To seek an approach toward the chemical conversion of C19- diterpenoid alkaloids to taxoids

Article abstract of DOI:10.1016/j.tet.2004.12.058

This study, as a part of conversion of the C₁₉-diterpenoid alkaloids to the taxoids, described the search of a suitable route to the key intermediate B with four approaches (ABC, ACB, BCA, and CAB) designed and examined. In these cases, a new and efficient approach (CAB) toward the synthesis of the vital intermediates 51 or 52 has been developed. The key steps include the use of a semipinacol rearrangement treatment of 41 with NaOH/DMF under refluxing conditions for 30 min to afford 42, and the rupture of the N-C-19 bond found in 45 or 48 to give 51 or 52, respectively, through NBS imination followed by the creation of the oxaziridine 47 or the nitrone 50 and finally HIO₄ oxidation cleavages.

Full text of DOI:10.1016/j.tet.2004.12.058

Tetrahedron 61 (2005) 2149–2167
To seek an approach toward the chemical conversion of
C19-diterpenoid alkaloids to taxoids
*
Feng-Peng Wang and Liang Xu
Department of Chemistry of Medicinal Natural Products, West China College of Pharmacy, Sichuan University, No. 17, Duan 3,
Renmin Nan Road, Chengdu 610041, People’s Republic of China
Received 9 October 2004; revised 17 December 2004; accepted 17 December 2004
Available online 20 January 2005
Abstract—This study, as a part of conversion of the C19-diterpenoid alkaloids to the taxoids, described the search of a suitable route to the
key intermediate B with four approaches (ABC, ACB, BCA, and CAB) designed and examined. In these cases, a new and efficient approach
(CAB) toward the synthesis of the vital intermediates 51 or 52 has been developed. The key steps include the use of a semipinacol
rearrangement treatment of 41 with NaOH/DMF under refluxing conditions for 30 min to afford 42, and the rupture of the N-C-19 bond found
in 45 or 48 to give 51 or 52, respectively, through NBS imination followed by the creation of the oxaziridine 47 or the nitrone 50 and finally
HIO4 oxidation cleavages.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
starting materials has focused on the C19-diterpenoid
alkaloids from Aconitum species, which are widely
distributed in southwest area of China.15 Among the
numerous naturally occurring this type alkaloids, only
several compounds such as yunaconitine (3), indaconitine
(4), and crassicauline A (5), etc. isolated from many plants
are considered to be very useful.
Since Taxolw (paclitaxel, 1)1 and Taxoterew (docetaxel, 2)2
are currently two of the most exciting drugs in cancer
chemotherapy,3–4 efforts to synthesize taxol (1) have
produced a wide variety of strategies for construction of
the core structures5 and to-date six total syntheses have been
reported.6–11 The diterpenoid alkaloids are a group of highly
oxygenated complex natural products displaying a lot of
interesting chemical reactions.12 They were isolated
mainly from both Aconitum and Delphinium plants
(Ranunculaceae) as a rich source.13 With careful skeletal
analysis we have designed a strategy toward conversion of
the C19-diterpenoid alkaloids to the taxoids via a series of
the degradational steps (Scheme 1). As showed in Scheme 1,
the key steps for conversion from A (C19-diterpenoid
alkaloids) include mainly modifications of the A ring
(de-amination, e.g. cleavage of the N-C-19 and N-C-17
bonds), the B ring (cleavage of the C-17–C-7 and C-10–
C-11 bonds), and the C ring (C-10 or C-12 functionality and
cleavage of the C-10–C-12 and C-12–C-13 bonds). After
these cleavages to give the key intermediate D which was
converted to the taxoids E via a cyclization by pinacol-like
coupling developed by Swindell.14
In the course of studies on the chemistry of C19-diterpenoid
alkaloids,16 we have broken through the key cleavages of
rings A, B, and C in these alkaloids (Scheme 1, F). Although
the results already have provided an important base for
conversion into the taxoids, it takes still great effort to afford
the vital intermediate C (Scheme 1). This is due to the most
rigidly complex fused polycyclic system, chemical com-
plexity derived from the N-atom, and strong dependence up
on the substrates of the C19-diterpenoid alkaloids. In an
effort to seek an effective sequence allowed us to convert A
obtained from the starting material yunaconitine (3) into the
key intermediate C (Scheme 1) we describe in this paper a
number of chemical transformation and other new findings
for the purpose. To this end, four different lines of attack
(approaches ABC, ACB, BCA, and CAB) designed
according to modified sequence of the ring systems have
been undertaken.
On the basis of these considerations, our search for the
2. Results and discussion
2.1. Approach ABC
Keywords: C19-diterpenoid alkaloid; Yunaconitine; N,19-seco C19-diter-
penoid alkaloid; Semipinacol rearrangement; Imine; Oxaziridine; Nitrone;
Taxoid.
* Corresponding author. Tel./fax: C86 28 85501368;
e-mail: wfp@wcums.edu.cn
We reported that HIO4 oxidation of the N,O-mixed acetal 6
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.058

2150
F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
Scheme 1.
gave oxaziridine (7)16t,17 which is unstable to acids,
bases, and heating due to decomposition or formation of
nitrone 816t probably because of participation of the
hydroxyl at C-8 and the aldehyde group (Scheme 2).
But an attempt to reduce the aldehyde group with
NaBH4–CH3OH, or KBH4–AcOH, which should permit
avoiding reformation of the N-C-19 bond in 7 or 9,
gave only compounds 10 (49%) or 11 (73%), respec-
tively. Treatment of 7 with K2CO3 in CH3OH–H2O
afforded compounds 9 and 12 (ca.3:1) in 98% total
yield (Scheme 3). The presence of N-CH3 group in 10
1
and 11 was supported by the H and 13C NMR spectra
(dH 2.60, s; dC 42.2, q for 10; dH 2.64, s; dC 42.5, q for
11). The 13C NMR spectrum of 12 exhibited a distinctic
lactam signal at dC 174.4 s. The afore-mentioned results
might prove the aldehyde group in 7 to be recalcitrant
mainly due to the bulkiness of hydroxyl or acetyl group at C-
3 which was found in our subsequent research.18

F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
2151
Scheme 2.
Our studies also showed that after the first fragmentation of
C-7–C-17 bond in the molecule it is very difficult to prepare
the N,19-seco compounds with the lower yield of
the intermediate imines which are neccessary. Taking the
findings into account, we decided prepare, at first, the imines
such as 14 based on our developing protocol,16i,t,v followed
by deamination and cleavaging the C-7–C-17 bond to give
B (Scheme 1).
quantitative yield, along with an important finds to be
obviously enhancing the yield of imines using NBS/AcOH
rather than NBS/t-BuOH previously reported by us,16t and
the quantitative obtainment of N-deethyl product 15 with a
three-fold amount of NBS (Scheme 4).
Attempted treatment of imine 14 with SOCl2-pyridine or
SOCl2–C6H6 followed by NaBH4 to fragment the C-7–C-17
bond via an intermediate 8-chlorro derivative, as previously
reported by us,16n,w gave compounds 16 (70%) or 17 (59%)
Selective hydrolysis of the starting material yunaconitine
(3) in diglyme-H2O (4:1) under refluxing conditions gave
compound 13 which reacted with a mixture of glacial acetic
acid and 8 equiv of NBS to give imine 14 in nearly
1
respectively. In the H and 13C NMR spectra of 16, the
signals at dH 5.66, d, JZ6.2 Hz (H-15); dC 144.2 s (C-8),
116.7 d (C-15) for a trisubstituted double bond and at dH
Scheme 3.

2152
F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
Scheme 4.
4.83, dd, JZ4.4, 2.0 Hz (H-6); dH 4.66, s (H-19); dC 87.6 d
(C-19) for an N,O-mixed acetal moiety which also was
supported by showing the correlation between H-6 and C-19
in the HMBC spectrum of 16. The structure of 16 was
method from this laboratory16q,s resulted in the complex
products, which led us to try again reduction of the nitro
group followed by protecting the amino group using TsCl.
The 3,13-diacetylyunaconitine (19)17 was exposed to NBS
(8 equiv)-AcOH to give nearly quantitatively the imine 20
which was reacted with m-CPBA at room temperature to
afford nitrone 21 (100%). An imine group (dH 6.72, d, JZ
1.2 Hz, H-19; dC 135.4 d, C-19) was observed in the 1H and
13C NMR spectra of 21. Treatment of 21 with molar excess
of HIO4 at room temperature gave the nitroso compound 22
as a blue amorphous powder. In the 1H and 13C NMR
spectra of 22, a g-lactone moiety (dH 4.92, d, JZ7.2 Hz
(H-6b); dC 173.2 s (C-19)) was showed, and a methine
carbon signal at dC 105.8 (d) can be assigned to C-17
bearing a nitroso group by comparison with those of the
analogues.16t Reduction of 22 with Zn–conc. HCl gave the
amine 23 (69%) together with the other two by-products 24
(18%) and 25 (8%) (Scheme 5). The carbon signals at dC
55.5 d (C-17) and 54.3 d (C-7) in 23 compared with those
of 22 were obviously upfield-shifted (C-17: Dd-50.3; C-7:
Dd-2.7). The MS spectrum of 24, C36H45O15 (HRMS), gave
1
established based on 2D NMR spectrum (Table 1). The H
NMR spectrum of 17 showed an imine signal at dH 7.47 (br
s, H-19) and a trisubstituted double bond at dH 5.82 (d, JZ
6.2 Hz, H-15). Interestingly, the N-deethyl compound 15
was exposed to SOCl2 followed by NaBH4 in similar pro-
cedure16n,w also produced the pyro product 18 (41%) instead
of the desired 7,17-seco compound. This seems to show that
the obtainment of 7,17-seco compounds, in our cases,
required to meet simultaneously an anti-periplanar relation-
ship between the lone pair of nitrogen atom and the C-8-Cl
bond, and the tertiary amine patterns of the nitrogen atom.
2.2. Approach ACB
This approach was fashioned after the unsuccesseful ABC
sequence. Attempt to strong alkaline rearrangement of the
nitro compounds to the C-nor compounds by a reported

