The Reductive Fragmentation of 7-Hydroxy-9,10-dioxotaxoids

Article abstract of DOI:10.1002/ejoc.200300376

The retro-aldol reductive fragmentation of different structural types of 7-hydroxy-9,10-dioxotaxoids was investigated, showing that the reaction is typical of taxanes and requires cerium(III) promotion with NaBH₄ in protic medium and alkylboron (aluminium) hydrides in aprotic solvents. The resulting 7,8-seco-taxanes are key intermediates for the synthesis of a novel class of anticancer taxanes endowed with a unique pattern of in vivo biological activity. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300376

FULL PAPER
The Reductive Fragmentation of 7-Hydroxy-9,10-dioxotaxoids
Giovanni Appendino,*[a] Alain Noncovich,[a] Piergiorgio Bettoni,[a] Paolo Dambruoso,[a]
Olov Sterner,[b] Gabriele Fontana,[c] and Ezio Bombardelli[c]
Dedicated to Professor Paola Vita-Finzi on the occasion of her 70th birthday
Keywords: Antitumour agents / Natural products / Taxoids / Terpenoids
The retro-aldol reductive fragmentation of different struc-
sulting 7,8-seco-taxanes are key intermediates for the syn-
tural types of 7-hydroxy-9,10-dioxotaxoids was investigated, thesis of a novel class of anticancer taxanes endowed with a
showing that the reaction is typical of taxanes and requires unique pattern of in vivo biological activity.
cerium(III) promotion with NaBH4 in protic medium and al-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
kylboron (aluminium) hydrides in aprotic solvents. The re- Germany, 2003)
Introduction
nylisoserine and norstatin amino acidic side chains.[7] One
of these compounds, the N-BOC-norstatin ester 3b (IDN,
5390), showed cytotoxicity and tubulin binding similar to
those of Taxol, and was selected for further biological
evaluation.[7] In vivo assays of 3b in xenografted nude mice
showed high antimetastatic and cytostatic activity, coupled
with a surprisingly low toxicity.[8] This unique biological
profile qualifies 3b as a new and interesting anticancer can-
didate, and prompted us to investigate the reductive frag-
mentation of taxanes 2a/b further, optimising the yield of
the seco compound 3a, and exploring the extension of this
reaction to other structural types of taxoids.
The retro-aldol epimerisation of the 7-hydroxy group of
Taxol (paclitaxel) from a β-equatorial to an α-axial orien-
tation is one of the first reactions described for this an-
ticancer drug,[1] and is typical of baccatin III (1a) deriva-
tives.[2] Under mildly basic conditions, the aldol motif
bridging rings B and C equilibrates with a C-seco aldehyde
enolate, which then re-aldolises mainly to the 7-α epimer,
stabilised by intramolecular hydrogen bonding between the
7-hydroxy and the 4-acetate carbonyl groups (1b, Figure 1,
A).[3] This epimerisation takes place under physiological
conditions,[4] and is a major problem for the formulation of
anticancer taxoids.[5]
The seco-aldehyde enolate re-aldolises too rapidly to al-
low its trapping or spectroscopic detection, but we reasoned
that the replacement of the 10-acetoxy group with a car-
bonyl should stabilise the enolate by conjugation, making
it possible to trap the fledging seco-aldehyde intermediate
in a nucleophilic and/or reductive fashion (Figure 1, B). In-
deed, we have reported in a preliminary communication
that treatment of an epimeric mixture of 10-deacetyl-10-de-
hydrobaccatins (2a/b) with NaBH4 in the presence of
CeCl3·7H2O gave, in modest yield, the C-seco-taxoid 3a,[6]
which was next elaborated into a series of Taxol analogues
by esterification of the 13-hydroxy group with various phe-
Results and Discussion
1. Synthesis of the Reductive Fragmentation Precursors
2a/b and 9
The 9,10-α-diketone motif is rare in natural taxoids,[9] but
its corresponding ketol version is present in 10-deacetylbac-
catin III (10-DAB III, 4a). This compound is available in
multigram amounts from the leaves of the European yew,[10]
and was selected as a starting material for this study. Oxi-
dative remodelling of the α-ketol system of 4a could be ef-
fected by autoxidation in the presence of CuII salts
(Scheme 1). The autoxidation of 4a occurs selectively at the
allylic 13-hydroxy group,[11] but the presence of CuII salts
redirects the reaction to the allylic ketolic hydroxy group, in
accordance with the chemoselectivity observed in the CuII-
mediated autoxidation of corticosteroids.[12] Only trace
amounts (Ͻ 5%) of the 10,13-didehydro derivative 5 were
obtained, while extensive epimerisation at C-7 was ob-
served, resulting in the formation of a ca. 3:1 mixture of
[a]
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche
e Farmacologiche,
V.le Ferrucci 33, 28100 Novara, Italy
E-mail: appendino@pharm.unipmn.it
[b]
Department of Organic Chemistry, Lund University,
P.O. Box 124, 22100 Lund, Sweden
[c]
Indena S.p.A.,
V.le Ortles 12, 20139 Milano, Italy
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DOI: 10.1002/ejoc.200300376
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The Reductive Fragmentation of 7-Hydroxy-9,10-dioxotaxoids
FULL PAPER
Figure 1. The retro-aldol epimerization of baccatin III derivatives and its exploitation for the synthesis of C-seco-taxoids
epimers at this carbon (2a/b). Attempts to separate the mix- compete with the 7α-hydroxy group for the formation of
ture by gravity column chromatography afforded the pure intramolecular hydrogen bonding with the 4-acetate, and
7α epimer 2b, while purification of the 7β epimer 2a proved therefore has a long-range stabilising effect on the β con-
elusive on account of its configurational instability under figuration of the 7-hydroxy group.[13]
chromatographic conditions. While the 7α epimer 2b was
On account of the strong intramolecular hydrogen bond-
stable in solvents spanning a wide range of polarity (from ing, the 7α-hydroxy group of 2b is essentially unreactive in
CHCl3 to methanol), partially purified samples of the 7β acylation and silylation reactions, and its cryptic nature was
epimer eventually transformed into the 7α epimer both in exploited for the synthesis of an 11(15Ǟ1)abeotaxane pre-
solution and under prolonged chromatographic conditions, cursor for the reductive fragmentation (Scheme 1). Thus,
showing that the epimerisation is essentially irreversible. treatment with triethylsilyl chloride (TES-Cl) converted 2a/
The 7α-hydroxy group of baccatin V is engaged in fairly b into a mixture of two products, which could be easily
strong intramolecular hydrogen bonding with the 4-acetate, separated by chromatography. The major one (6, 49Ϫ58%)
which stabilises its axial configuration.[3] The observation was the 13-TES derivative of 2b, accompanied by variable
that the 10,13-didehydro derivative 5 was obtained in a dia- minor amounts (3Ϫ7%) of the 7,13-diTES derivative of 10-
stereomerically pure 7α-hydroxy configuration backs up the dehydroDAB III (7). The low reactivity of the 13α-hydroxy
idea that the 13α-hydroxy group of baccatin derivatives can group of taxanes is essentially due to intramolecular hydro-
Scheme 1. Synthesis of taxoid precursors for the reductive fragmentation: (i) Cu(OAc)2·H2O, MeOH (75% 2a/b, 2.5% 5), (ii) TES-Cl,
imidazole, CH2Cl2 (53% 6, 3% 7), (iii) SOCl2, pyridine, CH2Cl2 (80%), (iv) DBU, toluene, 95% (see ref.[15]
)
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G. Appendino et al.
FULL PAPER
gen bonding with the 4-acetate carbonyl moiety.[14] The en-
gagement of this carbonyl moiety in hydrogen bonding with
the 7α-hydroxy group leaves the 13-hydroxy group uncom-
plexed and reactive, thus explaining the diastereomeric ki-
netic resolution observed in the silylation of 2a/b. The
choice of the base employed in the silylation was important.
While the epimeric mixture 2a/b is stable in the presence
of imidazole, stronger bases such as triethylamine or 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) triggered a spectacu-
lar rearrangement to lactols 9.[15] The 7-unprotected silyl
ether 6a was next treated with SOCl2/pyridine to effect the
WagnerϪMeerwein rearrangement of the A,B ring sys-
tem,[16] cleanly affording the 11(15Ǟ1)abeotaxane 8, a suit-
able substrate for the reductive fragmentation (Scheme 1).
