The synthesis and biological activity of 9- and 2'-cAMP 7- deoxypaclitaxel analogues from 5-cinnamoyltriacetyltaxicin-I

Article abstract of DOI:10.1016/S0040-4020(00)00073-9

The synthesis and biological activity of new 7-deoxypaclitaxel analogues 3 and 4 in which the hydroxy group at C-2' of the side-chain, C-9 and C-10 in the B-ring are substituted by cAMP and benozoyloxy group respectively are presented. These derivatives have been first synthesized from a natural taxoid 5-cinnamoyltriacetyltaxicin-15 and tested in vitro for cytotoxicity against three human tumor cell lines. The biologically tested results indicate 3 having more potent cytotoxicity and 4 having a remarkably reduced cytotoxicity as well as 33 having no much effect on cytotoxicity against all human tumor cell lines tested in comparison to that of paclitaxel. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00073-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1667–1679
The Synthesis and Biological Activity of 9- and 20-cAMP
7-Deoxypaclitaxel Analogues from 5-Cinnamoyltriacetyltaxicin-I
*
Qian Cheng, Takayuki Oritani and Tohru Horiguchi
Laboratory of Applied Bioorganic Chemistry, Division of Life Science, Graduate School of Agricultural Science, Tohoku University,
1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received 17 December 1999; accepted 26 January 2000
Abstract—The synthesis and biological activity of new 7-deoxypaclitaxel analogues 3 and 4 in which the hydroxy group at C-20 of the side-
chain, C-9 and C-10 in the B-ring are substituted by cAMP and benozoyloxy group respectively are presented. These derivatives have been
first synthesized from a natural taxoid 5-cinnamoyltriacetyltaxicin-I 5 and tested in vitro for cytotoxicity against three human tumor cell
lines. The biologically tested results indicate 3 having more potent cytotoxicity and 4 having a remarkably reduced cytotoxicity as well as 33
having no much effect on cytotoxicity against all human tumor cell lines tested in comparison to that of paclitaxel. ᭧ 2000 Elsevier Science
Ltd. All rights reserved.
Introduction
benzoyloxy and acetoxy at C-2 and C-4 respectively plus
the oxetane ring in the southern hemisphere, and the side
chain at C-13 are essential for activity.8,11,14,16 However,
only a few modifications of C-9 such as dihydrogenation
and decarboxylation have been reported.17 Further chemical
and SAR studies of C-9 have appeared recently in the
literature. The mechanism of action studies indicate that the
anticancer activity of paclitaxel is believed to be mediated
by a combination of its primary action on microtubule
assembly and secondarily by inhibiting DNA synthesis
and promoting DNA fragmentation of the cell.18 These
actions are found to be related with a nucleotide, such as
GTP and ATP,19 which can be converted from GMP and
AMP via GDP and ADP in the organism. In addition, twin
drugs combining two biologically active components into a
single molecule have been applied in numerous domains of
medicinal chemistry.20 With this in mind and the known
SAR studies in which show 7-deoxylation having no signifi-
cant effect on activity, we thus expected to explore the
possibility of taxoid combined with the nucleotide for the
synthesis of the new taxoids 3 and 4 possessing anticancer
activity or other biological activity, and the additional
knowledge for SAR of paclitaxel.
The diterpenoid paclitaxel (Taxol᭨ 1), originally isolated
from the Pacific yew tree Taxus brevifolia,1 is a powerful
therapeutic drug for cancer chemotherapy2 and exhibits
remarkably high cytotoxicity and strong antitumor activity
against different types of cancer that are resistant to existing
anticancer drugs.3 Its outstanding results of clinical studies
have led to be approved for treatment of advanced ovarian
and breast cancers,4,5 and it is currently in clinical trials for
treatment of lung, skin, and head and neck cancers with
encouraging results.2,6 Over the past two decades, structural
complexity, important biological activity and novel
mechanism of action7 of paclitaxel have stimulated exten-
sive chemical, biological and medicinal research,8 and a
number of research groups have attempted to synthesize it
and its improved analogues for clinical use. Up to now, six
total syntheses of paclitaxel have been achieved.9 Among
many studies of structural modifications of paclitaxel,
numerous analogues have been prepared by contractions
and changes to A-ring,10 B-ring,11 C-ring,12 the oxetane
ring,13 and the side chain14 which have led to the discovery
of the biologically potent taxoid docetaxol15 (Taxotere᭨ 2) in
the semisynthesis of paclitaxel from 10-deacetylbaccatin III.
Although the semisyntheses of 7-deoxypaclitaxel analogues
have been reported,21 all investigations have been carried
out using taxine B and isotaxine B22 as starting materials.
To our knowledge no attention to date has been paid to
5-cinnamoyltriacetyltaxicin-I 5,23 which is an available
taxoid existing in the needles of different Taxus species,
as a precursor for the synthesis of either paclitaxel or its
analogues. In this paper, we describe our efforts on the
synthesis and biological activity of new 7-deoxypaclitaxel
analogues 3 and 4 from 5 (Scheme 1).
From a large number of the structure-activity relationship
(SAR) studies of paclitaxel, it is known that the function
group at C-7, C-9, C-10, and double bond in the northern
hemisphere have no significant effect on activity, while the
Keywords: biologically active compounds; taxoids; phosphoric acid and
derivatives.
* Corresponding author. Fax: 81ϩ(022)-717-8783;
e-mail: chengq@biochem.tohoku.ac.jp
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00073-9

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Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
Scheme 1.
Results and Discussion
to give a polyalcohol 6 at 0ЊC in the presence of NaOCH3.21a
Attempted protection of the polyalcohol 6 with triphosgene
(2 equiv.) and Et3N (4 equiv.) in CH2Cl2 at rt yielded a sole
reaction product 9,10-cyclic carbonate alcohol 7 in 90%
yield. But the compound 7 was further protected with
As the synthetic protocol is depicted in Scheme 2, the
5-cinnamoyltriacetyltaxicin-I 5, easily isolated from the
needles of Japanese yew T. cuspidata, underwent deacetylation
Scheme 2. Reagents and conditions: (i) NaOCH3, CH3OH-CH2Cl2, 0ЊC, 86%; (ii) (Cl3CO)2CO (2 equiv.), Et3N (4 equiv.), CH2Cl2, rt, 90%; (iii) (Cl3CO)2CO
(2 equiv.), CH2Cl2-pyridine (2:1), 0ЊC, 91%; (iv) (Cl3CO)2CO (5 equiv.), CH2Cl2-pyridine (2:1), 0ЊC, 86%; (v) OsO4, NMO, THF-H2O (2:1), rt, 85%; (vi) 10%
KOAc, CH3OH, reflux, 0.5 h, 11 (36%), 12 (45%); (vii) K2CO3 or NaHCO3, CH3OH, 0ЊC, overall yield 83%.

Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
1669
triphosgene (2 equiv.) in CH2Cl2-pyridine (v/v 2:1) at 0ЊC
leading to a 1:2,9:10-dicyclic carbonate 8, which could be
prepared in 86% yield directly from the polyalcohol 6 under
similar conditions using triphosgene (5 equiv.). Following
the previously reported methods by Saicic,21d osmylation of
8 with OsO4 (2.5% int-BuOH) in the presence of 4-methyl-
morpholine N-oxide generated an intermediate 9, which was
followed by treatment with methanolic 10% KOAc under
reflux to afford the desired triol 11 in 36% yield and the
9-hydroxy tetraol 12 in 45% yield together with an optically
pure (2S, 3R)-(Ϫ)-methyl-2,3-dihydroxy-3-phenylpropion-
ate 10 which was determined by NMR and optical rotation
data in comparison to those of its commercial sample. The
stereochemistry of 11 was established by a NOESY experi-
ment. The NOESY correlations of H3-19 (dH 1.17, s) to
H2-20 (dH 4.03 and 3.54, d, Jˆ10.8 Hz), and H-20a to
H-5b (dH 3.69, t, Jˆ3.0 Hz) and H-6b (dH 1.72, m)
demonstrated 11 possessing the b-orientation of the
4-hydroxymethylene group located at C-4. The similar
stereochemistry of 12 was established by the NOESY corre-
lations of H3-19 (dH 1.11, s) to H2-20 (dH 4.04 and 3.54, d,
Jˆ10.5 Hz), and H-20a to H-5b (dH 3.63, t, Jˆ3.0 Hz) and
H-6b (dH 1.65, m).
not take place under these conditions. The above demon-
strated that the key intermediate triol 11 which is a direct
precursor for construction of the oxetane ring could be
successfully prepared from 5, but the yield was in compara-
tively low (overall yield 22.6% from 5) due to the low
selectivity in the hydrolysis of the cinnamate ester in the
last step.
In order to explore an effective access to the triol 11 from 5,
the second synthetic protocol for the preparation of 11 via
the intermediate 13 (Scheme 3) was employed. First selec-
tive removal of the cinnamate ester according to the known
method25 gave a 5-hydroxytriacetyltaxicin-I 17, subsequent
protection of the 5-hydroxy group by chlorotriethylsilane,
deacetylation, and further protection with triphosgene
afforded the protected taxoid 20. Deprotection of 20 with
a solution of tetrabutylammonium fluoride (1.0 M in THF)
led to 13 in quantitative yield which subsequently was
osmylated with OsO4/NMO to furnish successfully only
the triol 11 in 83% yield as the reaction product. It was
worthy to note that this route was longer than the first, but
the overall yield (33%) of 11 prepared from 5 via 13 was
higher than that of the first route. Construction of the
oxetane ring 23 was achieved in overall yield 60% from
11 following the previously established methods.21 Acetyla-
tion of 23 with acetic anhydride catalyzed by DMAP9a in
CH2Cl2 gave 24, which subsequently was treated with
phenyllithium in THF at Ϫ78ЊC to furnish two separable
isomers 25 and 26 in 4:1 ratio. The structure and stereo-
Alternatively, attempted conversion of 8 into a precursor 13
for the direct preparation of 11 using either K2CO3 or
NaHCO3 at 0ЊC even with NaOAc/NH2OH.HCl system in
MeOH–H2O under reflux, all induced the methanolysis of
the 9,10-cyclic carbonate generating two separable isomers
14 and 15 in 4:1 ratio and the 9,10-deprotected diol 1624
1
chemistry of 25 and 26 were determined by H NMR, 13C
1
1
which were determined by their H NMR, 13C NMR data
NMR, and 2D NMR experiments. The H NMR data of 25
(see Experimental) and 2D NMR (1H-1H COSY and
HMBC) studies. The hydrolysis of the cinnamate ester did
showed two downfield signals at dH 6.45 (d, Jˆ9.4 Hz) and
dH 5.62 (d, Jˆ7.0 Hz) assigned to be the H-10 and H-2,
Scheme 3. Reagents and conditions: (i) NH2OH.HCl, NaOAc, EtOH-H2O, reflux, 70%; (ii) TESC1 (10 equiv.), pyridine, rt, 81%; (iii) NaOCH3, CH3OH-
CH2Cl2, 0ЊC, 81%; (iv) (Cl3CO)2CO (5 equiv.), CH2Cl2-pyridine (v/v 2:1), 0ЊC, 88%; (v) TBAF/THF, rt, 100%; (vi) OsO4, NMO, THF-H2O (2:1), rt, 83%; (vii)
TBDMSCl, imidazole, DMF, rt, 95%; (viii) MsCl, pyridine, rt, 83%; (ix) a: TBAF, THF, rt, b: TBAOAc, butanone, reflux, 76%; (x) Ac2O, DMAP, rt, 93%; (xi)
PhLi, THF, -78ЊC, 25 (64%), 26 (15%).

