Synthesis of novel 2-O,3′-N-linked macrocyclic taxoids with variable ring size

Article abstract of DOI:10.1002/ejoc.200390092

A series of macrocyclic taxoids was prepared by connecting the 2-OH and 3′-NH moieties with aliphatic chains to mimic the docetaxel solid-state conformation. The synthesis was achieved by acylation of both positions with various bromoalkanoic acids, and ring closure was carried out with sodium sulfide. Nine 19- to 27-membered macrocyclic taxoids were obtained and evaluated as inhibitors of microtubule disassembly as well as for their cytoxicity. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390092

FULL PAPER
Synthesis of Novel 2-O,3Ј-N-Linked Macrocyclic Taxoids with
Variable Ring Size
[a]
[a]
[a]
[a][‡]
¨
Olivier Querolle, Joelle Dubois,* Sylviane Thoret, Christophe Dupont,
[a]
[a]
´
´
Francoise Gueritte, and Daniel Guenard
¸
Keywords: Antitumor agents / Bioactive conformation / Sulfides / Macrocycles
A series of macrocyclic taxoids was prepared by connecting
the 2-OH and 3Ј-NH moieties with aliphatic chains to mimic
the docetaxel solid-state conformation. The synthesis was
achieved by acylation of both positions with various bromoal-
kanoic acids, and ring closure was carried out with sodium
sulfide. Nine 19- to 27-membered macrocyclic taxoids were
obtained and evaluated as inhibitors of microtubule disas-
sembly as well as for their cytoxicity.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
Paclitaxel (Taxol) (1a) and docetaxel (Taxotere) (1b)
(Figure 1) are very useful anticancer drugs in the treatment
of breast, ovarian, and non-small-cell lung cancers.[1] These
compounds block cell-cycle progression during mitosis by
binding to microtubules and stabilizing them against disas-
sembly.[2] The structure of tubulin has recently been deter-
mined by electron crystallography on zinc-induced sheets of
Figure 1. Structure of paclitaxel (Taxol) (1a: R ϭ Ac; RЈ ϭ Bz)
and docetaxel (Taxotere) (1b: R ϭ H; RЈ ϭ Boc)
described in which the ester group at C-4 is linked with the
tubulin stabilized with paclitaxel.[3] The 3.7 A resolution
˚
3Ј-phenyl group to model the ‘‘T-shaped’’ conformer.[12]
A
allowed visualization of the location of the paclitaxel bind-
ing site but not a complete determination of the ligand con-
formation. Several studies have led to propose three con-
formations that could interact with tubulin. The so-called
‘‘polar’’ conformer, with 2-O-benzoyl and 3Ј-phenyl groups
exhibiting hydrophobic collapse, and the ‘‘nonpolar’’ form
where the 2-O and 3Ј-NH-substituents are in hydrophobic
interaction, were first proposed on the basis of NMR spec-
tra[4,5] and X-ray crystal structures.[6,7] Then, refinement at
few of these analogues were still able to interact with tubu-
lin but they were less active than paclitaxel. For example
three of the 17- and 18-membered macrocyclic taxoids
described by Ojima et al.[11] showed relative activities of 19,
21, and 36% as compared to paclitaxel whereas the 4,3Ј-
linked macrocycles reported by Kingston et al.[12] (19- and
21-membered rings) were 10- and 30-fold less active than
paclitaxel. Recently, the first derivatives mimicking the
‘‘nonpolar’’ conformer with bridges linking the 3Ј-NH
moiety to the 2-position were described but their activity
on tubulin was not reported.[13]
In the course of our study on the bioactive conformation
of docetaxel, we designed new conformationally restricted
taxoids mimicking the ‘‘nonpolar’’ conformation, which is
found in the docetaxel crystal structure. Therefore, we syn-
thesized macrocyclic taxoids with bridges linking the 3Ј-NH
moiety to the 2-position. The macrocycle that best fitted
the crystal conformation of docetaxel was calculated by
molecular modeling to be a 19-membered ring. To account
for the ‘‘T-shaped’’ conformer calculated from the crystallo-
graphic density, we decided to vary the size of the macrocy-
cle and to correlate it with the activity on cold-induced mic-
rotubule disassembly. To synthesize these macrocyclic
taxoids, we chose to effect ring-closure by the classical addi-
tion of sulfide to α,ω-dibromo derivatives.[14] The large vari-
[8]
˚
3.5 A of the previous αβ-tubulin model led to propose an
intermediate conformation, in which the phenyl ring of the
2-benzoyl group is almost equidistant from both hydro-
phobic groups at the 3Ј-position (T-shaped structure).[9]
Syntheses of analogues with built-in conformational re-
strictions have been designed to investigate the bound con-
formation of taxoids on tubulin. Most published studies
have involved compounds mimicking the ‘‘polar’’ con-
formation, with bridges linking the 2-O-benzoyl and
3Ј-phenyl groups.[10,11] Recently, two analogues have been
[a]
ICSN-CNRS,
Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France
Fax: (internat.) ϩ 33-1/69077247
E-mail: joelle.dubois@icsn.cnrs-gif.fr
Present address: Orga-Link,
[‡]
2, route de la Noue, 91193 Gif sur Yvette Cedex, France
E-mail: contact@orga-link.com
542
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0203Ϫ0542 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 542Ϫ550

Synthesis of Novel 2-O,3Ј-N-Linked Macrocyclic Taxoids with Variable Ring Size
FULL PAPER
ety of bromoalkanoic acids commercially available allowed acid at 0 °C before protection of the 7- and 10-hydroxy
us to prepare several taxoid precursors bearing two bro- groups. We chose triethylsilyl as the protective group for
moalkyl chains at the 2-O and 3Ј-N-positions.
these alcohols but had to substitute another solvent for
We describe here a short and efficient synthesis of a series DMF, which is often used as the solvent in this reaction,
of eight novel macrocyclic taxoids 2 bearing 19- to 27-mem- because of the potential formylation of the free amino
bered rings (Figure 2). We also discuss their biological group in the 3Ј-position. The best yield in this protection
evaluation in relation to their macrocyclic ring size and step was obtained in a solution of dichloromethane and
their restricted conformation.
acetonitrile (50:50, v/v) using chlorotriethylsilane in the
presence of imidazole. Among the reagents described for
deacylation of the 2-position,[15Ϫ18] Red-Al was the most
efficient and reproducible. In summary, compound 4 was
obtained in four steps from docetaxel (1b) with an overall
yield of 24%. (Scheme 2)
Figure 2. New C-2,3Ј-N-macrocyclic taxoids
Results and Discussion
The retrosynthetic analysis of the target macrocyclic
taxoids 2 is shown in Scheme 1. As described in this scheme,
compound 2 can be obtained by addition of sodium sulfide
to the ω,ωЈ-dibromotaxoid precursor 3, which can be syn-
thesized from the 2-OH/3Ј-NH2 taxoid 4. The deacylated
derivative 4 could be obtained from docetaxel (1b) after
suitable protection of the 2Ј-, 7-, and 10-hydroxy groups,
which are not involved in the transformation.
Scheme 2. a) TBSCl, imidazole, DMF, room temp. (87%); b) TFA,
CH2Cl2, 0 °C (87%); c) TESCl, imidazole, CH3CN/CH2Cl2, 60 °C
(58%); d) Red-Al, THF, 0 °C (54%)
Synthesis of Macrocyclic Taxoids 2
The introduction of the bromoalkyl chains on 4 was per-
formed by acylation of 2-OH and 3Ј-NH2 with
Br[CH2]nCOOH (n ϭ 3, 4, 5, or 7). Taking advantage of
the great difference in reactivity between the amino group
in 3Ј-position and the hydroxy group in 2-position, different
alkyl chains could be added in the two positions. In this
way, acylation of the amine was realized with only 2 equiv.
of the bromo acid in the presence of dicyclohexylcarbodiim-
ide (DCC) and 4-(dimethylamino)pyridine (DMAP). Then,
addition in the same pot of a large excess of another bromo
acid and of the coupling reagents allowed the esterification
of the 2-hydroxy group. For compounds 3 with n ϭ nЈ, a
large amount of the appropriate bromo acid was added at
one time to perform both acylations together. Compounds
3aϪh were thus synthesized in medium to good yield
(45Ϫ90%; Scheme 3). Macrocyclization was carried out by
Scheme 1. Retrosynthesis of compound 2
Preparation of 2-Debenzoyl-2Ј-OTBS-3Ј-(de-tert-
butoxycarbonyl)-7,10-diTES-docetaxel (4)
It was important to design the most rapid and efficient adding sodium sulfide in anhydrous acetone. As previously
synthesis for compound 4, starting from docetaxel. The hy- described,[14] high dilution was not necessary for ring-clo-
droxy group in 2Ј-position was first protected with the sure, but the solvent was critical and the acetone needed
bulky tert-butyldimethylsilyl group to prevent hydrolysis of to be freshly distilled to obtain macrocyclic taxoids with
the ester group at C-13 during further debenzoylation.[15] acceptable yields. Final deprotection of the silyl groups at
The Boc group was removed by addition of trifluoroacetic the 2Ј-, 7-, and 10-positions was easily achieved by HF/
Eur. J. Org. Chem. 2003, 542Ϫ550
543

´
´
O. Querolle, J. Dubois, S. Thoret, C. Dupont, F. Gueritte, D. Guenard
FULL PAPER
pyridine to afford macrocyclic taxoids 2aϪh with 19- to 27- be oxidized to a disulfide macrocyclic compound prompted
membered rings (Scheme 3).
us to use the dithioacetyl derivative as the reference for the
noncyclic analogue. Then, the silyl groups of 8 and 9 were
removed to afford compounds 10 and 11 corresponding to
a 20-membered ring macrocyclic taxoid and its noncyclic
analogue.