F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
Table 1. H and 13C NMR data for compound 16 (1H: 400 MHz; 13C: 100 MHz, CDCl3)
2153
1
No.
dC
dH Mult (JZHz)
1H–1HCOSY
HMBC (H/C)
C-17, C-10, C-11, C-2, C-10
C-1, C-3, C-4, C-11
C-1, C-3, C-4, C-11
C-19, C-18, C-4, C-5, C-2, 3-OCOCH3
—
C-19, C-1, C-6, C-18, C-3, C-7, C-4, C-11, C-10
C-19, C-17, C-4, C-5, C-11
C-6, C-17, C-5, C-11, C-9
—
C-8, C-15, C-13, C-14, C-11, C-12
C-8, C-1, C-17, C-11, C-9
—
1
2
83.5 d
30.2 t
3.40 dd (6.0, 12.8)
2.54 m (hidden)
2.39 m
5.44 dd (6.8, 12.0)
—
2.55 dd (hidden)
4.83 dd (2.0, 4.4)
3.10 br s
H-2a, H-2b
H-2, H-1, H-3
H-2, H-1, H-3
H-2a, H-2b
—
H-6, H-19 (w)
H-5, H-17 (w)
H-17
3
4
5
6
7
8
9
10
11
12
70.7 d
50.6 s
50.5 d
80.1 d
56.4 d
144.2 s
45.1 d
48.2 d
49.0 s
37.9 t
—
—
2.64 t (3.0)
2.23 m
—
1.99 dd (6.4, 14.8)
1.92 dd (7.2, 14.8)
—
4.91 dd (0.8, 3.6)
5.66 d (6.2)
3.40 (hidden)
3.27 br s (hidden)
3.23 ABq (9.2)
3.15 ABq (9.2)
4.66 br s
H-10, H-14
H-12a, H-12b, H-9
—
H-10, H-12
H-10, H-12
—
C-16, C-13, C-14, C-11, C-10
C-16, C-13, C-14, C-10, C-9
—
13
14
15
16
17
18
78.2 s
78.0 d
116.7 d
83.4 d
68.3 d
74.5 t
C-16, C-13, C-9, C-100, C-8
C-16, C-14, C-7, C-9
H-9, H-16 (w)
H-16
C-8, C-15, C-13, C-14, -160, C-12
C-19, C-1, C-6, C-5, C-11
H-15, H-14
H-7, H-6
H-18 (d 3.15)
H-18 (d 3.23)
—
—
—
—
—
C-19, C-3, C-180, C-4, C-5
C-19, C-3, C-180, C-4, C-5
19
10
160
180
87.6 d
56.8 q
57.4 q
59.1 q
170.3 s
21.0 q
C-6, C-18, C-17, C-4, C-5
C-10
C-160
C-180
-
3.29 s
3.35 s
3.25 s
2.05 s
2.05 s
—
CO
168.0 s
122.5 s
131.9 d
113.4 d
163.3 s
55.3 q
—
—
—
—
H-400
H-300
—
—
—
7.98 AA0BB0 (8.8)
6.90 AA0BB0 (8.8)
—
C-100, C-500, C-700, C-200, C-400
C-500, C-600, C-300, C-200
—
C-500
3.85 s
—
the molecular ion peak at m/z 731 which is 16 more unit than
1
that the tautomerism between the nitroso and the oxime under
alkaline condition was found by TLC detection (neutral silica
gel GF254: CHCl3–MeOHZ7:3, one spot; alkalized silica gel
GF254: CHCl3–MeOHZ95:5, two spots) and the NMR trial.
When measuring the sample containing a few saturated
Na2CO3 the 1H and 13C NMR spectra of 22 showed a
distinctic signal at d 155.7 (s) for the oxime group16t, with
ratio of about 3:1 based on the peak area of the H-14b signals
at dH 4.99 for 22 and dH 4.84 for the oxime. Compound 23
was subjected to protection of the amino group, hydrolysis
using 5% NaOH followed by sulfonation to give successively
compounds 28 (95%), 29 (90%) and 30 (93%). The proton
signal of H-17 (dH 5.66, d JZ2.4 Hz) in the 1H NMR
spectrum of 28 compared with those of 23 was downfield-
shifted due to the substitution of the OTs group. The 1H and
13C NMR spectra of 30 showed two OMs groups (dH 2.94,
2.97, each 3H, s; dC 38.1 q, 38.4 q), and the downfield-shift
signals at dH 4.76 (1H, d, JZ5.0 Hz, H-3b) and dH 4.43 (1H,
d, JZ4.2 Hz, H-14b) as compared with those of 29.
However, semipinacol rearrangement of 30 under various
conditions (NaOH/DMF, reflux, 20 h16q; DBN/o-xylene,
sealed tube, 180 8C, 12 h; NaOAc/HOAc, sealed tube,
150 8C, 24 h) resulted in formation of 31 (70%) rather than
the desired product 32 (Scheme 5). This is incomprehensibly
different from the results described in the literature.16q
those of 23. The H and 13C NMR spectra of 24 are very
similar to those of 23, except for C-17 (dC 64.5 d) being
downfield-shifted by 9 ppm compared with those of 23.
From these facts mentioned above, the structure of 24 can be
determined. The structure of 25 was established on the basis
of the following key points: the odd molecular weight (m/z
716); a methine carbon signal at dC 74.7 (d) bearing to C-17;
and a negative result to Dragendorff’s reagent, which
resulted from deamination. Acetylation of 23 and 25 with
1
Ac2O gave compounds 26 and 27, respectively. In the H
NMR spectrum of 27, an additional acetyl group was
assigned at C-17 by the presence of the townfield signal at
dH 5.03 (H-17) as compared with those of 25. Apparently,
configurations of C-17 in compounds 23, 24, and 26, except
for 25 and 27, as the parent compound 22, are deduced to
be S. A plausible origin of these compounds 23w27 can
be rationalized mechanistically as shown in Scheme 6.
Reduction of the nitro compound 22, at first, gave the
nitroso form A which was reduced again successively to
give compounds 24 and 23. In addition, there is an
equilibration of the nitroso (A)-oxime (B) tautomerism.19
Hydrolysis of B led to the ketone C, further reduction of C
afforded 25. Acetylation of 23 and 25 with AcOH resulted in
obtainment of 26 and 27, respectively. It is worth of note

2154
F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
Scheme 5.
2.3. Approach BCA
to modification of the ring C or A. According to the
literature,16w the 7,17-seco compound 34 from 19 via 33
was prepared smoothly in 74% yield (Scheme 7). Its
structure was established by spectral data and comparison
with the authentic sample. Alkaline hydrolysis of 34
Owing to the unsuccesseve efforts described herein, we are
forced to propose another approach BCA aiming at cleaving
the C-7–C-17 bond using our developing protocol16n,w prior

F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
2155
trisubstituted double bond (dH 5.61, hidden, H-7; dC 131.5 s,
C-8; 125.7 d, C-7). Apparently the N,19-seco compound 30
in the approach ACB or the 7,17-seco compound 38 in the
approach BCA approach was not an adequate form of
semipinacol rearrangement probably due to harsh require-
ment on the substrates.
As mentioned above, all three approaches turned out to be
ineffective and the last-mentioned method gave rise to the
expected key intermediates 51 and 52.
2.4. Approach CAB
Scheme 6.
The synthesis began with the starting material yunaconitine
(3) afforded compound 43 in 50% overall yield through one-
pot four step method16s including a key semipinacol
rearrangement (Scheme 8). Its structure was determined
by TLC comparison (silica gel GF254, CHCl3–MeOHZ9:1)
with the authentic sample. Reduction of 43 with NaBH4 to
avoid a negative participation of the keton group at C-3
followed by acetylation and subsequent formation of the
imine afforded successively compounds 44, 45, and 46 in
70% overall yield in three steps from 43 to 46 (Scheme 8).
followed by sulfonation using MsCl/pyridine gave the
desired product 36 (51%) along with the by-product 37
(17%) (Scheme 7). But, treatment of 36 under different
conditions (DBN/ o-xylene, sealed tube, 180 8C; NaOH/
DMF, reflux, 12 h16q) gave compound 38 instead of the
1
expected C-nor product 39 (Scheme 7). The H and 13C
NMR spectra of 38 exhibited the presence of a disubstituted
double bond (dH 5.92, dd, JZ9.8, 2.0 Hz for H-3; 5.59,
hidden for H-2; dC 136.8 d for C-2, 129.0 d for C-3), and a
Scheme 7.

2156
F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
Scheme 8.
In the 1H and 13C NMR spectra of 46, the signals at dH 7.39
(d, JZ1.2 Hz, H-19) and dC 164.2 (d) (C-19) can be
assigned to the imine group. The a-configuration of the
hydroxyl group at C-3 in 44, 45, and 46 was supported from
surprise, m-CPBA oxidation of 46 in an apotic media, e.g.
CH2Cl2, resulted in formation of oxaziridine 47 in highly
84% yield where the addition to C]N is not favored
presumably by participation of the more electron-donating
hydroxyl group than the acetyl group as 49 at C-8.20 The 1H
3
their larger J2a,3a coupling constant (9–13 Hz). In slight

F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
2157
of g-lactones [51: dH 5.63 (d, JZ7.2 Hz, H-6b); dC 83.6 d
(C-6), 177.7 s (C-19); 52: dH 5.11 (d, JZ7.2 Hz, H-6b); dC
81.9 d (C-6), 174.1 s (C-19)] was confirmed. Their IR
spectra also showed absorption of the nitro groups (51:
1558–1378 cmK1; 52: 1550–1380 cmK1). The a-orien-
tation of H-13 in compounds 44–52 was deduced from the
coupling constants (J13,16Z6.4–12 Hz) (see Section 4),
especially including NOESY of 51 (Fig. 1), in which the
correlations of OAc-13 (dH 2.18, 3H, s) with H-9b, H-14b,
and H-16b as well as OCH3-16a with H-13a and H-17 were
observed. Similarly, a-configuration of the OAc group at
C-3 in 51 also was confirmed due to the NOESY
correlations between H-3b and H2-18 (Fig. 1) as well as a
3
larger J2a,3a coupling constant (9.2 Hz). The NOESY
correlation of H-5b with H-6b in the NOESY spectrum of
51 suggested that the g-lactone was located under the rings
A and B, showing mechanically that the g-lactone was
formed prior to the O-demethylation of 6-OCH3 group. The
2D NMR experiments (HMQC, 1H–1H COSY, HMBC,
Figure 1. Key NOESY and 1H–1H COSY correlations of 51.
and 13C NMR spectra of 47 showed the absence of the imine
or the nitrone group and the apparance of a methine carbon
signal at dC 76.0 bearing an additional oxygen atom,
together with consideration of the more 16 mass unit as
compared with the molecular ion peak (m/z 491) of 46,
indicating that 47 had an oxaziridine moiety (dH 4.17, s,
H-19; dC 76.0 d, C-19). In constract with 46, treatment of
triacetyl derivative 49 from 44 via 48 with m-CPBA under
similar conditions afforded the desired nitrone 50 in modest
yield of 40% which was oxidized using HIO4 to the key
intermediate 52 in only 40% yield. Wheres compound 47
was exposed to HIO4 rather than bases or acids, where the
decomposition was observed by bases, to give the analogue
51 in poor 26% yield differing from the report in the
literature,16t indicating that obviously effect of the
rearranged C-nor compounds such as 49 on formation of
the nitrone. However, this is a new useful method for the
ring opening of oxaziridines. In the 1H and 13C NMR
spectra of 51 (Table 3) and 52 (see Section 4), the presence
1
NOESY) of 51 further gave the assignments of all the H
and 13C signals (Table 3). Comparison of the 13C NMR
spectra of 51 and 52 showed that there, as expected, are only
minor differences mainly restricted to the vicinity of the C-8
function (Scheme 9).
Compound 47 was converted into 51 presumably via a
several step mechanism, the first step being protonation of
HC to the oxygen atom (A), followed by an nucleophilic
attack of OHK to A and a subsequent glycol-like cleavage in
company with formation of the g-lacton moiety16t to afford
C and its oxidized form D (Scheme 10).
3. Conclusion
This study, as a part of conversion of the C19-diterpenoid
Scheme 9.

2158
F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
Scheme 10.
alkaloids to the taxoids, made us to drop the idea to seek a
suitable route toward the key intermediate C (Scheme 1)
with four approaches designed and examined based on our
previous break-through results.
Taking three unsuccessful approaches mentioned above into
accunt, we offer the fourth approach CAB which at first
involved in treatment of yunaconitine (3) using our
method16q via semipinacol rearrangement to give the
C-nor compound, and then, in cleaving the N-C-19 bond
through three steps mainly including imination, formation
of the oxaziridine or the nitrone, and HIO4 oxidation
fragmentation. Interestingly, an expected preparations of
nitrone from 46 by m-CPBA oxidation resulted in the
obtainment of oxaziridine 47 (84%) in constrast to those
where m-CPBA oxidation of 49 led to produce nitrone 50 in
moderate yield being much lower than those of N-oxidation
of the imines from the substrates without the ring C
rearrangment. Thus effect of the 8-OR (RZH, Ac) on
formation of the nitrones or the oxaziridines was observed,
which is worth to further research. Finally, we have found
that treatment of oxaziridine 47 or nitrone 50 with HIO4
afforded successively the key intermediate 51 or 52 in
modest to moderate yield, which provided an important base
for synthesis toward the vital intermediate C in Scheme 1.
Further optimization of the reaction and application for
synthesis of the key intermediates 51 and 52 are currently in
progress.
In the approach ABC (route 1), an attempt to reduce the
aldehyde group in 7 using various regents failed mainly due
to the bulkiness of hydroxyl or acetyl group at C-3.
Formation of the key imines followed by cleaving the
C-7–C-17 bond or preparation of the 7,17-seco compound
using the secondary amine with respect of a protocol
developed by this laboratory16j,t,n,u,w was then attempted.
Consequently, these were proved to be unsuccessful along
with the obtainment of 16 having the new N,O-mixed acetal
moiety. This seems to show that when preparing the
7,17-seco compounds it is necessary to meet both an anti-
periplanar relationship between the lone pair of nitrogen atom
and the C-8–Cl bond, as well as the tertiary pattern of the
nitrogen atom in the substrates. In addition, an optimazed
procedure was found to be very useful for imination or N-
deethylation using 8 or 3 equiv of NBS, respectively with
good application scope in the C19-diterpenoid alkaloids.
In the course of our afore-mentioned studies, 43 C19-diter-
penoid alkaloids were obtained, of which 33 are structurely
the new or novel compounds which were determined by
spectral data (1H and 13C NMR, 2D NMR, HRMS).
The second approach (ACB) involves treatment of the
nitroso 22 with Zn/AcOH–HCl to afford the desired
compound 23 in high yield along with two interesting
by-products 24 and 25. After pretection of the amino group
followed by hydrolysis and sulfonation the key compound
30 from 23 was obtained. However, to attempt conversion of
30 or 36 in the approach BCA (route 3) to the corresponding
C-nor compoumd 32 or 39, respectively, under various
conditions via semipinacol rearrangement failed. This led to
conclude that the N,19-seco compound 30 in the approach
ACB or the 7,17-seco compound 36 in the approach BCA
was not an adequate form of semipinacol rearrangement
probably due to harsh requirement on the substrates.
4. Experimental
4.1. General
Melting points were determined on a Kofler block
(uncorrected); optical rotations were measured in a 1.0 dm
cell with a PE-314 polarimeter at 20G1 8C; IR spectra were

