Semisynthesis of 7-deoxypaclitaxel derivatives devoid of an oxetane D-ring, starting from taxine B

FULL PAPER

Semisynthesis of 7-Deoxypaclitaxel Derivatives Devoid of an Oxetane D-Ring,

Starting from Taxine B

Patrick H. Beusker,^[a]Harald Veldhuis,^[a]Johan Brinkhorst,^[a]Dennis G. H. Hetterscheid,^[a]

Nicolas Feichter,^[a]Anthony Bugaut,^[a]and Hans W. Scheeren*^[a]

Keywords: Antitumor agents / Natural products / Paclitaxel / Structure-activity relationships / Taxine B

Six 7-deoxypaclitaxel derivatives have been prepared from

taxine B; they contribute to understanding of the effect of

the oxetane D-ring in paclitaxel on the cytotoxic activity of

paclitaxel. Three of these analogues each contain a double

bond instead of a D-ring at the C-4 position, while two others

etane ring in paclitaxel. All the derivatives demonstrated

considerably reduced in vitro cytotoxic activity − relative to

paclitaxel − against a panel of seven well-characterized hu-

man tumor cell lines. The general picture coming out of the

structure-activity relationships of the paclitaxel derivatives

each contain a three-membered ring in place of the oxetane reported here is that the presence of an oxygen atom at a

ring. Both the C-4 double bond and the small D-ring in these

paclitaxel derivatives were intended to act as substitutes for

the paclitaxel oxetane D-ring and were expected to impose

on the taxane skeleton and the pendant groups a kind of

spatial position resembling that of the oxygen atom in the

oxetane ring of paclitaxel is important if a paclitaxel derivat-

ive is to retain considerable cytotoxic activity.

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

rigidity and conformation similar to that produced by the ox- Germany, 2003)

Introduction

Paclitaxel (1a, see Figure 1) is a natural diterpene first

reported by Wani and co-workers^[1]in 1971 following its

isolation in the 1960s from an extract of the bark of the

Pacific yew Taxus brevifolia, and is considered to be one of

the most effective anticancer agents known to date. Paclit-

axel has been approved by the United States Food and

Drug Administration (FDA) for the treatment of patients

suffering from breast cancer, ovarian cancer, non-small cell

lung cancer, and AIDS-related Kaposi’s sarcoma.^[2]

Thanks to its high cytotoxic activity and unique mechan-

ism of action, based on stabilization of microtubules and

suppression of microtubule dynamics with consequent in-

duction of apoptosis, but also because of its poor water

solubility and induction of multidrug resistance, paclitaxel

has become the subject of extensive structure-activity rela-

tionship (SAR) studies. These should eventually result in

the development of new paclitaxel derivatives with im-

proved pharmacological properties, ideally retaining strong

cytotoxic activity against multidrug-resistant tumors.

The contribution of the oxetane D-ring to the biological

activity of paclitaxel is not yet fully understood. With re-

spect to microtubule binding, the oxetane D-ring in paclit-

axel is believed to serve two functions.^[3,4]The oxetane ring

oxygen atom may have a stabilizing dipolar or hydrogen-

bonding interaction with an amino acid residue facing the

Figure 1. Structures of paclitaxel (1a), docetaxel (1b), paclitaxel

analogues 2Ϫ10, and taxines 11aϪ11f

[a]

Department of Organic Chemistry, NSR Center for Molecular

Structure, Design and Synthesis, University of Nijmegen,

Toernooiveld, 6525 ED Nijmegen, The Netherlands

Fax: (internat.) ϩ 31-24/3652929

paclitaxel binding pocket on β-tubulin,^[5]one of the build-

ing blocks of a microtubule. Alternatively, the rigid oxetane

ring may force the molecule to adopt the biologically active

E-mail: jsch@sci.kun.nl

Eur. J. Org. Chem. 2003, 689Ϫ705  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0204Ϫ0689 $ 20.00ϩ.50/0

689

H. W. Scheeren et al.

FULL PAPER

conformation and thus position the essential groups in the lack a hydroxy group at C-7 and sometimes have a substitu-

desired spatial orientation through its rigidifying effect on tion pattern at C-9 and C-10 that differs from that of paclit-

the whole taxane skeleton.

axel. SAR studies have shown, however, that variations at

Previously prepared flexible paclitaxel derivatives with at these positions usually affect cytotoxic activity only margin-

least one oxygen atom at about the same spatial position as ally.^[22]

the oxetane ring oxygen atom in paclitaxel, which include

We believed that taxine should be a convenient starting

taxanes 2,^[6,7]3,^[8]4,^[9]and 5,^[9]all exhibited strongly re- material with which to prepare 7-deoxypaclitaxel derivat-

duced in vitro cytotoxic activities. This may be due to the ives of general structures I and II by the general route de-

absence of an apolar 4α-substituent able to mimic the essen- picted in Scheme 1. The route towards paclitaxel derivatives

tial 4α-acetoxy group in paclitaxel and/or because of unfav- I involves a net migration of the exocyclic double bond at-

orable steric interactions between the 4β-acetoxymethyl or tached to the C-ring to an endocyclic position with the con-

4β-methoxy group and the receptor on β-tubulin.^[8]The in- comitant introduction of a suitable C-4 substituent, while

creased flexibility of these taxanes, as well as the slightly the small D-ring in paclitaxel derivatives II could be intro-

different spatial position of the oxygen atom(s) of the 4β- duced either by a cycloaddition approach involving a suit-

substituent with respect to that of the oxetane ring oxygen able intermediate taxane with an endocyclic C-4 double

atom in paclitaxel, may also contribute to the observed re- bond or by an intramolecular substitution process.

duced cytotoxicities.

Rigid D-ring-modified paclitaxel derivatives 6 and 7,

each containing an azetidine D-ring, proved inactive in an

in vitro cytotoxicity assay.^[10]The strongly reduced cytotox-

icity of 7 was explained in terms of unfavorable steric inter-

actions between the N-benzyl group and the receptor on β-

tubulin, while the low cytotoxic activity of 6 was attributed

to protonation of the basic nitrogen under physiological

conditions.^[10]

Rigid D-ring-modified derivatives 8^[11]and 9,^[12]each

containing a thietane D-ring, also demonstrated strongly

reduced in vitro cytotoxicities, attributed to unfavorable

steric interactions between the receptor and the thietane

ring, which is bulkier than the oxetane ring due to the

elongated CϪS bond and the relatively large sulfur atom.

This may also further weaken hydrogen bonding between

the sulfur atom and an amino acid residue, perhaps a

threonine residue,^[3]in β-tubulin.^[12]

5(20)-Deoxydocetaxel^[13](10) displayed only twofold re-

duced tubulin disassembly activity relative to docetaxel, but

was nevertheless shown to exhibit strongly reduced cyto-

toxic activity.^[14]This seems to indicate that the presence of

a suitably positioned oxygen atom is of considerable im-

portance.

It follows from the above that it is not possible to use

these previously prepared, oxetane ring-free paclitaxel de-

rivatives to discriminate completely between the proposed

rigidifying function and the hydrogen bond acceptor func-

tion of the oxetane ring as the decisive contributor to the

cytotoxicity of paclitaxel. More SAR data are therefore

needed in order to identify the structural moiety at C-4/C-

5 required for cytotoxic activity to be retained.

Scheme 1. General scheme for the preparation of paclitaxel deriva-

tives I and II

Results and Discussion

The crude alkaloid mixture from T. baccata, containing

Here we wish to report the semisynthesis of some 7-de- taxines 11aϪ11f, was converted into a mixture of taxanes

oxypaclitaxel analogues that do not contain an oxetane D- 12 and 13 in three steps (Scheme 2) as described previ-

ring. This semisynthesis starts from taxine, an alkaloid mix- ously.^[9]Depending on the reaction conditions required in

ture obtained in 0.5Ϫ1% yield by acid extraction of dried the remaining steps to the desired 7-deoxypaclitaxel derivat-

leaves of the European yew Taxus baccata. Taxine B (11a) ives, the two vicinal hydroxy groups at C-1 and C-2 in 12

and the related taxines 11bϪ11f constitute the major pro- were protected either as a benzaldehyde-derived acetal or

portion (ca. 40%) of this alkaloid mixture.^[15]Although the as a carbonate, giving taxanes 14 and 15, respectively. On

structures of taxines 11aϪ11f are quite distinct from that treatment of the mixture of 12 and 13 with carbonyldiimid-

of paclitaxel, several groups have used them to prepare 7- azole, 13 was converted into 16. On treatment with benzal-

deoxypaclitaxel and derivatives.^[9,16Ϫ21]These derivatives all dehyde dimethyl acetal, though, 13 remained unchanged.

690

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Semisynthesis of 7-Deoxypaclitaxel Derivatives Devoid of an Oxetane D-Ring

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Diastereoselective dihydroxylation of 17 with osmium

tetroxide afforded 18 in high yield. The configuration at C-

4 in 18 was established from NOE data. Reduction of the

C-13 carbonyl group was carried out with sodium borohyd-

ride in the presence of cerium() chloride, which afforded

a 4:1 mixture of epimers 19a and 19b. When the reaction

was carried out without cerium() chloride, the 19a/19b ra-

tio changed to 1:10. Coordination of the transition metal

complex to the 4α-hydroxy group is believed to block the

approach of sodium borohydride towards the 13-carbonyl

group from the concave face of the molecule and thus favor

the formation of 19a.

The crude mixture of 19a and 19b was oxidized with so-

dium periodate to afford 20a and 20b, which were easily

separable by column chromatography. The C-13 hydroxy

group in 20a was protected with a triethylsilyl group, which

gave 21.

Attempts to enolize the C-4 carbonyl moiety and to trap

the enolate with an acetyl group all failed to give the desired

enol acetate. The only products isolated when a strong base

was used were products resulting from C-acetylation. At-

tempts to create a methyl enol ether moiety at C-4 were

also unsuccessful.

We therefore settled for the preparation of paclitaxel de-

rivatives with a cyclohexene C-ring containing a C-4 alkyl

substituent. These were to be accessible from 21 by treat-

ment of 21 with an alkyllithium reagent and subsequent

dehydration. As 4-deacetoxypaclitaxel has been shown to

exhibit considerable cytotoxicity,^[24]albeit significantly less

than paclitaxel, the preparation of a rigid paclitaxel derivat-

ive with a cyclohexene C-ring and no C-4 substituent was

also considered useful.

Reduction of the C-4 carbonyl group in 21 with sodium

borohydride proceeded with complete facial selectivity and

provided 22 in quantitative yield (Scheme 4). The complete

facial selectivity most probably results from the upward ori-

entation of the carbonyl oxygen atom with respect to the

mean plane of the C-ring, causing shielding of the β-face of

the double bond by the C-8 methyl group.

Scheme 2. Conversion of taxines 11 into 13 and 14, and into 15

and 16; reagents and conditions: (a)Ϫ(d) ref.^[9]; (e) CDI, butanone,

reflux, 3 h, 15: 86%, 16: 9%

Attempts to prepare paclitaxel derivatives I from 14 and

15 by a single-step isomerization of the exocyclic double

bond in 14, 15, and their analogues (e.g., by a base-cata-

lyzed or palladium-catalyzed isomerization process) proved

unsuccessful.^[23]A route towards paclitaxel derivatives I in-

volving an intermediate taxane with a C-4 oxo group was

therefore developed. Conversion of this oxo group into an

enol acetate moiety would provide a suitable intermediate

that could be converted into taxanes I.

Starting from 15, we prepared intermediate 21, con-

taining a C-4 oxo group, by the route depicted in Scheme 3.

The C-5 cinnamate side chain in 15 was removed by palla-

dium-catalyzed hydrogenolysis with formate as the hydride

donor, as described previously for 14.^[9]The reaction pro-

ceeded at virtually the same rate as the reaction with 14,

demonstrating the independence of the reaction rate of the

size of the C-2 substituent.

Scheme 3. Preparation of key intermediate 21 from 15; reagents

Scheme 4. Preparation of compounds 23, 24, 25a, and 25b from

and conditions: (a) HCOOH, NEt₃, Pd(dba)₂, PPh₃, THF, reflux, 21; reagents and conditions: (a) NaBH₄, MeOH, 0 °C, 30 min; (b)

2 d, 97%; (b) OsO₄, NMO, THF/H₂O, 5 d, 91%; (c) NaBH₄, CeCl₃,

MeOH, 0 °C, 30 min; (d) NaIO₄, THF/H₂O, 3 h, 20a: 49% (2

steps), 20b: 12% (2 steps); (e) TESCl, imidazole, DMF, 4 h, 86%

(I) (CF₃SO₂)O, pyridine, CH₂Cl₂, 2 d, 23/24 (1:10 mixture): 34%,

25a/25b: 16% and 4%, or (II) CF₃SO₂Cl, DMAP, CH₂Cl₂, 2 d, 23/

24 (9:1 mixture): 31%, 25a/25b: 17% and 4%

Eur. J. Org. Chem. 2003, 689Ϫ705

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As dehydration of 22 under acidic conditions might be

Regioselective opening of the carbonate moiety in 23

accompanied by deprotection of some hydroxy groups and/ with phenyllithium gave 26. Desilylation of the C-13 hy-

or rearrangements, conversion of the secondary C-4 hy- droxy group was followed by attachment of the paclitaxel

droxy group into a suitable leaving group was undertaken side chain to the C-13 hydroxy group in 27 through coup-

so that elimination could be achieved under mildly basic ling with β-lactam 28 under strongly basic conditions. Desi-

conditions.

lylation of the C-2Ј hydroxy group in 29 gave 30. Deprotec-

tion of the hydroxy groups at C-9 and C-10 under acidic

conditions afforded paclitaxel derivative 31.

Conversion of the C-4 hydroxy group in 22 into a methyl-

sulfonyloxy group proved unsuccessful under common con-

ditions. In contrast, treatment of 22 with trifluoromethanes-

ulfonic anhydride and pyridine in dichloromethane afforded

four products. Two of these, compounds 23 and 24, were

obtained as a 1:10 mixture in 34% overall yield. The other

two products turned out to be the stereoisomeric trifluoro-

methanesulfinates 25a and 25b. The less polar of the two

epimers was isolated in 16% yield, while the other was isol-

ated in only 4% yield. The formation of 25a and 25b from

22 must be a consequence of partial reduction of trifluoro-

methanesulfonic anhydride by pyridine,^[25,26]although no

evidence was obtained for this.

The same products were obtained when 22 was treated

with trifluoromethanesulfonyl chloride and 4-(dimethylami-

no)pyridine (DMAP) in dichloromethane. Compounds 23

and 24, however, were now obtained in a 9:1 ratio in 31%

overall yield, while 25a and 25b were obtained in about the

same yields as in the reaction with trifluoromethanesulfonic

anhydride. An increase in the reaction temperature from

room temperature to 40 °C increased the relative amounts

of 25a and 25b with respect to the amount of the mixture

of 23 and 24. A decrease in the reaction temperature to 4

°C suppressed the formation of 25a and 25b, but did not

increase the yield of the mixture of 23 and 24, nor did it

alter the ratio between 23 and 24. Furthermore, the reaction

proceeded extremely slowly at this temperature.

A paclitaxel derivative analogous to 30 but with a C-4

methyl group was prepared from 21 by a route similar to

that used to prepare 30, except that 21 was treated in the

first step with methyllithium rather than sodium borohyd-

ride. This gave the desired 32, along with some 33

(Scheme 6). The configuration at C-4 in 32, and thus in 33,

was established from NOE data. Treatment of 32 with tri-

fluoromethanesulfonyl chloride and DMAP in dichlorome-

thane afforded a 10:1 mixture of 34/35 in 19% overall yield,

together with compounds 36a and 36b, each in approxim-

ately 30% yield. The reaction proceeded only at the same

rate as the corresponding reaction of 22 when the amount

of trifluoromethanesulfonyl chloride was increased tenfold,

indicative of increased steric hindrance at the site of reac-

tion. This may also explain the lower yields of 34 and 35

and the relatively high yields of side products 36a and 36b.

Most noticeably, elimination to give a C-3 double bond,

which would result in the formation of a taxane analogous

to 24, did not occur in this case. AM1 gas-phase calcula-

tions indicate the taxane analogous to 24 to be considerably

more stable than 34 and 35, and so it is conceivable that the

C-3 proton cannot be abstracted, resulting in the exclusive

formation of 34 and 35.

As 23 proved to be inseparable from 24 by chromato-

graphic means, the 9:1 mixture of 23 and 24 obtained from

treatment of 22 with trifluoromethanesulfonyl chloride and

DMAP was used in the next step towards the paclitaxel

derivatives 30 and 31 (Scheme 5). As separation of the cor-

responding isomers also proved impossible after this step,

and after all following steps as well, compounds 26Ϫ27 and

29Ϫ31 were obtained contaminated with their respective

isomers.

Scheme 6. Conversion of 21 into a mixture of 34 and 35, 36a, and

36b; reagents and conditions: (a) MeLi, THF, Ϫ78 °C, 15 min, 32:

82%, 33: 4%; (b) CF₃SO₂Cl, DMAP, CH₂Cl₂, 2 d, 34/35 (10:1 mix-

ture): 19%, 36a/36b: 32% and 29%

As 34 proved to be inseparable from 35 by column chro-

matography, the 10:1 mixture of 34 and 35 was used to pre-

pare paclitaxel derivative 40 by the reaction sequence de-

picted in Scheme 7, meaning that compounds 37Ϫ40 were

obtained slightly contaminated with their respective iso-

mers. Opening of the carbonate moiety in 34 gave 37, which

Scheme 5. Preparation of paclitaxel derivatives 30 and 31 from 23;

reagents and conditions: (a) PhLi, THF, Ϫ78 °C, 30 min, 100%; (b)

TBAF, THF, 5 min, 95%; (c) 28, NaHMDS, THF, Ϫ78 °C, 20 min,

84%; (d) TBAF, THF, 5 min, 92%; (e) PTSA, MeOH, 3 h, 80%

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Scheme 7. Preparation of paclitaxel analogue 40 from 34; reagents

and conditions: (a) PhLi, THF, Ϫ78 °C, 30 min, 80%; (b) TBAF,

THF, 5 min, 84%; (c) 28, NaHMDS, THF, Ϫ78 °C, 20 min, 66%;

(d) TBAF, THF, 5 min, 79%

was deprotected with tetrabutylammonium fluoride

(TBAF). Coupling of 28 to the C-13 hydroxy group in 38

gave 39, which was converted into 40 by fluoride-mediated

Scheme 8. Preparation of paclitaxel analogue 46 from 21; reagents

and conditions: (a) LDA, TMSCl, THF, Ϫ78 °C Ǟ Ϫ20 °C, 1 h,

92%; (b) CH₂I₂, Zn/Cu, Et₂O/DME, 50 °C, 60 h, 58%; (c) PhLi,

THF, Ϫ78 °C, 2.5 h, 86%; (d) TBAF, THF, 30 min, 58%; (e) 28,

NaHMDS, THF, Ϫ78 °C, 45 min, 45%; (f) TBAF, THF, 5 min,

76%

deprotection.

