Selective synthesis of 14β-amino taxanes

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,^bMaria Luisa Gelmi,^cAndrea Guerrini^aand Donato Pocar^c

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 NaN₃induced 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.

1. Introduction

baccatin III,³the enol ester 12, 13-isobaccatin III,⁴and their

12, 13-isotaxanes analogues.⁵In 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)¹is an intermediate of

choice for studies on taxane chemistry, being used for the

synthesis of 12, 13-dihydro-10-DAB III,²the 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

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).⁶The 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.⁷A 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–dEven 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),⁹display cytotoxic activity in cell lines, which

express multi-drug resistance (MDR). The lead compound,

Ortataxel, is now in phase II clinical trial.¹⁰We 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.¹¹Our 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),¹⁵and

tosyl azide (8)¹⁶were 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,⁶failed.

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.¹³To 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.¹⁴Namely, the 7-TES derivative 1 was obtained

by sequential silylation and acetylation of the C-7 and C-10

hydroxy groups followed by MnO₂oxidation 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.¹⁷Among 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,¹⁹the 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).²⁰For 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,⁶can 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).

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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 24.¹³No 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).²²These 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 CH₂Cl₂under 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).²¹Compounds 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

A^a

B^b

C^c

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

21/22Z0.94^d(1.14)^e

—

27 (80%)^f

23/24Z1.1^d(1.6)^e

23/24Z1.4^f

25/26Z1.2

25 (20%)^f

25

—

23/24Z4

3 (%5%)^d,e

3 (%5%)

—

21C22C23C24Z87^d

23C24Z92^f

25C26Z93^f

25C27Z100

25Z94

—

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)

21C22C3Z53^f

21C22C23C24Z100^f

^aA: 13-oxo 21-ortho esters.

^bB: 13-silyl enol 21-ortho esters.

^cC: 13-Silyl enol ethers.

^dProduct distribution and overall yield after chromatography on silica.

1

^eProduct 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),⁷afforded

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.²⁴Harsh

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 CH₂Cl₂with 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

NaN₃represents 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.²⁵This reagent has been suc-

cessfully experimented mainly with silyl enol ethers bearing a

sterically encumbered TIPS substituent, such as 29.²⁶The

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 NaN₃and

3.0 equiv of CAN.

to a condensation of the hydride reagents with the 14-NH₂

group.²⁷For this reason, the 14-NH₂and 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 NaBH₄in 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%).²⁸N-Boc-norstatinic acid 35, protected as

N,O-(2,4-dimethoxy-benzylidene) derivative,²⁹was

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,³⁰affording 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 PPh₃in 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

NaBH₄in 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-NH₂groups 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 NaN₃under 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 cm^K1units. 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, cm^K1): 3394, 2993,

2920, 1725, 1342, 1212; [a]²_D⁰C53.6 (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, cm^K1): 3408, 2980, 2933, 1728, 1682,

1369, 1255, 1155; [a]_D²⁰C57.0 (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, cm^K1): 3397, 2983, 2930, 1728, 1393, 1252;

[a]²_D⁰C58.4 (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, cm^K1): 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, cm^K1):

3358, 3261, 2957, 2877, 2097, 1727, 1628, 1369, 1306,

1161; [a]²_D⁰₁C66.0 (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, cm^K1): 3497, 2956, 2878, 2117, 1730, 1689,

1370, 1238, 1094; [a]_D²⁰C79.4 (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

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, cm^K1): 2976, 2935, 2122, 1731, 1272, 1094; [a]²_D⁰

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,

cm^K1): 3359, 2957, 2878, 2097, 1726, 1630, 1305; [a]²_D⁰

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, cm^K1): 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 CH₂Cl₂was 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 CH₂Cl₂was 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, cm^K1):

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

CH₂Cl₂at 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, cm^K1):

1721, 1255, 1238, 1107, 1068; [a]²_D⁰K44.0 (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, cm^K1): 1735, 1719,

1376, 1232. (25): [a]_D²⁰C8.7 (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 CH₂Cl₂at 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, cm^K1):

3483, 1739, 1722, 1704, 1376, 1242; [a]²_D⁰K6.0 (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]²_D⁰C8.8 (c 0.40, CH₃COCH₃); IR (nujol,

cm^K1): 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,

cm^K1): 3483, 1725, 1376, 1239; [a]²_D⁰K21.0 (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, cm^K1):

3053, 2960, 1726, 1478, 1434, 1090; [a]²_D⁰C31.7 (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 CH₂Cl₂at 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, cm^K1):

3342, 2956, 1732, 1452, 1238, 1090; [a]²_D⁰C28.5 (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,

cm^K1): 3396, 3204, 2956, 2878, 2255, 1728, 1452, 1370,

1105; [a]²_D⁰₁C18.1 (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, cm^K1): 3493, 2956,

