Novel synthesis of 12,13-seco norditerpenoid alkaloids via semipinacol rearrangement and reaction with Br2-HOAc

Article abstract of DOI:10.1016/S0040-4020(01)00395-7

Treatment of 14-methylsulfonyl pseudaconine 3 with DMF-NaOH at 150 °C for 10 h afforded the desired C-nor and 12,13-seco norditerpenoid alkaloids 16α-methoxyl ketone 7 (70%) and 16β-methoxyl ketone 8 (15%) as a pair of epimers. Reaction of 7 with Br₂-HOAc at room temperature for 1.5-2 h produced the phenols 9 (40%), 10 (10%) and 13 (29%). Whereas, treatment of 8 with Br₂-HOAc under same conditions as the case for 7 gave phenolic compound 9 (38%) besides the by-product α-bromoketone 14 (25%).

Full text of DOI:10.1016/S0040-4020(01)00395-7

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 4705±4712
Novel synthesis of 12,13-seco norditerpenoid alkaloids via
semipinacol rearrangement and reaction with Br2±HOAc
Feng-Peng Wang,a,p Qiao-Hong Chena and Bo-Gang Lib
aDepartment of Chemistry of Medicinal Natural Products, School of Pharmacy, West China University of Medical Sciences,
610041 Chengdu, People's Republic of China
bChengdu Institute of Biology, Chinese Academy of Sciences, 610041 Chengdu, People's Republic of China
Received 2 January 2001; revised 12 March 2001; accepted 30 March 2001
AbstractÐTreatment of 14-methylsulfonyl pseudaconine 3 with DMF±NaOH at 1508C for 10 h afforded the desired C-nor and 12,13-seco
norditerpenoid alkaloids 16a-methoxyl ketone 7 (70%) and 16b-methoxyl ketone 8 (15%) as a pair of epimers. Reaction of 7 with
Br2±HOAc at room temperature for 1.5±2 h produced the phenols 9 (40%), 10 (10%) and 13 (29%). Whereas, treatment of 8 with Br2±HOAc
under same conditions as the case for 7 gave phenolic compound 9 (38%) besides the by-product a-bromoketone 14 (25%). q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
temperature gave compound 3 in good yield (77%) besides
the minor by-products 4 and 5. The site(s) of sulfonation
were ascertained by the respective down®eld shifts of the
corresponding compounds. Treatment of 5 with glacial
acetic acid in an attempt to perform a Wagner±Meerwein
rearrangement produced only the eliminative compound 6.
The NMR spectra of 6 showed distinctive signals at dH 5.79
(1H, d, Jˆ9.7 Hz), 5.99 (1H, dd, Jˆ9.7, 3.5 Hz); dC 137.6,
124.9, for a disubstituted double bond. After optimization of
the reaction conditions, it was ®nally found that reaction of
3 with NaOH in DMF under drastic conditions (1508C, 10 h)
afforded the desired rearrangement products, the 12,13-seco
norditerpenoid alkaloids 7 (70%) and 8 (15%) as a pair of
C-16 epimers. The MS (EI and HREI) of both compounds
showed the same molecular ion (M1) at m/z 465 corre-
sponding to the formula C25H39NO7. The IR and 13C NMR
spectra of 7 and 8 exhibited characteristic signals at
1707 cm21, dC 211.1 and 1709 cm21, dC 208.7, respec-
tively, for six-membered cyclic ketones, attributed to C-13
Many norditerpenoid alkaloids display important biological
activities1 and are a synthetic or structural modi®ed target.2
We have previously reported on the synthesis of various
derivatives of norditerpenoid alkaloids for evaluation of
their biological activities.3 After many unsuccessful
attempts to cleave the 12,13-bond of norditerpenoid
alkaloids, we ®nally found that 12,13-seco norditerpenoid
alkaloids can be prepared via a semipinacol rearrangement
followed by reaction with Br2±HOAc. Herein, we wish to
report the isolation and characterization of these novel
12,13-seco norditerpenoid alkaloids.
2. Results and discussion
The semipinacol rearrangement is very useful for cleavage
and formation of the C±C bonds in organic molecules.4 We
attempted to access the 12,13-seco norditerpenoid alkaloids
as shown in Scheme 1: tosylation of diol A afforded
sulfonate ester B that gave rise to ketone C via a semi-
pinacol rearrangement, subsequent treatment with HX
(XˆBr, Cl) to give the desired alkyl halide.
1
due to the presence of the multi-bond H±13C correlations
between H-12, H-14 and C-13 in the HMBC spectrum
(Table 1). In comparison to the NMR spectra of compound
3, those of compounds 7 and 8 showed the disappearance of
the signals of the OMs group and the appearance of one
ketone group at C-13, in addition to the up®eled shift of
H-14 from 4.70 (d, Jˆ5.2 Hz) to 2.90 (dd, Jˆ16.8,
10.0 Hz) and 2.93 (dd, Jˆ9.6, 6.4 Hz), in compounds 7
and 8, respectively. These observations suggest that 3
could rearrange to 7 and 8 as shown in Scheme 2. The
NOESY spectrum (Fig. 3) of 7 displayed the key correla-
tions of H-9 with H-6b, H-15b and H-16b, indicating a cis-
fused C/D ring system and the con®guration at C-16.