The preparation of paclitaxel analogues II, each con-

taining a small, non-oxetane D-ring, seemed achievable

through an intermediate taxane with an endocyclic C-4

double bond, as pointed out in Scheme 1. D-rings could

then be introduced by means of [2 ϩ 2] or [2 ϩ 1] cycloaddi-

tions to this double bond. Since enol ether double bonds thylsilyloxy group and correlations of the proton on C-20

are generally more reactive than alkyl-substituted double and trans to 5-H both with 3-H and with 14α-H clearly

bonds towards cycloaddition reactions with electron-defi- indicated an (R) configuration at C-4. Although the cyclo-

cient cycloaddition partners, we set out to prepare a taxane propane ring protrudes from the α face of the C-ring

with an enol ether moiety at C-4.

whereas the oxetane D-ring in paclitaxel protrudes from the

Although the introduction of an enol acetate or methyl β face, cytotoxicity data from paclitaxel derivatives derived

enol ether moiety at C-4 had proven unsuccessful when from 43 could still afford valuable SAR data as they could

starting from 21 (vide supra), an attempt was made to trap provide insight into the effect on cytotoxicity of a different

the enolate of 21 with trimethylsilyl chloride, trapping of kind of rigidity exerted by the presence of a small D-ring,

the enolate of a similar taxane by trimethylsilyl chloride especially since the hydrogen bond acceptor properties of

having been reported before.^[27Ϫ29]Silyl enol ether forma- the oxetane ring might be taken over by the 4β-hydroxy

tion was indeed achieved by treatment of 21 with lithium group.

diisopropylamide and trimethylsilyl chloride in THF at Ϫ78

Conversion of 43 into the paclitaxel derivative 46 was

°C. Taxane 41 was obtained in high yield (Scheme 8).

accomplished in three steps. Desilylation of the C-4 and C-

[2 ϩ 2] Cycloadditions at atmospheric pressure between 13 hydroxy groups in 43 was accomplished with TBAF and

41 and dichloroketene, prepared in situ from dichloroacetyl afforded 44 in 58% yield. Coupling of β-lactam 28 to the

chloride and triethylamine, and also between 41 and ketene, C-13 hydroxy group in 44 afforded 45 in only 45% yield.

did not yield any cycloadduct. Similarly, cycloadditions be- The low yields of these steps are due to partial decomposi-

tween 41 and tetracyanoethylene at pressures of up to 3 tion, possibly as a consequence of base-promoted re-

kbar in different solvents all failed to give the desired cyclo- arrangement of the cyclopropanol moiety. Deprotection of

adduct. At pressures above 3 kbar the starting material 45 with TBAF smoothly afforded paclitaxel derivative 46.

slowly decomposed.

A route to a paclitaxel derivative similar to 46, but with

The reaction between 41 and SimmonsϪSmith carbene an epoxide D-ring rather than a cyclopropane D-ring, was

proceeded slowly in refluxing ether and afforded one main unexpectedly found when 47 was oxidized with pyridinium

product, identified as 42. The configuration at C-4 was es- chlorochromate (PCC) with the intent to create an

tablished from NOE correlations observed for 43, obtained outer,outer heterodiene moiety incorporating C-4 and C-5.

from 42 on treatment with phenyllithium in THF at Ϫ78 Such a moiety should enable the construction of rigid five-

°C. NOE correlations of the proton on C-20 and cis to 5- and six-membered D-rings through a cycloaddition ap-

H both with 5-H and with the methyl protons of the trime- proach. A related taxane bearing such a heterodiene moiety

Eur. J. Org. Chem. 2003, 689Ϫ705

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H. W. Scheeren et al.

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was reported to dimerize by [4 ϩ 2] cycloaddition, which

indicates that such a heterodiene moiety should be reactive

towards alkenes.^[30]

PCC oxidation of 47, prepared from 14 by hydrolysis,^[9,21]

did not afford the desired product resulting from straight-

forward oxidation, but instead gave taxanes 48, 49, and 50

(Scheme 9). Taxane 50 was completely converted into 49

when the reaction time exceeded 3 h and excess PCC was

used. The formation of these products must be a result of

complexation of chromium() to the allylic C-5 hydroxy

group, followed by a sigmatropic rearrangement. Oxidation

then affords 48, while epoxidation, which most probably oc-

curs through intramolecular oxygen transfer from the chro-

mium atom to the double bond, followed by hydrolysis and/

or oxidation affords 49 and 50.^[31]The configuration at C-

4 in 49 and 50 was established from the NOE data of the

methyl ether of 50.

Scheme 10. Conversion of 49 into paclitaxel derivative 58; reagents

and conditions: (a) NaBH₄, MeOH, 0 °C, 1 h, 77%; (b) NaH, MeI,

THF, 3 h, 69%; (c) NaBH₄, CeCl₃, MeOH, 0 °C, 30 min, 73%; (d)

TESCl, imidazole, DMF, 2 h, 97%; (e) tBuOOH, Pd(OAc)₂, tolu-

ene, 70 °C, 20 h, 35%; (f) TBAF, THF, 15 min, 85%; (g) 28,

NaHMDS, THF, Ϫ78 °C, 1 h, 49%; (h) TBAF, THF, 5 min, 81%

The preparation of a paclitaxel derivative with an epoxide

D-ring protruding from the convex face of the molecule was

considered valuable, as comparison of its biological activity

with that of 10 could provide information about the import-

ance of the oxetane ring oxygen atom for cytotoxic activity,

while comparison of its biological activity with that of 58

could provide information about the effect of a differently

exerted rigidity on cytotoxic activity.

It was envisaged that the approach towards such a paclit-

axel derivative would involve intermediate 59, which was

prepared from 14 by a reaction sequence similar to that

depicted in Scheme 3.^[9]Construction of a β-oriented epox-

ide ring would be feasible through the introduction of an

α-oriented leaving group at C-5, reduction of the C-4 car-

bonyl group, and subsequent ring-closure by intramolecu-

lar substitution.

Scheme 9. Conversion of 47 into 48Ϫ50 and 51 by PCC oxidation

and Swern oxidation, respectively; reagents and conditions: (a)

PCC, CH₂Cl₂, 3.5 h, 48: 5%, 49: 43%, 50: 2%; (b) (COCl)₂, DMSO,

CH₂Cl₂, Ϫ50 °C, 10 min, then 47, Ϫ10 °C, 20 min, then Et₃N, Ϫ10

°C Ǟ room temp., 40 min, 21%

While oxidation with Collin’s reagent gave similar results,

Conversion of 59 to 60 was accomplished by treatment

no reaction took place with activated manganese oxide or of a THF solution of 59 with phenyltrimethylammonium

tetrapropylammonium perruthenate. Swern oxidation gave tribromide (Scheme 11). Reduction of 60 with sodium

51 as the main product, albeit in low yield. Compound 51 borohydride gave compounds 61 and 62 in an approximate

is probably formed by an S_N2Ј-type substitution of the ac- 6:5 ratio. Ring-closure on the epimer of 62 occurred under

tivated C-5 hydroxide group by chloride.

the reaction conditions involved, affording 61. NOE cor-

The aldehyde group in 49 was reduced with sodium relations of 4-H with 5-H, 3-H, and 14α-H clearly denoted

borohydride, which gave 50 (Scheme 10). Conversion of the a β orientation of the epoxide oxygen atom.

primary hydroxy group in 50 into a methoxy group was

Coupling of the C-13 hydroxy group in 61 to β-lactam

carried out with excess methyl iodide and sodium hydride. 28 afforded 63. Unfortunately, palladium()-catalyzed oxid-

Stereoselective reduction of the C-13 carbonyl group in 52 ative opening of the acetal moiety in 63 with tert-butyl hy-

with sodium borohydride in the presence of cerium() droperoxide failed to give the desired product, and so desi-

chloride gave 53 in good yield. After protection of the C- lylation was carried out first. Oxidative opening of the ace-

13 hydroxy group with a triethylsilyl group, giving 54, the tal moiety in 64 gave several products, from which we were

acetal moiety was oxidatively opened by means of a palla- only able to obtain the main product pure. NMR spectro-

dium()-mediated reaction with tert-butyl hydroperoxide. scopy and mass spectrometry showed the compound to be

Fluoride-assisted desilylation of 55 gave 56, which was then taxane 65, which contains the desired C-2 benzoyloxy

coupled to β-lactam 28. Finally, the C-2Ј hydroxy group group, but also a vicinal diol moiety at C-4/C-5. Appar-

in 57 was deprotected with TBAF, which afforded 58 in ently, opening of the epoxide by water occurred under the

good yield.

reaction conditions involved. NOE correlations of 4-H with

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though 40 bears a C-4 methyl group intended as a substi-

tute for the acetoxy group, this group may well be too small

to be a good replacement. On the other hand, 4-deacetoxy-

paclitaxel shows considerably higher cytotoxicity than 30,

31, and 40^[24], which may point to an important contribu-

tion of the oxetane ring oxygen atom in 4-deacetoxypaclit-

axel to its cytotoxicity.

At first glance, the low cytotoxicity exhibited by 46 and

58 may be ascribed to a preferred conformation different

from that preferably adopted by paclitaxel. Comparison of

the AM1 energy-minimized polar conformations of paclit-

axel, 46, and 58 shows that the C-rings in 46 and 58 prefer-

ably adopt boat conformations. A change to a flattened

chair conformation, as adopted by the C-ring in paclitaxel,

however, is accompanied by only a small increase in energy

and should therefore be attainable for 46 and 58. It is more

likely that the cyclopropane methylene group in 46 and the

epoxide oxygen atom in 58 are unsuitable replacements for

the C-4 acetoxy group in paclitaxel. Furthermore, models

show that the 4β-methoxymethyl group in 58 requires more

space than the oxetane ring in paclitaxel, which may cause

steric congestion upon binding of 58 to the receptor on β-

tubulin. Although this cannot be true for 46, the oxygen

atom of the 4β-hydroxy group may be so far displaced from

the spatial position occupied by the oxetane ring oxygen

in paclitaxel that an energy-lowering interaction with the

receptor is no longer achievable.

Scheme 11. Conversion of 59 into paclitaxel derivative 65; reagents

and conditions: (a) PTAB, THF, Ϫ15 °C Ǟ 10 °C, 3 h, 77%; (b)

NaBH₄, THF/MeOH, 0 °C, 2 h, 61: 36%, 62: 31%; (c) 28,

NaHMDS, THF, Ϫ78 °C, 1 h, 74%; (d) TBAF, THF, 5 min, 96%;

(e) tBuOOH, Pd(OAc)₂, toluene, 70 °C, 40 h, 17%

both 3-H and 14α-H and correlations of 5-H with 6α-H are

supportive of nucleophilic attack at C-5.

Taxanes 30, 31, 40, 46, 58, and 65 were evaluated for

their in vitro cytotoxicities against seven well-characterized

human tumor cell lines (MCF7, EVSA-T, WIDR, IGROV,

M19 MEL, A498, and H226) by a previously reported pro-

cedure.^[32]The ID₅₀values, which reflect the concentrations

at which cell proliferation is inhibited by 50%, are listed

in Table 1.

The ID₅₀values listed in Table 1 clearly show that com-

pounds 30, 31, 40, 46, 58, and 65 all exhibit strongly re-

duced cytotoxicities with respect to paclitaxel (ID₅₀/ID_50,pa-

Comparison of 65 with 66^[24](Figure 2), which exhibits a

cytotoxic activity against human CA46 Burkitt lymphoma

ten times lower than that of paclitaxel and is even somewhat

more active than 4-deacetoxypaclitaxel, supports the idea

that the presence of a hydrogen bond acceptor in the proper

position in space significantly contributes to cytotoxic ac-

tivity.

Ͼ 550). Comparison of the biological activity of 30

clitaxel

with that of 31 reveals that the presence of the isopropylid-

ene protecting group in 30 hardly affects cytotoxicity. This

is in full agreement with previously obtained results that

have demonstrated that modifications at C-9 and C-10 gen-

erally affect cytotoxicity only marginally.^[18,22]

The low biological activities exhibited by 30, 31, and 40,

which have AM1 energy-minimized polar conformations

similar to the polar conformation of paclitaxel,^[33]may be

attributable to the absence of a suitable substitute for paclit-

Figure 2. Paclitaxel derivative 66

In conclusion, paclitaxel analogues 30, 31, 40, 46, 58, and

axel’s 4α-acetoxy group, which has been shown to be an 65 were prepared from taxine in 13Ϫ16 steps. All paclitaxel

important group for retention of cytotoxic activity.^[22,24]Al- derivatives exhibited strongly reduced cytotoxicities against

Table 1. ID₅₀values [µ] of paclitaxel, 30, 31, 40, 46, 58, and 65 against 7 human tumor cell lines (MCF7: breast cancer; EVSA-T: breast

cancer; WIDR: colon cancer; IGROV: ovarian cancer; M19 MEL: melanoma; A498: renal cancer; H226: non-small cell lung cancer)

Compound

MCF7

EVSA-T

WIDR

IGROV

M19 MEL

A498

H226

Paclitaxel

Ͻ 0.0037

3.3

5.2

2.3

13

6.0

9.1

Ͻ 0.0037

2.2

5.4

2.0

14

5.4

10

Ͻ 0.0037

4.0

10

3.4

15

9.1

10

Ͻ 0.0037

3.8

10

4.5

8.9

8.2

14

30

31

40

46

58

65

3.6

11

3.4

15

12

10

4.6

12

4.6

16

19

18

4.5

10

4.6

15

13

14

Eur. J. Org. Chem. 2003, 689Ϫ705

695

H. W. Scheeren et al.

FULL PAPER

4.95 (d, J_10Ϫ9ϭ 9.1 Hz, 1 H, 10-H), 5.36 (br. s, 1 H, 20-H), 5.38

(m, 1 H, 5-H), 5.73 (dd, J_2Ϫ1ϭ 1.9, J_2Ϫ3ϭ 6.5 Hz, 1 H, 2-H), 6.44

[d, J ϭ 15.9 Hz, 1 H, C(O)CHCHPh], 7.08 (m, 1 H, imidazole),

7.37Ϫ7.48 (m, 4 H, Ph ϩ imidazole), 7.68 [d, J ϭ 15.9 Hz, 1 H,

C(O)CHCHPh], 7.77 (m, 2 H, Ph), 8.13 (br. s, 1 H, imidazole)

ppm. FAB-MS: m/z ϭ 615 [M ϩ H]^ϩ, 637 [M ϩ Na]^ϩ, 1230 [2 M

ϩ H]^ϩ, 1252 [2 M ϩ Na]^ϩ. C₃₆H₄₂O₇N₂(614.7): calcd. C 70.34, H

6.89; found C 70.22, H 6.94.

a range of seven well-defined human tumor cell lines. Al-

though no definite conclusion can be drawn from these bio-

logical data with respect to the way in which the oxetane

ring contributes to the cytotoxicity of paclitaxel, it seems

plausible that at least the interaction of the oxetane ring

oxygen atom in paclitaxel with the receptor on β-tubulin

significantly contributes to the cytotoxicity profile exhibited

by paclitaxel.

Conversion of 15 into 17: Triphenylphosphane (161 mg,

0.615 mmol) was added at room temperature to a stirred solution

of bis(dibenzylideneacetone)palladium(0) (70.7 mg, 0.123 mmol) in

THF (40 mL). The yellow solution was cooled to 0 °C, and triethyl-

amine (1.71 mL, 12.3 mmol), formic acid (0.470 mL, 12.3 mmol),

and 15 (3.46 g, 6.15 mmol) were added successively. The solution

was stirred at reflux temperature for 2 d. The solution was cooled

down to room temperature, diluted with ethyl acetate (60 mL),

washed with a saturated aqueous NH₄Cl solution, water, a satur-

ated aqueous NaHCO₃solution, and brine, dried with anhydrous

Na₂SO₄, filtered, and concentrated under reduced pressure. Col-

umn chromatography (EtOAc/heptanes, 2:7) afforded 17 (2.49 g,

Experimental Section

General Remarks: When necessary, solvents were dried and distilled

by standard procedures prior to use. ¹H NMR (300 MHz) and ¹³C

NMR (75 MHz) spectra were recorded with a Bruker AC 300 spec-

trometer in CDCl₃with TMS as the internal standard, unless

otherwise stated. 2D NMR experiments (NOESY) were performed

in CDCl₃with a Bruker AM 400 spectrometer, unless otherwise

stated. Chemical shifts are reported in parts per million (ppm) and

coupling constants (J) are given in Hertz (Hz). Mass spectra were

recorded with a Finnigan MAT900S double-focusing mass spectro-

meter coupled to an ICIS data system in FAB and EI modes. High-

resolution FAB spectra were recorded with a JEOL JMS SX/

SX102A four-sector mass spectrometer coupled to an MS-

MP 21D/UPD data system. Elemental analyses were carried out

with a Carlo Erba Instruments CHNSO EA 1108 element analyzer.

Thin layer chromatography (TLC) was carried out on Merck pre-

coated silica gel 60 F-254 plates (thickness: 0.25 mm). All reactions

were monitored by TLC. Compounds were viewed by UV or by

dipping the TLC plate into a 6.2% aqueous sulfuric acid solution

containing ammonium molybdate (42 g/L) and ceric ammonium

sulfate (3.6 g/L) followed by charring. Column chromatography

was carried out with Baker silica gel (63Ϫ200 mesh). Generally,

products were freeze-dried after chromatographic purification. Ex-

perimental procedures for the isolation of taxine and the prepara-

tion of 12, 13, 14, 47, and 59 are described in refs.^[9,21]

1

5.98 mmol, 97%) as a white solid. H NMR: δ ϭ 1.11 (s, 3 H, 19-

H), 1.40 (s, 3 H, 17-H), 1.44 (s, 3 H, acetonide), 1.48 (s, 3 H, aceton-

ide), 1.67 (s, 3 H, 16-H), 2.05 (s, 3 H, 18-H), 2.47 (d, J_3Ϫ2ϭ 5.8 Hz,

1 H, 3-H), 2.90 (s, 2 H, 2 ϫ 14-H), 4.12 (d, J_9Ϫ10ϭ 9.2 Hz, 1 H,

9-H), 4.82 (d, J_10Ϫ9ϭ 9.2 Hz, 1 H, 10-H), 4.88 (d, J_2Ϫ3ϭ 5.8 Hz,

1 H, 2-H), 5.05 (br. s, 1 H, 20-H), 5.33 (br. s, 1 H, 20-H) ppm.

FAB-MS: m/z ϭ 417 [M ϩ H]^ϩ, 439 [M ϩ Na]^ϩ, 856 [2 M ϩ Na]^ϩ.

C₂₄H₃₂O₆(416.5): calcd. C 69.21, H 7.74; found C 69.61, H 7.77.