2. Reductive Fragmentation of Taxoids of the 9,10-Dioxo
Type
The reductive fragmentation was investigated and op-
timised with the diastereomeric mixture of 9,10-dioxotax-
anes 2a/b. Reduction with NaBH4 in alcohols (methanol,
ethanol, 2-propanol) was practically instantaneous, and
gave a mixture with 10-deacetylbaccatin III (4a) as the
major component (ca. 20% isolated yield), the result of re-
duction of the 10-carbonyl and reepimerisation at C-7
Scheme 2. Treatment of 10-dehydro-10-deacetylbaccatin (2a/b)
with NaBH4
(Scheme 2). The same result was obtained when starting lationship between these proton(s) and the 19- and 16-
from the pure 7α epimer 2b, and in both cases only traces methyls. As to the configuration of the 7-hydroxy group,
of the more stable 7α epimer 4b could be detected in the inspection of the splitting pattern of the corresponding
1
reaction mixture by H NMR or TLC analysis. These ob- methine allowed a straightforward assignment, with H-7 re-
servations showed that reduction of the starting α-diketone sonating as a well spaced doublet of doublets (J ϭ ca. 10
was faster than retroaldolisation of the seco-aldehyde inter- and 7 Hz) when axial (α), and as a narrow doublet of dou-
mediate. Attack at the allylic and less hindered 10-carbonyl blets (J ഠ 4 and 2 Hz) when equatorial (β). The 10α-
was not unexpected, owing to the hindered nature of the 9- hydroxy group apparently overrides the 7α-hydroxy group
keto group of taxanes.[17] On the other hand, the overall as hydrogen-bonding donor to the 4-acetate, thus ex-
stereochemical course of the reaction was surprising. Thus, plaining the prevalence of the 7β configuration in the epi-
under the same conditions, a 2,7-disilylated derivative of mers from the unnatural 10α series (10a/b). The 13-dehydro
taxol exclusively gave the unnatural 10-α alcohol,[18] while derivative 10c is presumably derived from 10a by air oxi-
10-deacetylbaccatin III (4a) is known to equilibrate with its dation[11] during workup or chromatographic purification
7α epimer 4b under mildly basic conditions, such as those of the reduction mixture. Compound 3a showed only broad
expected in the course of a borohydride reduction.[4]
humps in its NMR spectra. Eventually, all 1H NMR signals
The reducing properties of NaBH4 can be substantially and most 13C resonances could be detected and assigned by
modified by various additives, especially metal ions.[19] In working at 130 °C in [D6]DMSO.[6] These data showed that
the absence of a clear mechanistic rationale to pursue, the the α-diketone moiety was completely tautomerised to a di-
effect of various metal additives on the borohydride re- osphenol form. Since extensive line-broadening was also
duction of 2a/b was investigated. Addition of NiCl2, CoCl2 observed in the peracetyl and persilyl derivatives of 3a,[6]
a
or CuBr did not significantly alter the course of the re- conformational process is responsible for the dynamic equi-
duction. Conversely, lanthanides (CeCl3·7H2O, ScOTf3, librium evidenced by the NMR spectra. Modification of the
YbOTf3), especially cerium trichloride, had a dramatic re- 1-hydroxy group had a dramatic slowing effect on the pro-
directing effect on the course of the reaction. The long- cess. Thus, if the reaction sequence to 3a from 4a was re-
sought reductive fragmentation product 3a could be iso- peated starting from the 1,14-acetonide 11,[20] a seco-taxane
lated in 28% yield (reaction scale: 5 g 2a/b), accompanied was obtained (12, Scheme 3), its NMR spectra showing two
by four minor compounds with an intact taxane skeleton sets of sharp lines at room temperature, in a ca. 3:2 ratio.
10aϪd, obtained in 9%, 4%, 3% and 3% yields, respec- The NMR spectra of 12 were amenable to full assignment
1
tively (Scheme 2).
by 2D measurements (HMQC, HMBC). In the H NMR
The structure elucidation of 10aϪd was straightforward. spectrum, the major differences relate to the signals of the
The presence of a 7-oxymethine showed that the taxane oxetane-containing chain at C-3 and the allylic methyl C-
core had remained intact, while the β-orientation of the 10- 19, with inter-rotameric differences larger than 0.5 ppm for
hydrogen in 10aϪd and of the 9-hydrogen in 10d was evi- the proton signals of the 4-acetate, one of the diastereotopic
denced by NOE experiments, which established a syn re- 20-methylene protons and the 19-methyl group. The major
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The Reductive Fragmentation of 7-Hydroxy-9,10-dioxotaxoids
difference evidenced by NOE difference experiments is the
FULL PAPER
Modified borohydrides were first examined. With
lack of correlation between the 19-methyl group and one of NaBH3CN, reduction of the 10-keto group and counter-
the oxetane protons in the minor rotamer. Taken together, thermodynamic equilibration at C-7 were observed, 10-
these observations suggest that rotation around the C-3/C- DAB III (4a) being obtained as the only reaction product
4 bonds plays a key role in the conformational equilibration (56%). With Zn(BH4)2, a mixture of the C-seco compound
of C-seco-taxanes, while reduction of the mobility around 3a (11%) and unchanged 2b was obtained. However, our
the C-1/C-14 bond slows down the conformational equili- efforts to increase the conversion failed, since 2b was stable
bration, making it possible to observe the signals of species in the presence of Zn(BH4)2, and epimerization at C-7 was
differing in the orientation of the oxetane ring with respect apparently shut down under these reaction conditions.
to the bicyclic diterpene core. The reasons for the high bar- Raney nickel has been reported to reduce aldehydes in the
rier of rotation around the C-3/C-4 bond in C-seco-taxoids presence of ketones,[25] but with 2a/b only reduction of the
is unclear. It is worth noting that related compounds devoid 10-keto group and counter-thermodynamic epimerisation at
of the oxetane ring and the diosphenol system are inter- C-7 were observed, 4a being obtained as the only reaction
mediates in Wender’s synthesis of Taxol, but no dynamic product (41%).
process was reported for them.[21] One C,D-bis(seco-taxane)
Complex alanes and boranes gave remarkable results,
obtained from 7-dehydro-13-acetylbaccatin III was also re-
which eventually resulted in an optimised reductive frag-
mentation procedure. While the alkoxyalane Red-Al gave 4a
as the major reaction product (59%), alkyl alanes and bor-
anes such as DIBAL and L- and K-selectrides afforded the
C-seco compound 3a as the major or the exclusive reaction
product. The reaction with L-selectride was especially clean
and was further investigated, with optimisation of various
parameters (temperature, concentration) and the workup.
Thus, a temperature of Ϫ15 °C turned out to be an excellent
compromise between the sluggish reactivity observed at
Ϫ78 °C and the formation of the acyl rearranged product
13 when the reaction was carried out at room temperature.
Although the formation of 13 was modest (ca. 5Ϫ10%), it
significantly complicated the purification of 4a, owing to
its similar chromatographic mobility. On the other hand,
conventional oxidative workup[26] of the selectride reaction
mixture resulted in the complete degradation of 3a, presum-
ably because of its sensitivity to oxidants, while an acidic
workup followed by a quick purification by gravity column
chromatography was able to provide the C-seco diosphenol
taxane 3a in 90% yield (reaction scale: 5 g 2a/b as starting
material). The different behaviour of the alkoxyalane Red-
Al from the alkylalane DIBAL and the alkylboranes K-
and L-selectrides is remarkable and presumably related to
differences in oxyphilicity. Owing to the presence of two
oxygen ligands, the aluminium core of Red-Al might not
bind the diosphenolate moiety strongly enough to prevent
intramolecular aldol trapping of the fledging seco-aldehyde
intermediate at the expenses of intermolecular hydride trap-
ping.
ported to have normal NMR spectra.[22]
Scheme 3. Synthesis of the seco-acetal 12: (i) 1. Cu(OAc)2·H2O,
MeOH, 2. NaBH4, CeCl3·7H2O, MeOH (overall 21%)
The beneficial effect of cerium trichloride on the retro-
aldol reductive trapping is counterintuitive, since the pro-
cess involves the reduction of an aldehyde in the presence
of a ketone, and addition of CeCl3 has been shown to have
an opposite effect on the reduction of ketoaldehydes.[23]
A
possible interpretation is that the diosphenolate moiety
strongly chelates cerium(), producing a relatively stable
complex and a reduction in its nucleophilicity large enough
to permit the reductive trapping of the fledging 7-aldehyde
before retro-aldolisation. A full equivalent of CeCl3 was in-
deed necessary for the reaction, as would be expected of a
stoichiometric interaction of the additive with the substrate
and/or the reduction product.
While providing sufficient material to allow the elabor-
ation of 3a into a series of antitumour taxoids, the cerium-
promoted reductive fragmentation suffered from several
drawbacks. On the one hand, its yield was modest, and the
formation of a mixture made a careful chromatographic
step necessary for the purification of 3a. Furthermore, the
reaction could not be applied to taxanes bearing amino
acidic chains at C-13, since loss of the side chain was ob-
served. Protection of the 2Ј-hydroxy group as a silyl ether
could only reduce, not completely prevent, this loss during
the reductive fragmentation.[24] Clearly another approach
The L-selectride reductive fragmentation could also be
was needed to fuel additional biological studies on 3b and carried out on 2Ј-protected 9,10-dioxotaxanes bearing am-
sustain a significant structure-activity study for this novel ino acidic side chains, as exemplified by the conversion of
class of anticancer compounds.
cephalomannine (14a),[27] a side product of the isolation of
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G. Appendino et al.
