A novel approach to the taxane ABC ring system through chemical conversion from C19-diterpenoid alkaloid deltaline

Article abstract of DOI:10.1016/j.tet.2008.05.089

A novel approach to the highly functionalized taxane ABC ring system through chemical conversion of the C₁₉-diterpenoid alkaloid deltaline (1) was achieved in six steps (1→17) in 18% overall yield mainly by Grob fragmentation, fission of the Δ⁹⁽¹⁴⁾ double bond, followed by aldol condensation, and Pelletier's cleavage process.

Full text of DOI:10.1016/j.tet.2008.05.089

Tetrahedron 64 (2008) 7594–7604
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel approach to the taxane ABC ring system through chemical conversion
from C19-diterpenoid alkaloid deltaline
*
Chun-Lan Zou, Le Cai, Hong Ji, Guang-Bo Xie, Feng-Peng Wang , Xi-Xian Jian, Lei Song,
*
Xiao-Yu Liu, Dong-Lin Chen, Qiao-Hong Chen
Department of Chemistry of Medicinal Natural Products, West China College of Pharmacy, Sichuan University, No. 17, Duan 3, Renmin Nan Road, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the highly functionalized taxane ABC ring system through chemical conversion of
the C19-diterpenoid alkaloid deltaline (1) was achieved in six steps (1/17) in 18% overall yield mainly by
Grob fragmentation, fission of the D9(14) double bond, followed by aldol condensation, and Pelletier’s
cleavage process.
Received 22 February 2008
Received in revised form 20 May 2008
Accepted 20 May 2008
Available online 23 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to venerated Professor Xiao-Tian
Liang on the occasion of his 85th birthday
Keywords:
C19-Diterpenoid alkaloid
Deltaline
Grob fragmentation
Aldol condensation
Pelletier’s cleavage
Taxoid
1. Introduction
The diterpenoid alkaloids are a group of highly oxygenated,
complex natural products displaying a plethora of interesting
In spite of some remarkable successes, including six total syn-
theses1 and a plethora of ingenious synthetic designs, the conve-
nient practical assembly of the full-functionalized taxane core
structure or the synthesis of structurally simplified analogs, re-
mains a significant challenge, and substantial excellent studies are
still in progress.
Numerous methods to synthesize the ABC system of the taxoid
nucleus have been published,2 among which the most important
is to construct simultaneously the BC ring, following the com-
pletion of A ring. However, a method to derive the taxoid core
nucleus from natural products using the C19-diterpenoid alkaloids
as the starting material was not reported previously. On the other
hand, whereas the structure–activity relationships of the taxoids,
e.g., paclitaxel, are well studied,3 there is no information available
for the simplified nor-taxoids without the methyl groups at C-8, C-
12, and C-15, and this attracted our attention. Obviously, this study
may form the basis for searching for more active taxoids with
lower toxicity.
chemistry.4 They were isolated mainly from Aconitum and Del-
phinium plants (Ranunculaceae) as rich sources.5 During the course
of studies on the development of a novel method for the con-
struction of the unique taxane tricyclo[9.3,1.03,8]pentadecane nu-
cleus based on the chemical conversion of
C19-diterpenoid
alkaloids, as early as 1994, we initiated a decade long research
program using yunaconitine, a C19-diterpenoid alkaloid, as the
starting material according to the strategy shown in Scheme 1.6
Though repetitive studies were conducted, substantial success was
not achieved. After a long search, it became apparent that deltaline
(1) could be isolated from Delphinium bonvalotii Franch. on the
kilogram scale, and thus we designed two strategies to convert
deltaline (1) to taxane-like compounds according to Scheme 2, but
these attempts also failed.7 Based on these studies, we now present
an alternative strategy, depicted in Scheme 3, which represents
a novel construction of the unique taxane ABC system core. As
shown in Scheme 3, after the O-demethylation and selective
mesylation (path a), the mesylate (A) was subjected to Grob frag-
mentation (path b) to give the olefin B, followed by fission of the
C(9)–C(14) double bond leading to the key intermediate C (path c).
Subsequent aldol condensation–acetalation (path d) of C furnished
hemiacetal D. Finally, protection using CH3I–NaH (path e), followed
* Corresponding authors. Tel./fax: þ86 28 85501368.
E-mail address: wfp@scu.edu.cn (F.-P. Wang).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.089

C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
7595
OH
OCH3
13
16
12
CH3O
14
O
C
•
C
1
.
OAs
D
D
.
•
9
10B
2
A
15
11
5
B
N
4
8
A
3
6
OAc
HO
HO
7
HO
H
OCH3
B
A
OCH3
yunaconitine
[Aconitine-type ditepenoid alkaloid]
O
O
O
(18)
(10) (9)H
(7)
17
(12)
(11)
14
13
16
15
6
7
H
10
9
18
15
(6)
(5)
1
4
5
8
9
(16)O
16
11
8
HO
1
4
13
3
(17)
10
(13)
2
3
14
(15)
(3)
O
(4)
(14)
(1)
OH
(2)
O
O
C
OH
D
(
): the numbering of taxoids
Scheme 1. Approach to the taxane-like ABC system from yunaconitine by strategy I.
by Pelletier’s cleavage8 (path f), produced the desired taxane-like
cores 14 and 17. In this paper, we report some details of this novel
and stereospecific approach to the taxane-like ABC ring system
from deltaline (1).
selective acylation of 4 from the hydrolysis of 3 using BzCl in the
presence of Ag2O–KI10 (40 ꢁC, 2 h) furnished 5a (45%) and 5b (50%).
The latter could be recycled for the preparation of additional 5a.
Following mesylation to yield 6, exposure to 5% NaOH methanol
(reflux, 3 h) permitted Grob fragmentation to 7, which on methyl-
ation afforded the desired product 8, as a result of one-pot pro-
cedure, in a 70% isolated yield (Scheme 4). The molecular formula of
7, C23H31NO7, was established by the HR-ESIMS, and the 13C NMR
2. Results and discussion
The synthesis was initiated with deltaline (1), which afforded 3
in 64% overall yield for the two steps, including the O-demethyla-
tion as modified by us9 and KMnO4 oxidation to avoid the influence
of the N-atom. The IR and 13C NMR spectra of 3 exhibited distinct
signals for a lactam at 1648 cmꢀ1 and dC 169.5. After considerable
investigation of various alternative pathways, it was found that the
spectra of 7 showed a lactam group (1683 cmꢀ1
group (1642 cmꢀ1
dC 213.9), and a cis-disubstituted double bond
(1642 cmꢀ1
, dC 172.4), a ketone
,
;
dH 6.26 d, J¼10.0 Hz, dH 5.92 dd, J¼10.0, 6.0 Hz; dC133.9
d, 127.8 d). From the HMBC correlations of C-10/H-1, H-5, and H-17,
as well as H-9/C-13 and C-15, and H-14/C-8 and C-16, the ketone
16
OCH3
CH3O
OCH3
16
13
OCH3
OCH3
Pelletier's
cleavage
16
R' 12
CH3O
CH3O
C
C
9
10
14
OCH3
b
17
OH
11
a
14
14
D
1
D
8
R'
a
D
10
9
B8
10
9
2
A
A
B
15
11
5
15
.
N
.
A
R
8
O
B
6
3
4 H 6
7
O
7
O
6
19
4 H
7
O
H
O
OAc
CHO
19
O
NH
OAc
OAc
R
CHO
17
Deltaline (1)
A
B
R' = OH, OMs
b
13
12
H10
OCH3
CHO
OH
O
O
CH3O
CH3O c 12
R
14O
15 O
14
H
H10
6
7
9
4
1
8
3
2
1
4
O
9
O
5
11
16
11
9
CH3O
O
14
5
O
10
O
13
12
H
O
H
R
H
R
OCH3
H
O
OH
O
CHO
OAc
D
[Strategy II]
CHO
C
c
10(9) 14
O
CHO
O
O
CH3O
HO
R
H
O
H
O
O
O
O
H
R
H
O
CHO
H
OCH3
[Strategy III]
O
E
OH
Scheme 2. Approach to the taxane-like ABC system from deltaline by strategies II and III.

7596
C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
OR
OCH3
O
CH3O
16
CH3O
H
CH3O
17
O
OH 14
9
8
7
OMs
b
OR
OCH
3 a
14
9
22
10
•
•
10
6
b
9
1
c
c
11
2
3
15
N
N 5
N
21
O
O
4
O
H
O
H
O
O
H
19
O
18
OH
OAc
A
OAc
B
deltaline 1
O
OH
H
CH
H
OH
H
O
17
CH3O
OCH3
d
O
O
12
O
CH
CH3O
10
HO
CH3O
OCH3
d
O
e
11
O
N
N
N
H
O
OCH3
O
H
H
O
H
O
O
OH
OH
D
C
R1
OCH3
H
14 R2
H
O
CHO
O
CH3O
13
17
OCH3
CH3O
N
10
O (10)
(9)
H
16
12
NH
10
(12)
O
OCH3
R2
CH3O
f
OCH3
O
(7)
9
11
O
(15)
(1)
8
15
(13)
(14)
6
(4)
H
(2)
O
H
HN
R1
19 18
O
O
OCH3
H
O
CHO
OH
OCH3
( ): the numbering
of taxane system
E
14 R1 + R2 = O
17 R1= OCH3 R2 = H
Scheme 3. Conversional synthetic strategy IV of the taxane core starting from deltaline (1).