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Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
Scheme 4. Reagents and conditions: (i) DMAP, DMF, rt, 84%; (ii) TESCl, imidazole, DMAP, rt, 89%; (iii) NaBH4, CH3OH, rt, 77%; (iv) DCC, DMAP,
toluene, 75ЊC, (v) TFA, H2O, 0ЊC to rt, 74% from 30.
1
respectively by H-1H COSY indicating the presence of a
benzoyloxy group at C-10 and C-2. This was confirmed by
the HMBC correlations of H-10 and H-2 to their respective
quaternary carbon (CvO) at dc 166.8 (Bz-10) and dc 168.7
(Bz-2). Whereas a upfield signal at dH 4.19 (dd, Jˆ9.4,
3.4 Hz) was assigned to H-9 and a hydroxy (dH 2.65, d,
dH 5.12 (dd, Jˆ9.1, 4.0 Hz) assigned to be the H-10 by
1H-1H COSY. These implied a benzoyloxy group connected
to C-9 and C-2 respectively and a hydroxy located at C-10,
which were confirmed by the HMBC correlations of H-9
and H-2 to their respective quaternary carbon (CvO) at
dc 166.3 (Bz-9) and dc 168.2 (Bz-2), and the H-10 showing
only doublet signal in the D2O exchanged 1H NMR experi-
ment. Compound 25 was regarded as the key intermediate
for the synthesis of 9- and 20-cAMP coupling 7-deoxypacli-
taxel analogues 3 and 4.
Jˆ3.4 Hz) was located at C-9 by means of H-1H COSY,
1
which were confirmed by the H-9 showing doublet signal
and the absence of the signal of 9-hydroxy in the D2O
exchanged 1H NMR experiment. In comparison to the
NMR data of 25, those of 26 showed two downfield signals
at dH 6.37 (d, Jˆ9.1 Hz) and dH 5.63 (d, Jˆ6.8 Hz) assigned
to be the H-9 and H-2 respectively, and an upfield signal at
Our strategy for preparation of the 9-cAMP-7-deoxy-
paclitaxel 3 has been realized as shown in Scheme 4.
Scheme 5. Reagents and conditions: (i) TPAP, NMO, CH2Cl2, 70%; (ii) NaBH4. CH3OH, rt, 74%; (iii) DCC, DMAP, toluene, 75ЊC; (iv) TFA, H2O, 0ЊC, 78%;
(v) DMAP, DMF, rt, 78%.

Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
1671
Though direct coupling of 25 with (Ϫ)-adenosine 30, 50-
cyclic monophosphate was unsuccessful, it was found that
9-cAMP taxoid 28 was prepared in 84% yield by a coupling
of (Ϫ)-adenosine 30, 50-cyclic phosphate chloride 27
derived from acid (Ϫ)-adenosine 30, 50-cyclic monophos-
phate in the presence of DMAP at rt.26 In order to avoid
occuring coupling between 31 and the 20-hydroxy of cAMP
in esterification, the 9-cAMP taxoid 28 was first treated with
and 4 for tubulin-assembly assay and used as phosphatase-
activated prodrugs for cytotoxicity assay in vivo are in
progress.
Experimental
All commercially available reagents were used without
further purification. All anhydrous reactions were
performed in the oven-dried glassware under nitrogen.
Tetrahydrofuran and diethyl ether were distilled from
sodium and benzophenone, and dichloromethane was
refluxed and distilled from CaH2 under nitrogen. Chromato-
graphy was carried out on a Merck silica gel 60 (230–
400 mesh). Preparative TLC was performed on Merck silica
gel 60 F254 plates (0.85 mm thickness). 1H NMR, 13C NMR
and 2D NMR were performed on Varian Unity INOVA 500
and 600 spectrometers in CDCl3 except notes using TMS as
an internal standard. Chemical shifts are expressed in parts
per million (ppm) and coupling constants (J) are given in
Hertz (Hz). Optical rotation was recorded by a Horiba
SEPA-300 polarimeter. HRMS(EI) and HRMS(FAB) were
measured by a JEOL JMS-700 spectrometer.
9a
TESC1 followed by selective reduction using NaBH4 to
afford the desired 13a-hydroxy-9-cAMP taxoid 30. Finally,
the 9-cAMP-7-deoxypaclitaxel 3 was accomplished in over-
all yield 74% through esterification of 30 with 31 followed
by acidic hydrolysis.9f,27
Recently, studies on C-20 and C-7 paclitaxel phosphates
used as phosphatase-activated prodrugs of paclitaxel have
been reported.28 This result has prompted us to attempt to
synthesize the 20-cAMP paclitaxel analogue 4 (Scheme 5).
Oxidation of 25 with tetrapropylammonium perruthenate
and 4-methylmorpholine N-oxide29 gave a ketone 32
which underwent selective reduction to afford the desired
13a-hydroxy taxoid 33 in 74% yield. Esterification of 33
with 31 followed by acidic hydrolysis yielded a 10-O-
benzoyl-7-deoxypaclitaxel 34 in 78% yield. Finally,
attachment of cAMP at C-20 giving the desired 20-cAMP-
7-deoxypaclitaxel 4 was achieved in 78% yield through a
combination of 34 with (Ϫ)-adenosine 30, 50-cyclic
phosphate chloride 27 in the presence of DMAP.
2,9,10-Trideacetyl-5-O-cinnamoyltaxicin-I (6). To a solu-
tion of 2,9,10-triacetyl-5-O-cinnamoyltaxicin-I 5 (1.5 g,
2.78 mmol) in CH2Cl2–CH3OH (120 ml, v/v 1:1) was
added a solution of NaOCH3 (0.18 g, 3.33 mmol) in
CH3OH (2 ml). The reaction mixture was stirred at 0ЊC
under nitrogen for 24 h (the reaction was monitored by
TLC), subsequently acidified with glacial acetic acid and
concentrated. Water (25 ml) was added to the above
residue. This resulting solution was extracted with CH2Cl2
(150 ml) and the organic layer was washed with saturated
aqueous NaHCO3 and dried over MgSO4. After removal of
the solvent under reduced pressure, the residue was
chromatographed on silica gel (ethyl acetate:hexaneˆ1:1
v/v) to give 1.18 g (86%) of 6 as a white solid which
proved to be identical to the previously described
compound.21b
The biological results tested in vitro presented in Table 1
show the substitution of 9-hydroxy by cAMP 3 having more
potent cytotoxicity against three human tumor cell lines
(MCF-7, SK-OV3 and WIDR) in comparison with pacli-
taxel. On the other hand, the substitution of 20-hydroxy by
cAMP 4 exhibits less cytotoxicity against all human tumor
cell lines than paclitaxel. The reason that 4 shows only weak
activity against human tumor cell lines is not clear yet, but it
is probably attributed to the absence of a free hydroxy group
at C-20 of the side chain in accordance with the known SAR
studies of paclitaxel in which it is shown that the free
hydroxy at C-20 is necessary for activity.14 In addition, the
10-benzoyloxy-7-dexoypaclitaxel 34 shows a unremarkable
decrease of cytotoxicity compared to paclitaxel, this is
consistent with the previously reported SAR studies of
paclitaxel in which the hydroxy and acetyl groups at 7-
and 10-positions respectively might be removed
without significant loss of activity.16 Biological tests of 3
9:10 Cyclic carbonate-2,9,10-trideacetyl-5-O-cinnamoyl-
taxicin-I (7). To an ice-cooled solution of 6 (50 mg,
0.1 mmol) in CH2Cl2 (3 ml) containing Et3N (0.12 ml,
0.4 mmol) was added triphosgene (60 mg, 0.2 mmol). The
reaction mixture was stirred for 4 h at rt under nitrogen. The
saturated aqueous NaHCO3 (5 ml) was added and the result-
ing solution was extracted with CH2Cl2. The combined
organic layers were dried over MgSO4 and evaporated
under reduced pressure. The residue was chromatographed
on silica gel (ethyl acetate:hexaneˆ1:1 v/v) to give 47 mg
Table 1. Biological cytotoxicity of 7-deoxypaclitaxel analogues 3, 4 and 34
1
(90%) of 7 as a white solid. mp: 234–235ЊC, H NMR
Compound
Cytotoxicity against tumor cell (ED50/ED50)a–c
(500 MHz) d: 7.72 (m, 2H), 7.66 (d, 1H, Jˆ16.0 Hz),
7.45 (m, 3H), 6.28 (d, 1H, Jˆ16.0 Hz), 5.65 (d, 1H, Jˆ
11.5 Hz), 55.5 (s, 1H), 5.45 (s, 1H), 5.36 (t, 1H, Jˆ
3.0 Hz), 5.02 (d, 1H, Jˆ11.5 Hz), 4.04 (t, 1H, Jˆ7.0 Hz),
3.07 (d, 1H, Jˆ7.0 Hz), 2.75 (d, 1H, Jˆ20.0 Hz), 2.70 (d, 1H,
Jˆ20.0 Hz), 2.60 (d, 1H, Jˆ7.0 Hz, OH), 2.19 (s, 3H), 2.07
(m, 1H), 1.83 (dddd, 1H, Jˆ14.5, 11.5, 5.0, 3.0 Hz), 1.71 (m,
H), 1.59 (m, 1H), 1.58 (s, 3H), 1.42 (s, 3H), 1.20 (s, 3H). 13C
NMR (125 MHz) d: 198.4 (s), 166.0 (s), 153.4 (s), 149.6 (s),
146.4 (d), 142.9 (s), 141.7 (s), 134.1 (s), 130.7 (d), 129.0 (d),
128.4 (d), 118.5 (d), 116.9 (t), 84.9 (d), 79.1 (s), 78.7 (d), 77.6
MCF-7 (breast)
SK-OV3 (ovarian)
WIDR (colon)
3
4
34
0.41
5.42
0.93
1.00
0.53
6.47
0.95
1.00
0.30
4.86
0.89
1.00
paclitaxel 1
a ED50 is the concentration which produces 50% inhibition of prolifera-
tion after 72 h of incubation.
b Ratio of ED50 relative to paclitaxel is 1.00.
c MCF-7: human breast cancer; SK-OV3: human ovarian cancer; WIDR:
human colon cancer.

1672
Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
(d), 71.6 (d), 45.6 (d), 44.0 (t), 42.4 (s), 41.1 (s), 34.4 (q), 28.6
(t), 27.0 (t), 20.6 (q), 17.1 (q), 14.3 (q). HRMS (EI) Calcd for
C30H34O8 (Mϩ) 522.2252, found 522.2247.
NMR (125 MHz) d: 196.8 (s), 173.1 (s), 154.3 (s), 152.7 (s),
150.1 (s), 139.8 (s), 136.7 (s), 128.7 (d), 128.1 (d), 126.4 (d),
89.1 (s), 84.2 (d), 82.3 (s), 79.8 (d), 78.7 (d), 77.2 (d), 74.5
(d), 74.2 (d), 62.4 (t), 44.2 (s), 43.7 (d), 41.6 (t), 40.1 (s),
32.5 (q), 27.2 (t), 26.7 (t), 20.4 (q), 17.9 (q), 14.5 (q).
(ءexchangeable by D2O).