FULL PAPER
Scheme 4. Synthesis of the C-seco-taxane15 from cephalomannine (14a): (i) H2O2, NaHCO3 (88%), (ii) TES-Cl, imidazole, DMF (51%),
(iii) Cu(OAc)2.H2O, MeOH, (iv) -selectride, THF, (v) HCl, MeOH (47% from 14d)
Taxol, into its corresponding C-seco-taxane 15 (Scheme 4). reaction product. Owing to the highly congested environ-
After chemoselective deacetylation of the 10-hydroxy ment, it is not inconceivable that the α-diketone system of
group,[28] the 2Ј-hydroxy group was protected as a TES the abeotaxane 8 resists reduction by L-selectride, a bulky
ether, and the α-ketol system was subjected to autoxidation reagent, rather undergoing an alkoxide-induced benzil re-
conditions in the presence of Cu(OAc)2. The reductive frag- arrangement. The benzil rearrangement is not unpre-
mentation was then uneventful, affording, after deprotec- cedented in 9,10-dioxotaxoids.[15,30] Whatever the mecha-
tion, 15 in overall 21% yield from 14a.
nism is, the transformation of 8 into 18 adds to the growing
Application of both reductive fragmentation procedures and puzzling inventory of non-reductive reactions observed
to the 11(15Ǟ1)abeobaccatin 8 failed to afford compounds upon treatment of taxoids with metal hydrides.[31]
of the C-seco type. Thus, treatment with the NaBH4/
CeCl3·7H2O system in methanol gave the triol 16 as the
only reaction product (89% yield), the result of a twofold
hydride attack from the β-face of the molecule (Scheme 5).
Conclusions
The chemistry presented here testifies vividly to our lim-
Compound 16 showed rather broad NMR spectra, a fea- ited predictive capacity in the realm of multifunctional
ture not unusual in 11(15Ǟ1)abeotaxanes,[29] and its struc- compounds. A procedure for the reductive fragmentation of
ture elucidation was confirmed by its conversion into the 9,10-dioxotaxoids with 10-deacetyl-10-dehydrobaccatin III
cyclic acetonides 17a/b by treatment with 2,2-dimeth- (2a/b) as a model compound has been developed. While of
oxypropane and acids. Two aspects of the acetalisation were immediate relevance for the synthesis of the drug candidate
somewhat unexpected, namely the formation of a six-mem- IDN 5390 (3b), the solution turned out to be very ad hoc,
bered acetonide rather than the expected dioxolane deriva- and not even applicable to compounds closely related to 2a/
tive of the cis-diol system, and the solvolytic replacement b. The intriguing biological profile of C-seco-taxoids justi-
of the 13-silyl ether by a methyl ether, with methanol being fies efforts to optimise their synthesis, and the solution of
released in the ketalisation step. On the other hand, treat- the problem came as a result of a ‘‘shotgun’’ approach,
ment with L-selectride gave the γ-lactone 18 as the only which raises a series of intriguing mechanistic issues of
Scheme 5. Attempted reductive fragmentation of the abeotaxane 8: (i) NaBH4, CeCl3·7H2O, MeOH (98%), (ii) dimethoxypropane, PTSA
(45%), (iii) L-selectride, THF (18%)
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The Reductive Fragmentation of 7-Hydroxy-9,10-dioxotaxoids
FULL PAPER
H), 4.11 (d, J ϭ 7.1 Hz, 3-H), 4.32 (d, J ϭ 8.3 Hz, 20b-H), 4.45
(d, J ϭ 9.2 Hz, 7-OH), 4.44 (d, J ϭ 8.3 Hz, 20a-H), 4.94 (m, 13-H
ϩ 5-H), 5.84 (d, J ϭ 7.1 Hz, 2-H), 7.51 (BBЈ-Bz), 7.59 (C-Bz), 8.14
(AAЈ-Bz) ppm. 13C NMR (CDCl3): δ ϭ 14.6 (C-18), 15.0 (C-19),
22.1 (C-16), 22.5 (OAc), 26.3 (C-17), 35.3 (C-6), 38.9 (C-14), 39.8
(C-15), 39.6 (C-3), 57.3 (C-8), 67.5 (C-13), 77.3 (C-7), 74.9 (C-2),
77.2 (C-20), 79.0 (C-1), 81.2 (C-4), 82.5 (C-5), 128.8 (Bz), 129.2
(Bz), 130.1 (Bz), 133.9 (Bz), 140.5 (C-11), 146.6 (C-12), 167.1 (Bz),
172.5 (OAc), 189.2 (C-10), 208.4 (C-9 ppm. HRMS (70 eV): m/z ϭ
542.2155 (calcd. for C29H34O10, 542.2152).
more general relevance and worth further investigation in
other multifunctional molecular assemblies.
Experimental Section
General: Column chromatography: Merck silica gel. IR: Shimadzu
DR 8001 spectrophotometer. NMR: Bruker DRX 500 (500 MHz
and 125 MHz for 1H and 13C, respectively). The spectra were re-
corded in C6D6, CDCl3, [D6]DMSO, or [D4]MeOH, and the sol-
vent signals (δ ϭ 7.22/128.39, 7.26/77.0, 2.49/39.7, and 3.35/49.3
ppm respectively) were used as reference. The chemical shifts (δ)
are given in ppm, and the coupling constants (J) in Hz. COSY,
HMQC, and HMBC experiments were recorded with gradient en-
hancements by use of sine-shaped gradient pulses. For the 2D het-
eronuclear correlation spectroscopy, the refocusing delays were op-
Silylation of 10-Dehydro-10-deacetylbaccatin (2a/b): Imidazole
(753 mg, 11.1 mmol, 4 mol equiv.) and TES-Cl (1  in CH2Cl2,
11.1 mL, 11.1 mmol, 4 mol equiv.) were added to a solution of a
ca. 1:3 mixture (1H NMR analysis) of 10-dehydro-10-deacetylbac-
catins III and V (1.5 g, 2.77 mmol) in dry CH2Cl2 (16.6 mL). After
stirring overnight at room temperature, the reaction mixture was
worked up by dilution with EtOAc and washing with 2  H2SO4.
After washing with brine, drying (Na2SO4) and evaporation, the
residue was purified by column chromatography on silica gel (34 g)
1
n
timised for JC,H ϭ 145 Hz and JC,H ϭ 10 Hz. The crude data
were transformed and the spectra were evaluated with the standard
Bruker XWIN NMR software (rev. 010101). CH2Cl2 was dried by
distillation from CaH2, and THF from distillation from Na/benzo- eluted with a petroleum ether/EtOAc gradient (9:1 to 3:7), afford-
phenone. Na2SO4 was used to dry solutions before the evaporation.
Reactions were monitored by TLC on Merck 60 F254 (0.25 mm)
plates, which were visualised by UV inspection and/or by staining
with 5% H2SO4 in ethanol and heating. Taxoids retain solvents
strongly, and are not amenable to elemental analysis.
ing 7 (56 mg, 3%), 6 (956 mg, 53%) and starting material (108 mg).
13-TES-10-dehydro-10-deacetylbaccatin V (6): Foam. IR (KBr):
1
ν˜ ϭ 3496, 1711, 1696, 1267, 1244, 1125, 936, 889 cmϪ1. H NMR
(CDCl3): δ ϭ 0.61 (q, J ϭ 7.9 Hz, OTES), 0.70 (q, J ϭ 7.9 Hz,
OTES), 0.97 (t, J ϭ 7.9 Hz, OTES), 1.03 (t, J ϭ 7.9 Hz, OTES),
1.20 (s, 16-H/3), 1.57 (s, 17-H/3), 1.70 (s, 19-H/3), 2.03 (br. s, 18-
H/3), 2.30 (s, OAc), 3.65 (d, J ϭ 7.2 Hz, 3-H), 4.20 (dd, J ϭ 10,
3 Hz,, 7-H), 4.18 (d, J ϭ 8.2 Hz, 20b-H), 4.33 (d, J ϭ 8.2 Hz, 20a-
H), 5.00 (br. t, J ϭ 7.5 Hz, 13-H), 4.92 (br. d, J ϭ 9 Hz, 5-H), 5.76
(d, J ϭ 7.2 Hz, 2-H), 7.49 (BBЈ-Bz), 7.65 (C-Bz), 8.11 (AAЈ-Bz)
ppm. HRMS (70 eV): m/z ϭ 770.3897 (calcd. for C41H62O10Si2,
770.3882).
Copper(II)-Mediated Autoxidation of 10-Deacetylbaccatin III (4a):
In a 1-L two-necked flask, 4a (2 g, 3.7 mmol) was suspended in
methanol (150 mL), and Cu(OAc)2H2O (5 g) was added in small
portions, with vigorous mechanical stirring, over ca. 10 min. The
pale blue suspension darkened during the course of the reaction,
and stirring was continued with the flask neck unstoppered to al-
low contact with air. After 72 h, the reaction mixture was worked
up by concentration and addition of water (200 mL) and EtOAc
(350 mL), dissolving most of the voluminous precipitate. The or-
ganic phase was washed with 2  NH3 to remove copper salts, and
then with brine. After drying (Na2SO4) and evaporation, the resi-
due was purified by column chromatography on silica gel, with a
petroleum ether/EtOAc gradient. Fractions eluted with petroleum
ether/EtOAc (5:5) afforded 50 mg (2.5%) of 5. Those eluted with
petroleum ether/EtOAc (3:7) gave 2b (100 mg, 5%) and a mixture
of 2a and 2b (1.4 g, ca. 1:3 as evidenced by 1H NMR spectroscopy;
overall yield of 2a/b: 75%).