group and the double bond in 7 were assigned to C-10 and to be-
tween C-9 and C-14, e.g.,
9(14), respectively. The structure of 7 was
13, as a single compound, exhibited characteristic signals at
D
1790 cmꢀ1 and dC 173.6 for a
g-lactone moiety. Finally, starting from
established based on 2D NMR spectral analysis (Table 1). After
osmylation, HIO4 oxidation of 9 provided easy access to the key
intermediate 10 (70%). Compared with 9, the 1H and 13C NMR
spectra of 10 (C25H35NO9, HR-ESIMS) displayed an additional
hemiacetal moiety (dH 5.58 d, J¼3.2 Hz, dC 95.8 d; dH 5.44 d,
J¼6.0 Hz, dC 75.0 d), which was located by the 2D NMR spectrum
between C-14 and C-9 (Table 2). The absolute configuration of C-14
in 10 was determined as S due to the NOESY observation between
H-14 and H-15 (Table 2). Subsequent reduction using B2H6 (THF,
reflux, 1.5 h) furnished 11 (96%). The 13C NMR spectrum of 11
showed the absence of the lactam group and the acetal moiety, as
compared with 10. Attempted treatment of 11 under various basic
conditions to initiate Grob fragmentation–hydrolysis in order to
prepare the target taxane core failed. To overcome this difficulty, an
alternative approach using Pelletier’s cleavage8 was used. Re-
duction using B2H6, followed by selective protection of the 9-, 14-
hydroxyl groups of 12 by the oxidation (Ag2CO3, reflux, 17 h)11 to
the lactone 13 (30%) was carried out. The IR and 13C NMR spectra of
13, according to Pelletier’s cleavage,8 the desired target taxane-like
core 14 was achieved in a 78% isolated yield (Scheme 5). The IR, 1H,
and 13C NMR spectra of 14 (C25H37NO8, HR-ESIMS) showed an ad-
ditional aldehyde group (1719 cmꢀ1
; dH 9.58 s; dC 200.9 d) and
a trisubstituted double bond (dH 5.47 d, J¼2.0 Hz; dC 125.5 d,137.9 s)
as compared with those of 13. Location of the double bond was
achieved according to the HMBC correlations of C-2/H-4 and H-8 or
H-2/C-4, C-8, C-14, and C-15, as well as C-3/H-5 and H-9 (using the
taxoid numbering) (Table 3). The structure of 14 was determined by
2D NMR spectral analysis (Table 3), and comparison with the data
for 18, whose structure was established based on X-ray crystallo-
graphic analysis. However, owing to the long reaction time and the
toxicity of osmylation, attention was turned to the alternative route
for the taxane core shown in Scheme 6. As described in Scheme 6,
starting with the olefin 8, the acetal 15 via 10 was prepared in 70%
yield through one-pot procedure via O3 oxidation followed by
an aldol condensation–acetalation–methylation process. The HR-
ESIMS of 15 gave the quasi-molecular ion peak at m/z 530.2335
OR2
OAc
O
OCH3
CH3O
N
CH3O
N
CH3O
N
CH3O
N
OAc
OR
OH
OH
OR1
f
OAc
c
OCH3
a
●
●
●
O
O
O
O
H
O
O
H
O
H
O
H
O
OCH3
OAc
R = H2
R = O
R
OH
O
OAc
deltaline
4 R1= R2= H
1
2
7
R = H
R = CH3
b
1
g
3
d
5a R1= H R2= Bz (45%)*
5b R1= Bz R2= H (50%)
6 R1= Ms R2= Bz
2
3
8
e
Scheme 4. (a) 6.5% HBr–HOAc, 85 ꢁC, 50 h, 85%; (b) KMnO4, acetone–H2O–glacial acetic acid, room temperature, 1 h, 75%; (c) 5% NaOH methanol, reflux, 1 h, 100%; (d) BzCl, Ag2O–
KI, THF, 40 ꢁC, 2 h, 5a: 90% yield after removing 50% of the recovered 5b; (e) MsCl, pyridine, room temperature, 2 h, 100%; (f) 5% NaOH methanol, reflux, 3 h, 88%; (g) CH3I, NaH,
room temperature, 4 h, 80% (* after recovering the starting material from 5b, 90%).

C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
7597
Table 1
NMR data for compound 7
Carbon
dC
dH mult (J in Hz)
1H–1HCOSY
HMBC (H/C)
NOESY
1
2
78.9 d
26.4 t
3.23 dd (10.0, 8.0)
H-2
H-1, H-2
H-1, H-2
H-2
H-2
d
a
, H-2
b
C-10, C-17, C-10
d
H-3b
1.58 m (hidden) (
2.17 m (
a
)
b, H-3
a
a
, H-3
, H-3
, H-3
, H-3
a
b
b
H-10, H-21
d
b
)
a
, H-3
C-4, C-11
C-5
C-1, C-5
d
3
36.3 t
1.32 m (
1.92 m (
d
b
a
)
)
b
b
, H-2
, H-2
a
a
d
b
H-18
d
4
5
6
7
8
9
10
11
12
42.7 s
53.8 d
81.6 d
98.2 s
81.3 s
133.9 d
213.9 s
62.5 s
48.5 t
2.40 d (3.2)
4.03 d (11.2)
d
H-17 (W-type)
6-OH
d
C-3, C-7, C-10, C-17
C-4, C-11, C-17
d
H-1, H-3b, H-18
H-18, OCH2O
d
d
d
d
d
d
d
d
d
6.26 d (10.0)
d
H-14
d
C-13, C-15
d
d
d
d
2.88 d (10.8) (
3.89 d (10.8) (
b
a
)
)
H-12
H-12
H-16, H-12
H-9, H-13
H-15
H-15
H-13, H-14, H-15
a
b
, H-13
, H-13
C-11, C-16
C-14, C-16
C-9, C-15
C-8, C-16
C-7
C-7, C-9
C-12, C-14
C-5, C-6, C-10, C-19, C-21
H-15
H-15
d
a
b
, H-16, H-17, H-10
13
14
15
41.0 d
127.8 d
45.1 t
2.89 m (hidden)
5.92 dd (10.0, 6.0)
1.52 m (hidden) (
2.79 m (hidden) (
4.42 t (7.2)
4.21 d (3.2)
1.32 s
b
a
)
)
a
b
, H-16
, H-16
H-13
d
16
17
18
19
21
72.3 d
63.9 d
21.2 q
172.4 s
43.9 t
a
, H-15
b
H-17
H-16
H-5 (W-type)
d
C-3, C-5, C-19
d
H-3
d
a, H-5, H-6
d
d
2.82 m (hidden)
4.25 m
1.19 t (7.2)
3.33 s
4.98 s
5.03 s
H-21 (
H-21 (
H-21
d
d
d
4.25), H-22
2.82), H-22
C-17, C-19
C-17, C-19
d
d
d
22
10
OCH2O
12.6 q
56.1 q
91.4 t
d
C-1
C-8
C-7, C-8
d
d
d
H-6
d
d
6-OH
d
2.33 d (11.2)
d
d
corresponding to the C26H37NO9Na which is 14 times units than
that of 10. The 1H and 13C NMR spectra of 15 were very similar to
those of 10, except for C-12 (dC 54.8 d), C-14 (dC 102.4 d), and C-15
target taxane-like core compound 17, representing a new class of
nor-taxanes without the 16-, 17-, 18-, and 19-methyl groups, but
with oxygenation at C-15, was afforded by B2H6 reduction of 15,
followed by Pelletier’s cleavage of 16 as described above, in a 64%
(dC 35.6 t), indicating that 15 was the methyl ether of 10. Another
Table 2
NMR data for compounds 10 and 15
Carbon no.
10
15
dC
dH mult (J in Hz)
1H–1HCOSY
HMBC (H/C)
NOESY
dC
1
2
81.2 d
24.8 t
4.48 dd (10.4, 7.2)
H-2
H-1, H-2
H-1, H-2
a
, H-2
b
C-10, C-17, C-10
C-4
C-4, C-11
C-1, C-5, C-18, C-19
C-1, C-5, C-18, C-19
d
H-5
d
H-10
H-18, H-22
H-18
d
H-60, H-18
H-18, OCH2O
d
81.4 d
24.9 t
1.51 m (
2.10 m (
a
b
)
)
b, H-3
a
a
, H-3
, H-3
, H-3
, H-3
a
b
b
a
, H-3
3
35.4 t
1.42 m (
1.92 m (
d
b
a
)
)
H-2
H-2
d
b
b
, H-2
, H-2
a
a
35.5 t
b
4
5
6
7
8
9
10
11
12
13
14
15
43.5 s
57.1 d
93.4 d
92.7 s
85.8 s
75.0 d
210.4 s
63.6 s
56.0 d
49.0 d
95.8 d
38.4 t
43.6 s
57.2 d
93.5 d
92.7 s
86.0 s
75.0 d
210.5 s
63.7 s
54.8 s
48.4 d
102.4 d
35.6 s
1.87 d (2.8)
3.80 s
d
H-17 (W-type)
d
C-3, C-10, C-18, C-19
C-4, C-8, C-11, C-17, C-60
d
d
d
d
d
d
5.44 d (6.0)
d
H-12
d
C-7, C-13, C-14, C-15
d
H-60
d
d
d
d
d
3.92 dd (6.4, 4.8)
2.80 t (4.0)
5.58 d (3.2)
1.83 dd (13.6, 10.8) (
2.38 dd (14.0, 6.4) (
4.02 m
4.43 d (2.8)
1.26 s
H-9, H-13
H-12, H-16
14-OH
H-15
H-15
H-13, H-15
H-5 (W-type)
d
C-8, C-11, C-14, C-16
C-9, C-15
C-9, C-12, C-16
C-7
C-7, C-9, C-13
C-14, C-160
C-5, C-6, C-7 C-10, C-19, C-21
C-3, C-5, C-19
d
d
H-160
H-15
H-14
H-160, H-17
H-17
H-15
b
b
)
a
b
, H-16
, H-16
a
)
16
17
18
19
21
72.8 d
63.0 d
20.5 q
171.3 s
42.8 t
a
, H-15
b
72.9 d
63.0 d
20.6 q
717.3 s
42.9 t
a
, H-16, H-21, H-22
H-3b
d
, H-5, H-6, H-60
d
d
2.89 m
4.31 m
1.16 t (7.2)
3.27 s
3.26 s
d
H-21 (
H-21 (
H-21
d
d
4.31), H-22
2.89), H-22
C-17, C-19
C-17, C-19
d
H-17
H-17
H-10, H-17
d
d
22
12.2 q
56.4 q
58.0 q
d
12.3 q
56.4 q
58.2 q
56.6 q
56.5 q
92.9 t
10
C-1
C-6
d
60
d
H-18
d
H-10
H-6, H-60
H-15a
d
140
d
106
OCH2O
56.5 q
91.4 t
3.37 s
4.99 s
5.13 s
3.87 d (3.2)
d
C-16
d
C-7, C-8
C-7, C-8
d
d
14-OH
d
H-14

7598
C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
OH
14 H
H
O
O
O
CH3O
CH3O
CH3O
OCH3
OCH3
a
OH
OH
OCH3
O
b
c
N
N
N
O
O
H
H
H
O
H
O
O
O
O
O
O
OCH3
10
OCH3
8
OCH3
9
H
O
OH
O
H
14
CH3O
OH
OH
OH
CH3O
CH3O
OCH3
d
OH
OH
OCH3
e
N
O
OCH3
f
9
N
N
H
O
H
H
O
O
O
OCH3
O
O
OCH3
12
OCH3
13
11
(10')
CHO
OCH3
H (7')
(7'''')
O
O
(7''')
H
(7'')
CH3O
O
(11)
(10)
(9)
(12)
NH
O
O
OCH3
(7)
(6)
O
(15)
(1)
O
CH3O (13)
(14')
(14)
(5)
(3)
H
(4)
HN
(2)
O
OCH
3CHO
14
H
OCH3
[Taxoids]
(
): the numbering of taxoids
Scheme 5. (a) OsO4, NMO, 5 h, 100%; (b) HIO4, THF, aq Na2SO3, 70%; (c) B2H6, THF, reflux, 1.5 h, 96%; (d) B2H6, THF, reflux, 20 h, 52%; (e) Ag2CO3, Celite, toluene, reflux, 17 h, 30%; (f)
(i) SOCl2–pyridine, room temperature, 1 h, (ii) CH3OH–H2O (9:1), 70 ꢁC, 2 h, 78%.