1:2, 9:10 Cyclic carbonate-2,9,10-trideacetyl-5-O-cinna-
moyltaxicin-I (8). Pathway A (from 7): To an ice-cooled
solution of 7 (26 mg, 0.05 mmol) in CH2Cl2-pyridine (v/v
2:1, 1.5 ml) was added triphosgene (30 mg, 0.1 mmol). The
reaction mixture was stirred for 30 min at 0ЊC under
nitrogen, and saturated aqueous NaHCO3 (1 ml) was
added and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and evaporated under
reduced pressure. The residue was chromatographed on
silica gel (ethyl acetate:hexaneˆ1:1 v/v) to give 25 mg
(91%) of 8 as a white solid. Pathway B (from 6): To an
ice-cooled solution of 6 (50 mg, 0.1 mmol) in CH2Cl2-
pyridine (v/v 2:1, 3 ml) was added triphosgene (148 mg,
0.5 mmol). The reaction mixture was stirred for 30 min at
0ЊC under nitrogen, and saturated aqueous NaHCO3 (3 ml)
was added and extracted with CH2Cl2. The combined
organic layers were dried over MgSO4 and evaporated
under reduced pressure. The residue was chromatographed
on silica gel to give 47.5 mg (86%) of 8. mp: 253–255ЊC, 1H
NMR (600 MHz) d:7.69 (m, 2H), 7.66 (d, 1H, Jˆ16.0 Hz),
7.45 (m, 3H), 6.19 (d, 1H, Jˆ16.0 Hz), 5.62 (d, 1H,
Jˆ11.5 Hz), 5.56 (d, 1H, Jˆ1.5 Hz), 5.46 (s, 1H), 5.40 (t,
1H, Jˆ3.0 Hz), 4.85 (d, 1H, Jˆ11.5 Hz), 4.83 (d, 1H,
Jˆ6.0 Hz), 3.11 (brd, 1H), 3.02 (d, 1H, Jˆ19.5 Hz), 2.97
(d, 1H, Jˆ19.5 Hz), 2.24 (s, 3H), 2.08 (m, 1H), 1.86
(dddd, 1H, Jˆ13.5, 11.5, 5.0, 3.0 Hz), 1.76 (ddd, 1H,
Jˆ13.5, 5.0, 2.0 Hz), 1.65 (s, 3H), 1.54 (dd, 1H,
Jˆ13.5, 5.0 Hz), 1.48 (s, 3H), 1.24 (s, 3H). 13C NMR
(125 MHz) d: 195.0 (s), 165.6 (s), 154.4 (s), 152.6 (s),
151.7 (s), 146.6 (d), 146.1 (s), 137.7 (s), 134.0 (s),
130.7 (d), 129.0 (d), 128.4 (d), 119.3 (t), 116.6 (d),
89.1 (s), 85.1 (d), 79.0 (d), 78.5 (d), 76.7 (d), 42.3
(d), 42.2 (t), 40.9 (s), 40.8 (s), 33.0 (q), 27.3 (t), 26.4
(t), 20.0 (q), 16.9 (q), 15.1 (q). HRMS (EI) Calcd for
C31H32O9 (Mϩ) 548.2044, found 548.2031.
Hydrolysis of 9 to 10, 11 and 12
A solution of 9 (40 mg) and KOAc (0.3 g, about 10%) in
CH3OH (3 ml) was refluxed for 30 min and water (1 ml)
was added. The reaction mixture was extracted with
CH2Cl2 and the organic layer was dried over MgSO4, and
evaporated under reduced pressure. The residue was
chromatographed by preparative TLC (ethyl acetate:
hexaneˆ2:1 v/v) to give 10 mg (83%) of 10 as a white
solid, 11 mg (36%) of 11 and 14 mg (45%) of 12.
Methyl (2S, 3R)-(Ϫ)-2,3-dihydroxy-3-phenylpropionate
(10). mp: 85–87ЊC, [a]2D2ˆϪ10.5Њ (cˆ0.7, CHCl3),
[a]2D1ˆϪ10Њ (cˆ1.0, CHCl3) in Aldrich Products Catalogue.
1H NMR (500 MHz) d: 7.39–7.26 (m, 5H), 5.04 (d, 1H,
Jˆ3.0 Hz), 4.39 (d, 1H, Jˆ3.0 Hz), 3.83 (s, 3H), 3.11
(brs, 1H, OH), 2.74 (brs, 1H, OH). 13C NMR (125 MHz)
d: 173.1 (s), 139.8 (s), 128.5 (d), 128.1 (d), 126.1 (d), 74.6
(d), 74.3 (d), 52.9 (d).
1:2, 9:10 Cyclic carbonate-2,9,10-trideacetyl-4,20-
dihydro-4a,20-dihydroxytaxicin-I (11). A colorless oil.
[a]2D3ˆϩ178Њ (cˆ0.3, CHCl3). 1H NMR (600 MHz) d:
5.53 (d, 1H, Jˆ11.4 Hz), 4.79 (d, 1H, Jˆ11.4 Hz), 4.71
(d, 1H, Jˆ4.8 Hz), 4.03 (d, 1H, Jˆ10.8 Hz), 3.95 (d, 1H,
Jˆ19.2 Hz), 3.94 (brs, 1H, OHء), 3.69 (t, 1H, Jˆ3.0 Hz),
3.54 (d, 1H, Jˆ10.8 Hz), 2.86 (d, 1H, Jˆ19.2 Hz), 2.71 and
2.63 (brs, 2H, 2OHء), 2.60 (d, 1H, Jˆ4.8 Hz), 2.14 (s, 3H),
1.96 (ddd, 1H, Jˆ14.4, 6.0, 3.0 Hz), 1.72 (m, 1H), 1.65 (m,
1H), 1.61 (s, 3H), 1.52 (m, 1H), 1.45 (s, 3H), 1.17 (s, 3H).
13C NMR (150 MHz) d: 196.4 (s), 152.6 (s), 151.2 (s), 147.8
(s), 145.0 (s), 89.2 (s), 84.7 (d), 83.9 (s), 79.9 (d), 78.4 (d),
70.4 (d), 62.0 (t), 41.4 (s), 40.8 (d), 39.7 (t), 32.8 (s), 29.7
(q), 23.4 (t), 23.0 (t), 20.3 (q), 18.5 (q), 14.8 (q). HRMS
(FAB) Calcd for C22H29O10 (MHϩ) 453.1759, found
453.1754. (ءexchangeable by D2O).
1:2, 9:10 Cyclic carbonate-2,9,10-trideacetyl-4,20,20,30-
tetrahydro-4a,20,20,30-tetrahydroxy-5-O-cinnamoyl-
taxicin-I (9). To a solution of 8 (45 mg, 0.082 mmol) in
THF–H2O (v/v 2:1, 3 ml) was added N-methylmorpholine
N-oxide (15 mg, 0.113 mmol) and a solution of OsO4 (2.5%
in t-BuOH, 0.14 ml). After stirring for 20 h at rt, florisil
(20 mg), water (0.7 ml) and Na2O4S2 (6 mg) were added.
The resulting mixture was stirred for an additional 10 min
and filtered. The filtrate was treated with saturated
aqueous NH4Cl (5 ml) and extracted with EtOAc. The
organic layers were washed with brine, dried over
MgSO4, and evaporated under reduced pressure to
give 43 mg (85%) of 9 as a colorless oil which was
allowed to be used for next step without further purifi-
1:2 Cyclic carbonate-2,9,10-trideacetyl-10-O-methoxy-
carbonate-4,20-dihydro-4a,20-dihydroxytaxicin-I (12).
1
A colorless oil. [a]D23ˆϩ225Њ (cˆ0.4, CHCl3). H NMR
(600 MHz) d: 5.73 (d, 1H, Jˆ9.6 Hz), 4.69 (d, 1H,
Jˆ4.8 Hz), 4.04 (d, 1H, Jˆ10.5 Hz), 4.03 (dd, 1H, Jˆ9.6,
3.4 Hz), 3.99 (d, 1H, Jˆ19.2 Hz), 3.92 (brs, 1H, OHء), 3.83
(s, 3H), 3.63 (t, 1H, Jˆ3.0 Hz), 3.54 (d, 1H, Jˆ10.5 Hz),
3.09 (s, 1H, OHء), 2.90 (d, 1H, Jˆ4.8 Hz), 2.81 (d, 1H,
Jˆ19.2 Hz), 2.68 (d, 1H, Jˆ3.4 Hz, OHء), 2.58 (brs, 1H,
OHء), 2.22 (s, 3H), 1.90 (m, 1H), 1.72 (m, 1H), 1.65 (m,
1H), 1.54 (s, 3H), 1.50 (dd, 1H, Jˆ13.8, 4.2 Hz), 1.33 (s,
3H), 1.11 (s, 3H). 13C NMR (150 MHz) d: 197.8 (s), 156.6
(s), 154.8 (s), 148.8 (s), 143.4 (s), 89.1 (s), 82.9 (s), 80.3 (d),
79.6 (d), 75.7 (d), 70.7 (d), 62.5 (t), 55.4 (q), 43.7 (s), 41.6
(d), 41.4 (t), 41.0 (s), 32.3 (q), 23.7 (t), 23.2 (t), 20.3 (q),
19.2 (q), 13.9 (q). HRMS (FAB) Calcd for C23H32O11Na
(MϩNa)ϩ 507.1840, found 507.1829. (ءexchangeable by
D2O).
1
cation. H NMR (500 MHz) d: 7.42–7.27 (m, 5H), 5.57 (d,
1H, Jˆ11.5 Hz), 5.27 (t, 1H, Jˆ3.0 Hz), 5.05 (d, 1H, Jˆ
3.0 Hz), 4.78 (d, 1H, Jˆ11.5 Hz), 4.74 (d, 1H, Jˆ4.8 Hz),
4.39 (d, 1H, Jˆ3.0 Hz), 4.05 (d, 1H, Jˆ10.8 Hz), 3.91 (brs,
1H, OHء), 3.85 (d, 1H, Jˆ19.2 Hz), 3.56 (d, 1H, Jˆ
10.8 Hz), 3.11 (brs, 1H, OHء), 2.88 (d, 1H, Jˆ19.2 Hz),
2.78 (d, 1H, Jˆ4.8 Hz), 2.73 and 2.69 (brs, 2H, 2OHء),
2.17 (s, 3H), 1.99 (m, 1H), 1.80 (m, 1H), 1.74 (m, 1H),
1.63 (s, 3H), 1.54 (m, 1H), 1.46 (s, 3H), 1.20 (s, 3H). 13C

Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
1673
Hydrolysis of 8 to 14, 15 and 16
HRMS (FAB) Calcd for C30H35O8 (MHϩ) 523.2330, found
523.2326. (ءexchangeable by D2O).
To a solution of 8 (28 mg, 0.051 mmol) in CH3OH (1 ml)
was added a solution of K2CO3 (69 mg, 0.5 mmol) in
CH3OH (1 ml). The reaction mixture was stirred for 12 h
at 0ЊC and extracted with CH2Cl2. The organic layer was
washed with brine, dried over MgSO4, and evaporated under
reduced pressure. The residue was chromatographed by
preparative TLC (ethyl acetate:hexaneˆ1:1 v/v) to give
12 mg (40%) of 14, 3 mg (10%) of 15, and 6 mg (23%) of
16 as white amorphous solids.
