Selective synthesis of 14β-amino taxanes

Article abstract of DOI:10.1016/j.tet.2005.05.087

The base induced deprotonation of H-14 of 7-triethylsilyl- (7-TES-) and 7-tert-butoxycarbonyl- (7-BOC-) protected 13-oxo-baccatins gave the corresponding enolates, which were selectively aminated with electrophilic nitrogen donors, such as azodicarboxylat

Full text of DOI:10.1016/j.tet.2005.05.087

Tetrahedron 61 (2005) 7727–7745
Selective synthesis of 14b-amino taxanes
a,
b
c
Arturo Battaglia,a, Eleonora Baldelli, Ezio Bombardelli, Giacomo Carenzi,
*
*
Gabriele Fontana,b Maria Luisa Gelmi,c Andrea Guerrinia and Donato Pocarc
a
`
Istituto CNR per la Sintesi Organica e Fotoreattivita “I.S.O.F.”, Area della Ricerca di Bologna, via P. Gobetti 101, 40129 Bologna, Italy
bIndena SPA, viale Ortles 12, 20139 Milano, Italy
` `
Istituto di Chimica Organica “A. Marchesini”, Facolta di Farmacia, via Venezian 21, Universita di Milano, 20133 Milano, Italy
c
Received 16 March 2005; revised 11 May 2005; accepted 26 May 2005
Available online 16 June 2005
Dedicated to Professor J. Ojima on the occasion of his 60th birthday
Abstract—The base induced deprotonation of H-14 of 7-triethylsilyl- (7-TES-) and 7-tert-butoxycarbonyl- (7-BOC-) protected 13-oxo-
baccatins gave the corresponding enolates, which were selectively aminated with electrophilic nitrogen donors, such as azodicarboxylates
and tosyl azide. In particular, tosyl azide gave the corresponding 7-BOC- and 7-TES-13-oxo-14b-azido-baccatin III. Alternatively, the last
compound was prepared via NaN3 induced azidation of the 13-silyl enol ether of 7-TES-13-oxo-baccatin III under oxidative (cerium
ammonium nitrate) conditions. The 13-silyl enol ether was obtained in a multistep process by DBU induced silylation of 7-TES-13-oxo-
baccatin III. The 7-TES-13-oxo-14b-azido-baccatin III was used as a key intermediate for the synthesis of a new family of antitumour
taxanes containing amino based functional groups at the C-14 position, such as: 14b-azido, 14b-amino, 14b-amino 1, 14-carbamate,
14b-amino 1, 14-thiocarbamate, and 14b-amino N-tert-butoxycarbonyl-1,14-carbamate.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
baccatin III,3 the enol ester 12, 13-isobaccatin III,4 and their
12, 13-isotaxanes analogues.5 In addition, the 13-oxo group
activates the functionalization of the C-14 atom via enolate
chemistry. For example, the base induced hydroxylation
with oxaziridines of the potassium enolate of 1 and its
7-TES-13-oxo-baccatin III (1, Fig. 1)1 is an intermediate of
choice for studies on taxane chemistry, being used for the
synthesis of 12, 13-dihydro-10-DAB III,2 the 13-epi-7-TES-
Figure 1. Baccatin III derivatives and Ortataxel.
Keywords: 14b-Amino taxanes; 10-DAB III; Silyl enol ethers; Electrophilic amination; 13-Oxo-baccatins.
*
Corresponding authors. Tel.: C39 051 6398311; fax: C39 051 6398349; e-mail: battaglia@isof.cnr.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.087

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A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
7-BOC analogue 2 gave 7-TES- and 7-BOC-13-oxo-14b-
OH-baccatin III (Fig. 1).6 The enolate of 1 was employed
for the synthesis of the 13-OTMS enol ether 3, which was
converted into 7-TES-13-oxo-14b-OH-baccatin III by
mCPBA oxidation.7 A part from these results, the enolate
chemistry was no longer explored since 13-oxobaccatins
display a remarkable tendency to skeleton rearrangements
when treated with bases such as NaH, pyridine, and
DBU.8a–d Even so, the inherent potentiality of this chemistry
opens new perspectives for innovative functionalizations of
the C-14 position. For example, we performed the reduction
of the 13-oxo group of 7-TES- and 7-BOC-13-oxo-14b-OH-
baccatin III 1, 14-carbonate to afford the corresponding
14b-OH-baccatin III derivatives (Fig. 1), which are suitable
intermediates of potent anticancer taxanes bearing 1,14
carbonate as masked 14b-OH group. These taxanes, which
have been so far synthesized from the natural occurring
14b-OH-10-DAB III, a scarcely available chemical feed-
stock (Fig. 1),9 display cytotoxic activity in cell lines, which
express multi-drug resistance (MDR). The lead compound,
Ortataxel, is now in phase II clinical trial.10 We envisioned
that the ‘enolate chemistry’ could be useful for the synthesis
of new antitumor taxanes isosters of 14b-OH carbonates.
The main support to this project was the observation that
SAR studies have established that changes to the ‘southern
hemisphere’, comprising C-14, exert a strong effect on
taxol’s activity.11 Our efforts produced other potent
antitumor taxanes, which bear an unsaturated and saturated
baccatin[14, 1-d]-furan-2-one nucleus via aldol addition of
ethyl glyoxylate to the enolate of 1.12
relatively stable enolates. Alternatively, base induced
silylation affords 13-silyl enol ethers via a multistep
process. The selective amination of both the enolates of 1
and 2 (protocol A) and the 13-silyl enol ethers (protocol B)
afforded the key intermediates 13-oxo-14b-azido-baccatins
4 and 5 (Fig. 1).
2.1.1. Protocol A. Amination of the enolates of 1 and 2.
Among the variety of bases available for the synthesis of the
enolates of 1 and 2, potassium tert-butoxide (tBuOK) in a
4:1 mixed solvent THF/DMPU at K72 8C turned out to be
the best one. The enolate is stable for several hours in a
range of temperatures (K70/K40 8C) even in the presence
of the polar additive DMPU (10–25%). Dibenzyl- and di-
tert-butyl-azodicarboxylate (6 and 7, respectively),15 and
tosyl azide (8)16 were selected as amination reagents.
(i) Reaction of 1 and 2 with azodicarboxylates. The
amination of enolates 1 and 2 with azodicarboxylates 6
and 7 provided 14-hydrazino baccatins, as possible
precursors of the corresponding 14-amino taxanes. In
particular, the addition of dibenzyl-azodicarboxylate 6 to
the enolates of 1 and 2 afforded the 14-N,N0-di(benzyl-
oxycarbonyl)-hydrazino derivatives 9 (76%) and 10 (65%),
respectively, as single b-epimer (Scheme 1). Similarly, the
stereoselective addition of di-tert-butyl-azodicarboxylate 7
to the enolate of 2 gave the b-isomer of the N,N0-di(tert-
butyloxycarbonyl)hydrazino derivative 11 in 72% yield.
The stereochemistry of the C-14 stereogenic center of
compounds 9–11 was assessed by qualitative homonuclear
NOE experiments. An enhancement of the H-14 proton
(7–9%) upon irradiation of the H-3 proton clearly indicated
a b-face selectivity of the reaction. As expected, no effect
was observed upon irradiation of the vicinal H-2. Thus, the
hydrazino group is placed on the b-face of the taxane
skeleton. The chemoselective reduction of the 13-oxo group
of compounds 9–11 with sodium or alkyl boron hydrides,
according to the methodology developed for the reduction
of 13-oxo-14b-OH-baccatins 1, 14-carbonates,6 failed.
Here, we wish to report our studies on the electrophilic
amination of the enolates of 13-oxobaccatins 1 and 2, and
the 13-silyl enol ether 3, to afford a new class of antitumor
taxanes. It is worth noting that the insertion of the nitrogen
functionality at the C-14 position can afford two epimers,
since the new substituent may be located on the lower face
of the baccatin skeleton (a-face), or the upper b-face. These
a/b descriptors are defined observing the molecule with the
methyl group at C-8 placed in the ‘northern hemisphere’ and
pointing toward the observer.13 To obtain isosteres of
Ortataxel, only b-selective amination procedures, and a
selective reduction of the C-13 oxo group to afford 13a-OH
epimers, must be developed since the antitumor activity of
the resulting taxane is related to the stereochemistry of the
13 and 14 positions of the precursor 14b-OH-10-DAB III.
Next, the conversion of compounds 9–11 into the
corresponding 13-oxo-14b-amino baccatins was in vain
attempted. In fact, the deprotection of the BOC groups of 11
with formic acid, or TFA in MeOH, yielded several products
derived from rearrangements of the taxane skeleton whose
structures were no further investigated. Instead, the
debenzylation of 9 with 10% Pd/C, followed by one-pot
thermal decarbonylation, successfully gave the N,N0-
unsubstituted hydrazino derivative 12, which, however,
was thermally unstable and rapidly decomposed in solution
or in a neat state. In conclusion, all intermediates 9–12 were
not workable to achieve our targets.
2. Results and discussion
2.1. Amination studies of 13-oxobaccatins 1 and 2
Our synthesis of the target 14b-amino substituted taxanes
starts from the natural synthon 10-DAB III. This economic-
ally available reagent can be transformed into suitable
7-protected 13-oxobaccatins III according to standard
protocols.14 Namely, the 7-TES derivative 1 was obtained
by sequential silylation and acetylation of the C-7 and C-10
hydroxy groups followed by MnO2 oxidation of the 13-OH,
while the 7-BOC analogue 2 was prepared by ozonolysis of
10-DAB III followed by acetylation and carbonylation of
the C-10 and C-7 hydroxy groups. The treatment of 1 and 2
with metallic bases at low temperatures (K78 8C) afforded
(ii) Reaction of 1 and 2 with tosyl azide 8. It is well known
that azides are useful reagents for synthesis of a-azido
ketones.17 Among the electrophilic azides usually employed
for ketone enolates (phenylsulfonyl-, tosyl-, and the
encumbered 2,4,6-triisopropylbenzenesulfonyl azide18) we
selected the less sterically demanding tosyl azide 8. Since
this azide may serve both for diazo or azide transfer
reactions,19 the parameters of the quenching step must be
carefully evaluated. The reaction of the enolate of 1 with 8,
performed at K78 8C in a THF/DMPUZ4:1 mixed solvent,

A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
7729
Scheme 1. Reagents and conditions: (i) tBuOK, 4:1 THF/DMPU, K70 8C; (ii) K50 8C, then saturated NH4Cl; (iii) H2, 10% Pd/C.
proceeded through transient intermediates, probably a
mixture of two tautomeric triazenes 13 and 15, which
quickly converted into products derived from diazo and
azide transfer reactions (Scheme 2).20 For this reason, we
attempted to optimize the azido transfer reaction. As soon as
the reagent 1 disappeared, the quenching with saturated
aqueous NH4Cl solution selectively transformed the
mixture of 13 and 15 into the 14-azido derivative 4 (92%,
Fig. 1) as a single b-epimer. Instead, a clean diazo transfer
reaction occurred when the reaction was quenched with an
excess of acetic acid, which afforded the 7-TES-13-oxo-14-
diazo-baccatin III (17) (82% yield). The 7-BOC derivative 2
behaved identically. When the reaction was quenched
with NH4Cl the triazenes 14 and 16 were transformed into
the azido derivative 5 (85%), while quenching with acetic
acid yielded the diazo derivative 18 in 72%. The
b-stereochemistry of the C-14 stereogenic center of 4 and
5 was assessed by NOE experiments. An enhancement of
the H-14 proton (9–11%) was observed upon irradiation of
the H-3 proton. The b-selectivity of all amination reactions,
similar to that observed in the hydroxylation of these
enolates,6 can be explained by the folded terpenoid
structure, which precludes an approach to the sterically
demanding electrophile from the more hindered a-face of
the A ring, thus promoting the formation of the 14b epimers.
2.2. Silylation of 13-oxobaccatin III (1) and amination of
the silyl enol ethers under oxidative conditions
It has been reported that the reaction of 1 with TMSCl and
DBU gave a mixture of silylated compounds consisting of
the major product 1, 13-bis-OTMS enol ether 19, traces of
the target 13-OTMS enol ether 3 and the rearranged taxane
20 (Scheme 3). Selective solvolysis of the 1-OTMS group of
19 gave the enol ether 3 in good yield.7
Surprisingly, when we repeated the silylation reaction of 1
we obtained a mixture of products different from that
reported in the literature. We were unable to explain these
differences due to a lack of information about the
experimental procedures and analytical data products. For
this reason, we have revisited the silylation of 1 employing a
variety of silylating agents (TMSCl, TESCl, TIPSCl, and
BSA), bases and solvents. From these studies the correct
Scheme 2. Reagents and conditions: (i) tBuOK, 4:1 THF/DMPU; (ii) CH3COOH (17, 18); (iii) NH4Cl (4, 5).

7730
A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
esters 23 and 24 was based on 1H and 13C NMR
spectroscopic evidences (see Appendix A of Section 4).
In particular, we established that the OTMS group of the
C-21 carbon atom of the ortho ester has b orientation in
compounds 21 and 23 and a orientation in compounds 22
and 24.13 No significant selectivity was found in the
formation of these epimers (see Table 1), while the relative
ratio between the 13-oxo ortho esters and their 13-OTMS
enol ethers depended on the relative 1/TMSCl ratio. Polar
solvents, like CH3CN, increased the reactivity but did not
affect the products distribution. Instead, this distribution
was altered by chromatography on silica gel due to a partial
desilylation of the ortho esters, which reverted to the
starting reagent 1 and the silyl enol ether 3 (entry 1). The
best conversion of 1 into 13-OTMS ortho esters 23 and 24,
valuable precursors of the enol ether 3, was obtained with a
large excess of base and silylating agent according to
standard silylation protocols (entry 2).22 These compounds
were quantitatively isolated by chromatography on alumina.
Scheme 3.
structures of the intermediates involved in these reactions
were assessed and the best reaction conditions to selectively
obtain 13-silyl enol ethers were found.
2.2.1. Silylation studies. (i) Silylation of 1 with Me3SiCl
and DBU. The reaction of 1 (1.0 equiv) with TMSCl
(2.5 equiv) and DBU (2.0 equiv) in CH2Cl2 under reflux
provided, after a few hours, a complex mixture of
13-oxobaccatins consisting of two ortho esters 21 and 22
and minor amounts of their corresponding 13-OTMS enol
ethers 23 and 24, and traces of the 13-OTMS enol ether 3
(Scheme 4).21 Compounds having a structure consistent
with those of the 1-OTMS enol ether 19 and the rearranged
taxane 20 were not detected.
t
(ii) Silylation of 1 with TESCl and DBU or BuOK. The
DBU induced silylation of 1 with the more sterically
demanding triethylsilyl chloride only occurred in the very
polar solvent CH3CN and required strong excesses of base
and silylating agent. The epimeric pair of 13, 21-bis-OTES
ortho esters 25 (21 b-OTES) and 26 (21a-OTES) was
obtained in 93% yield (entry 3). A different product
distribution was found when we performed the silylation
of 1 in the presence of tBuOK as the base. The reaction was
run at K75 8C with 2.5 equiv of base. Sequential addition of
2.0 equiv of TESCl at this temperature stereoselectively
gave the 21b-epimers of 13-oxo-21-OTES ortho ester 27, as
the major product (80%, entry 4), and its 13, 21-bis-OTES
ortho ester 25 as the minor (20%). Only 25 was obtained
with a large excess of TESCl. This compound was isolated
The ortho esters are formed by DBU induced hydrogen
abstraction of 1-OH of 1. The nucleophilic attack of the
resulting 1-oxyanion to the carbonyl of the 2-benzoyl group
affords an epimeric mixture of cyclic 1,2-benzylidene
oxyanions (ortho esters), which are quenched by the
silylating agent. The stereochemical assessments of ortho
esters 21, 22, the 13-enol derivative 3, and the 13-enol ortho
Scheme 4.
Table 1. Product distribution of the silylation of 1 (1.0 equiv) with TMSCl, TESCl, TIPSCl, and BSA
Entry
Reaction conditions eq:eq:eq
Aa
Bb
Cc
Overall yield %
1
2
3
4
5
6
7
8
1/TMSCl/DBU 1.0:2.5:2.0 (CH2Cl2)
1/TMSCl/DBU 1.0:7.0:6.0 (CH2Cl2)
1/TESCl/DBU 1.0:6.0:7.0 (CH3CN)
1/TESCl/tBuOK 1.0:1.7:2.5 (THF)
1/TESCl/tBuOK 1.0:6.0:5.0 (THF)
1/TIPSCl/tBuOK 1.0:5.0:6.0
21/22Z0.94d (1.14)e
—
—
27 (80%)f
23/24Z1.1d (1.6)e
23/24Z1.4f
25/26Z1.2
25 (20%)f
25
—
—
23/24Z4
3 (%5%)d,e
3 (%5%)
—
—
—
21C22C23C24Z87d
23C24Z92f
25C26Z93f
25C27Z100
25Z94
—
21/22Z1.5
21/22Z1.5
29 (55%)
3 (33%)f
29C1Z86
1/BSA 1.0:2.5 (CD3CN)
1/BSA/DMAP 1.0:2.5:0.2 (CD3CN)
21C22C3Z53f
21C22C23C24Z100f
a A: 13-oxo 21-ortho esters.
b B: 13-silyl enol 21-ortho esters.
c C: 13-Silyl enol ethers.
d Product distribution and overall yield after chromatography on silica.
1
e Product distribution as determined by H NMR.
f
Product distribution and overall yield after chromatography on alumina.