isolated yield (Scheme 6). The 1H and 13C NMR spectra of 16 (see
Section 4) showed distinct twin signals, implying that it is the
epimeric pair at C-10. The 1H and 13C NMR spectra of 17, as com-
C-14, and C-140 (Tables 3 and 4). The structure of 17, including the
absolute configuration based on a derivation from the known
C
19-diterpenoid alkaloid deltaline (1),12 was established un-
pared with those of 14, showed the absence of the
g
-lactone group,
ambiguously by the 2D NMR (Table 4) and single crystal X-ray
leading to noticeable differences, especially in C-1, C-2, C-8, C-11,
analysis (Fig. 1) of the analogue 18 prepared by N-acetylation and
Table 3
NMR data for compound 14a
Carbon
dC
dH mult (J in Hz)
1H–1H COSY
HMBC (H/C)
1
2
3
4
5
41.7 d
125.5 d
137.9 s
80.9 d
25.0 t
3.71 m (hidden)
5.47 d (2.0)
d
H-2, H-14, H-15
H-1
d
C-3, C-11, C-13, C-140
C-4, C-8, C-14, C-15
d
C-2, C-6, C-8, C-40
C-7
3.65 m (hidden)
1.79 m (hidden) (
H-5
a
, H-5
b
a
a
)
)
H-4, H-5
H-4, H-5
b
a
, H-6
, H-6
a
a
, H-6
, H-6
a
b
b
1.93 m (
1.23 m (
b
b
)
)
C-3, C-7
6
27.3 t
H-5
H-5
d
a
a
, H-5
, H-5
b
b
, H-6
, H-6
C-4, C-8, C-70, C-700
1.82 m (hidden) (
d
b
C-70
d
7
8
9
10
11
12
36.8 s
42.0 d
84.5 d
91.3 s
83.6 s
30.5 t
2.75 d (7.2)
4.16 d (7.2)
d
H-9
H-8
d
C-2, C-4, C-6, C-10, C-70
C-3, C-11, C-90, C-100
d
d
d
d
1.83 m (hidden) (
b)
H-12
H-12
H-12
a
b
a
, H-13
, H-13
, H-12
C-10
C-10, C-14, C-15
C-130
C-12, C-15
C-12, C-14, C-140
C-4
C-6, C-8, C-700
2.64 dd (15.6, 6.4) (
3.68 m (hidden)
2.99 m
6.16 d (5.2)
3.31 s
1.38 s
3.39 s
9.58 s
3.44 s
d
a
)
13
14
15
40
70
90
100
130
140
700
71.8 d
44.5 d
77.5 d
55.4 q
26.7 q
61.7 q
200.9 d
56.6 q
173.1 s
57.6 t
b, H-14
H-1, H-13
H-1
d
d
d
C-9
d
d
d
C-13
d
d
H-700
H-700
2.79 m (hidden)
3.22 m (hidden)
3.01 m (hidden)
3.27 m (hidden)
1.49 t (7.2)
5.33 s
(
(
d
d
3.22)
2.79)
C-8
d
7%
44.2 t
H-7% (
H-7% (
H-7%
d
d
d
3.27), H-7&
3.01), H-7&
C-7&
C-7&
d
7&
OCH2O
11.2 q
91.7
C-10, C-11
C-10, C-11
d
5.80 s
7.14 br s
d
NH
d
d
a
The numbering of taxoids.

C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
7599
OCH3
H
OR
OH
H
O
O
H
CH3O
N
H
CH3O
N
CH3O
N
OCH3
a
OCH3
OCH3
O
O
c
5
O
H
H
H
O
O
O
O
O
O
O
OCH3
8
OCH3
OCH3
16
10 R = H
b
4
15 R = CH3
OCH3
H
OCH3
H
CH3O
NAc
CH3O
H
H
OCH3
OCH3
f
O
O
d
6
H
OH
H
O
O
OCH3
19
R1
e
O
OCH3
N
R2
17 R1 = H R2 = CHO
18 R1 = Ac R2 = CH2OAc
(10')
CH2OAc
(7')
CH3O
(7''') (7'''')
O
OCH3
H
(7'')
O
CH3
HO
O
E
H
(10)
(10)
(9)
(12)
(9)
NAc
NAc
(11)
(11)
H
H
(12O)
(7)
(7)
(6)
(5)
(6)
(5)
A
(8)
(8)
B
CH3O
(14')O
D
(15)
(1)
CH3O
(15)
(1)
18
C
(14')
(13)
(13)
(3)
(3)
(4)
(4)
(14)
(14)
(2)
(2)
CH3O
CH3O
H
H
OCH3
OCH3
[Taxoids]
[Taxoids]
Scheme 6. (a) (i) O3, CH2Cl2, ꢀ78 ꢁC, (ii) Me2S, room temperature, (iii) Na2SO3, THF–H2O, room temperature, 70%; (b) CH3I, NaH, THF, room temperature, 100%; (c) B2H6, THF, reflux,
78%; (d) (i) SOCl2, pyridine, room temperature, (ii) MeOH–H2O (9:1), reflux, 84%; (e) (i) Ac2O–pyridine, room temperature, (ii) NaBH4, room temperature, (iii) Ac2O–pyridine, room
temperature, 91%; (f) (i) Ac2O–pyridine, room temperature, (ii) mCPBA/CHCl3, Na2CO3, (iii) HOAc–H2O, 69%.
Table 4
NMR data for compound 17a
Carbon
dC
dH mult (J in Hz)
1H–1H COSY
HMBC (H/C)
1
2
3
4
5
39.7 d
127.9 d
136.8 s
80.7 d
24.4 t
3.44 m (hidden)
5.62 d (2.0)
d
H-2, H-15
H-1
d
C-3, C-11, C-13, C-140
C-4, C-8, C-14, C-15
d
C-2, C-6, C-8, C-40
d
3.64 br s
H-5
a
, H-5
b
1.73 m (
1.93 m (
a
b
)
)
H-4, H-5
H-4, H-5
b
a
, H-6
, H-6
b
b
a
a
, H-6
, H-6
a
b
b
C-3, C-7
C-4
C-4, C-70, C-700
d
C-2, C-4, C-6, C-10, C-70, C-700
C-3, C-7, C-11, C-90, C-100
d
6
26.8 t
1.47 m (hidden) (
b)
H-5
H-5
d
a
a
, H-5
, H-5
, H-6
, H-6
1.80 m (
a
)
b
7
8
9
10
11
12
36.5 s
44.6 d
85.7 d
91.8 s
85.7 s
31.7 t
d
2.70 d (8.0)
3.95 d (8.0)
d
H-9
H-8
d
d
d
d
1.64 dd (14.4, 11.2) (
b
a)
)
H-12
H-12
a
b
, H-13
, H-13
C-10, C-14
C-10, C-14, C-15
C-11, C-130, C-140
C-2, C-12, C-15
C-12, C-14, C-140
C-4
C-6, C-8, C-700
C-9
d
2.34 dd (14.4, 6.0) (
3.49 m (hidden)
2.57 t (4.0)
5.32 d (5.6)
3.27 s
1.35 s
3.46 s
9.52 s
3.33 s
4.95 s
2.82 m
3.22 m (hidden)
3.41 s
3.05 m
3.26 m (hidden)
1.49 t (7.2)
5.19 s
13
14
15
40
70
90
100
130
140
700
72.8 d
48.3 d
76.4 d
55.0 q
26.3 q
61.3 q
199.4 d
56.3 q
101.1 d
57.4 t
H-14, H-12a, H-12b
H-1, H-13
H-1
d
d
d
d
d
C-13
d
C-1, C-13, C-15, C-1400
C-70, C-7%
C-6, C-70
C-140
H-700
H-700
d
(
(
d
d
3.22)
2.82)
1400
7%
54.9 q
44.2 t
H-7% (
H-7% (
H-7%
d
d
3.26), H-7&
3.05), H-7&
C-700
C-700
d
d
7&
OCH2O
11.0 q
91.4 t
C-10, C-11
C-10, C-11
5.59 s
d
a
The numbering of taxoids.

7600
C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
supported the S configuration at C-140, the same as 10. Finally,
acetylation of 17 with Ac2O–pyridine, followed by mCPBA oxidation
and HOAc hydrolysis, furnished compound 19 in 69% yield (Scheme
6). TheIR and 13C NMR spectra (Table 6)of 19 (C26H41NO8, HR-ESIMS)
showed the distinct ketone and ester signals at 1712 cmꢀ1 and dC
199.1 s, as well as at 1633 cmꢀ1 and
d 171.8 s, 21.6 q, respectively. It is
important to point out that the conversion of 1/3, 3(/4)/5a,
5a/8, 8/15, 15/16, and 16/17 shown in Schemes 4 and 6 and
Section 4 was carried out in six steps in an overall yield of 18%.
3. Conclusion
In conclusion, a short, efficient, and effective conversional syn-
thesis, based on diterpenoid alkaloid chemistry, of the taxane-like
ABC ring system, and yielding a new class of nor-taxanes, has been
developed. The route is mainly based on the Grob fragmentation
and Pelletier’s cleavage, using readily available starting material,
operationally simple reactions employing cheap chemical reagents,
and in good overall yield (18% for 6 steps from deltaline 1). Further
research on the synthetic conversion to the taxanes based on the
strategy shown in Scheme 3 is continuing.
Figure 1. X-ray structure of 18.