5-Hydroxytriacetyltaxicin-I (17). To a solution of 5-cinna-
moyltriacetyltaxicin-I (2.5 g, 4.0 mmol) and hydroxylamine
hydrochloride (2.5 g, 36 mmol) in EtOH (250 ml), NaOAc
(5.0 g, 61 mmol) in H2O (250 ml) was added and the reac-
tion mixture was heated at 80ЊC for 24 h. The reaction
mixture was cooled to rt, diluted with H2O, and extracted
with CHCl3. The combined organic phase was dried over
MgSO4. After removal of the solvent, the resulting
product was purified by column on silica gel (ethyl
acetate: hexaneˆ1:1 v/v) to give 1.42 g (70%) of 17
which proved to be identical to the previously described
compound.30
1:2 Cyclic carbonate-2,9,10-trideacetyl-10-O-methoxy-
carbonate-5-O-cinnamoyltaxicin-I (14). 1H NMR
(600 MHz) d: 7.74 (m, 2H), 7.66 (d, 1H, Jˆ16.0 Hz),
7.45 (m, 3H), 6.31 (d, 1H, Jˆ16.0 Hz), 5.75 (d, 1H,
Jˆ9.0 Hz), 5.53 (d, 1H, Jˆ1.2 Hz), 5.37 (s, 1H), 5.36 (t,
1H, Jˆ3.0 Hz), 4.81 (d, 1H, Jˆ5.4 Hz), 4.16 (dd, 1H,
Jˆ9.0, 3.6 Hz), 3.84 (s, 3H), 3.36 (brd, 1H), 2.96 (high, s,
2H), 2.69 (d, 1H, Jˆ3.6 Hz, OH), 2.32 (s, 3H), 2.02 (m, 1H),
1.96 (m, 1H), 1.80 (m, 1H), 1.57 (s, 3H), 1.48 (dd, 1H,
Jˆ13.8, 4.8 Hz), 1.35 (s, 3H), 1.21 (s, 3H). 13C NMR
(125 MHz) d: 196.4 (s), 166.0 (s), 154.9 (s), 152.5 (s),
150.4 (s), 146.0 (d), 142.1 (s), 139.8 (s), 134.2 (s), 130.4
(d), 128.9 (d), 128.4 (d), 118.3 (t), 117.3 (d), 88.7 (s), 79.8
(d), 79.4 (d), 77.4 (d), 76.0 (d), 55.4 (q), 44.9 (s), 43.1 (d),
41.1 (t), 40.9 (s), 32.5 (q), 27.7 (t), 25.9 (t), 20.2 (q), 17.7
(q), 14.4 (q). HRMS (FAB) Calcd for C32H37O10 (MHϩ)
581.2384, found 581.2376.
5-O-Triethylsilyltriacetyltaxicin-I (18). To a solution of
17 (1.23 g, 2.5 mmol) in pyridine (5 ml) at 0ЊC was added
chlorotriethylsilane (4.2 ml, 25 mmol). The reaction
mixture was stirred for 40 min at rt, and saturated aqueous
NaHCO3 was added at 0ЊC. The mixture was extracted with
EtOAc. The organic layer was washed with saturated
aqueous CuSO4, water, brine, and dried over MgSO4.
After evaporation of the solvent under reduced pressure,
the crude product was purified by chromatography on silica
gel (ethyl acetate:hexaneˆ1:2 v/v) to give 1.23 g (81%) of
18 as a white amorphous solid. 1H NMR (500 MHz) d: 6.16
(d, 1H, Jˆ10.5 Hz), 5.89 (d, 1H, Jˆ10.5 Hz), 5.62 (d, 1H,
Jˆ6.5 Hz), 5.21 (s, 1H), 4.78 (s, 1H), 4.20 (t, 1H,
Jˆ3.0 Hz), 3.68 (d, 1H, Jˆ6.5 Hz), 2.84 (d, 1H,
Jˆ19.8 Hz), 2.62 (d, 1H, Jˆ19.8 Hz), 2.24 (s, 3H), 2.13
(s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 1.84 (m, 1H), 1.76 (m,
1H), 1.69 (s, 3H), 1.65–1.58 (m, 2H), 1.23 (s, 3H), 0.93 (s,
3H), 0.90 (m, 9H), 0.50–0.65 (m, 6H). HRMS (FAB) Calcd
for C32H50O9SiNa (MϩNa)ϩ 629.3119, found 629.3117.
1:2 Cyclic carbonate-2,9,10-trideacetyl-9-O-methoxy-
carbonate-5-O-cinnamoyltaxicin-I (15). 1H NMR
(600 MHz) d: 7.73 (m, 2H), 7.65 (d, 1H, Jˆ16.0 Hz),
7.42 (m, 3H), 6.30 (d, 1H, Jˆ16.0 Hz), 5.56 (d, 1H,
Jˆ1.2 Hz), 5.39 (s, 1H), 5.38 (d, 1H, Jˆ9.0 Hz), 5.34 (t,
1H, Jˆ3.0 Hz), 5.13 (dd, 1H, Jˆ9.0, 4.2 Hz), 4.92 (d, 1H,
Jˆ6.0 Hz), 3.88 (s, 3H), 3.37 (brd, 1H), 2.98 (d, 1H,
Jˆ19.2 Hz), 2.95 (d, 1H, Jˆ19.2 Hz), 2.49 (d, 1H,
Jˆ4.2 Hz, OH), 2.15 (s, 3H), 2.02 (m, 1H), 1.96 (m, 1H),
1.80 (m, 1H), 1.76 (s, 3H), 1.46 (dd, 1H, Jˆ13.8, 4.8 Hz),
1.43 (s, 3H), 1.09 (s, 3H). 13C NMR (125 MHz) d: 196.7
(s), 165.9 (s), 156.1 (s), 153.7 (s), 152.4 (s), 146.1 (d), 139.7
(s), 139.4 (s), 134.3 (s), 130.5 (d), 129.0 (d), 128.4 (d),
118.8 (t), 117.2 (d), 88.9 (s), 83.2 (d), 79.2 (d), 77.2 (d),
71.6 (d), 55.6 (q), 44.7 (s), 43.2 (d), 41.2 (t), 41.0 (s), 32.9
(q), 27.4 (t), 26.9 (t), 19.9 (q), 17.3 (q), 14.5 (q). HRMS
(FAB) Calcd for C32H37O10 (MHϩ) 581.2384, found
581.2380.
2,9,10-Detriacetyl-5-O-triethylsilyltaxicin-I (19). Follow-
ing the procedure for preparation of 6, using 18 (1.212 g,
2.0 mmol) gave 778 mg (81%) of 19 as white amorphous
solid after chromatography on silica gel (ethyl acetate:
1
hexaneˆ2:1 v/v). H NMR (500 MHz) d: 5.19 (s, 1H),
4.93 (d, 1H, Jˆ9.0 Hz), 4.77 (s, 1H), 4.18 (t, 1H,
Jˆ3.0 Hz), 4.16 (d, 1H, Jˆ9.0 Hz), 4.05 (d, 1H,
Jˆ6.5 Hz), 3.52 (s, 1H, OHء), 3.36 (d, 1H, Jˆ6.5 Hz),
2.69 (high, s, 2H), 2.47 (brs, 2H, 2OHء), 2.18 (s, 3H),
2.00–1.95 (m, 2H), 1.80–1.73 (m, 2H), 1.62 (s, 3H), 1.37
(s, 3H), 1.17 (s, 3H), 0.89–0.92 (m, 9H), 0.53–0.70 (m, 6H).
(ءexchangeable by D2O).
1:2, 9:10 Cyclic carbonate-2,9,10-trideacetyl-5-O-
triethylsilyltaxicin-I (20). Following the procedure for
preparation of 8, using 19 (720 mg, 1.5 mmol), triphosgene
(2.22 g, 7.5 mmol) in CH2Cl2–pyridine (v/v 2:1) gave
702 mg (88%) of 20 as white amorphous solid after
chromatography on silica gel (ethyl acetate:hexaneˆ1:1
1:2 Cyclic carbonate-2,9,10-trideacetyl-5-O-cinnamoyl-
taxicin-I (16). H NMR (600 MHz) d: 7.73 (m, 2H), 7.65
1
(d, 1H, Jˆ16.0 Hz), 7.44 (m, 3H), 6.32 (d, 1H, Jˆ16.0 Hz),
5.52 (d, 1H, Jˆ1.2 Hz), 5.35 (s, 1H), 5.34 (t, 1H, Jˆ3.0 Hz),
4.93 (d, 1H, Jˆ9.0 Hz), 4.85 (d, 1H, Jˆ5.4 Hz), 4.02 (d, 1H,
Jˆ9.0 Hz), 3.36 (brd, 1H), 2.95 (high s, 2H), 2.94 (s, 1H,
OHء), 2.92 (s, 1H, OHء), 2.15 (s, 3H), 2.00 (m, 1H), 1.88 (m,
1H), 1.79 (dddd, 1H, Jˆ13.8, 11.4, 4.8, 3.0 Hz), 1.65 (s,
3H), 1.44 (dd, 1H, Jˆ13.8, 4.8 Hz), 1.41 (s, 3H), 1.19 (s,
3H). 13C NMR (125 MHz) d: 196.9 (s), 166.0 (s), 154.9 (s),
152.8 (s), 145.9 (d), 140.0 (s), 139.6 (s), 134.3 (s), 130.5 (d),
128.9 (d), 128.4 (d), 118.1 (t), 117.4 (d), 89.1 (s), 79.3 (d),
78.2 (d), 77.5 (d), 73.3 (d), 44.5 (s), 43.1 (d), 41.2 (t), 41.1
(s), 32.8 (q), 27.7 (t), 26.0 (t), 20.2 (q), 17.7 (q), 14.2 (q).
1
v/v). H NMR (600 MHz) d: 5.60 (d, 1H, Jˆ11.0 Hz),
5.24 (s, 1H), 4.87 (d, 1H, Jˆ11.0 Hz), 4.80 (s, 1H), 4.83
(d, 1H, Jˆ6.0 Hz), 4.16 (t, 1H, Jˆ3.0 Hz), 3.07 (d, 1H,
Jˆ6.0 Hz), 3.00 (d, 1H, Jˆ19.5 Hz), 2.96 (d, 1H,
Jˆ19.5 Hz), 2.19 (s, 3H), 2.02 (m, 1H), 1.87 (dddd, 1H,
Jˆ13.6, 11.5, 5.0, 3.0 Hz), 1.75 (ddd, 1H, Jˆ13.6, 5.0,
2.4 Hz), 1.66 (s, 3H), 1.56 (dd, 1H, Jˆ13.6, 5.0 Hz), 1.49
(s, 3H), 1.21 (s, 3H), 0.89–0.91 (m, 9H), 0.50–0.70 (m, 6H).

1674
Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
13C NMR (125 MHz) d: 196.5 (s), 154.7 (s), 152.8 (s), 150.2
(s), 145.8 (s), 139.6 (s), 116.7 (t), 89.0 (s), 84.9 (d), 79.1 (d),
78.3 (d), 74.5 (d), 43.7 (d), 42.7 (t), 42.5 (s), 38.9 (s), 32.4
(q), 27.4 (t), 26.5 (t), 20.1 (q), 17.2 (q), 14.7 (q), 6.9 (q) and
4.7 (t). HRMS (FAB) Calcd for C28H40O8SiNa (MϩNa)ϩ
555.2388, found 555.2381.