Scheme 3. a) Br[CH2]nCOOH (2 equiv.), DCC, DMAP, toluene,
room temp. 2.5 h, then Br[CH2]nЈCOOH (15 equiv.), DCC, DMAP,
toluene, room temp. 2 h; b) Na2S, acetone, room temp. 1 h; c) HF/
pyridine, 0 °C, 3 h
In the model of paclitaxel bound to tubulin described by
Snyder et al.[9] the imidazole ring of His 229 is located be-
tween the 2-benzoyl and the 3Ј-benzamido rings. Therefore,
the presence of a macrocycle at that position could prevent
interaction with tubulin and it was important to be able
to compare the bioactivity of a macrocyclic taxoid with its
noncyclic analogue. We chose to do this comparison only
for n ϭ nЈ ϭ 3 and so we designed the synthesis of the
noncyclic analogue of 2a. Deprotection of the silyl groups
on compound 3a did not lead to the desired derivative be-
cause of the bromide reactivity. Therefore, we considered
the synthesis of a derivative bearing a thiol group at the
end of both alkyl chains (Scheme 4). The sulfur atoms were
introduced as thioacetyl moieties by nucleophilic substitu-
tion of the bromides by potassium thioacetate leading to 8
in good yield. Unfortunately, hydrolysis of the acetyl groups
Scheme 4. a) KSAc, DMF, room temp. (84%); b) Na2CO3, MeOH,
room temp. (33%); c) HF/pyridine, CH3CN, 0 °C (10: 42%; 11:
64%)
Biological Activities
Macrocyclic taxoids 2aϪh, 10, and 11 were evaluated for
of compound 8 only afforded the macrocyclic taxoid 9 bear- their inhibition of cold-induced microtubule disassembly[19]
ing a disulfide bond, coming from oxidation in situ of the and for their cytotoxicity against the KB cell line.[20] The
expected ω,ωЈ-dithiotaxoid. The tendency of this dithiol to results are reported in Table 1.
Table 1. Biological evaluation of macrocyclic taxoids 2aϪh, 10, and 11
Compound
n
nЈ
Ring size
Microtubule disassembly inhibitory activity
IC50/IC50(paclitaxel)[a]
Cytotoxicity against the KB cell line
IC50 [µ][b]
2a
2b
2c
2d
2e
2f
2g
2h
10
11
3
4
4
5
5
7
7
7
3
3
3
3
4
4
5
4
5
7
3
3
19
20
21
22
23
24
25
27
inactive
inactive
42
inactive
inactive
inactive
80
inactive
23
18
45
21
15
65
6
26
3.5
4.6
15
5.5
20
noncyclic
[a]
IC50 is the concentration that inhibits 50% of the rate of microtubule disassembly. The ratio IC50/IC50(paclitaxel) gives the activity
[b]
with respect to paclitaxel. IC50(paclitaxel) ϭ 1 µ.
IC50 measures the drug concentration required for the inhibition of 50% cell
proliferation after 72 h incubation. IC50(docetaxel) ϭ 0.001 µ.
544
Eur. J. Org. Chem. 2003, 542Ϫ550

Synthesis of Novel 2-O,3Ј-N-Linked Macrocyclic Taxoids with Variable Ring Size
FULL PAPER
The cytotoxicity of all compounds is very low compared real active conformation of taxoids. We shall report the re-
to that of docetaxel and does not appear to follow the tubu- sults of this study in the near future.
lin activity. In the taxoid series, a few derivatives have al-
ready been reported to be inactive towards tubulin but still
cytotoxic.[21Ϫ23] This may be due to a different cellular
mode of action, which deserves further investigation.
Only three macrocyclic taxoids (2c, 2g, and 10) show an
interaction with microtubules, and they are much less active
than paclitaxel. The small difference in bioactivity between
macrocyclic taxoid 10 and its noncyclic analogue 11 sug-
gests that the presence of the macrocycle is not the main
factor responsible for the low interaction with tubulin. This
could instead be due to the presence of the heteroatoms in
the tether linking the taxane skeleton to the side chain. It
is worth noting that the disulfide taxoid 10 bearing a 20-
membered ring is the most active compound of this series,
whereas the sulfide 20-membered ring analogue 2b is com-
pletely inactive towards tubulin. This discrepancy could be
explained by the differences in length and geometry be-
tween CϪS and SϪS bonds or by a particular interaction
of the disulfide bond with the protein. The low but positive
interaction of the 25-membered ring taxoid 2g with micro-
tubules is difficult to explain unless, in this particular case,
the larger ring induces a greater mobility of the macrocycle
that allows it to approach the binding site.
Experimental Section
General: 1H and 13C NMR spectra were recorded with a Bruker
AM 300. Chemical shifts are given as δ values and are referenced
to the residual solvent proton or carbon peak, i.e. chloroform
[δ(C1HCl3) ϭ 7.27 ppm and δ(13CHCl3) ϭ 77.14 ppm]. For com-
pounds 2aϪh, 3aϪh, and 7aϪh all NMR spectra are very similar.
The only modifications are the added acyl chains, so only the first
compound of each series is fully described. For the following ones,
only the NMR characteristics of the chains are reported. Mass
spectra were obtained with an AQA Navigator ThermoQuest.
High-resolution mass spectra were performed with a Voyager-DE
STR (PerSeptive Biosystems) with gentisic acid as matrix and pa-
clitaxel and docetaxel as internal standards. Merck silica gel 60
(40Ϫ63 µm) was used for flash chromatography. All chemicals were
purchased from Fluka, Aldrich or Acros and were used without
further purification unless indicated otherwise. Solvents were pur-
chased from SDS. Toluene and THF were dried and distilled before
use. Standard workup means extraction with a suitable solvent
(EtOAc unless otherwise specified), washing the extract with H2O
or brine, drying with Na2SO4, and concentration under reduced
pressure. Docetaxel (1b) was a gift from Alain Commercon
¸
(AventisϪPharma). Microtubular proteins were purified from bo-
vine brain as described previously.[24]
2Ј-O-(tert-Butyldimethylsilyl)-3Ј-(de-tert-butoxycarbonyl)docetaxel
(5)
Conclusion
a)
2Ј-O-(tert-Butyldimethylsilyl)docetaxel:
Imidazole
(2 g,
29.4 mmol) and tert-butyldimethylsilyl chloride (3.8 g, 25.2 mmol)
in DMF (16 mL) were stirred at room temperature for 45 min.
Then, docetaxel (1b) (2 g, 2.48 mmol) in DMF (16 mL) was added
and the reaction mixture was stirred for 4 h at room temperature.
After workup with CH2Cl2, the residue was purified on silica gel
(CH2Cl2/MeOH, 96:4) to afford pure 2Ј-O-(tert-butyldimethylsilyl)-
We have synthesized nine new macrocyclic taxoids 2aϪh
and 10 designed to model the ‘‘nonpolar’’ conformation ob-
served in the crystal structure of docetaxel. The easy ring-
closure method by nucleophilic substitution of ω,ωЈ-dibro-
motaxoids with sodium sulfide afforded a series of 19- to
27-membered ring sulfides. Although less active than pacli-
taxel and docetaxel, all the compounds were cytotoxic
against the KB cell line even when they do not interact with
microtubules, suggesting another cellular mode of action
for these products. These results show that information on
the active conformation can only be obtained from the tu-
bulin activity. Although the results are disappointing in
terms of bioactivity, the information that tubulin recognized
taxoids 2c and 10, bearing 21- and 20-membered rings, re-
spectively, is valuable, since it shows that these compounds
can adopt a conformation close to the bioactive one. It
should be noted that a couple of the 2-O,3Ј-N-linked mac-
rocyclic taxoids bearing a 19- or a 20-membered ring[13]
have shown higher cytotoxicity than taxoids 2c and 10, but
no tubulin activity was reported for these compounds. The
low antitubulin activity of the sulfur-containing compounds
2c and 10 is not due to the presence of the macrocycle, as
proved by the similar activities of the disulfide compound
10 and its noncyclic analogue 11. Since we suspected that
the presence of the sulfur atom was detrimental to the activ-
ity, we have designed new macrocyclic taxoids without any
heteroatom on the macrocycle ring in order to increase the
1
docetaxel (2 g, 87%) as an amorphous solid. H NMR (300 MHz,
CDCl3): δ ϭ Ϫ0.30 (s, 3 H, CH3Si), Ϫ0.11 (s, 3 H, CH3Si), 0.74
[s, 9 H, (CH3)3CSi], 1.13 (s, 3 H, 16-H3), 1.27 (s, 3 H, 17-H3), 1.30
[s, 9 H, 3 CH3, Boc], 1.75 (s, 3 H, 19-H3), 1.88 (m, 1 H, 6-Hβ),
1.91 (s, 3 H, 18-H3), 2.14 (m, 1 H, 14-H), 2.40 (m, 1 H, 14-H), 2.56
3
(s, 3 H, CH3, OAc), 2.62 (m, 1 H, 6-Hα), 3.94 (d, JH,H ϭ 7.3 Hz,
1 H, 3-H), 4.27 (qAB, 2JH,H ϭ 8 Hz, 2 H, 20-H2), 4.26 (dd, 3JH,H ϭ
3
6.6, JЈH,H ϭ 10.5 Hz, 1 H, 7-H), 4.52 (br. s, 1 H, 2Ј-H), 4.98 (br.