A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
7731
in 94% yield after chromatography on Al2O3 (entry 5).23
Although we failed to directly obtain the 13-silyl enol
ether 28 through this route we successfully achieved a
total chemoselectivity in the formation of the precursors
13-OTES ortho esters 25 and 26.
achieved this target by performing a study of chemo-
selective solvolysis of the silyl group at the C-21 carbon
atom of the 13, 21-bis-OTMS-silyl enol ortho esters 23–26.
The desilylation of mixtures of 23/24 (or 25/26), performed
according to the reported procedure (1.0 M HCl),7 afforded
non-reproducible mixtures of silyl enol ethers 3 or 28 and
the reagent 1. Moreover, the b-epimers 23 and 25 were
desilylated more rapidly than the a-epimers 24 and 26, thus
favouring an uncontrolled formation of 1. This selectivity
was again the result of the folded structure of the baccatin
skeleton, since the 21-OTMS substituent of the a-epimers is
more embedded of the b-epimers and, for this reason, less
prone toward solvolysis. When we carried out solvolysis
studies at different pH values we found that the priority of
the desilylation at the C-13 and C-21 positions reversed with
the pH of the medium. In fact, the desilylation of 23 and 24
in a basic medium, such as a mixture of DBU/water,
afforded the 13-oxo ortho esters 21 and 22, which in turn
were hydrolyzed to 1. This was the reason why the reactions
of 1 with Me3SiCl, reported in section i, required an excess
of Me3SiCl with respect to DBU for their quantitative
conversion into 23 and 24 (entry 2). By contrast, the reaction
of 1 with TESCl gave 25 and 26 although it was carried out
with an excess of DBU, since the TES substituent is three
order more stable toward base-catalysed hydrolysis.24 Harsh
desilylation agents, such as TBAF and CsF2, gave random
mixtures of product of solvolysis at C-13, C-21, C-7, and
contaminants. These attempts suggested that the selective
C-21 desilylation could be carried out only in a very mild
acidic medium, that is, with catalytic PTSA (8%) in CH2Cl2
at 20 8C. When 23/24Z1.4, or 25/26Z1.25 mixtures were
desilylated under these conditions, the enol ethers 3 (95%)
and 28 (93%) were exclusively obtained (Scheme 6).
(iii) Silylation of 1 with TIPSCl and tBuOK. The reaction of
the enolate of 1 with 5.0 equiv of TIPSCl at K78 8C
required BuOK as base and a polar mixed solvent (THF/
t
DMPU, 4:1). The 13-OTIPS-enol ether derivative 29 was
obtained in 55% yield along with unreacted 1 (entry 6 and
Scheme 5). This result gave evidence that sterically
demanding silylating agents, such as TIPSCl, favor the
enolization pathway instead of the formation of products
derived from the 21-oxyanion.
Scheme 5.
(iv) Silylation of 1 with N, O bis(trimethylsilyl)acetamide
(BSA). The silylation of 1 with 2.5 equiv of BSA in CD3CN
gave the silyl enol ether 3 as the major product (33%) and
the 13-oxo-ortho esters 21 and 22 (20%) (entry 7). Only
ortho esters 21/22Z1.5 (65% yield) and 23/24Z4 (35%)
were obtained when the same reaction was performed in the
presence of the base DMAP (0.2 equiv, entry 8).
In conclusion, 1H NMR experiments clearly showed that the
DBU induced silylation of 1 with a slight excess of TMSCl
(1.5–2.0 equiv) initially gave a/b epimeric mixtures of the
13-oxo ortho esters 21 and 22 and traces of the 13- OTMS
silyl enol ether 3. Sequential silylation of 21 and 22
furnished the 13, 21-bis-silylated ortho esters 23 and 24.
Hence, variable mixtures of compounds 21–24 were
obtained, along with trace amounts of 3, depending on the
reagents’ stoichiometry. Only the potent BSA directly
afforded moderate amounts of the silyl enol ether 3 as the
major product, but in a non-basic medium (entry 7). The 13,
21-bis-silyl enol ortho esters 23–26 were obtained in very
high yield (92–94%, entries 2, 3, and 5 of Table 1) when an
excess of base and silylating agent was used. The folded
terpenoid structure of the taxane skeleton favors an attack to
the less hindered C-21b oxyanion only when the sterically
demanding TES-Cl and TIPSCl are the electrophilic
partners. Moreover, both the nature of the base, and the
temperature play a key role on the chemo and diastereo-
selectivity at the C-21 position. For example, face
discrimination was observed in the tBuOK induced reaction
of 1 with TESCl, which afforded only the b-epimers 25 and
27 at low temperatures (entries 4 and 5, Table 1). This
discrimination did not occur when this reaction was done in
refluxing CH2Cl2 with DBU as the base (entry 3).
Scheme 6.
2.2.3. Protocol B. CAN induced azidation of the silyl enol
ethers 3 and 29. Synthesis of 7-TES-13-oxo-14b-azido-
baccatin III (4). The azidation of silyl enol ethers with
NaN3 represents an interesting protocol of a-amination of
ketones. This protocol is based on the oxidation of sodium
azide by cerium-(IV) ammonium nitrate to give dinitrogen, a
very potent aminating agent.25 This reagent has been suc-
cessfully experimented mainly with silyl enol ethers bearing a
sterically encumbered TIPS substituent, such as 29.26 The
azidation of 29 in CH3CN occurred in 1 day under forced
conditions, such as a large excess of NaN3 (11.0 equiv) and
CAN (7.0 equiv), the target 4 being obtained in moderate
2.2.2. Solvolysis of the ortho esters enolates 23–26. While
we failed to directly synthesize the 13-silyl enol ethers 3 and
28 in good yield by silylation of the enolate of 1, we
Scheme 7.

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A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
Scheme 8. Reagents and conditions: (i) PPh3/H2O; (ii) NaBH4/EtOH; (iii) COCl2/Py; (iv) DCC/DMAP/PTSA.
amounts (55%) (Scheme 7). For this reason, we also probed
the less sterically demanding compound 3 even if the OTMS
silyl enol ethers are usually prone toward a concurrent
hydrolysis due to the acidic CAN medium. Gratifying,
compound 4 was obtained in 95% yield after 1 h at 20 8C
when 3 was reacted with only 4.0 equiv of NaN3 and
3.0 equiv of CAN.
to a condensation of the hydride reagents with the 14-NH2
group.27 For this reason, the 14-NH2 and the 1-OH groups of
30 were transformed into the 1, 14-carbamate group of
compound 32 by treatment with phosgene in pyridine
(86% yield). Next, 32 was reduced by NaBH4 in EtOH
affording the 13a-epimer of 7-TES-14b-amino baccatin III
1,14-carbamate (13a-33) in 56% and its 13b-OH epimer
(13b-34, 35%).28 N-Boc-norstatinic acid 35, protected as
N,O-(2,4-dimethoxy-benzylidene) derivative,29 was
selected as the partner of 13a-33 since this amino acid
was also present in Ortataxel. The esterification was carried
out with N,N0-dicyclohexyl-carbodiimide (DCC), 4-dimethyl-
amino-pyridine (DMAP) and catalytic p-toluenesulfonic
acid,30 affording the fully protected taxane 36.
2.3. Synthesis of 14b-amino taxanes
The reduction of the azido group of 4 and 5 was carried out
via the iminophosporane method with PPh3 in 9:1 CH3CN/
H2O to give the 7-TES-13-oxo-14b-amino-baccatin III (30)
in 88% yield, and its 7-BOC analogue 31 in 77% (Scheme
8). The attempted reduction of the 13-oxo group of 30 and
31 with sodium or alkyl boron hydrides failed, probably due
Next, we reasoned that a 14b-azido taxane, with the amino
Scheme 9. Reagents and conditions: (i) NaBH4, ETOH; (ii) DCC/DMAP/PTSA; (iii) H2/Pd-C; (iv) (2-Piridyl)2CZS; (v) BOC2O/Et3N/DMAP; (vi) COCl2/Py.

A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
7733
acid appendant and the terpenoid skeleton fully protected,
3. Conclusions
might be a key intermediate for synthesis of other taxanes
bearing the 14b-amino function. Hence, the 13-oxo group of
4 was reduced by sodium or alkylammonium borohydrides
to afford a mixture of 7-TES-14b-azido-baccatin III (13a-
37), as the major product, and its 13b-OH epimer (13b-38)
(Scheme 9). Best yield of 13a-37 (76%) were obtained with
NaBH4 in EtOH (a/bZ91:9).
A preliminary optimization of the synthesis of silyl enol
ethers has been carried out. We have clearly identified an
high yield protocol for the conversion of 1 into 13,21-bis-
silylated enol ethers ortho esters 23–26 using an excess of
silylating agent and base. The lability of the silyl substituent
at C-21 provides a way for an high recovery of the 13-silyl
enol ethers 3 and 28 only when a suitable reagent, PTSA, is
adopted for the chemoselective desilylation at C-21 of the
a/b-epimeric mixtures. The use of alumina instead of silica
for chromatographic purification was required to prevent
uncontrolled desilylation of the intermediates. Instead, the
13-OTIPS enol ether 29 was obtained in an one step process
but in a moderate amounts.
The stereochemistry at C-13 of 13a-37, assessed by NOE
experiments, was the same as the natural synthons DAB III
and 14b-OH-DAB, as required for pharmacologically active
taxanes. A 7% enhancement of the H-13 proton was
observed upon irradiation of the H-2 proton, while no effect
was noticed upon irradiation of H-14. This suggests that
H-13 and H-2 are located on the same b-face. An oppostite
trend was found for the epimer 13b-38: a NOE effect of 9%
was observed for the H-13 proton upon irradiation of H-14,
since the two protons are located on the same a-face. The
esterification of 13a-37 with the acid 35, following the
standard protocol, gave the fully protected 14b-azido taxane
39 in 80% yield. Catalytic hydrogenation (10% Pd/C) of the
azido group of 39 gave the 14b-amino analogue 40 in 90%
yield. The 1b-OH and 14b-NH2 groups of 40 were subjected
to further elaborations that allowed the synthesis of other
taxanes. Thiocarbonylation of 40 with di-2-pyridyl-thiono-
carbonate in CH3CN gave the 1,14-thiocarbamate deriva-
tive 41 in 73% yield, while the carbonylation of the 14b-
amino derivative 37 with excess of BOC2O, Et3N and
DMAP gave the N-BOC-1, 14-carbamate derivative 42 in
69%. It is worth noting that the taxane 1, 14 carbamate 36
was obtained in 74% yield by an independent route by
carbonylation of the amino derivative 40 with COCl2/
pyridine.
Moreover, we have developed useful protocols for the
synthesis of 14b-nitrogen functionalized taxanes. These
compounds were synthesized starting from the commer-
cially available 10-DAB III. Key steps of this protocol were
the azidation of the enolates of 13-oxo-baccatins 1 and 2
with tosyl azide, or the azidation of the 13-silyl enol ethers 3
and 29 with NaN3 under oxidative conditions. Both
amination protocols occurred with total b-stereoselectivity
regardless of the type of aminating agent (azodicarboxyl-
ates, tosyl azide, NaN3) to afford the key intermediate
14b-azido derivatives 4 and 5. This selectivity was induced
by the folded structure of the taxane skeleton, which favors
the approach of the aminating agent from the less hindered
b-face. In particular, we have prepared the fully protected
14b-azido taxane 39 from compound 4 using standard
procedures. This compound was the key intermediate for the
synthesis of a new family of 14b-amino taxanes (43–47)
whose study of antitumor in vitro and in vivo activity is
actively under way.31
Finally, the sequential desilylation of the 7-OTES group of
36, 39–42 with HF/pyridine, followed by N, O-deprotection
of the isoserine moiety with acetyl chloride in MeOH, gave
the target taxoids: 13-N-BOC-b-isobutylisoserinoyl-14b-
amino-baccatin III 14,1-carbamate (43), 13-(N-BOC-b-
isobutylisoserinoyl)-14b-azido-baccatin III (44), 13-(N-
BOC-b-isobutyl-isoserinoyl)-14b-amino-baccatin III (45),
13-(N-BOC-b-isobutylisoserinoyl)-14b-amino-baccatin III
14,1-thiocarbamate (46), 13-(N-BOC-b-isobutyl-isoseri-
noyl)-14b-t-butoxycarbamoyl-baccatin III 14,1-carbamate
(47) (Scheme 10).
4. Experimental
4.1. General techniques
Solvents were purified and dried prior to use. Reactions
were monitored by thin-layer chromatography on 0.25mm
E. Merck silica gel plates (60 F254) using UV light as a
visualizing agent or a 7% ethanolic phosphomolibdic acid as
developing agent. H and 13C NMR spectra were recorded
1
on a 400 MHz spectrometer with Me4Si or CHCl3 (in
Scheme 10.

7734
A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
CDCl3) as internal reference. Infrared Spectra were
recorded on a Fourier transform IR spectrometer, and
values are reported in cmK1 units. Positive Ion mass spectra
were obtained by direct infusion of 1.2 mM solutions in
0.02 M ammonium acetate/MeOH, 20/80 at an ion trap
mass spectrometer Thermoquest LCQ-duo (Finnigam USA)
equipped with an ESI ionization source.
7.15–7.30 (m, 10H, arom), 6.89 (s, 1H, NH), 6.56 (s, 1H,
H-10), 5.97 (d, 1H, H-2, JZ6.2 Hz), 5.62 (s, 1H, H-14),
5.18 (d, 1H, CH2Ph, JZ12.5 Hz), 5.34–5.38 (m, 1H, H-7),
5.12 (d, 1H, CH2Ph, JZ12.5 Hz), 5.06 (d, 1H, CH2Ph, JZ
12.5 Hz), 4.99 (d, 1H, CH2Ph, JZ12.5 Hz), 4.92 (dd, 1H,
H-5, JZ2.5, 9.5 Hz), 4.37 (d, 2H, H-20, JZ8.6 Hz), 4.14 (d,
1H, H-3, JZ6.2 Hz), 2.59 (ddd, 1H, Ha-6, JZ7.2, 9.5,
14.3 Hz), 2.19 (s, 3H, Me), 2.18 (s, 3H, Me), 2.13 (s, 3H,
Me), 1.97 (ddd, 1H, Hb-6, JZ2.5, 10.9, 14.3 Hz), 1.82 (s,
3H, Me), 1. 47 (s, 9H, 3 Me), 1.23 (s, 3H, Me), 0.86 (s, 3H,
Me); 13C NMR (CDCl3, 100 MHz) d 200.2, 196.4, 171.7,
168.4, 166.2, 158.0, 157.0, 153.3, 152.6, 138.4, 135.3,
135.0, 133.6, 131.1, 129.2, 128.9, 128.8, 128.7, 128.6,
128.5, 128.3, 127.5, 84.2, 83.3, 80.9, 76.8, 75.8, 75.2, 74.4,
73.6, 69.5, 68.8, 66.1, 57.2, 45.9, 43.5, 33.6, 27.9, 22.0,
21.0, 20.1, 14.4, 10.9. Anal. Calcd for C52H58N2O17: C,
63.53; H, 5.95; N, 2.85. Found: C, 63.50; H, 6.02; N, 2.77.
4.1.1. 7-TES-13-oxo-14-(N,N0-bis-(benzyloxycarbonyl)
hydrazino)-baccatin III (9). A solution of 1 (0.45 g,
0.64 mmol) in THF (12.0 mL) and DMPU (2.5 mL) was
t
cooled to K72 8C and stirred under nitrogen. BuOK
(1.61 mL, 1.61 mmol, 1.0 M in THF) was added dropwise
and the solution stirred at K65 8C for 45 min. Then
compound 6 (0.28 g, 0.82 mmol) was added and the reaction
monitored by TLC. After 2 h the conversion was not
complete, so a further amount of 6 (0.07 g, 0.2 mmol) was
added. After 1 h (total reaction time: 3 h) the reaction was
quenched with acetic acid (0.15 mL, 40% in THF) and
warmed to room temperature. After dilution with brine
(10.0 mL) the mixture was extracted with EtOAc and the
organic layer washed with brine (10.0 mL), dried and
evaporated. The residue was purified by chromatography
(SiO2, CH2Cl2/EtOAc, 1.0:0.2) to obtain 0.49 g (0.49 mmol,
76%) of 9 as a white solid. IR (KBr, cmK1): 3394, 2993,
2920, 1725, 1342, 1212; [a]2D0 C53.6 (c 0.12, CHCl3); MS
4.1.3. 7-BOC-13-oxo-14b-[N,N0-bis-(tert-butoxycarbo-
nyl)hydrazino]-baccatin III (11). tBuOK (0.16 g,
1.47 mmol) was suspended, under nitrogen and stirring, in
3.0 mL of anhydrous THF at K72 8C. Compound 2 (0.37 g,
0.54 mmol) in 2.5 mL of THF and 1.8 mL of DMPU was
added to the mixture. Compound 7 (0.27 g, 1.19 mmol),
dissolved in 3.0 mL of THF and 0.2 mL of DMPU, was
added after 15 min at K68 8C. After 1 h the reaction was
quenched by addition of 2.0 mL (0.03 mmol) of acetic acid,
diluted with ethyl ether and extracted with a saturated
aqueous solution of NH4Cl. The organic phase was washed
with water, dried, filtered and evaporated under reduced
pressure. Chromatography of the residue (SiO2, n-hexane/
EtOAc, 1.2:1.0) afforded 0.36 g (0.38 mmol, 72%) of 11 as
a solid. IR (KBr, cmK1): 3408, 2980, 2933, 1728, 1682,
1369, 1255, 1155; [a]D20 C57.0 (c 0.75, CH2Cl2); MS (m/z)
1
(m/z) ESI: 998 (MCH)C; H NMR (CDCl3, 200 MHz) d
8.27–8.32 (m, 2H, arom), 7.19–7.55 (m, 13H, arom), 6.87
(s, 1H, NH), 6.53 (s, 1H, H-10), 5.99 (d, 1H, H-2, JZ
6.6 Hz), 5.63 (s, 1H, H-14), 5.16 (d, 2H, JZ4.8 Hz, CH2Ph),
5.04 (d, 2H, JZ4.8 Hz, CH2Ph), 4.88 (d, 1H, H-5, JZ
4.0 Hz), 4.51 (dd, 1H, H-7, JZ6.6, 4.0 Hz), 4.34–4.36 (m,
2H, H-20), 4.01 (d, 1H, H-3, JZ6.6 Hz), 2.42–2.61 (m, 1H,
Ha-6), 2.23 (s, 3H, Me), 2.22 (s, 3H, Me), 2.15 (s, 3H, Me),
1.84–1.98 (m, 1H, Hb-6), 1.74 (s, 3H, Me), 1.29 (s, 3H, Me),
1.28 (s, 3H, Me), 0.90–0.98 (m, 9H, 3 Me), 0.58–0.66 (m,
6H, 3 CH2); 13C NMR (CDCl3, 50 MHz) d 200.1, 196.7,
171.9, 169.3, 166.3, 158.1, 157.1, 138.0, 135.5, 135.2,
133.6, 131.3, 129.5, 129.0, 128.9, 128.7, 128.5, 127.7, 84.6,
81.3, 75.8, 75.3, 74.0, 72.5, 69.6, 68.9, 66.3, 59.6, 46.0,
43.7, 37.6, 34.8, 22.2, 21.1, 20.2, 14.2, 10.2, 7.1, 5.6. Anal.
Calcd C53H64N2O15Si: C, 63.84; H, 6.47; N, 2.81. Found: C,
63.70; H, 6.51; N, 2.67.
1
ESI: 916 (MCH)C; H NMR (CDCl3, 400 MHz) d 8.27–
8.30 (m, 2H, arom), 7.50–7.55 (m, 1H, arom), 7.38–7.42 (m,
2H, arom), 6.58 (s, 1H, N–H), 6.53 (s, 1H, H-10), 5.97 (d,
1H, H-2, JZ6.4 Hz), 5.58 (s, 1H, H-14), 5.41 (dd, 1H, H-7,
JZ6.9, 10.7 Hz), 4.90 (dd, 1H, H-5, JZ2.6, 9.7 Hz), 4.35
(d, 1H, H-20, JZ8.4 Hz), 4.23 (d, 1H, H-20, JZ8.4 Hz),
4.15 (d, 1H, H-3, JZ6.4 Hz), 2.59 (ddd, 1H, Ha-6, JZ6.9,
9.7, 14.3 Hz), 2.21 (s, 3H, Me), 2.18 (s, 3H, Me), 2.17 (s,
3H, Me), 1.97 (ddd, 1H, Hb-6, JZ2.6, 10.7, 14.3 Hz), 1.82
(s, 3H, Me), 1.46 (s, 9H, 3 Me), 1.40 (s, 9H, 3 Me), 1.35 (s,
9H, 3 Me), 1.26 (s, 3H, Me), 1.00 (s, 3H, Me); 13C NMR
(CDCl3,100 MHz) d 200.4, 196.9, 171.7, 168.4, 166.2,
157.3, 155.8, 153.2, 152.6, 138.5, 133.3, 131.2, 129.4,
128.4, 84.2, 83.3, 83.2, 82.7, 80.9, 76.8, 76.1, 75.0, 74.5,
73.4, 65.1, 57.3, 45.9, 43.6, 34.6, 33.7, 28.2, 28.1, 27.9,
21.9, 21.0, 20.1, 14.3, 10.9. Anal. Calcd C46H62N2O17: C,
60.38; H, 6.83; N, 3.06. Found: C, 60.30; H, 6.71; N, 3.14.
4.1.2. 7-BOC-13-oxo-14b-[N,N0-bis-(benzyloxycarbonyl)
hydrazino]-baccatin III (10). BuOK (0.16 g, 1.47 mmol)
t
was suspended, under nitrogen and stirring, in 3.0 mL of
anhydrous THF at K72 8C. 7-BOC-13-oxo-baccatin III 2
(0.37 g, 0.54 mmol) in 2.5 mL of THF and 1.8 mL of
DMPU was added. After 15 min, 0.32 g (1.19 mmol) of 6,
dissolved in 3.0 mL of THF and 0.2 mL of DMPU was
added at K68 8C. Temperature was raised to K50 8C, and
after 8 h the reaction mixture was quenched by addition of
2.0 mL (0.03 mmol) of acetic acid, diluted with 10.0 mL of
ethyl ether, and extracted with 10.0 mL of saturated solution
of NH4Cl. The organic phases was washed with water,
dried, filtered, and evaporated under reduced pressure.
Chromatography of the residue (SiO2, n-hexane/EtOAc,
1.3:1.0) afforded 0.35 g (0.35 mmol, 65%) of 10 as a white
solid. IR (KBr, cmK1): 3397, 2983, 2930, 1728, 1393, 1252;
[a]2D0 C58.4 (c 0.42, CH2Cl2); MS (m/z) ESI: 984 (MC
4.1.4. 7-TES-13-oxo-14b-hydrazino-baccatin III (12).
A solution of 9 (0.50 g, 0.50 mmol) in EtOAc (45.0 mL)
was hydrogenated under balloon pressure with 10% Pd/C as
catalyst (0.05 g) for 45 min. The catalyst was filtered off
through celite, the solvent was evaporated under reduced
pressure without heating to obtain 0.35 g of 12 (0.48 mmol,
96%). This compound was unstable in various conditions
(chromatographic column) and solvents (CDCl3). (12): IR
1
(KBr, cmK1): 3340, 2980, 1734, 1252; H NMR (CDCl3,
1
H)C; H NMR (CDCl3, 400 MHz) d 8.24–8.37 (m, 2H,
200 MHz) relevant resonances at d 8.19–8.23 (m, 2H,
arom), 7.41–7.61 (m, 3H, arom), 6.54 (s, 1H, H-10), 5.85 (d,
arom), 7.50–7.55 (m, 1H, arom), 7.34–7.40 (m, 2H, arom),

