m, 2H), 4.41-4.15 (m, 4H), 3.89 (t,
1H, J ) 9.1 Hz), 3.72 (t, 1H, J ) 9.2 Hz), 3.63 (d, 1H, J ) 12.6
-66.7° (c 0.48, H2O); 1H NMR (pyridine-d5, 300 MHz) 6.39 (s,
1H), 5.84 (s, 1H), 5.30 (s, 1H), 5.01-4.87 (m, 3H), 4.84 (d, 2H,
J ) 7.8 Hz), 4.72-4.49 (m, 4H), 4.48-4.28 (m, 5H),4.28-4.15
(m, 5H), 4.14-3.81 (m, 5H), 3.64-3.55 (m, 2H), 3.25 (s, 3H),
2.85-2.65 (m, 2H); 13C NMR (pyridine-d5, 75 MHz) δ 140.9,
121.8, 112.7, 105.0, 102.9, 102.1, 100.3, 81.3, 78.7, 78.5, 78.1,
78.0, 77.8, 77.0, 75.2, 74.2, 74.0, 72.9, 72.8, 72.6, 71.8, 70.5,
69.6, 64.2, 62.9, 61.2, 56.6, 50.4, 47.3, 40.8, 40.5, 39.8, 39.1,
37.5, 37.2, 34.3, 32.2, 31.7, 30.9, 30.0, 28.1, 21.2, 19.4, 18.7,
18.5, 17.2, 16.3; ESI-MS m/z 1085 (M + Na), 1031 (M + 1 -
CH3OH).
Hz), 3.56-3.51(m, 1H), 2.67-2.45 (m,6H), 2.23 (dd, 1H, J 1
)
12.1 Hz, J 2 ) 6.3 Hz), 2.10-1.87 (m,5H), 1.87-1.73 (m,4H),
1.70-1.47 (m, 9H); 13C NMR (CDCl3, 100 MHz) δ 217.9, 213.3,
178.0, 176.6, 166.1, 165.8, 165.6, 165.4, 165.3, 165.2, 165.1,
164.9, 140.3, 133.4, 133.1, 132.9, 129.7, 129.4, 128.9, 128.6,
128.4, 128.3, 121.7, 101.0, 100.1, 98.4, 96.7, 80.3, 79.5, 77.9,
77.2, 74.6, 73.1, 72.1, 72.0, 71.8, 71.6, 71.2, 70.5, 70.1, 69.7,
68.4, 68.2, 67.3, 66.2, 63.4, 62.6, 51.3, 49.8, 43.3, 41.7, 40.2,
39.6, 39.0, 38.6, 37.2, 37.0, 30.9, 32.3, 31.7, 30.9, 28.4, 27.3,
27.2, 27.0, 26.7, 20.5, 19.4, 17.9, 17.5, 17.0, 15.4, 13.0; ESI-
MS m/z 2257 (M + 1), 2278 (M + Na).
Syn th esis of Com p ou n d 19. The mixture of compound 18
(1.7 g, 0.75 mmol) and NaBH4 (0.85 g, 22.6 mmol) in i-propanol
(70 mL) and CH2Cl2 (10 mL) was stirred at room temperature
for about 7.5 h. The reaction mixture was then extracted with
CH2Cl2 (100 mL × 2), the combined organic layer was washed
with water (100 mL × 3) and dried over anhydrous MgSO4,
and the solvent was removed under vacuum to give an almost
colorless oil, which was purified by flash column chromatog-
raphy (petroleum ether/ethyl acetate, 2:1) to give compound
Ack n ow led gm en t. The author is greatly indebted
to the National Natural Science Foundation of China
for financial support under Grant 30028023 and to the
folks of the Spectroscopic Service Center for assistance
in recording and interpreting high-field NMR spectra
and mass spectra.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
and ESI-MS spectra of compounds 1, 2, 3, 9, 13, 14, 15, and
16. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O020683W
3662 J . Org. Chem., Vol. 68, No. 9, 2003