1:2, 9:10 Cyclic carbonate-2,9,10-trideacetyl-4,20-di-
hydro-4a,20-dihydroxy-5-O-mesyl-20-O-tertbutyl-
dimethylsilyltaxicin-I (22). To a solution of the above
silylated compound 21 (402 mg, 0.71 mmol) in pyridine
(5 ml) at 0ЊC was added MsCl (0.36 ml). The reaction
mixture was stirred for 20 h at rt, and CH2Cl2 (50 ml) was
added. The resulting solution was washed with a solution of
10% citric acid in water (25 ml), saturated aqueous
NaHCO3, and dried over MgSO4. After removal of the
solvent under reduced pressure, the residue was chromato-
graphed on silica gel (ethyl acetate:hexaneˆ1:2 v/v) to give
1:2, 9:10 Cyclic carbonate-2,9,10-trideacetyl-5-hydroxy-
taxicin-I (13). To a solution of 20 (532 mg, 1.0 mmol) in
THF (5 ml) was added a solution of tetrabutylammonium
fluoride (1.0 M in THF, 2 ml). The reaction mixture was
stirred for 1 h at rt. EtOAc (50 ml) was added and the
organic layers were washed with saturated aqueous
NaHCO3, and dried over MgSO4. After evaporation of
the solvent under reduced pressure, the residue was purified
by chromatography on silica gel (ethyl acetate:hexaneˆ1:1
v/v) to give 418 mg of 13 in quantitative yield as a white
amorphous solid. [a]D23ˆϩ236Њ (cˆ0.05, CHCl3). 1H NMR
(500 MHz) d: 5.61 (d, 1H, Jˆ11.4 Hz), 5.17 (s, 1H), 4.89
(d, 1H, Jˆ11.4 Hz), 4.84 (d, 1H, Jˆ5.5 Hz), 4.65 (s, 1H),
4.09 (brt, 1H), 3.35 (d, 1H, Jˆ5.5 Hz), 2.98 (d, 1H,
Jˆ19.5 Hz), 2.94 (d, 1H, Jˆ19.5 Hz), 2.18 (s, 3H), 1.94
(m, 1H), 1.75 (m, 1H), 1.66 (m, 1H), 1.64 (s, 3H), 1.55
(m, 1H), 1.47 (s, 3H), 1.16 (s, 3H). 13C NMR (125 MHz)
d: 196.8 (s), 154.4 (s), 152.6 (s), 149.6 (s), 146.8 (s), 140.2
(s), 116.4 (t), 89.1 (s), 84.6 (d), 78.9 (d), 78.4 (d), 76.5 (d),
43.2 (s), 42.8 (d), 42.6 (t), 39.4 (s), 33.2 (q), 27.9 (t), 26.3 (t),
19.8 (q), 17.0 (q), 14.5 (q). HRMS (FAB) Calcd for
C22H27O8 (MHϩ) 419.1704, found 419.1699.
1
361 mg (83%) of 22 as a white solid. mp: 87–89ЊC. H
NMR (500 MHz) d: 5.56 (d, 1H, Jˆ11.5 Hz), 4.86 (brs,
1H), 4.79 (d, 1H, Jˆ11.5 Hz), 4.70 (d, 1H, Jˆ5.0 Hz),
4.15 (d, 1H, Jˆ10.5 Hz), 3.77 (d, 1H, Jˆ19.2 Hz), 3.54
(d, 1H, Jˆ10.5 Hz), 3.42 (s, 1H, OH), 2.97 (s, 3H), 2.82
(d, 1H, Jˆ19.2 Hz), 2.66 (d, 1H, Jˆ5.0 Hz), 2.13 (s, 3H),
1.99 (m, 1H), 1.80 (m, 1H), 1.74 (m, 1H), 1.66 (s, 3H), 1.57
(m, 1H), 1.44 (s, 3H), 1.13 (s, 3H), 0.85 (s, 9H), 0.05 (s, 3H),
0.03 (s, 3H). 13C NMR (125 MHz) d: 197.4 (s), 154.3 (s),
152.6 (s), 151.5 (s), 140.7 (s), 88.7 (s), 84.2 (d), 80.5 (s),
79.8 (d), 79.2 (d), 75.4 (d), 64.1 (t), 44.5 (s), 43.4 (d), 42.1
(t), 40.4 (s), 39.0 (q), 33.9 (q), 27.0 (t), 26.4 (t), 25.7 (q),
25.7 (q), 25.6 (q), 20.2 (q), 18.7 (q), 18.6 (s), 14.3 (q), Ϫ3.1
(q), Ϫ3.2 (q). HRMS (FAB) Calcd for C29H44O12SiNa
(MϩNa)ϩ 635.2497, found 635.2493.
1:2, 9:10 Cyclic carbonate-2,4,9,10,13-pentadeacetyl-7-
deacetoxy-13-oxo baccatine IV (23). To a solution of 22
(337 mg, 0.55 mmol) in THF (5 ml) was added a solution of
tetrabutylammonium fluoride (1.0 M in THF, 2 ml). The
reaction mixture was stirred for 1 h at rt. EtOAc (50 ml)
was added and the organic layers were washed with satu-
rated aqueous NaHCO3, and dried over MgSO4. After
evaporation of the solvent under reduced pressure, the
residue was dissolved in butanone (8 ml) and tetrabutyl-
ammonium acetate (1.46 g, 4.86 mmol) was added. The
mixture was refluxed for 20 h and diluted with EtOAc
(35 ml). The resulting solution was washed with saturated
aqueous NH4Cl, dried over MgSO4, and evaporated under
reduced pressure. The residue was chromatographed on
silica gel (ethyl acetate:hexaneˆ1:2 v/v) to give 181 mg
(76%) of 23 as a white amorphous solid. [a]2D5ˆϩ191Њ
(cˆ0.1, CHCl3). 1H NMR (600 MHz) d: 5.54 (d, 1H,
Jˆ11.4 Hz), 4.82 (dd, 1H, Jˆ9.4, 2.5 Hz), 4.80 (d, 1H,
Jˆ11.4 Hz), 4.74 (d, 1H, Jˆ4.8 Hz), 4.57 (dd, 1H, Jˆ8.4,
1.2 Hz), 4.32 (d, 1H, Jˆ8.4 Hz), 3.01 (d, 1H, Jˆ19.0 Hz),
2.75 (d, 1H, Jˆ19.0 Hz), 2.57 (dd, 1H, Jˆ4.8, 1.2 Hz), 2.53
(s, 1H, OH-4), 2.07 (m, 1H), 1.94 (s, 3H), 1.90 (dddd, 1H,
Jˆ13.8, 11.5, 5.0, 2.5 Hz), 1.78 (m, 1H), 1.67 (s, 3H), 1.58
(dd, Jˆ13.8, 5.0 Hz), 1.38 (s, 3H), 1.23 (s, 3H). 13C NMR
(125 MHz) d: 198.6 (s), 154.7 (s), 153.2 (s), 151.8 (s), 141.7
(s), 87.8 (s), 86.4 (d), 83.8 (d), 80.6 (t), 79.8 (d), 79.2 (d),
75.7 (s), 45.6 (d), 44.2 (s), 42.7 (t), 39.2 (s), 32.4 (q), 27.2
(t), 26.5 (t), 19.9 (q), 17.3 (q), 14.2 (q). HRMS (EI) Calcd
for C22H26O9 (Mϩ) 434.1575, found 434.1566.
Osmylation of 13 to 11
Following the procedure for preparation of 9, using 13
(397 mg, 0.95 mmol), NMO (174 mg, 1.3 mmol), OsO4
(2.5% in t-BuOH, 1.62 ml), florisil (231 mg), water
(1.5 ml), and Na2O4S2 (70 mg) gave 356 mg (83%) of 11
after chromatography on silica gel (ethyl acetate:
hexaneˆ2:1 v/v) which proved to be identical to the
previously described compound.
Silylation and mesylation of 11 to 22 via 21
1:2, 9:10 Cyclic carbonate-2,9,10-trideacety1-4,20-di-
hydro-4a,20-dihydroxy-20-O-tertbutyldimethylsilyltax-
icin-I (21). A solution of imidazole (735 mg, 10.8 mmol)
and tert-butyldimethylsilyl chloride (678 mg, 4.5 mmol) in
dry DMF (5 ml) was stirred for 15 min at rt. The triol 11
(339 mg, 0.75 mmol) was subsequently added and stirred
for an additional 3 h. The reaction mixture was diluted
with a solution of 10% citric acid in water (30 ml) and
extracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, and evaporated under reduced
pressure. The residue was purified by chromatography on
silica gel (ethyl acetate:hexaneˆ1:2 v/v) to give 403 mg
1
(95%) of 21 as a colorless oil. H NMR (500 MHz) d:
5.51 (d, 1H, Jˆ11.4 Hz), 4.81 (d, 1H, Jˆ11.4 Hz), 4.68
(d, 1H, Jˆ4.8 Hz), 4.17 (d, 1H, Jˆ10.5 Hz), 3.92 (d, 1H,
Jˆ19.2 Hz), 3.64 (t, 1H, Jˆ3.0 Hz), 3.58 (s, 1H, OH), 3.56
(d, 1H, Jˆ10.5 Hz), 2.87 (d, 1H, Jˆ19.2 Hz), 2.71 (s, 1H,
OH), 2.62 (d, 1H, Jˆ4.8 Hz), 2.15 (s, 3H), 1.95 (m, 1H),
1.74 (m, 1H), 1.65 (m, 1H), 1.60 (s, 3H), 1.54 (m, 1H), 1.43
(s, 3H), 1.12 (s, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
1:2, 9:10 Cyclic carbonate-2,9,10,13-tetradeacetyl-7-
deacetoxy-13-oxo baccatine IV (24). A solution of 23
(175 mg, 0.4 mmol) and 4-(dimethylamino)pyridine
(DMAP, 729 mg, 6.0 mmol) in CH2Cl2 (5 ml) was treated
with acetic anhydride (0.3 ml, 3.2 mmol), and stirred at rt
for 5 h. The reaction mixture was diluted with EtOAc

Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
1675
(30 ml), washed with 1N aqueous HCl and saturated
aqueous NaHCO3, dried over MgSO4, and evaporated
under reduced pressure. The residue was purified by chro-
matography on silica gel (ethyl acetate:hexaneˆ1:3 v/v) to
give 177 mg (93%) of 24 as a white amorphous solid.
[a]2D5ˆϩ203Њ (cˆ0.4, CHCl3). 1H NMR (500 MHz) d:
5.51 (d, 1H, Jˆ11.4 Hz), 4.94 (dd, 1H, Jˆ9.4, 2.5 Hz),
4.81 (d, 1H, Jˆ11.4 Hz), 4.72 (d, 1H, Jˆ5.0 Hz), 4.34
(brd, 1H), 4.21 (d, 1H, Jˆ8.4 Hz), 2.76 (d, 1H,
Jˆ19.2 Hz), 2.68 (d, 1H, Jˆ19.2 Hz), 2.54 (brd, 1H), 2.29
(m, 1H), 2.25 (s, 3H), 1.96 (s, 3H), 1.95 (dddd, 1H, Jˆ13.8,
11.5, 5.2, 2.5 Hz), 1.79 (ddd, 1H, Jˆ13.8, 11.5, 5.2 Hz),
1.68 (s, 3H), 1.56 (dd, Jˆ13.8, 5.2 Hz), 1.39 (s, 3H), 1.24
(s, 3H). 13C NMR (125 MHz) d: 196.9 (s), 170.5 (s), 154.4
(s), 152.9 (s), 151.2 (s), 140.6 (s), 88.6 (s), 86.6 (d), 83.5 (d),
81.2 (s), 79.6 (d), 78.9 (d), 76.8 (t), 42.9 (s), 42.7 (t), 41.7
(d), 39.5 (s), 33.4 (q), 27.4 (t), 26.6 (t), 22.8 (q), 20.1 (q),
16.8 (q), 14.5 (q). HRMS (FAB) Calcd for C24H29O10
(MHϩ) 477.1759, found 477.1752.