A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
7735
1H, H-2, JZ6.6 Hz), 5.37 (s, 1H), 5.18 (s, 1H), 4.92 (d, 1H,
H-5, JZ8.1 Hz), 4.51 (m, 1H, H-7), 4.29 (s, 2H, H-20), 3.92
(d, 1H, H-3, JZ7.0 Hz), 2.47–2.62 (m, 1H, Ha-6), 2.25 (s,
3H, Me), 2.23 (s, 3H, Me), 2.06 (s, 3H, Me), 1.84–1.98 (m,
1H, Hb-6), 1.74 (s, 3H, Me), 1.31 (s, 3H, Me), 1.28 (s, 3H,
Me), 0.90–0.98 (m, 9H, 3 Me).
168.3, 167.3, 152.5, 145.7, 141.1, 134.5, 130.4, 129.1,
128.3, 84.0, 83.5, 80.4, 79.5, 76.3, 76.2, 74.5, 73.7, 65.4,
56.6, 46.1, 43.0, 33.5, 32.9, 27.9, 21.0, 18.7, 14.4, 11.1.
Anal. Calcd C36H42N2O13: C, 60.84; H, 5.96; N, 3.94.
Found: C, 60.70; H, 5.85; N, 4.03.
4.1.7. 7-TES-13-oxo-14b-azido-baccatin III (4). A solu-
tion of 1.40 g (2.0 mmol) of 1 in 7.5 mL of THF and 3.7 mL
of DMPU, was added to a solution of BuOK (5.2 mL,
4.1.5. 7-TES-13-oxo-14-diazo-baccatin III (17). 0.8 mL of
a 1.0 M solution of tBuOK in THF was added under stirring
at K72 8C to a solution of 0.22 g (0.32 mmol) of 1 in
3.5 mL of THF and 1.0 mL of DMPU. Tosyl azide (0.11 g,
0.58 mmol), dissolved in 0.9 mL of THF was added after
15 min. The temperature was raised to K50 8C and the
reaction was quenched after 1 h by addition of 0.8 mL of
acetic acid. The reaction temperature was raised at 20 8C
and the mixture left for 12 h. The reaction mixture was
extracted with Et2O and the organic phase was dried, filtered
and evaporated under reduced pressure. Chromatography of
the residue (SiO2, n-hexane/EtOAc, 2.1:1.0) afforded 0.19 g
of 17 as a white solid (0.26 mmol, 82%). IR (KBr, cmK1):
3358, 3261, 2957, 2877, 2097, 1727, 1628, 1369, 1306,
1161; [a]2D01C66.0 (c 0.9, CH2Cl2); MS (m/z) ESI: 726
(MCH)C; H NMR (CDCl3, 400 MHz) d 8.10–8.20 (m,
2H, arom), 7.59–7.62 (m, 1H, arom), 7.42–7.50 (m, 2H,
arom), 6.50 (s, 1H, H-10), 5.84 (d, 1H, H-2, JZ7.2 Hz),
4.92 (dd, 1H, H-5, JZ2.2, 9.7 Hz), 4.47 (dd, 1H, H-7, JZ
6.7, 10.7 Hz), 4.33 (d, 1H, H-20, JZ8.2 Hz), 4.07 (d, 1H,
H-20, JZ8.2 Hz), 3.89 (d, 1H, H-3, JZ7.2 Hz), 2.53 (ddd,
1H, Ha-6, JZ6.7, 9.7, 14.2 Hz), 2.21 (s, 3H, Me), 2.20 (s,
3H, Me), 2.16 (s, 3H, Me), 1.85 (ddd, 1H, Hb-6, JZ2.2,
10.7, 14.2 Hz), 1.65 (s, 3H, Me), 1.28 (s, 3H, Me), 1.26 (s,
3H, Me), 0.89–92 (m, 9H, 3 Me), 0.54–0.58 (m, 6H, 3 CH2);
13C NMR (CDCl3, 100 MHz) d 200.6, 183.9, 170.3, 168.9,
167.0, 146.4, 140.4, 134.3, 130.4, 130.2, 129.0, 84.2, 80.6,
79.5, 76.5, 76.0, 74.0, 72.3, 69.6, 59.1, 45.9, 43.0, 37.4,
33.1, 22.0, 21.2, 18.9, 14.4, 10.4, 7.2, 5.7. Anal. Calcd
C37H48N2O11Si: C, 61.31; H, 6.67; N, 3.86. Found: C,
61.39; H, 6.75; N, 3.92.
t
5.2 mmol, 1.0 M in THF) at K72 8C under stirring. Tosyl
azide (0.70 g, 3.6 mmol), dissolved in 5.8 mL of THF, was
added after 10 min. The temperature was raised to K50 8C
and the reaction was quenched after 2 h by addition of
10.0 mL of saturated aqueous NH4Cl. The reaction mixture
was left at 25 8C for 12 h, diluted with 50.0 mL of Et2O and
extracted. The organic phase was washed with water, dried,
filtered and concentrated under reduced pressure. Chroma-
tography of the residue (SiO2, n-hexane/EtOAc/Et2O,
1.8:0.7:0.4) gave 1.34 g (1.8 mmol, 92%) of 4 as a white
solid. IR (KBr, cmK1): 3497, 2956, 2878, 2117, 1730, 1689,
1370, 1238, 1094; [a]D20 C79.4 (c 0.9, CH2Cl2); MS (m/z)
1
ESI: 741 (MCH)C; H NMR (CDCl3, 400 MHz) d 8.02–
8.04 (m, 2H, arom) 7.60–7.65 (m 1H, arom), 7.47–7.53 (m,
2H, arom), 6.53 (s, 1H, H-10), 5.82 (d, 1H, H-2, JZ6.7 Hz),
4.92 (dd, 1H, H-5, JZ2.0, 9.5 Hz), 4.46 (dd, 1H, H-7, JZ
6.7, 10.7 Hz), 4.33 (d, 1H, H-20, JZ8.6 Hz), 4.25 (s, 1H,
H-14), 4.24 (d, 1H, H-20, JZ8.6 Hz), 3.86 (d, 1H, H-3, JZ
6.7 Hz), 3.09 (s, 1H, OH), 2.54 (ddd, 1H, Ha-6, JZ6.7,
10.7, 14.2 Hz), 2.25 (s, 3H, Me), 2.22 (s, 3H, Me), 2.19 (s,
3H, Me), 1.91 (ddd, 1H, Hb-6, JZ2.0, 9.5, 14.2 Hz), 1.72
(s, 3H, Me), 1.27 (s, 3H, Me), 1.00 (s, 3H, Me), 0.90–0.96
(m, 9H, 3 Me), 0.55–0.64 (m, 6H, 3 CH2); 13C NMR
(CDCl3, 100 MHz,) d 199.5, 196.5, 169.9, 169.0, 165.3,
155.4, 138.2, 134.0, 129.9, 129.2, 129.0, 84.0, 81.3, 76.3,
75.6, 75.5, 72.8, 72.5, 65.5, 59.6, 45.7, 43.4, 37.4, 34.0,
22.1, 21.2, 19.4, 14.4, 10.1, 7.2, 5.6. Anal. Calcd
C37H49N3O11Si: C, 60.06; H, 6.68; N, 5.68. Found: C,
59.87; H, 6.79; N, 5.80.
4.1.6. 7-BOC-13-oxo-14-diazo-baccatin III (18). A solu-
tion of 2 (0.15 g, 0.22 mmol) in THF (0.7 mL) and DMPU
(0.4 mL) was added under nitrogen and stirring to a
4.1.8. 7-BOC-13-oxo-14b-azido-baccatin III (5). A solu-
tion of 2 (0.15 g, 0.22 mmol) in THF (1.8 mL) and DMPU
(0.8 mL) was added to a suspension of BuOK (0.06 g,
t
t
suspension of BuOK (0.06 g, 0.57 mmol) in anhydrous
0.57 mmol) in anhydrous THF (1.5 mL) at K72 8C, under
nitrogen and stirring. After 15 min, 0.08 g (0.40 mmol) of
tosyl azide, dissolved in 0.7 mL of THF, were added in
2 min at K75 8C. After 30 min, the temperature was raised
to K50 8C and the reaction was quenched after 2 h by
addition of 5.0 mL of saturated NH4Cl. The reaction
mixture was extracted with Et2O and the organic phase
was dried, filtered and evaporated under reduced pressure.
Chromatography of the residue (SiO2, n-hexane/EtOAc,
1.7:1.0) gave 0.14 g (0.19 mmol, 85%) of 5 as a white solid.
IR (KBr, cmK1): 2976, 2935, 2122, 1731, 1272, 1094; [a]2D0
THF (0.7 mL) at K72 8C. After 15 min, a solution of tosyl
azide (0.08 g, 0.39 mmol) in 0.5 mL of THF was added. The
temperature was raised to K50 8C and the reaction was
quenched after 2 h by addition of 1.0 mL of acetic acid.
Work-up of the reaction mixture was performed as
described for compound 17. Chromatography of the crude
residue (SiO2, n-hexane/EtOAc, 1.7:1.0) yielded 0.11 g of
compound 18 (0.16 mmol, 72%) as a white solid. IR (KBr,
cmK1): 3359, 2957, 2878, 2097, 1726, 1630, 1305; [a]2D0
1
C72.6 (c 0.3, CH2Cl2); MS (m/z) ESI: 712 (MCH)C; H
1
NMR (CDCl3, 400 MHz) d 8.17–8.22 (m, 2H, arom), 7.62–
7.68 (m, 1H, arom), 7.48–7.54 (m, 2H, arom), 6.50 (s, 1H,
H-10), 5.85 (d, 1H, H-2, JZ7.2 Hz), 5.41 (dd, 1H, H-7, JZ
6.8, 10.8 Hz), 4.95 (dd, 1H, H-5, JZ1.5, 8.0 Hz), 4.36 (d,
1H, H-20, JZ8.4 Hz), 4.08 (d, 1H, H-20, JZ8.4 Hz), 4.04
(d, 1H, H-3, JZ7.2 Hz), 2.63 (ddd, 1H, Ha-6, JZ6.8, 8.0,
14.0 Hz), 2.22 (s, 3H, Me), 2.19 (s, 3H, Me), 2.18 (s, 3H,
Me), 1.92 (ddd, 1H, Hb-6, JZ1.5, 8.0, 14.0 Hz), 1.77 (s,
3H, Me), 1.48 (s, 9H, 3Me), 1.31 (s, 3H, Me), 1.23 (s, 3H,
Me); 13C NMR (CDCl3, 100 MHz) d 200.9, 184.1, 170.4,
C69.4 (c 0.9, CH2Cl2); MS (m/z) ESI: 727 (MCH)C; H
NMR (CDCl3, 400 MHz) d 8.02–8.05 (m, 2H, arom), 7.60–
7.66 (m, 1H, arom), 7.48–7.52 (m, 2H, arom), 6.56 (s, 1H,
H-10), 5.81 (d, 1H, H-2, JZ6.8 Hz), 5.37 (dd, 1H, H-7, JZ
7.2, 10.8 Hz), 4.93 (dd, 1H, H-5, JZ2.0, 9.6 Hz), 4.33 (d,
1H, H-20, JZ8.4 Hz), 4.26 (s, 1H, H-14), 4.24 (d, 1H, H-20,
JZ8.4 Hz), 3.98 (d, 1H, H-3, JZ6.8 Hz), 3.11 (s, 1H, OH),
2.62 (ddd, 1H, Ha-6, JZ7.2, 9.6, 14.0 Hz), 2.24 (s, 3H,
Me), 2.20 (s, 3H, Me), 2.19 (s, 3H, Me), 1.96 (ddd, 1H,
Hb-6, JZ2.0, 10.8, 14.0 Hz), 1.81 (s, 3H, Me), 1.47 (s, 9H,