F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
2159
recorded on a Nicolet 200 SXV spectrometer; MS spectra
were obtained with a Auto-Spec-3000 instrument; H and
column chromatography (silica gel H, CHCl3–CH3OH/
98.5:1.5) afforded the pure product (white amorphous
powder, 94 mg, 49%). 10: mp 135–136 8C; Rf (95%
CHCl3–CH3OH) 0.54; [a]2D0ZC26.2 (c 0.8, CHCl3); nmax
(KBr) 3507 (OH), 2935, 1732 (COO), 1608, 1514, 1460,
1370, 1257, 1096 cmK1; dH (200 MHz, CDCl3) 1.33 (3H, s,
8-OAc), 2.04 (3H, s, 3-OAc), 2.60 (3H, s, N-CH3), 3.17,
3.18, 3.24, 3.50, 3.84 (each 3H, s, OCH3!5), 4.06 (1H, d,
JZ6.8 Hz, H-6b), 4.85 (1H, d, JZ5.0 Hz, H-14b),0 4.90
(1H, t, JZ5.8 Hz, H-3b), 6.90, 7.99 (each 2H, AA0BB , JZ
8.8 Hz, Ar-H); dC (50 MHz, CDCl3) 170.0 (COCH3), 169.7
(COCH3), 165.9 (COAr), 163.3 (C-400), 131.6 (C-200, C-600),
122.5 (C-100), 113.6 (C-300, C-500), 85.1 (C-8), 83.5 (C-16),
83.0 (C-1), 81.7 (C-6), 78.2 (C-14), 74.70 (C-130), 71.5
(C-18), 71.3 (C-3), 62.9 (0C0 -17), 58.6 (C-16 , C-18 ), 58.0
(C-60), 56.4 (C-10), 55.3 (4 -OCH3), 49.9 (C-11, C-19), 48.2
(C-7), 45.5 (C-5), 45.0 (C-9), 42.4 (C-4), 42.2 (C-21), 40.4
(C-10), 39.1 (C-15), 35.3 (C-12), 31.8 (C-2), 21.5 (COCH3),
21.0 (COCH3); m/z (EI) 687 (10, MC), 656 (65, MK
OCH3), 628 (55, MKOAc); HRMS (FAB): MCCH, found
688.3336, C36H50NO12 requires 688.3333.
1
13C NMR spectra were acquired on a Bruker AC-E 200 or a
Varian INOVA-400/54 spectrometer, with TMS as internal
standard; Silica gel GF254 and H (10–40 mm, Qingdao Sea
Chemical Factory, China) were used for TLC and CC. Only
key signals except for 16 and 51 in the 1H NMR spectra are
reported.
4.2. Approach ABC
4.2.1. Compounds 9 and 12. To a solution of compound 7
(100 mg, 0.14 mmol) in MeOH (5 mL), 10% K2CO3 (1 mL)
was added the solution was stirred at room temperature for
1.5 h, then saturated NH4Cl solution (80 mL) was added.
Diluting (H2O, 10 mL), extraction (CH3Cl, 50 mL!3),
drying (Na2SO4), evaporation and column chromatography
(silica gel H, CHCl3–CH3OH/98:2 to 95:5) afforded the
pure products 9 (white amorphous powder, 69 mg, 73%)
and 12 (white amorphous powder, 23 mg, 25%).
4.2.2. Compound 9. Mp 173–174 8C; Rf (95% CHCl3–
CH3OH) 0.52; [a]D20ZC28.5 (c 0.6, CHCl3); nmax (KBr)
3469 (OH), 2939, 2828, 1718 (COO), 1649, 1608, 1514,
1460, 1260, 1102 cmK1; dH (200 MHz, CDCl3) 1.36 (3H, s,
8-OAc), 3.00, 3.33, 3.42, 3.55, 3.87 (each 3H, s, OCH3!5),
4.83 (1H, d, JZ4.4 Hz, H-14b), 6.93, 8.00 (each 2H,
AA0BB0, JZ8.4 Hz, Ar-H), 10.3 (1H, s, H-19); dC (50 MHz,
CDCl3) 209.8 (C-19), 169.3 (COCH3), 165.3 (COAr), 163.5
(C-400), 131.6 (C-200, C-600), 122.1 (C-100), 113.7 (C-300,
C-500), 83.3 (C-16), 83.1 (C-1), 82.7 (C-8), 81.8 (C-6), 78.0
(C-14), 76.2 (C-20), 75.07 (C-13), 74.10(C-17), 71.5 0(C-18),
67.90 (C-3), 59.3 (C-18 ), 58.7 (C-16 ), 57.1 (C-6 ), 56.2
(C-1 ), 55.3 (40-OCH3), 55.2 (C-4), 53.3 (C-7), 51.9 (C-11),
51.3 (C-5), 45.8 (C-10), 42.8 (C-9), 39.7 (C-15), 33.9 (C-2),
33.5 (C-12), 21.2 (COCH3); m/z (EI) 675 (3, MC); HRMS
(FAB): MCCH, found 676.2950, C34H46NO13 requires
676.2969.
4.2.5. Compound 11. To a solution of compound 9
(100 mg, 0.15 mmol) in HOAc (8 mL), KBH4 (100 mg,
1.85 mmol) was added and the solution was stirred at room
temperature for 12 h. After pouring into ice water (10 mL),
the solution was basified with conc. NH4OH to pH 9.
Extraction (CH3Cl, 10 mL!3), drying (Na2SO4), evapora-
tion and column chromatography (silica gel H, CHCl3–
CH3OH/95:5) afforded the pure product (white amorphous
powder, 50 mg, 52%). 11: mp 157–158 8C; Rf (90% CHCl3–
CH3OH) 0.50; [a]D20ZC30.5 (c 0.4, CHCl3); nmax (KBr)
3450 (OH), 2928, 1728 (COO), 1652, 1605, 1510, 1458,
1250, 1108 cmK1; dH (200 MHz, CDCl3) 1.35 (3H, s,
8-OAc), 2.64 (3H, s, N-CH3), 3.13, 3.29, 3.35, 3.56, 3.86
(each 3H, s, OCH3!5), 4.87 (1H, d, JZ5.0 Hz, H-14b),
6.93, 8.00 (each 2H, AA0BB0, JZ8.8 Hz, Ar-H); dC
(50 MHz, CDCl3) 169.9 (COCH3), 166.1 (COAr), 163.5
(C-400), 131.7 (C-200, C-600), 122.4 (C-100), 113.8 (C-300,
C-500), 84.8 (C-8), 83.2 (C-16), 82.7 (C-1), 81.4 (C-6), 78.2
(C-14), 74.6 (C-13), 71.00 (C-18), 70.7 (C-3), 64.4 (C-17),
59.0 (C-180), 58.9 (C-16 ), 57.9 (C-60), 56.2 (C-10), 55.3
(400-OCH3), 50.5 (C-11), 50.2 (C-19), 48.2 (C-7), 45.3 (C-9),
44.2 (C-5), 43.6 (C-4), 42.5 (C-21), 40.7 (C-10), 39.4
(C-15), 35.7 (C-12), 32.6 (C-2), 21.3 (COCH3); m/z (EI) 645
(6, MC), 627 (11, MKH2O), 614 (2, MKOMe); HRMS
(FAB): MCCH, found 646.3232, C34H48NO11 requires
646.3227.
4.2.3. Compound 12. Mp 163–164 8C; Rf (95% CHCl3–
CH3OH) 0.50; [a]D20ZC50.8 (c 0.50, CHCl3); nmax (KBr)
3452 (OH), 2930, 1718 (COO), 1650, 1607, 1514, 1461,
1371, 1259, 1102 cmK1; dH (200 MHz, CDCl3) 1.33 (3H, s,
8-OAc), 3.07, 3.29, 3.44, 3.50, 3.87 (each 3H, s, OCH3!5),
4.00, 4.15 (each 1H, JZ9.2 Hz, H2-18), 4.84 (1H, d, JZ
4.8 Hz, H-4b), 6.93, 8.00 (each 2H, AA0BB0, JZ8.4 Hz,
Ar-H); dC (50 MHz, CDCl3) 174.4 (C-19), 169.9 (COCH3),
166.0 (COAr), 163.5 (C0-0400), 131.6 (C-200, C-600), 122.3
(C-100), 113.6 (C-300, C-5 ), 82.8 (C-16), 82.7 (C-8), 82.6
(C-1), 80.5 (C-6), 78.90 (C-14), 76.3 (C-18), 75.0 (C-13),
68.50 (C-3), 58.90 (C-18 ), 58.6 (C-160), 57.9 (C-17), 57.1
(C-6 ), 55.7 (C-1 ), 55.3 (400-OCH3), 52.3 (C-11), 48.5 (C-4,
C-7), 45.3 (C-9), 43.1 (C-5), 40.3 (C-10), 36.8 (C-15), 34.9
(C-12), 33.9 (C-2), 21.4 (COCH3); m/z (EI) 645 (4, MC);
HRMS (FAB): MCCH, found 646.2859, C33H44NO12
requires 646.2864.
4.2.6. Compound 13. To a solution of compound 3 (1.05 g,
1.50 mmol) in diglyme (80 mL), H2O (20 mL) was added
and the solution was heated at reflux for 13 h. Removal of
solvent and column chromatography afforded the pure
product (white amorphous powder, 785 mg, 80%), which
was taken to next step directly.
4.2.7. Compound 14. To a solution of compound 13
(500 mg, 0.76 mmol) in HOAc (15 mL), NBS (1.08 g,
6.08 mmol) was added and the solution was stirred at room
temperature for 1.5 h. After pouring into ice water (20 mL),
the solution was basified with conc. NH4OH to pH 10.
Extraction (CHCl3, 15 mL!3), drying (Na2SO4), and
evaporation afforded the pure product (white amorphous
4.2.4. Compound 10. To a solution of compound 7
(200 mg, 0.28 mmol) in HOAc (12 mL), NaBH4 (200 mg,
5.26 mmol) was added and the solution was stirred at room
temperature for 12 h. After pouring into ice water (10 mL),
the solution was basified with NH4OH to pH 9. Extraction
(CH3Cl, 10 mL!3), drying (Na2SO4), evaporation and