1H, Jˆ4.0 Hz, OH), 2.27 (m, 1H), 2.23 (s, 3H), 2.17 (s, 3H),
1.98 (ddd, 1H, Jˆ13.6, 11.5, 5.2 Hz), 1.84 (ddd, 1H,
Jˆ13.6, 11.5, 5.2 Hz), 1.67 (s, 3H), 1.61 (dd, 1H, Jˆ13.6,
5.2 Hz), 1.39 (s, 3H), 1.21 (s, 3H). 13C NMR (125 MHz) d:
196.9 (s), 170.5 (s), 169.2 (s), 166.3 (s), 150.7 (s), 139.6 (s),
133.9 (d), 133.6 (d), 130.1 (d), 130.1 (d), 129.2 (s), 129.0
(s), 128.8 (d), 128.7 (d), 86.7 (d), 81.6 (s), 81.1 (s), 79.8 (d),
76.9 (t), 75.3 (d), 71.4 (d), 44.5 (s), 41.9 (d), 41.2 (t), 40.2
(s), 31.4 (q), 27.3 (t), 26.7 (t), 22.8 (q), 20.4 (q), 17.5 (q),
14.4 (q). HRMS (FAB) Calcd for C36H41O10 (MHϩ)
633.2697, found 633.2691.
Coupling of 25 with cAMP-Cl 27 to 28
A
solution of cAMP-Cl 27 (51 mg, 0.152 mmol),
4-(dimethylamino)pyridine (DMAP, 83 mg, 0.456 mmol),
and 25 (48 mg, 0.076 mmol) in DMF (3 ml) was stirred
for 6 h at rt. A solution of saturated aqueous NaHCO3 was
added, and the resulting mixture was extracted with EtOAc.
The organic layer was washed with brine, dried over
MgSO4, and evaporated under reduced pressure. The resi-
due was chromatographed by preparative TLC (methanol:
chloroformˆ1:1 v/v) to give 60 mg (84%) of 28 as a white
solid. mp: 296–298Њ (dec.). [a]2D5ˆϩ7.8Њ (cˆ0.7, CH3OH).
1H NMR (500 MHz, CD3ODϩD2O) d: 8.21 (s, 1H), 8.14 (s,
1H), 8.13 (d, 2H, Jˆ7.6 Hz), 8.09 (d, 2H, Jˆ7.5 Hz), 7.61
(t, 1H, Jˆ7.5 Hz), 7.59 (t, 1H, Jˆ 7.6 Hz), 7.49 (m, 2H),
7.47 (m, 2H), 6.54 (d, 1H, Jˆ 9.8 Hz), 6.11 (d, 1H,
Jˆ9.8 Hz), 6.09 (d, 1H, Jˆ0.9 Hz), 5.62 (d, 1H,
Jˆ6.5 Hz), 4.95 (d, 1H, Jˆ9.0 Hz), 4.75 (dd, 1H, Jˆ8.9,
5.2 Hz), 4.71 (dd, 1H, Jˆ5.2, 0.9 Hz), 4.60 (dd, 1H, Jˆ9.7,
4.8 Hz), 4.39 (dd, 1H, Jˆ10.7, 9.7 Hz), 4.37 (ddd, 1H,
Jˆ10.7, 8.9, 4.8 Hz), 4.34 (d, 1H, Jˆ8.1 Hz), 4.17 (d, 1H,
Jˆ8.1 Hz), 3.76 (d, 1H, Jˆ6.5 Hz), 2.89 (d, 1H,
Jˆ19.4 Hz), 2.70 (d, 1H, Jˆ19.4 Hz), 2.24 (s, 3H), 2.23
(m, 1H), 2.15 (s, 3H), 1.98 (m, 1H), 1.83 (ddd, 1H,
Jˆ13.8, 11.5, 5.2 Hz), 1.72 (s, 3H), 1.59 (m, 1H), 1.51 (s,
3H), 1.37 (s, 3H). 13C NMR (125 MHz) d: 197.4 (s), 170.4
(s), 167.8 (s), 167.2 (s), 156.2 (s), 153.8 (d), 150.3 (s), 149.1
(s), 140.8 (d), 140.3 (s), 133.6 (d), 133.4 (d), 130.2 (d),
130.0 (d), 129.2 (s), 129.1 (s), 128.7 (d), 128.6 (d), 119.5
(s), 92.7 (d), 86.3 (d), 82.1 (s), 81.4 (s), 78.6 (d), 78.5 (d),
77.5 (d), 77.0 (t), 75.1 (d), 73.5 (d), 72.9 (d), 68.5 (t), 44.2
(s), 41.9 (d), 41.7 (t), 40.1 (s), 33.2 (q), 27.6 (t), 26.9 (t), 22.7
(q), 19.8 (q), 17.4 (q), 14.3 (q). HRMS (FAB) Calcd for
C46H50O15N5PNa (MϩNa)ϩ 966.2935, found 966.2927.
Preparation of 25 and 26 from 24
A solution of 24 (167 mg, 0.35 mmol) in THF (10 ml) at
Ϫ78ЊC under nitrogen was treated with PhLi (1.8 M in
cyclohexane–ether, v/v 7:3, 1.94 ml, 3.5 mmol) and stirred
at Ϫ78ЊC for 20 min. The reaction was quenched with satu-
rated aqueous NH4Cl (1.5 ml), and the resulting mixture
was allowed to warm to rt. After dilution with EtOAc, the
organic was separated, dried over MgSO4, and evaporated
under reduced pressure. The residue was chromatographed
twice by preparative TLC (ethyl acetate:hexaneˆ1:1 v/v) to
give 142 mg (64%) of 25 and 33 mg (15%) of 26 as white
solids.
9-Hydroxy-2,10-dibenzoyl-2,9,10,13-tetradeacetyl-7-
deacetoxy-13-oxo baccatine IV (25). mp: 144–146ЊC.
[a]2D5ˆϩ127Њ (cˆ0.2, CHCl3). 1H NMR (500 MHz) d:
8.12 (d, 2H, Jˆ7.6 Hz), 8.10 (d, 2H, Jˆ7.6 Hz), 7.60 (t,
1H, Jˆ7.6 Hz), 7.59 (t, 1H, Jˆ7.6 Hz), 7.49 (m, 2H), 7.47
(m, 2H), 6.45 (d, 1H, Jˆ9.4 Hz), 5.62 (d, 1H, Jˆ7.0 Hz),
4.97 (d, 1H, Jˆ9.2 Hz), 4.33 (d, 1H, Jˆ8.3 Hz), 4.21 (d, 1H,
Jˆ8.3 Hz), 4.19 (dd, 1H, Jˆ9.4, 3.4 Hz), 3.85 (d, 1H,
Jˆ7.0 Hz), 2.78 (d, 1H, Jˆ19.5 Hz), 2.67 (d, 1H,
Jˆ19.5 Hz), 2.65 (d, 1H, Jˆ3.4, OH Hz), 2.28 (m, 1H),
2.25 (s, 3H), 2.18 (s, 3H), 1.96 (ddd, 1H, Jˆ13.6, 11.5,
5.2 Hz), 1.78 (ddd, 1H, Jˆ13.6, 11.5, 5.2 Hz), 1.69 (s,
3H), 1.57 (dd, 1H, Jˆ13.6, 5.2 Hz), 1.39 (s, 3H), 1.26 (s,
3H). 13C NMR (125 MHz) d: 197.2 (s), 170.5 (s), 168.7 (s),
166.8 (s), 151.6 (s), 140.5 (s), 133.9 (d), 133.7 (d), 130.2 (d),
129.9 (d), 129.1 (s), 129.0 (s), 128.7 (d), 128.7 (d), 86.5 (d),
81.7 (s), 81.4 (s), 77.5 (d), 76.7 (t), 76.1 (d), 75.0 (d), 43.0
(s), 41.8 (d), 41.3 (t), 40.1 (s), 33.2 (q), 27.5 (t), 26.8 (t), 22.6
(q), 20.6 (q), 17.2 (q), 14.3 (q). HRMS (FAB) Calcd for
C36H41O10 (MHϩ) 633.2697, found 633.2689.
Silylation of 28 to 29
A solution of imidazole (62 mg, 0.9 mmol), chlorotriethyl-
silane (0.1 ml, 0.6 mmol), and DMAP (11 mg, 0.06 mmol)
in dry DMF (2.5 ml) was stirred for 10 min at rt. The
compound 28 (57 mg, 0.06 mmol) was subsequently
added and stirred for an additional 4 h. The reaction mixture
was neutralized (about pHˆ6–7) with a solution of 10%
citric acid in water and extracted with EtOAc. The organic
layer was washed with saturated aqueous NaHCO3, brine,
dried over MgSO4, and evaporated under reduced pressure.
The residue was purified by chromatographed by prepara-
tive TLC (methanol:chloroformˆ1:1 v/v) to give 56 mg
(89%) of 29 as a white solid. mp: Ͼ300ЊC (dec.).
[a]2D5ˆϩ15.3Њ (cˆ0.08, CH3OH). 1H NMR (500 MHz,
CD3ODϩD2O) d: 8.20 (s, 1H), 8.14 (s, 1H), 8.13 (d, 2H,
10-Hydroxy-2,9-dibenzoyl-2,9,10,13-tetradeacetyl-7-
deacetoxy-13-oxo baccatine IV (26). mp: 137–139ЊC.