Finally, our hypothetical structure of 7 was con®rmed by
its 2D-NMR (Table 1) and single crystal X-ray analysis
The norditerpenoid alkaloid pseudaconine 2 was chosen as
the starting material from hydrolysis of yunnaconitine 1
available to us in kilogram quantities. Treatment of 2 with
MsCl (3.0 mmol) instead of TsCl in pyridine at room
Keywords: norditerpenoid alkaloid; 12,13-seco norditerpenoid alkaloid;
semi-pinacol rearrangement; aromatization.
Corresponding author. Tel./fax: 186-28-5501368;
e-mail: wfp@wcums.edu.cn
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00395-7

4706
F.-P. Wang et al. / Tetrahedron 57 (2001) 4705±4712
Scheme 1.
(Fig. 1). Similarly, the structure of 8 was determined
unambiguously on the basis of comparison of its 2D-NMR
spectra (Table 4, Fig. 4) with those of 7. Changes of the
chemical shifts for C-7, C-8, C-9, C-13, C-14 and C-15
caused by epimerization at C-16 in the 13C NMR spectra
of 8 were observed. The 12,14-bond cleavages were tried on
compound 7 with Br2±HOAc under different conditions
because 7 did not undergo reaction with HBr or HCl.
First, treatment of 7 in glacial acetic acid with Br2
(1.2 equiv.) in HOAc afforded two major products 9
(40%) and 10 (10%) as white amorphous powders. The
MS (HREI) showed the molecular ions (M1) at m/z
431.2335 and 417.2150 corresponding to C24H33NO6 for 9
and C23H31NO6 for 10, respectively. Their NMR spectra
suggested the presence of aromatic moieties (dH 6.59,
6.52, each 1H, s; dC 137.3, 129.0, 144.0, 107.4, 114.1,
144.7, for 9; dH 6.84, 7.04, each 1H, s; dC 138.3, 128.1,
145.1, 116.4, 113.0, 145.4, for 10) and new methylene
carbon (d 73.4) but the loss of one methoxyl group. These
changes suggested the formation of a tetrahydrofuran
Table 1. 1H and 13C NMR data of compound 7
No.
dH
Mult (JˆHz)
dC
HMBC (H!C)
1
2
3.08
2.19
2.52
3.71
±
dd (10.8, 7.2)
m (hidden) (b)
dd (11.2, 5.6) (a)
dd (12.8, 5.2)
±
80.9 d
34.4 t
C-10, C-11, C-17, C-10
C-1, C-3, C-4
C-1, C-3, C-4
C-4, C-5, C-18
±
C-3, C-4, C-6, C-7, C-
11, C-17, C-18
C-8, C-17, C-60
C-6, C-8, C-15, C-17
±
C-8, C-11, C-12
C-8, C-11, C-12
±
C-11
C-11, C-13
±
C-8, C-10, C-12, C-13
C-8, C-9, C-13, C-16
C-13, C-16
C-15, C-160
C-5, C-21
C-3, C-4, C-180
C-3, C-4, C-5, C-180
C-3, C-4, C-5
C-3, C-4, C-5, C-17
C-22
C-21
C-1
C-6
C-16
C-18
3
4
5
71.6 d
42.2 s
47.3 d
1.84
d (6.4)
6
7
8
9
10
11
12
3.97
2.00
±
2.28
3.67
±
2.28
2.58
±
2.90
2.05
2.51
4.15
3.36
3.56
3.75
2.21
2.98
2.43
1.05
3.17
3.37
3.50
3.32
dd (6.4, 1.6)
d (1.6)
±
dd (16.8, 10.0)
dd (11.2, 10.0)
±
m (hidden) (b)
m (hidden) (a)
±
dd (16.8, 10.0)
dd (9.6, 5.2) (b)
dd (9.6, 8.8) (a)
dd (8.8, 5.2)
d (5.6)
ABq (9.0)
ABq (9.0)
ABq (11.2)
ABq (11.2)
q (7.0)
83.5 d
52.0 d
76.5 s
43.7 d
44.5 d
47.8 s
30.6 t
13
14
15
211.1 s
38.8 d
39.8 t
1
moiety. As compared with 9, the H (13C) NMR spectra of
16
17
18
79.1 d
61.5 d
76.1 t
compound 10 showed the absence of an aromatic methoxyl
group but the presence of an additional phenolic hydroxyl
group by comparison of the MS spectra for both
compounds. In order to con®rm unambiguously the struc-
ture of compound 9, the acetyl derivatives 11 (42%) and 12
(a colorless rhombic crystals, 57%) were prepared from diol
9. The structure of 12 was proved by the single crystal X-ray
analysis (Fig. 2), leading to con®rmation of the structures of
19
46.7 t
21
22
10
48.6 t
13.2 q
55.9 q
58.1 q
58.1 q
59.0 q
t (7.0)
s
s
s
s
60
160
180
1
9 and 10. All the H and 13C signals of compound 9 were
assigned by its 2D-NMR spectra (Table 4). It is worth noting

F.-P. Wang et al. / Tetrahedron 57 (2001) 4705±4712
4707
Scheme 2. (a) DMF±NaOH, 1508C, 10 h; (b) Br2 (1.2 equiv.) in HOAc, rt, 1.5 h or 1 h; (c) Br2 (2 equiv.) in HOAc, rt, 2 h.