2160
F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
powder, 467 mg, 98%). 14: mp 135–136 8C; Rf (90%
CHCl3–CH3OH) 0.45; [a]2D0ZC87.5 (c 0.7, CHCl3); nmax
(KBr) 3468 (OH), 2936, 1715 (COO), 1608, 1514, 1459,
1257, 1106 cmK1; dH (400 MHz, CDCl3) 2.08 (3H, s,
3-OAc), 3.19, 3.24, 3.28, 3.40, 3.86 (each 3H, s, OCH3!4),
3.46, 4.16 (each 1H, ABq, JZ8.8 Hz, H2-18), 5.12 (1H, dd,
JZ5.6, 8.0 Hz, H-3b), 5.14 (1H, d, JZ4.8 Hz, H-14b),
6.93, 8.00 (each 2H, AA0BB0, JZ8.4 Hz, Ar-H), 7.45 (1H,
d, JZ1.2 Hz, 19-H); dC (100 MHz, CDCl3) 170.2 (COCH3),
166.5 (COAr), 164.1 (C-19), 163.5 (C-400), 131.7 (C-200,
C-600), 122.1 (C-100), 113.7 (C-300, C-500), 83.0 (C-16), 82.6
(C-6), 80.9 (C-1), 79.8 (C-14), 76.1 (C-13), 72.6 (C-3), 72.4
(C-18), 72.3 (C-8), 61.6 (C-17), 59.0 (C-7, C-180), 58.3
(C-160), 57.2 (C-60), 55.9 (C-10), 55.3 (400-OCH3), 50.4
(C-4), 49.9 (C-11), 46.4 (C-5), 44.7 (C-9), 41.9 (C-10), 40.8
(C-15), 35.7 (C-12), 30.4 (C-2), 21.9 (COCH3); m/z (EI) 629
(12, MC), 570 (13, MKOAc); HRMS (FAB): MCCH,
found 630.2911, C33H44NO11 requires 630.2914.
for 3 h. Evaporation in vacuum to dryness afforded a
residue, which was dissolved in MeOH (10 mL). To the
solution NaBH4 (100 mg) was added and this solution was
stirred at room temperature for 2 h. Removal of solvent gave
the residue which was basified with 10% Na2CO3.
Extraction (CHCl3, 5 mL!3), drying (Na2SO4), evapora-
tion and column chromatography (silica gel H, CHCl3–
CH3OH/98:2) afforded the pure product (white amorphous
powder, 20 mg, 41%).18: mp 137–138 8C; Rf (95% CHCl3–
CH3OH) 0.46; [a]D20ZC122.5 (c 0.5, CHCl3); nmax (KBr)
3466 (OH, NH), 2928, 1712 (COO), 1608, 1513, 1460,
1317, 1256, 1100 cmK1; dH (200 MHz, CDCl3) 2.04 (3H, s,
3-OAc), 3.22, 3.25, 3.34, 3.38, 3.85 (each 3H, s, OCH3!5),
4.90 (1H, dd, JZ5.0, 12.2 Hz, H-3b), 4.94 (1H, d, hidden,
H-14b), 5.70 (1H, d, JZ6.2 Hz, 15-H), 6.90, 8.00 (each 2H,
AA0BB0, JZ8.8 Hz, Ar-H); m/z (FAB) 614 (35, MCCH),
135 (100); HRMS (FAB): MCCH, found 614.2971,
C33H44NO10 requires 614.2965.
4.2.8. Compound 15. To a solution of compound 13
(200 mg, 0.30 mmol) in HOAc (10 mL), NBS (162 mg,
0.91 mmol) was added and the solution was stirred at room
temperature for 3 h. After pouring into ice water (20 mL),
the solution was basified with conc. NH4OH to pH 10.
Extraction (CHCl3, 15 mL!3), drying (Na2SO4), and
evaporation afforded the pure product (white amorphous
powder, 190 mg, 99%).
4.3. Approach ACB
4.3.1. Compound 20. To a solution of compound 1920
(2.20 g, 2.96 mmol) in HOAc (40 mL), NBS (4.22 g,
23.7 mmol) was added and the solution was allowed to
stand at room temperature for 1.5 h. After pouring into ice
water (50 mL), the solution was basified with conc. NH4OH
to pH 9. Extraction (CHCl3, 20 mL!3), drying (Na2SO4),
and evaporation afforded the pure product (white amor-
phous powder, 2.1 g, 95%). 20: dH (200 MHz, CDCl3) 1.29
(3H, s, 8-OAc), 2.05, 2.07 (each 3H, 3-OAc and 13-OAc),
3.09, 3.19, 3.24, 3.40, 3.86 (each 3H, s, OCH3!5), 5.12
(1H, d, JZ5.6 Hz, 14b-H), 5.13 (1H, t, JZ7.0 Hz, 3b-H),
6.90, 8.00 (each 2H, AA0BB0, JZ8.8 Hz, Ar-H), 7.37 (1H,
d, JZ1.0 Hz, 19-H).The structure of 20 was identified by
4.2.9. Compound 16. A solution of compound 14 (300 mg,
0.48 mmol) in pyridine (30 mL) was treated with SOCl2
(2 mL) and stirred at room temperature for 5 h. Removal of
solvent gave the residue, which was dissolved in MeOH
(30 mL). To the solution NaBH4 (300 mg) was added and
this solution was stirred at room temperature for 3 h.
Removal of solvent, basifying (NH4OH, pH 9), extraction
(CHCl3, 10 mL!3), drying (Na2SO4), evaporation and
column chromatography (silica gel H, cyclohexane–
acetone/3:1) afforded the pure product (white amorphous
powder, 200 mg, 70%). 16: mp 132–133 8C; Rf (50%
cyclohexane–acetone) 0.44; [a]2D0ZC17.6 (c 0.6, CHCl3);
nmax (KBr) 3465 (OH, NH), 2938, 2825, 1734 (COO), 1608,
1513, 1459, 1255, 1105 cmK1; dH (400 MHz, CDCl3) and
dC (100 MHz, CDCl3) see Table 1; m/z (ESI) 620 (100,
MC); HRMS (FAB): MCCH, found 598.2660,
C32H40NO10 requires 598.2652.
1
comparison of H NMR and TLC (cyclohexane–acetone/
1:1; CHCl3–CH3OH/9:1) with the authentic sample.
4.3.2. Compound 21. To a solution of compound 20
(2.00 g, 2.81 mmol) in CH2Cl2 (30 mL), m-CPBA (970 mg,
5.82 mmol) was added and the solution was stirred at room
temperature for 30 min. To the reaction solution was added
10% Na2CO3 solution and the mixture was stirred
vigorously. The organic layer was separated and the water
layer was extracted with CHCl3 (15 mL!2). Drying
(Na2SO4), and evaporation afforded the pure product
(white amorphous powder, 2.02 g, 100%). 21: mp 175–
176 8C; Rf (90% CHCl3–CH3OH) 0.42; [a]2D0ZC113.0 (c
0.5, CHCl3); nmax (KBr) 2937, 2828, 1736 (COO), 1608,
1514, 1461, 1257, 1104 cmK1; dH (400 MHz, CDCl3) 1.31
(3H, s, 8-OAc), 2.06, 2.07 (each 3H, s, 3- and 13-OAc),
3.11, 3.22, 3.27, 3.42, 3.68 (each 3H, s, OCH3!5), 5.11
(1H, d, JZ5.2 Hz, H-14b), 5.24 (1H, dd, JZ4.0, 6.4 Hz,
H-3b), 6.72 (1H, d, JZ1.2 Hz, 19-H), 6.94, 8.03 (each 2H,
AA0BB0, JZ8.8 Hz, Ar-H); dC (100 MHz, CDCl3) 170.4
(COCH3), 170.4 (COCH3), 169.1 (COCH3), 165.7 (COAr),
163.6 (C-400), 135.4 (C-19), 131.8 (C-200, C-600), 122.0
(C-100), 113.8 (C-300, C-500), 82.8 (C-8), 82.2 (C-16), 81.2
(C-1), 78.9 (C-6, C-14), 78.7 (C-13), 74.0 (C-3), 730.1
(C-17), 73.0 (C-18), 58.8 (C-180), 58.3 (C-160), 57.2 (C-6 ),
56.1 (C-10), 55.3 (400-OCH3), 54.2 (C-7), 51.5 (C-11), 45.3
(C-4), 43.3 (C-5), 41.2 (C-9), 39.3 (C-10), 38.4 (C-15), 35.3
(C-12), 28.4 (C-2), 21.2 (COCH3), 21.0 (COCH3), 20.9
(COCH3); m/z (EI) 729 (5, MC), 697 (3), 654 (40); HRMS
4.2.10. Compound 17. To a solution of compound 14
(35 mg, 0.056 mmol) in benzene (2 mL), SOCl2 (0.3 mmol)
was added and the solution was allowed to stand at room
temperature for 24 h. After removal of solvent, the solution
was neutralized with NaHCO3 (5 mL). Extraction (CHCl3,
3 mL!3), drying (Na2SO4), evaporation and column
chromatography (silica gel H, cyclohexane–acetone/2:1)
afforded the pure product (white amorphous powder, 20 mg,
59%). 17: dH (200 MHz, CDCl3) 2.06 (3H, s, 3-OAc), 3.21,
3.26, 3.29, 3.40, 3.85 (each 3H, s, OCH3!5), 4.94 (1H, d,
JZ4.4 Hz, H-14b), 5.00 (1H, dd, JZ4.6, 8.8 Hz, H-3b),
5.82 (1H, d, JZ6.0 Hz, 15-H), 6.90, 8.00 (each 2H,
AA0BB0, JZ8.8 Hz, Ar-H), 7.47 (1H, br s, H-19).
4.2.11. Compound 18. To a solution of compound 15
(50 mg, 0.08 mmol) in pyridine (3 mL), SOCl2 (0.2 mL)
was added and the solution was stirred at room temperature