NaBH4 reduction, and acetylation of 17. The X-ray crystallography
data of 18 are listed below: colorless crystals from cyclohexane–
acetone are monotectic, space group P21, a¼10.253 (1), b¼17.78 (1),
c¼17.594 (1) Å,
b
¼106.589 (1)ꢁ, V¼3074.7 (1) Å3, Z¼2, dx¼1.257 g/
cm3. Full-matrix least-squares refinements gave R(F)¼0.0567,
wR(F)¼0.0523 for 739 parameters and 12,499 reflections with
lꢂ3s(1). The X-ray diffraction analysis of 18 showed that the skel-
eton consists of one eight-membered ring B, two six-membered
rings A and C, each with the chair conformation, as well as two five-
membered heterocyclic rings D and E, having the envelope form. In
addition, the cis-fusion patterns of the A/B, A/D, B/D, and B/E rings
were also observed. Therefore, the stereochemistry of C-1, C-8, and
the bridge ring of 18 is the same as those of the taxoids, except for
the missing 16, 17, 18, and 19-methyl groups. In addition, the NOE
4. Experimental section
4.1. General methods
Melting points were determined on
a Kofler block (un-
corrected); optical rotations were measured in a 1.0 dm cell with
a PE-314 polarimeter at 20ꢃ1 ꢁC; IR spectra were recorded on
a Nicolet 200 SXV spectrometer; MS spectra were obtained with
relationships between H-140 (dH 4.93 s) and H-12
b (dH1.52 m) also
Table 5
NMR data for compound 18a
Carbon
dC
dH mult (J in Hz)
1H–1H COSY
HMBC (H/C)
1
2
3
4
5
40.0 d
129.0 d
139.6 s
79.9 d
23.3 t
3.39 m (hidden)
5.71 s
d
H-2, H-14, H-15
H-1
d
C-3, C-11, C-13, C-140
C-4, C-8, C-14, C-15
d
C-2, C-6, C-8, C-40
C-7
C-7
C-8
d
3.67 m
H-5
a
, H-5
b
1.55 m (
1.86 m (
1.23 m (
1.78 m (
d
a)
b)
b)
a)
H-4, H-5
H-4, H-5
b
a
, H-6
, H-6
a
a
, H-6
, H-6
a
b
b
6
26.6 t
H-5
H-5
d
a
a
, H-5
, H-5
b
b
, H-6
, H-6
b
7
8
9
10
11
12
39.7 s
51.3 d
86.0 d
87.7 s
87.6 s
32.8 t
d
2.69 d (8.4)
3.86 d (9.2)
d
H-9
H-8
d
C-2, C-4, C-6, C-10, C-7’
C-7, C-11, C-90, C-100
d
d
d
d
1.52 m (
b
)
H-12
H-12
a
b
, H-13
, H-13
C-10
C-10, C-14, C-15
C-130
C-12, C-15
C-10, C-12, C-14, C-140
C-4
C-6, C-8, C-700
2.67 m (
3.31 m
2.58 m
a
)
13
14
15
40
70
90
100
130
140
700
73.0 d
48.8 d
79.7 d
55.7 q
26.8 q
60.7 q
66.7 t
56.2 q
101.7 d
53.0 t
H-14, H-12
a
, H-12
b
H-1, H-13
H-1
d
5.28 d (6.0)
3.22 s
0.93 s
3.56 s
4.39 ABq (12.0)
3.37 s
4.96 s
3.33 m (hidden)
3.72 m
3.42 s
3.27 m (hidden)
3.47 m
d
d
C-9
H-100
d
C-9, C-11, OCO
C-13
d
C-1, C-13, C-15, C-1400
H-700
H-700
d
(
(
d
d
3.72)
3.33)
NCO
NCO
C-140
NCO
NCO
d
1400
7%
54.9 q
45.7 t
H-7% (
H-7% (
H-7%
d
d
d
3.47), H-7&
3.27), H-7&
7&
OCH2O
13.5 q
91.6 t
1.18 t (7.2)
4.92 s
5.17 s
d
C-10, C-11
C-10, C-11
d
d
NCO
NCOCH3
OCO
171.8 s
21.7 q
170.4 s
21.0 q
d
2.15 s
d
d
d
d
d
OCOCH3
2.10 s
d
d
a
The numbering of taxoids.

C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
7601
Table 6
NMR data for compound 19a
Carbon
dC
dH mult (J in Hz)
1H–1H COSY
HMBC (H/C)
1
2
3
4
5
39.6 d
128.2 d
136.7 s
80.3 d
26.4 t
3.38 m (hidden)
5.40 s
d
H-2, H-14, H-15
H-1
d
C-3, C-11, C-13, C-140
C-4, C-8, C-14, C-15
d
C-2, C-6, C-8, C-40
d
3.22 m
H-5
a
, H-5
b
1.54 m (
1.73 m (
1.23 m (
1.79 m (
d
a
)
H-4, H-5
H-4, H-5
b
a
, H-6
, H-6
a
a
, H-6
, H-6
a
b
b
b
)
d
6
25.3 t
b)
H-5
H-5
d
a
a
, H-5
, H-5
b
b
, H-6
, H-6
d
a
)
b
d
7
8
9
10
11
12
40.0 s
48.0 d
89.3 d
199.0 s
80.2 s
33.1 t
d
C-2, C-4, C-6, C-70
C-7, C-11, C-90
d
2.86 d (10.0)
3.88 d (10.4)
d
H-9
H-8
d
d
d
d
1.18 dd (13.2, 11.2) (
2.94 dd (13.2, 6.0) (
3.26 m
2.48 t (3.2)
5.23 d (5.6)
2.96 s
0.91 s
3.30 s
3.30 s
4.90 s
3.08 m
3.55 m
3.39 s
3.34 m
1.11 t (7.2)
d
b
)
H-12
H-12
a
b
, H-13
, H-13
C-10, C-15
C-10, C-14, C-15
C-130
C-12, C-15
C-12, C-14, C-140
C-4
C-6, C-8, C-700
a
)
13
14
15
40
70
90
130
140
700
72.2 d
48.5 d
79.9 d
56.3 q
24.4 q
57.6 q
56.2 q
102.2 d
53.3 t
H-14, H-12
a
, H-12
b
H-1, H-13
H-1
d
d
d
C-9
C-13
d
d
C-1, C-13, C-15, C-1400
H-700
H-700
d
(
(
d
d
3.55)
3.08)
C-70
C-6
C-140
C-700
d
1400
7%
7&
NCO
NCOCH3
54.9 q
45.8 t
13.4 q
171.7 s
21.6 q
H-7%, H-7&
H-7%
d
d
2.09 s
d
d
a
The numbering of taxoids.
Finnigan LCQ DECA mass spectrometer; HRMS spectra were
obtained with a Bruker BioTOFQ mass spectrometer; 1H and 13C
NMR spectra were acquired on a Bruker AC-E 200 or a Varian
INOVA-400/54 spectrometer, with TMS as internal standard; silica
for 1 h, to which Na2SO3 (5.0 g) in H2O (20 ml) was added for
stopping the reaction. Usual work-up and chromatography (silica
gel H, 130 g) using cyclohexane–acetone (5:1) as eluent furnished 3
(4.9 g, 75%). Method 2. A solution of deltaline (1) (11.0 g, 21.7 mmol)
in 6.5% HBr–HOAc (527 ml, w/v) was heated at 85 ꢁC for 50 h. The
usual work-up gave the crude 2 (13.0 g) and then exposed to
acetone–H2O–glacial acetic acid (165:42:3) (430 ml) under ice
bath, followed by KMnO4 (10.2 g, 65.1 mmol), then the reaction
mixture was stirred at room temperature for 1 h, to which Na2SO3
(10 g) in H2O (40 ml) was added for stopping the reaction. The same
gel GF254 and H (10–40
mm, Qingdao Sea Chemical Factory, China)
were used for TLC and CC.
4.1.1. Preparation of compound 2
A solution of deltaline (1) (11.0 g, 21.70 mmol) in 6.5% HBr–
HOAc (527 ml, w/v) was heated at 85 ꢁC for 50 h. Removal of
solvent gave a residue, which was diluted with water (100 ml).
Basification (NH4OH, pH 10), extraction (CHCl3, 200 mlꢄ3), drying
(Na2SO4), and evaporation in vacuum gave a residue (13.0 g), which
was chromatographed over silica gel H (220 g) eluted with cyclo-
work-up as method 1 furnished 3 (8.6 g, 64%). Compound 3: mp:
20
213–215 ꢁC; [
a
]
ꢀ23.0 (c 0.5, CHCl3); IR (KBr): 1739, 1648 cmꢀ1
;
D
1H NMR (400 MHz, CDCl3)
d
1.23 (3H, s, H3-18), 1.15 (3H, t, J¼7.2 Hz,
NCH2CH3), 2.04, 2.08, 2.08, 2.11 (each 3H, s, OCH3ꢄ4), 2.94–3.02,
3.99–4.08 (each 1H, m, NCH2CH3), 3.60 (1H, d, J¼3.2 Hz, H-17), 3.73
hexane–acetone (8:1) to give 2 (11.1 g, 85%). Compound 2: mp: 64–
20
66 ꢁC; [
a]
ꢀ28.4 (c 0.5, CHCl3); IR (KBr): 1739 cmꢀ1
;
1H NMR
(1H, t, J¼8.4 Hz, H-1
J¼9.6, 5.2 Hz, H-16
J¼1.6 Hz, H-6 ), 5.55 (1H, t, J¼5.2 Hz, H-6
CDCl3) 79.9 (d, C-1), 26.6 (t, C-2), 34.6 (t, C-3), 44.9 (s, C-4), 50.2 (d,
b
), 4.10 (1H, d, J¼5.2 Hz, H-9), 4.78 (1H, dd,
D
(400 MHz, CDCl3)
d
0.87 (3H, s, H3-18), 1.06 (3H, t, J¼7.2 Hz,
a
), 4.89, 4.97 (each 1H, s, OCH2O), 5.38 (1H, d,
); 13C NMR (50 MHz,
NCH2CH3), 2.02, 2.06, 2.06, 2.09 (each 3H, s, OCH3ꢄ4), 3.25 (3H, s,
OCH3), 3.53 (1H, dd, J¼9.6, 7.6 Hz, H-1 ), 4.20 (1H, d, J¼5.6 Hz, H-9),
4.76 (1H, dd, J¼9.6, 6.0 Hz, H-16 ), 4.85, 4.96 (each 1H, s, OCH2O),
5.44 (1H, s, H-6
), 5.53 (1H, t, J¼5.2 Hz, H-14
); 13C NMR (100 MHz,
CDCl3) 78.3 (d, C-1), 26.7 (t, C-2), 36.3 (t, C-3), 33.5 (s, C-4), 50.7 (d,
a
a
b
d
a
C-5), 75.7 (d, C-6), 94.7 (s, C-7), 89.6 (s, C-8), 46.8 (d, C-9), 80.3 (s,
C-10), 54.9 (s, C-11), 33.7 (t, C-12), 37.8 (d, C-13), 73.2 (d, C-14), 33.5
(t, C-15), 72.5 (d, C-16), 62.1 (d, C-17), 23.2 (q, C-18), 169.5 (s, C-19),
43.0 (t, C-21), 12.2 (q, C-22), 172.3 s, 170.6 s, 170.2 s, 169.5 s, 21.5 q,
21.3 q, 21.1 q (OAcꢄ4), 54.9 (q, C-10), 94.1 (t, OCH2O); ESIMS m/z 620
[MþH]þ; HR-ESIMS [MþNa]þ m/z calcd for C31H41NO12Na:
642.2521, found: 642.2497.
a
b
d
C-5), 77.3 (d, C-6), 91.0 (s, C-7), 81.3 (s, C-8), 47.2 (d, C-9), 95.4 (s, C-
10), 57.3 (s, C-11), 34.4 (t, C-12), 38.5 (d, C-13), 73.8 (d, C-14), 33.7 (t,
C-15), 73.2 (d, C-16), 63.1 (d, C-17), 25.3 (q, C-18), 56.4 (t, C-19), 50.1
(t, C-21), 13.6 (q, C-22), 170.6 s, 170.2 s, 170.0 s, 169.7 s, 23.2 q, 21.5 q,
21.2 q, 21.1 q (OAcꢄ4), 55.0 (q, C-10), 93.9 (t, OCH2O); ESIMS m/z 606
[MþH]þ; HR-ESIMS [MþH]þ m/z calcd for C31H44NO11: 606.2909,
found: 606.2889.