Conversion of 17 into 18: Osmium tetroxide (4.0 wt% solution in

water, 6.68 mL, 1.1 mmol) and 4-methylmorpholine N-oxide

(2.51 g, 18.6 mmol) were added at room temperature to a stirred

solution of 17 (4.55 g, 10.9 mmol) in THF (85 mL). The solution

was stirred at room temperature for 5 d, water (2 mL) being added

to the reaction mixture every day. The reaction was quenched by

addition of Na₂S₂O₄(585 mg, 3.36 mmol) and Florisil^(4.5 g).

After 20 min of additional stirring, the reaction mixture was fil-

tered through Celite^. The filter agent was rinsed with ethyl acetate

(90 mL). The aqueous layer of the filtrate was separated from the

organic layer and extracted with ethyl acetate (25 mL). The com-

bined organic fractions were washed with brine, dried with anhyd-

rous Na₂SO₄, filtered, and concentrated under reduced pressure.

Column chromatography (EtOAc/heptanes, 1:1) yielded 18 (4.46 g,

Conversion of a Mixture of 12 and 13 into 15 and 16: A solution of a

mixture of 12 and 13 (5.05 g, 9.41 mmol) and carbonyldiimidazole

(6.10 g, 37.6 mmol) in butanone (140 mL) was stirred at reflux tem-

perature for 3 h. The reaction mixture was allowed to cool to room

temperature, diluted with ethyl acetate (150 mL), and extracted

with water (200 mL). The aqueous fraction was extracted with ethyl

acetate (75 mL). The combined organic fractions were washed with

brine, dried with anhydrous Na₂SO₄, filtered, and concentrated un-

der reduced pressure. Column chromatography (EtOAc/heptanes,

2:5) afforded 15 (4.54 g, 8.07 mmol, 86%) as a white solid and 16

(514 mg, 0.836 mmol, 9%) as an off-white solid. 15: ¹H NMR: δ ϭ

1.16 (s, 3 H, 19-H), 1.43 (s, 3 H, 17-H), 1.45 (s, 3 H, acetonide),

1.50 (s, 3 H, acetonide), 1.68 (s, 3 H, 16-H), 2.17 (s, 3 H, 18-H),

2.96 (s, 2 H, 2 ϫ 14-H), 3.22 (d, J_3Ϫ2ϭ 5.7 Hz, 1 H, 3-H), 4.13 (d,

1 H, J_9Ϫ10ϭ 9.1 Hz, 9-H), 4.88 (d, J_10Ϫ9ϭ 9.1 Hz, 1 H, 10-H),

4.93 (d, J_2Ϫ3ϭ 5.7 Hz, 1 H, 2-H), 5.35 (br. s, 1 H, 5-H), 5.37 (br.

s, 1 H, 20-H), 5.52 (br. s, 1 H, 20-H), 6.27 [d, J ϭ 15.9 Hz, 1 H,

C(O)CHCHPh], 7.44 (m, 3 H, Ph), 7.64 [d, J ϭ 15.9 Hz, 1 H,

C(O)CHCHPh], 7.71 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 563 [M

ϩ H]^ϩ. C₃₃H₃₈O₈·0.5H₂O (571.7): calcd. C 69.33, H 6.88; found C

1

9.90 mmol, 91%) as a white solid. H NMR: δ ϭ 1.09 (s, 3 H, 19-

H), 1.39 (s, 3 H, 17-H), 1.42 (s, 3 H, acetonide), 1.46 (s, 3 H, aceton-

ide), 1.63 (s, 3 H, 16-H), 2.01 (s, 3 H, 18-H), 2.13 (d, J_3Ϫ2ϭ 4.7 Hz,

1 H, 3-H), 2.80 (d, J_gemϭ 19.2 Hz, 1 H, 14-H), 3.66 (br. dd, J_gemϭ

10.5, J_20ϪOHϭ 5.3 Hz, 1 H, 20-H), 3.97 (br. d, J_gemϭ 10.5 Hz, 1

H, 20-H), 4.02 (d, J_gemϭ 19.2 Hz, 1 H, 14-H), 4.09 (d, J_9Ϫ10

ϭ

8.8 Hz, 1 H, 9-H), 4.72 (d, J_10Ϫ9ϭ 8.8 Hz, 1 H, 10-H), 4.80 (d,

J_2Ϫ3ϭ 4.7 Hz, 1 H, 2-H). FAB-MS: m/z ϭ 451 [M ϩ H]^ϩ, 473 [M

ϩ Na]^ϩ. C₂₄H₃₄O₈·0.5H₂O (459.5): calcd. C 62.73, H 7.68; found

C 62.77, H 7.71.

Conversion of 18 into a Mixture of 19a and 19b: Cerium() chloride

heptahydrate (8.87 g, 23.8 mmol) was added at 0 °C to a stirred

solution of 18 (2.68 g, 5.95 mmol) in methanol (200 mL). After

5 min, sodium borohydride (900 mg, 23.8 mmol) was added in

small portions. The reaction mixture was stirred at 0 °C for 30 min.

Subsequently, the reaction was quenched by slow addition of a sat-

1

69.37, H 6.72. 16: H NMR: δ ϭ 1.12 (s, 3 H, 19-H), 1.29 (s, 3 H,

17-H), 1.46 (s, 3 H, acetonide), 1.54 (s, 3 H, acetonide), 1.81 (s, 3

H, 16-H), 2.19 (s, 3 H, 18-H), 2.46 (dd, J_1Ϫ2ϭ 1.9, J_1Ϫ14ϭ 7.1 Hz, urated aqueous NH₄Cl solution (50 mL). Ethyl acetate (300 mL)

1 H, 1-H), 2.46 (d, J_gemϭ 19.9 Hz, 1 H, 14-H), 2.94 (d, J_gem

19.9 Hz, 1 H, J_14Ϫ1ϭ 7.1 Hz, 14-H), 3.42 (d, J_3Ϫ2ϭ 6.5 Hz, 1 H,

ϭ

and a 10% aqueous citric acid solution (200 mL) were added to the

resulting suspension. The aqueous layer was separated from the

3-H), 4.31 (d, J_9Ϫ10ϭ 9.1 Hz, 1 H, 9-H), 4.67 (br. s, 1 H, 20-H), organic layer and extracted twice with ethyl acetate (2 ϫ 200 mL).

696 Eur. J. Org. Chem. 2003, 689Ϫ705

Semisynthesis of 7-Deoxypaclitaxel Derivatives Devoid of an Oxetane D-Ring

FULL PAPER

The combined organic fractions were washed with a saturated

aqueous NaHCO₃solution and brine, dried with anhydrous

Na₂SO₄, filtered, and concentrated under reduced pressure to give

3.88 (d, J_9Ϫ10ϭ 9.4 Hz, 1 H, 9-H), 4.59 (d, J_2Ϫ3ϭ 6.0 Hz, 1 H, 2-

H), 4.61 (m, 1 H, 13-H), 4.81 (d, J_10Ϫ9ϭ 9.4 Hz, 1 H, 10-H) ppm.

FAB-MS: m/z ϭ 557 [M ϩ Na]^ϩ, 1092 [2 M ϩ Na]^ϩ. C₂₉H₄₆O₇Si

a crude mixture of 19a and 19b (2.57 g, max. 5.68 mmol), which (534.8): calcd. C 65.13, H 8.67; found C 65.18, H 8.63.

was used as such in the next reaction step. 19a: ¹H NMR: δ ϭ 1.05

Conversion of 21 into 22: Sodium borohydride (58.0 mg, 1.53 mmol)

was slowly added at 0 °C to a stirred solution of 21 (745 mg,

1.39 mmol) in methanol (40 mL). The reaction mixture was stirred

at 0 °C for 30 min. The reaction was quenched by slow addition of

a saturated aqueous NH₄Cl solution (25 mL). The resultant mix-

ture was extracted twice with ethyl acetate (2 ϫ 75 mL). The com-

bined organic fractions were washed with a saturated aqueous

NaHCO₃solution, water, and brine, dried with anhydrous Na₂SO₄,

filtered, and concentrated under reduced pressure. This gave 22

(808 mg, max. 1.39 mmol), which was used as such in the next reac-

(s, 3 H, 19-H), 1.19 (s, 3 H, 17-H), 1.40 (s, 3 H, acetonide), 1.43 (s,

3 H, acetonide), 1.55 (s, 3 H, 16-H), 2.02 (s, 3 H, 18-H), 2.56 (d,

J_3Ϫ2ϭ 4.4 Hz, 1 H, 3-H), 2.67 (dd, J_gemϭ 15.8, J_14Ϫ13ϭ 9.7 Hz,

1 H, 14-H), 2.79 (dd, J_gemϭ 15.8, J_14Ϫ13ϭ 2.6 Hz, 1 H, 14-H),

3.42 (br. d, J_OHϪ13ϭ 8.8 Hz, 1 H, 13-OH), 3.64 (d, J_gemϭ 10.5 Hz,

1 H, 20-H), 3.74 (s, 1 H, 4-OH), 3.92 (d, J_9Ϫ10ϭ 9.4 Hz, 1 H, 9-

H), 4.07 (br. d, J_gemϭ 10.5 Hz, 1 H, 20-H), 4.53 (m, 1 H, 13-H),

4.64 (d, J_2Ϫ3ϭ 4.4 Hz, 1 H, 2-H), 4.69 (d, J_10Ϫ9ϭ 9.4 Hz, 1 H,

10-H) ppm. FAB-MS ϭ m/z: 453 [M ϩ H]^ϩ, 475 [M ϩ Na]^ϩ[after

purification by column chromatography (EtOAc/heptanes, 1:1)].

1

tion step. H NMR: δ ϭ 0.64 [q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃],

Conversion of a Mixture of 19a and 19b into 20a and 20b: NaIO₄

0.98 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.14 (m, 1 H, 7-H), 1.21

(4.86 g, 22.7 mmol) was added at room temperature to a clear solu- (s, 3 H, 17-H), 1.35 (m, 1 H, 5-H), 1.38 (s, 3 H, 19-H), 1.40 (s, 3

tion of a crude mixture of 19a and 19b (2.57 g, max. 5.68 mmol) in

H, acetonide), 1.42 (s, 3 H, acetonide), 1.53 (m, 1 H, 6-H), 1.55 (s,

THF/water (150 mL, 3:2, v/v). The reaction mixture, which became

3 H, 16-H), 1.85Ϫ1.92 (m, 3 H, 5-H ϩ 6-H ϩ 7-H), 1.91 (s, 3 H,

cloudy within a few minutes, was stirred at room temperature for 18-H), 2.10 (m, 1 H, 3-H), 2.14 (dd, J_gemϭ 15.3, J_14Ϫ13ϭ 3.8 Hz,

3 h, diluted with ethyl acetate (200 mL), and washed with water

(100 mL). The aqueous fraction was extracted with ethyl acetate

(100 mL). The combined organic fractions were washed with brine,

dried with anhydrous Na₂SO₄, filtered, and concentrated under re-

duced pressure. Column chromatography (EtOAc/heptanes, 1:1) af-

forded 20a [1.22 g, 2.90 mmol, 49% (2 steps)] and 20b [290 mg,

0.690 mmol, 12% (2 steps)], both as white solids. 20a: ¹H NMR:

1 H, 14-H), 2.15 (br. s, 1 H, 4-OH), 2.60 (dd, J_gemϭ 15.3, J_14Ϫ13ϭ

9.3 Hz, 1 H, 14-H), 3.89 (d, J_9Ϫ10ϭ 9.5 Hz, 1 H, 9-H), 4.20 (br. s,

1 H, 4-H), 4.64 (d, J_10Ϫ9ϭ 9.5 Hz, 1 H, 10-H), 4.70 (d, J_2Ϫ3

ϭ

5.0 Hz, 1 H, 2-H), 4.75 (m, 1 H, 13-H) ppm. ¹³C NMR: δ ϭ 4.8,

6.8, 16.5, 18.0, 20.2, 20.2, 26.8, 26.9, 28.6, 30.7, 32.4, 37.8, 38.1,

40.3, 44.0, 68.3, 68.8, 75.0, 81.0, 82.3, 91.5, 106.8, 132.9, 147.8,

153.6 ppm. FAB-MS: m/z ϭ 536 [M]^ϩ, 559 [M ϩ Na]^ϩ. C₂₉H₄₈O₇Si

δ ϭ 1.09 (s, 3 H, 19-H), 1.21 (s, 3 H, 17-H), 1.44 (s, 3 H, acetonide), (536.8): calcd. C 64.89, H 9.01; found C 65.06, H 8.64 [after puri-

1.45 (s, 3 H, acetonide), 1.55 (s, 3 H, 16-H), 1.59 (m, 1 H, 6-H/7-

H), 1.85Ϫ2.05 (m, 3 H, 3 ϫ 6-H/7-H), 2.10 (s, 3 H, 18-H), 2.18

(dd, J_gemϭ 15.7, J_14Ϫ13ϭ 3.5 Hz, 1 H, 14-H), 2.27Ϫ2.40 (m, 3 H,

2 ϫ 5-H ϩ 13-OH), 2.64 (dd, J_gemϭ 15.7, J_14Ϫ13ϭ 9.5 Hz, 1 H,

14-H), 3.33 (d, J_3Ϫ2ϭ 6.1 Hz, 1 H, 3-H), 3.90 (d, J_9Ϫ10ϭ 9.4 Hz,

fication by column chromatography (EtOAc/heptanes, 1:3)].

Dehydration of 22 with Trifluoromethanesulfonyl Chloride, Giving a

Mixture of 23 and 24, 25a, and 25b: Trifluoromethanesulfonyl

chloride (0.296 mL, 2.78 mmol) was added to a stirred solution of

crude 22 (808 mg, max. 1.39 mmol) and 4-(dimethylamino)pyridine

(5.09 g, 41.7 mmol) in dichloromethane (15 mL) at 0 °C. The reac-

tion mixture was stirred at room temperature for 2 d, additional

amounts of trifluoromethanesulfonyl chloride (2 ϫ 0.296 mL, 2 ϫ

2.78 mmol) being added at 0 °C after 24 and 30 h. The reaction

mixture was diluted with ethyl acetate (75 mL), washed with water

and brine, dried with anhydrous Na₂SO₄, filtered, and concentrated

under reduced pressure. Column chromatography (EtOAc/hept-

anes, 1:9) gave a 9:1 mixture of 23 and 24 [220 mg, 0.424 mmol,

31% (2 steps)], 25a or 25b (higher R_fvalue) [154 mg, 0.236 mmol,

17% (2 steps)], and 25b or 25a (lower R_fvalue) [32.3 mg, 49.4 µmol,

4% (2 steps)], all as white solids, together with recovered 22

(225 mg, 0.419 mmol). 23: ¹H NMR: δ ϭ 0.62 [q, J ϭ 7.9 Hz, 6 H,

Si(CH₂CH₃)₃], 0.96 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.08 (s, 3

1 H, 9-H), 4.61 (d, J_2Ϫ3ϭ 6.1 Hz, 1 H, 2-H), 4.82 (d, J_10Ϫ9

ϭ

9.4 Hz, 1 H, 10-H), 4.82 (m, 1 H, 13-H) ppm. FAB-MS: m/z ϭ 443

[M ϩ Na]^ϩ, 863 [2 M ϩ Na]^ϩ. C₂₃H₃₂O₇(420.5): calcd. C 65.70,

1

H 7.67; found C 65.65, H 7.66. 20b: H NMR: δ ϭ 1.07 (s, 3 H,

19-H), 1.42 (s, 3 H, acetonide), 1.44 (s, 3 H, acetonide), 1.48 (m, 1

H, 7-H), 1.49 (s, 3 H, 17-H), 1.53 (s, 3 H, 16-H), 1.82Ϫ2.07 (m, 3

H, 2 ϫ 6-H ϩ 7-H), 2.07 (s, 3 H, 18-H), 2.15Ϫ2.37 (m, 3 H, 2 ϫ

5-H ϩ 14-H), 2.56 (dd, J_gemϭ 15.3, J_14Ϫ13ϭ 9.5 Hz, 1 H, 14-H),

2.64 (d, J_3Ϫ2ϭ 6.2 Hz, 1 H, 3-H), 3.92 (d, J_9Ϫ10ϭ 9.4 Hz, 1 H, 9-

H), 4.10 (m, 1 H, 13-H), 4.63 (d, J_2Ϫ3ϭ 6.2 Hz, 1 H, 2-H), 4.74

(d, J_10Ϫ9ϭ 9.4 Hz, 1 H, 10-H) ppm. FAB-MS: m/z ϭ 443 [M ϩ

Na]^ϩ, 863 [2 M ϩ Na]^ϩ. C₂₃H₃₂O₇(420.5): calcd. C 65.70, H 7.67;

found C 65.36, H 7.37.