7736
A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
3 Me), 1.22 (s, 3H, Me), 1.01 (s, 3H, Me); 13C NMR
(CDCl3, 100 MHz) d 199.8, 196.6, 170.0, 168.2, 165.4,
153.8, 152.5, 138.8, 134.1, 130.0, 129.2, 129.1, 83.7, 83.5,
81.0, 76.1, 75.8, 75.5, 74.4, 72.5, 65.4, 57.2, 45.8, 43.3,
33.7, 33.5, 27.9, 21.9, 20.9, 19.2, 14.4, 10.8. Anal. Calcd
C36H43N3O13: C, 59.58; H, 5.97; N, 5.79. Found: C, 59.71;
H, 5.90; N, 5.83.
1.97 (s, 3H, Me), 1.76–1.88 (m, 1H, H-6), 1.78 (s, 3H, Me),
1.33 (s, 3H, Me), 1.20 (s, 3H, Me), 0.90–0.98 (m, 9H, 3 Me),
0.60–0.68 (m, 6H, 3 CH2), K0.03 (s, 9H, 3 Me); 13C NMR
(CD3COCD3, 100 MHz) d: 204.4, 201.4, 173.5, 172.2,
155.1, 145.1, 144.0, 132.2, 131.6, 128.9, 120.8, 87.1, 87.0,
83.1, 80.4, 80.3, 79.4, 75.5, 64.3, 46.6, 45.7, 45.0, 41.3,
1
34.8, 24.3, 23.3, 21.3, 17.0, 13.1, 9.7, 8.4, 3.7. (22); H
NMR (CD3COCD3, 100 MHz) d 7.60–7.64 (m, 2H, arom),
7.48–7.52 (m, 1H, arom), 7.37–7.46 (m, 2H, arom), 6.54 (s,
1H, H-10), 5.02 (dd, 1H, H-5, JZ0.5, 9.0 Hz), 4.70 (s, 2H,
H-20), 4.55 (dd, 1H, H-7, JZ7.6, 9.6 Hz), 3.90 (d, 1H, H-2,
JZ5.2 Hz), 3.57 (d, 1H, H-3, JZ5.2 Hz), 3.07 (d, 1H, H-14,
JZ20.4 Hz), 2.91 (d, 1H, H-14, JZ20.4 Hz), 2.59–2.69 (m,
1H, Ha-6), 2.15 (s, 3H, Me), 2.14 (s, 3H, Me), 2.08 (s, 3H,
Me), 1.76–1.88 (m, 1H, Hb-6), 1.65 (s, 3H, Me), 1.25 (s, 3H,
Me), 0.98 (s, 3H, Me), 0.90–0.98 (m, 9H, 3 Me), 0.60–0.68
(m, 6H, 3 CH2), 0.00 (s, 9H, 3 Me); 13C NMR (CD3COCD3,
100 MHz) d 204.1, 201.7, 173.7, 172.2, 154.9, 144.8, 144.0,
132.2, 131.8, 128.3, 120.8, 89.1, 87.2, 82.9, 82.7, 80.1, 79.4,
75.4, 64.0, 46.9, 46.1, 45.1, 41.3, 34.9, 24.4, 23.3, 21.1,
12.8, 9.7, 8.3, 3.8. Compounds 23 and 24. Anal. Calcd for
C43H66O11Si3: C, 61.25; H, 7.89. Found: C, 61.03; H, 7.75;
IR (nujol, cmK1): 1718, 1368, 1254, 1060, 842; MS (m/z)
ESI: 844 (MCH)C. (23); 1H NMR (CD3COCD3, 400 MHz)
d 7.64–7.68 (m, 2H, arom), 7.46–7.50 (m, 1H, arom), 7.34–
7.44 (m, 2H, arom), 6.43 (s, 1H, H-10), 5.02 (dd, 1H, H-5,
JZ0.5, 9.2 Hz), 4.64 (s, 2H, H-20), 4.52 (dd, 1H, H-7, JZ
8.0, 9.6 Hz), 4.48 (d, 1H, H-2, JZ5.6 Hz), 4.46 (s, 1H,
H-14), 3.35 (d, 1H, H-3, JZ5.6 Hz), 2.56–2.66 (m, 1H,
Ha-6), 2.14 (s, 3H, Me), 2.02 (s, 3H, Me), 2.00 (s, 3H, Me),
1.78–1.88 (m, 1H, Hb-6), 1.78 (s, 3H, Me), 1.37 (s, 3H, Me),
1.15 (s, 3H, Me), 0.90–0.98 (m, 9H, 3 Me), 0.58–0.66 (m,
6H, 3 CH2), 0.09 (s, 9H, 3 Me), K0.01 (s, 9H, 3 Me); 13C
NMR (CD3COCD3, 100 MHz) d 206.2, 173.1, 172.3, 156.3,
154.4, 142.3, 137.4, 131.9, 131.4, 128.9, 122.0, 114.2, 91.2,
87.2, 82.8, 82.7, 80.1, 79.8, 75.5, 62.3, 45.8, 41.7, 41.4,
31.8, 24.4, 23.5, 21.6, 17.4, 13.5, 9.8, 8.5, 3.7, 3.1. (24); 1H
NMR (CD3COCD3, 400 MHz) d 7.64–7.68 (m, 2H, arom),
7.46–7.50 (m, 1H, arom), 7.34–7.44 (m, 2H, arom), 6.41 (s,
1H, H-10), 5.42 (s, 1H, H-14), 5.00 (dd, 1H, JZ0.5, 8.4 Hz),
4.67 (d, 1H, H-20, JZ8.4 Hz), 4.64 (d, 1H, H-20, JZ
8.4 Hz), 4.52 (dd, 1H, H-7, JZ8.0, 9.6 Hz), 4.02 (d, 1H,
H-2, JZ6.0 Hz), 3.40 (d, 1H, H-3, JZ6.0 Hz), 2.56–2.66
(m, 1H, Ha-6), 2.12 (s, 3H, Me), 2.09 (s, 3H, Me), 2.06 (s,
3H, Me), 1.78–1.88 (m, 1H, Hb-6), 1.63 (s, 3H, Me), 1.42 (s,
3H, Me), 0.90–0.98 (m, 9H, 3 Me), 0.80 (s, 3H, Me), 0.58–
0.66 (m, 6H, 3 CH2), 0.34 (s, 9H, 3 Me), 0.03 (s, 9H, 3 Me);
13C NMR (CD3COCD3, 100 MHz) d 205.9, 173.4, 172.2,
155.9, 146.1, 142.4, 137.1, 132.0, 131.7, 128.3, 121.7,
115.4, 93.1, 87.3, 82.7, 80.7, 80.0, 79.6, 75.4, 62.5, 45.5,
41.8, 41.3, 31.9, 24.6, 23.4, 21.5, 17.5, 13.2, 9.7, 8.5, 3.8,
2.8.
4.1.9. Synthesis of 7-TES-13-oxo-1,2-[a-(b-O-TMS)-ben-
zylideneacetal)]-baccatin III (21); 7-TES-13-oxo-1,2-[a-
(b-O-TMS)-benzylideneacetal)]-baccatin III (22);
7-TES-13-TMS-13,14-dehydro-1, 2-[a-(b-O-TMS)-benz-
ylideneacetal)]-baccatin III (23); 7-TES-13-TMS-13,14-
dehydro-1,2-[a-(b-O-TMS)-benzylideneacetal)]-bacca-
tin III (24). A. DBU induced silylation of 1 with Me3SiCl.
(i) A solution of 0.30 g (0.42 mmol) of 1, 0.13 g
(0.84 mmol) of DBU, 0.11 g (1.05 mmol) of Me3SiCl, in
8.0 mL of CH2Cl2 was refluxed under nitrogen for 2 h. The
reaction solution was treated with saturated aqueous
solution of NH4Cl. The organic layer was separated and
extracted with water, dried, filtered, and evaporated under
reduced pressure. The 1H NMR spectrum of the crude
mixture (CD3COCD3) showed a product distribution of 21/
22/23/24Z41:36:11:7 and minor amounts of unreacted 1
and of the silyl enol ether 3. Chromatography (SiO2,
n-hexane/CH2Cl2/EtOAc, 14:6:3) gave 0.24 g (0.30 mmol,
71%) of a mixture of compounds 21 and 22 (21/22Z0.94),
0.06 g (0.07 mmol, 16%) of a mixture of compounds 23 and
24 (23/24Z1.1). All compounds are solid. (ii) A solution of
0.30 g (0.42 mmol) of 1, 0.39 g (2.52 mmol) of DBU, 0.38 g
(2.94 mmol) of Me3SiCl, in 8.0 mL of CH2Cl2 was refluxed
under nitrogen for 2 h. The crude reaction mixture, obtained
after the above described work up, was chromatographed on
Al2O3, (n-hexane/EtOAc, 10:1) to give a mixture of 23 and
24 (0.33 g, 0.38 mmol, 92%, 23/24Z1.4). B. Silylation of 1
with BSA. (i) 0.25 g (0.35 mmol) of 7-TES-13-oxo-baccatin
III 1 and BSA (0.18 g, 0.88 mmol) were reacted in 5.0 mL
of CD3CN at 25 8C for 24 h at 20 8C. The crude reaction
mixture, obtained after the above described work up, was
chromatographed on Al2O3, (n-hexane/EtOAc, 10:1) to give
compounds 3 (0.09 g, 0.11 mmol, 33%), 21 (0.03 g,
0.04 mmol, 12%), 22 (0.02 g, 0.03 mmol, 8%) and
unreacted 1 (0.12 g, 0,17 mmol, 47%). (ii) 0.25 g
(0.35 mmol) of 1 and BSA (0.18 g, 0.88 mmol) were
reacted in 5.0 mL of CD3CN and in the presence of 0.01 g
(0.07 mmol) of DMAP for 8 h. The reaction solution was
treated with saturated aqueous solution of NH4Cl. The
organic layer was separated and extracted with water, dried,
filtered, and evaporated under reduced pressure. Chroma-
tography (Al2O3, n-hexane/EtOAc, 10:1) gave 0.18 g
(0.23 mmol, 65%) of a mixture of compounds 21 and 22
(21/22Z1.5) and 0.10 g (0.12 mmol, 35%) of a mixture of
compounds 23 and 24 (23/24Z4.0). All compounds are
solid. Compounds 21 and 22. Anal. Calcd for C40H58O11Si2:
C, 62.31; H, 7.58. Found: C, 62.44; H, 7.62; IR (nujol, cmK1):
3474, 1724, 1369, 1254; MS (m/z) ESI: 772 (MCH)C. (21);
1H NMR (CD3COCD3, 400 MHz) d 7.60–7.64 (m, 2H,
arom), 7.48–7.52 (m, 1H, arom), 7.37–7.46 (m, 2H, arom),
6.57 (s, 1H, H-10), 5.02 (dd, 1H, H-5, JZ0.5, 9.0 Hz), 4.68
(s, 2H, H-20), 4.55 (dd, 1H, H-7, JZ7.6, 9.6 Hz), 4.39 (d,
1H, H-2, JZ5.2 Hz), 3.50 (d, 1H, H-3, JZ5.2 Hz), 2.59–
2.69 (m, 1H, H-6), 2.53 (d, 1H, H-14, JZ20.0 Hz), 2.29 (d,
1H, H-14, JZ20.0 Hz), 2.20 (s, 3H, Me), 2.11 (s, 3H, Me),
4.1.10. Synthesis of 7,13-bis-TES-13,14-dehydro-1,2-[a-
(b-O-TES)-benzylidene-acetal)]-baccatin III (25); 7,13-
bis-TES-13,14-dehydro-1,2-[a-(b-O-TES)-benzylidene-
acetal)]-baccatin III (26), 7- TES-13-oxo-1,2-[a-(b-O-
TES)-benzylideneacetal)]-baccatin III (27). Procedure A.
A solution of 0.35 g (0.49 mmol) of 7-TES-13-oxo-baccatin
III 1, 0.53 g (3.43 mmol) of DBU, 0.44 g (2.94 mmol) of
TESCl, in 8.0 mL of CH3CN was left at 20 8C for 5 h. After,
the solution was treated with saturated solution of NH4Cl.
The organic layer was separated, the aqueous phase was

A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
7737
extracted with CH2Cl2. The organic phases were combined,
dried, filtered, and evaporated under reduced pressure. The
1H NMR spectrum of the crude mixture (CD3COCD3)
showed a product distribution of 25/26Z1.2. Chroma-
tography (Al2O3, cyclohexane/EtOAc, 97:3 to 95:5) gave
0.43 g (0.46 mmol, 93%) of the mixture of 25 and 26.
Procedure B: (i) Compound 1 (0.14 g, 0.2 mmol) was
dissolved in THF (5.0 mL) and the solution was cooled to
H-7, JZ7.0, 9.6 Hz), 4.35 (d, 1H, H-2, JZ6.9 Hz), 3.45 (d,
1H, H-3, JZ6.9 Hz), 2.56–2.64 (m, 1H, Ha-6), 2.26–2.32
(m, 2H, H-14), 2.23 (s, 3H, Me), 2.14 (s, 3H, Me), 2.01 (s,
3H, Me), 1.87–1.95 (m, 1H, Hb-6), 1.79 (s, 3H, Me), 1.34 (s,
3H, Me), 1.22 (s, 3H, Me), 0.90–1.03 (m, 18H, 6 Me), 0.40–
0.85 (m, 12H, 6 CH2); 13C NMR (CDCl3, 100 MHz) d:
201.1, 198.0, 170.2, 168.9, 151.7, 142.1, 140.7, 128.6,
128.1, 125.6, 117.5, 85.7, 83.9, 79.8, 77.4, 77.0, 76.2, 72.2,
61.0, 43.4, 42.4, 41.8, 38.1, 31.5, 21.0, 20.0, 18.0, 13.7, 9.7,
6.5, 6.3, 5.9, 5.3. Anal. Calcd for C43H64O11Si2: C, 63.51;
H, 7.93. Found: C, 63.74; H, 8.04.
t
K70 8C. BuOK (1.0 M in THF, 0.5 mmol) was added and
the reaction mixture stirred for 15 min at K70 8C, then
TESCl (0.07 mL, 0.40 mmol) was added. After 45 min the
reaction was quenched with saturated aqueous solution of
NH4Cl (8.0 mL) and extracted with EtOAc, dried, and the
solvent was evaporated. The crude mixture was purified by
chromatography (Al2O3, n-hexane/EtOAc, 10:1) to afford
compounds 27 (0.13 g, 0.16 mmol, 80%) and 25 (0.04 g,
0.04 mmol, 20%). Attempted purification of 0.20 g of the
80:20 mixture of 25/27 (cyclohexane/EtOAc, 9:1) caused a
partial solvolysis of 25 and 27 affording the silyl enol ether
28 and the reagent 1. Final product distribution was 1/27/
28Z31:49:20. (ii): Compound 1 (0.14 g, 0.2 mmol) was
dissolved in THF (4.0 mL) and the solution was cooled to
4.1.11. Desilylation of compounds 23 and 24 into 7-TES-
13-TMS-13,14-dehydro-baccatin III (3). A mixture of 23/
24Z0.89 (0.20 g, 0.24 mmol) was dissolved in 4.0 mL of
CH2Cl2 at 20 8C, then 0.03 g (0.02 mmol) of PTSA was
added. After 20 min the reaction solution was treated with
saturated aqueous solution of NH4Cl. The organic layer was
separated and extracted with water, dried, filtered, and
evaporated under reduced pressure. Chromatography (SiO2,
n-hexane/CH2Cl2/EtOAc, 14:6:3) gave compound 3 as a
white solid (0.18 g, 0.23 mmol, 95%). IR (nujol, cmK1):
1721, 1255, 1238, 1107, 1068; [a]2D0 K44.0 (c 1.14, CHCl3);
MS (m/z) ESI: 772 (MCH)C; 1H NMR (CDCl3, 400 MHz)
d 8.08 (m, 2H, arom), 7.56–7.62 (m, 1H, arom), 7.44–7.50
(m, 2H, arom), 6.41 (s, 1H, H-10), 5.76 (d, 1H, H-2, JZ
7.2 Hz), 4.97 (dd, 1H, H-5, JZ9.6, 0.5 Hz), 4.73 (s, 1H,
H-14), 4.44 (dd, 1H, H-7, JZ6.9, 10.5 Hz), 4.29 (d, 1H,
H-20, JZ8.4 Hz), 4.14 (d, 1H, H-20, JZ8.4 Hz), 3.71 (d,
1H, H-3, JZ7.2 Hz), 2.46–2.56 (m, 1H, Ha-6), 2.19 (s, 3H,
Me), 2.18 (s, 3H, Me), 2.05 (s, 3H, Me), 1.82–1.90 (m, 1H,
Hb-6), 1.69 (s, 3H, Me), 1.26 (s, 3H, Me), 1.12 (s, 3H, Me),
0.88–0.95 (m, 9H, 3 Me), 0.52–0.60 (m, 6H, 6 CH2), 0.25 (s,
9H, 3 Me); 13C NMR (CDCl3, 100 MHz) d 202.2, 170.2,
169.6, 166.9, 153.5, 138.0, 135.2, 133.8, 130.3, 129.7,
128.8, 110.6, 84.2, 81.4, 80.7, 76.5, 76.2, 73.6, 72.4, 58.3,
45.1, 41.0, 37.4, 29.0, 21.9, 21.3, 19.1, 14.2, 10.3, 7.0, 5.5,
0.6. Anal. Calcd for C40H58O11Si2: C, 62.31; H, 7.58.
Found: C, 62.50; H, 7.68.
t
K60 8C. BuOK (1.0 M in THF, 1.0 mL, 1.0 mmol) was
added and the reaction mixture stirred for 15 min at
K60 8C, then TESCl (0.21 mL, 1.2 mmol) was added.
After 1 h the reaction was quenched with saturated aqueous
solution of NH4Cl and extracted with EtOAc, dried, and the
solvent was evaporated. The crude was purified by
chromatography (Al2O3, n-hexane/EtOAc, 10:1) to obtain
compound 25 (0.17 g, 0.19 mmol, 94%). Compounds 25
and 26. Anal. Calcd for C49H78O11Si3: C, 63.46; H, 8.48.
Found: C, 63.67; H, 8.55; IR (nujol, cmK1): 1735, 1719,
1376, 1232. (25): [a]D20 C8.7 (c 0.40, CH3COCH3); MS (m/
z) ESI: 928 (MCH)C; 1H NMR (CD3COCD3, 400 MHz) d:
7.68–7.73 (m, 2H), 7.40–7.44 (m, 3H, arom), 6.45 (s, 1H,
H-10), 5.05 (dd, 1H, H-5 JZ0.9, 7.7 Hz), 4.64–4.68 (m,
2H), 4.52 (dd, 1H, JZ7.0, 10.2 Hz), 4.50 (1H, H-2, JZ
5.9 Hz), 4.46 (s, 1H), 3.37 (d, 1H, H-3, JZ5.9 Hz), 2.57–
2.68 (m, 1H, Ha-6), 2.13 (s, 3H, Me), 2.07 (s, 3H, Me), 2.03
(s, 3H, Me), 1.80–1.90 (m, 1H, Hb-6), 1.79 (s, 3H, Me), 1.37
(s, 3H, Me), 1.17 (s, 3H, Me), 0.85–1.00 (m, 18H, 9 CH2),
0.50–0.70 (m, 27H, 9 Me); 13C NMR (CD3COCD3,
100 MHz) d: 202.9, 169.8, 168.9, 153.0, 143.1, 138.9,
134.0, 128.6, 128.0, 125.7, 118.6, 110.9, 89.7, 83.9, 79.6,
77.7, 76.8, 76.6, 72.2, 59.3, 42.3, 38.6, 38.1, 28.3, 21.2,
4.1.12. Desilylation of compounds 25 and 26 into 7, 13-
bis-TES-13,14-dehydro-baccatin III (28). A mixture of
25/26Z1.25 (0.25 g, 0.27 mmol) was dissolved in 4.0 mL
of CH2Cl2 at 20 8C then 0.03 g (0.02 mmol) of PTSA was
added. After 12 h the reaction was treated with saturated
aqueous solution of NH4Cl. The organic layer was separated
and extracted with water, dried, filtered, and evaporated
under reduced pressure. Chromatography (SiO2, n-hexane/
CH2Cl2/EtOAc, 14:6:3) gave compound 28 (0.20 g,
0.25 mmol, 93%) as a white solid. (28): IR (nujol, cmK1):
3483, 1739, 1722, 1704, 1376, 1242; [a]2D0 K6.0 (c 1.0,
1
20.3, 18.5, 14.0, 10.1, 6.5, 6.3, 6.2, 5.3, 5.2, 4.8. (26); H
NMR (CD3COCD3, 400 MHz) d: 7.48–7.53 (m, 2H, arom),
7.40–7.44 (m, 3H, arom), 6.40 (s, 1H, H-10), 5.36 (s, 1H,
H-14), 4.98 (dd, 1H, H-5, JZ0.9, 7.7 Hz), 4.64–4.68 (m,
2H, H-20), 4.52 (dd, 1H, H-7, JZ9.2, 6.8 Hz), 3.97 (d, 1H,
H-2, JZ6.0 Hz), 3.40 (d, 1H, H-3, JZ6.0 Hz), 2.57–2.68
(m, 1H, Ha-6), 2.14 (s, 3H, Me), 2.07 (s, 3H, Me), 2.02 (s,
3H, Me), 1.76–1.86 (m, 1H, Hb-6), 1.62 (s, 3H, Me), 1.42 (s,
3H, Me), 0.85–1.00 (m, 27H, 9 Me), 0.80 (s, 3H, Me), 0.50–
0.70 (m, 18H, 9 CH2); 13C NMR (CD3COCD3, 100 MHz) d:
202.5, 170.1, 168.9, 152.6, 142.3, 139.0, 133.9, 128.7,
128.4, 125.1, 118.5, 112.9, 87.1, 84.0, 79.4, 79.0, 76.7, 76.4,
72.1, 59.2, 42.4, 38.6, 38.1, 28.4, 21.3, 20.2, 18.4, 14.2, 9.9,
6.5, 5.3. (27): [a]2D0 C8.8 (c 0.40, CH3COCH3); IR (nujol,
cmK1): 3470, 1727, 1371, 1250; MS (m/z) ESI: 814 (MC
1
CHCl3); MS (m/z) ESI: 814 (MCH)C; H NMR (CDCl3,
400 MHz) d: 8.06–8.10 (m, 2H, arom), 7.54–7.60 (m, 1H,
arom), 7.40–7.46 (m, 2H, arom), 6.42 (s, 1H, H-10), 5.75 (d,
1H, H-2, JZ7.3 Hz), 4.95 (dd, 1H, H-5, JZ0.9, 9.7 Hz),
4.73 (s, 1H, H-14), 4.43 (dd, 1H, H-7, JZ6.9, 10.0 Hz), 4.27
(d, 1H, H-20, JZ8.0 Hz), 4.13 (d, 1H, H-20, JZ8.0 Hz),
3.71 (d, 1H, H-3, JZ7.3 Hz), 2.44–2.53 (m, 1H, Ha-6, JZ
7.3, 9.7, 14.5 Hz), 2.19 (s, 3H, Me), 2.17 (s, 3H, Me), 2.05
(s, 3H, Me), 1.80–1.88 (m, 1H, Hb-6), 1.67 (s, 3H, Me), 1.24
(s, 3H, Me), 1.10 (s, 3H, Me), 0.88–0.96 (m, 18H, 3 Me),
0.54–0.78 (m, 12H, 3 CH2); 13C NMR (CDCl3, 100 MHz) d:
202.1, 170.1, 169.6, 166.9, 153.5, 137.9, 135.1, 133.7,
1
H)C; H NMR (CDCl3, 400 MHz) d: 7.54–7.58 (m, 2H,
arom), 7.32–7.35 (m, 3H, arom), 6.55 (s, 1H, H-10), 4.99
(dd, 1H, JZ8.8, 0.9 Hz), 4.75 (s, 2H, H-20), 4.49 (dd, 1H,