4.1.3. Preparation of compound 4
A solution of 3 (8.9 g, 14.38 mmol) in 300 ml of 5% NaOH
methanol was refluxed for 1 h. Evaporation under reduced pres-
sure, dilution (H2O, 100 ml), acidification with 10% HCl to pH 4,
followed by basification (NH4OH, pH 10), extraction (n-butanol,
4.1.2. Preparation of compound 3
Method 1. To a solution of 2 (6.4 g, 10.58 mmol) in acetone–H2O–
glacial acetic acid (165:42:3) (210 ml) under ice bath, KMnO4 (5.0 g,
31.74 mmol) was added. Upon addition was completed, cold bath
was removed and the reaction mixture stirred at room temperature
250 mlꢄ3), and general work-up gave 4 (6.5 g, 100%). Compound 4:
20
mp: 234–236 ꢁC; [
a
]
D
ꢀ11.4 (c 0.5, CH3OH); IR (KBr): 3396,
1618 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 0.99 (3H, s, H3-18), 0.99

7602
C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
(3H, t, J¼7.2 Hz, NCH2CH3), 3.28 (3H, s, OCH3), 3.70 (1H, t, J¼6.4 Hz,
H-1 ), 5.11,
), 3.76–3.90 (1H, m, H-16), 4.89 (1H, t, J¼4.8 Hz, H-14
5.22 (each 1H, s, OCH2O); 13C NMR (100 MHz, CDCl3)
81.9 (d, C-1),
26.2 (t, C-2), 34.3 (t, C-3), 45.6 (s, C-4), 50.6 (d, C-5), 75.6 (d, C-6),
90.7 (s, C-7), 81.3 (s, C-8), 49.6 (d, C-9), 78.7 (s, C-10), 52.2 (s, C-11),
36.5 (t, C-12), 38.6 (d, C-13), 72.0 (C-14), 35.3 (t, C-15), 71.1 (d, C-16),
63.3 (d, C-17), 21.7 (q, C-18), 173.0 (s, C-19), 42.2 (t, C-21), 12.5 (q, C-
22), 55.2 (q, C-10), 93.4 (t, OCH2O); ESIMS m/z 452 [MþH]þ; HR-
ESIMS [MþNa]þ m/z calcd for C23H33NO8Na: 474.2098, found:
474.2075.
2.93–2.98, 3.97–4.04 (each 1H, m, NCH2CH3), 3.09 (3H, s, OMs), 3.26
(3H, s, OCH3), 3.63 (1H, d, J¼3.2 Hz, H-17), 3.74 (1H, d, J¼5.6 Hz,
b
b
d
H-9), 3.77 (1H, t, J¼8.8 Hz, H-1
b
), 4.21 (1H, d, J¼0.8 Hz, H-6
a
), 5.06,
), 5.49
), 7.44–8.11 (5H, m, Ar–H); 13C NMR
82.6 (d, C-1), 26.6 (t, C-2), 33.0 (t, C-3), 45.4 (s,
5.24 (each 1H, s, OCH2O), 5.11 (1H, dd, J¼9.2, 2.4 Hz, H-16
(1H, t, J¼5.2 Hz, H-14
(100 MHz, CDCl3)
a
b
d
C-4), 51.0 (d, C-5), 78.8 (d, C-6), 93.3 (s, C-7), 81.4 (s, C-8), 49.2 (d, C-
9), 79.5 (s, C-10), 53.5 (s, C-11), 36.5 (t, C-12), 38.8 (d, C-13), 75.1 (d,
C-14), 34.7 (t, C-15), 72.1 (d, C-16), 62.5 (d, C-17), 21.8 (q, C-18),
173.2 (s, C-19), 43.1 (t, C-21), 12.4 (q, C-22), 55.0 (q, C-10), 93.8 (t,
OCH2O), 166.1 (s, Ar–COO), 130.0 (s, C-100), 129.7 (d, C-200, 600), 128.5
(d, C-300, 500), 133.2 (d, C-400), 38.3 (q, OMs); ESIMS m/z 634 [MþH]þ;
4.1.4. Preparation of compounds 5a and 5b
To a solution of 4 (2.3 g, 5.10 mmol) in fresh THF (100 ml), were
added sequentially KI (169 mg, 1.02 mmol), Ag2O (1.77 g,
7.65 mmol), and BzCl (1.1 ml, 9.18 mmol) under argon steam and
the mixture was heated at 40 ꢁC for 2 h, to which water (3 ml) was
added to stop the reaction. A general work-up procedure gave
a residue, which was diluted with H2O (20 ml). Basifying (NH4OH,
pH 10), extraction (CHCl3, 30 mlꢄ3), drying (Na2SO4), evaporation,
and column chromatography (silica gel H, 75 g, CHCl3–MeOH 95:5
to 19:1) furnished 5a (1.27 g, 45%, after recovering the starting
material from 5b, 90%) and 5b (1.42 g, 50%). The latter was hydro-
HR-ESIMS [MþNa]þ m/z calcd for C31H39NO11SNa: 656.2136, found:
20
656.2108. Compound 7: mp: 68–70 ꢁC; [
a
]
D
þ22.6 (c 0.5, CHCl3); IR
(KBr): 3518, 3389, 1683, 1642 cmꢀ1; 1H NMR (400 MHz, CDCl3) and
13C NMR (100 MHz, CDCl3) see Table 1; ESIMS m/z 434 [MþH]þ; HR-
ESIMS [MþNa]þ m/z calcd for C23H31NO7Na: 456.1993, found:
456.1982.
4.1.6. Preparation of the key intermediate 8
The olefin-ketone 8, employed as the key intermediate, could be
synthesized by one-pot mesylation–Grob fragmentation–methyl-
ation procedure. Alcohol 5a (1.65 g, 2.97 mmol) was first mesylated
with MsCl (0.82 ml, 8.91 mmol) in dry pyridine (60 ml) at room
temperature for 2 h, then exposed to 5% sodium hydroxide–
methanol (60 ml) under reflux for 3 h. Finally, the C-6 and C-16
hydroxyl groups were protected using CH3I (1.65 ml, 26.10 mmol)
and NaH (935 mg, 39.14 mmol) in THF (50 ml) at room temperature
for 4 h (TLC monitoring). Adding H2O to stop the reaction, and the
usual work-up, followed by chromatography (silica gel H, 30 g;
lyzed with 5% NaOH methanol to recover the starting material 4 for
20
the next use. Compound 5a: mp: 148–150 ꢁC; [
a
]
ꢀ19.8 (c 0.5,
D
CHCl3); IR (KBr): 3422, 1712, 1623 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.16 (3H, t, J¼7.2 Hz, NCH2CH3), 1.29 (3H, s, H3-18), 2.93–2.98,
3.97–4.03 (each 1H, m, NCH2CH3), 3.25 (3H, s, OCH3), 3.43 (1H, d,
J¼5.2 Hz, H-9), 3.65 (1H, d, J¼3.2 Hz, H-17), 3.76 (1H, t, J¼8.4 Hz, H-
1
a), 4.18 (1H, br s, H-6
a
), 4.80 (1H, t, J¼4.8 Hz, H-14
b
), 5.05, 5.22
), 7.43–8.04 (5H, m,
82.2 (d, C-1), 26.5 (t, C-2), 33.3
(each 1H, s, OCH2O), 5.12–5.14 (1H, m, H-16
a
Ar–H); 13C NMR (100 MHz, CDCl3)
d
cyclohexane–acetone 7:1), furnished 8 (962 mg, 70%). Compound
20
(t, C-3), 45.4 (s, C-4), 50.8 (d, C-5), 75.3 (d, C-6), 90.4 (s, C-7), 82.4 (s,
C-8), 50.8 (d, C-9), 79.9 (s, C-10), 53.3 (s, C-11), 37.1 (t, C-12), 39.7 (d,
C-13), 73.4 (d, C-14), 34.4 (t, C-15), 71.5 (d, C-16), 62.6 (d, C-17), 21.7
(q, C-18), 173.7 (s, C-19), 43.1 (t, C-21), 12.3 (q, C-22), 55.0 (q, C-10),
93.8 (t, OCH2O),165.9 (s, Ar–COO),129.9 (s, C-100),129.5 (d, C-200, 600),
128.3 (d, C-300, 500), 133.1 (d, C-400); ESIMS m/z 556 [MþH]þ; HR-
8: mp: 67–69 ꢁC; [
a
]
þ30.6 (c 0.5, CHCl3); IR (KBr): 2935, 1699,
D
1649 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.21 (3H, t, J¼7.2 Hz,
NCH2CH3), 1.30 (3H, s, H3-18), 3.20 (1H, dd, J¼10.0, 8.0 Hz, H-1
a
a
),
),
3.29, 3.30, 3.26 (each 3H, s, OCH3ꢄ3), 3.60 (1H, d, J¼12.0 Hz, H-6
3.85 (1H, t, J¼7.2 Hz, H-16), 4.21 (1H, d, J¼2.8 Hz, H-17), 2.70–2.79,
4.21–4.31 (each 1H, m, NCH2CH3), 4.89, 5.05 (each 1H, s, OCH2O),
ESIMS [MþNa]þ m/z calcd for C30H37NO9Na: 578.2361, found:
5.85 (1H, dd, J¼10.0, 6.8 Hz, H-14), 6.08 (1H, d, J¼10.0 Hz, H-9); 13
C
20
578.2338. Compound 5b: mp: 266–268 ꢁC; [
a
]
D
ꢀ18.0 (c 0.5,
NMR (100 MHz, CDCl3) d 81.8 (d, C-1), 26.3 (t, C-2), 36.0 (t, C-3), 43.0
CHCl3); IR (KBr): 3520, 3378, 1716, 1621 cmꢀ1
CDCl3)
;
1H NMR (400 MHz,
(s, C-4), 49.8 (d, C-5), 90.3 (d, C-6), 97.3 (s, C-7), 81.5 (s, C-8), 133.2
(d, C-9), 213.9 (s, C-10), 61.5 (s, C-11), 49.4 (t, C-12), 35.7 (d, C-13),
126.7 (d, C-14), 43.9 (t, C-15), 80.8 (d, C-16), 63.7 (d, C-17), 21.5 (q, C-
18),172.5 (s, C-19), 41.2 (t, C-21),12.5 (q, C-22), 55.9 (q, C-10), 57.9 (q,
C-60), 56.1 (q, C-160), 91.0 (t, OCH2O), ESIMS m/z 484 [MþNa]þ; HR-
ESIMS [MþNa]þ m/z calcd for C25H35NO7Na: 484.2306, found:
484.2295.