Conversion of 20a into 21: Chlorotriethylsilane (2.13 mL, H, 19-H), 1.22 (s, 3 H, 17-H), 1.41 (s, 3 H, acetonide), 1.44 (s, 3

12.7 mmol) was added at room temperature to a solution of imida- H, acetonide), 1.57 (s, 3 H, 16-H), 1.87 (s, 3 H, 18-H), 2.07Ϫ2.16

zole (2.25 g, 33.1 mmol) in DMF (30 mL). After 20 min, 20a (m, 3 H, 2 ϫ 6-H/7-H ϩ 14-H), 2.54 (dd, J_gemϭ 15.2, J_14Ϫ13

ϭ

(1.07 g, 2.54 mmol) in DMF (20 mL) was added. The reaction mix-

ture was then stirred for 4 h, diluted with ethyl acetate (200 mL),

and washed with water (100 mL). The aqueous fraction was ex-

tracted with ethyl acetate (100 mL), and the combined organic frac-

tions were washed with brine, dried with anhydrous Na₂SO₄, fil-

9.1 Hz, 1 H, 14-H), 2.88 (m, 1 H, 3-H), 4.02 (d, J_9Ϫ10ϭ 9.6 Hz, 1

H, 9-H), 4.58 (d, 1 H, 2-H), 4.60 (d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H),

4.77 (m, 1 H, 13-H), 5.57Ϫ5.66 (m, 2 H, 4-H ϩ 5-H) ppm. FAB-

MS: m/z ϭ 519 [M ϩ H]^ϩ, 541 [M ϩ Na]^ϩ, 1038 [2 M ϩ H]^ϩ,

1060 [2 M ϩ Na]^ϩ, 1578 [3 M ϩ Na]^ϩ. C₂₉H₄₆O₆Si (518.8): calcd.

tered, and concentrated under reduced pressure. Column chroma- C 67.14, H 8.94; found C 67.27, H 9.04. 25a or 25b (higher R_f

tography (EtOAc/heptanes, 2:7) afforded 21 (1.17 g, 2.19 mmol,

value): ¹H NMR: δ ϭ 0.66 [q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 0.99

[t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.20 (s, 3 H, 17-H), 1.29 (s, 3

86%) as a white solid. ¹H NMR: δ ϭ 0.63 [q, J ϭ 7.9 Hz, 6 H,

Si(CH₂CH₃)₃], 0.96 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.08 (s, 3 H, 19-H), 1.40 (s, 3 H, acetonide), 1.42 (s, 3 H, acetonide), 1.55 (s,

H, 19-H), 1.20 (s, 3 H, 17-H), 1.43 (s, 3 H, acetonide), 1.44 (s, 3 3 H, 16-H), 1.92 (s, 3 H, 18-H), 2.04 (dd, J_gemϭ 15.5, J_14Ϫ13

ϭ

H, acetonide), 1.53 (s, 3 H, 16-H), 2.02 (s, 3 H, 18-H), 2.09 (dd, 3.6 Hz, 1 H, 14-H), 2.35 (dd, J_3Ϫ2ϭ 5.0, J_3Ϫ4ϭ 2.3 Hz, 1 H, 3-

J_gemϭ 15.6, J_14Ϫ13ϭ 3.5 Hz, 1 H, 14-H), 2.60 (dd, J_gemϭ 15.6, H), 2.64 (dd, J_gemϭ 15.5, J_14Ϫ13ϭ 9.3 Hz, 1 H, 14-H), 3.90 (d,

J_14Ϫ13ϭ 9.4 Hz, 1 H, 14-H), 3.31 (d, J_3Ϫ2ϭ 6.0 Hz, 1 H, 3-H),

J_9Ϫ10ϭ 9.4 Hz, 1 H, 9-H), 4.61 (d, J_2Ϫ3ϭ 5.0 Hz, 1 H, 2-H), 4.65

Eur. J. Org. Chem. 2003, 689Ϫ705

697

H. W. Scheeren et al.

FULL PAPER

(d, J_10Ϫ9ϭ 9.4 Hz, 1 H, 10-H), 4.70 (m, 1 H, 4-H), 4.72 (m, 1 H, anhydrous Na₂SO₄, filtered, and concentrated under reduced pres-

13-H) ppm. FAB-MS: m/z ϭ 653 [M ϩ H]^ϩ, 675 [M ϩ Na]^ϩ, 1328

sure. Column chromatography (EtOAc/heptanes, 2:3) gave 27

[2 M ϩ Na]^ϩ. C₃₀H₄₇F₃O₈SSi·2H₂O (688.9): calcd. C 52.31, H (176 mg, 0.365 mmol, 95%) as a white solid. ¹H NMR: δ ϭ 1.13

7.46; found C 52.40, H 6.97. 25b or 25a (lower R_fvalue): ¹H NMR:

(s, 3 H, 19-H), 1.19 (s, 3 H, 17-H), 1.45 (s, 3 H, acetonide), 1.52 (s,

δ ϭ 0.65 [q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 0.98 [t, J ϭ 7.9 Hz, 9 3 H, acetonide), 1.66 (s, 3 H, 16-H), 1.97 (s, 3 H, 18-H), 2.23 (dd,

H, Si(CH₂CH₃)₃], 1.20 (s, 3 H, 17-H), 1.32 (s, 3 H, 19-H), 1.40 (s, J_gemϭ 15.3, J_14Ϫ13ϭ 4.9 Hz, 1 H, 14-H), 2.53 (dd, J_gemϭ 15.3,

3 H, acetonide), 1.42 (s, 3 H, acetonide), 1.54 (s, 3 H, 16-H), 1.92

J_14Ϫ13ϭ 9.7 Hz, 1 H, 14-H), 3.26 (br. s, 1 H, 3-H), 4.41 (d, J_9Ϫ10ϭ

(s, 3 H, 18-H), 2.05 (dd, J_gemϭ 15.5 Hz, 1 H, 14-H), 2.37 (dd, 1 9.6 Hz, 1 H, 9-H), 4.70 (d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 4.85 (m, 1

H, 3-H), 2.65 (dd, J_gemϭ 15.5, J_14Ϫ13ϭ 9.1 Hz, 1 H, 14-H), 3.91 H, 13-H), 5.52 (m, 2 H, 2-H ϩ 4-H/5-H), 5.77 (m, 1 H, 4-H/5-H),

(d, J_9Ϫ10ϭ 9.4 Hz, 1 H, 9-H), 4.65 (d, J_10Ϫ9ϭ 9.4 Hz, 1 H, 10-

H), 4.68 (d, 1 H, 2-H), 4.72 (m, 1 H, 13-H), 4.79 (m, 1 H, 4-H) MS: m/z ϭ 505 [M ϩ Na]^ϩ. C₂₉H₃₈O₆·2H₂O (518.6): calcd. C

ppm. FAB-MS: m/z ϭ 653 [M ϩ H]^ϩ, 675 [M ϩ Na]^ϩ.

67.16, H 8.16; found C 67.18, H 7.83.

7.47 (m, 2 H, Ph), 7.58 (m, 1 H, Ph), 8.07 (m, 2 H, Ph) ppm. FAB-

Dehydration of 22 with Trifluoromethanesulfonic Anhydride, Giving Coupling of 27 to β-Lactam 28, Affording 29: Sodium bis(trimethyl-

a Mixture of 23 and 24, 25a, and 25b: Trifluoromethanesulfonic

anhydride (15.7 µL, 93.1 µmol) was added at Ϫ30 °C to a solution

of 22 (25.0 mg, 46.6 µmol) and pyridine (113 µL, 1.40 mmol) in

dichloromethane (1 mL). The reaction mixture was stirred at room

silyl)amide (1.0  solution in THF, 0.389 mL, 0.39 mmol) was ad-

ded at Ϫ78 °C to a stirred solution of 27 (75.0 mg, 0.155 mmol)

and β-lactam 28 (94.9 mmol, 0.249 mmol) in THF (3 mL). The re-

action mixture was stirred at Ϫ78 °C for 20 min. Subsequently, the

temperature for 2 d, additional trifluoromethanesulfonic anhydride reaction was quenched by addition of a saturated aqueous NH₄Cl

(15.7 µL, 93.1 µmol) being added at Ϫ30 °C after 1 d. The reaction

mixture was diluted with ethyl acetate (20 mL), washed with water

and brine, dried with anhydrous Na₂SO₄, filtered, and concentrated

under reduced pressure. Column chromatography (EtOAc/hept-

anes, 1:9) afforded a 1:10 mixture of 23 and 24 (8.1 mg, 16 µmol,

solution (5 mL). The mixture was allowed to warm to room tem-

perature, ethyl acetate (20 mL) and brine (20 mL) were added, and

the two layers were separated. The organic fraction was dried with

anhydrous Na₂SO₄, filtered, and concentrated under reduced pres-

sure. Column chromatography (EtOAc/heptanes, 1:3) yielded 29

34%), 25a or 25b (higher R_fvalue, 5.0 mg, 7.7 µmol, 16%), and 25b (113 mg, 0.131 mmol, 84%) as a white solid. ¹H NMR: δ ϭ 0.45

or 25a (lower R_fvalue, 1.3 mg, 2.0 µmol, 4%), all as white solids, [m, 6 H, Si(CH₂CH₃)₃], 0.82 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃],

1

together with recovered 22 (7.2 mg, 13 µmol). 24: H NMR: δ ϭ 1.17 and 1.19 (2 ϫ s, 6 H, 17-H ϩ 19-H), 1.46 (s, 3 H, acetonide),

0.63 [q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 0.98 [t, J ϭ 7.9 Hz, 9 H, 1.53 (s, 3 H, acetonide), 1.66 (s, 3 H, 16-H), 1.78 (s, 3 H, 18-H),

Si(CH₂CH₃)₃], 1.19 (s, 3 H, 19-H), 1.24 (s, 3 H, 17-H), 1.42 (s, 3 2.30 (dd, J_gemϭ 15.7, J_14Ϫ13ϭ 4.0 Hz, 1 H, 14-H), 2.47 (dd, J_gemϭ

H, acetonide), 1.46 (s, 3 H, acetonide), 1.58 (s, 3 H, 16-H), 1.85 (s, 15.7, J_14Ϫ13ϭ 9.9 Hz, 1 H, 14-H), 3.36 (br. s, 1 H, 3-H), 4.45 (d,

3 H, 18-H), 2.40Ϫ2.51 (m, 2 H, 2 ϫ 14-H), 4.10 (d, J_9Ϫ10ϭ 9.4 Hz,

J_9Ϫ10ϭ 9.5 Hz, 1 H, 9-H), 4.53 (d, J_2ЈϪ3Јϭ 1.5 Hz, 1 H, 2Ј-H),

1 H, 9-H), 4.67 (m, 1 H, 13-H), 4.76 (d, J_10Ϫ9ϭ 9.4 Hz, 1 H, 10- 4.70 (d, J_10Ϫ9ϭ 9.5 Hz, 1 H, 10-H), 5.57Ϫ5.64 (m, 2 H, 2-H ϩ 4-

H), 4.96 (s, 1 H, 2-H), 5.92 (m, 1 H, 4-H) ppm. FAB-MS: m/z ϭ H/5-H), 5.73 (dd, J_3ЈϪNHϭ 8.8, J_3ЈϪ2Јϭ 1.5 Hz, 1 H, 3Ј-H), 5.97

519 [M ϩ H]^ϩ, 541 [M ϩ Na]^ϩ, 1038 [2 M ϩ H]^ϩ, 1060 [2 M ϩ

Na]^ϩ. C₂₉H₄₆O₆Si (518.8): calcd. C 67.14, H 8.94; found C 67.17,

H 9.07.

(m, 1 H, 13-H), 6.14 (m, 1 H, 4-H/5-H), 7.24Ϫ7.55 (m, 12 H, Ph

ϩ NH), 7.85 (m, 2 H, Ph), 8.26 (m, 2 H, Ph) ppm. FAB-MS:

m/z ϭ 864 [M ϩ H]^ϩ, 886 [M ϩ Na]^ϩ. C₅₁H₆₅NO₉Si (864.2): calcd.

C 70.89, H 7.58, N 1.62; found C 71.01, H 7.81, N 1.57.

Conversion of 23 into 26: Phenyllithium (1.8  solution in cyclohex-

ane/diethyl ether, 0.535 mL, 0.96 mmol) was added at Ϫ78 °C to a

stirred solution of 23 (200 mg, 0.386 mmol) in THF (4 mL). The

reaction mixture was stirred at Ϫ78 °C for 30 min, after which the

reaction was quenched by slow addition of a 10% aqueous citric

acid solution (10 mL). The mixture was allowed to warm to room

Conversion of 29 into 30: Tetrabutylammonium fluoride (1.0  solu-

tion in THF, 0.167 mL, 0.17 mmol) was added at room temperature

to a stirred solution of 29 (103 mg, 0.119 mmol) in THF (8 mL).

After 5 min, the reaction mixture was poured into water (20 mL).

The mixture was extracted twice with ethyl acetate (2 ϫ 20 mL).

temperature and extracted twice with ethyl acetate (2 ϫ 15 mL). The combined organic fractions were washed with brine, dried with

The combined organic fractions were washed with brine, dried with

anhydrous Na₂SO₄, filtered, and concentrated under reduced pres-

sure. Column chromatography (EtOAc/heptanes, 2:3) afforded 30

1

sure. Column chromatography (EtOAc/heptanes, 1:4) afforded 26

(82.2 mg, 0.110 mmol, 92%) as a white solid. H NMR: δ ϭ 1.17

1

(230 mg, 0.386 mmol, 100%) as a white solid. H NMR: δ ϭ 0.66 and 1.20 (2 ϫ s, 6 H, 17-H ϩ 19-H), 1.46 (s, 3 H, acetonide), 1.53

[q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 1.01 [t, J ϭ 7.9 Hz, 9 H, (s, 3 H, acetonide), 1.67 (s, 3 H, 16-H), 1.79 (s, 3 H, 18-H), 2.44

Si(CH₂CH₃)₃], 1.12 (s, 3 H, 19-H), 1.18 (s, 3 H, 17-H), 1.44 (s, 3

(dd, J_gemϭ 15.9, J_14Ϫ13ϭ 9.5 Hz, 1 H, 14-H), 2.56 (dd, J_gemϭ

H, acetonide), 1.51 (s, 3 H, acetonide), 1.65 (s, 3 H, 16-H), 1.88 (s, 15.9, J_14Ϫ13ϭ 3.8 Hz, 1 H, 14-H), 3.38 (br. s, 1 H, 3-H), 4.44 (d,

3 H, 18-H), 2.24 (dd, J_gemϭ 14.9, J_14Ϫ13ϭ 4.9 Hz, 1 H, 14-H), J_9Ϫ10ϭ 9.5 Hz, 1 H, 9-H), 4.63 (d, J_2ЈϪ3Јϭ 1.6 Hz, 1 H, 2Ј-H),

2.39 (dd, J_gemϭ 14.9, J_14Ϫ13ϭ 9.2 Hz, 1 H, 14-H), 3.29 (m, 1 H,

3-H), 4.39 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-H), 4.70 (d, J_10Ϫ9ϭ 9.6 Hz,

4.68 (d, J_10Ϫ9ϭ 9.5 Hz, 1 H, 10-H), 5.60 (m, 2 H, 2-H ϩ 4-H/5-

H), 5.84 (dd, J_3ЈϪNHϭ 9.4, J_3ЈϪ2Јϭ 1.6 Hz, 1 H, 3Ј-H), 6.06 (m,

1 H, 10-H), 4.81 (m, 1 H, 13-H), 5.44Ϫ5.51 (m, 2 H, 2-H ϩ 4-H/ 1 H, 13-H), 6.18 (m, 1 H, 4-H/5-H), 6.94 (d, J_NHϪ3Јϭ 9.4 Hz, 1

5-H), 5.73 (m, 1 H, 4-H/5-H), 7.46 (m, 2 H, Ph), 7.58 (m, 1 H, Ph), H, NH), 7.28Ϫ7.55 (m, 11 H, Ph), 7.80 (m, 2 H, Ph), 8.31 (m, 2

8.05 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 597 [M ϩ H]^ϩ, 619 [M

H, Ph) ppm. FAB-MS: m/z ϭ 750 [M ϩ H]^ϩ, 772 [M ϩ Na]^ϩ,

ϩ Na]^ϩ, 1216 [2 M ϩ Na]^ϩ. C₃₅H₅₂O₆Si (596.9): calcd. C 70.43, 1500 [2 M ϩ H], 1522 [2 M ϩ Na]. C₄₅H₅₁NO₉·0.5H₂O (758.9):

H 8.78; found C 70.37, H 8.84.

calcd. C 71.22, H 6.91, N 1.84; found C 70.97, H 6.99, N 1.93.

Conversion of 26 into 27: Tetrabutylammonium fluoride (1.0  solu-

tion in THF, 0.771 mL, 0.77 mmol) was added at room temperature

Conversion of 30 into 31: p-Toluenesulfonic acid monohydrate

(12.7 mg, 66.7 µmol) was added at room temperature to a stirred

to a solution of 26 (230 mg, 0.385 mmol) in THF (15 mL). After solution of 30 (50.0 mg, 66.7 µmol) in methanol (4 mL). After 3 h,

5 min, the solution was diluted with ethyl acetate (75 mL), washed

with a saturated aqueous NaHCO₃solution and brine, dried with

the reaction mixture was diluted with ethyl acetate (50 mL) and

washed with a saturated aqueous NaHCO₃solution. The aqueous

698

Eur. J. Org. Chem. 2003, 689Ϫ705

Semisynthesis of 7-Deoxypaclitaxel Derivatives Devoid of an Oxetane D-Ring

fraction was extracted with ethyl acetate (30 mL), and the com- of 36a or 36b (higher R_fvalue, 0.270 mmol, 32%), and 167 mg of

FULL PAPER

1

bined organic fractions were washed with brine, dried with anhyd-

rous Na₂SO₄, filtered, and concentrated under reduced pressure.

36b or 36a (lower R_fvalue, 0.250 mmol, 29%). 34: H NMR: δ ϭ

0.64 [q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 0.97 [t, J ϭ 7.9 Hz, 9 H,

Column chromatography (EtOAc/heptanes, 5:1) afforded 31 Si(CH₂CH₃)₃], 1.14 (s, 3 H, 19-H), 1.23 (s, 3 H, 17-H), 1.42 (s, 3

(37.4 mg, 53.3 µmol, 80%) as a white solid. ¹H NMR: δ ϭ 1.12

H, acetonide), 1.45 (s, 3 H, acetonide), 1.59 (s, 3 H, 16-H), 1.86 (s,

and 1.15 (2 ϫ s, 6 H, 17-H ϩ 19-H), 1.32 (s, 3 H, 16-H), 1.77 (s, 3 3 H, 18-H), 1.91 (s, 3 H, 20-H), 2.40 (dd, J_gemϭ 15.3, J_14Ϫ13

H, 18-H), 2.16 (dd, J_gemϭ 14.5, J_14Ϫ13ϭ 7.5 Hz, 1 H, 14-H), 2.39 3.6 Hz, 1 H, 14-H), 2.63 (dd, J_gemϭ 15.3, J_14Ϫ13ϭ 9.4 Hz, 1 H,

(dd, J_gemϭ 14.5, J_14Ϫ13ϭ 7.0 Hz, 1 H, 14-H), 2.73 (m, 1 H, 3-H), 14-H), 2.99 (br. s, 1 H, 3-H), 4.06 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-H),

4.22 (br. d, J_9Ϫ10ϭ 9.5 Hz, 1 H, 9-H), 4.36 (d, J_10Ϫ9ϭ 9.5 Hz, 1 4.60 (d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 4.76 (m, 1 H, 13-H), 4.77 (d,

ϭ

H, 10-H), 4.74 (d, J_2ЈϪ3Јϭ 2.7 Hz, 1 H, 2Ј-H), 5.35 (m, 1 H, 4-H/

J_2Ϫ3ϭ 4.3 Hz, 1 H, 2-H), 5.37 (br. s, 1 H, 5-H) ppm. FAB-MS: m/

5-H), 5.52 (m, 1 H, 4-H/5-H), 5.69 (d, J_2Ϫ3ϭ 8.2 Hz, 1 H, 2-H), z ϭ 532 [M]^ϩ, 555 [M ϩ Na]^ϩ, 647 [M ϩ TES]^ϩ, 1088 [2 M ϩ

5.75Ϫ5.80 (m, 2 H, 3Ј-H ϩ 13-H), 7.01 (d, J_NHϪ3Јϭ 9.1 Hz, 1 H, Na]^ϩ. C₃₀H₄₈O₆Si·H₂O (550.8): calcd. C 65.42, H 9.15; found C

NH), 7.27Ϫ7.57 (m, 11 H, Ph), 7.79 (m, 2 H, Ph), 8.06 (m, 2 H,

65.52, H 8.72. 35: ¹H NMR: δ ϭ 0.62 [q, J ϭ 7.9 Hz, 6 H,

Ph) ppm. FAB-MS: m/z ϭ 710 [M ϩ H]^ϩ, 732 [M ϩ Na]^ϩ. Si(CH₂CH₃)₃], 0.96 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.07 (s, 3

C₄₂H₄₇NO₉·1.5H₂O (736.9): calcd. C 68.46, H 6.84, N 1.90; found

C 68.58, H 6.84, N 1.96.