that when compound 7 was treated with Br2 (2 equiv.) in
HOAc, another new compound 13 (29%) was formed. As
compared with 9, compound 13 has only an additional
bromine atom, locating at C-14 by 13C NMR, and con-
comitant shift changes of the carbons C-8, C-13, C-14 and
C-15 were observed. Thus, the structure of compound 13
was determined simply by comparison of the 13C NMR data
with those of 9.
Finally, it was interesting to ®nd that treatment of compound
8 with Br2 (1.2 equiv.) in HOAc under the same conditions
as for 7 gave the a-bromoketone 14 (25%) along with 9
(38%). Comparison of the 13C NMR spectra (Table 4) of
compounds 8 and 14 displayed differences only in the
signals of carbons C-5, C-9, C-10, C-12, C-13 and C-14,
strongly suggesting the bromine atom in 14 to be located at
C-14.
In conclusion, a novel ®rst access to the 12,13-seco
norditerpenoid alkaloids, with aromatization of the D ring
in the ®nal products, has been developed. The amount of
bromine in the cleavage reactions has a strong in¯uence on
the 12,13-seco norditerpenoid alkaloids. The results
described here should prove helpful for similar modi®ca-
tions of other norditerpenoid alkaloids.
Figure 1. ORTEP drawing of 7.

4708
F.-P. Wang et al. / Tetrahedron 57 (2001) 4705±4712
Figure 2. ORTEP drawing of 12.
3. Experimental
(C-8), 71.7 (C-3), 61.2 (C-17), 59.0 (C-180), 58.0 (C-160),
57.6 (C-60), 55.7 (C-10), 53.2 (C-7), 50.2 (C-11), 48.7
(C-21), 48.5 (C-5), 47.6 (C-9), 47.0 (C-19), 43.1 (C-4),
42.1 (C-15), 41.2 (C-10), 38.4 (14-SO2CH3), 35.2 (C-2),
33.5 (C-12), 13.3 (C-22); m/z (EI) 561 (3 M1), 546 (3
M215), 530 (100% M231); HRMS (EI): M1 found
561.2598. C26H43NO10S requires 561.2607.
3.1. General
Melting points were determined on a Ko¯er block
(uncorrected); optical rotations were measured in a 1.0 dm
tube with a PE-341 polarimeter at 20^18C. IR spectra were
recorded on a Nicolet 200 SXV spectrometer; MS spectra
were obtained with a Spec-3000 VG 7070 E GC/MS/DES
Compound 4. White amorphous powder; mp 137±1398C; Rf
20
instrument; H and 13C NMR spectra were acquired on a
1
(50% cyclohexane±acetone) 0.28; [a]D ˆ123.1 (c 0.38,
CHCl3); nmax(KBr) 3420 (OH), 2918, 2840, 1635, 1350,
1178, 1100 cm21; dH (200 MHz, CDCl3) 5.02 (1H, d,
Jˆ5.1 Hz, H-14b), 3.39, 3.29, 3.29, 3.23 (each 3H, s,
OCH3£4), 3.14, 3.06 (each 3H, s, O3SCH3£2), 1.11 (3H,
t, Jˆ6.9 Hz, NCH2CH3); dC (50 MHz, CDCl3) 90.1 (C-13),
84.1 (C-1), 82.2 (C-6), 82.2 (C-14), 79.9 (C-16), 77.0
(C-18), 72.6 (C-8), 71.5 (C-3), 61.4 (C-17), 59.0 (C-180),
57.5 (C-160), 57.0 (C-60), 55.7 (C-10), 52.8 (C-7), 50.1
(C-11), 48.9 (C-21), 47.7 (C-5), 47.3 (C-19), 43.3 (C-9),
43.2 (C-4), 41.9 (C-15), 41.5 (C-10), 40.2 (13-SO2CH3),
39.1 (14-SO2CH3), 34.8 (C-2), 30.0 (C-12), 13.4 (C-22);
m/z (EI) 639 (2 M1,) 608 (100%); HRMS (EI): M1, found
639.2396, C27H45NO12S2, requires 639.2383.
Bruker AC-E 200 or Varian INOVA-400/54 spectrometer,
in CDCl3 with TMS as internal standard; Silica gel GF254
and H (10±40 mm, Qingdao Sea Chemical Factory, China)
were used for TLC, Chromatotron and CC. Spots on
chromatograms were detected with modi®ed Dragendorff's
reagent. Only key signals in the 1H NMR spectra are
reported.