d, 3JH,H ϭ 8.8 Hz, 1 H, 5-H), 5.21 (s, 1 H, 10-H), 5.3 (br. d, 3JH,H ϭ
3
9 Hz, 1 H, 3Ј-H), 5.48 (d, JH,H ϭ 9 Hz; 1 H, 3Ј-NH), 5.69 (d,
3
3JH,H ϭ 7.3 Hz, 1 H, 2-H), 6.32 (t, JH,H ϭ 8.8 Hz, 1 H, 13-H),
3
7.30 (m, 5 H, CH, 3Ј-Ph), 7.49 (t, JH,H ϭ 7.3 Hz, 2 H, m-CH, 2-
OBz), 7.59 (t, 3JH,H ϭ 7.3 Hz, 1 H, p-CH, 2-OBz), 8.12 (d, 3JH,H ϭ
7.3 Hz, 2 H, o-CH, 2-OBz) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
Ϫ6.0 and Ϫ5.5 [(CH3)2Si], 10.1 (C-19), 14.4 (C-18), 21.3 (C-16),
23.0 (CH3, OAc), 25.6 [(CH3)3CSi], 26.5 (C-17), 28.3 (CH3, Boc),
35.9 (C-14), 37.0 (C-6), 43.3 (C-15), 46.5 (C-3), 56.9 (C-3Ј), 57.7
(C-8), 71.3 (C-13), 72.0 (C-7), 74.5 (C-10), 75.2 (C-2), 75.8 (C-2Ј),
76.9 (C-20), 79.2 (C-1), 80.1 (C, Boc), 81.2 (C-4), 84.4 (C-5), 126.6,
127.8, and 128.7 (C, 3Ј-Ph), 129.4 (m-C, 2-OBz), 130.3 (o-C, 2-
OBz), 133.7 (p-C, 2-OBz), 135.7 (C-11), 139.2 (C-12 and i-C, 3Ј-
Ph), 155.3 (CO, Boc), 167.2 (CO, Bz), 170.1 (CO, Ac), 171.5 (C-
1Ј), 211.4 (C-9) ppm. MS (ESIϩ): m/z ϭ 944 [M ϩ Naϩ].
b) 2Ј-O-(tert-Butyldimethylsilyl)-3Ј-(de-tert-butoxycarbonyld)ocet-
interaction with tubulin and consequently to approach the axel (5): 2Ј-O-(tert-Butyldimethylsilyl)docetaxel (2 g, 2.17 mmol) in
Eur. J. Org. Chem. 2003, 542Ϫ550 545

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´
O. Querolle, J. Dubois, S. Thoret, C. Dupont, F. Gueritte, D. Guenard
FULL PAPER
CH2Cl2 (30 mL) was stirred at 0 °C for 20 min before dropwise
addition of trifluoroacetic acid (10 mL, 25% total volume). The
reaction mixture was stirred for 45 min at 0 °C before careful neut-
ralization with sodium hydrogen carbonate. After standard
a 0.7  solution in THF, 0.62 mmol) was added at 0 °C to a THF
solution (2.1 mL) of 6 (330 mg, 0.31 mmol), previously cooled to 0
°C for 15 min. The reaction mixture was stirred at 0 °C for 30 min
and the reaction was stopped by careful addition of a saturated
workup, the residue was precipitated with a mixture of heptane/ Kϩ/Naϩ tartrate solution. After standard workup, the residue was
EtOAc (45:55) to afford pure 5 (1.1 g). Additional pure 5 (385 mg)
was obtained by purification of the filtrate on silica gel (CH2Cl2/
purified by silica-gel chromatography (CH2Cl2/MeOH, 97:3) to af-
ford 4 (160 mg, 54%) as a white amorphous solid. 1H NMR
(300 MHz, CDCl3): δ ϭ Ϫ0.14 (s, 3 H, CH3Si), Ϫ0.01 (s, 3 H,
MeOH, 95:5). Compound 5 was thus obtained as an amorphous
1
solid in 83% yield. H NMR (300 MHz, CDCl3): δ ϭ Ϫ0.50 (s, 3 CH3Si), 0.43Ϫ0.70 (m, 12 H, CH2Si), 0.86 [s, 9 H, (CH3)3CSi],
H, CH3Si), 0.0 (s, 3 H, CH3Si), 0.86 [s, 9 H, (CH3)3CSi], 1.04 (s, 3 0.93Ϫ1.08 [m, 18 H, 2 (CH3CH2)3Si], 1.07 (s, 3 H, 16-H3), 1.20 (s,
H, 16-H3), 1.14 (s, 3 H, 17-H3), 1.64 (m, 1 H, 14-H), 1.65 (s, 3 H,
3 H, 17-H3), 1.61 (s, 3 H, 19-H3), 1.74 (s, 3 H, 18-H3), 1.77 (m, 1
19-H3), 1.78 (m, 1 H, 6-Hβ), 1.79 (s, 3 H, 18-H3), 1.94 (m, 1 H, H, 14-H), 1.81Ϫ1.99 (m, 2 H, 6-Hβ and 14-H), 2.28 (s, 3 H, CH3,
3
14-H), 2.33 (s, 3 H, CH3, OAc), 2.48 (m, 1 H, 6-Hα), 3.77 (d, OAc), 2.52 (m, 1 H, 6-Hα), 3.41 (d, JH,H ϭ 6.7 Hz, 1 H, 3-H),
3
3
3JH,H ϭ 7 Hz, 1 H, 3-H), 4.05Ϫ4.32 (m, 5 H, 20-H2, 7-H, 2Ј-H, 3Ј-
3.86 (d, JH,H ϭ 6.7 Hz, 1 H, 2-H), 4.22 (d, JH,H ϭ 4.5 Hz, 1 H,
H), 4.90 (br. d, 3JH,H ϭ 7.9 Hz, 1 H, 5-H), 5.13 (s, 1 H, 10-H), 5.56 3Ј-H), 4.28 (d, JH,H ϭ 4.5 Hz, 1 H, 2Ј-H), 4.32 (dd, JH,H ϭ 6.6,
3
3
(d, JH,H ϭ 7 Hz, 1 H, 2-H), 6.05 (t, JH,H ϭ 9 Hz, 1 H, 13-H), 3JЈH,H ϭ 10.6 Hz, 1 H, 7-H), 4.58 (qAB, JH,H ϭ 9.1 Hz, 2 H, 20-
3
3
2
3
3
7.24Ϫ7.35 (m, 5 H, CH, 3Ј-Ph), 7.49 (t, JH,H ϭ 7.3 Hz, 2 H, m-
H2), 4.90 (d, JH,H ϭ 9.2 Hz, 1 H, 5-H), 5.07 (s, 1 H, 10-H), 6.09
3
3
CH, 2-OBz), 7.61 (t, JH,H ϭ 7.3 Hz, 1 H, p-CH, 2-OBz), 8.01 (d, (t, JH,H ϭ 8.8 Hz, 1 H, 13-H), 7.27Ϫ7.42 (m, 5 H, CH, 3Ј-Ph)
3JH,H ϭ 7.3 Hz, 2 H, o-CH, 2-OBz) ppm. 13C NMR (75 MHz, ppm. 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.3 and Ϫ4.9 [(CH3)2Si],
CDCl3): δ ϭ Ϫ5.2 and Ϫ5.5 [(CH3)2Si], Ϫ4.6 [C(CH3)3Si], 9.9 (C-
5.3 and 6.1 (CH2Si), 7.0 and 7.1 (CH3CH2Si), 10.8 (C-19), 14.0 (C-
19), 14.6 (C-18), 20.8 (C-16), 22.8 (CH3, OAc), 25.6 [(CH3)3CSi], 18), 20.7 (C-16), 23.1 (CH3, OAc), 25.8 [(CH3)3CSi], 26.3 (C-17),
26.3 (C-17), 35.2 (C-14), 36.6 (C-6), 43.0 (C-15), 46.2 (C-3), 57.5 35.5 (C-14), 37.5 (C-6), 42.8 (C-15), 46.7 (C-3), 58.4 (C-3Ј), 59.3
(C-3Ј), 59.4 (C-8), 70.9 (C-13), 71.6(C-7), 74.3 (C-10), 75.0 (C-2), (C-8), 71.5 (C-13), 72.9 (C-7), 74.6 (C-2), 75.6 (C-10), 77.7 (C-2Ј),
75.8 (C-2Ј), 76.9 (C-20), 78.2 (C-1), 81.0 (C-4), 84.3 (C-5), 127.3,
78.2 (C-20), 78.5 (C-1), 82.5 (C-4), 83.8 (C-5), 127.1, 127.2, 128.0
128.2 and 128.5 (o-, m-, p-C, 3Ј-Ph), 129.4 (m-C, 2-OBz), 130.0 (o- and 128.6 (o-, m-, p-C, 3Ј-Ph), 134.4 (C-11), 137.7 (C-12), 141.4 (i-
C, 2-OBz), 133.7 (p-C, 2-OBz), 135.5 (C-11), 139.0 (i-C, 3Ј-Ph),
139.2 (C-12), 166.8 (CO, Bz), 169.9 (CO, Ac), 172.1 (C-1Ј), 211.2
(C-9) ppm. MS (ESIϩ): m/z ϭ 822 [M ϩ Hϩ].