H, 19-H), 1.21 (s, 3 H, 17-H), 1.41 (s, 3 H, acetonide), 1.44 (s, 3

H, acetonide), 1.56 (s, 3 H, 16-H), 1.98 (s, 3 H, 18-H), 2.16 (dd,

J_gemϭ 15.3, J_14Ϫ13ϭ 4.0 Hz, 1 H, 14-H), 2.54 (dd, J_gemϭ 15.3,

J_14Ϫ13ϭ 9.4 Hz, 1 H, 14-H), 2.81 (d, J_3Ϫ2ϭ 5.5 Hz, 1 H, 3-H),

3.94 (d, J_9Ϫ10ϭ 9.4 Hz, 1 H, 9-H), 4.70Ϫ4.79 (d ϩ d ϩ m, 3 H,

2-H ϩ 9-H ϩ 13-H), 5.00 (br. s, 1 H, 20-H), 5.29 (br. s, 1 H, 20-

H). 36a or 36b (higher R_fvalue): ¹H NMR: δ ϭ 0.66 [q, J ϭ 7.9 Hz,

6 H, Si(CH₂CH₃)₃], 0.98 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.21

(s, 3 H, 17-H), 1.33 (s, 3 H, 19-H), 1.39 (s, 3 H, acetonide), 1.43 (s,

3 H, acetonide), 1.58 (s, 3 H, 16-H), 1.88 (s, 3 H, 18-H), 1.90 (s, 3

H, 20-H), 2.09 (d, J_3Ϫ2ϭ 4.3 Hz, 1 H, 3-H), 2.38 (dd, J_gemϭ 15.6,

Conversion of 21 into 32 and 33: Methyllithium (1.6  solution in

diethyl ether, 0.617 mL, 0.99 mmol) was slowly added at Ϫ78 °C

to a solution of 21 (440 mg, 0.823 mmol) in THF (18 mL). After

the addition of methyllithium had been completed, the reaction

mixture was stirred at Ϫ78 °C for 15 min. The reaction was

quenched by slow addition of a saturated aqueous NH₄Cl solution

(10 mL). The reaction mixture was allowed to warm to room tem-

perature, ethyl acetate (75 mL) and water (75 mL) were added, and

the resultant two layers were separated. The aqueous fraction was

extracted with ethyl acetate (50 mL), and the combined organic

fractions were washed with brine, dried with anhydrous Na₂SO₄,

filtered, and concentrated under reduced pressure. Column chro-

matography (EtOAc/heptanes, 2:7) yielded 32 (371 mg,

0.674 mmol, 82%) and 33 (19.6 mg, 34.6 µmol, 4%), both as a white

J_14Ϫ13ϭ 3.1 Hz, 1 H, 14-H), 2.62 (dd,, J_gemϭ 15.6, J_14Ϫ13

9.6 Hz 1 H, 14-H), 3.98 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-H), 4.62 (d,

_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 4.68 (d, J_2Ϫ3ϭ 4.3 Hz, 1 H, 2-H), 4.73

ϭ

J

(m, 1 H, 13-H) ppm. FAB-MS: m/z ϭ 666 [M]^ϩ, 781 [M ϩ TES]^ϩ,

1356 [2 M ϩ Na]^ϩ. C₃₁H₄₉O₈SF₃Si (666.9): calcd. C 55.83, H 7.41;

found C 55.63, H 7.28. 36b or 36a (lower R_fvalue): ¹H NMR: δ ϭ

0.65 [q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 0.98 [t, J ϭ 7.9 Hz, 9 H,

Si(CH₂CH₃)₃], 1.21 (s, 3 H, 17-H), 1.30 (s, 3 H, 19-H), 1.39 (s, 3

H, acetonide), 1.43 (s, 3 H, acetonide), 1.57 (s, 3 H, 16-H), 1.89 (s,

3 H, 18-H), 1.90 (s, 3 H, 20-H), 2.12 (d, J_3Ϫ2ϭ 4.4 Hz, 1 H, 3-H),

2.40 (dd, J_gemϭ 15.6, J_14Ϫ13ϭ 3.1 Hz, 1 H, 14-H), 2.63 (dd, J_gemϭ

15.6, J_14Ϫ13ϭ 9.6 Hz, 1 H, 14-H), 3.99 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-

H), 4.62 (d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 4.73 (d, J_2Ϫ3ϭ 4.4 Hz, 1

H, 2-H), 4.73 (m, 1 H, 13-H) ppm. FAB-MS: m/z ϭ 666 [M]^ϩ, 689

[M ϩ Na]^ϩ, 781 [M ϩ TES]^ϩ, 1356 [2 M ϩ Na]^ϩ. C₃₁H₄₉O₈SF₃Si

(666.9): calcd. C 55.83, H 7.41; found C 55.47, H 7.31.

1

solids. 32: H NMR: δ ϭ 0.64 [q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃],

0.97 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.04 (m, 1 H, 7-H), 1.20

(m, 1 H, 5-H), 1.22 (s, 3 H, 17-H), 1.38 (s, 3 H, 19-H), 1.39 (s, 3

H, acetonide), 1.42 (s, 3 H, acetonide), 1.46 (s, 3 H, 20-H), 1.47

(m, 1 H, 6-H), 1.57 (s, 3 H, 16-H), 1.72Ϫ1.93 (m, 3 H, 5-H ϩ 6-H

ϩ 7-H), 1.88 (s, 3 H, 18-H), 1.92 (d, J_3Ϫ2ϭ 4.5 Hz, 1 H, 3-H),

2.49 (dd, J_gemϭ 15.4, J_14Ϫ13ϭ 4.1 Hz, 1 H, 14-H), 2.58 (dd, J_gemϭ

15.4, J_14Ϫ13ϭ 8.9 Hz, 1 H, 14-H), 3.97 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-

H), 4.60 (d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 4.75 (m, 1 H, 13-H), 4.76

(d, J_2Ϫ3ϭ 4.5 Hz, 1 H, 2-H) ppm. FAB-MS: m/z ϭ 550 [M]^ϩ, 573

[M ϩ Na]^ϩ, 1102 [2 M ϩ H]^ϩ, 1124 [2 M ϩ Na]^ϩ. C₃₀H₅₀O₇Si

(550.8): calcd. C 65.42, H 9.15; found C 65.83, H 9.17. 33: ¹H

Conversion of 34 into 37: The same procedure as used for the pre-

NMR: δ ϭ 0.64 [q, 6 H, J ϭ 7.9 Hz, Si(CH₂CH₃)₃], 0.98 [t, 9 H, paration of 26 was applied. In this way, 85.0 mg of 34 (0.160 mmol)

J ϭ 7.9 Hz, Si(CH₂CH₃)₃], 1.11 (s, 3 H, 19-H), 1.28 (s, 3 H, 17-H),

afforded 78.2 mg of 37 (0.128 mmol, 80%) as a white solid. ¹H

1.39 (s, 3 H, acetonide), 1.45 (s, 3 H, acetonide), 1.57 (s, 3 H, 20- NMR: δ ϭ 0.67 [q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 1.00 [t, J ϭ

H), 1.59 (s, 3 H, 16-H), 1.85 (s, 3 H, 18-H), 2.10 (d, J_3Ϫ2ϭ 3.9 Hz, 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.11 and 1.16 (2 ϫ s, 6 H, 17-H ϩ 19-

1 H, 3-H), 2.16 [s, 3 H, C(O)CH₃], 2.27 (dd, J_gemϭ 15.3, J_14Ϫ13

ϭ

H), 1.44 (s, 3 H, acetonide), 1.51 (s, 3 H, acetonide), 1.70 (s, 3 H,

9.9 Hz, 1 H, 14-H), 2.44 (dd, J_gemϭ 15.3, J_14Ϫ13ϭ 3.9 Hz, 1 H, 16-H), 1.86 (s, 3 H, 18-H), 2.15 (s, 3 H, 20-H), 2.39 (dd, J_gem

14-H), 4.21 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-H), 4.67 (d, J_10Ϫ9ϭ 9.6 Hz, 15.2, J_14Ϫ13ϭ 9.7 Hz, 1 H, 14-H), 2.56 (dd, J_gemϭ 15.2, J_14Ϫ13

ϭ

1 H, 10-H), 4.75 (m, 1 H, 13-H), 5.48 (d, J_2Ϫ3ϭ 3.9 Hz, 1 H, 2-

H) ppm. ¹³C NMR: δ ϭ 4.8, 6.9, 17.1, 17.4, 19.8, 20.6, 21.7, 26.9, 1 H, 9-H), 4.67 (d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 4.81 (m, 1 H, 13-

27.3, 28.9, 30.9, 33.7, 39.3, 39.9, 43.1, 43.8, 49.4, 69.5, 74.0, 74.6, H), 5.37 (br. s, 1 H, 5-H), 5.82 (d, J_2Ϫ3ϭ 2.9 Hz, 1 H, 2-H), 7.45

4.0 Hz, 1 H, 14-H), 3.30 (br. s, 1 H, 3-H), 4.42 (d, J_9Ϫ10ϭ 9.6 Hz,

76.2, 78.2, 82.1, 106.7, 134.2, 144.7, 171.8 ppm. FAB-MS: m/z ϭ (m, 2 H, Ph), 7.57 (m, 1 H, Ph), 8.01 (m, 2 H, Ph) ppm. FAB-MS:

549 [M Ϫ OH]^ϩ, 566 [M]^ϩ, 589 [M ϩ H]^ϩ, 1156 [2 M ϩ Na]^ϩ. m/z ϭ 611 [M ϩ H]^ϩ, 633 [M ϩ Na]^ϩ, 725 [M ϩ TES]^ϩ, 1244 [2

C₃₁H₅₄O₇Si (566.8): calcd. C 65.69, H 9.60; found C 66.11, H 9.65.

M ϩ Na]^ϩ. C₃₆H₅₄O₆Si (610.9): calcd. C 70.78, H 8.91; found C

70.85, H 8.66.

Dehydration of 32 with Trifluoromethanesulfonyl Chloride, Giving a

Mixture of 34 and 35, 36a, and 36b: The same procedure as used

for the preparation of 23 and 24 from 22 was followed, except that

20, 10, and 0 equivalents of trifluoromethanesulfonyl chloride were

added at the beginning of the reaction, after 24 h, and after 30 h,

Conversion of 37 into 38: The same procedure as used for the pre-

paration of 27 was applied. In this way, 68.0 mg of 37 (0.111 mmol)

gave 46.2 mg of 38 (93.0 µmol, 84%) as a white solid. ¹H NMR:

δ ϭ 1.13 and 1.15 (2 ϫ s, 6 H, 17-H ϩ 19-H), 1.44 (s, 3 H, aceton-

respectively. In this way, 470 mg of 32 (0.853 mmol) afforded ide), 1.52 (s, 3 H, acetonide), 1.70 (s, 3 H, 16-H), 1.94 (s, 3 H, 18-

85.0 mg of a 10:1 mixture of 34 and 35 (0.160 mmol, 19%), 180 mg

H), 2.17 (s, 3 H, 20-H), 2.48 (dd, J_gemϭ 15.4, J_14Ϫ13ϭ 9.5 Hz, 1

Eur. J. Org. Chem. 2003, 689Ϫ705

699

H. W. Scheeren et al.

FULL PAPER

H, 14-H), 2.58 (dd, J_gemϭ 15.4, J_14Ϫ13ϭ 4.2 Hz, 1 H, 14-H), 3.30 [M]^ϩ, 629 [M ϩ Na]^ϩ, 679 [M ϩ TMS]^ϩ, 721 [M ϩ TES]^ϩ.

(br. s, 1 H, 3-H), 4.44 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-H), 4.66 (d, C₃₂H₅₄O₇Si₂(606.9): calcd. C 63.33, H 8.97; found C 62.93, H 8.67.

J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 4.83 (m, 1 H, 13-H), 5.38 (br. s, 1 H,

Conversion of 41 into 42: Diiodomethane (20.0 µL, 0.248 mmol)

5-H), 5.84 (d, J_2Ϫ3ϭ 3.1 Hz, 1 H, 2-H), 7.44 (m, 2 H, Ph), 7.57

and 41 (755 mg, 1.24 mmol) were added successively to a stirred

(m, 1 H, Ph), 8.01 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 519 [M ϩ

suspension of activated zinc^[34](244 mg, 3.73 mmol) in diethyl

Na]^ϩ. C₃₀H₄₀O₆·0.5H₂O (505.7): calcd. C 71.26, H 8.17; found C

ether/1,2-dimethoxyethane (1.5 mL, 4:1, v/v). The suspension was

71.04, H 8.05.

warmed to 50 °C, after which diiodomethane (0.301 mL,

Coupling of 38 to β-Lactam 28, Affording 39: The same procedure

as used for the preparation of 29 was applied. In this way, 39.8 mg

of 38 (80.1 µmol) gave 46.4 mg of 39 (52.8 mmol, 66%) after col-

umn chromatography (EtOAc/heptanes, 1:4). ¹H NMR: δ ϭ 0.44

3.73 mmol) was added. The reaction mixture was stirred at 50 °C

for 60 h, additional activated zinc (122 mg, 1.87 mmol) and diiodo-

methane (0.150 mL, 1.87 mmol) being added after 40 h. The reac-

tion mixture was cooled down to room temperature, diluted with

[m, 6 H, Si(CH₂CH₃)₃], 0.82 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], ethyl acetate (50 mL), and filtered through Celite^. The filter agent

1.20 (s, 6 H, 17-H ϩ 19-H), 1.45 (s, 3 H, acetonide), 1.53 (s, 3 H,

acetonide), 1.71 (s, 3 H, 16-H), 1.77 (s, 3 H, 18-H), 2.33 (s, 3 H,

20-H), 2.42 (dd, J_gemϭ 15.7, J_14Ϫ13ϭ 10.3 Hz, 1 H, 14-H), 2.66

was thoroughly rinsed with ethyl acetate (50 mL). The filtrate was

washed with a saturated aqueous NaHCO₃solution, water, and

brine, dried with anhydrous Na₂SO₄, filtered, and concentrated un-

(dd, J_gemϭ 15.7, J_14Ϫ13ϭ 4.2 Hz, 1 H, 14-H), 3.29 (br. s, 1 H, 3- der reduced pressure. Column chromatography (EtOAc/heptanes,

1

H), 4.51 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-H), 4.58 (d, J_2ЈϪ3Јϭ 1.6 Hz, 1 1:10) afforded 42 (447 mg, 0.720 mmol, 58%) as a white solid. H

H, 2Ј-H), 4.65 (d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 5.48 (br. s, 1 H, 5- NMR: δ ϭ 0.09 [s, 9 H, Si(CH₃)₃], 0.20 (dd, 1 H, 20-H), 0.61 [q,

H), 5.70 (dd, J_3ЈϪNHϭ 8.8, J_3ЈϪ2Јϭ 1.6 Hz, 1 H, 3Ј-H), 5.88 (d, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 0.96 [t, J ϭ 7.9 Hz, 9 H,

J_2Ϫ3ϭ 3.3 Hz, 1 H, 2-H), 6.16 (m, 1 H, 13-H), 7.24 (d, J_NHϪ3Ј

ϭ

Si(CH₂CH₃)₃], 0.96 (m, 1 H, 5-H), 1.05 (d, J_3Ϫ2ϭ 8.7 Hz, 1 H, 3-

H), 1.26 (dd, 1 H, 20-H), 1.34 and 1.36 and 1.37 and 1.41 (4 ϫ s,

12 H, 17-H ϩ 19-H ϩ 2 ϫ acetonide), 1.63 (s, 3 H, 16-H), 1.64

8.8 Hz, 1 H, NH), 7.26Ϫ7.57 (m, 11 H, Ph), 7.84 (m, 2 H, Ph),

8.11 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 877 [M]^ϩ, 900 [M ϩ Na]^ϩ,

993 [M ϩ TES]^ϩ. C₅₂H₆₇NO₉Si (878.2): calcd. C 71.12, H 7.69, N (dd, 1 H, 14-H), 1.80 (s, 3 H, 18-H), 2.38 (dd, J_gemϭ 13.4, J_14Ϫ13ϭ

1.59; found C 70.80, H 7.70, N 1.46.

5.9 Hz, 1 H, 14-H), 3.73 (d, J ϭ 10.1 Hz, 1 H, 9-H/10-H), 4.17 (d,

J ϭ 10.1 Hz, 1 H, 9-H/10-H), 4.70 (m, 1 H, 13-H), 4.80 (d, J_2Ϫ3ϭ

8.7 Hz, 1 H, 2-H) ppm. FAB-MS: m/z ϭ 621 [M ϩ H]^ϩ, 643 [M

ϩ Na]^ϩ, 693 [M ϩ TMS]^ϩ, 735 [M ϩ TES]^ϩ, 1242 [2 M ϩ H]^ϩ,

1264 [2 M ϩ Na]^ϩ. C₃₃H₅₆O₇Si₂(621.0): calcd. C 63.83, H 9.10;

found C 63.87, H 9.10.