7,13-DiTES-10-dehydro-10-deacetylbaccatin III (7): Foam. IR
(KBr): ν˜ ϭ 3462, 1717, 1451, 1107, 1007, 986, 712 cmϪ1. 1H NMR
(CDCl3): δ ϭ 0.69 (q, J ϭ 7.9 Hz, OTES), 1.02 (t, J ϭ 7.9 Hz,
OTES), 1.11 (s, 16-H/3), 1.16 (s, 17-H/3), 1.71 (s, 19-H/3), 1.94 (br.
s, 18-H/3), 2.39 (s, OAc), 3.85 (br. d, J ϭ 10 Hz, 7-H), 4.02 (d, J ϭ
7.4 Hz, 3-H), 4.31 (d, J ϭ 8.2 Hz, 20b-H), 4.43 (d, J ϭ 8.2 Hz, 20a-
H), 4.57 (d, J ϭ 10 Hz, OH), 4.96 (m, 5-H ϩ 13-H), 5.82 (d, J ϭ
7.4 Hz, 2-H), 7.51(BBЈ-Bz), 7.70 (C-Bz), 8.11 (AAЈ-Bz) ppm.
HRMS (70 eV): m/z ϭ 656.3003 (calcd. for C35H48O10Si, 656.3017).
Wagner؊Meerwein Rearrangement of 13-TES-10-dehydro-10-de-
acetylbaccatin V (6): Dry pyridine (3.0 mL, 2.9 g, 37.1 mmol, 24.4
mol equiv.) and thionyl chloride (757 µL, 1.24 g, 10.4 mmol, 6.8
mol equiv.) were added to a cooled (0 °C) solution of 6 (1.0 g,
1.52 mmol) in dry CH2Cl2 (18 mL). After stirring for 5 min at 0
°C, the reaction mixture was worked up by dilution with EtOAc
and neutralisation with satd. NaHCO3. After washing with 2 
H2SO4 and brine, the organic phase was dried (Na2SO4) and the
solvents were evaporated. The residue was purified by column chro-
matography on silica gel (25 g, elution with petroleum ether/
EtOAc, 8:2) to afford crude 8 (780 mg, 80%).
10,13-Bis(dehydro)-10-deacetylbaccatin V (5): White powder, m.p.
183Ϫ185 °C. IR (KBr): ν˜ ϭ 3581, 3453, 3303, 1716, 1709, 1668,
1
1277, 1115, 1053, 1005, 711 cmϪ1. H NMR (CDCl3): δ ϭ 1.14 (s,
16-H/3), 1.26 (s, 17-H/3), 1.70 (s, 19-H/3), 1.88 (s, 18-H/3), 2.27 (s,
OAc), 2.74 (d, J ϭ 15.5 Hz, 14b-H), 3.12 (d, J ϭ 15.5 Hz, 14a-H),
3.85 (ddd, J ϭ 10, 5, 3 Hz, 7-H), 4.12 (d, J ϭ 7.1 Hz, 3-H), 4.27(d,
J ϭ 8.3 Hz, 20b-H), 4.29 (d, J ϭ 9.2 Hz, 7-OH), 4.44 (d, J ϭ
8.3 Hz, 20a-H), 4.89 (m, 5-H), 5.91 (d, J ϭ 7.1 Hz, 2-H), 7.52 (BBЈ-
Bz), 7.66 (C-Bz), 8.09 (AAЈ-Bz) ppm. 13C NMR (CDCl3): δ ϭ 15.2
(C-19), 15.4 (C-18), 23.9 (C-16), 23.1 (OAc), 33.8 (C-17), 34.4 (C-
6), 37.4 (C-15), 41.1 (C-3), 41.4 (C-14), 60.2 (C-8), 75.0 (C-2), 77.9
(C-7), 77.9 (C-20), 81.42 (C-4), 83.2 (C-1), 84.2 (C-5), 130.5 (Bz),
130.9 (Bz), 132.4 (Bz), 136.3 (Bz), 141.5 (C-12), 160.3 (C-11), 168.9
(Bz), 174.1 (OAc), 189.4 (C-10), 199.9 (C-13), 208.5 (C-9) ppm.
HRMS (70 eV): m/z ϭ 540.2008 (calcd. for C29H32O10, 540.1996).
13-TES-10-deacetyl-10-dehydro-11(15Ǟ1)abeobaccatin
V
(8):
Foam. IR (KBr): ν˜ ϭ 3492, 1719, 1672, 1603, 1372, 1260, 1105,
853, 716 cmϪ1. 1H NMR (CDCl3): δ ϭ 0.56 (q, J ϭ 7.9 Hz, OTES),
0.98 (t, J ϭ 7.9 Hz, OTES), 1.68 (s, 19-H/3), 1.72 (br. s, 16-H/3),
10-Dehydrobaccatin V (2b): White powder, m.p. 162 °C. IR (KBr): 2.16 (s, OAc ϩ 18-H/3), 3.88 (d, J ϭ 8.2 Hz, 3-H), 4.02 (m, 7-H),
ν˜ ϭ 3420, 1720, 1265, 1100, 1070, 1010, 720 cmϪ1
(CDCl3): δ ϭ 1.09 (s, 17-H/3), 1.10 (s, 16-H/3), 1.72 (s, 19-H/3),
1.97 (br. s, 18-H/3), 2.39 (s, OAc), 3.86 (ddd, J ϭ 10, 5, 3 Hz, 7-
.
1H NMR
3.56 (d, J ϭ 8.4 Hz, 20b-H), 4.09 (d, J ϭ 9 Hz, OH), 4.42 (d, J ϭ
8.4 Hz, 20a-H), 4.50 (br. t, J ϭ 7.5 Hz, 13-H), 4.64 (br. s, 17b-H),
4.75 (br. s, 17a-H), 4.99 (br. d, J ϭ 7 Hz, 5-H), 5.82 (d, J ϭ 8.2 Hz,
Eur. J. Org. Chem. 2003, 4422Ϫ4431
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4427

G. Appendino et al.
FULL PAPER
2-H), 7.49 (BBЈ-Bz), 7.63 (C-Bz), 8.03 (AAЈ-Bz) ppm. HRMS
(70 eV): m/z ϭ 638.2919 (calcd. for C35H46O9Si, 638.2911).
2.10 (br. s, 18-H/3), 2.29 (s, OAc), 3.84(d, J ϭ 7.4 Hz, 3-H), 4.32
(br. s, 9-H), 4.36 (m, 7-H), 4.39 (d, J ϭ 8.6 Hz, H-20b), 4.59 (br. s,
10-H), 4.88 (br. s, 13-H), 4.89 (d, J ϭ 8.1, 5-H), 5.88 (d, J ϭ 7.4 Hz,
2-H), 7.59 (BBЈ-Bz), 7.63 (C-Bz), 8.10 (AAЈ-Bz) ppm. HRMS
(70 eV): m/z ϭ 546.2455 (calcd. for C29H38O10, 546.2465).
Reductive Fragmentation of 10-Dehydro-10-deacetylbaccatin (III ؉
V) (2a/b) with NaBH4/CeCl3: NaBH4 (ca. 600 mg) was added por-
tionwise to a stirred suspension of 2a/b (5 g, 9.2 mmol) and
CeCl3·7H2O (3.4 g, 9.2 mmol, 1 mol equiv.) in methanol (300 mL)
until TLC (petroleum ether/EtOAc, 1:9) showed the disappearance
of the starting material. The reaction was then worked up by the
addition of satd. NH4Cl (300 mL) and extraction with EtOAc (3
ϫ 200 mL). The organic phase was washed with brine and dried
(Na2SO4), and the solvents were evaporated, affording a white pow-
der, which was purified by column chromatography on silica gel
(250 g), with use of a petroleum ether/EtOAc gradient. Fractions
eluted with petroleum ether/EtOAc (7:3) afforded 10c (150 mg,
3%), 10a (450 mg, 9%), 10b (200 mg, 4%) and 10d (150 mg, 3%).
Fractions eluted with petroleum ether/EtOAc (1:9) gave 3a (1.4 g,
28%).
10-Dehydro-7,8-seco-10-deacetylbaccatin III (3a): White powder,
m.p. 159Ϫ163 °C. IR (KBr): ν˜ ϭ 3453, 1751, 1718, 1682, 1647,
1277, 1223, 1131, 1028, 712 cmϪ1. 1H NMR (CD3OD, 50 °C): δ ϭ
1.08 (s, 16-H/3), 1.12 (s, 17-H/3), 1.81 (br. s, 19-H/3), 1.83 (br. s,
OAc), 1.91 (br. s, 18-H/3), 1.95 (br. m, 6b-H), 2.36 (br. m,. 14b-H),
2.55 (br. m, 6a-H), 2.81 (br. m, 14a-H), 3.57 (br. m, 7b-H), 3.77
(br. m, 7a-H), 4.21 (d, J ϭ 8.3 Hz, 20b-H), 4.29 (d, J ϭ 7.5 Hz, 3-
H), 4.87 (m, 13-H), 5.15 (d, J ϭ 8.3 Hz, 20a-H), 5.27 (br. d, J ϭ
8.0 Hz, 5-H), 5.63 (d, J ϭ 7.5 Hz, 2-H), 7.52 (BBЈ-Bz), 7.65 (C-
Bz), 8.11 (AAЈ-Bz) ppm. 13C NMR ([D6]DMSO, 130 °C): δ ϭ 14.3
(C-19), 14.9 (C-18), 22.0 (OAc), 21.4 (C-16), 24.9 (C-17), 37.1 (C-
14), 37.4 (C-6), 43.2 (C-15), 44.4 (C-3), 59.6 (C-7), 69.1 (C-13), 74.8
(C-2), 74.9 (C-20), 80.4 (C-1), 86.2 (C-4), 87.2 (C-5), 124.6 (C-8),
128.4 (Bz), 129.03 (Bz), 129.3 (Bz), 133.9 (Bz), 127.0 (C-12), 142.4
(C-11), 149.6 (C-9), 167.4 (Bz), 169.2 (OAc), 191.2 (C-10) ppm.