d
1.14 (3H, t, J¼7.2 Hz, NCH2CH3), 1.27 (3H, s, H3-18), 2.91–
2.96, 3.98–4.03 (each 1H, m, NCH2CH3), 3.22 (3H, s, OCH3), 3.60 (1H,
d, J¼2.8 Hz, H-17), 3.70 (1H, d, J¼4.8 Hz, H-9), 3.78 (1H, t, J¼8.8 Hz,
H-1
b
), 3.87 (1H, br d, J¼8.8 Hz, H-16
a), 5.10, 5.19 (each 1H, s,
OCH2O), 5.77 (1H, t, J¼4.8 Hz, H-14
b C
), 7.37–7.59 (5H, m, Ar–H); 13
NMR (50 MHz, CDCl3) 79.7 (d, C-1), 24.7 (t, C-2), 32.7 (t, C-3), 43.4
d
(s, C-4), 48.6 (d, C-5), 73.7 (d, C-6), 88.3 (s, C-7), 79.3 (s, C-8), 46.4 (d,
C-9), 78.0 (s, C-10), 51.0 (s, C-11), 36.0 (t, C-12), 38.3 (d, C-13), 72.7
(d, C-14), 35.3 (t, C-15), 68.3 (d, C-16), 60.8 (d, C-17), 20.1 (q, C-18),
171.1 (s, C-19), 40.5 (t, C-21), 10.7 (q, C-22), 91.6 (t, OCH2O), 53.2 (q,
C-10), 164.1 (s, Ar–COO), 128.8 (s, C-100), 127.9 (d, C-200,þ600), 126.8 (d,
C-300, 500), 131.2 (d, C-400); ESIMS m/z 556 [MþH] ; HR-ESIMS
[MþNa]þ m/z calcd for C30H37NO9Na: 578.2361, found: 578.2338.
4.1.7. Preparation of compound 9
To a solution of 8 (428 mg, 0.93 mmol) in t-BuOH–THF–H2O
(10:3:1, 15 ml) NMO (1.34 mg, 11.44 mmol) and OsO4 (64 mg,
0.25 mmol) were added and the reaction solution was stirred at
room temperature for 5 h, then, to this solution 10 ml of saturated
Na2SO3 solution was added and stirred vigorously for 15 min. The
removal of solvent, basification (NH4OH, pH 10), extraction (CHCl3,
4.1.5. Preparation of compounds 6 and 7
20 mlꢄ3), drying (Na2SO4), and evaporation afforded compound 9
20
Alcohol 5a (1.65 g, 2.97 mmol) was first mesylated with MsCl
(0.82 ml, 8.91 mmol) in dry pyridine (60 ml) at room temperature
for 2 h, stopping the reaction with H2O, and the usual work-up gave
6, and then exposed to 5% sodium hydroxide–methanol (60 ml)
under reflux for 3 h. Evaporation under reduced pressure, dilution
(H2O, 100 ml), extraction (CHCl3, 100 mlꢄ3), drying (Na2SO4), and
evaporation in vacuum gave a residue (1.29 g), followed by chro-
(460 mg, 100%). Compound 9: mp: 180–182 ꢁC; [
a]
þ43.2 (c 0.6,
D
CHCl3); IR (KBr): 3406, 2927, 1689, 1641 cmꢀ1
CDCl3)
;
1H NMR (400 MHz,
1.18 (3H, t, J¼7.2 Hz, NCH2CH3), 1.36 (3H, s, H3-18), 3.15 (1H,
d
dd, J¼10.0, 7.6 Hz, H-1
b
a
), 3.32, 3.34, 3.43 (each 3H, s, OCH3ꢄ3), 3.80
(1H, t, J¼8.8 Hz, H-16
), 4.21 (1H, t, J¼4.4 Hz, H-14), 4.39 (1H, d,
J¼3.2 Hz, H-17), 4.50 (1H, d, J¼5.2 Hz, H-9); 13C NMR (50 MHz,
CDCl3) d 81.2 (d, C-1), 26.2 (t, C-2), 35.4 (t, C-3), 43.9 (s, C-4), 49.3 (d,
matography (silica gel H, 25 g; cyclohexane–acetone 6:1) furnished
C-5), 92.4 (d, C-6), 95.4 (s, C-7), 81.3 (s, C-8), 68.9 (d, C-9), 212.0 (s,
C-10), 61.6 (s, C-11), 43.7 (d, C-12), 39.7 (d, C-13), 62.2 (d, C-14), 35.6
(t, C-15), 80.6 (d, C-16), 62.9 (d, C-17), 21.8 (q, C-18), 172.4 (s, C-19),
46.3 (t, C-21), 12.3 (q, C-22), 56.1 (q, C-10), 58.2 (q, C-60), 56.6 (q,
20
7 (1.13 g, 88%). Compound 6: mp: 152–154 ꢁC; [
a
]
D
ꢀ33.9 (c 0.8,
CHCl3); IR (KBr): 3412, 1713, 1623, 1354 cmꢀ1
;
1H NMR (400 MHz,
CDCl3)
d
1.16 (3H, t, J¼7.2 Hz, NCH2CH3), 1.30 (3H, s, H3-18),

C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
7603
C-160), 91.0 (t, OCH2O); ESIMS m/z 518 [MþNa]þ; HR-ESIMS
[MþNa]þ m/z calcd for C25H37NO9Na: 518.2361, found: 518.2334.
þ2.0 (c 0.8, CHCl3); IR (KBr): 3555, 1790 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d
0.93 (3H, s, H3-18), 1.03 (3H, t, J¼7.2 Hz, NCH2CH3), 3.27
(1H, dd, J¼10.4, 6.8 Hz, H-1
3.61 (1H, s, H-6
), 3.64 (1H, d, J¼2.4 Hz, H-17), 3.88–3.93 (1H, m, H-
16
b), 3.35, 3.39, 3.40 (each 3H, s, OCH3ꢄ3),
4.1.8. Preparation of compound 10
a
To
a
solution of
9
(703 mg, 1.42 mmol) in THF (16 ml),
a
), 4.25 (1H, d, J¼11.2 Hz, H-10), 4.94, 5.14 (each 1H, s, OCH2O),
HIO4$2H2O (647 mg, 2.84 mmol) was added and the mixture stir-
red at room temperature for 30 min. After basifying with saturated
Na2SO3 solution (30 ml) to pH 7–8, the reaction solution was stirred
vigorously for 10 h. Evaporation, extraction (CHCl3, 35 mlꢄ3), and
the removal of solvent gave a residue that was recrystallized from
5.79 (1H, d, J¼6.4 Hz, H-9); 13C NMR (100 MHz, CDCl3)
d 82.3 (d, C-
1), 25.6 (t, C-2), 37.1 (t, C-3), 32.2 (s, C-4), 51.9 (d, C-5), 92.5 (d, C-6),
94.9 (s, C-7), 84.9 (s, C-8), 72.4 (d, C-9), 72.7 (d, C-10), 55.3 (s, C-11),
45.6 (d, C-12), 51.3 (d, C-13), 173.6 (s, C-14), 38.4 (t, C-15), 77.5 (d, C-
16), 64.8 (d, C-17), 25.7 (q, C-18), 55.5 (t, C-19), 49.9 (t, C-21),13.8 (q,
C-22), 56.6 (q, C-10), 58.4 (q, C-60), 56.6 (q, C-160), 92.9 (t, OCH2O);
ESIMS m/z 502 [MþNa]þ; HR-ESIMS [MþNa]þ m/z calcd for
ether to afford compound 10 (490 mg, 70%). Compound 10: mp:
20
181–183 ꢁC; [
1640 cmꢀ1
a
]
þ5.6 (c 0.5, CHCl3); IR (KBr): 3378, 1669,
D
;
1H NMR (400 MHz, CDCl3) and 13C NMR (100 MHz,
C25H37NO8Na: 502.2411, found: 502.2416.
CDCl3) see Table 2; ESIMS m/z 516 [MþNa]þ; HR-ESIMS [MþNa]þ
m/z calcd for C25H35NO9Na: 516.2204, found: 516.2180.
4.1.12. Preparation of 4
methyl-7 -(N-ethylmethylamine)-10,11-dioxymethylen-taxa-2-
ene-14 -lide (14)
a,9b,13b-trimethoxy-16,17,18,19-nor-7b-
a
4.1.9. Preparation of compound 11
b
To a solution of 10 (197.0 mg, 0.40 mmol) in 10 ml of THF, B2H6–
THF (1.2 ml, 1.2 mmol) was added and the reaction solution was
refluxed for 1.5 h under argon gas steam. Quenching the reaction
with H2O, evaporation, dilution (H2O, 5 ml), basifying (NH4OH, pH
10), extraction (CHCl3, 10 mlꢄ3), drying (Na2SO4), and the removal
of solvent and chromatography (silica gel H, 4.2 g, cyclohexane–
To a solution of 13 (18 mg, 0.038 mmol) in pyridine (1 ml), SOCl2
(0.05 ml) was added and the reaction solution was stirred at room
temperature for 1 h. Stopping the reaction with H2O (0.1 ml),
evaporation, basification (saturated NaHCO3 solution), extraction
(CHCl3, 5 mlꢄ3), drying (Na2SO4), and the removal of solvent gave
a residue that was dissolved in a mixture of methanol–H2O (2 ml,
9:1). The solution was heated at 70 ꢁC for 21 h. Evaporation and
chromatography (silica gel H, 500 mg, CHCl3–MeOH 20:0.35/
acetone 16:1) afforded 11 (184.7 mg, 96%). Compound 11: mp: 76–
20
78 ꢁC; [
a
]
D
ꢀ24.8 (c 0.5, CHCl3); IR (KBr): 3381,1685 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d
0.89 (3H, s, H3-18), 1.03 (3H, t, J¼7.2 Hz,
95:5) afforded 14 (13 mg, 78%). Compound 14: mp: 178–180 ꢁC;
ꢀ24.3 (c 0.6, CHCl3); IR (KBr): 3422, 1786, 1719 cmꢀ1; 1H NMR
20
NCH2CH3), 3.23, 3.24, 3.45 (each 3H, s, OCH3ꢄ3), 3.57 (1H, s, H-6
a
),
[a
]
D
3.60–3.66 (H-14, hidden), 3.74 (1H, dd, J¼11.2, 6.8 Hz, H-1
b), 3.91
(400 MHz, CDCl3) and 13C NMR (100 MHz, CDCl3) see Table 3;
(1H, d, J¼2.0 Hz, H-17), 4.00 (1H, dd, J¼6.4, 5.2 Hz, H-14), 4.98, 5.15
ESIMS m/z 480 [MþH]þ; HR-ESIMS [MþH]þ m/z calcd for
(each 1H, s, OCH2O), 5.15 (1H, d, J¼2.4 Hz, H-9); 13C NMR (50 MHz,
C25H38NO8: 480.2592, found: 480.2592.