3.1.1. Compound 2. A solution of yunnaconitine (1) (4 g,
6 mmol) in an 8% NaOH solution in methanol (60 mL) was
heated at 608C for 30 min, and evaporated in vacuo to give a
residue that was diluted with H2O (5 mL), and extracted
with CHCl3 (10 mL£4). The combined chloroform
solutions were dried over anhydrous Na2SO4 and after
removal of the solvent pseudaconine (2) (2.92 g, 99.6%
yield) was obtained as white amorphous powder that was
identi®ed by comparison of mp (92±928C, lit.5; 91±928C),
Compound 5. White amorphous powder; mp 172±1738C; Rf
20
(50% cyclohexane±acetone) 0.61; [a]D ˆ19.3 (c 0.41,
CHCl3). nmax (KBr) 3438 (OH), 2920, 2820, 1640, 1450,
1350, 1180, 1100 cm21, dH (200 MHz, CDCl3) 5.00 (1H, d,
Jˆ5.1 Hz, H-14b), 4.70 (1H, d, Jˆ5.6 Hz, H-3b), 3.37,
3.34, 3.25, 3.22, (each 3H, s, OCH3£4), 3.13, 3.05, 2.99,
(each 3H, s, O3SCH3£3), 1.05 (3H, t, Jˆ7.1 Hz, NCH2CH3);
dC (50 MHz, CDCl3) 90.1 (C-13), 84.0 (C-14), 82.5 (C-16),
81.4 (C-1), 81.0 (C-6), 79.6 (C-3), 72.6 (C-8), 71.0 (C-18),
61.0 (C-17), 58.4 (C-180), 57.7 (C-160), 57.0 (C-60), 56.1
(C-10), 53.3 (C-7), 49.5 (C-11), 48.8 (C-21), 47.8 (C-5), 47.0
(C-19), 45.8 (C-9), 42.9 (C-4), 41.8 (C-15), 41.1 (C-10),
40.2 (13-SO2CH3), 39.1 (14-SO2CH3), 37.9 (14-SO2CH3),
34.7 (C-2), 33.8 (C-12), 13.4 (C-22); m/z (EI) 621 (2
M12CH3SO3H) 606 (100%); HRMS (EI): 717.2186,
C28H47NO14S3 requires 717.2158.
[a]D ˆ149.8 (c 0.56, CHCl3) [lit.5 149 (CHCl3)], TLC
20
(silica gel GF254, ether±acetone/4:1; CHCl3/MeOH/9:1)
and an H(13C) NMR data with the authentic sample.
1
3.1.2. Compounds 3, 4, 5 and 6. To a mixture of MsCl
(0.09 mL, 1.15 mmol) and pyridine (2 mL), pseudaconine
(2, 185 mg, 0.38 mmol) was added and the solution was
allowed to stand at room temperature for 1 day. The crude
reaction mixture was subjected to column chromatography
on silica gel H (30 g) using cyclohexane±acetone (7:3) as
eluent to yield compounds 3 (165 mg, 77%), 4 (10 mg, 4%)
and 5 (15 mg, 6%).
Compound 3. White amorphous powder; mp 129±1308C; Rf
20
To a solution of compound 5 (50 mg, 0.07 mmol) in
glacial acetic acid (13 mL) was added water (5 mL).
The solution was heated at 1308C for 1 h and basi®ed to
pH 11 with NH4OH solution, and then extracted with
CHCl3 (5 mL£3). The combined chloroform solutions
were dried over anhydrous Na2SO4 and evaporation of
the solvent in vacuo gave compound 6 (30 mg, 80%) as
a white amorphous powder, mp 158±1598C; Rf (50%
(50% cyclohexane±acetone) 0.31; [a]D ˆ122.3 (c 0.34,
CHCl3); nmax(KBr) 3432 (OH), 2922, 2840, 1638, 1454,
1352, 1180, 1095 cm21; dH (200 MHz, CDCl3) 4.70 (1H,
d, Jˆ5.2 Hz, H-14b), 4.02 (1H, d, Jˆ6.7 Hz, H-6b), 3.66
(1H, d, Jˆ5.9 Hz, H-3b), 3.42, 3.29, 3.29, 3.19 (each 3H, s,
OCH3£4), 3.09 (3H, s, SO2CH3), 1.05 (3H, t, Jˆ7.0 Hz,
NCH2CH3); dC (50 MHz, CDCl3), 85.9 (C-14), 82.4 (C-6),
82.4 (C-16), 82.1 (C-1), 77.3 (C-18), 74.8 (C-13), 73.4

F.-P. Wang et al. / Tetrahedron 57 (2001) 4705±4712
4709
20
cyclohexane±acetone) 0.70; [a]D ˆ132.0 (c 0.46,
CHCl3); nmax (KBr) 3430 (OH), 2920, 2820, 1638, 1450,
1350, 1175, 1100 cm21; dH (200 MHz, CDCl3) 5.99 (1H,
dd, Jˆ9.7, 3.5 Hz, H-2), 5.79 (1H, d, Jˆ9.7 Hz, H-3), 3.38,
3.34, 3.31, 3.30 (each 3H, s, OCH3£4), 3.14, 3.07 (each 3H,
s, CH3SO2£2), 1.08 (3H, t, Jˆ7.0 Hz, NCH2CH3); dC
(50 MHz, CDCl3) 137.6 (C-2), 124.9 (C-3), 89.1 (C-13),
84.3 (C-14), 83.0 (C-16), 81.8 (C-6), 79.9 (C-1), 78.1
(C-18), 74.0 (C-8), 59.2 (C-180), 58.0 (C-17), 57.7
(C-160), 57.0 (C-60), 56.1 (C-10), 52.6 (C-21), 50.4 (C-7),
48.7 (C-11), 47.6 (C-19), 47.3 (C-5), 47.3 (C-9), 43.5
(C-15), 41.4 (C-10), 40.7 (C-4), 40.2 (3-SO2CH3), 39.1
(14-SO2CH3), 33.1 (C-12), 12.6 (C-22); m/z (EI) 621 (11
M1), 606 (23 M1215), 590 (19% M1231); HRMS (EI)
621.2273, C27H43NO11S2 requires 621.2277.