C, 3Ј-Ph), 169.6 (CO, Ac), 172.4 (C-1Ј), 206.1 (C-9) ppm. MS
(ESIϩ): m/z ϭ 946 [M ϩ Hϩ].
General Procedure for the Synthesis of Compounds 3a؊h
2Ј-O-(tert-Butyldimethylsilyl)-3Ј-(de-tert-butoxycarbonyl)-7,10-bis-
(triethylsilyl)docetaxel (6): Compound 5 (1.4 g, 1.7 mmol) was
heated at 60 °C in CH3CN/CH2Cl2 (50:50, 30 mL) for 40 min.
Meanwhile, imidazole (4 g, 58.7 mmol) and chlorotriethylsilane
(8.5 mL, 62.3 mmol) were also heated at 60 °C in CH3CN/CH2Cl2
(50:50, 20 mL) and both solutions were mixed quickly and stirred
at 60 °C for 1.5 h. After standard workup, the crude product was
purified on silica gel (heptane/EtOAc, 60:40) to afford pure 6
Method
A (for n ؍ nЈ: 3a, c, e, h): Bromoalkanoic acid
(Br[CH2]nCO2H, 16.5 equiv.) was added dropwise to a toluene solu-
tion of 4 (1 equiv., 13 m), DCC (16.5 equiv.) and DMAP (16.5
equiv.). The reaction mixture was stirred at room temperature for
1.5 h.
Method
B (for n ϶ nЈ: 3b, d, f, g): Bromoalkanoic acid
(Br[CH2]nCO2H, 2 equiv.) was added dropwise to a toluene solu-
tion of 4 (1 equiv., 0.16  initial concentration), DCC (2 equiv.),
and DMAP (2 equiv.). The reaction mixture was stirred at room
temperature for 2.5 h. Then, a toluene solution of DCC (15 equiv.),
DMAP (15 equiv.), and another bromoalkanoic acid
(Br[CH2]nЈCO2H, 15 equiv., 0.26  final concentration) was added
and the reaction mixture was stirred for an additional 2 h. Workup
was the same for both methods. The reaction mixture was filtered
through silica gel and the crude product was rapidly eluted with
the purification solvent. After standard workup, the residue was
purified by silica-gel chromatography.
1
(1.03 g, 58%) as an amorphous white solid. H NMR (300 MHz,
CDCl3): δ ϭ 0.02 (s, 3 H, CH3Si), 0.06 (s, 3 H, CH3Si), 0.60 [m,
12 H, 2 (CH3CH2)3Si], 0.90Ϫ1.05 [m, 27 H, (CH3)3CSi and 2
(CH3CH2)3Si], 1.15 (s, 3 H, 16-H3), 1.18 (s, 3 H, 17-H3), 1.62 (m,
1 H, 14-H), 1.64 (s, 3 H, 19-H3), 1.78 (s, 3 H, 18-H3), 1.80Ϫ2.01
(m, 2 H, 6-Hβ and 14-H), 2.34 (s, 3 H, CH3, OAc), 2.52 (m, 1 H,
3
6-Hα), 3.76 (d, JH,H ϭ 7 Hz, 1 H, 3-H), 4.18 and 4.27 (qAB,
3
2JH,H ϭ 8.3 Hz, 2 H, 20-H2), 4.26 (d, JH,H ϭ 6 Hz, 1 H, 2Ј-H),
3
3
3
4.30 (d, JH,H ϭ 6 Hz, 1 H, 3Ј-H), 4.36 (dd, JH,H ϭ 6.5, JЈH,H
ϭ
3
10.5 Hz, 1 H, 7-H), 4.89 (br. d, JH,H ϭ 8.3 Hz, 1 H, 5-H), 5.12 (s,
3
3
1 H, 10-H), 5.60 (d, JH,H ϭ 7 Hz, 1 H, 2-H), 6.01 (t, JH,H
ϭ
8.8 Hz, 1 H, 13-H), 7.28Ϫ7.42 (m, 5 H, CH, 3Ј-Ph), 7.51 (t, 3JH,H ϭ
3a (n ؍ nЈ ؍ 3): Application of Method A on 4 (130 mg,
0.137 mmol) with 4-bromobutanoic acid, and purification with
heptane/EtOAc (60:40) afforded 3a (102 mg, 60%). 1H NMR
(300 MHz, CDCl3): δ ϭ Ϫ0.27 (s, 3 H, CH3Si), Ϫ0.11 (s, 3 H,
CH3Si), 0.54Ϫ0.69 [m, 12 H, 2 (CH3CH2)3Si], 0.80 [s, 9 H,
(CH3)3CSi], 0.89Ϫ1.02 [m, 18 H, 2 (CH3CH2)3Si], 1.17 (s, 3 H, 16-
H3), 1.21 (s, 3 H, 17-H3), 1.63 (s, 3 H, 19-H3), 1.81 (s, 3 H, 18-H3),
3
7.4 Hz, 2 H, m-CH, 2-OBz), 7.64 (t, JH,H ϭ 7.3 Hz, 1 H, p-CH,
2-OBz), 8.04 (d, JH,H ϭ 7.4 Hz, 2 H, o-CH, 2-OBz) ppm. 13C
3
NMR (75 MHz, CDCl3): δ ϭ Ϫ5.1 and Ϫ4.8 [(CH3)2Si], 5.4 and
6.1 (CH2Si), 7.0 and 7.1 (CH3CH2Si), 10.5 (C-19), 14.2 (C-18), 20.6
(C-16), 23.1 (CH3, OAc), 25.8 [(CH3)3CSi], 26.5 (C-17), 35.0 (C-
14), 37.4 (C-6), 43.2 (C-15), 46.8 (C-3), 58.4 (C-3Ј), 59.6 (C-8), 71.2
(C-13), 72.8 (C-7), 75.2 (C-2), 75.5 (C-10), 77.3 (C-2Ј), 78.5 (C-20),
78.9 (C-1), 81.2 (C-4), 84.2 (C-5), 127.5, 128.2 and 128.4 (o-, m-,
p-C, 3Ј-Ph), 128.6 (m-C, Bz), 129.6 (i-C, Bz), 130.2 (o-C, Bz), 133.7
(p-C, Bz), 134.7 (C-11), 137.6 (C-12), 140.1 (i-C, 3Ј-Ph), 167.1 (CO,
Bz), 169.9 (CO, Ac), 172.1(C-1Ј), 205.4 (C-9) ppm. MS (ESIϩ):
m/z ϭ 1050 [M ϩ Hϩ], 1072 [M ϩ Naϩ], 1088 [M ϩ Kϩ].
1.92 (m,
1 H, 6β-H), 2.05Ϫ2.28 (m, 6 H, 14-H2 and 2
CH2CH2CH2), 2.42 (s, 3 H, CH3, OAc), 2.43Ϫ2.66 (m, 5 H, 6-Hα,
CH2CON and CH2COO), 3.49 (m, 4 H, 2 CH2Br), 3.75 (d, 3JH,H ϭ
2
7 Hz, 1 H, 3-H), 4.20 and 4.49 (qAB, JH,H ϭ 8 Hz, 2 H, 20-H2),
4.35 (dd, JH,H ϭ 6.6 Hz and 3JЈH,H ϭ 10.5 Hz, 1 H, 7-H), 4.49
3
3
(br. s, 1 H, 2Ј-H), 4.93 (d, JH,H ϭ 8.4 Hz, 1 H, 5-H), 5.13 (s, 1 H,
10-H), 5.43 (d, 3JH,H ϭ 7 Hz, 1 H, 2-H), 5.46 (br. d, 3JH,H ϭ 9 Hz,
3
3
2-Debenzoyl-2Ј-O-(tert-butyldimethylsilyl)-3Ј-(de-tert-butoxy-
carbonyl)-7,10-bis(triethylsilyl)docetaxel (4):[25] Red-Al (0.89 mL of
1 H, 3Ј-H), 6.15 (t, JH,H ϭ 9 Hz, 1 H, 13-H), 6.47 (d, JH,H ϭ
9 Hz, 1 H, NH), 7.21Ϫ7.43 (m, 5 H, 5 CH, 3Ј-Ph) ppm. 13C NMR
546
Eur. J. Org. Chem. 2003, 542Ϫ550

Synthesis of Novel 2-O,3Ј-N-Linked Macrocyclic Taxoids with Variable Ring Size
FULL PAPER
(75 MHz, CDCl3): δ ϭ Ϫ5.6 and Ϫ5.3 (CH3Si), 5.4 and 6.1
(CH3CH2Si), 7.1 (CH3CH2Si), 10.5 (C-19), 13.9 (C-18), 20.7 (C- ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 23.3 (CH2), 28.0 (CH2),
16), 23.3 (CH3, OAc), 25.7 [(CH3)3CSi], 26.7 (C-17), 27.7 and 28.3 28.5 (CH2), 29.1 (CH2), 31.8 (CH2), 32.8 (CH2), 33.4 (BrCH2), 33.9
3JH,H ϭ 6.6 Hz, 2 H, CH2Br), 3.45 (t, 3JH,H ϭ 6.6 Hz, 2 H, CH2Br)
(CH2CH2CH2), 32.8 (CH2Br and CH2COO), 33.4 (CH2Br), 34.4 (BrCH2 and CH2COO), 36.2 (CH2CON), 172.6 (COO), 174.2
(CH2CON), 35.4 (C-14), 37.4 (C-6), 43.4 (C-15), 46.6 (C-3), 55.5 (CON) ppm. MS (ESIϩ): m/z ϭ 1336 [M ϩ Naϩ].