7738
A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
130.2, 129.7, 128.8, 110.6, 84.4, 81.4, 80.7, 76.5, 76.2, 73.8,
72.3, 58.3, 45.2, 40.9, 37.4, 28.7, 21.9, 21.2, 19.2, 14.0,
10.3, 7.0, 6.9, 5.5, 5.2. Anal. Calcd for C43H64O11Si2: C,
63.51; H, 7.93. Found: C, 63.29; H, 7.84.
6.4, 10.4 Hz), 4.30 (d, 1H, H-20, JZ8.8 Hz), 4.24 (d, 1H,
H-20, JZ8.8 Hz), 3.84 (d, 1H, H-3, JZ6.8 Hz), 3.57 (s, 1H,
H-14), 2.52 (ddd, 1H, Ha-6, JZ6.4, 9.2, 14.0 Hz), 2.21 (s,
3H, Me), 2.19 (s, 3H, Me), 2.12 (s, 3H, Me), 1.90 (ddd, 1H,
Hb-6, JZ2.0, 11.2, 14.0 Hz), 1.73 (s, 3H, Me), 1.27 (s, 3H,
Me), 0.93 (m, 9H, 3 Me), 0.84 (s, 3H, Me), 0.55–0.62 (m,
6H, 3 CH2); 13C NMR (100 MHz, CDCl3) d 201.5, 200.2,
169.9, 169.2, 165.4, 151.7, 138.1, 133.7, 129.9, 129.8,
128.9, 84.1, 81.4, 76.4, 75.5, 73.4, 72.9, 72.4, 59.1, 57.9,
45.4, 43.1, 37.3, 33.1, 21.8, 21.0, 19.9, 14.1, 10.1, 6.9, 5.5.
Anal. Calcd C37H51NO11Si: C, 62.25; H, 7.20; N, 1.96.
Found: C, 62.33; H, 7.29; N. 1.90.
4.1.13. 7-TES-13-TIPS-13,14-dehydro-baccatin III (29).
Compound 1 (0.57 g, 0.81 mmol) was dissolved in 4:1 THF/
DMPU mixture (21.0 mL) and the solution was cooled to
t
K78 8C. BuOK (1.0 M in THF, 0.5 mmol) was added and
the reaction mixture stirred for 15 min at K70 8C, then
TIPSCl (0.06 mL, 0.34 mmol) was added. After 3.0 h the
reaction was quenched with saturated NH4Cl (8.0 mL) and
extracted with EtOAc, dried, and the solvent was
evaporated. The crude mixture was purified by chromato-
graphy (SiO2, n-hexane/EtOAc/Et2O, 18:6:4) gave the
reagent 1 (0.17 g, 0.31 mmol, 31%) and compound 29
(0.38 g, 0.45 mmol, 55%) as a white solid. (29): IR (nujol,
cmK1): 3483, 1725, 1376, 1239; [a]2D0 K21.0 (c 0.9,
4.1.16. 7-BOC-13-oxo-14b-amino-baccatin III (31). PPh3
(0.09 g, 0.34 mmol) was added to a solution of 0.20 g
(0.27 mmol) of 5 in 7.5 mL of a mixture of acetonitrile/
water Z7:1. After 2 h the reaction mixture was concen-
trated under reduced pressure. Chromatography of the
residue (SiO2, n-hexane/EtOAc, 1.4:1.0) yielded 0.14 g
(0.21 mmol, 77%) of 31 as a white solid. IR (KBr, cmK1):
3053, 2960, 1726, 1478, 1434, 1090; [a]2D0 C31.7 (c 0.4,
1
CHCl3); MS (m/z) ESI: 856 (MCH)C; H NMR (CDCl3,
400 MHz) d: 8.05–8.10 (m, 2H, arom), 7.57–7.61 (m, 1H,
arom), 7.44–7.49 (m, 2H, arom), 6.40 (s, 1H, H-10), 5.77 (d,
1H, H-2, JZ7.6 Hz), 4.95 (dd, 1H, H-5, JZ1.2, 9.5 Hz),
4.82 (s, 1H, H-14), 4.47 (dd, 1H, H-7, JZ6.4, 10.0 Hz), 4.28
(d, 1H, H-20, JZ8.4 Hz), 4.17 (d, 1H, JZ8.4 Hz), 3.74 (d,
1H, H-3, JZ7.6 Hz), 2.45–2.54 (ddd, 1H, Ha-6, JZ7.6, 9.5,
14.5 Hz), 2.22 (s, 3H, Me), 2.19 (s, 3H, Me), 2.10 (s, 3H,
Me), 1.84–1.92 (m, 1H, Hb-6), 1.70 (s, 3H, Me), 1.25 (s, 3H,
Me), 1.15 (s, 3H, Me), 1.05–1.15 (m, 21H), 0.90–0.94 (t,
9H, 2 Me), 0.54–0.72 (m, 6H, 3 CH2); 13C NMR (CDCl3,
100 MHz) d: 201.7, 170.0, 169.3, 166.7, 153.5, 137.8,
134.8, 133.6, 130.2, 129.7, 128.7, 110.6, 84.4, 81.9, 80.8,
76.5, 76.2, 74.2, 72.4, 58.4, 45.6, 41.0, 37.5, 28.5, 22.3,
21.4, 19.8, 18.5, 18.4, 14.2, 13.0, 10.7, 7.2, 5.7. Anal. Calcd
for C46H70O11Si2: C, 64.60; H, 8.25 Found: C, 64.45; H,
8.17.
1
CH2Cl2); MS (m/z) ESI: 701 (MCH)C; H NMR (CDCl3,
400 MHz) d 7.8–8.15 (m, 2H, arom), 7.58–7.63 (m, 1H,
arom), 7.44- 7.50 (m, 2H, arom), 6.55 (s, 1H, H-10), 5.86 (d,
1H, H-2, JZ6.8 Hz), 5.40 (dd, 1H, H-7, JZ10.8, 7.0 Hz),
4.94 (dd, 1H, H-5, JZ2.1, 9.6 Hz), 4.33 (d, 1H, H-20, JZ
8.4 Hz), 4.26 (d, 1H, H-20, JZ8.4 Hz), 4.01 (d, 1H, H-3,
JZ6.4 Hz), 3.58 (s, 1H, H-14), 2.61 (ddd, 1H, Ha-6, JZ7.0,
9.6, 14.4 Hz), 2.22 (s, 3H, Me), 2.19 (s, 3H, Me), 2.14 (s,
3H, Me), 1.98 (ddd, 1H, Hb-6, JZ2.1, 10.8, 14.4 Hz), 1.84
(s, 3H, Me), 1.48 (s, 9H, 3 Me), 1.25 (s, 3H, Me), 0.89 (s,
3H, Me); 13C NMR (CDCl3, 100 MHz) d 201.2, 200.1,
170.0, 168.0, 165.3, 151.8, 150.5, 138.2, 133.9, 130.0,
129.2, 129.1, 83.6, 82.4, 80.7, 76.9, 75.6, 75.4, 74.6, 72.4,
65.0, 56.2, 45.1, 42.9, 33.7, 33.7, 26.7, 21.9, 20.5, 19.1,
14.4, 10.7. Anal. Calcd C36H45NO13: C, 61.79; H, 6.48; N,
2.00. Found: C, 61.86; H, 6.42; N. 2.12.
4.1.14. 7-TES-13-oxo-14 b-azido-baccatin III (4). A
solution of 0.21 g (0.27 mmol) of 3 in 5.0 mL of CH3CN
were added 0.08 g of NaN3 (1.2 mmol) and 0.45 g
(0.81 mmol) of CAN under nitrogen stream at 0 8C. The
mixture was stirred for 1.0 h, diluted with 7.0 mL of H2O
and extracted with 5.0 mL of Et2O. The organic phase was
dried, the solvent evaporated and the residue was
chromatographed (SiO2, cyclohexane/EtOAc/Et2O, 8:1:1)
giving 0.19 g of compound 4 (0.26 mmol, 95%) as a white
solid. In a similar experiment compound 29 (0.07 g,
0.08 mmol) was reacted with 0.06 g of NaN3 (0.57 mmol)
and 0.49 g of CAN (0.9 mmol) to afford compound 4
(0.03 g, 0.04 mmol, 55%).
4.1.17. 7-TES-13-oxo-14b-amino-baccatin III 14,1-car-
bamate (32). A 1.93 M solution of phosgene in toluene
(0.32 mL, 0.62 mmol) and 0.1 mL (1.20 mmol) of pyridine
were added under stirring to a solution of 0.44 g
(0.62 mmol) of 30 in 6.0 mL of CH2Cl2 at K78 8C. After
1 h the reaction mixture was quenched by addition of
10.0 mL of water and extracted with 10.0 mL of CH2Cl2;
the organic phase was washed with brine, dried, filtered,
and evaporated under reduced pressure. Chromatography
(SiO2, n-hexane/EtOAc/Et2O, 1.8:0.7:0.3) gave 0.39 g
(0.53 mmol, 86%) of 32 as a white solid. IR (KBr, cmK1):
3342, 2956, 1732, 1452, 1238, 1090; [a]2D0 C28.5 (c 1.0,
1
4.1.15. 7-TES-13-oxo-14b-amino-baccatin III (30). PPh3
(0.11 g, 0.43 mmol) was added to a solution of 0.29 g
(0.39 mmol) of 4 in 11.7 mL of a CH3CN/H2OZ9:1 mixed
solvent. The reaction was cooled at 5 8C, and after 18 h was
evaporated under reduced pressure. Chromatography of the
residue (SiO2, n-hexane/EtOAc/Et2O, 1.8:0.7:0.3) afforded
0.24 g (0.34 mmol, 88%) of 30 as a white solid. IR (KBr,
cmK1): 3396, 3204, 2956, 2878, 2255, 1728, 1452, 1370,
1105; [a]2D01C18.1 (c 0.5, CH2Cl2); MS (m/z) ESI: 715
(MCH)C; H NMR (CDCl3, 400 MHz) d 7.99–8.01 (m,
2H, arom), 7.61–7.66 (m, 1H, arom), 7.43–7.45 (m, 2H,
arom), 6.50 (s, 1H, H-10), 5.86 (d, 1H, H-2, JZ6.8 Hz),
4.89 (dd, 1H, H-5, JZ2.0, 9.6 Hz), 4.47 (dd, 1H, H-7, JZ
CH2Cl2); MS (m/z) ESI: 741 (MCH)C; H NMR (CDCl3,
400 MHz) d 7.96–7.98 (m, 2H, arom), 7.58–7.61 (m, 1H,
arom), 7.42–7.45 (m, 2H, arom), 6.48 (s, 1H, H-10), 6.06 (d,
1H, H-2, JZ6.9 Hz), 6.02 (s, 1H, N-H), 4.90 (dd, 1H, H-5,
JZ1.9, 9.5 Hz), 4.46 (dd, 1H, H-7, JZ10.7, 6.5 Hz), 4.32
(d, 1H, H-20, JZ8.8 Hz), 4.23 (d, 1H, H-20, JZ8.8 Hz),
4.17 (s, 1H, H-14), 3.83 (d, 1H, H-3, JZ6.9 Hz), 2.52 (ddd,
1H, Ha-6, JZ6.5, 9.7, 14.0 Hz), 2.22 (s, 3H, Me), 2.20 (s,
3H, Me), 2.15 (s, 3H, Me), 1.92 (ddd, 1H, Hb-6, JZ1.9,
10.8, 14.0 Hz), 1.73 (s, 3H, Me), 1.34 (s, 3H, Me), 1.14 (s,
3H, Me), 0.91–0.95 (m, 9H, 3 Me), 0.58–0.62 (m, 6H, 3
CH2); 13C NMR (CDCl3, 100 MHz) d 199.3, 195.6, 170.1,
168.9, 164.6, 155.7, 151.1, 138.9, 134.2, 129.9, 129.0,