Conversion of 39 into 40: The same procedure as used for the pre-

paration of 30 was applied. In this way, 32.6 mg of 39 (37.1 µmol)

gave 22.4 mg of 40 (29.3 µmol, 79%) as a white solid. ¹H NMR:

δ ϭ 1.18 and 1.20 (2 ϫ s, 6 H, 17-H ϩ 19-H), 1.44 (s, 3 H, aceton-

ide), 1.52 (s, 3 H, acetonide), 1.71 (s, 6 H, 16-H ϩ 18-H), 2.27 (s,

3 H, 20-H), 2.47 (dd, J_gemϭ 15.9, J_14Ϫ13ϭ 10.5 Hz, 1 H, 14-H),

2.74 (dd, J_gemϭ 15.9, J_14Ϫ13ϭ 3.9 Hz, 1 H, 14-H), 3.27 (br. s, 1

H, 3-H), 3.32 (br. s, 1 H, 2Ј-OH), 4.49 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-

Conversion of 42 into 43: Phenyllithium (1.8  solution in cyclohex-

ane/diethyl ether, 2.00 mL, 3.6 mmol) was added at Ϫ78 °C to a

stirred solution of 42 (447 mg, 0.720 mmol) in THF (20 mL). The

H), 4.63 (d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 4.69 (br. s, 1 H, 2Ј-H), reaction mixture was stirred at Ϫ78 °C for 2.5 h. The reaction was

5.43 (br. s, 1 H, 5-H), 5.79 (dd, J_3ЈϪNHϭ 9.0, J_3ЈϪ2Јϭ 2.1 Hz, 1 quenched by slow addition of a saturated aqueous NH₄Cl solution

H, 3Ј-H), 5.87 (d, J_2Ϫ3ϭ 3.3 Hz, 1 H, 2-H), 6.16 (m, 1 H, 13-H), (25 mL). The mixture was allowed to warm to room temperature

6.98 (d, J_NHϪ3Јϭ 9.0 Hz, 1 H, NH), 7.31Ϫ7.57 (m, 11 H, Ph), 7.80

and extracted twice with ethyl acetate (2 ϫ 50 mL). The combined

(m, 2 H, Ph), 8.10 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 786 [M ϩ organic fractions were washed with a saturated aqueous NaHCO₃

Na]^ϩ. C₄₆H₅₃NO₉·2H₂O (800.0): calcd. C 69.07, H 7.18, N 1.75;

found C 69.12, H 6.79, N 1.44.

solution, water, and brine, dried with Na₂SO₄, filtered, and concen-

trated under reduced pressure. Column chromatography (EtOAc/

heptanes, 1:10) yielded 43 (432 mg, 0.618 mmol, 86%) as a white

Conversion of 21 into 41: A solution of lithium diisopropylamide,

prepared from diisopropylamine (57.0 µL, 0.407 mmol) and butylli-

thium (1.6  solution in hexane, 0.236 mL, 0.38 mmol) in THF

(0.234 mL) at 0 °C, was added at Ϫ78 °C to a solution of 21

(101 mg, 0.189 mmol) in THF (2 mL). After 10 min, trimethylsilyl

chloride (0.240 mL, 1.89 mmol) was added. The reaction mixture

was stirred for 1 h, the reaction temperature gradually being raised

to Ϫ20 °C, and then diluted with diethyl ether (10 mL). The reac-

tion was quenched by addition of a saturated aqueous NH₄Cl solu-

tion (10 mL). The aqueous layer was separated from the organic

layer and extracted with diethyl ether (10 mL). The combined or-

ganic fractions were washed with water and brine, dried with an-

hydrous Na₂SO₄, filtered, and concentrated under reduced pres-

sure. Column chromatography (EtOAc/heptanes/triethylamine,

15:75:1) yielded 41 (106 mg, 0.175 mmol, 92%) as a white solid.

1

solid. H NMR: δ ϭ Ϫ0.32 [s, 9 H, Si(CH₃)₃], 0.26 (dd, 1 H, 20-

H), 0.65 [q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 0.65 (m, 1 H, 6-H),

0.87 (dd, J_gemϭ 5.8, J_20Ϫ5ϭ 9.3 Hz, 1 H, 20-H), 1.02 [t, J ϭ

7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.09 (s, 3 H, 17-H), 1.21 (s, 3 H, 16-

H), 1.22 (m, 1 H, 5-H), 1.26 (d, J_3Ϫ2ϭ 8.4 Hz, 1 H, 3-H), 1.36 (m,

1 H, 7-H), 1.42 (s, 3 H, acetonide), 1.42 (s, 3 H, 19-H), 1.45 (s, 3

H, acetonide), 1.81 (s, 3 H, 18-H), 1.85 (m, 1 H, 7-H), 2.07 (m, 1

H, 6-H), 2.15 (dd, J_gemϭ 14.0, J_14Ϫ13ϭ 7.0 Hz, 1 H, 14-H), 2.24

(dd, J_gemϭ 14.0, J_14Ϫ13ϭ 6.5 Hz, 1 H, 14-H), 4.17 (d, J_10Ϫ9

ϭ

9.9 Hz, 1 H, 10-H), 4.31 (d, J_9Ϫ10ϭ 9.9 Hz, 1 H, 9-H), 4.58 (m, 1

H, 13-H), 6.02 (d, J_2Ϫ3ϭ 8.4 Hz, 1 H, 2-H), 7.40 (m, 2 H, Ph),

7.52 (m, 1 H, Ph), 8.04 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 698

[M]^ϩ, 721 [M ϩ Na]^ϩ, 771 [M ϩ TMS]^ϩ, 1420 [2 M ϩ Na]^ϩ.

C₃₉H₆₂O₇Si₂(699.1): calcd. C 67.01, H 8.94; found C 66.95, H 8.84.

¹H NMR: δ ϭ 0.19 [s, 9 H, Si(CH₃)₃], 0.64 [q, J ϭ 7.9 Hz, 6 H, Conversion of 43 into 44: Tetrabutylammonium fluoride (1.0  solu-

Si(CH₂CH₃)₃], 0.98 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.18 and tion in THF, 1.80 mL, 1.8 mmol) was added at room temperature

1.24 (2 ϫ s, 6 H, 17-H ϩ 19-H), 1.41 (s, 3 H, acetonide), 1.44 (s, 3

to a stirred solution of 43 (420 mg, 0.601 mmol) in THF (20 mL).

H, acetonide), 1.55 (s, 3 H, 16-H), 1.88 (s, 3 H, 18-H), 2.47 (dd, After 30 min, the reaction mixture was poured into water (100 mL).

J_gemϭ 15.1, J_14Ϫ13ϭ 9.3 Hz, 1 H, 14-H), 2.72 (dd, J_gemϭ 15.1, The resultant mixture was extracted twice with ethyl acetate (2 ϫ

J_14Ϫ13ϭ 4.7 Hz, 1 H, 14-H), 3.14 (br. s, 1 H, 3-H), 4.02 (d, J_9Ϫ10ϭ 100 mL). The combined organic fractions were washed with brine,

9.6 Hz, 1 H, 9-H), 4.60 (d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 4.66 (m, 2 dried with anhydrous Na₂SO₄, filtered, and concentrated under re-

H, 2-H ϩ 5-H), 4.83 (m, 1 H, 13-H) ppm. FAB-MS: m/z ϭ 606

duced pressure. Column chromatography (EtOAc/heptanes, 3:2)

700

Eur. J. Org. Chem. 2003, 689Ϫ705

Semisynthesis of 7-Deoxypaclitaxel Derivatives Devoid of an Oxetane D-Ring

FULL PAPER

gave 44 (178 mg, 0.347 mmol, 58%) as a white solid. ¹H NMR: δ ϭ

Ph) ppm. FAB-MS: m/z ϭ 780 [M ϩ H]^ϩ, 802 [M ϩ Na]^ϩ, 1560

0.23 (m, 1 H, 20-H), 0.75Ϫ0.95 (m, 2 H, 5-H ϩ 20-H), 1.09 (s, 3 [M ϩ H]^ϩ, 1582 [M ϩ Na]^ϩ. C₄₆H₅₃NO₁₀·0.5H₂O (788.9): calcd.

H, 17-H), 1.22 (s, 3 H, 16-H), 1.39 (d, J_3Ϫ2ϭ 8.7 Hz, 1 H, 3-H),

1.44 and 1.46 and 1.48 (3 ϫ s, 9 H, 19-H ϩ 2 ϫ acetonide), 1.90

(s, 3 H, 18-H), 2.14 (dd, J_gemϭ 14.1, J_14Ϫ13ϭ 7.3 Hz, 1 H, 14-H),

2.43 (dd, J_gemϭ 14.1, J_14Ϫ13ϭ 6.7 Hz, 1 H, 14-H), 4.23 (d, J ϭ

9.8 Hz, 1 H, 9-H/10-H), 4.41 (d, J ϭ 9.8 Hz, 1 H, 9-H/10-H), 4.69

(m, 1 H, 13-H), 6.11 (d, J_2Ϫ3ϭ 8.7 Hz, 1 H, 2-H), 7.42 (m, 2 H,

Ph), 7.52 (m, 1 H, Ph), 8.03 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ

513 [M ϩ H]^ϩ, 535 [M ϩ Na]^ϩ, 1026 [2 M ϩ H]^ϩ, 1048 [2 M ϩ

Na]^ϩ. C₃₀H₄₀O₇(512.6): calcd. C 70.29, H 7.86; found C 70.21,

H 7.92.

C 70.03, H 6.90, N 1.78; found C 69.91, H 7.03, N 2.22.

Conversion of 47 into 48, 49, and 50: Pyridinium chlorochromate

(3.63 g, 16.9 mmol) in dichloromethane (100 mL) was added at

room temperature to a stirred solution of 47 (2.78 g, 5.62 mmol)

in dichloromethane (30 mL). After 3.5 h, the reaction mixture was

diluted with diethyl ether (100 mL) and filtered through Celite^.

The filter agent was rinsed with diethyl ether (50 mL). The filtrate

was washed with brine, dried with anhydrous Na₂SO₄, filtered, and

concentrated under reduced pressure. Column chromatography

(EtOAc/heptanes, 2:5) gave 48 (141 mg, 0.286 mmol, 5%), 49

Coupling of 44 to β-Lactam 28, Affording 45: Sodium bis(trimethyl-

silyl)amide (1.0  solution in THF, 0.488 mL, 0.49 mmol) was ad- white solids. 48: H NMR: δ ϭ 1.21 (s, 3 H, 19-H), 1.40 (s, 3 H,

ded at Ϫ78 °C to a stirred solution of 44 (100 mg, 0.195 mmol) 17-H), 1.48 (s, 3 H, acetonide), 1.54 (s, 3 H, acetonide), 1.72 (s, 3

(1.23 g, 2.42 mmol, 43%), and 50 (57.3 mg, 0.112 mmol, 2%), all as

1

and β-lactam 28 (149 mg, 0.390 mmol) in THF (5 mL). The reac-

tion mixture was stirred at Ϫ78 °C for 45 min. Subsequently, the

H, 16-H), 1.95 (s, 3 H, 18-H), 2.84 (d, J_gemϭ 19.7 Hz, 1 H, 14-H),

3.01 (m, 1 H, 3-H), 3.94 (d, J_gemϭ 19.7 Hz, 1 H, 14-H), 4.35 (d,

reaction was quenched by slow addition of a saturated aqueous J_2Ϫ3ϭ 4.1 Hz, 1 H, 2-H), 4.48 (d, J_9Ϫ10ϭ 9.6 Hz, 1 H, 9-H), 4.70

NH₄Cl solution (5 mL). The mixture was allowed to warm to room

temperature. Water (20 mL) and ethyl acetate (20 mL) were added.

(d, J_10Ϫ9ϭ 9.6 Hz, 1 H, 10-H), 5.76 (s, 1 H, PhCH), 6.55 (m, 1 H,

5-H), 7.35Ϫ7.47 (m, 5 H, Ph), 9.49 (s, 1 H, CHO) ppm. FAB-MS:

The aqueous layer was separated from the organic layer and ex- m/z ϭ 492 [M]^ϩ, 515 [M ϩ Na]^ϩ, 986 [2 M ϩ H]^ϩ, 1008 [2 M ϩ

tracted with ethyl acetate (20 mL). The combined organic fractions

were washed with a saturated aqueous NaHCO₃solution, water,

and brine, dried with anhydrous Na₂SO₄, filtered, and concentrated

under reduced pressure. Column chromatography (EtOAc/hept-

anes, 2:5) yielded 45 (79.2 mg, 88.6 µmol, 45%) as a white solid.

¹H NMR: δ ϭ 0.30 (m, 1 H, 20-H), 0.50 [m, 6 H, Si(CH₂CH₃)₃],

Na]^ϩ. C₃₀H₃₆O₆(492.6): calcd. C 73.15, H 7.37; found C 72.99, H

1

7.39. 49: H NMR: δ ϭ 1.30 and 1.35 (2 ϫ s, 3 H, 17-H ϩ 19-H),

1.45 (s, 3 H, acetonide), 1.52 (s, 3 H, acetonide), 1.68 (s, 3 H, 16-

H), 1.93 (s, 3 H, 18-H), 2.05 (d, J_3Ϫ2ϭ 6.7 Hz, 1 H, 3-H), 2.63 (d,

J_gemϭ 19.7 Hz, 1 H, 14-H), 2.72 (d, J_gemϭ 19.7 Hz, 1 H, 14-H),

3.05 (d, J_5Ϫ6ϭ 3.6 Hz, 1 H, 5-H), 4.33 (d, J_9Ϫ10ϭ 9.3 Hz, 1 H, 9-

0.87 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 0.95 (m, 2 H, 5-H ϩ 20- H), 4.39 (d, J_2Ϫ3ϭ 6.7 Hz, 1 H, 2-H), 4.70 (d, 1 H, J_10Ϫ9ϭ 9.3 Hz,

H), 1.12 (s, 3 H, 17-H), 1.20 (s, 3 H, 16-H), 1.39 (d, J_3Ϫ2ϭ 8.6 Hz, 10-H), 5.96 (s, 1 H, PhCH), 7.35 (m, 5 H, Ph), 9.57 (s, 1 H, CHO)

1 H, 3-H), 1.43 and 1.43 and 1.48 (3 ϫ s, 9 H, 19-H ϩ 2 ϫ aceton-

ppm. ¹³C NMR: δ ϭ 14.4, 18.6, 19.7, 20.2, 25.6, 26.7, 27.1, 33.5,

ide), 1.64 (s, 3 H, 18-H), 2.32 (dd, J_gemϭ 14.2, J_14Ϫ13ϭ 7.4 Hz, 1 36.2, 41.6, 45.7, 47.5, 57.7, 63.6, 75.7, 77.2, 81.3, 84.7, 102.4, 108.3,

H, 14-H), 2.45 (dd, J_gemϭ 14.2, J_14Ϫ13ϭ 6.9 Hz, 1 H, 14-H), 4.16 126.0, 128.5, 129.2, 137.1, 141.4, 151.4, 193.5, 198.6 ppm. FAB-

(d, J ϭ 9.8 Hz, 1 H, 9-H/10-H), 4.43 (d, J ϭ 9.8 Hz, 1 H, 9-H/10-

MS: m/z ϭ 509 [M ϩ H]^ϩ, 531 [M ϩ Na]^ϩ, 1039 [2 M ϩ Na]^ϩ.

H), 4.64 (d, J_2ЈϪ3Јϭ 1.9 Hz, 1 H, 2Ј-H), 5.65 (dd, J_3ЈϪNHϭ 8.7, C₃₀H₃₆O₇·0.25H₂O (513.1): calcd. C 70.22, H 7.17; found C 69.95,

J_3ЈϪ2Јϭ 1.9 Hz, 1 H, 3Ј-H), 5.70 (m, 1 H, 13-H), 6.12 (d, J_2Ϫ3

ϭ

H 6.85. 50: ¹H NMR: δ ϭ 1.19 (s, 3 H, 19-H), 1.39 (s, 3 H, 17-H),

8.6 Hz, 1 H, 2-H), 7.26Ϫ7.56 (m, 12 H, Ph ϩ NH), 7.83 (m, 2 H,

1.45 (s, 3 H, acetonide), 1.51 (s, 3 H, acetonide), 1.68 (s, 3 H, 16-

Ph), 7.98 (m, 2 H, Ph) ppm. ¹³C NMR: δ ϭ 4.4, 6.6, 11.5, 19.7, H), 1.96 (s, 3 H, 18-H), 2.32 (d, J_3Ϫ2ϭ 4.6 Hz, 1 H, 3-H), 2.90 (d,

22.1, 23.7, 24.0, 24.4, 26.6, 26.9, 27.9, 28.9, 35.3, 38.2, 49.0, 55.5,

56.0, 69.6, 69.9, 72.0, 75.5, 76.5, 81.0, 81.9, 108.6, 126.6, 127.0, 3.14 (br. s, 1 H, 5-H), 3.22 (br. d, J_gemϭ 12.6 Hz, 1 H, 20-H), 4.07

127.7, 128.4, 128.4, 128.7, 129.4, 131.1, 131.7, 132.6, 134.3, 136.2, (br. d, J_gemϭ 12.6 Hz, 1 H, 20-H), 4.30 (d, J_9Ϫ10ϭ 9.3 Hz, 1 H,

138.9, 147.3, 166.2, 166.4, 171.6 ppm. FAB-MS: m/z ϭ 894 [M 9-H), 4.42 (d, J_2Ϫ3ϭ 4.6 Hz, 1 H, 2-H), 4.68 (d, J_10Ϫ9ϭ 9.3 Hz,

ϩ H]^ϩ, 916 [M ϩ Na]^ϩ, 1788 [2 M ϩ H]^ϩ, 1810 [2 M ϩ Na]^ϩ.

1 H, 10-H), 5.84 (s, 1 H, PhCH), 7.44 (m, 5 H, Ph) ppm. FAB-MS:

J_gemϭ 19.5 Hz, 1 H, 14-H), 2.97 (d, J_gemϭ 19.5 Hz, 1 H, 14-H),

C₅₂H₆₇NO₁₀Si·0.5H₂O (903.2): calcd. C 69.15, H 7.59, N 1.55; m/z ϭ 511 [M ϩ H]^ϩ, 533 [M ϩ Na]^ϩ, 1021 [2 M ϩ H]^ϩ, 1043 [2 M

found C 69.25, H 7.55, N 1.42.

ϩ Na]^ϩ. C₃₀H₃₈O₇·0.5H₂O (519.6): calcd. C 69.34, H 7.56; found C

69.27, H 7.68.

Conversion of 45 into 46: Tetrabutylammonium fluoride (1.0  solu-

tion in THF, 0.116 mL, 0.12 mmol) was added at room temperature

Conversion of 47 into 51: A solution of dimethyl sulfoxide

to a stirred solution of 45 (69.3 mg, 77.5 µmol) in THF (3 mL). (0.241 mL, 3.40 mmol) in dichloromethane (0.5 mL) was added at

After 5 min, the reaction mixture was poured into water (20 mL).

The mixture was extracted twice with ethyl acetate (2 ϫ 15 mL).

The combined organic fractions were washed with brine, dried with

anhydrous Na₂SO₄, filtered, and concentrated under reduced pres-

sure. Column chromatography (EtOAc/heptanes, 1:1) gave 46

(46.1 mg, 59.1 µmol, 76%) as a white solid. ¹H NMR: δ ϭ 0.35 (br.