F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
2161
(FAB): MCCH, found 730.3073, C37H48NO14 requires
730.3075.
MKOAcCH); HRMS (FAB): MCCH, found 716.2918,
C36H46NO14 requires 716.2918.
4.3.6. Compound 24. Mp 191–192 8C; Rf (99% CHCl3–
CH3OH) 0.52; [a]D20ZC15.0 (c 1.4, CHCl3); nmax (KBr)
3470 (OH), 2929, 2856, 1782 (g-lactone), 1737 (COO),
1608, 1514, 1461, 1258, 1100 cmK1; dH (200 MHz, CDCl3)
1.31 (3H, s, 8-OAc), 2.03, 2.12 (each 3H, s, 3 and 13-OAc),
3.25, 3.29, 3.34, 3.84 (each 3H, s, OCH3!4), 4.77 (1H, d,
JZ6.2 Hz, H-6b), 4.99 (1H, dd, JZ3.8, 10.2 Hz, H-3b),
5.01 (1H, d, JZ4.8 Hz, H-14b),0 5.48 (1H, br s, NH-OH),
6.91, 8.00 (each 2H, AA0BB , JZ8.6 Hz, Ar-H); dC
(50 MHz, CDCl3) 174.1 (C-19), 170.6 (COCH3), 170.4
(COCH3), 169.2 (COCH3), 166.0 (COAr), 163.6 (C-400),
131.8 (C-200, C-600), 122.0 (C-100), 113.8 (C-300, C-500), 82.5
(C-8), 82.3 (C-13), 81.9 (C-1), 81.7 (C-16), 79.6 (C-6), 760.6
(C-14), 74.2 (C-18), 67.4 (C-3), 64.5 (C-17), 59.4 (C-18 ),
58.3 (C-160), 56.6 (C-10), 55.4 (400-OCH3), 51.8 (C-4), 51.4
(C-7), 49.9 (C-11), 49.5 (C-5), 44.9 (C-9), 42.2 (C-10), 40.7
(C-15), 34.2 (C-12), 30.7 (C-2), 21.3 (COCH3), 21.1
(COCH3), 21.0 (COCH3); m/z (FAB) 732 (100, MCCH),
672 (15, MKOAcCH); HRMS (FAB): MCCH, found
732.2870, C36H46NO15 requires 732.2867.
4.3.3. Compound 22. To a solution of compound 21
(550 mg, 1.33 mmol) in MeOH (25 mL), HIO4$2H2O
(906 mg, 3.98 mmol) was added and the mixture was stirred
at room temperature for 20 h. Removal of solvent, basifying
(10% Na2CO3, 20 mL), extraction (CHCl3, 10 mL!3),
drying (Na2SO4), evaporation and column chromatography
(silica gel H, CHCl3–CH3OH/70:1) afforded the pure
product (blue crystal powder, 390 mg, 71%). 22: mp 185–
186 8C; Rf (97% CHCl3–CH3OH) 0.50; [a]2D0ZC59.2 (c
1.1, CHCl3); nmax (KBr) 2940, 2843, 1783 (g-lactone), 1738
(COO), 1608, 1514, 1460, 1257, 1102 cmK1; dH (200 MHz,
CDCl3) 1.25 (3H, s, 8-OAc), 1.94, 2.07 (each 3H, s, 3 and
13-OAc), 3.07, 3.25, 3.33, 3.76 (each 3H, s, OCH3!4), 4.92
(1H, d, JZ7.2 Hz, H-6b), 4.99 (1H, d, JZ4.6 Hz, H-14b),
5.21 (1H, dd, JZ3.2, 12.8 Hz, H-3b), 6.84, 7.92 (each 2H,
AA0BB0, JZ8.4 Hz, Ar-H); dC (50 MHz, CDCl3) 173.2
(C-19), 170.5 (COCH3), 170.1 (COCH3), 168.9 (COCH3),
165.8 (COAr), 163.6 (C-400), 131.8 (C-200, C-600), 121.7
(C-100), 113.7 (C-300, C-500), 105.8 (C-17), 82.1 (C-8, C-13),
81.6 (C-1, C-16), 79.3 (C-6), 78.2 (C-14), 75.01 (C-18), 68.3
(C-3), 59.5 (C-180), 58.2 (C-160), 57.2 (C-6 ), 57.0 (C-7),
56.2 (C-10), 55.4 (400-OCH3), 53.2 (C-5), 51.8 (C-11), 51.7
(C-4), 44.8 (C-9), 42.1 (C-10), 40.3 (C-15), 33.9 (C-12),
31.2 (C-2), 21.0 (COCH3), 21.0 (COCH3), 20.9 (COCH3);
m/z (EI) 730 (25, MCCH), 699 (4, MKOCH3), 670 (15);
HRMS (FAB): MCCH, found 730.2714, C36H44NO15
requires 730.2711.
4.3.7. Compound 25. Mp 188–190 8C; Rf (99% CHCl3–
CH3OH) 0.48; [a]D20ZC45.8 (c 0.6, CHCl3); nmax (KBr)
3461 (OH), 2928, 2856, 1778 (g-lactone), 1733 (COO),
1608, 1514, 1461, 1259, 1099 cmK1; dH (200 MHz, CDCl3)
1.30 (3H, s, 8-OAc), 2.02, 2.09 (each 3H, s, 3 and 13-OAc),
3.31!2, 3.35, 3.83 (each 3H, s, OCH3!4), 4.06 (1H, s,
H-17), 4.77 (1H, d, JZ6.2 Hz, H-6b), 5.00 (1H, d, JZ
4.6 Hz, H-14b), 5.04 (1H, d, JZ4.6, 12.0 Hz, H-3b), 6.90,
7.98 (each 2H, AA0BB0, JZ8.6 Hz, Ar-H); dC (50 MHz,
CDCl3) 173.7 (C-19), 170.5 (COCH3), 170.3 (COCH3),
169.2 (COCH3), 165.9 (COAr), 163.6 (C-400), 131.8 (C-200,
C-600), 121.9 (C-100), 113.8 (C-300, C-500), 82.3 (C-8), 82.2
(C-13), 81.8 (C-1), 81.6 (C-16), 79.6 (C-6), 76.5 (C-14),
75.4 (C-18), 74.7 (C-17), 67.3 (C-3), 59.4 (C-180), 58.2
(C-160), 56.6 (C-10), 55.4 (400-OCH3), 54.9 (C-7), 51.8
(C-4), 51.1 (C-11), 50.6 (C-5), 43.6 (C-9), 41.4 (C-10), 40.6
(C-15), 34.1 (C-12), 31.8 (C-2), 21.2 (COCH3), 21.0
(COCH3), 21.0 (COCH3); m/z (FAB) 717 (20, MCCH),
657 (18, MKOAcCH); HRMS (FAB): MCCH, found
717.2753, C36H45O15 requires 717.2758.
4.3.4. Compounds 23, 24 and 25. To a solution of
compound 22 (450 mg, 0.62 mmol) in HOAc (8 mL) and
excess Zn dust (1.0 g), conc. HCl (1 mL) was added
dropwise with stirring vigorously. The mixture was stirred
at room temperature for 12 h. After filtration, the filtrate was
poured into ice water (10 mL). Basifying (conc. NH4OH,
pH 9), extraction (CHCl3, 10 mL!3), drying (Na2SO4),
evaporation and column chromatography (silica gel H,
CHCl3–CH3OH/200:1.5) afforded the pure product 23
(colorless crystal needle, 304 mg, 69%), 24 (white amor-
phous powder, 80 mg, 18%) and 25 (white amorphous
powder, 35 mg, 8%).
4.3.5. Compound 23. Mp 244–245 8C; Rf (99% CHCl3–
CH3OH) 0.58; [a]D20ZC26.8 (c 0.4, CHCl3); nmax (KBr)
3461 (OH), 2929, 2856, 1780 (g-lactone), 1736 (COO),
1608, 1514, 1403, 1257, 1100 cmK1; dH (200 MHz, CDCl3)
1.31 (3H, s, 8-OAc), 2.03, 2.08 (each 3H, s, 3 and 13-OAc),
3.30, 3.32, 3.37, 3.84 (each 3H, s, OCH3!4), 3.94 (1H, s,
H-17), 4.77 (1H, d, JZ6.2 Hz, H-6b), 5.02 (1H, d, JZ
5.0 Hz, H-14b), 5.04 (1H, dd, JZ4.2, 9.6 Hz, H-3b), 6.90,
8.00 (each 2H, AA0BB0, JZ8.8 Hz, Ar-H); dC (50 MHz,
CDCl3) 174.1 (C-19), 170.7 (COCH3), 170.4 (COCH3),
169.3 (COCH3), 165.9 (COAr), 163.6 (C-400), 131.8 (C-200,
C-600), 122.0 (C-100), 113.8 (C-300, C-500), 82.6 (C-1, C-8,
C-13), 81.1 (C-16), 79.7 (C-6), 76.6 (C-14), 74.6 (C-18),
67.9 (C-3), 590.04 (C-180), 58.2 (C-160), 56.5 (C-10), 55.5
(C-17), 55.3 (4 -OCH3), 54.3 (C-7), 51.8 (C-4), 51.3 (C-5),
50.6 (C-11), 44.5 (C-9), 41.8 (C-10), 40.9 (C-15), 34.2
(C-12), 30.2 (C-2), 21.2 (COCH3), 21.1 (COCH3),
21.0 (COCH3); m/z (FAB) 716 (100, MCCH), 656 (7,
4.3.8. Compound 26. To a solution of compound 23
(30 mg, 0.04 mmol) in Ac2O (2 mL), p-TsOH (20 mg) was
added and the mixture was stirred at room temperature for
20 h. After pouring into ice water (5 mL), the solution was
basified with conc. NH4OH to pH 9. Extraction (CHCl3,
5 mL!3), drying (Na2SO4) and evaporation afforded the
pure product (white amorphous powder, 32 mg, 100%). 26:
mp 162–163 8C; Rf (75% cyclohexane–acetone) 0.55;
[a]2D0ZC46.0 (c 0.5, CHCl3); nmax (KBr) 3410 (NH),
2929, 1776 (g-lactone), 1738 (COO), 1674 (CONH), 1608,
1514, 1461, 1259, 1099 cmK1; dH (400 MHz, CDCl3) 1.33
(3H, s, 8-OAc), 2.01, 2.07, 2.16 (each 3H, s, OAc!3), 3.25,
3.37, 3.42, 3.86 (each 3H, s, OCH3!4), 4.46 (1H, d, JZ
8.8 Hz, H-17), 4.84 (1H, d, JZ6.4 Hz, H-6b), 5.02 (1H, dd,
JZ3.0, 8.0 Hz, H-3b), 5.06 (1H, d, JZ5.2 Hz, H-14b),
5.72 (1H, brd, JZ8.8 Hz, 17-NHAc), 6.94, 8.03 (each 2H,
AA0BB0, JZ8.8 Hz, Ar-H); dC (100 MHz, CDCl3) 174.0
(C-19), 170.2 (COCH3), 170.0 (COCH3), 169.1 (COCH3),