A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
7739
128.4, 86.2, 84.2, 80.9, 76.3, 74.9, 72.3, 69.7, 59.3, 59.2,
45.4, 42.6, 37.3, 32.9, 22.1, 21.1, 19.8, 14.2, 10.4, 7.2, 5.7.
Anal. Calcd C38H49NO12Si: C, 61.69; H, 6.68; N, 1.89.
Found: C, 61.76; H, 6.75; N, 1.81.
to K30 8C. After 4 days, at K30 8C, the reaction was
quenched by addition of 2.0 mL of acetic acid and extracted
three times with 15.0 mL of EtOAc. The organic phase was
1
dried, filtered and evaporated under reduced pressure. H
NMR spectrum of the residue showed the presence of
7-TES-14b-azido-baccatin III (13a-37) and its 13b epimer
(13b-38) in an a/b Z91:9 ratio. Chromatography (SiO2,
n-hexane/EtOAc, 2.1:1.0) afforded 0.35 g of 13a-37
(0.47 mmol, 76%) and 0.04 g of 13b-38 (0.06 mmol, 9%)
as white solids. (13a-37): IR (KBr, cmK1): 3493, 2956,
2881, 2112, 1728, 1371, 1233; [a]2D0 C20.0 (c 0.8, CH2Cl2);
MS (m/z) ESI: 743 (MCH)C; 1H NMR (CDCl3, 400 MHz)
d 8.07–8.1 (m, 2H, arom), 7.58–7.62 (m, 1H, arom), 7.44–
7.50 (m, 2H, arom), 6.41 (s, 1H, H-10), 5.82 (d, 1H, H-2,
JZ7.1 Hz), 4.97 (dd, 1H, H-5, JZ1.9, 9.5 Hz), 4.80 (m, 1H,
H-13), 4.46 (dd, 1H, H-7, JZ6.5, 10.4 Hz), 4.33 (d, 1H,
H-20, JZ8.4 Hz), 4.23 (d, 1H, H-20, JZ8.4 Hz), 3.98 (d,
1H, H-14, JZ7.3 Hz), 3.82 (d, 1H, H-3, JZ7.1 Hz), 3.00 (s,
1H, OH), 2.82 (b, 1H, OH), 2.53 (ddd, 1H, Ha-6, JZ6.5,
9.5, 14.2 Hz), 2.34 (s, 3H, Me), 2.20 (s, 3H, Me), 2.18 (s,
3H, Me), 1.90 (ddd, 1H, Hb-6, JZ1.9 Hz, 10.7, 14.2 Hz),
1.71 (s, 3H, Me), 1.24 (s, 3H, Me), 0.98 (s, 3H, Me), 0.90–
0.96 (m, 9H, 3 Me), 0.55–0.60 (m, 6H, 3 CH2); 13C NMR
(CDCl3, 100 MHz) d 201.4, 170.4, 169.4, 165.8, 140.9,
134.3, 133.8, 130.1, 129.4, 128.8, 84.3, 81.3, 76.9, 76.6,
75.7, 75.4, 74.6, 72.5, 68.8, 59.0, 46.8, 43.3, 37.5, 30.1,
26.6, 22.8, 22.1, 21.3, 15.2, 10.4, 7.2, 5.7. Anal. Calcd
C37H51N3O11Si: C, 59.90; H, 6.93; N, 5.66. Found: C,
60.11; H, 6.89; N, 5.70. Compound 13b-38: MS (m/z) ESI:
4.1.18. 13a-OH and 13b-OH epimers of 7-TES-14b-
amino-baccatin III 14,1-carbamate (13a-33 and 13b-34).
Sodium borohydride (0.18 g, 4.5 mmol) was added, under
stirring, to a solution of 0.22 g (0.30 mmol) of 32 in 8.0 mL
of ethanol at K40 8C. The temperature was raised to
K18 8C, then an additional amount of sodium borohydride
(0.12 g, 3.0 mmol) was added. After 18 h, the reaction
mixture was quenched by addition of 2.0 mL of acetic acid
and extracted with 10.0 mL of EtOAc. The organic phase
was dried, filtered, and evaporated under reduced pressure.
The 1H NMR spectrum of the residue showed the presence
of 7-TES-14b-amino-baccatin III 14,1-carbamate as a
mixture of epimers 13a-33 and 13b-34 in an a/b ratio of
1.6:1. Chromatography (SiO2, CH2Cl2/EtOAc, 1.0:0.9)
yielded 0.12 g of 13a-33 (0.17 mmol, 56%) and 0.08 g of
13b-34 (0.11 mmol, 35%) as solids. (13a-33): IR (KBr,
cmK1): 3364, 2955, 1731, 1452, 1372, 1089; [a]2D0 C16.2 (c
0.7, CH2Cl2); MS (m/z) ESI: 742 (MCH)C; 1H NMR
(CDCl3, 400 MHz) d 7.98–8.01 (m, 2H, arom), 7.58–7.61
(m 1H, arom), 7.41–7.45 (m, 2H, arom), 6.73 (s, 1H, N-H),
6.42 (s, 1H, H-10), 5.98 (d, 1H, H-2, JZ7.2 Hz), 4.93 (dd,
1H, H-5, JZ2.0, 9.5 Hz), 4.66 (m, 1H, H-13), 4.44 (dd, 1H,
H-7, JZ7.2, 10.0 Hz), 4.23 (d, 1H, H-20, JZ8.4 Hz), 4.15
(d, 1H, H-20, JZ8.4 Hz), 3.98 (d, 1H, H-14, JZ6.0 Hz),
3.75 (d, 1H, H-3, JZ7.2 Hz), 3.66 (b, 1H, OH), 2.52 (ddd,
1H, Ha-6, JZ7.2, 9.5 Hz, 13.5 Hz), 2.19 (s, 3H, Me), 2.17
(s, 3H, Me), 2.15 (s, 3H, Me), 1.88 (ddd, 1H, Hb-6, JZ2.0,
10.0, 13.5 Hz), 1.70 (s, 3H, Me), 1.26 (s, 3H, Me), 1.08 (s,
3H, Me), 0.90–0.96 (m, 9H, 3 Me), 0.55–0.59 (m, 6H, 3
CH2); 13C NMR (CDCl3, 100 MHz) d 201.3, 170.3, 169.2,
165.3, 158.2, 143.1, 134.0, 132.5, 129.9, 128.9, 128.8, 88.9,
84.3, 80.7, 75.4, 73.4, 72.3, 71.1, 61.1, 58.9, 46.5, 42.2,
37.4, 30.1, 26.2, 22.6, 22.1, 21.3, 15.1, 10.6, 7.2, 5.7. Anal.
Calcd C38H51NO12Si: C, 61.52; H, 6.93; N, 1.89. Found: C,
61.38; H, 6.84; N, 1.85. (13b-34): IR (KBr, cmK1): 3360,
1
743 (MCH)C; H NMR (CDCl3, 400 MHz) d 8.01–8.17
(m, 2H, arom), 7.52–7.58 (m 1H, arom), 7.42–7.48 (m, 2H,
arom), 6.51 (s, 1H, H-10), 5.88 (d, 1H, H-2, JZ6.8 Hz),
4.95 (dd, 1H, H-5, JZ2.2, 9.6 Hz), 4.70 (m, 1H, H-13), 4.48
(dd, 1H, H-7, JZ7.1, 9.9 Hz), 4.33 (d, 1H, H-20, JZ
8.4 Hz), 4.25 (d, 1H, H-20, JZ8.4 Hz), 3.90 (d, 1H, H-14,
JZ7.4 Hz), 3.78 (d, 1H, H-3, JZ6.8 Hz), 2.52 (ddd, 1H,
Ha-6, JZ9.6, 7.1, 14.1 Hz), 2.30 (s, 3H, Me), 2.22 (s, 3H,
Me), 2.12 (s, 3H, Me), 1.92 (ddd, 1H, Hb-6, JZ2.2, 9.9,
14.1 Hz), 1.72 (s, 3H, Me), 1.30 (s, 3H, Me), 1.26 (s, 3H,
Me), 0.88–0.92 (m, 9H, 3 Me), 0.55–0.60 (m, 6H, 3 CH2);
13C NMR (CDCl3, 100 MHz) d 200.8, 170.0, 169.3, 165.6,
138.9, 138.3, 135.8, 131.5, 129.4, 128.8, 84.3, 81.0, 76.9,
76.6, 76.3, 75.1, 74.3, 71.2, 69.4, 59.4, 54.5, 47.2, 40.5,
30.5, 30.0, 22.2, 21.6, 21.2, 20.2, 10.2, 7.2, 5.7. Anal. Calcd
C37H51N3O11Si: C, 59.90; H, 6.93; N, 5.66. Found: C,
60.21; H, 6.99; N, 5.60.
1
1734; MS (m/z) ESI: 743 (MCH)C; H NMR (CDCl3,
400 MHz) d 7.97–8.01 (m, 2H, arom), 7.60–7.64 (m, 1H,
arom), 7.44–7.48 (m, 2H, arom), 7.00 (s, 1H, N-H), 6.38 (s,
1H, H-10), 5.98 (d, 1H, H-2, JZ6.8 Hz), 4.82 (dd, 1H, H-5,
JZ2.4, 8.0 Hz), 4.38 (dd, 1H, H-7, JZ6.8, 10.4 Hz), 4.25
(m, 1H, H-13), 4.23 (d, 1H, H-20, JZ8.4 Hz), 4.12 (d, 1H,
H-20, JZ8.4 Hz), 3.98 (d, 1H, H-14, JZ5.9 Hz), 3.62 (d,
1H, H-3, JZ6.8 Hz), 2.50 (ddd, 1H, Ha-6, JZ8.0, 6.8,
13.6 Hz), 2.19 (s, 3H, Me), 2.17 (s, 3H, Me), 1.98 (s, 3H,
Me), 1.87 (ddd, 1H, Hb-6, JZ2.4, 10.4, 13.6 Hz), 1.68 (s,
3H, Me), 1.30 (s, 3H, Me), 1.28 (s, 3H, Me), 0.89–0.93 (m,
9H, 3 Me), 0.55–0.68 (m, 6H, 3 CH2); 13C NMR (CDCl3,
100 MHz) d 200.7, 169.9, 169.1, 165.1, 158.9, 141.0, 138.1,
134.0, 129.9, 129.0, 128.9, 93.4, 84.3, 81.1, 76.3, 75.5, 72.1,
70.0, 68.2, 59.2, 54.0, 46.1, 41.4, 30.8, 30.1, 22.0, 21.4,
21.2, 20.2, 10.4, 7.2, 5.7. Anal. Calcd C38H51NO12Si: C,
61.52; H, 6.93; N, 1.89. Found: C, 61.70; H, 7.01; N, 1.88.
4.1.20. 7-TES-13-[N-BOC-N,O-(2,4-dimethoxybenzyl-
idene)-b-isobutylisoserinoyl]-14b-azido-baccatin III
(39). A solution of 0.45 g (1.12 mmol) of 35 in 5.0 mL of
toluene, cooled to 0 8C, was added under nitrogen stream
and stirring, with 0.50 g (0.67 mmol) of a-37, 0.23 g
(1.12 mmol) of DCC, 0.90 g (0.08 mmol) of DMAP, and
0.02 g (0.12 mmol) of p-toluenesulfonic acid (PTSA). After
1 h at 70 8C the reaction mixture was cooled and filtered.
The solid was extracted with CH2Cl2, and the organic phase
was evaporated under reduced pressure. Chromatography of
the crude mixture (SiO2, n-hexane/EtOAc, 2.2:1.0) afforded
0.63 g (0.54 mmol, 80%) of 39 as a white solid. IR (KBr,
cmK1): 3491, 2957, 2111, 1731, 1614, 1508, 1368; [a]2D0
4.1.19. 13a-OH and 13b-OH epimers of 7-TES-14b-
azido-baccatin III (13a-37 and 13b-38). Sodium boro-
hydride (0.47 g, 12.5 mmol) was added at K40 8C to a
solution of 0.46 g (0.62 mmol) of 4 in 0.7 mL of THF and
12.0 mL of EtOH under stirring. The temperature was raised
1
C1.8 (c 0.7, CH2Cl2); MS (m/z) ESI: 1134 (MCH)C; H
NMR (CDCl3, 400 MHz) d 8.07–8.1 (m, 2H, arom), 7.58–
7.62 (m, 1H, arom), 7.42–7.50 (m, 1H, arom), 7.22–7.28 (m,

7740
A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
1H, arom), 6.40–6.52 (m, 4H, 2H arom, H-10, N–CH–O),
6.25 (d, 1H, H-13, JZ8.8 Hz), 5.88 (d, 1H, H-2, JZ7.6 Hz),
4.94 (dd, 1H, H-5, JZ1.5, 9.7 Hz), 4.45–4.62 (m, 3H, H-7,
H0-3, H0-2), 4.32 (d, 1H, H-20, JZ8.0 Hz), 4.24 (d, 1H,
H-20, JZ8.0 Hz), 4.04 (d, 1H, H-14, JZ8.8 Hz), 3.87 (s,
3H, OMe), 3.83 (s, 3H, OMe), 3.83 (d, 1H, H-3, JZ7.6 Hz),
2.52 (ddd, 1H, Ha-6, JZ6.8, 9.6, 14.0 Hz), 2.33 (s, 3H,
Me), 2.19 (s, 3H, Me), 2.11 (s, 3H, Me), 1.91 (ddd, 1H, 0Hb-
6, JZ1.5, 11.2, 14.0 Hz), 1.72–1.82 0(m, 2H, H0-4, H -5),
1.71 (s, 3H, Me), 1.54–1.64 (m, 1H, H -4), 1.27 (s, 3H, Me),
1.22–1.40 (s, 9H, 3 Me), 1.16 (s, 3H, Me), 1.06 (d, 6H, 2 Me,
JZ6.0 Hz), 0.90–0.98 (m, 9H, 3 Me), 0.58–0.4 (m, 6H, 3
CH2); 13C NMR (CDCl3, 100 MHz) d 201.2, 170.7, 170.1,
169.4, 165.9, 161.8, 159.3, 153.5, 137.1, 135.8, 134.0,
130.2, 130.1, 129.4, 128.9, 104.4, 101.5, 91.8, 86.5, 84.3,
81.2, 80.5, 76.6, 76.4, 74.8, 74.7, 72.3, 65.5, 58.7, 58.1,
55.6, 55.5, 46.4, 43.8, 43.5, 37.3, 28.4, 28.3, 26.6, 25.8,
23.2, 22.9, 22.6, 22.2, 21.0, 14.4, 10.3, 6.9, 5.5. Anal. Calcd
C58H80N4O17Si: C, 61.47; H, 7.11; N, 4.94. Found: C,
61.60; H, 7.17; N, 5.05.
The organic phase was dried, filtered, and evaporated under
reduced pressure. Chromatography of the residue (SiO2,
n-hexane/EtOAc/CH2Cl2, 1.4:1.0:2.0) afforded 0.13 g
(0.11 mmol, 73%) of 41 as a white solid. IR (KBr, cmK1):
3446, 2958, 1732, 1694, 1595, 1278, 1167; [a]2D0 K21.3 (c
1
0.9, CH2Cl2); MS (m/z) ESI: 1150 (MCH)C; H NMR
(CDCl3, 400 MHz, 55 8C) d 8.54–8.68 (b, 1H, HNCS),
7.96–7.98 (m, 2H, arom), 7.54–7.57 (m, 1H, arom), 7.37–
7.41 (m, 2H, arom), 7.19 (m, 1H, arom), 6.42–6.54 (m, 4H,
2H arom, H-10, N–CH–O), 6.03–6.13 (m, 2H, H-13, H-2),
4.90 (dd, 1H, H-5, JZ1.5, 9.7 Hz), 4.53–4.62 (m, 2H, H0-2,
H0-3), 4.49 (dd, 1H, H-7, JZ6.6, 10.5 Hz), 4.23–4.29 (m,
3H, H-14, H-20, H-20), 3.87 (s, 3H, Me), 3.82 (s, 3H, Me),
3.76 (d, 1H, H-3, JZ7.4 Hz), 2.51 (ddd, 1H, Ha-6, JZ6.6,
9.7, 14.3 Hz), 2.23 (s, 3H, Me), 2.19 (s, 3H, Me), 2.13 (s,
3H, Me), 1.86–1.94 (d0 dd, 1H, Hb-6, JZ1.5, 10.5, 14.3 Hz),
1.75–1.88 (m, 2H, H -4, H0-5), 1.73 (s, 3H, Me), 1.50–1.60
(m, 1H, H0-4), 1.36 (s, 3H, Me), 1.20–1.40 (s, 9H, 3 Me),
1.27 (s, 3H, Me), 1.09 (d, 3H, Me, JZ6.0 Hz), 1.05 (d, 3H,
Me, JZ6.0 Hz), 0.88–0.98 (m, 9H, 3 Me), 0.55–0.60 (m,
6H, 3 CH2); 13C NMR (CDCl3, 100 MHz) d 200.4, 187.5,
171.5, 169.9, 169.2, 164.8, 161.6, 159.0, 137.9, 134.7,
133.8, 129.9, 129.1, 128.8, 127.9, 118.9, 104.3, 98.6, 95.8,
87.0, 84.2, 81.6, 80.7, 80.3, 76.3, 76.0, 74.6, 72.1, 70.6,
62.8, 58.8, 55.7, 55.6, 46.4, 43.8, 42.7, 37.5, 30.8, 28.5,
26.3, 25.8, 23.3, 22.8, 22.6, 22.3, 21.2, 15.0, 10.7, 7.2, 5.7.
Anal. Calcd C59H80N2O17SSi: C, 61.65; H, 7.02; N, 2.44.
Found: C, 61.52; H, 7.10; N, 2.53.
4.1.21. 7-TES-13-[N-BOC-N,O-(2,4-dimethoxy-benzyl-
idene)-b-isobutylisoserinoyl]-14b-amino-baccatin III
(40). A solution of 0.25 g (0.23 mmol) of 39 in 9.0 mL of
MeOH was reduced under balloon pressure of H2 in the
presence of 10% Pd/C (0.05 g). After 18 h at room
temperature, the reaction mixture was filtered through celite
bed, and the solid was washed with 25.0 mL of EtOAc. The
organic phase was heated to 45 8C for 20 min and
subsequently evaporated under reduced pressure. Chroma-
tography of the residue (SiO2, n-hexane/EtOAc/CH2Cl2,
0.7:0.3:1.0) yielded 0.22 g (0.20 mmol, 90%) of 40 as a
white solid. IR (KBr, cmK1): 3449, 2957, 1726, 1617, 1368,
1237, 1105; [a]2D01 K39.6 (c 0.5, CH2Cl2); MS (m/z) ESI:
1108 (MCH)C; H NMR (CDCl3, 400 MHz) d 8.00–8.02
(m, 2H, arom), 7.54–7.60 (m, 1H, arom), 7.42–7.45 (m, 2H,
arom), 7.22–7.28 (m, 1H, arom), 6.45–6.59 (m, 4H, 2H
arom, H-10, N–CH–O), 6.06 (m, 1H, H-13), 5.85 (d, 1H,
H-2, JZ7.2 Hz), 4.93 (d, 1H, H-5, JZ2.0, 10.5 Hz), 4.46–
4.60 (m, 3H, H-7, H0-3, H0-2), 4.20–4.28 (m, 2H, H-20),
3.88 (s, 3H, OMe), 3.80–3.84 (m, 4H, OMe, H-3), 3.35 (d,
1H, H-14, JZ8.8 Hz), 2.51 (ddd, 1H, Ha-6, JZ6.4, 10.4,
14.4 Hz), 2.30 (s, 3H, Me), 2.18 (s, 3H, Me), 2.12 (s, 3H,
Me), 1.91 (ddd, 1H, Hb-6, JZ2.0, 10.5, 13.5 Hz), 1.74–1.84
(m, 1H, H0-5), 1.72 (s, 3H, Me), 1.54–1.64 (m, 2H, H0-4),
1.20–1.40 (s, 9H, 3 Me), 1.11 (s, 3H, Me), 1.09 (d, 3H, Me,
JZ6.0 Hz), 1.06 (d, 3H, Me, JZ6.0 Hz), 0.90–0.97 (m, 9H,
3 Me), 0.54–0.62 (m, 6H, 3 CH2); 13C NMR (CDCl3,
100 MHz) d 201.4, 172.4, 169.9, 169.5, 165.6, 161.8, 159.3,
153.5, 136.9, 136.0, 133.5, 130.1, 129.9, 128.9, 128.8,
128.5, 104.4, 98.6, 84.2, 81.3, 81.1, 80.1, 78.8, 76.4, 75.2,
75.1, 75.0, 72.3, 58.8, 58.5, 55.6, 54.1, 46.1, 43.8, 43.4,
37.4, 28.3, 28.1, 26.5, 25.7, 23.4, 23.1, 22.6, 22.3, 21.0,
14.7, 10.4, 7.0, 5.5. Anal. Calcd C58H82N2O17Si: C, 62.91;
H, 7.46; N, 2.53. Found: C, 63.03; H, 7.35; N, 2.62.
4.1.23. 7-TES-13-[N-BOC-N,O-(2,4-dimethoxybenzyl-
idene)-b-isobutylisoserinoyl]-14b-amino-baccatin III
14,1-carbamate (36). Procedure A. A solution of 0.12 g
(0.30 mmol) of the acid 35 in 6.0 mL of toluene, cooled at
0 8C, was added with 0.10 g (0.14 mmol) of 13a-33, 0.06 g
(0.30 mmol) of DCC, 0.02 g (0.15 mmol) of DMAP, and
0.005 g (0.03 mmol) of PTSA, under stirring and nitrogen
stream. After 2 h at 70 8C, an additional amount of 0.04 g
(0.11 mmol) of 36 and 0.02 g (0.11 mmol) of DCC were
added. After 3 h, the reaction was cooled and filtered. The
solid was washed with CH2Cl2, and the organic phase was
concentrated under reduced pressure. Chromatography of
the reaction mixture (SiO2, n-hexane/EtOAc/CH2Cl2,
1.0:0.6:0.6) yielded 0.13 g (0.11 mmol, 80%) of 36 as a
white solid. Procedure B. A 1.93 M solution of phosgene in
toluene (0.50 mL, 0.81 mmol) and 0.1 mL (1.29 mmol) of
pyridine were added to a solution of 0.36 g (0.32 mmol) of
40 in 9.0 mL of CH2Cl2 at 0 8C under stirring. After 12 h at
room temperature the reaction mixture was quenched by
addition of 10.0 mL of water and extracted with 10.0 mL of
CH2Cl2. The organic phase was washed with brine, dried,
filtered, and evaporated under reduced pressure. Chroma-
tography (SiO2, n-hexane/EtOAc/CH2Cl2, 0.7:0.3:1.0) gave
0.27 g (0.24 mmol, 74%) of 36 as a white solid. IR (KBr,
cmK1): 3435, 2956, 1735, 1454, 1369, 1235; [a]2D0 K38.7 (c
1
0.7, CH2Cl2); MS (m/z) ESI: 1134 (MCH)C; H NMR
(CDCl3, 400 MHz) d 7.98–7.99 (m, 2H, arom), 7.56–7.60
(m, 1H, arom), 7.40–7.44 (m, 2H, arom), 7.18–7.22 (m, 1H,
arom), 6.40–6.50 (m, 5H, 2H arom, H-10, N–CH–O,
HNC]O), 6.00–6.08 (m, 2H, H-2, H-13),0 4.90 0(dd, 1H,
H-5, JZ2.0, 10.4 Hz), 4.53–4.62 (m, 2H, H -2, H -3), 4.49
(dd, 1H, H-7, JZ6.6, 10.5 Hz), 4.26 (d, 1H, H-20, JZ
7.6 Hz), 4.22 (d, 1H, H-20, JZ7.6 Hz), 4.08–4.14 (m, 1H,
H-14), 3.88 (s, 3H, OMe), 3.87 (s, 3H, OMe), 3.76 (d, 1H,
4.1.22. 7-TES-13-[N-BOC-N,O-(2,4-dimethoxybenzyl-
idene)-b-isobutylisoserinoyl]-14b-amino-baccatin III
14,1-thiocarbamate (41).
A
solution of 0.17 g
(0.15 mmol) of 40 in 7.0 mL of CH3CN was added, at
20 8C, with 0.14 g (0.61 mmol) of di-2-pyridyl-thiono-
carbonate. After 2 h, the reaction mixture was quenched
by addition of 4.0 mL of water and extracted with CH2Cl2.