Ϫ50 °C to a stirred solution of oxalyl chloride (0.141 mL,

1.62 mmol) in dichloromethane (2 mL). After 10 min, the reaction

mixture was allowed to warm to Ϫ10 °C, and 47 (100 mg,

0.202 mmol) in dichloromethane (0.8 mL) was added slowly. The

resultant mixture was stirred at Ϫ10 °C for 20 min, treated with

triethylamine (0.564 mL, 4.04 mmol), stirred at Ϫ10 °C for 20 min,

s, 1 H, 20-H), 0.81Ϫ1.02 (m, 2 H, 5-H ϩ 20-H), 1.13 (s, 3 H, 17- allowed to warm to room temperature, and stirred for another

H), 1.21 (s, 3 H, 16-H), 1.41 (d, J_3Ϫ2ϭ 8.6 Hz, 1 H, 3-H), 1.44 20 min. The reaction mixture was diluted with dichloromethane

and 1.46 and 1.49 (3 ϫ s, 9 H, 19-H ϩ 2 ϫ acetonide), 1.77 (s, 3

(10 mL), washed with water and brine, dried with anhydrous

H, 18-H), 2.40 (dd, J_gemϭ 14.5, J_14Ϫ13ϭ 7.2 Hz, 1 H, 14-H), 2.48 Na₂SO₄, filtered, and concentrated under reduced pressure. Col-

(dd, J_gemϭ 14.5, J_14Ϫ13ϭ 6.9 Hz, 1 H, 14-H), 4.23 (d, J ϭ 9.8 Hz,

umn chromatography (EtOAc/heptanes, 1:6) gave 51 (21.8 mg, 42.5

1 H, 9-H/10-H), 4.43 (d, J ϭ 9.8 Hz, 1 H, 9-H/10-H), 4.72 (d, µmol, 21%) as a white solid. ¹H NMR: δ ϭ 1.20 (s, 3 H, 19-H),

J_2ЈϪ3Јϭ 2.2 Hz, 1 H, 2Ј-H), 5.76Ϫ5.82 (m, 2 H, 3Ј-H ϩ 13-H), 1.40 (s, 3 H, 17-H), 1.48 (s, 3 H, acetonide), 1.54 (s, 3 H, acetonide),

6.14 (d, J_2Ϫ3ϭ 8.6 Hz, 1 H, 2-H), 7.00 (d, J_NHϪ3Јϭ 9.1 Hz, 1 H, 1.72 (s, 3 H, 16-H), 1.97 (s, 3 H, 18-H), 2.90 (d, J_gemϭ 19.6 Hz, 1

NH), 7.23Ϫ7.54 (m, 11 H, Ph), 7.78 (m, 2 H, Ph), 8.03 (m, 2 H,

H, 14-H), 2.99 (m, 1 H, 3-H), 3.55 (d, J_gemϭ 19.6 Hz, 1 H, 14-H),

Eur. J. Org. Chem. 2003, 689Ϫ705

701

H. W. Scheeren et al.

FULL PAPER

4.04 (d, J_gemϭ 11.0 Hz, 1 H, 20-H), 4.43 (d, J_2Ϫ3ϭ 4.0 Hz, 1 H,

1 H, 9-H), 4.19 (d, J_2Ϫ3ϭ 4.6 Hz, 1 H, 2-H), 4.61 (m, 1 H, 13-H),

2-H), 4.46 (d, J_9Ϫ10ϭ 9.5 Hz, 1 H, 9-H), 4.72 (d, J_10Ϫ9ϭ 9.5 Hz, 4.64 (d, J_10Ϫ9ϭ 9.3 Hz, 1 H, 10-H), 5.72 (s, 1 H, PhCH), 7.39 (m,

1 H, 10-H), 4.92 (d, J_gemϭ 11.0 Hz, 1 H, 20-H), 5.75 (s, 1 H,

3 H, Ph), 7.50 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 549 [M ϩ Na]^ϩ,

PhCH), 5.92 (m, 1 H, 5-H), 7.39Ϫ7.50 (m, 5 H, Ph) ppm. ¹³C 1076 [2 M ϩ Na]^ϩ. C₃₁H₄₂O₇·0.25H₂O (531.2): calcd. C 70.10, H

NMR: δ ϭ 14.1, 18.1, 20.3, 23.0, 26.6, 26.8, 27.2, 34.0, 38.4, 40.6, 8.06; found C 69.77, H 8.03.

43.0, 45.8, 50.7, 75.7, 80.8, 82.1, 85.1, 103.4, 108.2, 127.0, 128.6,

Conversion of 53 into 54: Chlorotriethylsilane (0.161 mL,

129.7, 132.9, 135.1, 137.0, 141.5, 152.8, 199.8 ppm. FAB-MS: m/

0.959 mmol) was added at room temperature to a stirred solution

z ϭ 513 [M ϩ H]^ϩ. C₃₀H₃₇ClO₅(513.1): calcd. C 70.23, H 7.27;

of imidazole (170 mg, 2.49 mmol) in DMF (4 mL). After 20 min,

found C 70.24, H 7.32.

53 (101 mg, 0.192 mmol) in DMF (3 mL) was added. After 2 h, the

Conversion of 49 into 50: Sodium borohydride (36.6 mg,

0.967 mmol) was added at 0 °C in small portions to a stirred solu-

tion of 49 (1.23 g, 2.42 mmol) in methanol (100 mL). The reaction

mixture was stirred at 0 °C for 1 h, additional sodium borohydride

(36.6 mg, 0.967 mmol) being added after 30 min. The reaction was

quenched by slow addition of a saturated aqueous NH₄Cl solution

(50 mL). The resultant mixture was concentrated to 75 mL under

reaction mixture was diluted with water (25 mL) and extracted

twice with ethyl acetate (2 ϫ 30 mL). The combined organic frac-

tions were washed with brine, dried with anhydrous Na₂SO₄, fil-

tered, and concentrated under reduced pressure. Column chroma-

tography (EtOAc/heptanes/dichloromethane, 1:2:2) gave 54

(119 mg, 0.186 mmol, 97%) as a white solid. ¹H NMR: δ ϭ 0.63

[q, J ϭ 7.9 Hz, 6 H, Si(CH₂CH₃)₃], 0.99 [t, J ϭ 7.9 Hz, 9 H,

reduced pressure and then extracted three times with ethyl acetate Si(CH₂CH₃)₃], 1.16 and 1.21 (2 ϫ s, 6 H, 17-H ϩ 19-H), 1.42 (s, 3

(3 ϫ 50 mL). The combined organic fractions were washed with

brine, dried with anhydrous Na₂SO₄, filtered, and concentrated un-

der reduced pressure. Column chromatography (EtOAc/heptanes,

1:2) afforded 50 (950 mg, 1.86 mmol, 77%) as a white solid.

H, acetonide), 1.46 (s, 3 H, acetonide), 1.59 (s, 3 H, 16-H), 1.89 (s,

3 H, 18-H), 2.11 (dd, J_gemϭ 15.2, J_14Ϫ13ϭ 5.1 Hz, 1 H, 14-H),

2.29 (d, J_3Ϫ2ϭ 5.4 Hz, 1 H, 3-H), 2.42 (dd, J_gemϭ 15.2, J_14Ϫ13

ϭ

9.2 Hz, 1 H, 14-H), 3.14 (s, 3 H, OCH₃), 3.41 (m, 1 H, 5-H), 3.63

(d, J_gemϭ 12.0 Hz, 1 H, 20-H), 3.88 (d, J_gemϭ 12.0 Hz, 1 H, 20-

H), 4.13 (d, 1 H, J_9Ϫ10ϭ 9.5 Hz, 9-H), 4.13 (d, J_2Ϫ3ϭ 5.4 Hz, 1

H, 2-H), 4.65 (d, J_10Ϫ9ϭ 9.5 Hz, 1 H, 10-H), 4.76 (m, 1 H, 13-H),

5.73 (s, 1 H, PhCH), 7.40 (m, 3 H, Ph), 7.51 (m, 2 H, Ph) ppm.

FAB-MS: m/z ϭ 641 [M ϩ H]^ϩ, 663 [M ϩ Na]^ϩ. C₃₇H₅₆O₇Si

(640.9): calcd. C 69.34, H 8.81; found C 69.12, H 8.75.

Conversion of 50 into 52: Sodium hydride (179 mg, 7.44 mmol) and

methyl iodide (1.16 mL, 18.6 mmol) were added successively at 0

°C to a stirred solution of 50 (950 mg, 1.86 mmol) in THF (30 mL).

The reaction mixture was stirred at room temperature for 3 h. The

reaction was quenched by slow addition of a saturated aqueous

NH₄Cl solution (30 mL). The resultant mixture was extracted twice

with ethyl acetate (2 ϫ 40 mL). The combined organic fractions

were washed with brine, dried with anhydrous Na₂SO₄, filtered,

and concentrated under reduced pressure. Column chromatography

(EtOAc/heptanes, 2:5) gave 52 (677 mg, 1.29 mmol, 69%) as a white

Conversion of 54 into 55: tert-Butyl hydroperoxide (5.0Ϫ6.0  solu-

tion in decane, 0.161 mL, min. 0.81 mmol) was added at room tem-

perature to a solution of 54 (51.7 mg, 80.7 µmol) and palladium()

acetate (3.6 mg, 16 µmol) in toluene (1 mL). The reaction mixture

solid. ¹H NMR: δ ϭ 1.17Ϫ1.27 (m, 2 H, 6-H ϩ 7-H), 1.19 (s, 3 H, was stirred at 70 °C for 20 h, additional tert-butyl hydroperoxide

19-H), 1.36 (s, 3 H, 17-H), 1.45 (s, 3 H, acetonide), 1.50 (s, 3 H,

(5.0Ϫ6.0  solution in decane, 0.161 mL, min. 0.81 mmol) being

acetonide), 1.66 (s, 3 H, 16-H), 1.76 (m, 1 H, 7-H), 1.93 (m, 1 H, added after 12 h. The reaction mixture was cooled down to room

6-H), 1.94 (s, 3 H, 18-H), 2.12 (d, J_3Ϫ2ϭ 5.3 Hz, 1 H, 3-H), 2.83 temperature, and water (5 mL) and ethyl acetate (5 mL) were ad-

(d, J_gemϭ 19.5 Hz, 1 H, 14-H), 3.00 (d, J_gemϭ 19.5 Hz, 1 H, 14-H),

3.10 (s, 3 H, OCH₃), 3.36 (m, 1 H, 5-H), 3.59 (d, J_gemϭ 11.7 Hz, 1 extracted with ethyl acetate (5 mL). The combined organic frac-

H, 20-H), 3.75 (d, J_gemϭ 11.7 Hz, 1 H, 20-H), 4.29 (d, J_9Ϫ10tions were washed with brine, dried with anhydrous Na₂SO₄, fil-

ded. The aqueous layer was separated from the organic layer and

ϭ

9.3 Hz, 1 H, 9-H), 4.31 (d, J_2Ϫ3ϭ 5.3 Hz, 1 H, 2-H), 4.68 (d, tered, and concentrated under reduced pressure. Column chroma-

J_10Ϫ9ϭ 9.3 Hz, 1 H, 10-H), 5.80 (s, 1 H, PhCH), 7.41 (m, 3 H, tography (EtOAc/heptanes, 1:8) afforded 55 (18.6 mg, 28.3 µmol,

Ph), 7.48 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 524 [M]^ϩ, 547 [M ϩ

Na]^ϩ, 1072 [2 M ϩ Na]^ϩ. C₃₁H₄₀O₇·1.25H₂O (547.2): calcd. C

68.05, H 7.83; found C 67.87, H 7.36.

35%) as a white solid. ¹H NMR: δ ϭ 0.70 [q, J ϭ 7.9 Hz, 6 H,

Si(CH₂CH₃)₃], 1.05 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.15 and

1.20 (2 ϫ s, 6 H, 17-H ϩ 19-H), 1.44 (s, 3 H, acetonide), 1.50 (s, 3

H, acetonide), 1.63 (s, 3 H, 16-H), 1.90 (s, 3 H, 18-H), 2.34 (dd,

Conversion of 52 into 53: Sodium borohydride (111 mg, 2.94 mmol)

was added at 0 °C to a stirred solution of 52 (386 mg, 0.736 mmol)

and cerium() chloride heptahydrate (1.10 g, 2.94 mmol) in meth-

anol (50 mL). The reaction mixture was stirred at 0 °C for 30 min.

The reaction was quenched by slow addition of a 10% aqueous

citric acid solution (25 mL). The resultant mixture was concen-

trated to 35 mL under reduced pressure, diluted with water

(15 mL), and then extracted three times with ethyl acetate (3 ϫ

50 mL). The combined organic fractions were washed with a satur-

ated aqueous NaHCO₃solution and brine, dried with anhydrous

Na₂SO₄, filtered, and concentrated under reduced pressure. Col-

J

_gemϭ 15.2, J_14Ϫ13ϭ 9.3 Hz, 1 H, 14-H), 2.54 (m, 2 H, 3-H ϩ 14-

H), 2.96 (s, 3 H, OCH₃), 3.36 (m, 1 H, 5-H), 3.41 (d, J_gem

ϭ

11.2 Hz, 1 H, 20-H), 3.48 (d, J_gemϭ 11.2 Hz, 1 H, 20-H), 4.25 (d,

1 H, J_9Ϫ10ϭ 9.4 Hz, 9-H), 4.66 (d, J_10Ϫ9ϭ 9.4 Hz, 1 H, 10-H),

4.79 (m, 1 H, 13-H), 5.70 (d, J_2Ϫ3ϭ 6.1 Hz, 1 H, 2-H), 7.47 (m, 2

H, Ph), 7.58 (m, 1 H, Ph), 8.10 (m, 2 H, Ph) ppm. FAB-MS: m/

z ϭ 657 [M ϩ H]^ϩ, 679 [M ϩ Na]^ϩ.

Conversion of 55 into 56: Tetrabutylammonium fluoride (1.0  solu-

tion in THF, 82.2 µL, 82 µmol) was added at room temperature to

a stirred solution of 55 (36.0 mg, 54.8 µmol) in THF (3 mL). After

umn chromatography (EtOAc/heptanes, 1:2) yielded 53 (283 mg, 15 min, the reaction mixture was poured into water (20 mL). The

0.537 mmol, 73%) as a white solid. ¹H NMR: δ ϭ 1.16 and 1.18

mixture was extracted three times with ethyl acetate (3 ϫ 15 mL).

(2 ϫ s, 6 H, 17-H ϩ 19-H), 1.43 (s, 3 H, acetonide), 1.47 (s, 3 H, The combined organic fractions were washed with brine, dried with

acetonide), 1.57 (s, 3 H, 16-H), 1.98 (s, 3 H, 18-H), 2.15 (dd, J_gemϭ anhydrous Na₂SO₄, filtered, and concentrated under reduced pres-

16.0, J_14Ϫ13ϭ 4.2 Hz, 1 H, 14-H), 2.37 (d, J_3Ϫ2ϭ 4.6 Hz, 1 H, 3-

H), 2.74 (dd, J_gemϭ 16.0, J_14Ϫ13ϭ 10.1 Hz, 1 H, 14-H), 3.13 (s, 3 (25.3 mg, 46.6 µmol, 85%) as a white solid. H NMR: δ ϭ 1.10 (s,

sure. Column chromatography (EtOAc/heptanes, 1:1) afforded 56

1

H, OCH₃), 3.51 (m, 1 H, 5-H), 3.73 (d, J_gemϭ 12.1 Hz, 1 H, 20-

H), 3.81 (d, J_gemϭ 12.1 Hz, 1 H, 20-H), 4.12 (d, J_9Ϫ10ϭ 9.3 Hz,

3 H, 19-H), 1.19 (s, 3 H, 17-H), 1.45 (s, 3 H, acetonide), 1.51 (s, 3

H, acetonide), 1.60 (s, 3 H, 16-H), 2.00 (s, 3 H, 18-H), 2.50 (dd,

702

Eur. J. Org. Chem. 2003, 689Ϫ705

Semisynthesis of 7-Deoxypaclitaxel Derivatives Devoid of an Oxetane D-Ring

J_gemϭ 15.9, J_14Ϫ13ϭ 3.8 Hz, 1 H, 14-H), 2.65 (dd, J_gemϭ 15.9, to a stirred solution of 59 (510 mg, 1.06 mmol) in THF (10 mL).

FULL PAPER

J_14Ϫ13ϭ 9.7 Hz, 1 H, 14-H), 2.75 (d, J_3Ϫ2ϭ 4.8 Hz, 1 H, 3-H),

3.00 (s, 3 H, OCH₃), 3.42 (d, J_gemϭ 11.4 Hz, 1 H, 20-H), 3.51 (m,

The reaction mixture was stirred for 3 h. During this period, the

reaction temperature was slowly raised from Ϫ15 °C to 10 °C. The

reaction mixture was poured into a mixture of a saturated aqueous

1 H, 5-H), 3.64 (d, J_gemϭ 11.4 Hz, 1 H, 20-H), 4.25 (d, J_9Ϫ10

ϭ

9.4 Hz, 1 H, 9-H), 4.61 (d, J_10Ϫ9ϭ 9.4 Hz, 1 H, 10-H), 4.61 (m, 1 solution of NaHCO₃(20 mL) and a 0.2  Na₂S₂O₃solution

H, 13-H), 5.78 (d, J_2Ϫ3ϭ 4.8 Hz, 1 H, 2-H), 7.49 (m, 2 H, Ph), (20 mL). The resultant mixture was extracted twice with ethyl acet-

7.61 (m, 1 H, Ph), 8.10 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 565 ate (2 ϫ 30 mL). The combined organic fractions were washed with

[M ϩ Na]^ϩ. C₃₁H₄₂O₈(542.7): calcd. C 68.61, H 7.80; found C

68.50, H 7.79.

brine, dried with anhydrous Na₂SO₄, filtered, and concentrated un-

der reduced pressure. Column chromatography (EtOAc/heptanes,

2:5) gave 60 (454 mg, 0.809 mmol, 77%) as a white solid. ¹H NMR:

δ ϭ 1.11 (s, 3 H, 19-H), 1.26 (s, 3 H, 17-H), 1.45 (s, 3 H, acetonide),

1.48 (s, 3 H, acetonide), 1.61 (s, 3 H, 16-H), 1.83 (dd, J_gemϭ 15.9,

J_14Ϫ13ϭ 6.2 Hz, 1 H, 14-H), 1.98 (m, 2 H, 2 ϫ 7-H), 2.21 (s, 3 H,

Coupling of 56 to β-Lactam 28, Giving 57: Sodium bis(trimethylsilyl)-

amide (1.0  solution in THF, 78.3 µL, 78 µmol) was added at Ϫ78

°C to a stirred solution of 56 (17.0 mg, 31.3 µmol) and β-lactam

28 (19.1 mg, 50.1 µmol) in THF (2 mL). The reaction mixture was

stirred at Ϫ78 °C for 1 h, additional sodium bis(trimethylsilyl)am-

ide (1.0  solution in THF, 78.3 µL, 78 µmol) and β-lactam 28

(19.1 mg, 50.1 µmol) being added after 30 min. The reaction was

quenched by slow addition of a saturated aqueous NH₄Cl solution

(2 mL). The mixture was allowed to warm to room temperature.