(C-3Ј), 58.5 (C-8), 72.1 (C-13), 72.8 (C-7), 75.0 (C-2), 75.3 (C-10),
3g (n ؍ 7, nЈ ؍ 5): Application of Method B on 4 (116 mg,
75.5 (C-2Ј), 77.2 (C-20), 78.8 (C-1), 81.2 (C-4), 84.3 (C-5), 126.7,
0.123 mmol) with 4- and 5-bromooctanoic acids, and purification
128.1, and 128.8 (o-, m-, p-C, 3Ј-Ph), 134.4 (C-11), 138.0 (C-12),
with heptane/EtOAc (85:15) afforded 3g (91 mg, 56%). 1H NMR
138.6 (i-C, 3Ј-Ph), 170.1 (CO, Ac), 171.4 (C-1Ј), 171.8 (2-OCO),
(300 MHz, CDCl3): δ ϭ 1.23Ϫ1.47 (m, 6 H, 3 CH2CH2CH2),
173.5 (3Ј-NHCO), 205.4 (C-9) ppm. MS (ESIϩ): m/z ϭ 1266 [M
1.49Ϫ1.74 (m, 6 H, 3 CH2CH2CH2), 1.79Ϫ1.96 (m, 5 H, 2
ϩ Naϩ].
CH2CH2CH2 and 6-Hβ), 2.24Ϫ2.39 (m, 3 H, CH2CON and
CHCOO), 2.41Ϫ2.60 (m, 2 H, 6-Hα and CHCOO), 3.35Ϫ3.44 (m,
4 H, CH2Br) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 23.9 (CH2),
27.7 (CH2), 28.0 (CH2), 29.1 (CH2), 32.5 (CH2), 32.8 (CH2), 33.6
(BrCH2), 33.9 (BrCH2), 35.2 (CH2COO), 36.6 (CH2CON), 172.6
(COO), 174.5 (CON) ppm. MS (ESIϩ): m/z ϭ 1350 [M ϩ Naϩ].
3b (n ؍ 4, nЈ ؍ 3): Application of Method B on 4 (150 mg,
0.159 mmol) with 4- and 5-bromopentanoic acids, and purification
with CH2Cl2/acetone (95:5) afforded 3b (146 mg, 73%); NMR
1H (300 MHz, CDCl3):
δ
ϭ
1.74Ϫ1.94 (m,
5
H,
H,
BrCH2CH2CH2CH2CON and 6-Hβ), 1.95Ϫ2.05 (m,
2
BrCH2CH2CH2CO), 2.32 (m, 2 H, CH2CON), 2.43Ϫ2.66 (m, 3 H,
6-Hα and CH2COO), 3.38Ϫ3.60 (m, 4 H, 2 CH2Br) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 24.3 (CH2), 27.7 (CH2), 32.0 (CH2),
32.8 (BrCH2), 33.0 (CH2COO), 33.4 (BrCH2), 35.5 (CH2CON),
172.0 (COO), 173.5 (CON) ppm. MS (ESIϩ): m/z ϭ 1280 [M ϩ
Naϩ].
3h (n ؍ nЈ ؍ 7): Application of Method A on 4 (150 mg,
0.159 mmol) with 4-bromohexanoic acid, and purification with
heptane/EtOAc (80:20) afforded 3h (148 mg, 69%). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.23Ϫ1.40 (m, 12 H, 6 CH2CH2CH2),
1.61Ϫ1.75 (m, 4 H, 2 CH2CH2CH2), 1.75Ϫ2.00 (m, 5 H, 2
BrCH2CH2CH2 and 6-Hβ), 2.22Ϫ2.42 (m, 4 H, CH2CON and
CH2COO), 3.23Ϫ3.49 (m, 4 H, CH2Br) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 24.8 (CH2), 25.3(CH2), 28.0 (CH2), 28.5 (CH2), 28.6
(CH2), 28.9 (CH2), 29.0 (CH2), 29.1 (CH2), 32.7 (CH2), 33.9
(BrCH2), 35.8 (CH2COO), 36.6 (CH2CON), 172.7 (COO), 174.8
(CON) ppm. MS (ESIϩ): m/z ϭ 1378 [M ϩ Naϩ].
3c (n ؍ nЈ ؍ 4): Application of Method A on 4 (150 mg,
0.159 mmol) with 4-bromopentanoic acid, and purification with
heptane/EtOAc (75:25) afforded 3c (183 mg, 91%). 1H NMR
(300 MHz, CDCl3):
δ
ϭ
1.72Ϫ1.98 (m,
9
H,
2
BrCH2CH2CH2CH2CO and 6-Hβ), 2.34 (m, 2 H, CH2CON),
2.42Ϫ2.56 (m, 3 H, 6-Hα and CH2COO), 3.35Ϫ3.50 (m, 4 H, 2
CH2Br) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 24.0 (CH2), 24.8
(CH2), 32.0 (CH2), 32.8 (CH2), 33.4 (BrCH2), 33.9 (BrCH2), 34.7
(CH2COO), 35.4 (CH2CON), 171.9(COO), 174.2 (CON) ppm. MS
(ESIϩ): m/z ϭ 1294 [M ϩ Naϩ].
General Procedure for Ring Closure (Compounds 7a؊h): Anhydrous
sodium sulfide (Na2S, 1.05 equiv.) was added to a dry acetone solu-
tion of compound 3a؊h (1 equiv., 12 m) and the reaction mixture
was stirred at room temperature for 1 h. After standard workup,
the residue was purified by silica-gel chromatography (CH2Cl2/
acetone, 95:5) unless otherwise specified.
3d (n ؍ 5, nЈ ؍ 4): Application of Method B on 4 (150 mg,
7a (n ؍ nЈ ؍ 3): Ring closure of 3a (100 mg, 0.080 mmol) afforded
7a (45 mg, 50%) as a white amorphous solid. H NMR (300 MHz,
0.159 mmol) with 4- and 5-bromohexanoic acids, and purification
with CH2Cl2/acetone (98:2) afforded 3d (152 mg, 75%). H NMR
1
1
CDCl3): δ ϭ Ϫ0.36 (s, 3 H, CH3Si), Ϫ0.12 (s, 3 H, CH3Si),
0.55Ϫ0.79 [m, 12 H, 2 (CH3CH2)3Si], 0.70 [s, 9 H, (CH3)3CSi],
0.95Ϫ1.02 [m, 18 H, 2 (CH3CH2)3Si], 1.15 (s, 3 H, 16-H3), 1.25 (s,
3 H, 17-H3), 1.63 (s, 3 H, 19-H3), 1.65 (m, 2 H, CH2CH2CH2), 1.87
(300 MHz, CDCl3): δ ϭ 1.46 (m, 2 H, CH2CH2CH2), 1.66 (m, 2
H, CH2CH2CH2), 1.80Ϫ2.00 (m, 7 H, 3 CH2CH2CH2 and 6-Hβ),
2.32 (m, 2 H, CH2CON), 2.41Ϫ2.57 (m, 3 H, 6-Hα and CH2COO),
3.37Ϫ3.50 (m, 4 H, 2 CH2Br) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 23.3 (CH2), 24.9 (CH2), 27.8 (CH2), 31.8 (CH2), 32.5 (CH2),
33.5 (BrCH2), 33.9 (BrCH2 and CH2COO), 36.3 (CH2CON), 172.3
(COO), 174.2 (CON) ppm. MS (ESIϩ): m/z ϭ 1308 [M ϩ Naϩ].
(s,
3 H, 18-H3), 1.81Ϫ2.20 (m, 5 H, 6-Hβ, 14-H2, and
CH2CH2CH2), 2.30Ϫ2.69 (m, 9 H, 2 CH2S, 6-Hα, CH2CON, and
3
CH2COO), 2.52 (s, 3 H, CH3, OAc), 3.74 (d, JH,H ϭ 7.3 Hz, 1 H,
3-H), 4.17 (qAB, 2JH,H ϭ 8 Hz, 1 H, 20-H), 4.32Ϫ4.49 (m, 2 H, 7-
3
3e (n ؍ nЈ ؍ 5): Application of Method A on 4 (50 mg,
0.053 mmol) with 4-bromohexanoic acid, and purification with
heptane/EtOAc (50:50) afforded 3e (58 mg, 84%). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.20Ϫ1.26 (m, 4 H, 2 CH2CH2CH2),
1.58Ϫ1.74 (m, 4 H, 2 CH2CH2CH2), 1.76Ϫ1.94 (m, 5 H, 2
BrCH2CH2CH2 and 6-Hβ), 2.30 (m, 2 H, CH2CON), 2.35Ϫ2.41
(m, 3 H, 6-Hα and CH2COO), 3.33Ϫ3.44 (m, 4 H, 2 CH2Br) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 23.3 (CH2), 24.5 (CH2), 24.8
(CH2), 27.7 (CH2), 27.8 (CH2), 32.7 (CH2), 33.6 (BrCH2), 33.7
(BrCH2), 35.5 (CH2COO), 36.2 (CH2CON), 172.3(COO), 174.5
(CON) ppm. MS (ESIϩ): m/z ϭ 1322 [M ϩ Naϩ].