HRMS (70 eV): m/z ϭ 544.2319 (calcd. for C29H36O10, 544.2309).
10-Epi-10-deacetylbaccatin III (10a): White powder, m.p. 128Ϫ130
°C. IR (KBr): ν˜ ϭ 3410, 1720, 1705, 1250, 1110, 1070, 975, 705
cmϪ1 1H NMR (CDCl3): δ ϭ 1.13 (s, 17-H/3), 1.15 (s, 16-H/3),
.
1.69 (s, 19-H/3), 1.90 (m, 6β-H), 2.10 (m, 14-H/2), 2.18 (br. s, 18-
H/3), 2.31 (s, OAc), 2.52 (m, 6α-H), 4.18 (d, J ϭ 8.3 Hz, 20b-H),
4.26 (d, J ϭ 6.8 Hz, 3-H), 4.33 (d, J ϭ 8.3 Hz, 20a-H), 4.76 (m,
13-H ϩ 7-H), 5.03 (d, J ϭ 8.1 Hz, 5-H), 5.20 (br. s, 10-H), 5.68 (d,
J ϭ 6.8 Hz, 2-H), 7.49 (BBЈ-Bz), 7.58 (C-Bz), 8.12 (AAЈ-Bz) ppm.
13C NMR ([D6]DMSO): δ ϭ 11.0 (C-19), 14.0 (C-18), 22.5 (C-16),
22.7 (OAc), 26.8 (C-17), 36.3 (C-6), 39.3 (C-14), 43.0 (C-15), 45.2
(C-3), 60.0 (C-8), 66.7 (C-13), 69.9 (C-7), 75.6 (C-2), 76.1 (C-20),
77.1 (C-1), 80.3 (C-4), 82.0 (C-10), 84.2 (C-5), 129.1 (Bz), 129.9
(Bz), 130.7 (Bz), 131.3 (C-11), 133.6 (Bz), 135.5 (C-12), 165.7 (Bz),
169.7 (OAc), 208.4 (C-9) ppm. HRMS (70 eV): m/z ϭ 544.2324
(calcd. for C29H36O10, 544.2309).
Synthesis of 14-Hydroxy-10-dehydro-7,8-seco-10-deacetylbaccatin
III 1,14-Acetonide (12): Cu(OAc)2·H2O (1.2 g) was added in small
portions over ca. 5 min to a magnetically stirred suspension of
11[20] (604 mg, 1 mmol) in methanol (10 mL). After stirring over-
night, the reaction mixture was worked up by concentration and
addition of water (60 mL) and EtOAc (60 mL). The organic phase
was washed with 2  NH3 to remove copper salts, and then with
brine. After drying (Na2SO4) and evaporation, the residue was
taken up in methanol (5 mL) and treated with CeCl3·7H2O
(371 mg, 1 mmol, 1 mol equiv.) and next NaBH4 (60 mg). After
stirring for 20 min at room temp., the reaction mixture was worked
up by the addition of satd. NH4Cl (30 mL) and extraction with
EtOAc (3 ϫ 20 mL). The organic phase was washed with brine and
dried (Na2SO4), and the solvents were evaporated. The residue was
purified by column chromatography on silica gel (25 g), with use of
a petroleum ether/EtOAc gradient. Fractions eluted with petroleum
ether/EtOAc (3:7) gave a complex mixture of taxanes that was not
further characterized, while fractions eluted with petroleum ether/
EtOAc (1:9) afforded 12 (124 mg, 21% from 11) as a white powder.
M.p. 109Ϫ112 °C. IR (KBr): ν˜ ϭ 3432, 1736, 1649, 1269, 1159,
1092, 1026, 714 cmϪ1. 1H NMR (CDCl3) Major rotamer: δ ϭ 1.05
(s, acetonide), 1.11 (s, 17-H/3), 1.17 (s, 16-H/3), 1.43 (s, acetonide),
1.72 (s, OAc), 1.82 (br. s, 19-H/3), 2.02 (br. s, 18-H/3), 2.03 (br. m,
6b-H), 2.48 (br. m, 6a-H), 3.83 (br. m, 7b-H), 3.91 (br. m, 7a-H),
4.28 (d, J ϭ 8.1 Hz, 20b-H), 4.35 (d, J ϭ 7.5 Hz, 3-H), 4.84 (d,
J ϭ 2 Hz, 14-H), 4.98 (d, J ϭ 2 Hz, 13-H), 5.18 (d, J ϭ 8.1 Hz,
20a-H), 5.36 (br. d, J ϭ 8.0 Hz, 5-H), 6.01 (d, J ϭ 7.5 Hz, 2-H),
7.49 (BBЈ-Bz), 7.59 (C-Bz), 8.00 (AAЈ-Bz) ppm. Minor rotamer:
δ ϭ 1.03 (s, acetonide), 1.13 (s, 17-H/3), 1.13 (s, 16-H/3), 1.39 (s,
acetonide), 1.92 (br. s, 18-H/3), 2.00 (br. m, 6b-H and 6a-H), 2.35
(s, OAc),), 2.44 (br. s, 19-H/3), 3.14 (br. m, 7b-H and 7a-H), 4.29
(d, J ϭ 2 Hz, 14-H), 4.36 (d, J ϭ 8.1 Hz, 20b-H), 4.42 (d, J ϭ
8.1 Hz, 20a-H), 4.86 (d, J ϭ 7.5 Hz, 3-H), 4.85 (d, J ϭ 2 Hz, 13-
H), 4.99 (br. d, J ϭ 8.0 Hz, 5-H), 5.98 (d, J ϭ 7.5 Hz, 2-H), 7.49
(BBЈ-Bz), 7.62 (C-Bz), 8.16 (AAЈ-Bz) ppm. 13C NMR (CDCl3):
Major rotamer: δ ϭ 14.3 (C-19), 14.7 (C-18), 22.0 (OAc), 22.2 (C-
16), 26.8 (C-17), 38.1 (C-6), 42.7 (C-15), 44.5 (C-3), 59.0 (C-7), 63.7
(C-2), 73.4 (C-13), 74.9 (C-20), 90.3 (C-1), 83.5 (C-14), 86.3 (C-4),
86.4 (C-5), 125.0 (C-8), 129.0 (Bz), 129.1 (Bz), 129.5 (Bz), 133.6
10-Epi-10-deacetylbaccatin V (10b): White powder, m.p. 198Ϫ200
°C. IR (KBr): ν˜ ϭ 3380, 2250, 1710, 1600, 1270, 1100, 1070, 980,
1
730 cmϪ1. H NMR (CDCl3): δ ϭ 1.04 (s, 17-H/3), 1.06 (s, 16-H/
3), 1.66 (s, 19-H/3), 2.18 (br. s, 18-H/3), 2.38 (s, OAc), 3.84 (ddd,
J ϭ 10, 5, 3 Hz, 7-H), 4.38 (d, J ϭ 8.3 Hz, 20b-H), 4.42 (d, J ϭ
8.3 Hz, 20a-H), 4.46 (d, J ϭ 7.3 Hz, 3-H), 4.68 (m, 13-H), 4.94 (m,
5-H ϩ 10-H), 5.71 (d, J ϭ 7.3 Hz, 2-H), 5.98 (d, J ϭ 11.3 Hz, 7-
OH), 6.09 (d, J ϭ 11.6 Hz, 10-OH), 7.52 (BBЈ-Bz), 7.61 (C-Bz),
8.12 (AAЈ-Bz) ppm. 13C NMR (CDCl3): δ ϭ 13.7 (C-18), 17.1 (C-
19), 21.39 (C-16), 22.6 (OAc), 25.7 (C-17), 34.8 (C-6), 38.3 (C-14),
43.0 (C-15), 41.6 (C-3), 59.6 (C-8), 68.5 (C-13), 75.1 (C-7), 76.4 (C-
2), 77.7 (C-20), 78.4 (C-1), 81.6 (C-4), 81.2 (C-10), 82.4 (C-5), 128.7
(Bz), 129.4 (Bz), 130.1 (Bz), 130.7 (Bz), 133.7 (Bz), 134.2 (C-11),
134.3 (C-12), 167.1 (Bz), 173.1 (OAc), 211.6 (C-9) ppm. HRMS
(70 eV): m/z ϭ 544.2327 (calcd. for C29H36O10, 544.2309).