Figure 3. Key NOESY correlations of 7.
3.1.3. Compounds 7 and 8. To a solution of compound 3
(160 mg, 0.28 mmol) in DMF (10 mL) was added NaOH
(30 mg), and the resulting solution heated under re¯ux at
1508C for 10 h. After work up, the crude reaction mixture
was chromatographed on silica gel H (10 g) eluting with
cyclohexane±acetone (9:1) to give compounds 7 (95 mg,
70%) and 8 (20 mg, 15%).
Compound 7. Colorless rhombic crystals; mp 214±2158C;
20
Rf (70% cyclohexane±acetone) 0.36; [a]D ˆ186.9 (c
0.68, CHCl3); nmax (KBr) 3496 (OH), 2966, 2913, 2871,
2807, 1707 (CvO, six-membered cyclic ketone), 1458,
1103 cm21; dH (400 MHz, CDCl3) and dC (100 MHz,
CDCl3) see Table 1; NOESY see Fig. 3; m/z (EI) 465 (14
M1), 434 (100% M1231); HRMS (EI): 465.2718,
C25H39NO7 requires 465.2726; Crystal structure for 7: a
colorless orthorhombic crystal from acetone was mounted
Figure 4. Key NOESY correlations of 8.
1
Table 2. H and 13C NMR data of compound 9
No.
dH
Mult (JˆHz)
dC
HMBC (H!C)
NOESY
1
2
3.71
2.17
3.14
3.98
±
1.90
3.72
3.05
±
±
2.98
±
3.73
4.37
±
6.59
6.52
±
2.98
3.43
3.95
2.46
3.26
2.48
1.05
3.35
3.86
3.35
5.83
m (hidden)
80.6 d
33.5 t
C-2, C-11, C-17
C-1, C-3, C-4, C-11
H-3, H-5, H-12b
H-12a
m (hidden) (b)
dd (12.0, 10.0 (a)
dd (10.0, 5.2)
3
4
5
6
7
8
9
10
11
12
75.4 d
43.5 s
47.0 d
91.7 d
49.3 d
137.3 s
129.0 s
44.4 d
51.3 s
73.4 t
C-4, C-5, C-19
±
C-10, C-11, C-17, C-19
C-4, C-7, C-8, C-17, C-60
C-5, C-9, C-11, C-15, C-17
H-18
±
H-1, H-3, H-7, H-18
H-10, H-18, H-180
H-5, H-12b
d (6.4)
hidden
t (8.4)
±
±
±
±
±
±
C-5, C-8, C-9, C-11, C-14, C-7
±
C-1, C-9, C-11
br.s (W1/2ˆ8.4)
H-1, H-14
±
H-2, H-17
H-1, H-7
±
H-10, H-160
dd (9.6, 8.4) (a)
dd (9.6, 8.0) (b)
±
13
14
15
16
17
18
144.0 s
107.4 d
114.1 d
144.7 s
66.7 d
±
C-8, C-9, C-10, C-13
C-7, C-8, C-13, C-16
±
C-5, C-6, C-7, C-19, C-21
C-3, C-4, C-5, C-180
C-3, C-4, C-5, C-180
C-3
C-4, C-5, C-17, C-18
C-22
C-21
C-6
s
s
±
br.s (W1/2ˆ8.4)
H-12b, H-60, H-21
H-3, H-5
H-5, H-6
H-17
ABq (9.0)
ABq (9.0)
78.4 t
19
ABq (12.0)
ABq (12.0)
m (hidden)
t (6.8)
s
s
47.1 t
H-21
21
22
60
160
180
13-OH
48.8 t
13.1 q
58.0 q
55.9 q
59.3 q
H-17, H-19
H-17, H-19
H-17
H-14, HO-13
H2-18
H-160
C-16
C-18
s
br.s

4710
F.-P. Wang et al. / Tetrahedron 57 (2001) 4705±4712
on a P4 four circle diffractometer and exposed to graphite-
monochromated MoKa irradiation. The unit cell parameters
(COO), 1615, 1502, 1450, 1200, 1100 cm21
;
dH
(200 MHz, CDCl3) 6.66, 6.61 (each 1H, s, Ar±H), 4.33
(1H, dd, Jˆ9.8, 8.2 Hz, H-12b), 3.78, 3.31, 3.30 (each
3H, s, OCH3£3), 2.25 (3H, s, OAc), 1.03 (3H, t,
Jˆ7.2 Hz, NCH2CH3); dC (50 MHz, CDCl3) see Table 3;
m/z (EI) 473 (59 M1), 458 (42 M1215), 442 (100 M1231),
430 (18), 400 (24%); HRMS (EI) 473.2408, C26H35NO7
requires 473.2413.