H and 20-H), 4.52 (br. s, 1 H, 2Ј-H), 4.89 (d, JH,H ϭ 8.2 Hz, 1 H,
3
5-H), 5.11 (s, 1 H, 10-H), 5.41 (d, JH,H ϭ 7.3 Hz, 1 H, 2-H), 5.52
3
3
(br. d, JH,H ϭ 9.1 Hz, 1 H, 3Ј-H), 6.29 (d, JH,H ϭ 9.1 Hz, 1 H,
3
NH), 6.37 (t, JH,H ϭ 8.8 Hz, 1 H, 13-H), 7.15Ϫ7.39 (m, 5 H, 5
CH, 3Ј-Ph) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ6.1 and Ϫ5.4
(CH3Si), 5.4 and 6.1 (CH3CH2Si), 7.0 and 7.1 (CH3CH2Si), 10.7
(C-19), 13.7 (C-18), 21.3 (C-16), 23.4 (CH3OAc), 25.5 [(CH3)3CSi],
25.9 (CH2CH2CH2), 26.8 (C-17), 30.6 and 30.9 (CH2S), 33.6
(CH2COO), 35.2 (CH2CON), 35.8 (C-14), 37.3 (C-6), 43.4 (C-15),
46.8 (C-3), 54.8 (C-3Ј), 58.3 (C-8), 70.7 (C-13), 72.6 (C-7), 75.1 and
75.2 (C-2, C-10, and C-2Ј), 77.2 (C-20), 79.7 (C-1), 80.8 (C-4), 84.4
(C-5), 126.5, 127.8, and 128.6 (o-, m-, p-C, 3Ј-Ph), 134.0 (C-11),
137.6 (C-12), 138.3 (i-C, 3Ј-Ph), 170.1 (CO, Ac), 171.2 (C-1Ј), 171.6
(2-OCO), 174.2 (3Ј-NHCO), 205.2 (C-9). MS (ESIϩ): m/z ϭ 1138
[M ϩ Naϩ].
3f (n ؍ 7, nЈ ؍ 4): Application of Method B on 4 (150 mg,
0.159 mmol) with 4- and 5-bromooctanoic acids, and purification
with CH2Cl2/acetone (95:5) afforded 3f (90 mg, 43%). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.22Ϫ1.49 (m, 6 H, 3 CH2CH2CH2), 1.66
(m, 2 H, CH2CH2CH2), 1.79Ϫ1.89 (m, 4 H, 2 CH2CH2CH2), 7b (n ؍ 4, nЈ ؍ 3): Ring closure of 3b (120 mg, 0.095 mmol)
1.89Ϫ2.02 (m, 3 H, CH2CH2CH2 and 6-Hβ), 2.27 (m, 2 H,
afforded 7b (55 mg, 51%) as a white amorphous solid. 1H
CH2CON), 2.30Ϫ2.57 (m, 3 H, 6-Hα and CH2COO), 3.38 (t, NMR (300 MHz, CDCl3):
Eur. J. Org. Chem. 2003, 542Ϫ550
δ
ϭ
1.41Ϫ1.76 (m,
4
H,
547

´
´
O. Querolle, J. Dubois, S. Thoret, C. Dupont, F. Gueritte, D. Guenard
FULL PAPER
SCH2CH2CH2CH2CON), 1.85Ϫ2.03 (m, 3 H, SCH2CH2CH2CO (CH2-COO), 36.1 (CH2-CON), 172.5 (COO), 175.0 (CON) ppm.
and 6-Hβ), 2.27 (m, 1 H, CHCON), 2.35Ϫ2.47 (m, 3 H, CHCON MS (ESIϩ): m/z ϭ 1250 [M ϩ Naϩ].
and CH2COO), 2.50Ϫ2.71 (m, 5 H, 6-Hα and 2 CH2S) ppm. 13C
General Procedure for Removal of the Silyl Groups: HF/pyridine
NMR (75 MHz, CDCl3): δ ϭ 23.9 (CH2), 25.2 (CH2), 28.9 (CH2),
(70:30, 40 equiv.) was added dropwise at 0 °C to a solution of 7a؊h
(1 equiv., 30 m) in pyridine/acetonitrile (7:93), and the mixture
was stirred at 0 °C for 3 h. The reaction was quenched with satur-
ated aqueous sodium hydrogen carbonate solution. After standard
workup, the crude extract was purified by silica-gel chromato-
graphy (CH2Cl2/acetone, 95:5).
30.5 (SCH2), 32.1 (SCH2), 34.4 (CH2COO), 34.7 (CH2CON), 172.0
(COO), 174.2 (CON) ppm. MS (ESIϩ): m/z ϭ 1152 [M ϩ Naϩ].
7c (n ؍ nЈ ؍ 4): Ring closure of 3c (100 mg, 0.079 mmol) afforded
1
7c (47 mg, 52%) as a white amorphous solid. H NMR (300 MHz,
CDCl3): δ ϭ 1.45Ϫ1.80 (m, 8 H, 2 SCH2CH2CH2CH2CO), 2.30
(m, 2 H, CHCON and CHCOO), 2.36Ϫ2.49 (m, 4 H, CHCON,
CHCOO, and 2 SCHCH2), 2.49Ϫ2.70 (m, 3 H, 6-Hα and 2
SCHCH2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 23.5 (CH2), 24.5
(CH2), 28.2 (CH2), 28.5 (CH2), 30.1 (SCH2), 31.3 (SCH2), 34.5
(CH2COO), 34.7 (CH2CON), 171.9(COO), 174.2 (CON) ppm. MS
(ESIϩ): m/z ϭ 1166 [M ϩ Naϩ].
2a (n ؍ nЈ ؍ 3): Removal of the silyl groups of 7a (10 mg,
0.009 mmol) afforded 2a (3.6 mg, 52%) as a white amorphous solid.
1H NMR (300 MHz, CDCl3): δ ϭ 1.08 (s, 3 H, 16-H3), 1.27 (s, 3
H, 17-H3), 1.73 (s, 3 H, 19-H3), 1.77Ϫ1.91 (m, 2 H, 6-Hβ and
CH2CHCH2S), 1.94 (s, 3 H, 18-H3), 1.97Ϫ2.15 (m, 2 H, 14-H and
CH2CHCH2S), 2.18Ϫ2.28 (m, 1 H, 14-H), 2.29Ϫ2.44 (m, 2 H,
CHCON and CHCOO), 2.51 (s, 3 H, CH3, OAc), 2.48Ϫ2.75 (m, 5
7d (n ؍ 5, nЈ ؍ 4): Ring closure of 3d (120 mg, 0.093 mmol) af-
forded 7d (75 mg, 69%) as a white amorphous solid. 1H NMR
(300 MHz, CDCl3): δ ϭ 1.39 (m, 2 H, CH2CH2CH2), 1.54Ϫ1.76
(m, 8 H, 4 CH2CH2CH2), 2.24Ϫ2.45 (m, 4 H, CH2CON and
CH2COO), 2.47Ϫ2.60 (m, 5 H, 2 SCH2 and 6-Hα) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 24.2 (CH2), 24.4 (CH2), 27.2 (CH2), 28.7
(CH2), 30.6 (SCH2), 31.2 (SCH2), 34.6 (CH2COO), 35.4
(CH2CON), 172.2 (COO), 174.5 (CON) ppm. MS (ESIϩ): m/z ϭ
1180 [M ϩ Naϩ].
3
H, CHCON, CHCOO, 6-Hα and CH2S), 3.83 (d, JH,H ϭ 7.5 Hz,
3
1 H, 3-H), 4.16Ϫ4.32 (m, 2 H, 7-H and 20-H), 4.49 (d, JH,H
ϭ
3
8 Hz, 1 H, 20-H), 4.72 (br. s, 1 H, 2Ј-H), 4.95 (d, JH,H ϭ 9.1 Hz,
1 H, 5-H), 5.16 (s, 1 H, 10-H), 5.46 (d, JH,H ϭ 7.5 Hz, 1 H, 2-H),
5.87 (br. d, 1 H, JH,H ϭ 9.3 Hz, 3Ј-H), 6.14 (d, JH,H ϭ 9.3 Hz, 1
H, NH), 6.48 (t, JH,H ϭ 9 Hz, 1 H, 13-H), 7.29Ϫ7.47 (m, 5 H, 5
3
3
3
3
CH, 3Ј-Ph) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 10.1 (C-19),
13.8 (C-18), 21.5 (C-16), 22.9 (CH3, OAc), 25.5 and 25.7
(CH2CH2CH2S), 26.6 (C-17), 30.3 and 30.7 (CH2S), 33.3
(CH2CO), 35.1 (C-14), 36.2 (C-6 and CH2CON), 43.2 (C-15), 46.3
(C-3), 55.7 (C-3Ј), 57.5 (C-8), 71.1 (C-13), 71.5 (C-7), 72.9 (C-2Ј),
73.9 (C-2), 75.1 (C-10), 77.6 (C-20), 79.4 (C-1), 80.7 (C-4), 84.8 (C-
5), 126.6, 127.7 and 128.7 (o-, m-, p-C, 3Ј-Ph), 135.5 (C-11), 138.4
(C-12 and i-C, 3Ј-Ph), 171.1 (CO, Ac), 171.9 (2-OCO), 172.6 (C-
1Ј), 174.1 (CON), 210.9 (C-9) ppm. HRMS (MALDI-TOF): m/z
calcd. for [C39H51NO13S ϩ Naϩ] 796.2979, found 796.2988 (∆ ϭ
Ϫ1.1 ppm).