CDCl3) d 83.7 (d, C-1), 25.1 (t, C-2), 36.3 (t, C-3), 31.9 (s, C-4), 58.7 (d,
C-5), 91.4 (d, C-6), 94.0 (s, C-7), 86.1 (s, C-8), 64.9 (d, C-9), 213.1 (s, C-
10), 63.6 (s, C-11), 55.8 (d, C-12), 35.2 (d, C-13), 64.3 (d, C-14), 37.5
(t, C-15), 76.7 (d, C-16), 64.3 d (d, C-17), 24.7 (q, C-18), 55.6 (t, C-19),
50.1 (t, C-21), 13.9 (q, C-22), 56.3 (q, C-10), 57.8 (q, C-60), 57.2 (q, Cþ-
160), 92.2 (t, OCH2O); ESIMS m/z 482 [MþH]þ; HR-ESIMS [MþNa]
m/z calcd for C25H39NO8Na: 504.2568, found: 504.2544.
4.1.13. Preparation of compound 15
To a solution of 8 (1.5 g, 3.25 mmol) in CH2Cl2 (75 ml) was
passed ozone gas (50–100 cc/min) at ꢀ78 ꢁC for 1.5 h until the re-
action solution was changed into blue color and then oxygen gas
was passed to remove the remained ozone gas. To the reaction
mixture was added Me2S (2 ml) and the solution stirred at room
temperature for 30 min. The removal of solvent in vacuum gave
a residue, which was dissolved with THF (70 ml). After adding
saturated Na2SO3 solution (70 ml), the mixture was stirred vigor-
ously at room temperature for 10 h. The usual work-up gave the
crude 10 (1.43 g), and followed by recrystallization from ether to
furnish 10 (1.12 g, 70%), as colorless needle crystals. To a solution of
the crude 10, as above, (1.12 g, 2.27 mmol) in THF (25 ml) were
added sequentially NaH (545 mg, 22.72 mmol) and CH3I (0.41 ml,
682 mmol) and the reaction mixture was stirred at room temper-
4.1.10. Preparation of compound 12
To a solution of 11 (192 mg, 0.40 mmol) in THF (5 ml), B2H6–THF
(1.8 ml, 1.8 mmol) was added and the mixture was refluxed for 20 h
under argon gas steam. Quenching with H2O, evaporation, dilution
with H2O (5 ml), basification (NH4OH, pH 10), extraction (CHCl3,
10 mlꢄ3), drying (Na2SO4), removal of solvent, and chromatogra-
phy (silica gel H, 5 g, cyclohexane–acetone 5:1) gave compound 12
20
(100 mg, 51.8%). Compound 12: mp: 65–67 ꢁC; [
a
]
D
ꢀ5.9 (c 0.5,
CHCl3); IR (KBr): 3398 cmꢀ1; 1H NMR (400 MHz, CDCl3)
s, H3-18), 0.89 (3H, t, J¼7.2 Hz, NCH2CH3), 3.15 (1H, dd, J¼10.4,
6.8 Hz, H-1
), 3.34, 3.42, 3.45 (each 3H, s, OCH3ꢄ3), 3.58 (1H, s, H-
d
0.92 (3H,
ature for 2 h under argon steam. The general work-up furnished 15
(1.15 g, 100%). Compound 15: mp: 96–98 ꢁC; [
20
a]
þ33.0 (c 0.5,
D
b
CHCl3); IR (KBr): 1649, 1097 cmꢀ1; 1H NMR (400 MHz, CDCl3)
(3H, t, J¼7.2 Hz, NCH2CH3), 1.24 (3H, s, H3-18), 3.26, 3.26, 3.37, 3.38
(each 3H, s, OCH3ꢄ4), 3.79 (1H, s, H-6 ), 3.84 (1H, dd, J¼6.4, 4.8 Hz,
H-12), 3.97–4.02 (1H, m, H-16 ), 2.84–2.91, 4.29–4.36 (each 1H, m,
NCH2CH3), 4.42 (1H, d, J¼3.2 Hz, H-17), 4.47 (1H, dd, J¼10.4, 7.2 Hz,
d 1.15
6
a), 3.69–3.75 (1H, m, H-16
a
), 3.87 (1H, dd, J¼7.6, 5.6 Hz, H-10),
5.04 (1H, d, J¼2.4 Hz, H-9), 4.98, 5.12 (each 1H, s, OCH2O); 13C NMR
a
(100 MHz, CDCl3)
d
84.1 (d, C-1), 25.4 (t, C-2), 35.6 (t, C-3), 32.2 (s, C-
a
4), 52.8 (d, C-5), 92.8 (d, C-6), 94.1 (s, C-7), 85.1 (s, C-8), 65.9 (d, C-9),
75.9 (d, C-10), 55.0 (s, C-11), 47.9 (d, C-12), 37.6 (d, C-13), 64.2 (t, C-
14), 37.4 (t, C-15), 76.8 (d, C-16), 63.0 (d, C-17), 25.6 (q, C-18), 55.4 (t,
C-19), 49.9 (t, C-21), 13.8 (q, C-22), 56.7 (q, C-10), 56.9 (q, C-60), 58.5
(q, C-160), 91.8 (t, OCH2O); ESIMS m/z 506 [MþNa]þ; HR-ESIMS
[MþNa]þ m/z calcd for C25H41NO8Na: 506.2724, found: 506.2707.
H-1b), 4.99, 5.13 (each 1H, s, OCH2O), 5.07 (1H, s, H-14), 5.40 (1H, d,
J¼6.8 Hz, H-9); 13C NMR (100 MHz, CDCl3) see Table 2; ESIMS m/z
508 [MþH]þ; HR-ESIMS [MþNa]þ m/z calcd for C26H37NO9Na:
530.2361, found: 530.2335.
4.1.14. Preparation of compound 16
4.1.11. Preparation of compound 13
To a solution of 15 (1.09 g, 2.16 mmol) in THF (10 ml) was B2H6–
THF (8.36 ml, 8.63 mmol) and the mixture was refluxed for 6 h.
Quenching the reaction with H2O, evaporation, dilution with H2O
(10 ml), basification (NH4OH, pH 10), extraction (CHCl3, 15 mlꢄ3),
drying (Na2SO4), and the removal of CHCl3, followed by chroma-
tography (silica gel H, 30 g, cyclohexane–acetone 13:1) furnished
To a solution of 12 (100 mg, 0.21 mmol) in toluene (5 ml), fresh
silver carbonate-Celite (936 mg, 1.66 mmol) was added and the
reaction solution was refluxed for 17 h. The solution was filtrated,
and the filtrate was evaporated to give a residue that was chro-
matographed (silica gel H, 1.4 g, cyclohexane–acetone 7:1) afforded
compound 13 (30 mg, 30%). Compound 13: mp: 190–192 ꢁC; [
20
a
]
16 (504 mg, 78%). Compound 16: 1H NMR (400 MHz, CDCl3)
d 0.89/
D

7604
C.-L. Zou et al. / Tetrahedron 64 (2008) 7594–7604
0.89 (3H, s, H3-18), 1.03/1.02 (3H, t, J¼7.2 Hz, NCH2CH3), 3.32, 3.36,
3.38, 3.39/3.35, 3.36, 3.38, 3.39 (each 3H, s, OCH3ꢄ4), 3.62/3.57 (1H,
(159 mg, 0.46 mmol), and Na2CO3 (80 mg). The reaction solution
was stirred at room temperature for 22 h. After quenching with
H2O, extraction with CHCl3 (10 mlꢄ3), drying (Na2SO4), and the
removal of solvent gave a residue, to which 80% HOAc solution was
added and the mixture stirred at room temperature for 3.5 h. After
basifying to pH 8 with NH4OH, extraction with CHCl3 (10 mlꢄ3),
drying (Na2SO4), and the removal of solvent gave a residue that was
chromatographed over silica gel H (4 g) eluted with CHCl3–MeOH
s, H-6
a
), 3.73–3.78/3.73–3.79 (1H, m, H-16
a
), 3.80/3.59 (1H, d,
), 3.72 (1H, dd,
), 4.30 (1H, dd,
J¼2.4 Hz, H-17), 4.03 (1H, dd, J¼10.4, 7.2 Hz, H-1
b
J¼10.0, 7.2 Hz, H-1 ), 4.42 (1H, d, J¼10.0 Hz, H-10
b
a
J¼11.6, 1.2 Hz, H-10
b), 4.92, 5.08/4.92, 5.09 (each 1H, s, OCH2O),
4.99/4.94 (1H, s, H-14), 5.40/5.37 (1H, d, J¼6.4 Hz, H-9); 13C NMR
(100 MHz, CDCl3) d 79.4/82.6 (d, C-1), 25.5/25.6 (t, C-2), 37.2/37.3 (t,
C-3), 33.1/32.2 (s, C-4), 54.0/52.2 (d, C-5), 92.9/92.7 (d, C-6), 94.1/
94.3 (s, C-7), 87.0/87.3 (s, C-8), 78.8/74.1 (d, C-9), 74.2/72.9 (d, C-10),
53.8/55.1 (s, C-11), 47.4/48.7 (d, C-12), 44.4/48.1 (d, C-13), 102.4/
102.1 (d, C-14), 38.2/38.1 (t, C-15), 73.7/73.8 (d, C-16), 65.5/64.6 (d,
C-17), 25.1/25.7 (q, C-18), 55.6/55.7 (t, C-19), 50.0/49.8 (t, C-21),
13.8/13.8 (q, C-22), 59.8 q, 57.9 q, 56.2 q, 54.7 q/58.3 q, 56.7 q, 56.2
q, 54.7 q (C-10, 60, 140, 160), 92.4/92.4 (t OCH2O); ESIMS m/z 496
[MþH]þ; HR-ESIMS [MþNa]þ m/z calcd for C26H41NO8Na: 518.2724,
found: 518.2699.
(60:0.35) to give compound 19 (105 mg, 69%). Compound 19: mp:
þ22.2 (c 0.5, CHCl3); IR 3409, 1712, 1633 cmꢀ1
;
1H
20
94–96 ꢁC; [
a
]
D
NMR (400 MHz, CDCl3) and 13C NMR (100 MHz, CDCl3) see Table 6;
ESIMS m/z 518 [MþNa]þ; HR-ESIMS m/z calcd for C26H41NO8Na:
518.2724, found: 518.2695.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 30472075) and the Excellent Ph.D. Dissertation Foun-
dation of China (No. 200367) for financial support of this research.