Brine (15 mL) and ethyl acetate (15 mL) were added next. The

aqueous layer was separated from the organic layer and extracted

with ethyl acetate (15 mL). The combined organic fractions were

dried with anhydrous Na₂SO₄, filtered, and concentrated under re-

duced pressure. Column chromatography (EtOAc/heptanes, 2:5)

yielded 57 (14.1 mg, 15.3 µmol, 49%) together with recovered 56

(3.8 mg, 7.0 µmol). ¹H NMR: δ ϭ 0.44 [m, 6 H, Si(CH₂CH₃)₃],

0.80 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃], 1.15 (s, 3 H, 19-H), 1.22

(s, 3 H, 17-H), 1.44 (s, 3 H, acetonide), 1.52 (s, 3 H, acetonide),

1.62 (s, 3 H, 16-H), 1.85 (s, 3 H, 18-H), 2.39 (dd, J_gemϭ 15.6,

18-H), 2.24 (m, 1 H, 6-H), 2.50 (m, 1 H, 6-H), 2.50 (dd, J_gem

ϭ

15.9, J_14Ϫ13ϭ 9.6 Hz, 1 H, 14-H), 4.06 (d, J_3Ϫ2ϭ 5.7 Hz, 1 H, 3-

H), 4.12 (d, J_2Ϫ3ϭ 5.7 Hz, 1 H, 2-H), 4.13 (d, J_9Ϫ10ϭ 9.5 Hz, 1

H, 9-H), 4.36 (m, 1 H, 5-H), 4.79 (m, 1 H, 13-H), 4.92 (d, J_10Ϫ9ϭ

9.5 Hz, 1 H, 10-H), 5.85 (s, 1 H, PhCH), 7.35 (m, 3 H, Ph), 7.48

(m, 2 H, Ph) ppm. ¹³C NMR: δ ϭ 16.8, 18.8, 21.0, 25.7, 26.8, 27.2,

28.4, 31.3, 41.0, 43.6, 45.0, 49.1, 54.6, 69.1, 75.0, 78.1, 81.0, 86.0,

102.4, 107.4, 126.6, 128.2, 128.9, 133.4, 138.3, 146.2, 199.0 ppm.

EI-MS: m/z ϭ 481 [M Ϫ Br]^ϩ, 560/562 [M]^ϩ. C₂₉H₃₇BrO₆·0.5H₂O

(570.5): calcd. C 61.05, H 6.71; found C 61.28, H 6.88.

Conversion of 60 into 61 and 62: Sodium borohydride (15.5 mg,

0.463 mmol) was added at 0 °C to a stirred solution of 60 (200 mg,

0.356 mmol) in THF/methanol (12 mL, 1:5 v/v). The reaction mix-

ture was stirred at 0 °C for 2 h, additional sodium borohydride

(15.5 mg, 0.463 mmol) being added after 1 h. The reaction was

quenched by slow addition of a saturated aqueous NH₄Cl solution

(10 mL). The resultant mixture was extracted three times with ethyl

acetate (3 ϫ 15 mL). The combined organic fractions were washed

with brine, dried with anhydrous Na₂SO₄, filtered, and concen-

trated under reduced pressure. Column chromatography (EtOAc/

heptanes, 1:2) afforded 61 (62.7 mg, 0.130 mmol, 36%) and 62

(63.0 mg, 0.112 mmol, 31%), both as white solids. 61: ¹H NMR:

δ ϭ 1.18 (m, 1 H, 7-H), 1.24 (s, 3 H, 17-H), 1.33 (s, 3 H, 19-H),

1.41 (s, 3 H, acetonide), 1.45 (s, 3 H, acetonide), 1.61 (s, 3 H, 16-

H), 1.84 (dd, J_gemϭ 13.4, J_7Ϫ6ϭ 6.5 Hz, 1 H, 7-H), 1.96 (s, 3 H,

18-H), 1.96Ϫ2.05 (m, 2 H, 6-H ϩ 14-H), 2.12 (m, 1 H, 6-H), 2.50

(m, 2 H, 3-H ϩ 14-H), 3.11 (m, 1 H, 5-H), 3.44 (dd, J_4Ϫ3ϭ 1.4,

J_4Ϫ5ϭ 4.2 Hz, 1 H, 4-H), 4.10 (d, J_9Ϫ10ϭ 9.5 Hz, 1 H, 9-H), 4.19

(d, J_2Ϫ3ϭ 4.3 Hz, 1 H, 2-H), 4.59 (d, J_10Ϫ9ϭ 9.5 Hz, 1 H, 10-H),

4.83 (m, 1 H, 13-H), 5.88 (s, 1 H, PhCH), 7.36 (m, 3 H, Ph), 7.53

(m, 2 H, Ph) ppm. ¹³C NMR: δ ϭ 16.8, 19.4, 20.5, 20.6, 26.9, 27.0,

29.1, 37.6, 40.4, 41.3, 41.9, 50.1, 54.1, 68.8, 75.2, 78.7, 82.4, 84.8,

102.2, 106.5, 126.8, 128.1, 128.9, 135.1, 138.5, 145.3, 208.4 ppm.

FAB-MS: m/z ϭ 483 [M ϩ H]^ϩ, 505 [M ϩ Na]^ϩ, 988 [2 M ϩ Na]^ϩ.

C₂₉H₃₈O₆·0.75H₂O (496.1): calcd. C 70.21, H 8.02; found C 70.16,

H 8.12. 62: ¹H NMR: δ ϭ 1.18 (s, 3 H, 19-H), 1.25 (s, 3 H, 17-H),

1.44 (s, 3 H, acetonide), 1.47 (s, 3 H, acetonide), 1.60 (s, 3 H, 16-

H), 2.19 (s, 3 H, 18-H), 2.35 (dd, J_gemϭ 15.7, J_14Ϫ13ϭ 5.0 Hz, 1

H, 14-H), 2.49 (dd, J_3Ϫ2ϭ 4.6, J_3Ϫ4ϭ 10.5 Hz, 1 H, 3-H), 2.74

(dd, J_gemϭ 15.7, J_14Ϫ13ϭ 9.8 Hz, 1 H, 14-H), 3.87 (m, 1 H, 4-H),

4.08 (br. s, 1 H, 4-OH), 4.12 (d, J_9Ϫ10ϭ 9.4 Hz, 1 H, 9-H), 4.26

(d, J_2Ϫ3ϭ 4.6 Hz, 1 H, 2-H), 4.75 (m, 2 H, 5-H ϩ 13-H), 4.80 (d,

J_10Ϫ9ϭ 9.4 Hz, 1 H, 10-H), 5.78 (s, 1 H, PhCH), 7.37Ϫ7.47 (m, 5

H, Ph) ppm. FAB-MS: m/z ϭ 563/565 [M ϩ H]^ϩ, 585/587 [M ϩ

Na]^ϩ. C₂₉H₃₉BrO₆·0.5H₂O (572.5): calcd. C 60.84, H 7.04; found

C 60.81, H 6.96.

J_14Ϫ13ϭ 10.1 Hz, 1 H, 14-H), 2.59 (dd, J_gemϭ 15.6, J_14Ϫ13

ϭ

3.7 Hz, 1 H, 14-H), 2.74 (s, 3 H, OCH₃), 2.91 (d, J_3Ϫ2ϭ 4.8 Hz, 1

H, 3-H), 3.33 (m, 1 H, 5-H), 3.46 (d, J_gemϭ 10.8 Hz, 1 H, 20-H),

4.09 (d, J_gemϭ 10.8 Hz, 1 H, 20-H), 4.38 (d, J_9Ϫ10ϭ 9.4 Hz, 1 H,

9-H), 4.67 (d, J_2ЈϪ3Јϭ 1.6 Hz, 1 H, 2Ј-H), 4.69 (d, J_10Ϫ9ϭ 9.4 Hz,

1 H, 10-H), 5.79 (d, J_2Ϫ3ϭ 4.8 Hz, 1 H, 2-H), 5.91 (br. d, J_3ЈϪNHϭ

9.3 Hz, 1 H, 3Ј-H), 6.06 (m, 1 H, 13-H), 7.22Ϫ7.55 (m, 12 H, Ph

ϩ NH), 7.89 (m, 2 H, Ph), 8.30 (m, 2 H, Ph) ppm. FAB-MS: m/

z ϭ 946 [M ϩ Na]^ϩ. C₅₃H₆₉NO₁₁Si (924.2): calcd. C 68.88, H 7.52;

found C 68.97, H 7.35.

Conversion of 57 into 58: Tetrabutylammonium fluoride (1.0  solu-

tion in THF, 20.6 µL, 21 µmol) was added at room temperature to

a solution of 57 (13.6 mg, 14.7 µmol) in THF (2 mL). After 5 min,

the reaction mixture was poured into water (20 mL). The mixture

was extracted three times with ethyl acetate (3 ϫ 15 mL). The com-

bined organic fractions were washed with brine, dried with anhyd-

rous Na₂SO₄, filtered, and concentrated under reduced pressure.

Column chromatography (EtOAc/heptanes, 2:3) afforded 58

1

(9.7 mg, 12 µmol, 81%) as a white solid. H NMR: δ ϭ 1.12 and

1.15 (2 ϫ s, 6 H, 17-H ϩ 19-H), 1.41 (s, 3 H, acetonide), 1.49 (s, 3

H, acetonide), 1.59 (s, 3 H, 16-H), 1.60 (s, 3 H, 18-H), 2.56 (dd,

J_gemϭ 15.8, J_14Ϫ13ϭ 9.8 Hz, 1 H, 14-H), 2.72 (dd, J_gemϭ 15.8,

J_14Ϫ13ϭ 2.7 Hz, 1 H, 14-H), 2.87 (d, J_3Ϫ2ϭ 4.6 Hz, 1 H, 3-H),

3.00 (s, 3 H, OCH₃), 3.30 (m, 1 H, 5-H), 3.34 (d, J_gemϭ 10.7 Hz,

1 H, 20-H), 3.64 (d, J_gemϭ 10.7 Hz, 1 H, 20-H), 4.29 (d, J_9Ϫ10

ϭ

9.4 Hz, 1 H, 9-H), 4.57 (d, J_10Ϫ9ϭ 9.4 Hz, 1 H, 10-H), 4.59 (br. s,

1 H, 2Ј-OH), 4.77 (br. s, 1 H, 2Ј-H), 5.77 (m, 2 H, 2-H ϩ 13-H),

5.86 (dd, J_3ЈϪNHϭ 9.1, J_3ЈϪ2Јϭ 2.2 Hz, 1 H, 3Ј-H), 7.27Ϫ7.58 (m,

12 H, Ph ϩ NH), 7.87 (m, 2 H, Ph), 8.09 (m, 2 H, Ph) ppm. FAB-

MS: m/z ϭ 810 [M ϩ H]^ϩ, 832 [M ϩ Na]^ϩ. HRFAB-MS for

C₄₇H₅₅NNaO₁₁[M ϩ Na]^ϩ: calcd. 832.3673; found 832.3679 Ϯ

0.0166.

Coupling of 61 to β-Lactam 28, Furnishing 63: Sodium bis(tri-

methylsilyl)amide (1.0  solution in THF, 0.606 mL, 0.61 mmol)

Conversion of 59 into 60: Phenyltrimethylammonium tribromide

(418 mg, 1.11 mmol) in THF (5 mL) was slowly added at Ϫ15 °C was added at Ϫ78 °C to a stirred solution of 61 (117 mg,

Eur. J. Org. Chem. 2003, 689Ϫ705 703

H. W. Scheeren et al.

J_14Ϫ13ϭ 5.4 Hz, 1 H, 14-H), 2.56 (dd, J_gemϭ 15.3, J_14Ϫ13

FULL PAPER

0.242 mmol) and β-lactam 28 (148 mg, 0.388 mmol) in THF

ϭ

(4 mL). The reaction mixture was stirred at Ϫ78 °C for 1 h. The 9.6 Hz, 1 H, 14-H), 2.83 (dd, J_3Ϫ2ϭ 5.0, J_3Ϫ4ϭ 2.5 Hz, 1 H, 3-

reaction was quenched by slow addition of a saturated aqueous H), 3.97 (m, 1 H, 5-H), 4.27 (br. s, 1 H, 4-H), 4.29 (d, J_9Ϫ10

NH₄Cl solution (4 mL) and the reaction mixture was allowed to 9.4 Hz, 1 H, 9-H), 4.66 (d, J_2ЈϪ3Јϭ 3.7 Hz, 1 H, 2Ј-H), 4.83 (d,

ϭ

warm to room temperature. Water (10 mL) and ethyl acetate

(20 mL) were added, and the two resultant layers were separated.

The aqueous fraction was extracted with ethyl acetate (20 mL). The

combined organic fractions were washed with brine, dried with an-

hydrous Na₂SO₄, filtered, and concentrated under reduced pres-

sure. Column chromatography (EtOAc/heptanes, 1:2) afforded 63

(155 mg, 0.179 mmol, 74%) as a white solid. ¹H NMR: δ ϭ 0.48

[m, 6 H, Si(CH₂CH₃)₃], 0.84 [t, J ϭ 7.9 Hz, 9 H, Si(CH₂CH₃)₃],

1.27 (s, 3 H, 17-H), 1.34 (s, 3 H, 19-H), 1.40 (s, 3 H, acetonide),

1.44 (s, 3 H, acetonide), 1.61 (s, 3 H, 16-H), 1.67 (s, 3 H, 18-H),

1.86 (dd, J_gemϭ 13.4, J_7Ϫ6ϭ 6.5 Hz, 1 H, 7-H), 1.95Ϫ2.23 (m, 3

H, 2 ϫ 6-H ϩ 14-H), 2.46 (m, 1 H, 3-H), 2.51 (dd, J_gemϭ 15.9,

J_14Ϫ13ϭ 9.7 Hz, 1 H, 14-H), 3.15 (m, 1 H, 5-H), 3.62 (m, 1 H, 4-

J_10Ϫ9ϭ 9.4 Hz, 1 H, 10-H), 5.70 (d, J_2Ϫ3ϭ 5.0 Hz, 1 H, 2-H), 5.75

(dd, J_3ЈϪNHϭ 9.6, J_3ЈϪ2Јϭ 3.7 Hz, 1 H, 3Ј-H), 5.95 (m, 1 H, 13-

H), 7.07 (d, J_NHϪ3Јϭ 9.6 Hz, 1 H, NH), 7.25Ϫ7.60 (m, 11 H, Ph),

7.80 (m, 2 H, Ph), 7.90 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 784

[M ϩ H]^ϩ, 806 [M ϩ Na]^ϩ. C₄₅H₅₃NO₁₁·4H₂O (856.0): calcd. C

63.14, H 7.18, N 1.63; found C 62.76, H 6.77, N 1.20.

Acknowledgments

The authors gratefully acknowledge financial support from the

European Commission (FAIR CT96-1781) and Pharmachemie BV,

H), 4.12 (d, J_9Ϫ10ϭ 9.5 Hz, 1 H, 9-H), 4.19 (d, J_2Ϫ3ϭ 4.2 Hz, 1 Haarlem, The Netherlands.

H, 2-H), 4.53 (d, J_10Ϫ9ϭ 9.5 Hz, 1 H, 10-H), 4.61 (d, J_2ЈϪ3Ј

ϭ

2.0 Hz, 1 H, 2Ј-H), 5.64 (dd, J_3ЈϪNHϭ 8.9, J_3ЈϪ2Јϭ 2.0 Hz, 1 H,

3Ј-H), 5.81 (s, 1 H, PhCH), 5.98 (m, 1 H, 13-H), 7.17Ϫ7.55 (m, 14

H, Ph ϩ NH), 7.78 (m, 2 H, Ph) ppm. FAB-MS: m/z ϭ 864 [M ϩ

H]^ϩ, 886 [M ϩ Na]^ϩ, 1750 [2 M ϩ Na]^ϩ. C₅₁H₆₅NO₉Si·0.5H₂O

(873.2): calcd. C 70.15, H 7.62, N 1.60; found C 70.38, H 7.55,

N 1.76.

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Conversion of 63 into 64: Tetrabutylammonium fluoride (1.0  solu-

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anhydrous Na₂SO₄, filtered, and concentrated under reduced pres-

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(29.8 mg, 39.7 µmol, 96%) as a white solid. H NMR: δ ϭ 1.27 (s,

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H, acetonide), 1.62 (s, 3 H, 16-H), 1.79 (s, 3 H, 18-H), 1.86 (dd,

J_gemϭ 12.8, J_7Ϫ6ϭ 6.5 Hz, 1 H, 7-H), 1.95Ϫ2.21 (m, 2 H, 2 ϫ 6-

H), 2.22 (dd, J_gemϭ 16.1, J_14Ϫ13ϭ 4.8 Hz, 1 H, 14-H), 2.47 (m, 1

H, 3-H), 2.52 (dd, J_gemϭ 16.1, J_14Ϫ13ϭ 9.6 Hz, 1 H, 14-H), 3.15

(m, 1 H, 5-H), 3.44 (d, J_OHϪ2Јϭ 4.3 Hz, 1 H, 2Ј-OH), 3.69 (br. d,

J_4Ϫ5ϭ 4.1 Hz, 1 H, 4-H), 4.13 (d, J_9Ϫ10ϭ 9.5 Hz, 1 H, 9-H), 4.21

(d, J_2Ϫ3ϭ 4.2 Hz, 1 H, 2-H), 4.56 (d, J_10Ϫ9ϭ 9.5 Hz, 1 H, 10-H),

4.68 (m, 1 H, 2Ј-H), 5.73 (dd, J_3ЈϪNHϭ 9.0, J_3ЈϪ2Јϭ 2.5 Hz, 1 H,

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L. Merckle, J. Dubois, E. Place, S. Thoret, F. Gueritte, D.

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ϩ H]^ϩ, 1522 [2 M ϩ Na]^ϩ. C₄₅H₅₁NO₉(749.9): calcd. C 72.08, H

6.85, N 1.87; found C 72.38, H 6.99, N 1.82.

´

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tion in decane, 10.7 µL, min. 0.53 mmol) was added at room tem-

perature to a solution of 64 (40.0 mg, 53.3 µmol) and palladium()

acetate (3.0 mg, 13 µmol) in toluene (1 mL). The reaction mixture

was stirred at 70 °C for 40 h and allowed to cool to room temper-

ature, and water (5 mL) and ethyl acetate (5 mL) were added. The

aqueous layer was separated from the organic layer and extracted

with ethyl acetate (5 mL). The combined organic fractions were

washed with brine, dried with anhydrous Na₂SO₄, filtered, and con-

centrated under reduced pressure. Column chromatography

(EtOAc/heptanes/dichloromethane, 1:2:2) afforded 65 (7.1 mg, 9.27

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1.36 (s, 3 H, 19-H), 1.44 (s, 3 H, acetonide), 1.50 (s, 3 H, acetonide),

1.68 (s, 3 H, 16-H), 2.00 (s, 3 H, 18-H), 2.16 (dd, J_gemϭ 15.3,

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Semisynthesis of 7-Deoxypaclitaxel Derivatives Devoid of an Oxetane D-Ring

FULL PAPER

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Received August 5, 2002

[O02455]

Eur. J. Org. Chem. 2003, 689Ϫ705

705

Article Doi

Semisynthesis of 7-deoxypaclitaxel derivatives devoid of an oxetane D-ring, starting from taxine B

DOI: 10.1002/ejoc.200390109

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Article abstract of DOI:10.1002/ejoc.200390109

Full text of DOI:10.1002/ejoc.200390109

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