Ê
Ê
Ê
are aˆ9.160 (2) A, bˆ12.862 (2) A, cˆ10.307 (10) A in
space group P212121, of the 3771 measured with
1.98,u,27.508 scan, 3116 were independently observed
at the level of F0.4s (F0). The structure was solved by
the direct method using the program shelxtl and the
atomic squares on F2 method. The ®nal R indexes
[I . 2sꢀI†] was R1ˆ0.0375, WR2ˆ0.0840.
Table 3. 13C NMR data of compounds 10, 11, 12 and 13
Compound 8. White amorphous powder; mp 90±918C; Rf
No.
10
11
12
13
20
(70% cyclohexane±acetone) 0.63; [a]D ˆ167.0 (c 0.41,
CHCl3); nmax (KBr) 3407 (OH), 2927, 2854, 2820, 1709
;
1
2
3
4
5
6
7
8
81.2 d
35.1 t
70.7 d
44.5 s
45.5 d
92.9 d
49.8 d
138.3 s
128.1 s
44.4 d
51.9 s
73.2 t
145.1 s
116.4 d
113.0 d
145.4 s
70.7 d
74.0 t
47.8 t
49.1 t
13.2 q
58.0 q
±
80.4 d
33.4 t
75.2 d
43.5 s
46.9 d
91.0 d
48.9 d
137.9 s
128.6 s
44.8 d
51.2 s
73.3 t
144.4 s
122.1 d
109.0 d
149.1 s
66.3 d
78.1 t
47.0 t
48.8 t
13.0 q
58.1 q
55.9 q
59.2 q
±
79.8 d
30.3 t
79.6 d
33.4 t
74.9 d
43.4 s
46.4 d
91.8 d
50.7 d
138.8 s
129.6 s
44.8 d
52.2 s
72.6 t
141.3 s
110.9 s
106.9 d
145.0 s
65.8 d
78.1 t
47.0 t
48.8 t
13.0 q
58.1 q
56.3 q
59.2 q
±
(CvO, six-membered cyclic ketone), 1450, 1100 cm21
72.6 d
42.6 s
45.1 d
91.3 d
48.8 d
137.8 s
128.6 s
44.4 d
51.1 s
73.5 t
144.3 s
122.1 d
109.0 d
149.0 s
66.2 d
71.9 t
dH (400 MHz, CDCl3) and dC (100 MHz, CDCl3) see
Table 4; NOESY see Fig. 4; m/z (EI) 465 (8 M1), 434 (85
M1231), 422 (90%); HRMS (EI): 465.2705, C25H39NO7
requires 465.2726.
9
3.1.4. Compounds 9 and 10. To a solution of compound 7
(270 mg, 0.58 mmol) in glacial acetic acid (10 mL), was
added Br2 (0.035 mL, 0.68 mmol) in HOAc (3 mL) drop-
wise and the solution was stirred at room temperature for
1.5 h. After basifying to pH.9 with the NH4OH solution
was extracted with CHCl3 (15 mL£5) and the combined
chloroform solutions were dried over anhydrous Na2SO4.
Evaporation in vacuo afforded a residue (255 mg) that was
separated on a column (silica gel H 10 g) eluting with
hexane±acetone (5:1) to afford 9 (100 mg, 40%) and 10
(24 mg, 10%).
10
11
12
13
14
15
16
17
18
19
21
22
60
47.7 t
48.8 t
12.9 q
58.3 q
55.8 q
58.9 q
169.9 s
21.0 q
168.9 s
20.5 q
160
180
3-OAc
58.7 q
±
Compound 9. White amorphous powder; mp 134.5±1368C;
20
Rf (70% cyclohexane±acetone) 0.39; [a]D ˆ1140.0 (c
0.35, CHCl3); nmax (KBr) 3420 (OH), 2920, 2840, 1620,
1590, 1510, 1450, 1100 cm21; dH (400 MHz, CDCl3) and
dC (100 MHz, CDCl3) see Table 2; m/z (EI) 432 (40
M111), 416 (43 M1215), 400 (100% M1231); HRMS
(EI): 431.2335, C24H33NO6 requires 431.2307).