7e (n ؍ nЈ ؍ 5): Ring closure of 3e (50 mg, 0.038 mmol) afforded
1
7e (20 mg, 44%) as a white amorphous solid. H NMR (300 MHz,
CDCl3): δ ϭ 1.08Ϫ1.43 (m, 4 H, 2 CH2CH2CH2), 1.43Ϫ1.88 (m, 8
H, 2 CH2CH2CH2), 2.23Ϫ2.45 (m, 4 H, CH2CON and CH2COO),
2.45Ϫ2.58 (m, 5 H, 2 SCH2 and 6-Hα) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 24.5 (CH2), 25.0 (CH2), 27.6 (CH2), 29.0 (CH2), 29.3
(CH2), 31.1 (SCH2), 31.6 (SCH2), 34.4 (CH2COO), 35.5
(CH2CON), 172.2 (COO), 174.8 (CON) ppm. MS (ESIϩ): m/z ϭ
1194 [M ϩ Naϩ].
2b (n ؍ 4, nЈ ؍ 3): Removal of the silyl groups of 7b (44 mg,
0.039 mmol) afforded 2b (16 mg, 54%) as a white amorphous solid.
7f (n ؍ 7, nЈ ؍ 4): Ring closure of 3f (50 mg, 0.038 mmol) afforded
7f (26 mg, 58%) as a white amorphous solid. H NMR (300 MHz,
1
1H NMR (300 MHz, CDCl3):
δ
ϭ
1.80Ϫ1.94 (m,
5
3
H,
H,
CDCl3): δ ϭ 1.12Ϫ1.42 (m, 6 H, 3 CH2CH2CH2), 1.49Ϫ1.78 (m,
6 H, 3 CH2CH2CH2), 1.72Ϫ2.01 (m, 3 H, 6-Hβ and CH2CH2CH2),
2.21Ϫ2.47 (m, 4 H, CH2CON and CH2COO), 2.47Ϫ2.60 (m, 5 H,
SCH2 and 6-Hα) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 24.2
(CH2), 24.5 (CH2), 27.0 (CH2), 27.5 (CH2), 27.6 (CH2), 28.7 (CH2),
28.9 (CH2), 30.9 (SCH2), 31.4 (SCH2), 34.4 (CH2COO), 35.9
(CH2CON), 171.6 (COO), 172.3 (CON) ppm. MS (ESIϩ): m/z ϭ
1208 [M ϩ Naϩ].
SCH2CH2CH2CH2CON and 6-Hβ), 1.95Ϫ2.15 (m,
SCH2CH2CH2CO and 14-H), 2.36 (m, 2 H, CH2CON), 2.45Ϫ2.73
(m, 7 H, CH2COO, 6-Hα and 2 CH2S) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 24.0 (CH2), 25.1 (CH2), 28.8 (CH2), 30.5 (SCH2), 31.9
(SCH2), 34.4 (CH2COO), 34.6 (CH2CON), 173.3 (COO), 174.1
(CON) ppm. HRMS (MALDI-TOF): m/z calcd. for [C40H53NO13S
ϩ Naϩ] 810.3135, found 810.3138 (∆ ϭ Ϫ0.4 ppm).
2c (n ؍ nЈ ؍ 4): Removal of the silyl groups of 7c (20 mg,
0.017 mmol) afforded 2c (8.4 mg, 60%) as a white amorphous solid.
1H NMR (300 MHz, CDCl3): δ ϭ 1.56Ϫ1.87 (m, 9 H, 2
SCH2CH2CH2CH2CO and 6-Hβ), 2.11Ϫ2.38 (m, 6 H, 14-H2,
7g (n ؍ 7, nЈ ؍ 5): Ring closure of 3g (73 mg, 0.055 mmol) afforded
7g (29 mg, 44%) as a white amorphous solid. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.20Ϫ1.41 (m, 6 H, 3 CH2CH2CH2), 1.41Ϫ1.58 (m,
8 H, 4 CH2CH2CH2), 1.64 (m, 2 H, CH2CH2CH2), 2.26Ϫ2.41 (m,
4 H, CH2CON and CH2COO), 2.45Ϫ2.57 (m, 5 H, SCH2 and 6-
Hα) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 24.3 (CH2), 24.8
(CH2), 27.6 (CH2), 27.8 (CH2), 28.0 (CH2), 28.8 (CH2), 29.4 (CH2),
31.9 (SCH2), 34.5 (CH2COO), 36.0 (CH2CON), 172.4 (COO),
174.7 (CON) ppm. MS (ESIϩ): m/z ϭ 1222 [M ϩ Naϩ].
CH2CON, and CH2COO), 2.38Ϫ2.71(m,
5 H, 6-Hα and 2
SCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 23.6 (CH2),
24.5 (CH2), 28.5 (CH2), 28.6 (CH2), 31.0 (SCH2), 31.9 (SCH2), 34.7
(CH2COO), 34.8 (CH2CON), 173.4 (COO), 174.1 (CON) ppm.
HRMS (MALDI-TOF): m/z calcd. for [C41H55NO13S ϩ Naϩ]
824.3292, found 824.3284 (∆ ϭ 1.0 ppm).
7h (n ؍ nЈ ؍ 7): Ring closure of 3h (83 mg, 0.061 mmol) afforded
7h (30 mg, 40%) as a white amorphous solid [purification was per-
2d (n ؍ 5, nЈ ؍ 4): Removal of the silyl groups of 7d (40 mg,
formed with CH2Cl2/acetone (96:4) as solvent]. 1H NMR 0.035 mmol) afforded 2d (14 mg, 50%) as a white amorphous solid
(300 MHz, CDCl3): δ ϭ 1.22Ϫ1.36 (m, 12 H, 6 CH2CH2CH2), [purification was performed with CH2Cl2/acetone (97:3) as sol-
1.36Ϫ1.73 (m, 8 H, 4 CH2CH2CH2), 2.23Ϫ2.58 (m, 9 H, 2 SCH2,
vent]. 1H NMR (300 MHz, CDCl3):
δ ϭ 1.47 (m, 2 H,
6-Hα, CH2CON, and CH2COO) ppm. 13C NMR (75 MHz, CH2CH2CH2), 1.60Ϫ1.76 (m, 4 H, 2 CH2CH2CH2), 1.76Ϫ1.89 (m,
CDCl3): δ ϭ 24.7 (CH2), 25.2 (CH2), 27.9 (CH2), 28.2 (CH2), 28.5 5 H, 2 CH2CH2CH2 and 6-Hβ), 2.15Ϫ2.30 (m, 6 H, CH2CON,
(CH2), 29.2 (CH2), 29.4 (CH2), 31.5 (S-CH2), 31.7 (S-CH2), 34.7
CH2COO, and 14-H2), 2.48Ϫ2.66 (m, 5 H, 2 SCH2 and 6-Hα) ppm.
548
Eur. J. Org. Chem. 2003, 542Ϫ550

Synthesis of Novel 2-O,3Ј-N-Linked Macrocyclic Taxoids with Variable Ring Size
FULL PAPER
3
2
13C NMR (75 MHz, CDCl3): δ ϭ 24.5 (CH2), 24.6 (CH2), 27.2 3.72 (d, JH,H ϭ 7 Hz, 1 H, 3-H), 4.20 and 4.44 (qAB, JH,H
ϭ
(CH2), 28.7 (CH2), 31.4 (SCH2), 31.7 (SCH2), 34.9 (CH2COO),
8 Hz, 2 H, 20-H2), 4.34 (dd, 3JH,H ϭ 6.6 Hz and 3JЈH,H ϭ 10.6 Hz,
3
3
35.7 (CH2CON), 173.1 (COO), 174.3 (CON) ppm. HRMS 1 H, 7-H), 4.48 (d, JH,H ϭ 1.5 Hz, 1 H, 2Ј-H), 4.92 (d, JH,H
ϭ
(MALDI-TOF): m/z calcd. for [C42H57NO13S ϩ Naϩ] 838.3448,
found 838.3469 (∆ ϭ Ϫ2.5 ppm).
8.3 Hz, 1 H, 5-H), 5.11 (s, 1 H, 10-H), 5.44 (d, JH,H ϭ 7 Hz, 1 H,
3
2-H), 5.47 (dd, 3JH,H ϭ 9 Hz and 3JЈH,H ϭ 1.5 Hz, 1 H, 3Ј-H), 6.13
3
3
(t, JH,H ϭ 9 Hz, 1 H, 13-H), 6.59 (d, JH,H ϭ 9 Hz, 1 H, NH),
7.31 (m, 5 H, 5 CH, 3Ј-Ph) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
Ϫ5.7 and Ϫ5.3 (CH3Si), 5.3 and 6.1 [2 (CH3CH2)3Si], 7.0 and 7.1
[2 (CH3CH2)3Si], 10.5 (C-19), 13.9 (C-18), 20.8 (C-16), 23.3 (CH3,
OAc), 24.8 (CH2CH2CH2S), 25.6 [(CH3)3CSi], 26.6 (C-17), 28.3
and 28.4 (CH2CH2CH2S), 30.7 (CH3COS), 33.5 (2-OCOCH2), 34.9
(CH2CON), 35.5 (C-14), 37.4 (C-6), 43.4 (C-15), 46.5 (C-3), 55.4
(C-3Ј), 58.4 (C-8), 72.1 (C-13), 72.7 (C-7), 74.9 (C-2), 75.2 (C-2Ј),
75.4 (C-10), 76.9 (C-20), 78.5 (C-1), 81.1 (C-4), 84.3 (C-5), 126.7,
128.0 and 128.7 (o-, m-, p-C, 3Ј-Ph), 134.2 (C-11), 138.0 (C-12),
138.6 (i-C, 3Ј-Ph), 170.1 (CO, Ac), 171.6 (C-1Ј), 171.7 (2-OCO),
173.5 (3Ј-NHCO), 195.6 and 196.1 (COS), 205.4 (C-9). MS (ESIϩ):
m/z ϭ 1257 [M ϩ Naϩ].