A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
7741
H-3, JZ7.2 Hz), 2.52 (ddd, 1H, Ha-6, JZ6.6, 10.4,
14.4 Hz), 2.26 (s, 3H, Me), 2.19 (s, 3H, Me), 2.10–2.18 (s,
3H, Me), 1.91 (ddd, 1H, Hb-6, JZ2.0, 10.5, 14.4 Hz), 1.78–
1.83 (m, 2H, H0-4, H0-5), 1.75 (s, 3H, Me), 1.60–1.64 (m,
1H, H0-4), 1.34 (s, 3H, Me), 1.22–1.38 (m, 9H, 3 Me), 1.26
(s, 3H, Me), 1.09 (d, 3H, Me, JZ6.0 Hz), 1.06 (d, 3H, Me,
JZ6.0 Hz), 0.90–0.96 (m, 9H, 3 Me), 0.55–0.62 (m, 6H, 3
CH2); 13C NMR (CDCl3, 100 MHz) d 202.5, 173.5, 171.2,
169.6, 164.9, 156.4, 140.1, 134.1, 134.0, 130.0, 128.9,
128.7, 87.5, 84.4, 81.7, 81.2, 78.1, 76.4, 75.3, 73.0, 72.1,
71.2, 58.8, 57.8, 51.8, 44.9, 42.5, 41.8, 35.8, 30.1, 28.7,
26.3, 25.0, 23.8, 23.4, 21.8, 21.2, 15.4, 10.2. Anal. Calcd
C59H80N2O18Si: C, 62.53; H, 7.11; N, 2.47. Found: C,
62.70; H, 7.15; N, 2.38.
dissolved in 3.0 mL of CH2Cl2 and added at 0 8C to
1.4 mL of a 0.1 M solution of acetyl chloride in MeOH.
After 3 h the reaction was quenched by addition of 6.0 mL
of a NH4Cl aqueous saturated solution. The organic phase
was dried, filtered, and evaporated under reduced pressure.
Chromatography (SiO2, n-hexane/EtOAc, 1.0:1.2) yielded
0.08 g (0.10 mmol, 70%) of 44 as a white solid. IR (KBr,
cmK1): 3492, 2960, 2111, 1730, 1614, 1369, 1237, 1070;
[a]2D0 K27.7 (c 0.5, CH2Cl2); MS (m/z) ESI: 872 (MCH)C;
1H NMR (CDCl3, 400 MHz) d 8.07–8.1 (m, 2H, arom),
7.58–7.62 (m, 1H, arom), 7.44–7.50 (m, 2H, arom), 6.28 (s,
1H, H-10), 6.07 (d, 1H, H-13, JZ8.8 Hz), 5.88 (d, 1H, H-2,
JZ7.1 Hz), 4.98 (m, 1H, H-5, JZ2.3, 9.6 Hz), 4.72 (d, 1H,
HNBOC, JZ9.6 Hz), 4.39 (dd, 1H, H-7, JZ6.6, 10.7 Hz),
4.35 (d, 1H, H-20, JZ8.8 Hz), 4.26 (m, 2H, H-20, H0-2),
4.08–4.12 (m, 1H, H0-3), 4.04 (d, 1H, H-14, JZ8.8 Hz),
3.76 (d, 1H, H-3, JZ7.1 Hz), 2.57 (ddd, 1H, Ha-6, JZ6.6,
9.6, 14.9 Hz), 2.43 (s, 3H, Me), 2.24 (s, 3H, Me), 1.91 (ddd,
1H, Hb-6, JZ2.3, 10.7, 14.8 Hz), 1.88 (s,03H, Me), 1.71 (s,
3H, Me), 1.62–1.76 (m, 3H, H-50, 2H-4 ), 1.41 (s, 9H, 3
Me), 1.21 (s, 3H, Me), 1.20 (s, 3H, Me), 0.99 (d, 3H, Me,
JZ6.0 Hz), 0.97 (d, 3H, Me, JZ6.0 Hz); 13C NMR (CDCl3,
100 MHz) d 202.9, 173.4, 171.1, 170.0, 165.7, 156.2, 139.1,
134.9, 133.9, 130.1, 129.1, 128.9, 84.5, 81.6, 80.5, 77.6,
77.2, 76.5, 75.5, 74.8, 74.1, 72.3, 65.5, 59.0, 52.0, 45.3,
43.5, 40.8, 35.9, 28.6, 27.1, 25.1, 23.6, 22.7, 22.3, 21.3,
15.3, 10.0. Anal. Calcd C43H58N4O15: C, 59.30; H, 6.71; N,
6.43. Found: C, 59.36; H, 6.62, N, 6.34.
4.1.24. 7-TES-13-[N-BOC-N,O-(2,4-dimethoxybenzyl-
idene)-b-isobutylisoserinoyl]-14b-t-butoxy-carbamoyl-
baccatin III 14,1-carbamate (42). A solution of 0.11 g
(0.10 mmol) of 40 in 3.0 mL of CH2Cl2 was added with
0.04 g (0.20 mmol) of BOC2O, 0.03 mL (0.21 mmol) of
Et3N and 0.01 g (0.05 mmol) of DMAP, at 20 8C. After 3 h
the reaction was quenched by addition of 4.0 mL of a NH4Cl
aqueous saturated solution and extracted with 6.0 mL of
CH2Cl2. The organic phase was dried, filtered, and
evaporated under reduced pressure. Chromatography
(SiO2, n-hexane/EtOAc/CH2Cl2, 8.0:3.0:5.0) gave 0.09 g
(0.06 mmol, 69%) of 42 as a white solid. IR (KBr, cmK1):
3450, 2961, 1803, 1733, 1370, 1239, 1089; MS (m/z) ESI:
1
1234 (MCH)C; H NMR (CDCl3, 400 MHz) d 7.92–7.98
(m, 2H, arom), 7.51–7.58 (m, 1H, arom), 7.32–7.42 (m, 2H,
arom), 6.47–6.51 (m, 3H, 2H arom, N–CH–O), 6.40–6.44
(m, 1H, H-13), 6.36 (s, 1H, H-10), 6.01 (d, 1H, H-2, JZ
7.2 Hz), 4.93 (dd, 1H, H-5 JZ2.2, 10.0 Hz), 4.76 (d, 1H,
JZ7.2 Hz, HNBOC)0, 4.560 (dd, 1H, H-7, JZ6.4, 10.2 Hz),
4.48–4.60 (m, 2H, H -2, H -3), 4.24 (d, 1H, H-20), 4.18 (d,
1H, H-20, JZ8.0 Hz), 3.88 (s, 3H, OMe), 3.85 (d, 1H, H-3,
JZ7.2 Hz), 3.82 (s, 3H, OMe), 2.52 (ddd, 1H, Ha-6, JZ6.4,
10.0, 14.8 Hz), 2.46 (s, 3H, Me), 2.23 (s, 3H, Me), 2.19 (s,
3H, Me), 1.90 (ddd, 1H, Hb-6, JZ2.2, 10.2, 14.5 Hz), 1.72
(s, 3H, Me), 1.64–1.70 (m, 1H, H0-5), 1.38–1.50 (m, 2H,
H0-4), 1.37 (s, 9H), 1.35 (s, 3H, Me) 1.28 (s, 3H, Me), 1.12–
1.16 (m, 6H, 2 Me), 0.92–0.96 (m, 9H, 3 Me), 0.56–0.63
(m, 6H, 3 CH2); 13C NMR (CDCl3, 100 MHz) relevant
resonances at d 200.7, 171.0, 170.5 (b), 169.2 (b), 164.6,
161.6, 159.2, 151.2, 150.4, 148.0 (b), 139.5, 134.2, 133.9,
129.9, 129.0, 128.5, 127.4 (b), 117.8 (b), 104.5, 86.5, 85.5
(b), 84.8, (b), 84.4, 80.7 (b), 80.2, 76.2, 74.7, 74.1, 72.1,
71.3, 59.8, 58.7, 57.8 (b), 55.7, 55.5, 46.3, 43.7, 42.1, 37.4,
30.1 (b), 28.6 (b), 28.1, 26.7, 26.1 (CH), 23.7, 23.0, 22.4,
22.2, 21.2, 15.5, 10.7, 7.2, 5.7. Anal. Calcd C64H88N2O20Si:
C, 62.32; H, 7.19; N, 2.27. Found: C, 62.41; H, 7.16; N,
2.34.
4.1.26. 13-(N-BOC-b-isobutylisoserinoyl)-14b-amino-
baccatin III (45). Hydrofluoric acid-pyridine (2.2 mL,
0.1 mL/10 mg of substrate) was added, at 0 8C, to a solution
of 0.22 g (0.18 mmol) of 40 in 5.4 mL of acetonitrile and
5.4 mL of pyridine. After 30 min the temperature was raised
to 25 8C. After 3 h, the reaction was quenched by addition of
12.0 mL of a NH4Cl aqueous saturated solution and
extracted with 16.0 mL of EtOAc. The organic phase was
washed three times with a CuSO4 aqueous saturated
solution, dried, filtered, and evaporated under reduced
pressure. The residue was dissolved in 7.0 mL of CH2Cl2,
and added, at 0 8C, to 2.3 mL of a 0.1 M acetyl chloride
solution in MeOH. After 3 h, the reaction was quenched by
addition of 10.0 mL of a NH4Cl aqueous saturated solution
and extracted with 16.0 mL of EtOAc. The organic phases
was dried, filtered, and evaporated under reduced pressure.
Chromatography (SiO2, n-hexane/EtOAc, 1.0:1.2) yielded
0.10 g (0.12 mmol, 70%) of 45 as a white solid. IR (KBr,
cmK1): 3428, 2957, 1729, 1615, 1360, 1237; [a]2D0 K39.4 (c
0.8, CH2Cl2); MS (m/z) ESI: 846 (MCH)C; 1H NMR
(CDCl3, 400 MHz) d 8.0–8.06 (d, 2H, arom); 7.52–7.61 (m,
1H, arom), 7.42–7.46 (m, 2H, arom), 6.27 (s, 1H, H-10),
5.90 (dd, 1H, H-13, JZ1.2, 9.2 Hz), 5.81 (d, 1H, H-2, JZ
7.6 Hz), 4.92–4.96 (dd, 1H, H-5, JZ2.5, 9.6 Hz), 4.70 (d,
1H, HNBOC, JZ9.6 Hz), 4.39–4.43 (m, 1H, H-7), 4.18–
4.33 (m, 4H, H-20, H-30, H-20, H-20), 3.74 (d, 1H, H-3, JZ
7.2 Hz), 3.35 (d, 1H, H-14, JZ9.2 Hz), 2.55 (m, 1H, Ha-6,
JZ6.4, 9.6, 14.8 Hz), 2.39 (s, 3H, Me), 2.24 (s, 3H, Me),
1.84–1.94 (m, 1H, Hb-6, JZ2.05, 11.2,0 14.8 Hz), 1.88 (m,
3H, Me), 1.62–1.80 (m, 3H, 2H -4, H-5 ), 1.71 (s, 3H, Me),
1.32 (s, 9H, 3 Me), 1.19 (s, 3H, Me), 1.14 (s, 3H, Me), 1.01
(d, 3H, Me, JZ6.0 Hz), 0.98 (d, 3H, Me, JZ6.0 Hz); 13C
NMR (CDCl3, 100 MHz) d 203.3, 174.4, 171.4, 169.8,
165.6, 156.1, 138.8, 135.0, 133.4, 130.0, 129.8, 128.8, 84.5,
4.1.25. 13-(N-BOC-b-isobutylisoserinoyl)-14b-azido-
baccatin III (44). Hydrofluoric acid-pyridine (1.6 mL,
0.1 mL/10 mg of substrate) was added, at 0 8C, to a solution
of 0.16 g (0.14 mmol) of 39 in 4.0 mL of acetonitrile and
4 mL of pyridine. After half an hour, the temperature was
raised to 25 8C. After 3 h the reaction was quenched by
addition of 8.0 mL of a NH4Cl saturated solution and
extracted with EtOAc. The organic phase was washed with
an aqueous saturated solution of CuSO4, dried, filtered, and
evaporated under reduced pressure. The residue was