2162
F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
169.0 (COCH3), 166.0 (COAr), 163.7 (C-400), 131.9 (C-200,
C-600), 122.0 (C-100), 113.9 (C-300, C-500), 83.3 (C-1), 82.4
(C-8, C-13), 81.2 (C-16), 79.8 (C-6), 76.5 (C-14), 750.3
(C-18),0067.7 (C-3), 59.5 (C-180), 58.5 (C-160), 56.8 (C-1 ),
55.4 (4 -OCH3), 54.9 (C-17), 52.6 (C-7), 52.0 (C-4), 51.9
(C-5), 50.8 (C-11), 46.4 (C-9), 41.6 (C-10), 40.6 (C-15),
34.5 (C-12), 30.0 (C-2), 22.5 (COCH3), 21.2 (COCH3), 21.1
(COCH3), 21.0 (COCH3); m/z (EI) 758 (100, MCCH), 698
(33, MKOAcCH); HRMS (FAB): MCCH, found
758.3035, C38H48NO15 requires 758.3024.
(Na2SO4) and evaporation afforded the pure product
(colorless crystal needle, 240 mg, 90%). 29: mp 234–
235 8C; Rf (90% CHCl3–CH3OH) 0.50; [a]2D0ZC56.4 (c
0.5, CH3OH); nmax (KBr) 3427 (OH), 3108 (NH), 2928,
1768 (g-lactone), 1601, 1460, 1377, 1330, 1096 cmK1; dH
(200 MHz, CDCl3) 2.40 (3H, s, Ar-CH3), 2.97, 3.33, 3.43
(each 3H, s, OCH3!3), 5.14 (1H, d, JZ5.4 Hz, H-6b),
7.28, 7.73 (each 2H, AA0BB0, JZ8.0 Hz, Ts); dC (50 MHz,
CD3COCD3) see Table 2; m/z (FAB) 610 (100, MCCH);
HRMS (FAB): MCCH, found 610.2327, C29H40NO11S
requires 610.2322.
4.3.9. Compound 27. To a solution of compound 25
(20 mg, 0.03 mmol) in Ac2O (2 mL), p-TsOH (10 mg) was
added and the mixture was stirred at room temperature for
12 h. General work-up afforded the pure product (white
amorphous powder, 21 mg, 100%). 27: mp 157–158 8C; Rf
(75% cyclohexane–acetone) 0.50; [a]2D0ZK82.0 (c 0.7,
CHCl3); nmax (KBr) 2929, 1775 (g-lactone), 1741 (COO),
1608, 1514, 1461, 1371, 1241, 1101 cmK1; dH (400 MHz,
CDCl3) 1.31 (3H, s, 8-OAc), 2.06, 2.07, 2.17 (each 3H, s,
OAc!3), 3.28, 3.36, 3.42, 3.86 (each 3H, s, OCH3!4),
4.79 (1H, d, JZ6.4 Hz, H-6b), 5.03 (1H, hidden, H-17),
5.04 (1H, d, JZ4.8 Hz, H-14b), 5.05 (01H,0 dd, JZ4.0,
12.0 Hz, H-3b), 6.93, 8.03 (each 2H, AA BB , JZ8.8 Hz,
Ar-H); dC (100 MHz, CDCl3) 173.2 (C-19), 170.7
(COCH3), 170.2 (COCH3), 169.4 (COCH3), 168.8
(COCH3), 166.0 (COAr), 163.7 (C-400), 131.9 (C-200,
C-600), 122.0 (C-100), 113.9 (C-300, C-500), 82.4 (C-8), 82.0
(C-13), 81.4 (C-1), 81.0 (C-16), 79.6 (C-6), 76.3 (C-14),
75.8 (C-17), 74.4 (C-18), 67.6 (C-3), 59.4 (C-180), 58.4
(C-160), 56.7 (C-10), 55.4 (400-OCH3), 53.6 (C-7), 51.7
(C-5), 51.6 (C-4), 49.5 (C-11), 44.5 (C-9), 41.8 (C-10), 39.9
(C-15), 34.2 (C-12), 30.0 (C-2), 21.2 (COCH3), 21.2
(COCH3), 21.1 (COCH3), 21.0 (COCH3); m/z (ESI) 759
(40, MCCH); HRMS (FAB): MCCH, found 759.2870,
C38H46O16 requires 759.2864.
4.3.12. Compound 30. To a solution of compound 29
(300 mg, 0.49 mmol) in pyridine (10 mL), MsCl (0.20 mL,
2.57 mmol) was added and the solution was allowed to stand
at room temperature for 3 h. Removal of solvent, diluting
(H2O), basifying (10% Na2CO3, pH 11), extraction (CHCl3,
10 mL!3), drying (Na2SO4) and evaporation afforded the
pure product as a white amorphous powder, 350 mg, (93%).
30: mp 152–153 8C; Rf (95% CHCl3–CH3OH) 0.48;
[a]2D0ZC19.4 (c 0.6, CHCl3); nmax (KBr) 3507 (OH),
3320 (NH), 2935, 1771 (g-lactone), 1639, 1460, 1350, 1176,
1094 cmK1; dH (200 MHz, CDCl3CCD3OD) 2.28 (3H, s,
Ar-CH3), 2.94, 2.97 (each 3H, s, OMs!2), 3.05, 3.20, 3.26
(each 3H, s, OCH3!3), 4.43 (1H, d, JZ4.2 Hz, H-14b),
4.76 (1H, d, JZ5.0 Hz, H-3b), 5.03 (1H, d, JZ6.4 Hz,
H-6b), 7.19, 7.58 (each 1H, AA0BB0, JZ8.0 Hz, Ts); dC
(50 MHz, CDCl3CCD3OD) see Table 2; m/z (FAB) 766
(100, MCCH); HRMS (FAB): MCCH, found 766.1869,
C31H44NO15S3 requires 766.1873.
4.3.13. Compound 31. To a mixture of compound 30
(100 mg, 0.13 mmol) and anhydrous NaOAc (200 mg,
2.43 mmol) in sealed tube (20 mL), HOAc (3 mL) was
added and the solution was stirred at 150 8C for 24 h.
Diluting (ice water), basifying (NH4OH, pH 10), extraction
(CHCl3, 5 mL!3), drying (Na2SO4), evaporation and
column chromatography (silica gel H, CHCl3–CH3OH/
25:1) afforded the pure product as a white amorphous
powder, 80 mg, (70%). 31: mp 232–233 8C; Rf (90%
CHCl3–CH3OH) 0.51; [a]2D0ZK13.0 (c 0.7, CHCl3); nmax
(KBr) 3487 (OH), 3324 (NH), 2934, 1758 (g-lactone), 1638,
1460, 1353, 1167, 1091 cmK1; dH (200 MHz, CDCl3) 2.44
(3H, s, Ar-CH3), 3.12, 3.25, 3.31, 3.41 (each 3H, s, OCH3!
3), 4.68 (1H, d, JZ4.8 Hz, H-14b), 4.80 (1H, s, H-17), 5.12
(1H, d, JZ7.2 Hz, H-6b), 5.92 (1H, dd, JZ2.0, 10.4 Hz,
H-2), 6.04 (1H, dd, JZ1.6, 10.4 Hz, H-3), 7.31, 7.73 (each
1H, AA0BB0, JZ8.8 Hz, Ts); dC (50 MHz, CDCl3) see
Table 2; m/z (FAB) 670 (85, MCCH); HRMS (FAB):
MCCH, found 670.1988, C30H40NO12S2 requires
670.1992.
4.3.10. Compound 28. To a solution of compound 23
(300 mg, 0.42 mmol) in pyridine (15 mL), TsCl (240 mg,
1.26 mmol) was added and the solution was allowed to stand
at room temperature for 30 h. Removal of solvent, basifying
(10% Na2CO3, 20 mL), extraction (CHCl3, 10 mL!3),
drying (Na2SO4), evaporation and column chromatography
(silica gel H, CHCl3–CH3OH/100:1) afforded the pure
product as a white amorphous powder, 345 mg, (95%). 28:
mp 178–179 8C; Rf (98% CHCl3–CH3OH) 0.42; [a]2D0Z
C5.5 (c 1.7, CHCl3); nmax (KBr) 3466 (OH), 2939, 1778
(g-lactone), 1740 (COO), 1607, 1514, 1460, 1371, 1258,
1101 cmK1; dH (200 MHz, CDCl3) 1.27 (3H, s, 8-OAc),
1.96, 2.20 (each 3H, s, OAc!2), 2.41 (3H, s, Ar-CH3), 3.17,
3.31, 3.45, 3.86 (each 3H, s, OCH3!4), 4.84 (1H, d, JZ
6.4 Hz, H-6b), 5.00 (1H, d, JZ5.0 Hz, H-14b), 5.09 (1H,
dd, JZ2.8, 7.8 Hz, H-3b), 5.66 (1H, d, JZ2.4 Hz, H-17),
6.93, 8.00 (each 2H, AA0BB0, JZ8.8 Hz, OAs), 7.32, 7.80
(each 2H, AA0BB0, JZ8.4 Hz, Ts); dC (50 MHz, CDCl3)
see Table 2; m/z (FAB) 870 (20, MCCH), 810
(7, MKOAcCH); HRMS (FAB): MCCH, found
870.3013, C43H52NO16S requires 870.3007.
4.4. Approach BCA
4.4.1. Compound 33. To a solution of compound 19
(1.10 g, 1.48 mmol) in diglyme (40 mL), H2O (10 mL) was
added and the solution was heated at reflux for 12 h.
Diluting (H2O, 40 mL), basifying (NH4OH, pH 10),
extraction (CHCl3, 20 mL!3), drying (Na2SO4), evapora-
tion and column chromatography (silica gel H, CHCl3–
CH3OH/50:1) afforded the pure product as a white
amorphous powder, 900 mg, (87%), which was identified
4.3.11. Compound 29. A solution of compound 28
(380 mg, 0.44 mmol) in 5% methanolic NaOH (15 mL)
was heated at 50 8C for 20 min. Removal of solvent, diluting
(H2O, 30 mL), extraction (EtOAc, 20 mL!4), drying

F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
Table 2. 13C NMR data of compounds 28, 29, 30, and 31
2163
Carbon
28
29
30
31
1
2
3
4
5
6
7
8
82.1 d
28.9 t
83.9 d
32.2 t
67.1 d
52.8 s
51.5 d
81.3 d
52.0 d
78.0 s
48.3 d
46.1 d
51.0 s
36.2 t
72.4 s
78.8 d
43.9 t
85.3 d
58.1 d
78.6 t
178.5 s
56.3 q
58.7 q
59.4 q
—
83.2 d
30.0 t
73.3 d
52.0 s
48.8 d
79.3 d
57.2 d
75.1 s
44.5 d
44.0 d
50.4 s
33.8 t
70.8 s
83.9 d
42.0 t
81.6 d
58.1 d
75.8 t
174.0 s
56.1 q
58.2 q
59.0 q
—
82.4 d
128.1 d
127.9 d
50.7 s
48.9 d
78.6 d
57.0 d
75.4 s
45.6 d
43.7 d
50.1 s
33.6 t
70.3 s
84.2 d
42.3 t
81.6 d
57.1 d
78.2 t
175.7 d
56.6 q
58.3 q
59.4 q
—
66.5 d
51.6 s
50.4 d
79.6 d
52.1 d
82.0 s
45.5 d
40.9 d
50.4 s
34.4 t
82.0 s
76.5 d
39.8 t
80.3 d
57.7 d
76.6 t
173.5 s
56.6 q
58.4 q
59.4 q
170.2 s
170.2 s
168.7 s
21.1 q
21.1 q
21.0 q
137.2 s
129.3 d
127.9 d
143.4 s
21.5 q
9
10
11
12
13
14
15
16
17
18
19
10
160
180
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
138.0 s
130.3 d
128.5 d
144.0 s
21.3 q
135.8 s
129.4 d
127.3 d
143.7 s
21.1 q
136.1 s
129.5 d
127.7 d
143.6 s
21.4 q
165.9 s
121.8 s
131.8 d
113.8 d
163.6 s
55.4 q
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
OMs
—
—
—
—
38.4 q
38.1 q
38.7 q
—
by comparison with the authentic sample [TLC: cyclohex-
ane–acetone/2:1; CHCl3–CH3OH/98:2].
50 8C for 20 min. Removal of solvent, diluting (H2O, 50 mL),
extraction (CHCl3, 10 mL!3), drying (Na2SO4) and evapor-
ation afforded the pure product (white amorphous powder,
274 mg, 100%). 35: mp 92–93 8C; Rf (90% CHCl3–CH3OH)
0.42; [a]2D0ZC40.4 (c 0.5, CHCl3); nmax (KBr) 3427 (OH),
2930, 1639, 1451, 1376, 1180, 1100 cmK1; dH (400 MHz,
CDCl3) 0.98 (3H, t, JZ7.2 Hz, N-CH2CH3), 3.33, 3.33, 3.34,
3.45 (each 3H, s, OCH3!4), 4.15 (1H, d, JZ2.8 Hz, H-14b),
5.58 (1H, br s, H-7); dC (100 MHz, CDCl3) 133.5 (C-8), 126.8
(C-7), 85.4 (C-1, C-16), 82.6 (C-6), 79.8 (C-14), 77.8 (C-13),
74.3 (C-18), 70.5 (C-3), 59.1 (C-180), 57.7 (C-160), 57.6 (C-
60), 56.1 (C-10), 52.1 (C-19), 51.6 (C-17), 49.5 (NCH2CH3),
43.9 (C-5), 43.7 (C-11), 42.2 (C-4), 41.6 (C-9), 40.9 (C-10),
38.9 (C-15), 38.5 (C-12), 35.3 (C-2), 12.0 (NCH2CH3); m/z
(EI) 467 (15, MC), 452 (100, MKCH3), 436 (75, MKOCH3),
378 (85); HRMS (FAB): MCCH, found 468.2959,
C25H42NO7 requires 468.2961.
4.4.2. Compound 34. To a solution of compound 33
(900 mg, 1.28 mmol) in pyridine (20 mL), SOCl2 (1.0 mL)
was added and the solution was stirred at room temperature
for 12 h. To the reaction solution was added excess NaBH4
and the reaction solution continued to stand at room
temperature for 3 h. Removal of solvent, diluting (H2O,
40 mL), basifying (conc. NH4OH, pH 10), extraction
(CHCl3, 20 mL!3), drying (Na2SO4), evaporation and
column chromatography (silica gel H, cyclohexane–
acetone/4:1) afforded the pure product as a white amorphous
powder, 650 mg, (74%), which was identified by compari-
son with the authentic sample [TLC: cyclohexane–acetone/
2:1; CHCl3–CH3OH/96:4].
4.4.3. Compound 35. A solution of compound 34 (400 mg,
0.59 mmol) in 5% methanolic NaOH (15 mL) was heated at
4.4.4. Compounds 36 and 37. To a solution of compound