13-OAc
±
169.0 s
20.5 q
±
±
Compound 12. Colorless rhombic crystals (95% EtOH); mp
201±2028C; Rf (70% cyclohexane±acetone) 0.52;
Compound 10. White amorphous powder; mp 185±1868C;
20
20
Rf (70% cyclohexane±acetone) 0.20; [a]D ˆ1132.0 (c
[a]D ˆ1123.6 (c 0.44, CHCl3); nmax (KBr) 3060, 2928,
0.37, EtOH); nmax (KBr) 3405 (OH), 3220 (OH), 2920,
2880, 2830, 1620, 1608, 1515, 1460, 1100 cm21; dH
(200 MHz, C5D5N) 7.04, 6.84 (each 1H, s, Ar±H), 4.29
(1H, dd, Jˆ15.6, 9.6 Hz, H-12b), 3.21, 3.17 (each 3H, s,
OCH3£2), 0.81 (3H, t, Jˆ7.1 Hz, NCH2CH3); dC (50 MHz,
C5D5N) see Table 3; m/z (EI) 417 (49 M1), 402 (38
M1215), 386 (100% M1231); HRMS (EI) 417.2150,
C23H31NO6 requires 417.2151.
2868, 2835, 1755, 1740, 1620, 1508, 1450, 1380, 1250,
1230, 1210, 1120, 1100 cm21; dH (200 MHz, CDCl3)
6.66, 6.59 (each 1H, s, Ar±H), 5.12 (1H, dd, Jˆ11.4,
5.0 Hz, H-3b), 4.32 (1H, dd, Jˆ10.0, 8.2 Hz, H-12b),
3.77, 3.30, 3.19 (each 3H, s, OCH3£3), 2.24, 2.05 (each
3H, s, OAc£2), 1.01 (3H, t, Jˆ7.1 Hz, NCH2CH3); dC
(50 MHz, CDCl3) see Table 3; m/z (EI) 515 (60 M1), 500
(35 M1215), 484 (100 M1231), 473 (15), 456 (14), 442
(22%); HRMS (EI) 515.2501, C28H37NO8 requires
515.2519; crystal structure for 12: a colorless orthorhombic
crystal from 95% EtOH was mounted on the same instru-
ment and method as 7. The unit cell parameters are
3.1.5. Acetylation of 9: compounds 11 and 12. To a solu-
tion of compound 9 (120 mg, 0.27 mmol) in pyridine
(5 mL), acetic anhydride (0.5 mL, 4.5 mmol) was added
and the solution was stirred at room temperature for 20 h,
and then evaporated to dryness under reduced pressure to
give a residue (159 mg) that was separated on a column
(silica gel H, 5 g) eluting with hexane±acetone (6:1) to
afford the compounds 11 (55 mg, 42%) and 12 (82 mg,
57%).
Ê
Ê
Ê
aˆ8.3730 (10) A, bˆ17.916 (2) A, cˆ17.934 (2) A in
space group P212121, of the 3522 measured with
1.61,u,26.018 scan, 3337 were independently observed
at the level of F0.4s (F0). The ®nal R indices
[I . 2sꢀI†] was R1ˆ0.0375, WR2ˆ0.0703.
3.1.6. Compound 13. To a solution of compound 7
(110 mg, 0.23 mmol) in glacial acetic acid (5 mL), was
added Br2 (0.025 mL, 0.48 mmol) in HOAc (2 mL) drop-
wise and the solution was stirred at room temperature for
Compound 11. White amorphous powder; mp 137±1388C;
20
Rf (70% cyclohexane±acetone) 0.46; [a]D ˆ1121.4 (c
0.70, CHCl3); nmax (KBr) 3420 (OH), 2920, 2860, 1760

F.-P. Wang et al. / Tetrahedron 57 (2001) 4705±4712
4711
Table 4. NMR data for compounds 8 and 14
No.