4.1.15. Preparation of 4
16,17,18,19-nor-7 -methyl-7
dioxymethylen-tax-2-ene-14
a,9
b
,13
-(N-ethylmethylamine)-10
-acetal (17)
b
,140
b
-tetramethoxy-10
a
-formyl-
b
a
b
,11
b-
b
Reaction of asolution of 16 (1.10 g, 2.22 mmol) inpyridine (20 ml)
with SOCl2 (0.32 ml, 4.44 mmol) at room temperature for 8 min was
carried out. Stopping the reaction with H2O, followed by chilling at
0 ꢁC, and the removal of pyridine, gave a residue. Diluting (H2O,
15 ml), basification (5% NaHCO3, pH 8), extraction (CHCl3, 20 mlꢄ3),
and evaporation gave a residue (1.18 g), which was dissolved in
MeOH–H2O (30 ml, 9:1), and the solution was refluxed for 15 h. The
usual work-up, followed by chromatography (silica gel H, 20 g,
References and notes
1. (a) Holton, R. A.; Kim, H. B.; Somoza, C.; Liang, F.; Biediger, R. T.; Boatinan, P. D.;
Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Tao, C.; Vu, P.; Tang, S.; Zhang,
P.; Murthi, K. K.; Gentle, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116, 1599–1600;
(b) Nicolaou, K. C.; Yang, E.; Liu, J. J.; Ueno, H.; Nanfermet, P. G.; Guy, R. K.;
Claiborne, C. F.; Renaude, J.; Couladouuroa, E. A.; Paulvannan, K.; Sorensen, E. J.
Nature 1994, 367, 630–634; (c) Danishefsky, S. J.; Masters, J. J.; Young, W. B.;
Link, T.; Sneder, L. B.; Magee, T. V.; Jung, D. K.; Isaaes, R. A.; Bornmann, W. G.;
Alaimo, C. A.; Coburn, C. A.; Digrandi, M. J. J. Am. Chem. Soc. 1996, 118, 2843–
2869; (d) Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancing, P. E.; Glass, T.
E.; Krauss, N. E.; Lee, D.; Marquess, D. G.; Mcgtrane, P. L.; Meng, W.; Natchus, M.
G.; Shuker, A. J.; Sutton, J. C.; Taylor, R. E. J. Am. Chem. Soc. 1997, 119, 2755–2756;
(e) Mukaiyama, T.; Shiian, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.;
Sakoh, H.; Nishimura, K.; Tani, Y.; Hasegawa, M.; Yamada, K.; Saitoh, K.
Chem.dEur. J. 1999, 5, 121–161; (f) Morihira, K.; Hara, R.; Kawahara, S.;
Nishimori, T.; Nakamura, N.; Kusama, H.; Kuwajima, I. J. Am. Chem. Soc. 1998,
120, 12980–12981.
2. For reviews, see: Boa, A. N.; Jenkins, P. R.; Lawrente, N. J. Contemp. Org. Synth.
1994, 1, 47–75; Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew. Chem., Int. Ed. Engl.
1994, 33, 15–44; (a) Hermando, J. I. M.; Ferreira, M. R. R.; Lena, J. I. C.; Birlirakis,
N.; Arseniyadi, S. Tetrahedron: Asymmetry 2000, 11, 951–973; (b) Petit, M.;
Chouraqui, G.; Phansavath, P.; Aubert, C.; Malacria, M. Org. Lett. 2002, 4, 1027–
1029; (c) Smil, N. V.; Caurent, A.; Spassova, N. S.; Fallis, A. G. Tetrahedron Lett.
2003, 44, 5129–5132; (d) Yap, G. P. A.; Fallis, A. G. Synlett 2003, 1263–1266; (e)
Iwamoto, M.; Miyano, M.; Utsugi, M.; Kawada, H.; Nakada, M. Tetrahedron Lett.
2004, 45, 8653–8656; (f) Garcvia-Fandino, R.; Codesido, E. M.; Sobarzo-San-
chez, E.; Castedeo, L.; Granja, J. R. Org. Lett. 2004, 6, 193–196; (g) Kawada, H.;
Iwamoto, M.; Utsugi, M.; Miyano, M.; Nakada, M. Org. Lett. 2004, 6, 4491–4494;
(h) Brennan, N. K.; Guo, X.; Paguentte, L. A. J. Org. Chem. 2005, 70, 732–734; (i)
Hamon, S.; Feffeira, M. R. R.; Moral, J. Q.; Hernando, J. I. M.; Lena, J. I. C.; Bir-
lirakis, N.; Toupet, L.; Arseniyadis, S. Tetrahedron: Asymmetry 2005, 16, 3241–
3255; (j) Hamon, S.; Birlirakis, N.; Toupet, L.; Arseniyadis, S. Eur. J. Org. Chem.
2005, 4082–4092.
CHCl3–MeOH 80:1.4 to 95:5), furnished 923 mg of 17 (84%). Com-
20
pound 17: mp: 48–50 ꢁC; [
a]
þ61.2 (c 0.6, CHCl3); IR (KBr): 3421,
D
1721, 1650, 1098 cmꢀ1 1H NMR (400 MHz, CDCl3) and 13C NMR
;
(100 MHz, CDCl3) see Table 4; ESIMS m/z 496 [MþH]þ; HR-ESIMS
[MþH]þ m/z calcd for C26H42NO8: 496.2905, found: 496.2909.
4.1.16. Preparation of 4
acetoxymethylen-16,17,18,19-nor-7
ethylmethylamine)-10 ,11 -dioxymethylen-tax-2-en-
14 -acetal (18)
A mixture of 17 (562 mg, 1.14 mmol), Ac2O (2 ml), and pyridine
a,9
b,13b
,140
b
-tetramethoxy-10
a-
b
-methyl-7 -(N-acetyl-N-
a
b
b
b
(2 ml) was stirred at room temperature for 1 h. The reaction solu-
tion was evaporated to yield a residue, which was diluted with H2O
(10 ml) and after basifying to pH 8 using NH4OH solution was
extracted with CHCl3 (15 mlꢄ3). Evaporation of the combined
CHCl3 solutions gave a residue, to which THF (10 ml) and NaBH4
(110 mg, 2.89 mmol) were added. The reaction solution was stirred
at room temperature for 2.5 h. After quenching with H2O, extrac-
tion with CHCl3 (15 mlꢄ3), drying (Na2SO4), and the removal of
solvent gave a residue, to which Ac2O (2 ml) and pyridine (2.5 ml)
were added, and the mixture was stirred at 50 ꢁC for 12 h. The usual
work-up, followed by chromatography (silica gel H, 15 g, cyclo-
3. (a) Kingston, D. G. I. Pharmacol. Ther. 1991, 52, 1–34; (b) Datta, A.; Jayasinghe,
L. R.; Georgy, G. I. J. Med. Chem. 1994, 37, 4258–4260.
4. (a) Wang, F. P.; Liang, X. T. The Alkaloids; Cordell, G. A., Ed.; Academic: New York,
NY, 1992; Vol. 42, pp 151–247; (b) Wang, F. P.; Liang, X. T. The Alkaloids; Cordell,
G. A., Ed.; Elsevier Science: New York, NY, 2002; Vol. 59, pp 1–280.
5. Pelletier, S. W.; Mody, N. V.; Joshi, B. S.; Scharmm, L. C. Alkaloids; Pelletier, S. W.,
Ed.; John Wiley & Sons: New York, NY, 1984; Vol. 2, pp 205–462.
6. (a) Wang, F. P.; Yang, J. S.; Chen, Q. H.; Xu, L.; Li, B. G. Chem. Pharm. Bull. 2000,
48, 1912–1916; (b) Wang, F. P.; Chen, Q. H.; Xu, L.; Li, B. G. Tetrahedron 2001, 57,
4705–4712; (c) Chen, Q. H.; Xu, L.; Wang, F. P. Tetrahedron 2002, 58, 9431–9444;
(d) Wang, F. P.; Xu, L. Tetrahedron 2005, 61, 2149–2167.
hexane–acetone 7:1) furnished 18 (600 mg, 91%). Compound 18:
20
mp: 173–175 ꢁC; [
a
]
D
þ58.4 (c 0.5, CHCl3); IR (KBr): 1739,
1643 cmꢀ1 1H NMR (400 MHz, CDCl3) and 13C NMR (100 MHz,
;
CDCl3) see Table 5; ESIMS m/z 604 [MþNa]þ; HR-ESIMS [MþNa]þ
m/z calcd for C30H47NO10Na: 604.3092, found: 604.3120.
7. (a) Cai, L. Ph.D. Dissertation, Sichuan University, 2006; p 55; (b) Zou C.-L. Ph.D.
Dissertation, Sichuan University, 2008.
8. Srivastava, S. K.; Joshi, B. S.; Newton, M. G.; Lee, D.; Pelletier, S. W. Tetrahedron
Lett. 1995, 36, 519–522.
9. Zou, C. L; Ji, H.; Xie, G. B.; Chen, D. L.; Wang, F. P. J. Asian Nat. Prod. Res.,
in press.
10. (a) Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945–5948; (b) Bouzide, A.;
Sauve, G. Org. Lett. 2002, 4, 2329–2332.
11. Fetizon, M.; Golfier, M.; Louis, J. M. Tetrahedron 1975, 31, 171–176.
12. (a) Pelletier, S. W.; Mody, N. V.; Dailley, O. D., Jr. Can. J. Chem. 1980, 58, 1875–
1879; (b) Pelletier, S. W.; Dailey, O. D.; Mody, N. V.; Olsen, J. D. J. Org. Chem. 1981,
46, 3284–3293; (c) Pelletier, S. W.; Mody, N. V.; Varughese, K. I.; Maddry, J. A.;
Desai, H. K. J. Am. Chem. Soc. 1981, 103, 6536–6538.
4.1.17. Preparation of 11-hydroxyl-4
16,17,18,19-nor-7 -methyl-7 -(N-acetyl-N-ethylmethylamine)-tax-
2-en-14 -acetal-10-one (19)
A mixture of 17 (152 mg, 0.31 mmol), Ac2O (1 ml), and pyridine
(1 ml) was stirred at room temperature for 1 h. The reaction solu-
tion was evaporated to give a residue, which was diluted with H2O
(10 ml) and after basifying to pH 8 using NH4OH solution, extracted
with CHCl3 (10 mlꢄ3). Evaporation of the combined CHCl3 solu-
tions gave a residue, to which were added CHCl3 (5 ml), mCPBA
a,9b,13b b-tetramethoxy-
,140
b
a
b