2164
F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
35 (220 mg, 0.47 mmol) in pyridine (15 mL), MsCl
(0.14 mL, 1.80 mmol) was added and the solution was
stirred at room temperature for 6 h. Removal of solvent,
diluting (H2O, 50 mL), basifying (10% Na2CO3, 20 mL),
extraction (CHCl3, 10 mL!3), drying (Na2SO4), evapor-
ation and column chromatography (silica gel H, CHCl3–
CH3OH/100:0.7) afforded the pure products as white
amorphous powder (36: 150 mg, 51%; 37: 55 mg, 17%).
(13, MKCH3), 432 (100, MKOMs); HRMS (FAB): MCC
H, found 528.2640, C26H42NO8S requires 528.2631.
4.5. Approach CAB
4.5.1. Compound 43. To a solution of yunaconitine (3)
(1.55 g, 2.35 mmol) in acetone (10 mL), Jones reagent
(3 mL, 8.22 mmol) was added dropwise under ice-water
bath and the solution was stirred at room temperature for
30 min. Diluting (H2O, 30 mL), basifying (conc. NH4OH,
pH 11), extraction (CHCl3, 15 mL!4), drying (Na2SO4)
and evaporation afforded the white amorphous powder,
which was dissolved in 5% methanolic NaOH (15 mL) and
heated at 50 8C for 30 min. Removal of solvent, diluting
(H2O, 30 mL), extraction (CHCl3, 15 mL!3), drying
(Na2SO4) and evaporation afforded the white amorphous
powder (1.06 g, 100%). This residue (1.06 g, 2.35 mmol)
was dissolved in pyridine (30 mL), MsCl (0.35 mL,
4.70 mmol) was added and the solution was stirred at
room temperature for 1.5 h. Removal of solvent, diluting
(H2O, 30 mL), extraction (CHCl3, 15 mL!3), drying
(Na2SO4), and evaporation afforded the pure product
(white amorphous powder, 1.17 g, 95%), which was
dissolved in DMF (50 mL), NaOH (200 mg) was added
and the solution was refluxed for 30 min. General work-up
afforded the white amorphous powder (912 mg, 90%).
4.4.5. Compound 36. Mp 113–114 8C; Rf (99% CHCl3–
CH3OH) 0.56; [a]D20ZC18.4 (c 0.5, CHCl3); nmax (KBr)
3477 (OH), 2934, 1638, 1458, 1352, 1176, 1102 cmK1; dH
(400 MHz, CDCl3) 0.97 (3H, t, JZ7.2 Hz, N-CH2CH3),
3.03, 3.07 (each 3H, s, OMs!2), 3.29, 3.37, 3.37, 3.34
(each 3H, s, OCH3!4), 4.66 (1H, d, JZ2.0 Hz, 14b-H),
4.83 (1H, dd, JZ6.4, 11.6 Hz, H-3b), 5.56 (1H, br s, H-7);
dC (100 MHz, CDCl3) 131.8 (C-8), 127.0 (C-7), 88.8 (C-
14), 85.1 (C-16), 84.3 (C-1), 81.1 (C-6), 79.5 (C-3), 76.8 (C-
13), 71.2 (C-18), 58.5 (C-180), 57.8 (C-60, C-160), 56.1 (C-
10), 51.6 (C-19), 50.8 (C-17), 49.4 (NCH2CH3), 43.3 (C-11),
42.9 (C-5), 42.2 (C-4), 40.8 (C-9), 40.5 (C-10), 38.7 (C-15),
38.6 (C-12), 38.2 (OMs), 38.2 (OMs), 33.2 (C-2), 11.8
(NCH2CH3); m/z (EI) 623 (1, MC), 608 (3, MKCH3), 432
(100, MKOMs!2-H); HRMS (FAB): MCCH, found
624.2520, C27H46NO11S2 requires 624.2512.
4.4.6. Compound 37. Mp 110–111 8C; Rf (99% CHCl3–
CH3OH) 0.5; [a]D20ZC8.8 (c 0.5, CHCl3); nmax (KBr) 2938,
1639, 1459, 1355, 1170, 1105 cmK1; dH (400 MHz, CDCl3)
0.96 (1H, t, JZ7.2 Hz, N-CH2CH3), 3.03, 3.10, 1.13 (each
3H, s, OMs!3), 3.29, 3.35, 3.37, 3.41 (each 3H, s, OCH3!
4), 4.83 (1H, dd, JZ5.2, 11.6 Hz, H-3b), 4.90 (1H, br s, H-
14b), 5.69 (1H, br s, H-7); dC (100 MHz, CDCl3) 130.5 (C-
8), 127.4 (C-7), 90.8 (C-13), 86.8 (C-14), 83.8 (C-1), 830.3
(C-16), 80.8 (C-6), 79.1 (C-3), 71.2 (C-18), 58.5 (C-18 ),
57.7 (C-160), 56.7 (C-60), 56.0 (C-10), 51.4 (C-19), 50.5 (C-
17), 49.4 (NCH2CH3), 43.2 (C-11), 42.2 (C-4), 42.1 (C-5),
40.5 (C-9), 40.4 (C-10), 40.2 (OMs), 39.2 (C-15), 39.1 (C-
12), 38.9 (OMs), 38.4 (OMs), 33.2 (C-2), 11.8 (NCH2CH3);
m/z (EI) 701 (1, MC), 605 (14, MKOMs-1), 510 (75, MK
OMs!2-1), 414 (25, MKOMs!3-H-H); HRMS (FAB):
MCCH, found 702.2287, C28H48NO13S3 requires
702.2288.
To a solution of the residue (912 mg, 2.12 mmol) in 95%
EtOH (30 mL), 10% Pd–C (90 mg) was added and the
solution was stirred under hydrogen steam at room
temperature for 1 h. Filtration was evaporated under
reduced pressure to give the pure product 43 (white
amorphous powder, 915 mg, 100%), which was identified
by comparison with the authentic sample [TLC: silica gel
GF254, cyclohexane–acetone/3:1; CHCl3–CH3OH/95:5].
4.5.2. Compound 44. To a solution of compound 43
(800 mg, 1.85 mmol) in MeOH (30 mL), NaBH4 (500 mg,
13.15 mmol) was added and the solution was stirred at room
temperature for 3 h. Removal of solvent, diluting (H2O,
40 mL), extraction (CHCl3, 15 mL!3), drying (Na2SO4),
and evaporation afforded the pure product (white amor-
phous powder, 726 mg, 90%). 44: mp 160–161 8C; Rf (90%
CHCl3–CH3OH) 0.44; [a]2D0ZC12.5 (c 0.2, CHCl3); nmax
(KBr) 3426 (OH), 2930, 1649, 1459, 1379, 1203, 1175,
1101 cmK1; dH (400 MHz, CDCl3) 1.08 (3H, t, JZ7.2 Hz,
N-CH2CH3), 3.32, 3.33, 3.39 (each 3H, s, OCH3!3), 3.87
(1H, dd, JZ2.8, 6.0 Hz, H-13), 4.08 (1H, dd, JZ2.4,
9.6 Hz, H-3b); dC (100 MHz, CDCl3) 84.3 (C-6), 77.7 (C-
8), 77.0 (C-16), 760.7 (C-18), 74.04 (C-3), 64.6 (C-13), 62.8
(C-17), 59.0 (C-18 ), 57.8 (C-16 ), 56.0 (C-60), 52.0 (C-7),
48.6 (NCH2CH3), 48.0 (C-5), 47.1 (C-19), 43.9 (C-11), 42.9
(C-9), 42.3 (C-4), 40.3 (C-10), 34.5 (C-15), 29.6 (C-14),
29.1 (C-12), 25.9 (C-2), 21.8 (C-1), 13.4 (NCH2CH3); m/z
(EI) 437 (25, MC), 422 (100, MKCH3); HRMS (FAB):
MCCH, found 438.2854, C24H40NO6 requires 438.2856.
4.4.7. Compound 38. To a mixture of compound 36
(100 mg, 0.13 mmol) and o-xylene (2.5 mL) in sealed tube
(20 mL), DBN (0.5 mL) was added and the solution was
heated at 150 8C for 5 h. Removal of o-xylene and column
chromatography (silica gel H, CHCl3–CH3OH/9:1) afforded
the pure product (oil, 30 mg, 89%). 38: mp 240–241 8C; Rf
(80% CHCl3–CH3OH) 0.50; [a]2D0ZK13.4 (c 0.5, CHCl3);
nmax (KBr) 3468 (OH), 3324, 2930, 1612, 1459, 1353, 1276,
1170, 1106 cmK1; dH (400 MHz, CDCl3) 0.93 (3H, t, JZ
7.2 Hz, N-CH2CH3), 3.03 (3H, s, OMs), 3.30, 3.31, 3.36,
3.40 (each 3H, s, OCH3!4), 4.65 (1H, d, JZ3.0 Hz, H-
14b), 5.59 (1H, dd, hidden, H-2), 5.61 (1H, br s, H-7), 5.92
(1H, dd, JZ2.0, 9.8 Hz, H-3); dC (100 MHz, CDCl3) 136.8
(C-2), 131.5 (C-8), 129.0 (C-3), 125.7 (C-7), 88.3 (C-14),
87.4 (C-1), 84.8 (C-16), 79.03 (C-6), 78.01 (C-18), 77.3 (C-
12), 59.2 (C-180), 58.1 (C-16 ), 57.9 (C-6 ), 56.4 (C-10), 53.2
(C-19), 51.6 (C-17), 50.8 (NCH2CH3), 43.8 (C-5), 43.3 (C-
4), 43.2 (C-11), 41.9 (C-9, C-10), 38.8 (C-12), 38.6 (C-15),
38.3 (OMs), 10.9 (NCH2CH3); m/z (EI) 527 (7, MC), 521
4.5.3. Compound 45. To a solution of compound 44
(700 mg, 1.60 mmol) in pyridine (30 mL), Ac2O (3 mL)
was added and the solution was heated at room temperature
for 28 h. Removal of solvent, basifying (10% Na2CO3,
20 mL), extraction (CHCl3, 10 mL!3), drying (Na2SO4),
and evaporation afforded the pure product (white