7742
A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
81.5, 80.6, 76.6, 75.7, 75.3, 75.1, 72.9, 72.3, 58.7, 53.5,
51.4, 45.0, 43.3, 42.2, 35.8, 28.6, 26.9, 25.1, 24.4, 23.7,
23.0, 22.3, 21.3, 15.3, 10.1. Anal. Calcd C43H60N2O15: C,
61.12; H, 7.16; N, 3.32. Found: C, 61.33; H, 7.09; N, 3.24.
3420, 2089, 1742, 1636, 1370, 1093; [a]2D0 K53.4 (c 0.7,
1
CH2Cl2); MS (m/z) ESI: 872 (MCH)C; H NMR (CDCl3,
400 MHz) d 8.02–8.1 (m, 2H, arom), 7.54–7.58 (m, 1H,
arom), 7.54 (d, 1H, HNCO, JZ8.6 Hz), 7.42–7.45 (m, 2H,
arom), 6.26 (s, 1H, H-10), 6.11 (dd, 1H, H-13, JZ1.5,
6.8 Hz), 6.02 (d, 1H, H-2, JZ7.2 Hz), 4.94 (dd, 1H, H-5,
JZ2.6, 9.8 Hz), 4.73 (d, 1H, HNBOC, JZ9.6 Hz), 4.36–
4.39 (m, 1H, H-7), 4.24–4.32 (m, 2H, H-20, H0-20), 4.15–
4.22 (m, 3H, H-14, H-20, H-30), 3.76 (d, 1H, H-3, JZ
7.2 Hz), 2.55 (ddd, 1H, Ha-6, JZ6.5, 9.8, 14.5 Hz), 2.33 (s,
3H, Me), 2.25 (s, 3H, Me), 1.86–1.96 (ddd, 1H, Hb-6, JZ
2.5, 11.0, 14.5 Hz), 1.86 (s, 3H, Me), 1.78–1.84 (m, 1H,
H0-5), 1.73 (s, 3H, Me), 1.66–1.76 (m, 1H, H0-4), 1.37 (s,
9H, 3 Me), 1.31 (s, 3H, Me), 1.20–1.40 (m, 9H, 3 Me), 1.25
(s, 3H, Me), 1.25–1.30 (m, 1H, H0-4), 1.01 (d, 3H, 1 Me, JZ
6.5 Hz), 0.98 (d, 3H, 1 Me, JZ6.5 Hz); 13C NMR (CDCl3,
100 MHz) d 202.5, 173.5, 171.2, 169.6, 164.9, 156.4, 140.1,
134.1, 134.0, 130.0, 128.9, 128.7, 87.5, 84.4, 81.7, 81.2,
78.1, 76.4, 75.3, 73. 0, 72.1, 71.2, 58.8, 57.8, 51.8, 44.9,
42.5, 41.8, 35.8, 30.1, 28.7, 26.3, 25.0, 23.8, 23.4, 21.8,
21.2, 15.4, 10.2. Anal. Calcd C44H58N2O16: C, 60.68; H,
6.71; N, 3.22. Found: C, 60.52; H, 6.79; N, 3.16.
4.1.27. 13-(N-BOC-b-isobutylisoserinoyl)-14b-amino-
baccatin III 14,1-thiocarbamate (46). Hydrofluoric acid-
pyridine (1.7 mL, 0.1 mL/10 mg of substrate) was added, at
0 8C, to a solution of 0.17 g (0.15 mmol) of 41 in 4.0 mL of
acetonitrile and 4.0 mL of pyridine. After 30 min the
temperature was raised to 25 8C. After 3 h, the reaction
was quenched by addition of 12.0 mL of a NH4Cl aqueous
saturated solution and extracted with 16.0 mL of EtOAc.
The organic phase was washed with aqueous saturated
CuSO4, dried, filtered, and evaporated under reduced
pressure. The residue was dissolved in 6.0 mL of CH2Cl2
and chilled at 0 8C. A 0.1 M solution of acetyl chloride in
MeOH (1.2 mL) was added. The reaction was quenched
after 3 h by addition of 12.0 mL of saturated aqueous NH4Cl
and extracted with EtOAc. The organic phase was dried,
filtered, and evaporated under reduced pressure. Chroma-
tography of the residue (SiO2, EtOAc/n-hexane, 1.4:1) gave
0.09 g (0.01 mmol, 67%) of 46 as a white solid. IR (KBr,
cmK1): 3343, 2960, 1733, 1686, 1595, 1239, 1088, 733;
[a]2D0 K4.7 (c 0.4, CH2Cl2); MS (m/z) ESI: 888 (MCH)C;
1H NMR (CDCl3, 400 MHz) d 9.34 (s, 1H, HNCS), 7.99–
8.01 (m, 2H, arom), 7.49–7.52 (m, 1H, arom), 7.40–7.45 (m,
2H, arom), 6.26 (s, 1H, H-10), 6.09–6.14 (m, 2H, H-2,
H-13), 4.94 (dd, 1H, H-5, JZ2.5, 9.7 Hz), 4.78 (d, 1H,
HNBOC, JZ9.2 Hz), 04.34–4.40 (m, 2H, H-7, H-14), 4.28–
4.32 (m, 2H, H-20, H -20), 4.10–4.18 (m, 2H, H-30, H-20),
3.72 (d, 1H, H-3, JZ7.5 Hz), 2.48 (m, 1H, Ha-6, JZ6.6,
9.7, 14.5 Hz), 2.31 (s, 3H, Me), 2.24 (s, 3H, Me), 1.90 (m,
3H, Hb-6, JZ2.5, 10.8, 14.5 Hz), 1.86 (s, 3H, Me), 1.70–
1.85 (m, 3H, 2H0-4, H0-5), 1.73 (s, 3H, Me), 1.41 (s, 9H, 3
Me), 1.29 (s, 6H, 2 Me), 1.02 (d, 3H, Me, JZ6.0 Hz), 0.98
(d, 3H, Me, JZ6.0 Hz); 13C NMR (CDCl3, 100 MHz) d
202.3, 173.5, 171.0, 169.5, 164.8, 156.2, 139.9, 134.1,
133.9, 130.0, 129.8, 128.8, 94.8, 84.4, 82.1, 81.6, 81.2, 76.7,
76.4, 75.3, 72.8, 72.0, 70.7, 62.0, 58.9, 52.0, 45.3, 42.7,
41.6, 35.9, 28.7, 26.2, 25.0, 23.7, 23.1, 21.9, 21.2, 15.3,
10.2. Anal. Calcd C44H58N2O15S: C, 59.58; H, 6.59; N,
3.16. Found: C, 59.40; H, 6.64; N, 3.22.
4.1.29. 13-(N-BOC-b-isobutylisoserinoyl)-14b-t-butoxy-
carbamoyl-baccatin III 14,1-carbamate (47). Hydro-
fluoric acid–pyridine (1.6 mL, 0.1 mL/10 mg of substrate)
was added, at 0 8C, to a solution of 0.16 g (0.14 mmol) of 42
in 4.0 mL of acetonitrile and 4.0 mL of pyridine. After
30 min the temperature was raised to 25 8C. After 3 h, the
reaction was quenched by addition of 12.0 mL of a NH4Cl
aqueous saturated solution and extracted with 12.0 mL of
EtOAc. The organic phase was washed with a saturated
aqueous solution of CuSO4, dried, filtered, and evaporated
under reduced pressure. The residue ws dissolved in 6.0 mL
of CH2Cl2, then added with 1.6 mL of a 0.1 M solution of
acetyl chloride in MeOH, at 0 8C. After 3 h the reaction was
quenched by addition of 15.0 mL of saturated aqueous
NH4Cl and extracted with 15.0 mL of EtOAc. The organic
phase is dried, filtered, and evaporated under reduced
pressure. Chromatography of the residue (SiO2, n-hexane/
EtOAc, 1.0:1.2) yield 0.08 g (0.08 mmol, 57%) of 47 as a
white solid. IR (KBr, cmK1): 3450, 2961, 1803, 1733, 1506,
1370, 1239, 1089, 732; [a]2D0 K37.2 (c 0.8, CH2Cl2); MS
1
(m/z) ESI: 972 (MCH)C; H NMR (CDCl3, 400 MHz) d
4.1.28. 13-N-BOC-b-isobutylisoserinoyl-14b-amino-bac-
catin III 14,1-carbamate (43). Hydrofluoric acid-pyridine
(1.1 mL, 0.1 mL/10 mg of substrate) was added, at 0 8C, to a
solution of 0.11 g (0.10 mmol) of 36 in 2.7 mL of
acetonitrile and 2.7 mL of pyridine. After 30 min the
temperature was raised to 25 8C. After 3 h, the reaction
was quenched by addition of 6.0 mL of a NH4Cl aqueous
saturated solution and extracted with 16.0 mL of EtOAc.
The organic phase was washed three times with a CuSO4
aqueous saturated solution, dried, filtered, and evaporated
under reduced pressure. The residue was dissolved in
3.5 mL of CH2Cl2, and then, at 0 8C, added with 1.15 mL of
a 0.1 M acetyl chloride solution in MeOH. After 3 h, the
reaction was quenched by addition of 5.0 mL of a NH4Cl
aqueous saturated solution and extracted with 8.0 mL of
EtOAc. The organic phase was dried, filtered, and
evaporated under reduced pressure. Chromatography
(SiO2, n-hexane/EtOAc/Et2O 1:0.7:0.3) afforded 0.06 g
(0.06 mmol, 66%) of 43 as a white solid. IR (KBr, cmK1):
7.95–7.97 (m, 2H, arom), 7.54–7.58 (m, 1H, arom), 7.38–
7.42 (m, 2H, arom), 6.26 (m, 2H, H-10, H-13), 6.01 (d, 1H,
H-2, JZ7.2 Hz), 4.96 (dd, 1H, H-5, JZ2.4, 9.2 Hz), 4.89
(d, 1H, HNBOC, JZ8.8 Hz), 4.74 (d, 1H, H-14, JZ7.6 Hz),
4.42 (dd, 10H, H-7, JZ6.4, 10.8 Hz), 4.22–4.28 (m, 3H,
2H-20, H-2 ), 4.20–4.12 (m, 1H, H-30), 3.82 (d, 1H, H-3,
JZ7.2 Hz), 2.57 (ddd, 1H, Ha-6, JZ6.4, 9.2, 14.5 Hz), 2.53
(s, 3H, Me), 2.25 (s, 3H, Me), 1.91 (s, 3H, Me), 1.86–1.94
(ddd, 1H, Hb-6, JZ2.4, 10.8, 14.5 Hz), 1.72 (s, 3H, Me),
1.62–1.72 (m, 2H, H0-4, H0-5), 1.48–1.58 (m, 1H, H0-4),
1.43 (s, 9H, 3 Me), 1.38 (s, 9H, 3 Me), 1.31 (s, 3H, Me), 1.28
(s, 3H, Me), 0.97 (d, 3H, 1 Me, JZ6.5 Hz), 0.98 (d, 3H, 1
Me, JZ6.5 Hz); 13C NMR (CDCl3, 100 MHz) d 202.5,
171.2, 171.0, 169.5, 164.4, 155.9, 150.2, 141.4, 134.0,
133.3, 129.9, 129.0, 128.4, 85.4, 84.6, 80.7, 80.1, 76.3, 75.3,
74.2, 72.1, 71.2, 59.5, 58.9, 51.6, 45.2, 42.0, 40.6, 35.9,
33.4, 32.0, 30.0, 28.7, 28.1, 27.0, 25.3, 23.5, 23.3, 22.6,
21.2, 16.0, 10.2. Anal. Calcd C49H66N2O18: C, 60.61; H,
6.85; N, 2.88. Found: C, 60.44; H, 6.74; N, 2.93.

A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
7743
Table 2. Relevant 1H NMR resonances of 13-oxo ortho esters (21, 22, and 27), 13-silyl enol ethers (3, 28, and 29), and 13, 21-bis-silyl-enol ortho esters
(23–26)
Resonances
29
28
3
27
26
25
24
23
22
21
H-2
5.77
4.82
—
3.74
1.70
1.15
5.75
4.73
—
3.71
1.67
1.10
5.76
4.73
—
3.71
1.69
1.12
4.35
2.37
2.37
3.45
1.79
1.22
3.97
5.36
—
3.40
1.62
0.80
4.50
4.46
—
3.37
1.79
1.17
4.02
5.42
—
3.40
1.63
0.80
4.48
4.46
—
3.35
1.78
1.15
3.90
3.07
2.91
3.57
1.65
0.98
4.39
2.53
2.29
3.50
1.78
1.20
H-14
H-140
H-3
Me-19
Me-16
Appendix A. Stereochemical assessments of ortho esters
21, 22, and 27, of 13-enol derivatives 3, 28, and 29 and
effect on the H-14 protons. These protons are located on the
a-face, being syn to the phenyl group of the 21b-OTMS
epimers. Hence, the two H-14 protons of the b-epimer 21
absorbed at higher field (2.53 and 2.29 ppm) with respect to
those of its a-epimer 22 (3.07 and 2.91 ppm). Similarly, the
H-14 protons of the b-epimers 23 and 25 absorbed at higher
field (4.46 ppm) with respect to those of the a-epimers 24
and 26 (5.42 and 5.36 ppm, respectively). (ii) ASIS effect on
the H-3 protons. The H-3 protons of the 21b-OTMS epimers
21, 23, and 25 absorbed at higher field with respect to those
of the a-epimers 22, 24, and 29. since this proton and the
phenyl substituent are both located in the a-face. (iii) ASIS
effect on the H-2 protons. The trends on the H-2 protons, are
opposite to those of H-14 and H-3 because this proton is
located in the opposite b-face. (iv) ASIS effect on the Me-19
and Me-16. The Me-16 and Me-19 substituents are located
on the a-face and for this reason behave similarly to the
H-2 protons. In particular, the Me-16 protons of the
b-epimers 21, 23, and 25 absorbed at lower field (1.20,
1.15, and 1.17 ppm, respectively) with respect to those of
the a-epimers 22, 24, and 26 (0.98, 0.80 and 0.80 ppm).
Similarly, the Me-19 protons of the b-epimers 21, 23,
and 25 absorbed at lower field (1.78, 1.78 and 1.79 ppm,
respectively) with respect to those of the a-epimers 22,
24, and 26 (1.65, 1.63 and 1.79 ppm). The b-stereo-
chemistry of compound 27 was assigned on the basis that
the H-2, H-14, H-140, H-3, Me-19, and Me-16 proton
resonances were fully consistent with those of the
b-epimeric 13-oxo ortho ester 21 instead of the a-epimer
22. In particular, the Me-16 and Me-19 resonances of 27
were typical of all b-epimers.
1
13-enol ortho esters 23–26 based on H and 13C NMR
spectroscopic evidences
(a): 1H NMR evidences. The structures of 13-oxo-ortho
esters 21, 22, and 27 were supported by the presence of two
relevant resonances for the hydrogen atoms at C-14 (H-14
and H0-14), and one resonance for the silyl subsituent at
C-21. The 13-silyl enol ethers 3, 28, and 29 showed one
resonance for the H-14 hydrogen atom, and one for the silyl
substituent at C-13. The 13, 21-bis-silyl ortho esters 23–26
showed one resonance for the H-14 hydrogen atom, and two
resonances for the silyl substituents at the C-13 and C-21
oxygen atoms, respectively, (Table 2).
(b): 13C NMR evidences. The structures of the 13-oxo-ortho
esters 21, 22, and 27 were supported by the relevant 13C
NMR resonances (Table 3) of the keto group at C-13,
in the range of 198.0–201.7 ppm, the ortho ester group at
C-21 (117.5–120.8 ppm), and the CH2 at C-14 (41.3–
42.4 ppm). The structures of the 13-enol derivatives 3, 28,
and 29 were supported by the resonances of the O–C]CH
carbon atom at C-13 (153.5 ppm), the O–C]CH enolic
carbon atom at C-14 (110.6 ppm), and the C6H5C]O at
C-2 (166.7–166.9 ppm). The structures of the 13-enol
ortho esters 24–26 were supported by the resonances of
the O–C]CH enolic carbon atom at C-13 (152.6–
155.9 ppm), the O–C]CH enolic carbon atom at C-14
(110.9–115.4 ppm), and the ortho ester group at C-21
(118.5–121.7 ppm).
(c) ASIS effect. The ASIS effect of the C-21 phenyl
substituent on the absorptions of H-2, H-14, H-140, H-3,
Me-19, and Me-16 protons (Table 2) was a proper tool for
the stereochemical assessment at C-21 of ortho esters 21–
26. In fact, the relative positions of these resonances of the
21-a/b epimers are explained by the shielding effect of
the phenyl substituent, which is located in the a-face of the
C-21 carbon atom of the 21b-OTMS epimers 21, 23, and 25,
and in the b-face of the 21a-OTMS epimers 22, 24 and 26.
In particular, the following trends were observed: (i) ASIS
(d) Qualitative homonuclear NOE difference spectra
studies. NOE difference spectra studies allowed the
stereochemical assessment at the C-21 stereogenic center
of the ortho esters 21–24. The irradiation of the 21b-OTMS
substituents of 21 and 23 (K0.03 and K0.01 ppm,
respectively) caused a consistent enhancement (7–9%) of
their corresponding H-2 protons, this suggesting that the
TMSO group are located on the b-face. No enhancement of
the H-2 protons was observed upon irradiation of the TMSO
groups of 22 and 24.
Table 3. Relevant 13C NMR resonances (C-13, C-14, C-21, O–C]O at C2) of 13-oxo ortho esters (21, 22, and 27), 13-silyl enol ethers (3, 28, and 29) and 13,
21-bis-enol ortho esters (23–26)
Resonances
29
28
3
27
26
25
24
23
22
21
C-13
C-14
C-21
O–C]O at C2
153.5
110.6
—
153.5
110.6
—
153.5
110.6
—
198.0
42.4
117.5
—
152.6
112.9
118.5
—
153.0
110.9
118.6
—
155.9
115.4
121.7
—
156.3
114.2
—
201.7
41.3
120.8
201.4
41.3
120.8
—
166.7
166.9
166.9
—

7744
A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745
Morazzoni, P.; Bombardelli, E.; Mancuso, S.; Scambia, G.
References and notes
Curr. Med. Chem. Anti-Canc. Agents 2003, 3, 133–138.
11. Kingston, D. J. I. J. Nat. Prod. 2000, 726–734 and references
therein.
1. Abbreviations and Acronyms: 10-Deacetylbaccatin (10-DAB),
trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl
(TIPS), tert-butoxycarbonyl (BOC), 1,8-Diazabicyclo[5.4.0]
undec-7-ene (DBU), potassium hexamethyldisilazide
(KHMDS), m-chloroperbenzoic acid (MCPBA), N,O-bis(tri-
methylsilyl) acetamide (BSA), di-tert-butyl dicarbonate
(BOC2O), N-methylimidazole (MEIM), 4-dimethylamino-
pyridine (DMAP), acetic anhydride (Ac2O), 2,3-dimethyl-
3,4,5,6-tetrahydro-2-(1H)-pyrimidone (DMPU), m-chloroper-
benzoic acid (mCPBA), p-toluenesulphonic acid (PTSA).
2. (a) Marder-Karsenti, R.; Dubois, J.; Guenard, D.; Gueritte-
Voegelein, F.; Potier, P. Tetrahedron 1995, 51, 1985–1994.
(b) Appendino, G.; Jakupovic, J.; Cravotto, G.; Enriu, R.;
Varese, M.; Bombardelli, E. Tetrahedron Lett. 1995, 36,
3233–3236.
12. Battaglia, A.; Baldelli, E.; Bombardelli, E.; Carenzi, G.;
Fontana, G.; Gambini, A.; Gelmi, M. L.; Guerrini, A.; Pocar,
D. J. Org. Chem. 2004, 69, 6610–6616.
13. The structures of the present paper are drawn according to
Miller and Kingston representation. It is worth noting that in
this representation the Me-16 substituent of the C15 carbon
atom is drawn with a thickened line, being cis to Me-19 and the
H-2 proton. See: (a) Appendino, G. In The Chemistry an
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(b) Miller, R. W. J. Nat. Prod. 1980, 43, 425. (c) Kingston,
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the Chemistry of Organic Natural Products; Springer: Vienna,
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14. For the synthesis of 7-TES-13-oxo-baccatin II, see: (a) Greene,
D. J.-N.; Guenard, D.; Gueritte-Voegelein, F.; Manganatal, L.;
Potier, P. J. Am. Chem. Soc. 1988, 110, 5917–5919.
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21. The formation of ortho esters is seldom observed in taxane
chemistry, being these compounds unstable and very easily
hydrolysed. For example, an ortho ester derivative of
paclitaxel was obtained when the DMAP induced carbonyl-
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Gunatilaka, A. A. L.; Higgs, P. I.; Rimoldi, J. M.; Samala, L.;
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10. Ortataxel (IDN-5109, BAY 59-8862) is currently being
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22. Taniguchi, Y.; Inanaga, J.; Yamaguchi, M. Bull. Chem. Soc.
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´
with Indena (Sanofi-Synthelabo) in Italy. It is also in phase II
23. Instead, chromatography on SiO2 caused a partial solvolysis at
C-21, which afforded a mixture of the reagent 1 (from 27), and
the 13-OTES-enol ether 28 (from 25).
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26. Magnus, P.; Barth, L. Tetrahedron 1995, 51, 11075–11086.
27. An identical failure was observed when the reduction of
7-TES-and 7-BOC-13oxo-14b-OH-baccatins was attempted
under identical conditions. See Refs. 6 and 7.
30. Kingston, D. G. I.; Chaudhary, A. G.; Gunatilaka, A. A. L.;
Middleton, M. L. Tetrahedron Lett. 1994, 35, 4483–4484.
31. Preliminary results on in vitro sudies of compounds 14b-amino
taxanes 43–47 are reported in: Fontana, G.; Battaglia, A.,
Gelmi, M. L.; Baldelli, E.; G. Carenzi, G.; Contini, A.,
Bombardelli, E.; Manzotti, C., Bernacki, R. J.; Zucchetti. M.
228th ACS National Meeting, Philadelphia, Poster Abstract #
755981, August 22–26, 2004.
28. Similarly, the reduction of 7-TES-13-oxo-14b-OH-baccatin III
1, 14 carbonate with sodium- and alkyl-boron hydrides gave
the corresponding 7-TES-14b-OH-baccatin III 1,14-carbonate
and its 13b-OH epimer. See Ref. 6.