[a]2D5ˆϩ97Њ (cˆ0.08, CHCl3). 1H NMR (500 MHz) d:
8.10 (m, 4H), 7.60 (m, 2H), 7.49–7.47 (m, 4H), 6.37 (d,
1H, Jˆ9.1 Hz), 5.63 (d, 1H, Jˆ6.8 Hz), 5.12 (dd, 1H,
Jˆ9.1, 4.0 Hz), 4.99 (d, 1H, Jˆ9.2 Hz), 4.34 (d, 1H, Jˆ
8.4 Hz), 4.23 (d, 1H, Jˆ8.4 Hz), 3.78 (d, 1H, Jˆ6.8 Hz),
2.98 (d, 1H, Jˆ19.5 Hz), 2.89 (d, 1H, Jˆ19.5 Hz), 2.50 (d,

1676
Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
Jˆ7.6 Hz), 8.09 (d, 2H, Jˆ7.6 Hz), 7.60–7.59 (m, 2H), 7.49
(m, 2H), 7.47 (m, 2H), 6.54 (d, 1H, Jˆ9.8 Hz), 6.10 (d, 1H,
Jˆ0.9 Hz), 6.09 (d, 1H, Jˆ9.8 Hz), 5.63 (d, 1H, Jˆ6.6 Hz),
4.96 (d, 1H, Jˆ9.0 Hz), 4.77 (dd, 1H, Jˆ9.0, 5.2 Hz), 4.73
(dd, 1H, Jˆ5.2, 0.9 Hz), 4.60 (dd, 1H, Jˆ9.7, 4.8 Hz), 4.39
(dd, 1H, Jˆ10.5, 9.7 Hz), 4.37 (ddd, 1H, Jˆ10.5, 9.0,
4.8 Hz), 4.34 (d, 1H, Jˆ8.1 Hz), 4.18 (d, 1H, Jˆ8.1 Hz),
3.74 (d, 1H, Jˆ6.6 Hz), 2.88 (d, 1H, Jˆ19.4 Hz), 2.69 (d,
1H, Jˆ19.4 Hz), 2.24 (s, 3H), 2.23 (m, 1H), 2.16 (s, 3H),
1.98 (ddd, 1H, Jˆ13.8, 11.5, 5.1 Hz), 1.82 (ddd, 1H,
Jˆ13.8, 11.5, 5.1 Hz), 1.71 (s, 3H), 1.59 (dd, 1H, Jˆ13.8,
5.1 Hz), 1.50 (s, 3H), 1.39 (s, 3H), 0.89–0.92 (m, 9H),
0.53–0.72 (m, 6H). 13C NMR (125 MHz) d: 197.5 (s),
170.3 (s), 167.7 (s), 167.4 (s), 156.3 (s), 153.9 (d), 151.1
(s), 148.9 (s), 140.9 (d), 139.8 (s), 133.7 (d), 133.5 (d), 130.0
(d), 129.9 (d), 129.0 (s), 128.9 (s), 128.7 (d), 128.6 (d),
119.7 (s), 93.2 (d), 88.5 (s), 86.2 (d), 82.5 (s), 78.7 (d),
78.5 (d), 77.6 (d), 76.8 (t), 74.9 (d), 74.8 (d), 73.2 (d),
68.5 (t), 43.9 (s), 42.3 (d), 41.7 (t), 40.5 (s), 32.8 (q), 27.4
(t), 27.0 (t), 22.6 (q), 20.1 (q), 17.6 (q), 14.5 (q), 6.9 (q), 4.6
(t). HRMS (FAB) Calcd for C52H64O15N5PSiNa (MϩNa)ϩ
1080.3799, found 1080.3786.
(37 mg, 0.035 mmol) and DMAP (10 mg, 0.071 mmol) in
toluene (2 ml) was added DCC (43 mg, 0.21 mmol) at rt.
The reaction mixture was stirred at 75ЊC for 1.5 h by slow
evaporation of the solvent. The residue was chromato-
graphed by preparative TLC to give the protected compound
which was further treated with trifluoroacetic acid (1.0 ml)
and water (0.1 ml) at rt. The reaction mixture first was stir-
red at 0ЊC for 20 min and then at rt for an additional 20 min.
EtOAc and saturated aqueous NaHCO3 were added at 0ЊC,
and separated. The organic layer was washed with water,
brine, and dried over MgSO4. After evaporation of the
solvent under reduced pressure, the residue was purified
by preparative TLC (1% NH4OH in methanol:chloro-
formˆ3.2 v/v) to give 31 mg (74%) of 3 as a white solid.
1
mp: Ͼ300ЊC (dec.). [a]2D5ˆϪ45Њ (cˆ0.03, CH3OH). H
NMR (600 MHz, CD3ODϩD2O) d: 8.22 (s, 1H), 8.15 (dd,
2H, Jˆ8.4, 1.3 Hz), 8.14 (s, 1H), 8.13 (d, 2H, Jˆ7.6 Hz),
7.83 (dd, 2H, Jˆ8.4, 1.2 Hz), 7.62 (m, 1H), 7.60 (t, 1H,
Jˆ7.6 Hz), 7.55 (m, 1H), 7.51 (m, 2H), 7.48 (m, 2H),
7.47–7.44 (m, 4H), 7.35 (m, 2H), 7.27 (m, 1H), 6.53 (d,
1H, Jˆ9.8 Hz), 6.13 (t, 1H, Jˆ8.5 Hz), 9.11 (d, 1H, Jˆ
1.0 Hz), 6.09 (d, 1H, Jˆ9.8 Hz), 5.72 (d, 1H, Jˆ5.7 Hz),
5.62 (d, 1H, Jˆ3.0 Hz), 4.95 (d, 1H, Jˆ8.7 Hz), 4.76 (dd,
1H, Jˆ9.0, 5.3 Hz), 4.71 (dd, 1H, Jˆ5.3, 1.0 Hz), 4.59 (dd,
1H, Jˆ9.6, 5.0 Hz), 4.55 (d, 1H, Jˆ3.0 Hz), 4.40 (dd, 1H,
Jˆ10.5, 9.6 Hz), 4.37 (ddd, 1H, Jˆ10.5, 9.0, 5.0 Hz), 4.34
(d, 1H, Jˆ8.5 Hz), 4.17 (d, 1H, Jˆ8.5 Hz), 3.04 (d, 1H,
Jˆ5.7 Hz), 2.36 (dd, 1H, Jˆ15.1, 8.5 Hz), 2.25 (s, 3H),
2.18 (m, 1H), 2.16 (dd, 1H, Jˆ15.1, 8.5 Hz), 1.94 (m,
1H), 1.86 (s, 3H), 1.82 (m, 1H), 1.64 (s, 3H), 1.58 (dd,
1H, Jˆ14.5, 4.8 Hz), 1.31 (s, 3H), 1.12 (s, 3H). 13C NMR
(150 MHz) d: 172.6 (s), 170.4 (s), 167.6 (s), 167.1 (s), 166.9
(s), 156.4 (s), 153.9 (d), 149.3 (s), 142.4 (s), 141.1 (d), 138.3
(s), 133.8 (s), 133.7 (d), 133.6 (s), 133.6 (d), 131.9 (d), 130.1
(d), 130.0 (d), 129.1 (s), 129.1 (s), 129.0 (d), 128.7 (d),
128.7 (d), 128.6 (d), 128.3 (d), 127.1 (d), 127.0 (d), 119.6
(s), 92.8 (d), 86.0 (d), 82.4 (s), 79.2 (s), 78.6 (d), 78.4 (d),
76.7 (d), 76.6 (t), 74.9 (d), 73.7 (d), 73.2 (d), 73.1 (d), 72.5
(d), 68.9 (t), 55.8 (d), 43.8 (s), 43.1 (s), 42.0 (d), 35.8 (t),
27.3 (t), 27.0 (q), 26.8 (t), 22.5 (q), 21.7 (q), 17.6 (q), 14.8
(q). HRMS (FAB) Calcd for C62H65O17N6PNa (MϩNa)ϩ
1219.4037, found 1219.4029.
Reduction of 29 to 30
A solution of 29 (53 mg, 0.05 mmol) in CH3OH (5 ml) was
treated with an excess of NaBH4 (15 mg, 0.4 mmol) for 3 h
at rt. The reaction was quenched with aqueous NH4Cl
(2 ml), and the resulting mixture was stirred for 15 min.
After dilution with water, the reaction mixture was extracted
with CH2Cl2 and dried over MgSO4. After removal of the
solvent under reduced pressure, the crude product was puri-
fied by preparative TLC (methanol:chloroformˆ1:1 v/v) to
give 41 mg (77%) of 30 as a white solid. mp: 276–79ЊC.
[a]2D5ˆϪ27Њ (cˆ0.2, CH3OH). 1H NMR (600 MHz,
CD3ODϩD2O) d: 8.20 (s, 1H), 8.14 (s, 1H), 8.12 (d, 2H,
Jˆ7.6 Hz), 8.09 (d, 2H, Jˆ7.6 Hz), 7.61 (t, 1H, Jˆ7.6 Hz),
7.59 (t, 1H, Jˆ7.6 Hz), 7.49 (m, 2H), 7.47 (m, 2H), 6.51 (d,
1H, Jˆ9.8 Hz), 6.10 (d, 1H, Jˆ0.9 Hz), 6.08 (d, 1H,
Jˆ9.8 Hz), 5.62 (d, 1H, Jˆ5.5 Hz), 4.94 (d, 1H, Jˆ
9.0 Hz), 4.77 (dd, 1H, Jˆ9.0, 5.2 Hz), 4.72 (dd, 1H,
Jˆ5.2, 0.9 Hz), 4.61 (dd, 1H, Jˆ9.7, 4.8 Hz), 4.39 (dd,
1H, Jˆ10.5, 9.7 Hz), 4.37 (ddd, 1H, Jˆ10.5, 9.0, 4.8 Hz),
4.31 (d, 1H, Jˆ8.2 Hz), 4.15 (d, 1H, Jˆ8.2 Hz), 3.83 (m,
1H), 3.73 (d, Jˆ5.5 Hz), 2.32 (dd, 1H, Jˆ15.2, 9.0 Hz), 2.29
(m, 1H), 2.24 (s, 3H), 2.17 (s, 3H), 2.13 (dd, 1H, Jˆ15.2,
8.0 Hz), 2.01 (m, 1H), 1.82 (m, 1H), 1.63 (s, 3H), 1.57 (dd,
1H, Jˆ13.8, 5.2 Hz), 1.44 (s, 3H), 1.09 (s, 3H), 0.88–0.91
(m, 9H), 0.56–0.75 (m, 6H). 13C NMR (125 MHz) d: 170.4
(s), 168.4 (s), 167.6 (s), 156.3 (s), 154.0 (d), 140.8 (d), 140.7
(s), 135.6 (s), 133.6 (d), 133.4 (d), 130.1 (d), 129.8 (d),
129.1 (s), 128.9 (s), 128.7 (d), 128.6 (d), 119.6 (s), 93.3
(d), 85.9 (d), 82.4 (s), 78.7 (s), 78.6 (d), 78.4 (d), 77.1 (d),
76.8 (t), 74.8 (d), 74.6 (d), 73.2 (d), 69.8 (d), 68.7 (t), 44.2
(s), 42.3 (s), 42.1 (d), 37.2 (t), 29.3 (q), 27.5 (t), 26.6 (t), 22.6
(q), 20.6 (q), 17.4 (q), 15.8 (q), 6.8 (q), 4.7 (t). HRMS (FAB)
Calcd for C52H66O15-N5PSiNa (MϩNa)ϩ 1082.3956, found
1082.3949.
Oxidation of 25 to 32
To a solution of 25 (63 mg, 0.1 mmol) in CH2Cl2 (3.0 mL)
was added 4-methylmorpholine N-oxide (34 mg,
0.3 mmol), molecular sieves 4A (activated 24 mg) and tetra-
propylammonium perruthenate (10 mg, 0.03 mmol) at 0ЊC.