F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
2165
amorphous powder, 791 mg, 95%). 45: mp 72–73 8C; Rf
(95% CHCl3–CH3OH) 0.46; [a]2D0ZC56.5 (c 0.5, CHCl3);
nmax (KBr) 3452 (OH), 2932, 1738 (COO), 1639, 1459,
1378, 1247, 1112, 1100 cmK1; dH (400 MHz, CDCl3) 0.91
(3H, t, JZ6.8 Hz, N-CH2CH3), 2.05, 2.13 (each 3H, s,
OAc!2), 3.22, 3.34, 3.36 (each 3H, s, OCH3!3), 4.97 (1H,
dd, JZ5.2, 12.4 Hz, H-3b), 5.22 (1H, dd, JZ6.4, 7.2 Hz, H-
13); dC (50 MHz, CDCl3) 170.5 (COCH3), 170.2 (COCH3),
84.4 (C-6), 77.7 (C-8), 75.1 (C-3), 74.0 (C-16), 71.7 (C-18),
66.2 (C-13), 64.1 (C-17), 58.7 (C-180), 57.9 (C-160) 56.3 (C-
60), 51.8 (C-7), 48.4 (NCH2CH3), 48.0 (C-19), 46.2 (C-5),
43.7 (C-11), 42.3 (C-9), 41.4 (C-4), 40.0 (C-10), 36.5 (C-
15), 29.6 (C-12), 29.4 (C-14), 25.9 (C-2), 22.8 (C-1), 21.1
(COCH3), 20.8 (COCH3), 13.3 (NCH2CH3); m/z (ESI) 522
(100, MCCH); HRMS (FAB): MCCH, found 522.3061,
C28H44NO8 requires 522.3067.
65.0 (C-17), 58.8 (C-180), 58.0 (C-7), 58.2 (C-160), 56.3 (C-
60), 44.9 (C-11), 44.4 (C-4), 43.9 (C-5), 42.6 (C-9), 39.5 (C-
10), 36.1 (C-15), 29.1 (C-14), 25.8 (C-12), 25.1 (C-2), 23.1
(C-1), 20.9 (COCH3), 20.8 (COCH3); m/z (EI) 507 (13,
MC), 492 (85, MKCH3), 432 (100, MKCH3–HOAc);
HRMS (EI): MC, found 507.2455, C26H37NO9 requires
507.2468.
4.5.6. Compound 48. To a solution of compound 44
(45 mg, 0.10 mmol) in Ac2O (2 mL), p-TsOH (50 mg) was
added and the solution was heated at 50 8C for 12 h.
Diluting (ice water), basifying (conc. NH4OH, pH 10),
extraction (CHCl3, 5 mL!3), drying (Na2SO4) and evap-
oration afforded the pure product (white amorphous powder,
50 mg, 86%). 48: mp 70–71 8C; Rf (95% CHCl3–CH3OH)
0.44; [a]2D0ZC48.1 (c 0.7, CHCl3); nmax (KBr) 3451 (OH),
2934, 1738 (COO), 1459, 1375, 1244, 1112 cmK1; dH
(400 MHz, CDCl3) 1.12 (3H, t, JZ7.2 Hz, N-CH2CH3),
2.02, 2.05, 2.14 (each 3H, s, OAc!3), 3.21, 3.32, 3.33 (each
3H, s, OCH3!3), 4.97 (1H, dd, JZ6.4, 11.6 Hz, H-3b),
5.26 (1H, dd, JZ3.2, 8.8 Hz, H-13); dC (100 MHz, CDCl3)
170.3 (COCH3), 170.2 (COCH3), 160.1 (COCH3), 89.4 (C-
8), 85.0 (C-6), 75.3 (C-16), 73.9 (C-3), 71.6 (C-18), 66.9 (C-
13), 63.0 (C-17), 58.6 (C-180), 58.1 (C-160), 56.7 (C-60),
48.2 (C-7), 48.1 (NCH2CH3), 47.4 (C-19), 46.6 (C-5), 43.8
(C-11), 43.0 (C-9), 41.3 (C-4), 39.4 (C-10), 31.8 (C-15),
30.6 (C-14), 25.8 (C-2), 25.5 (C-12), 22.2 (C-1), 21.4
(COCH3), 21.1 (COCH3), 20.9 (COCH3), 13.2 (NCH2CH3);
m/z (EI) 562 (10, MC-H), 548 (10, MKCH3), 503 (12, MK
HOAc), 472 (40, MKOCH3–HOAc), 444 (100, MKOAc!
2-H); HRMS (EI): MC, found 563.3081, C30H45NO9
requires 563.3094.
4.5.4. Compound 46. To a solution of compound 45
(760 mg, 1.45 mmol) in HOAc (40 mL), NBS (2.08 g,
11.77 mmol) was added and the solution was stirred at room
temperature for 2 h. After pouring into ice water (50 mL),
the solution was basified with conc. NH4OH to pH 10.
Extraction (CHCl3, 10 mL!3), drying (Na2SO4), evapora-
tion and column chromatography (silica gel H, CHCl3–
CH3OH/25:1) afforded the pure product (white amorphous
powder, 585 mg, 82%). 46: mp 110–111 8C; Rf (90%
CHCl3–CH3OH) 0.41; [a]2D0ZC111.0 (c 0.7, CHCl3); nmax
(KBr) 3452 (OH), 2937, 1736 (COO), 1650 (C]N), 1461,
1378, 1246, 1210, 1108 cmK1; dH (400 MHz, CDCl3) 2.06,
2.12 (each 2H, s, OAc!2), 3.28, 3.32, 3.34 (each 3H, s,
OCH3!3), 4.11 (each 1H, ABq, JZ8.8 Hz, H2-18), 4.04
(1H, dd, JZ1.2, 6.8 Hz, H-6b), 3.59 (1H, s, H-17), 4.97
(1H, dd, JZ4.4, 11.2 Hz, H-3b), 5.18 (1H, dd, JZ3.6,
10.0 Hz, H-13), 7.39 (1H, d, JZ1.2 Hz, H-19); dC
(100 MHz, CDCl3) 170.7 (COCH3), 169.8 (COCH3),
164.2 (C-19), 84.9 (C-6), 75.4 (C-8), 74.7 (C-16), 73.3
(C-3), 69.90 (C-18), 66.0 0(C-13), 64.8 (C-17), 60.8 (C-7),
58.9 (C-18 ), 57.9 (C-16 ), 56.3 (C-60), 49.8 (C-11), 45.2
(C-5), 43.5 (C-4), 42.9 (C-9), 39.2 (C-10), 36.0 (C-15), 29.3
(C-14), 26.4 (C-12), 26.3 (C-2), 23.5 (C-1), 20.9 (COCH3),
20.7 (COCH3); m/z (EI) 491 (15, MC), 432 (100, MKOAc);
HRMS (FAB): MCCH, found 492.2601, C26H38NO8
requires 492.2597.
4.5.7. Compound 49. To a solution of compound 48
(55 mg, 0.10 mmol) in HOAc (2 mL), NBS (139 mg,
0.78 mmol) was added and the solution was stirred at
room temperature for 3 h. General work-up and column
chromatography (silica gel H, CHCl3–CH3OH/98:2)
afforded the pure product as a white amorphous powder,
28 mg, (54%). 49: mp 80–81 8C; Rf (95% CHCl3–CH3OH)
0.46; [a]2D0ZC98.0 (c 0.7, CHCl3); nmax (KBr) 2943, 1775
(COO), 1717 (COO), 1648 (C]N), 1432, 1375, 1241,
1108 cmK1; dH (400 MHz, CDCl3) 2.00, 2.07, 2.13 (each
3H, s, OAc!3), 3.28, 3.31, 3.35 (each 3H, s, OCH3!3),
4.97 (1H, dd, JZ4.8, 12.0 Hz, H-3b), 5.22 (1H, dd, JZ4.0,
8.0 Hz, H-13), 7.41 (1H, br s, H-19); dC (100 MHz, CDCl3)
170.2 (COCH3), 169.8 (COCH3), 169.8 (COCH3), 164.0 (C-
19), 86.5 (C-8), 85.5 (C-6), 75.3 (C-16), 73.1 (C-3), 69.6 (C-
18), 67.4 (C-13), 63.1 (C-17), 58.8 (C-180), 58.2 (C-160),
57.8 (C-7), 57.0 (C-60), 49.9 (C-11), 45.7 (C-5), 43.6 (C-4),
41.4 (C-9), 39.3 (C-10), 32.5 (C-15), 26.3 (C-2), 26.2 (C-
12), 23.2 (C-1), 22.3 (C-14), 20.9 (COCH3), 20.9 (COCH3),
20.9 (COCH3); m/z (ESI) 533 (100, MC); HRMS (FAB):
MCCH, found 534.2707, C28H40NO9 requires 534.2703.
4.5.5. Compound 47. To a solution of compound 46
(520 mg, 1.06 mmol) in CH2Cl2 (35 mL), m-CPBA
(367 mg, 2.12 mmol) was added and the solution was
stirred at room temperature for 2 h. To the reaction mixture
was added 10% Na2CO3 (20 mL) with stirring vigorously.
The organic layer was separated and the aqueous layer was
extracted with CHCl3 (10 mL!3). Drying (Na2SO4) and
evaporation afforded the pure product (white amorphous
powder, 450 mg, 84%). 47: mp 117–118 8C; Rf (95%
CHCl3–CH3OH) 0.45; [a]2D0ZC52.8 (c 0.5, CHCl3); nmax
(KBr) 3452 (OH), 2931, 1739 (COO), 1460, 1378, 1245,
1210, 1108 cmK1; dH (400 MHz, CDCl3) 2.10, 2.13 (each
3H, s, OAc!2), 3.28, 3.34, 3.38 (each 3H, s, OCH3!3),
3.50, 4.18 (each 1H, ABq, JZ10.0 Hz, H2-18), 3.86 (1H, s,
H-17), 3.88 (1H, dd, JZ2.4, 8.8 Hz, H-6b), 4.17 (1H, s,
H-19), 4.99 (1H, dd, JZ4.8, 12.0 Hz, H-3b), 5.17 (1H, dd,
JZ3.6, 10.0 Hz, H-13); dC (100 MHz, CDCl3) 170.6
(COCH3), 169.6 (COCH3), 83.7 (C-6), 77.0 (C-8), 76.0
(C-19), 74.8 (C-16), 73.1 (C-3), 68.7 (C-18), 66.1 (C-13),
4.5.8. Compound 50. To a solution of compound 49
(28 mg, 0.053 mmol) in CH2Cl2 (2 mL), m-CPBA (18 mg,
0.105 mmol) was added and the solution was stirred at room
temperature for 30 min. General work-up and column
chromatography (silica gel H, CHCl3–CH3OH/99:1)
afforded the pure product as a white amorphous powder,
12 mg, (40%). 50: mp 105–106 8C; Rf (96% CHCl3–
CH3OH) 0.50; [a]D20ZC16.7 (c 0.3, CHCl3); nmax (KBr)

2166
F.-P. Wang, L. Xu / Tetrahedron 61 (2005) 2149–2167
Table 3. 1H and 13C NMR data of 51 (1H: 400 MHz, 13C: 100 MHz; CDCl3)
No.
dH Mult (JZHz)
dC
HMBC (H/C)
1
2
w1.80 m
1.50 m (a)
1.80 m (b)
5.22 dd (9.2, 5.6)
—
22.6 t
18.0 t
C-2, C-10, C-11
C-11
C-1, C-11
C-1, C-2, C-4, C-5, C-18, C-19
—
C-7, C-17, C-18, C-19
C-5, C-11, C-19
C-6, C-8, C-17
3
4
5
6
7
8
9
10
11
12
13
14
15
66.4 d
52.2 s
48.0 d
83.6 d
55.8 d
76.2 s
49.9 d
37.4 d
49.7 s
24.9 t
66.2 d
29.1 d
37.7 t
2.54 m
5.63 d (7.2)
3.80 s
—
—
C-8
2.50 m
w2.30 m
—
1.40 m
5.05 dd (12.8, 3.2)
3.02 m
w2.00 m
w2.30 m
3.57 m
C-5, C-8, C-9, C-14
—
C-9, C-11
C-16, OOCCH3 (dC 169.1)
C-8, C-10, C-12, C-16
C-8, C-13, C-16
C-8, C-13, C-16
C-8
C-6, C-7, C-8
C-19
C-19
—
C-16
C-18
OOCCH3 (dC 170.2)
16
17
18
74.2 d
91.8 d
77.1 t
4.90 s
3.33 ABq (hidden)
3.51 ABq (hidden)
—
3.33 s
3.33 s
2.02 s
19
177.7 s
56.4 q
59.4 q
170.2 s
20.9 q
169.1 s
20.5 q
16-OCH3
18-OCH3
3-OAc
13-OAc
2.18 s
OOCCH3 (dC 169.1)
2936, 1736 (COO), 1656, 1432, 1375, 1241, 1108 cmK1; dH
(400 MHz, CDCl3) 2.00, 2.08, 2.11 (each 3H, s, OAc!3),
3.28, 3.32, 3.39 (each 3H, s, OCH3!3), 5.01 (1H, dd, JZ
6.4, 13.2 Hz, H-3b), 5.27 (1H, dd, JZ3.6, 8.4 Hz, H-13),
6.17 (1H, br s, H-19); m/z (ESI) 572 (58, MCCNa); HRMS
(FAB): MCCH, found 550.2656, C28H40NO10 requires
550.2652.
1108 cmK1; dH (400 MHz, CDCl3) 2.06, 2.07, 2.13 (each
3H, s, OAc!3), 3.33 (6H, s, OCH3!2), 5.00 (1H, dd, JZ
4.0, 7.6 Hz, H-13), 5.24 (1H, dd, JZ5.6, 9.2 Hz, H-3b), 5.11
(1H, d, JZ7.2 Hz, H-6b), 5.49 (1H, s, H-17); dC (100 MHz,
CDCl3) 174.1 (C-19), 170.3 (COCH3), 170.1 (COCH3),
169.3 (COCH3), 89.0 (C-17), 84.1 (C-8), 81.9 (C-6), 76.7
(C-18), 75.1 (C-16), 67.1 (C-13), 66.7 (C-3), 59.3 (C-180),
57.0 (C-160), 56.1 (C-7), 51.5 (C-4), 51.1 (C-5), 49.5 (C-9),
49.4 (C-11), 37.0 (C-15), 36.9 (C-10), 29.2 (C-14), 24.7
(C-12), 21.9 (C-1, COCH3), 20.9 (COCH3), 20.5 (COCH3),
19.7 (C-2); m/z (ESI) 588 (58, MCCNa); HRMS (EI): MC,
found 565.2160, C27H35NO12 requires 565.2159.
4.5.9. Compound 51. To a solution of compound 47
(300 mg, 0.59 mmol) in MeOH (15 mL), excess
HIO4$2H2O (800 mg, 3.76 mmol) was added and the
mixture was stirred at room temperature for 4 h. Removal
of solvent, basifying (10% Na2CO3, 30 mL), extraction
(CHCl3, 15 mL!4), drying (Na2SO4), evaporation and
column chromatography (silica gel H, petroleum ether–
acetone/3:1) afforded the pure product 51 (white amorphous
powder, 80 mg, 26%) and a by-product 47 (white amor-
phous powder, 120 mg, 40%). 51: mp 114–115 8C; Rf (50%
petroleum ether–acetone) 0.48; [a]2D0ZK1.70 (c 0.5,
CHCl3); nmax (KBr) 3450 (OH), 2941, 1780 (g-lactone),
1740 (COO), 1558, 1461, 1378, 1243, 1107 cmK1; dH
(400 MHz, CDCl3) and dC (100 MHz, CDCl3) see Table 3;
m/z (EI) 523 (4, MC), 507 (3, MKCH3), 463 (40, MKCH3-
NO2), 419 (100); HRMS (EI): MC, found 523.2057,
C25H33NO11 requires 523.2054.
Acknowledgements
Financial support for this research was provided from the
National Natural Science Foundation of China (No.
30472075). We also thank Ms. Jian-Li Wang and Professor
Xiao-Tian Liang for writing and ckecking the experimental
section of this manuscript, as well as for helpful revisions on
the manuscript, respectively.
References and notes
4.5.10. Compound 52. To a solution of compound 50
(12 mg, 0.022 mmol) in MeOH (2 mL), excess HIO4$2H2O
(50 mg, 0.23 mmol) was added and the mixture was stirred
at room temperature for 12 h. A general work-up and
column chromatography (silica gel H, CHCl3–CH3OH/
100:1) afforded the pure product (white amorphous powder,
5 mg, 40%). 52: mp 96–97 8C; Rf (98% CHCl3–CH3OH)
0.46; [a]2D0ZK28.4 (c 0.5, CHCl3); nmax (KBr) 2938, 1776
(g-lactone), 1738 (COO), 1550, 1458, 1380, 1243,
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