2881, 2112, 1728, 1371, 1233; [a]²_D⁰C20.0 (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,

cm^K1): 3364, 2955, 1731, 1452, 1372, 1089; [a]²_D⁰C16.2 (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, cm^K1): 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,

cm^K1): 3491, 2957, 2111, 1731, 1614, 1508, 1368; [a]²_D⁰

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, cm^K1):

3446, 2958, 1732, 1694, 1595, 1278, 1167; [a]²_D⁰K21.3 (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 (d₀dd, 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 H₂in 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, cm^K1): 3449, 2957, 1726, 1617, 1368,

1237, 1105; [a]²_D⁰₁K39.6 (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 CH₂Cl₂at 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,

cm^K1): 3435, 2956, 1735, 1454, 1369, 1235; [a]²_D⁰K38.7 (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),₀4.90 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 CH₂Cl₂and 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,

cm^K1): 3492, 2960, 2111, 1730, 1614, 1369, 1237, 1070;

[a]²_D⁰K27.7 (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 CH₂Cl₂was 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, cm^K1):

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 CuSO₄aqueous 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,

cm^K1): 3428, 2957, 1729, 1615, 1360, 1237; [a]²_D⁰K39.4 (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, 11.2,₀14.8 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]²_D⁰K53.4 (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,

cm^K1): 3343, 2960, 1733, 1686, 1595, 1239, 1088, 733;

[a]²_D⁰K4.7 (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, cm^K1): 3450, 2961, 1803, 1733, 1506,

1370, 1239, 1089, 732; [a]²_D⁰K37.2 (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, cm^K1):

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

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 CH₂at 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

—

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

Pharmacology of Taxol and Related Compounds; Farina, V.,

Ed.; Elsevier: New York, 1995; and references therein.

(b) Miller, R. W. J. Nat. Prod. 1980, 43, 425. (c) Kingston,

D. G. I.; Molinero, A. A.; Rimoldi, J. M. In Herz, W., Kirby,

G. W., Moore, R. E., Steglich, W., Tamm, C., Eds.; Progress in

the Chemistry of Organic Natural Products; Springer: Vienna,

1993; Vol. 61, p 1.

3. Ahn, Y. M.; Vander Velde, D. G.; Georg, G. I. J. Org. Chem.

2002, 67, 7140–7143.

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.

(b) Chordia, M. D.; Kingston, D. G. I. Tetrahedron 1997, 53,

5699–5710. For the synthesis of 7-BOC-13-oxo-baccatin III

see Ref. 6.

4. Kelly, R. C.; Wicnienski, N. A.; Gebhard, I.; Qualls, S. J.; Han,

F.; Dobrowolski, P. J.; Eldon, G.; Nidy, E. G.; Roy, A.;

Johnson, R. A. J. Am. Chem. Soc. 1996, 118, 919–920.

5. Johnson, R. A.; Dobrowolski, P. J.; Nidy, E. G.; Gebhard, I.;

Qualls, S. J.; Wicnienski, N. A.; Kelly, R. C.; Pitts, T. W.;

Lopes, N. M.; DeKoning, T. F.; Speaker, S. J.; Weed, S. D.;

McGovern, J. P.; Chidester, C. J. J. Med. Chem. 1997, 40,

2810–2812.

15. (a) Kobayashi, S.; Yamashita, Y.; Ishitani, H. Chem. Lett.

1999, 28, 307–308. (b) Yamashita, Y.; Ishitani, H.; Kobayashi,

S. Can. J. Chem. 2000, 78, 666–672.

6. Baldelli, E.; Battaglia, A.; Bombardelli, E.; Carenzi, G.;

Fontana, G.; Gambini, A.; Gelmi, M. L.; Guerrini, A.; Pocar,

D. J. Org. Chem. 2003, 68, 9773–9779.

16. Doering, W. E.; De Puy, C. H. J. Am. Chem. Soc. 1953, 75,

5955–5957.

17. Hennessy, M. J.; Ruckle, R.E, Jr.; Taber, D. F. J. Org. Chem.

1986, 51, 4077–4078.

7. Fang, W. S.; Fang, Q. C.; Liang, X. T. Chin. Chem. Lett. 2001,

12, 675–678.

18. (a) Regitz, M.; Maas, G. In Diazo Compounds, Properties and

Synthesis; Academic: New York, 1986; Charter 13. (b) Regitz,

R. Angew. Chem., Int. Ed. Engl. 1967, 6, 733–749.

19. (a) Ku¨hlein, K.; Jensen, H. Liebigs Ann. Chem. 1974, 369–402.

(b) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L.