13-Dehydro-10-epi-10-deacetylbaccatin III (10c): Amorphous foam.
IR (KBr): ν˜ ϭ 3453, 1721, 1665, 1603, 1375, 1244, 1178, 1071, 947
cmϪ1 1H NMR (CDCl3): δ ϭ 1.16 (s, 17-H/3), 1.19 (s, 16-H/3),
.
1.71 (s, 19-H/3), 2.29 (br. s, 18-H/3), 2.31 (s, OAc), 2.65 (d, J ϭ
20 Hz, H-14b), 3.02 (d, J ϭ 20 Hz, H-14b), 4.19 (d, J ϭ 8.3 Hz,
20b-H), 4.30(d, J ϭ 8.3 Hz, 20a-H), 4.39 (d, J ϭ 6.8 Hz, 3-H),
4.82(dd, J ϭ 7, 4 Hz, 7-H), 4.98 (d, J ϭ 8.1 Hz, 5-H), 5.41 (br. s,
10-H), 5.69 (d, J ϭ 6.8 Hz, 2-H), 7.50 (BBЈ-Bz), 7.59 (C-Bz), 8.06
(AAЈ-Bz) ppm. HRMS (70 eV): m/z ϭ 542.2140 (calcd. for
C29H34O10, 546.2152).
10-Epi-10-deacetyl-9βH-dihydrobaccatin
foam. IR (KBr): ν˜ ϭ 3431, 2934, 1716, 1601, 1450, 1373, 1315,
1026, 719 cmϪ1 1H NMR (CDCl3 /[D6]DMSO, after D2O ex- (Bz), 137.5 (C-12), 142.5 (C-11), 148.9 (C-9), 165.5 (Bz), 169.1
change): δ ϭ 1.09 (s, 17-H/3), 1.39 (s, 16-H/3), 1.46 (s, 19-H/3), (OAc), 191.3 (C-10) ppm. Minor rotamer: δ ϭ 13.6 (C-19), 14.3
V
(10d): Amorphous
.
4428
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4422Ϫ4431

The Reductive Fragmentation of 7-Hydroxy-9,10-dioxotaxoids
(C-18), 22.5 (OAc), 21.4 (C-16), 27.2 (C-17), 34.0 (C-6), 42.1 (C-
FULL PAPER
6b-H), 2.48 (br. m, 6a-H), 3.83 (br. m, 7b-H), 3.91 (br. m, 7a-H),
3), 43.2 (C-15), 60.3 (C-7), 69.9 (C-2), 74.7 (C-13), 76.5 (C-20), 89.1 4.28 (d, J ϭ 8.1 Hz, 20b-H), 4.35 (d, J ϭ 7.5 Hz, 3-H), 4.84 (d,
(C-1), 84.1 (C-14), 85.8 (C-4), 85.8 (C-5), 125.0 (C-8), 128.7 (Bz), J ϭ 2 Hz, 14-H), 4.98 (d, J ϭ 2 Hz, 13-H), 5.18 (d, J ϭ 8.1 Hz,
129.8 (Bz), 129.9 (Bz), 133.6 (Bz), 138.6 (C-12), 142.5 (C-11), 148.8 20a-H), 5.36 (br. d, J ϭ 8.0 Hz, 5-H), 6.01 (d, J ϭ 7.5 Hz, 2-H),
(C-9), 165.6 (Bz), 170.0 (OAc), 191.4 (C-10) ppm. HRMS (70 eV):
m/z ϭ 600.2588 (calcd. for C32H40O11, 600.2571).
7.49 (BBЈ-Bz), 7.59 (C-Bz), 8.00 (AAЈ-Bz) ppm. Minor rotamer:
δ ϭ 1.03 (s, acetonide), 1.13 (s, 17-H/3), 1.13 (s, 16-H/3), 1.39 (s,
acetonide), 1.92 (br. s, 18-H/3), 2.00 (br. m, 6b-H and 6a-H), 2.35
(s, OAc),), 2.44 (br. s, 19-H/3), 3.14 (br. m, 7b-H and 7a-H), 4.29
(d, J ϭ 2 Hz, 14-H), 4.36 (d, J ϭ 8.1 Hz, 20b-H), 4.42 (d, J ϭ
8.1 Hz, 20a-H), 4.86 (d, J ϭ 7.5 Hz, 3-H), 4.85 (d, J ϭ 2 Hz, 13-
H), 4.99 (br. d, J ϭ 8.0 Hz, 5-H), 5.98 (d, J ϭ 7.5 Hz, 2-H), 7.49
(BBЈ-Bz), 7.62 (C-Bz), 8.16 (AAЈ-Bz) ppm. 13C NMR (CDCl3):
Major rotamer: δ ϭ 14.3 (C-19), 14.7 (C-18), 22.0 (OAc), 22.2 (C-
16), 26.8 (C-17), 38.1 (C-6), 42.7 (C-15), 44.5 (C-3), 59.0 (C-7), 63.7
(C-2), 73.4 (C-13), 74.9 (C-20), 90.3 (C-1), 83.5 (C-14), 86.3 (C-4),
86.4 (C-5), 125.0 (C-8), 129.0 (Bz), 129.1 (Bz), 129.5 (Bz), 133.6
(Bz), 137.5 (C-12), 142.5 (C-11), 148.9 (C-9), 165.5 (Bz), 169.1
(OAc), 191.3 (C-10) ppm. Minor rotamer: δ ϭ 13.6 (C-19), 14.3
(C-18), 22.5 (OAc), 21.4 (C-16), 27.2 (C-17), 34.0 (C-6), 42.1 (C-
3), 43.2 (C-15), 60.3 (C-7), 69.9 (C-2), 74.7 (C-13), 76.5 (C-20), 89.1
(C-1), 84.1 (C-14), 85.8 (C-4), 85.8 (C-5), 125.0 (C-8), 128.7 (Bz),
129.8 (Bz), 129.9 (Bz), 133.6 (Bz), 138.6 (C-12), 142.5 (C-11), 148.8
(C-9), 165.6 (Bz), 170.0 (OAc), 191.4 (C-10) ppm. HRMS (70 eV):
m/z ϭ 600.2588 (calcd. for C32H40O11, 600.2571).
Reductive Fragmentation of 10-Dehydro-10-deacetylbaccatin (III ؉
V) (2a/b) with L-Selectride: In a two-necked 250 mL flask, 2a/b
(5.00 g, 9.22 mmol) was suspended in dry THF (100 mL). With vig-
orous magnetic stirring, the reaction mixture was cooled to Ϫ15
°C (bath temperature) while L-selectride (1.0  in THF, 37 mL,
36.9 mmol, 4 mol equiv.) was added dropwise over ca. 3 min. At
the end of the addition, the cooling bath was removed, and the
yellow-orange reaction mixture was worked up by the addition of
wet EtOAc and 2  H2SO4. The organic phase was washed sequen-
tially with 2  H2SO4 and brine, and then dried (Na2SO4). Removal
of the solvent gave a deep orange oil, which was purified by gravity
column chromatography on silica gel (50 g). Fraction eluted with
petroleum ether/EtOAc (6:4) gave a reddish oil, while fractions
eluted with petroleum ether/EtOAc (5:5) afforded 3a (4.48 g, 90%)
as a white powder. When the reaction was carried out at room
temperature, the seco-taxane 3a was contaminated with compound
13, structurally elucidated as its 7,9-bis(triethylsilyl) derivative
[TES-Cl (4 equiv.), imidazole (4 equiv.), CH2Cl2]. IR (KBr): ν˜ ϭ
3460, 1759, 1722, 1679, 1649, 1270, 1283, 1140, 1031, 719 cmϪ1
.
Synthesis of 10-Dehydro-7,8-seco-10-deacetylcephalomannine (15).