8
14
dH
Mult (JˆHz)
dC
HMBC (H!C)
dC
1
2
3.09
2.21
2.51
3.70
±
dd (10.8, 7.2)
m (hidden) (a)
m (hidden) (b)
dd (12.4, 4.4)
±
81.0 d
34.3 t
C-3, C-10, C-11, C-17, C-10
C-1, C-3, C-4
C-1, C-3, C-4
C-2, C-18, C-19
±
C-4, C-7, C-10, C-11, C-17,
C-18
C-4, C-7, C-8, C-60, C-17
C-5, C-6, C-8, C-15, C-17
81.0 d
34.0 t
3
4
5
72.0 d
42.4 s
47.6 d
71.7 d
42.3 s
50.5 d
1.79
d (6.4)
6
7
8
9
10
11
12
4.03
2.03
±
2.91
2.37
±
2.37
2.53
±
2.93
2.44
3.59
3.23
3.60
3.84
2.25
3.00
2.44
1.08
3.18
3.36
3.34
3.31
dd (6.4, 1.6)
d (2.0)
±
dd (9.6, 6.4)
m (hidden)
±
m (hidden) (a)
m (hidden) (b)
±
dd (9.6, 6.4)
m (hidden)
d (3.2)
br.s
ABq (8.8)
ABq (8.8)
ABq (11.2)
ABq (11.2)
m (hidden)
t (7.1)
82.9 d
50.3 d
72.7 s
46.8 d
44.3 d
47.8 s
31.3 t
82.9 d
50.5 d
73.4 s
59.5 d
41.7 d
47.2 s
40.9 t
±
C-8, C-11, C-13
C-8, C-9, C-12
±
C-1, C-11, C-13
C-9, C-10, C-16
±
C-8, C-10, C-12, C-13
C-8, C-9, C-16
C-8, C-13. C-160
C-5, C-6, C-8, C-10, C-11
C-5, C-180
C-3, C-4, C-5, C-180
C-3, C-4, C-18, C-21
C-3, C-21
C-22
C-21
C-1
C-6
C-16
C-18
13
14
15
16
17
18
208.7 s
36.3 d
37.5 t
80.7 d
61.5 d
76.9 t
203.2 s
47.4 s
37.7 t
80.4 d
61.4 d
76.5 t
19
46.9 t
47.0 t
21
22
10
48.7 t
13.1 q
55.8 q
57.7 q
58.1 q
59.1 q
48.8 t
13.0 q
55.7 q
57.9 q
58.6 q
59.0 q
s
s
s
s
60
160
180
2 h, and then after being basi®ed to pH.9 with saturated
aqueous Na2CO3 the solution was extracted with chloroform
(15 mL£5). The combined chloroform solutions were dried
over anhydrous Na2SO4, and then evaporation in vacuo
afforded a residue that was chromatographed on a column
(Si gel 5 g) eluting with cyclohexane±acetone (6:1) to
give 13 as a white amorphous powder (30 mg, 29%); mp
287±2888C; Rf (70% cyclohexane±acetone) 0.53;
Compound 14. White amorphous powder; mp 130±1318C;
20
Rf (70% cyclohexane±acetone) 0.70; [a]D ˆ110.3 (c
0.42, CHCl3). nmax (KBr) 3500 (OH), 2930, 2820, 1725,
1635, 1450, 1100 cm21; dH (200 MHz, CDCl3) 4.44 (1H,
brs, exchangeable in D2O, OH), 3.90 (1H, dd, Jˆ6.4,
2.0 Hz, H-6b), 3.80, 3.54 (each 1H, ABq, Jˆ9.0 Hz,
H2-18), 3.39, 3.32, 3.27, 3.14 (each 3H, s, OCH3£4), 1.04
(3H, t, Jˆ7.0 Hz, NCH2CH3); dC (50 MHz, CDCl3) see
Table 4; m/z (EI) 545 (14 M11), 543 (14 M21), 530 (15
M1215), 528 (17 M2215), 514 (100 M1231), 512 (100
M2231), 434 (87%); HRMS (EI) 543.1814 (M21),
C25H38NO7Br requires 543.1831.
20
[a]D ˆ1143.9 (c 0.90, CHCl3); nmax (KBr) 3432 (OH),
2938, 2860, 1610, 1570, 1490, 1470, 1450, 1110 cm21; dH
(200 MHz, CDCl3) 6.55 (1H, s, H-15), 5.96 (1H, brs,
exchangeable in D2O, HO-13), 4.72 (1H, t, Jˆ9.2 Hz,
H-12b), 3.86 (3H, s, aromatic methoxyl), 3.30, 3.28 (each
3H, s, OCH3£2), 1.04 (3H, t, Jˆ7.1 Hz, NCH2CH3); dC
(50 MHz, CDCl3) see Table 3; m/z (EI) 511 (51 M11), 509
(53 M21), 496 (56 M1215), 494 (57 M2215), 480 (10
M1231), 478 (15 M2231), 431 (58), 416 (29), 400
(100%); HRMS (EI): 509.1361 (M21), C24H32NO6 Br
requires 509.1413.
Acknowledgements
The authors thank the National Natural Science Foundation
of China (No. 30070888) and the Chengdu Diao Pharama-
ceutical Company for support of this work. We also thank
Professor Xiao-Tian Liang for helpful discussions on the
subject.
3.1.7. Compounds 9 and 14. To a solution of compound 8
(176 mg, 0.38 mmol) in HOAc (7 mL), was added Br2
(0.023 mL, 0.45 mmol) in HOAc (2 mL) dropwise and the
solution was stirred at room temperature for 1 h. After being
basi®ed to pH.9 with saturated Na2CO3, the solution was
extracted with chloroform (10 mL£5). The combined
chloroform solutions were dried over anhydrous Na2SO4,
and evaporated in vacuo to give a residue (172 mg) that
was chromatographed on a column (silica gel H, 6 g) eluting
with cyclohexane±acetone (6:1) to give 9 (62 mg, 38%) and
14 (42 mg, 25%).
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