J. Am. Chem. Soc. 1990, 112, 4011–4030.

8. (a) Yu, C.-Z.; Liu, Z.-Y. Tetrahedron Lett. 1997, 38,

4133–4136. (b) Marder-Karsenti, R.; Dubois, J.; Chiaroni,

A.; Riche, C.; Guenard, D.; Gueritte, F.; Potier, P. Tetrahedron

1998, 54, 15833–15844. (c) Pinciroli, V.; Ceccarelli, W.;

Fusar-Bassini, D.; Menichincheri, M.; Mongelli, N.; Vanotti,

E. Tetrahedron Lett. 1996, 37, 9365–9368. (d) Uoto, K.;

Takenoshita, H.; Ishiyama, T.; Terasawa, H.; Soga, T. Chem.

Pharm. Bull. 1997, 45, 2093.

20. Only the encumbered trisyl azide afforded relatively stable and

isolable tautomeric mixtures of N-trisyl triazenes. See Ref.

18b.

9. (a) Ojima, I.; Slater, J. C.; Kuduk, S. D.; Takeuchi, C. S.; Gimi,

R. H.; Sun, C.-M.; Park, Y. H.; Pera, P.; Veith, J. M.; Bernacki,

R. J. J. Med. Chem. 1997, 40, 267–278. (b) Ojima, I.; Fenoglio,

I.; Park, Y. H.; Pera, P.; Bernacki, R. J. Bioorg. Med. Chem.

Lett. 1994, 37, 1571–1574. (c) Ojima, I.; Park, Y. H.; Sun,

C.-M.; Fenoglio, I.; Appendino, G.; Pera, P.; Bernacki, R. J.

J. Med. Chem. 1994, 37, 1408–1410. (d) Distefano, M.;

Scambia, G.; Ferlini, C.; Saggini, C.; De Vincenzo, R.; Riva,

A.; Bombardelli, E.; Ojima, I.; Fattorossi, A.; Panici, P. B.;

Mancuso, S. Int. J. Cancer 1997, 72, 844–850. (e) Battaglia,

A.; Bernacki, R. J.; Bertucci, C.; Bombardelli, E.; Cimitan, S.;

Ferlini, C.; Fontana, G.; Guerrini, A.; Riva, A. J. Med. Chem.

2003, 46, 4822–4825.

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-

ation of taxol with BOC₂O was attempted. See: (a) Kingston,

D. G. I.; Chaudhary, A. G.; Chordia, M. D.; Gharpure, M.;

Gunatilaka, A. A. L.; Higgs, P. I.; Rimoldi, J. M.; Samala, L.;

Prakash, G. J.; Giannakakou, P.; Jiang, Y. Q.; Lin, C. M.;

Hamel, E.; Long, B. H.; Fairchild, C. R.; Johnston, K. A.

J. Med. Chem. 1998, 41, 3715–3726. (b) Kingston, D. G. I.;

Jagtap, P. G. Tetrahedron Lett. 1999, 40, 189–192. (c) Kelly,

R. C.; Wicnienski, N. A.; Gebhard, I.; Qualls, S. J.; Han, F.;

Dobrowolski, P. J.; Nidy, E. G.; Johnson, R. A. J. Am. Chem.

Soc. 1996, 118, 919–920.

10. Ortataxel (IDN-5109, BAY 59-8862) is currently being

developed by Bayer but was initially developed at the State

University of New York (SUNY) in the USA, in conjunction

22. Taniguchi, Y.; Inanaga, J.; Yamaguchi, M. Bull. Chem. Soc.

Jpn. 1981, 3229, 3. See also Ref. 3.

´

with Indena (Sanoﬁ-Synthelabo) in Italy. It is also in phase II

23. Instead, chromatography on SiO₂caused 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).

development for non-small cell lung cancer, breast cancer and

renal cancer. See also: (a) Minderman, H.; Brooks, T. A.;

O’Loughlin, K. L.; Ojima, I.; Bernacki, R. J.; Baer, M. R.

Cancer Chemother. Pharmacol. 2004, 53, 263–269.

(b) Ferlini, C.; Ojima, I.; Distefano, M.; Gallo, D.; Riva, A.;

24. Denmark, S. E.; Hammer, R. P.; Weber, E. J.; Habermas, K. L.

J. Org. Chem. 1987, 52, 165–168.

25. (a) Sommer, E.; Pincas, H. Chem. Ber. 1963, 1915, 48.

A. Battaglia et al. / Tetrahedron 61 (2005) 7727–7745

7745

(b) Grove, E. L.; Braman, R. S.; Combs, H. F.; Nicholson, S. R.

Anal. Chem. 1962, 34, 682.

29. Pontiroli, A.; Bombardelli, E. PCT Int. Appl. 20020444161;

Chem. Abstr. 2002, 137, 6295.

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.

Article Doi

Selective synthesis of 14β-amino taxanes

DOI: 10.1016/j.tet.2005.05.087

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

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

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