a. Chemoselective Deacetylation and Silylation of Cephalomannine
(14a): H2O2 (30%, 100 mL) and NaHCO3 (20 g) were added to a
solution of cephalomannine (14a, 2.0 g, 2.40 mmol) in THF
1H NMR (C6D6): δ ϭ 0.69 (q, J ϭ 7.6 Hz, TES), 0.88 (q, J ϭ
7.6 Hz, TES), 0.93 (s, 17-H/3), 1.09 (t, J ϭ 7.6 Hz, TES), 1.11 (t,
J ϭ 7.6 Hz, TES), 1.34 (s, 16-H/3), 1.95 (m, 6b-H), 1.95 (s, 19-H/
3), 2.02 (s, 18-H/3), 2.06 (s, OAc), 2.55 (br. m, 6b-H), 3.22 (br. m, (200 mL). After stirring at room temperature for 24 h, the reaction
14a,b-H), 3.91 (br. m, 7a,b-H), 3.92 (m, 20b-H), 4.24 (d, J ϭ 10 Hz, mixture was worked up by dilution with EtOAc and washed with
3-H), 4.30 (m, 13-H), 4.37 (d, J ϭ 7.4 Hz, 20a-H), 4.68 (br. d, J ϭ 5% Na2S2O3 and then with brine. After drying (Na2SO4) and evap-
11.4 Hz, 5-H), 5.92 (d, J ϭ 10 Hz, 2-H), 7.07 (C-Bz), 7.11 (BBЈ- oration, the residue was dissolved in petroleum ether/EtOAc (5:5)
Bz), 8.10 (AAЈ-Bz) ppm. 13C NMR (C6D6): δ ϭ 5.2 (TES-CH2), and purified by column chromatography (30 g silica gel, petroleum
7.0 (TES-CH2), 7.5 (TES-Me), 7.7 (TES-Me), 14.8 (C-18), 16.0 (C- ether/EtOAc, 5:5, as eluent) to give 10-deacetylcephalomannine
19), 22.4 (OAc), 25.1 (C-17), 26.7 (C-16), 37.8 (C-14), 38.3 (C-6), (14b, 1.67 g, 88%) as a white, fluffy powder.[32] This was dissolved
43.9 (C-15), 44.4 (C-3), 58.7 (C-7), 67.4 (C-13), 73.6 (C-2), 80.7 (C- in dry DMF (20 mL) and treated sequentially with imidazole
20), 80.8 (C-4), 91.8 (C-1), 93.2 (C-5), 128.9 (Bz), 130.2 (Bz), 132.3 (573 mg, 8.42 mmol, mol equiv.) and TES-Cl (1.42 mL,
(C-8), 133.0 (Bz), 133.0 (Bz), 142.2 (C-12), 142.9 (C-11), 149.6 (C- 8.42 mmol, 4 mol equiv.). After stirring at room temperature for
4
9), 165.8 (Bz), 170.1 (OAc), 192.2 (C-10) ppm.
1 h , the reaction mixture was worked up by pouring into a stirred
suspension of Celite (3.2 g) in water (80 mL) and filtration through
a sintered glass. The cake was washed with water to remove most
of the DMF and next with EtOAc to recover the silylated product.
After washing with brine, drying (Na2SO4) and evaporation, the
residue was purified by column chromatography on silica gel to
afford 14c (967 mg, 51%) as a white powder, m.p. 111 °C. IR (KBr):
ν˜ ϭ 3493, 1752, 1724, 1716, 1680, 1375, 1271, 1244, 1138, 984
cmϪ1. 1H NMR (CDCl3): δ ϭ 0.59 (q, J ϭ 7.9 Hz, OTES), 0.99 (t,
J ϭ 7.9 Hz, OTES), 1.14 (s, 17-H/3), 1.21 (s, 16-H/3), 1.68 (s, 19-
H/3), 1.71 (br. s, Tigl),), 1.79 (br. s, Tigl ϩ 18-H/3), 2.35 (br. s, Ac),
3.90 (d, J ϭ 7.5 Hz, 3-H), 4.19 (d, J ϭ 9 Hz, 20b-H), 4.31 (dd, J ϭ
11, 7 Hz, 7-H), 4.32 (d, J ϭ 9 Hz, 20b-H), 4.70 (d, J ϭ 3 Hz, 2Ј-
H), 4.95 (br. d, J ϭ 7.5 Hz, 5-H), 5.18 (s, 10-H), 5.60 (dd, J ϭ 9,
3 Hz, 3Ј-H), 5.69 (d, J ϭ 7.5 Hz, 2-H), 6.19 (br. t, J ϭ 7.5 Hz, 13-
H), 6.44 (br. q, J ϭ 7 Hz, Tigl), 6.65 (br. d, J ϭ 9 Hz, NH), 7.40
(m, Ph), 7.52 (BBЈ-Bz), 7.65 (C-Bz), 8.11 (AAЈ-Bz) ppm.
Synthesis of 14-Hydroxy-10-dehydro-7,8-seco-10-deacetylbaccatin
III 1,14-Acetonide (12): Cu(OAc)2·H2O (1.2 g) was added in small
portions over ca. 5 min to a magnetically stirred suspension of
11[20] (604 mg, 1 mmol) in methanol (10 mL). After stirring over-
night, the reaction mixture was worked up by concentration and
addition of water (60 mL) and EtOAc (60 mL). The organic phase
was washed with 2  NH3 to remove copper salts, and then with
brine. After drying (Na2SO4) and evaporation, the residue was
taken up in methanol (5 mL) and treated with CeCl3·7H2O
(371 mg, 1 mmol, 1 mol equiv.) and next NaBH4 (60 mg). After
stirring 20 min at room temp., the reaction mixture was worked up
by the addition of satd. NH4Cl (30 mL) and extraction with EtOAc
(3 ϫ 20 mL). The organic phase was washed with brine and dried
(Na2SO4), and the solvents were evaporated. The residue was puri-
fied by column chromatography on silica gel (25 g), with use of a
petroleum ether/EtOAc gradient. Fractions eluted with petroleum
ether/EtOAc (3:7) gave a complex mixture of taxanes that was not
further characterized, while fractions eluted with petroleum ether/
EtOAc (1:9) afforded 12 (124 mg, 21% from 11) as a white powder.
b. Autoxidation, Reductive Fragmentation and Desilylation of 14c:
Cu(OAc)2·H2O (10 g) was added to a solution of 14c (904 mg,
1.07 mmol) in methanol (20 mL), and the suspension was magneti-
M.p. 109Ϫ112 °C. IR (KBr): ν˜ ϭ 3432, 1736, 1649, 1269, 1159, cally stirred for 24 h in a flask open to the air. The reaction mixture
1092, 1026, 714 cmϪ1. 1H NMR (CDCl3) Major rotamer: δ ϭ 1.05
(s, acetonide), 1.11 (s, 17-H/3), 1.17 (s, 16-H/3), 1.43 (s, acetonide),
was worked up by concentration under reduced pressure, filtration
through Celite and washing of the cake with EtOAc. The organic
1.72 (s, OAc), 1.82 (br. s, 19-H/3), 2.02 (br. s, 18-H/3), 2.03 (br. m, phase was washed with 2% NH3 and brine and dried (Na2SO4).
Eur. J. Org. Chem. 2003, 4422Ϫ4431
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4429

G. Appendino et al.
FULL PAPER
Removal of the solvent left a pale bluish powder, which was puri-
fied from copper impurities by filtration through silica gel, provid-
2), 71.0 (C-10), 74.4 (C-13), 76.0 (C-20), 81.2 (C-4), 83.4 (C-5),
112.2 (C-16), 128.6 (Bz), 129.7 (Bz), 129.9 (Bz), 133.5 (Bz), 135.9
ing 14d (860 mg, 89%) as an off-white powder (ca. 4:1 mixture of (C-11), 143.6 (C-12), 145.5 (C-15), 165.6 (Bz), 172.0 (OAc) ppm.
7α-hydroxy and 7β-hydroxy epimers). 1H NMR spectroscopic data
The signals of C-7, C-8 and C-9 could not be detected. HRMS
(CDCl3) of the major epimer, which could be purified after desilyl-
ation: H NMR: δ ϭ 1.14 (s, 16-H/3), 1.25 (s, 17-H/3), 1.74 (s, 19-
(70 eV): m/z ϭ 642.3229 (calcd. for C35H50O9Si, 642.3224).
1
Treatment of 16 with dimethoxypropane and p-toluenesulfonic acid
afforded 17a/b (45%). NMR spectroscopic data for the major iso-
mer (17a) were: 1H NMR (CDCl3): δ ϭ 1.38 (s, 19-H/3), 1.50 (ace-
tonide methyls), 1.80 (s, 17-H/3), 2.05 (m, 14a-H), 1.98 (s, 18-H/3),
2.18 (m, 6a-H), 2.19 (m, 14a-H), 2.27 (s, Ac), 2.43 (m, 6b-H), 3.18
(d, J ϭ 8.2 Hz, 3-H), 3.34 (s,. OMe), 3.83 (d, J ϭ 7 Hz,, 9-H), 3.91
(m, 7 H), 4.05 (d, J ϭ 7.4 Hz, 13-H), 4.09 (d, J ϭ 8.0 Hz, 20a-H),
4.48 (d, J ϭ 7 Hz, 10-H), 4.68 (d, J ϭ 8.0 Hz, 20a-H), 4.79 (s, 16a-
H), 4.90 (s, 16b-H), 4.92 (m, 5-H), 5.78 (d, J ϭ 8.2 Hz, 2-H), 7.48
(BBЈ-Bz), 7.60 (C-Bz), 8.05 (AAЈ-Bz) ppm. 13C NMR (CDCl3): δ ϭ
12.8 (C-18), 18.5 (C-19), 21.5 (C-17), 22.3 (Ac), 29.2 (acetonide
methyls), 32.9 (C-6), 33.5 (C-14) 36.4 (C-3), 37.3 (C-8), 57.3 (OMe),
62.6 (C-1), 69.2 (C-10), 72.6 (C-2), 73.8 (C-7), 78.6 (C-20), 80.9 (C-
9), 82.6 (C-5), 84.3 (C-4), 89.1 (C-13), 99.7 (acetonide), 112.7 (C-
16), 128.6 (Bz), 129.8 (Bz), 130.1 (Bz), 133.3 (Bz), 137.3 (C-11),
141.9 (C-12), 147.2 (C-15), 165.9 (Bz), 168.9 (OAc) ppm.