The reaction mixture was stirred at rt for 3 h and diluted
with EtOAc at 0ЊC. After filtration of the resulting mixture
through a short pad of silica gel and evaporation of the
solvent, the residue was chromatographed by preparative
TLC (ethyl acetate-hexane 1:1 v/v) to give 44 mg (70%)
of 32 as a white solid. mp: 166–168ЊC. [a]2D5ˆϪ8Њ
1
(cˆ0.12, CH3OH). H NMR (500 MHz) d: 8.09 (m, 4H),
7.64 (t, 1H, Jˆ7.2 Hz), 7.59 (t, 1H, Jˆ7.2 Hz), 7.48–7.47
(m, 4H), 6.72 (s, 1H), 5.68 (d, 1H, Jˆ7.0 Hz), 4.93 (dd, 1H,
Jˆ9.4, 2.3 Hz), 4.35 (d, 1H, Jˆ8.5 Hz), 4.17 (d, 1H,
Jˆ8.5 Hz), 3.89 (d, 1H, Jˆ7.0 Hz), 3.01 (d, 1H,
Jˆ19.8 Hz), 2.66 (d, 1H, Jˆ19.8 Hz), 2.25 (s, 3H), 2.17
(s, 3H), 2.12 (m, 1H), 1.96 (m, 1H), 1.82 (m, 1H), 1.74 (s,
3H), 1.64 (m, 1H), 1.22 (s, 3H), 1.17 (s, 3H). 13C NMR
Coupling of 30 with the side chain acid 31 leads to
compound 3
To a solution of carboxylic acid 31 (85 mg, 0.21 mmol), 30

Q. Cheng et al. / Tetrahedron 56 (2000) 1667–1679
1677
(125 MHz) d: 204.5 (s), 197.8 (s), 170.3 (s), 167.6 (s), 167.2
(s), 152.8 (s), 140.4 (s), 134.1 (d), 133.7 (d), 130.2 (d), 129.9
(d), 129.1 (s), 128.9 (s), 128.3 (d), 128.0 (d), 84.6 (d), 81.4
(s), 79.6 (s), 77.8 (d), 76.7 (t), 74.8 (d), 53.7 (s), 44.8 (t),
43.2 (s), 42.7 (d), 34.5 (t), 32.7 (q), 27.1 (t), 22.1 (q), 18.9
(q), 14.7 (q), 13.8 (q). HRMS (FAB) Calcd for C36H39O10
(MHϩ) 631.5408, found 631.5406.
Esterification of 34 with cAMP-Cl 27 leads to compound
4
Following the procedure for preparation of 28, using cAMP-
Cl 27 (20 mg, 0.06 mmol), 4-(dimethylamino)pyridine
(DMAP, 33 mg, 0.18 mmol), and 34 (27 mg, 0.03 mmol)
gave 28 mg (78%) of 4 as a white solid. mp: Ͼ300ЊC
(dec.). [a]2D5ˆϪ96Њ (cˆ0.01, CH3OH). 1H NMR
(600 MHz, CD3OD) d: 8.23 (s, 1H), 8.15 (s, 1H), 8.14 (d,
2H, Jˆ7.6 Hz), 8.12 (d, 2H, Jˆ7.6 Hz), 7.74 (dd, 2H,
Jˆ8.4, 1.2 Hz), 7.62 (t, 1H, Jˆ7.6 Hz), 7.60 (t, 1H,
Jˆ7.6 Hz), 7.50 (m, 3H), 7.48–7.43 (m, 6H), 7.31–7.29
(m, 3H), 6.87 (d, 1H, Jˆ9.0 Hz), 6.69 (s, 1H), 6.27 (t, 1H,
Jˆ8.9 Hz), 6.08 (d, 1H, Jˆ1.0 Hz), 6.02 (dd, 1H, Jˆ9.0,
3.0 Hz), 5.66 (d, 1H, Jˆ7.2 Hz), 4.94 (dd, 1H, Jˆ9.4,
2.3 Hz), 4.76 (dd, 1H, Jˆ9.0, 5.3 Hz), 4.70 (dd, 1H,
Jˆ5.3, 1.0 Hz), 4.68 (d, 1H, Jˆ3.0 Hz), 4.60 (dd, 1H,
Jˆ9.6, 5.0 Hz), 4.39 (dd, 1H, Jˆ10.5, 9.6 Hz), 4.36 (d,
1H, Jˆ8.5 Hz), 4.35 (ddd, 1H, Jˆ10.5, 9.0, 5.0 Hz), 4.15
(d, 1H, Jˆ8.5 Hz), 3.78 (d, 1H, Jˆ7.2 Hz), 2.37 (dd, 1H,
Jˆ15.4, 8.9 Hz), 2.36 (m, 1H), 2.26 (s, 3H), 2.23 (dd, 1H,
Jˆ15.4, 8.9 Hz), 2.05 (s, 3H), 1.95 (m, 1H), 1.86 (m, 1H),
1.73 (s, 3H), 1.59 (dd, 1H, Jˆ14.1, 5.8 Hz), 1.21 (s, 3H),
1.13 (s, 3H). 13C NMR (150 MHz) d: 207.2 (s), 172.8 (s),
170.5 (s), 168.2 (s), 167.6 (s), 167.3 (s), 156.3 (s), 154.0 (d),
149.3 (s), 145.9 (s), 140.9 (d), 137.6 (s), 133.7 (d), 133.5 (s),
133.3 (d), 132.7 (s), 132.2 (d), 130.0 (d), 129.9 (d), 129.2
(s), 129.0 (d), 128.9 (d), 128.7 (d), 128.6 (d), 128.5 (d),
128.3 (d), 127.0 (d), 126.7 (d), 119.8 (s), 92.6 (d), 85.1
(d), 81.3 (s), 80.6 (s), 79.8 (d), 78.7 (d), 78.6 (d), 76.8 (t),
74.9 (d), 73.8 (d), 73.2 (d), 73.1 (d), 68.9 (d), 57.2 (d), 53.3
(s), 43.2 (d), 42.3 (s), 39.6 (t), 34.6 (t), 27.5 (q), 26.8 (t), 22.4
(q), 20.8 (q), 15.3 (q), 14.5 (q). HRMS (FAB) Calcd for
C62H63O17N6PNa (MϩNa)ϩ 1217.3881, found 1217.3879.
Reduction of 32 to 33
Following the procedure for preparation of 30, using 32
(41 mg, 0.065 mmol) gave 31 mg (74%) of 33 as a white
amorphous solid after chromatography by preparative TLC
(ethyl acetate-hexane 3:2 v/v). [a]2D5ˆϪ39Њ (cˆ0.05,
1
CH3OH). H NMR (500 MHz) d: 8.12 (d, 2H, Jˆ7.8 Hz),
8.10 (d, 2H, Jˆ7.8 Hz), 7.60 (t, 1H, Jˆ7.8 Hz), 7.59 (t, 1H,
Jˆ7.8 Hz), 7.48–7.47 (m, 4H), 6.64 (s, 1H), 5.62 (d, 1H,
Jˆ7.0 Hz), 4.96 (dd, 1H, Jˆ9.4, 2.3 Hz), 4.87 (m, 1H), 4.32
(d, 1H, Jˆ8.5 Hz), 4.15 (d, 1H, Jˆ8.5 Hz), 3.84 (d, 1H,
Jˆ7.0 Hz), 2.57 (brs, 1H, OH-13), 2.36–2.35 (m, 2H),
2.26 (s, 3H), 2.18 (dd, 1H, Jˆ15.3, 7.6 Hz), 2.07 (d, 3H,
Jˆ1.1 Hz), 1.95 (dddd, 1H, Jˆ14.0, 11.6, 5.5, 2.3 Hz), 1.88
(ddd, 1H, Jˆ14.0, 11.6, 5.5 Hz), 1.74 (s, 3H), 1.58 (dd, 1H,
Jˆ14.0, 5.5 Hz), 1.15 (s, 3H), 1.11 (s, 3H). 13C NMR
(125 MHz) d: 206.8 (s), 170.4 (s), 168.2 (s), 167.5 (s),
145.7 (s), 133.9 (d), 133.7 (d), 131.9 (s), 130.1 (d), 130.0
(d), 129.2 (s), 129.1 (s), 128.5 (d), 128.3 (d), 85.2 (d), 81.2
(s), 80.1 (s), 78.1 (d), 76.8 (t), 74.9 (d), 68.7 (d), 53.3 (s),
43.1 (d), 41.8 (s), 38.9 (t), 34.7 (t), 27.2 (q), 26.8 (t), 22.4
(q), 20.5 (q), 15.2 (q), 14.6 (q). HRMS (FAB) Calcd for
C36H41O10 (MHϩ) 633.2697, found 633.2693.
Coupling of 33 with the side chain acid 31 leads to 34
Following the procedure for preparation of 3, using 33
(30 mg, 0.047 mmol), carboxylic acid 31 (114 mg,
0.282 mmol), DMAP (13 mg, 0.094 mmol), DCC (58 mg,
0.282 mmol), and TFA (1.0 ml containing 0.1 ml of H2O)
gave 32.4 mg (78%) of 34 as a white solid after chromato-
graphy by preparative TLC (ethyl acetate-hexane 3:1 v/v).
Acknowledgements
Financially supported by Grant-in-Aid for scientific
research from the Ministry of Education, Science and
Culture of Japan and the JSPS fellowship to Q.C. are
acknowledged. We are indebted to Prof. Y. Mong of the
Graduate School of Medicine, Tohoku University and
Institute of Laboratory Animal Science, CAMS & PUMC,
Beijing, for biological assay and to Mrs T. Yamada for
measuring 2D NMR, MS and HRMS spectra.
mp: 196–198ЊC. [a]D25ˆϪ62Њ (cˆ0.03, CH3OH). H NMR
1
(500 MHz) d: 8.16 (dd, 2H, Jˆ8.3, 1.3 Hz), 8.12 (d, 2H,
Jˆ7.6 Hz), 7.71 (dd, 2H, Jˆ8.4, 1.2 Hz), 7.63 (t, 1H,
Jˆ7.2 Hz), 7.59 (t, 1H, Jˆ7.6 Hz), 7.51–7.50 (m, 3H),
7.48–7.44 (m, 6H), 7.31 (m, 2H), 7.29 (m, 1H), 6.93 (d,
1H, Jˆ9.0 Hz, NH), 6.72 (s, 1H), 6.25 (dd, 1H, Jˆ9.2,
8.8 Hz), 5.98 (dd, 1H, Jˆ9.0, 2.6 Hz), 5.67 (d, 1H, Jˆ
7.2 Hz), 4.96 (dd, 1H, Jˆ9.5, 2.3 Hz), 4.59 (dd, 1H,
Jˆ4.0, 2.6 Hz), 4.33 (d, 1H, Jˆ8.4 Hz), 4.19 (d, 1H, Jˆ
8.4 Hz), 3.75 (d, 1H, Jˆ7.2 Hz), 3.56 (d, 1H, Jˆ4.0 Hz,
OH-20), 2.38 (dd, 1H, Jˆ15.5, 9.2 Hz), 2.35 (m, 1H), 2.26
(dd, 1H, Jˆ15.5, 8.8 Hz), 2.25 (s, 3H), 2.03 (s, 3H), 1.93–
1.89 (m, 2H), 1.72 (s, 3H), 1.57 (dd, 1H, Jˆ14.0, 5.6 Hz),
1.23 (s, 3H), 1.14 (s, 3H). 13C NMR (125 MHz) d: 206.8 (s),
172.4 (s), 170.5 (s), 167.8 (s), 167.5 (s), 167.1 (s), 145.2 (s),
138.5 (s), 133.7 (d), 133.6 (s), 133.4 (d), 132.3 (s), 132.1 (d),
130.1 (d), 129.9 (d), 129.1 (s), 128.9 (d), 128.8 (d), 128.7
(d), 128.6 (d), 128.4 (d), 128.4 (d), 127.0 (d), 126.9 (d), 84.9
(d), 80.2 (s), 79.8 (s), 78.4 (d), 76.8 (t), 74.9 (d), 73.7 (d),
72.6 (d), 55.6 (d), 53.6 (s), 43.7 (d), 42.0 (s), 39.2 (t), 34.2
(t), 27.4 (q), 26.9 (t), 22.2 (q), 21.0 (q), 15.6 (q), 14.8 (q).
HRMS (FAB) Calcd for C52H53O12NNa (MϩNa)ϩ
906.3462, found 906.3453.
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