H/3), 1.71 (br. s, Tigl),), 1.79 (br. s, Tigl ϩ 18-H/3), 2.52 (br. s, Ac),
3.87 (br. d, J ϭ 10 Hz, 7-H), 4.03 (d, J ϭ 7.5 Hz, 3-H), 4.36 (d,
J ϭ 9 Hz, 20b-H), 4.42 (d, J ϭ 10 Hz, OH), 4.54 (d, J ϭ 9 Hz,
20b-H), 4.72 (d, J ϭ 3 Hz, 2Ј-H), 4.95 (m, 5-H), 5.62(dd, J ϭ 9,
3 Hz, 3Ј-H), 5.89 (d, J ϭ 7.5 Hz, 2-H), 6.19 (br. t, J ϭ 7.5 Hz, 13-
H), 6.44 (br. q, J ϭ 7 Hz, Tigl), 6.53 (br. d, J ϭ 9 Hz, NH), 7.40
(m, Ph), 7.53 (BBЈ-Bz), 7.66 (C-Bz), 8.11 (AAЈ-Bz) ppm.
This was directly employed for the reductive fragmentation. To this
end, a solution of 14d (860 mg, 0.95 mmol) was dissolved in dry
THF (ca. 10 mL). After this mixture had been cooled to Ϫ15 °C,
a solution of -selectride (1.0 , 2.86 mL, 2.86 mmol, 3 mol equiv.)
was added dropwise. At the end of the addition, the yellow solution
was worked up by dilution with EtOAc and the addition of 2 
H2SO4. After washing with brine and evaporation, the residue of
the organic phase was dissolved in methanol (10 mL) and treated
with 2 mL of a solution of acetyl chloride in methanol (560 µL in
10 mL). After stirring at room temperature for 15 min, the reaction
mixture was diluted with EtOAc and washed with satd. NaHCO3
and brine. After drying (Na2SO4) and evaporation, the residue was
purified by column chromatography on silica gel (25 mL, petro-
leum ether/EtOAc, 5:5, as eluent) to afford 15 (355 mg, 47% from
14d).
Reduction of 13-TES-10-deacetyl-10-dehydro-11(15Ǟ1)abeobacca-
tin V (8) with L-Selectride: L-Selectride (1  in THF, 312 µL,
0.31 mmol, 2 mol equiv.) was added dropwise to a cooled (Ϫ78 °C)
solution of 8 (100 mg, 0.16 mmol) in dry THF. After 5 min, the
yellow/orange reaction mixture was worked up by dilution with
EtOAc and treatment wit 2  H2SO4. The organic phase was
sequentially washed with 2  H2SO4 and brine, and then dried
(Na2SO4). Removal of the solvent gave a deep orange oil, which
was purified by gravity column chromatography on silica gel (2.5 g,
petroleum ether/EtOAc, 8:2, as eluent) to give 18 (18 mg, 18%) as
a foam, IR (KBr): ν˜ ϭ 3400, 1780, 1721, 1273, 1100, 1067, 1048
10-Dehydro-7,8-seco-10-deacetylcephalomannine (15): White pow-
der, m.p. 150 °C. IR (KBr): ν˜ ϭ 3418, 1740, 1653, 1636, 1273, 1107,
1
1069, 99, 712 cmϪ1. H NMR (CDCl3, 40 °C): δ ϭ 1.20 (s, 16-H/
3), 1.40 (s, 17-H/3), 1.60 (br. s, 18-H/3 ϩ Tigl), 1.80 (br. s, Tigl),
1.92 (br. s, 19-H/3), 2.06 (br. s, OAc), 3.90 (br. m, 7b-H), 4.20 (br.
m, 7a-H), 4.28 (d, J ϭ 7.5 Hz, 3-H), 4.30 (m, 20a,b-H), 4.80 (m,
2Ј-H), 5.15 (br. d, J ϭ 8.0 Hz, 5-H), 5.60 (d, J ϭ 7.5 Hz, 2-H), 5.70
(dd, J ϭ 8, 2 Hz, 3Ј-H), 6.17 (br. t, J ϭ 6 Hz, 13-H), 6.36 (br. q,
J ϭ 7 Hz, Tigl), 6.30 (br. s, OH), 6.64 (d, J ϭ 9 Hz, NH), 7.20Ϫ7.36
(m, Ph), 7.42 (BBЈ-Bz), 7.52 (C-Bz), 8.04 (AAЈ-Bz) ppm. HRMS
(70 eV): m/z ϭ 789.3370 (calcd. for C43H54NO13, 789.3360).
cmϪ1 1H NMR (C6D6): δ ϭ 0.63 (q, J ϭ 7.6 Hz, TES), 1.00 (s,
.
OAc), 1.02 (t, J ϭ 7.6 Hz, TES), 1.56 (s, 19-H/3), 1.95 (s, 17-H/3),
2.12 (m. 6a-H), 2.15 (m, 14a-H), 2.43 (s, 18-H/3), 2.45 (m, 3-H),
2.47 (m, 14b-H), 2.64 (dd, J ϭ 5.9, 17.1 Hz, 6b-H), 4.59 (m, 13-
H), 4.59 (m, 7-H), 4.75 (d, J ϭ 5.9 Hz, 5-H), 4.67 (d, J ϭ 8.1 Hz,
20a-H), 4.75 (br. d, J ϭ 5.9 Hz, 5-H), 4.80 (m, 20a-H), 4.80 (s, 16a-
H), 5.01 (s, 16b-H), 6.17 (d, J ϭ 10 Hz, 2-H), 7.03 (C-Bz), 7.12
(BBЈ-Bz), 7.93 (AAЈ-Bz) ppm. 13C NMR (C6D6): δ ϭ 5.6 (TES-
CH2), 7.4 (TES-Me), 11.7 (C-19), 15.4 (C-18), 20.6 (OAc), 21.0 (C-
17), 30.6 (C-6), 38.9 (C-3), 44.4 (C-14), 47.1 (C-8), 59.6 (C-1), 70.4
(C-2), 74.4 (C-20), 78.4 (C-7), 78.5 (C-13), 79.1 (C-9), 79.3 (C-4),
83.6 (C-5), 113.8 (C-16), 129.0 (Bz), 130.4 (Bz), 130.8 (Bz), 132.7
(C-11), 133.5 (Bz), 148.9 (C-15), 151.3 (C-12), 165.3 (Bz), 168.8
Reduction of 13-TES-10-deacetyl-10-dehydro-11(15Ǟ1)abeobacca-
tin V (8) with NaBH4/CeCl3: CeCl3·7H2O (58 mg, 0.16 mmol, 1 mol
equiv.) was added to a solution of 8 (100 mg, 0.16 mmol) in MeOH
(10 mL). After the mixture had been stirred at room temperature
for 5 min, NaBH4 (10 mg) was added. After 10 min the reaction
mixture was worked up by dilution with EtOAc and brine. The
organic phase was washed with brine and dried (Na2SO4), and the
solvents were evaporated. The residue was purified by column chro-
matography on silica gel (2.5 g, petroleum ether/EtOAc, 5:5, as elu-
ent), affording 16 (98 mg, 98 %).
(OAc) ppm. HRMS (70 eV): m/z
C36H48O10Si Ϫ H2O, 638.2911).
ϭ 638.2928 (calcd. for
Acknowledgments
We are grateful to Dr. Jasmin Jakupovic (AnalytiCon Discovery
GmbH, Potsdam, Germany) for his useful suggestions and encour-
agement throughout this work.
13-TES-9-dihyhdro-10-deacetyl-10-epi-11(15Ǟ1)abeobaccatin
V
(16): Foam. IR (KBr): ν˜ ϭ 3850, 1719, 1630, 1458, 1273, 1096,
1069, 712 cmϪ1. 1H NMR (CDCl3): δ ϭ 0.64 (q, J ϭ 7.6 Hz, TES),
1.01 (t, J ϭ 7.6 Hz, TES), 1.61 (s, 19-H/3), 1.69 (s, 17-H/3), 1.76
(m, 14a-H), 1.98 (s, 18-H/3), 2.29 (s, Ac), 2.29 (m, 14a-H), 2.32 (m,
6a-H), 2.39 (m, 6b-H), 3.22 (m, 3-H), 3.70 (m, 9-H), 4.13 (m, 7 H),
4.27 (d, J ϭ 8.4 Hz, 20a-H), 4.40 (m, 10-H), 4.52 (m, 13-H), 4.52
(d, J ϭ 8.4 Hz, 20b-H), 4.75 (br. s, 16a-H), 4.83 (br. s, 16b-H), 5.02
(dd, J ϭ 8.4, 2.7 Hz, 5-H), 5.89 (d, J ϭ 8.0 Hz, 2-H), 7.48 (BBЈ-
Bz), 7.62 (C-Bz), 8.04 (AAЈ-Bz) ppm. 13C NMR (CDCl3): δ ϭ 4.9
(TES-CH2), 6.8 (TES-Me), 13.0 (C-18), 18.0 (C-19), 21.0 (C-17),
21.8 (Ac), 35.9 (C-6), 38.3 (C-3), 42.4 (C-14), 62.1 (C-1), 70.4 (C-
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Eur. J. Org. Chem. 2003, 4422Ϫ4431

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Received June 26, 2003
Eur. J. Org. Chem. 2003, 4422Ϫ4431
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