2e (n ؍ nЈ ؍ 5): Removal of the silyl groups of 7e (18 mg,
0.015 mmol) afforded 2e (7.1 mg, 57%) as a white amorphous solid.
1H NMR (300 MHz, CDCl3):
δ ϭ 1.37Ϫ1.60 (m, 4 H,
CH2CH2CH2), 1.60Ϫ1.97 (m, 9 H, 2 CH2CH2CH2 and 6-Hβ),
2.27Ϫ2.70 (m, 9 H, CH2CON, 2 SCH2, 6-Hα, and CH2COO) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 24.5 (CH2), 25.5 (CH2), 27.0
(CH2), 28.2 (CH2), 28.6 (CH2), 29.7 (CH2), 31.9 (SCH2), 32.1
(SCH2), 34.9 (CH2COO), 35.9 (CH2CON), 173.2 (COO), 173.9
(CON) ppm. HRMS (MALDI-TOF): m/z calcd. for [C43H59NO13S
ϩ Naϩ] 852.3605, found 852.3617 (∆ ϭ Ϫ1.4 ppm).
2f (n ؍ 7, nЈ ؍ 4): Removal of the silyl groups of 7f (26 mg,
0.022 mmol) afforded 2f (10.5 mg, 57%) as a white amorphous
solid [purification was performed with CH2Cl2/acetone (97:3) as
solvent]. 1H NMR (300 MHz, CDCl3): δ ϭ 1.29Ϫ1.48 (m, 6 H,
3 CH2CH2CH2), 1.50Ϫ1.93 (m, 9 H, 4 CH2CH2CH2 and 6-Hβ),
2.08Ϫ2.43 (m, 6 H, 14-H2, CH2CON, and CH2COO), 2.43Ϫ2.64
(m, 5 H, SCH2 and 6-Hα) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
24.3 (CH2), 24.8 (CH2), 27.3 (CH2), 27.5 (CH2), 27.8 (CH2), 28.0
(CH2), 28.6 (CH2), 31.5 (SCH2), 32.0 (SCH2), 34.7 (CH2COO),
36.2 (CH2CON), 172.9 (COO), 174.2 (CON) ppm. HRMS
(MALDI-TOF): m/z calcd. for [C44H61NO13S ϩ Naϩ] 866.3761,
found 866.3766 (∆ ϭ Ϫ0.5 ppm).
Synthesis of the Disulfide Derivative 9: Sodium carbonate was ad-
ded to a solution of 8 (30 mg, 0.024 mmol) in MeOH (0.56 mL)
and the solution was stirred for 3 h at room temperature. After
standard workup, the residue was purified by silica-gel chromato-
graphy (heptane/EtOAc, 50:50) to afford 9 (9.4 mg, 34%) as a white
amorphous solid. 1H NMR (300 MHz, CDCl3): δ ϭ Ϫ0.35 (s, 3
H, CH3Si), Ϫ0.09 (s, 3 H, CH3Si), 0.56 [m, 12 H, 2 (CH3CH2)3Si],
0.72 [s, 9 H, (CH3)3CSi], 0.99 [m, 18 H, 2 (CH3CH2)3Si], 1.16 (s, 3
H, 16-H3), 1.26 (s, 3 H, 17-H3), 1.63 (s, 3 H, 19-H3), 1.86 (s, 3 H,
18-H3), 1.79Ϫ2.27 (m, 7 H, 6-Hβ, 14-H2, and 2 CH2CH2CH2S),
2.30Ϫ2.60 (m, 5 H, 6-Hα, CH2COO, and CH2CON), 2.52 (s, 3 H,
2g (n ؍ 7, nЈ ؍ 5): Removal of the silyl groups of 7g (20 mg,
0.017 mmol) afforded 2g (7.6 mg, 53%) as a white amorphous solid.
1H NMR (300 MHz, CDCl3): δ ϭ 1.19Ϫ1.42 (m, 6 H, 3
CH2CH2CH2), 1.43Ϫ1.79 (m, 10 H, 5 CH2CH2CH2), 2.26Ϫ2.36
(m, 4 H, CH2CON and CH2COO), 2.37Ϫ2.55 (m, 5 H, 2 SCH2
and 6-Hα) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 24.5 (CH2), 25.0
(CH2), 27.9 (CH2), 28.7(CH2), 29.4 (CH2), 29.9 (CH2), 32.1
(SCH2), 34.8 (CH2COO), 36.2 (CH2CON), 173.1 (COO), 174.5
(CON) ppm. HRMS (MALDI-TOF): m/z calcd. for [C45H63NO13S
ϩ Naϩ] 880.3918, found 880.3895 (∆ ϭ 2.5 ppm).
3
CH3, OAc), 2.66Ϫ2.92 (m, 4 H, 2 CH2S), 3.76 (d, JH,H ϭ 7.5 Hz,
2
1 H, 3-H), 4.18 and 4.41 (qAB, JH,H ϭ 8 Hz, 2 H, 20-H2), 4.40
3
(m, 1 H, 7-H), 4.54 (br. s, 1 H, 2Ј-H), 4.9 (d, JH,H ϭ 9.5 Hz, 1 H,
3
5-H), 5.12 (s, 1 H, 10-H), 5.40 (d, JH,H ϭ 7.5 Hz, 1 H, 2-H), 5.61
(br. d, 3JH,H ϭ 9 Hz, 1 H, 3Ј-H), 6.33 (d, 3JH,H ϭ 9 Hz, 1 H, NH),
3
6.40 (t, JH,H ϭ 8.5 Hz, 1 H, 13-H), 7.15Ϫ7.42 (m, 5 H, 5 CH, 3Ј-
Ph) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ6.1 and Ϫ5.4
(CH3Si), 5.3 and 5.9 (CH3CH2Si), 6.8 and 6.9 (CH3CH2Si), 10.6
(C-19), 13.6 (C-18), 21.1 (C-16), 23.3 (CH3, OAc), 25.3
(CH2CH2CH2S), 25.4 [(CH3)3CSi], 26.7 (C-17), 33.6 (2-OCOCH2),
34.7 (CH2CON), 35.6 (C-14), 37.2 (C-6), 38.9 (CH2S), 43.3 (C-15),
46.6 (C-3), 54.7(C-3Ј), 58.2 (C-8), 70.8 (C-13), 72.6 (C-7), 74.8 (C-
2), 75.1 (C-2Ј and C-10), 77.3 (C-20), 79.4 (C-1), 80.8 (C-4), 84.2
(C-5), 126.4, 127.6, and 128.5 (o-, m-, p-C, 3Ј-Ph), 133.8 (C-11),
137.6 (C-12), 138.1 (i-C, 3Ј-Ph), 170.7 (CO, Ac), 171.2 (C-1Ј), 171.5
(2-OCO), 173.7 (3Ј-NHCOЈ), 205.1 (C-9) ppm. MS (ESIϩ): m/z ϭ
1170 [M ϩ Naϩ].
2h (n ؍ nЈ ؍ 7): Removal of the silyl groups of 7h (20 mg,
0.016 mmol) afforded 2h (7.4 mg, 53%) as a white amorphous solid.
1H NMR (300 MHz, CDCl3): δ ϭ 1.28Ϫ1.49 (m, 12 H, 3
CH2CH2CH2), 1.50Ϫ1.90 (m, 9 H, 4 CH2CH2CH2 and 6-Hβ),
2.10Ϫ2.31 (m, 4 H, 14-H2 and CH2CON),2.33Ϫ2.63 (m, 7 H, 2
SCH2, 6-Hα, and CH2COO) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 24.7 (CH2), 25.3 (CH2), 27.8 (CH2), 28.3 (CH2), 28.5 (CH2),
29.5 (CH2), 29.8 (CH2), 31.9 (SCH2), 34.9 (CH2COO), 36.3
(CH2CON), 173.2 (COO), 174.8 (CON) ppm. HRMS (MALDI-
TOF): m/z calcd. for [C47H67NO13S ϩ Naϩ] 908.4231, found
908.4248 (∆ ϭ Ϫ1.9 ppm).
Synthesis of Macrocyclic Taxoid 10: Removal of the silyl protecting
groups of 9 (20 mg, 0.017 mmol) was carried out according to the
general procedure but the solution was stirred for an additional 3
h at room temperature. After standard workup, the residue was
Synthesis of the Dithioacetyl Derivative 8: Potassium thioacetate
(30 mg, 0.26 mmol) was added to a solution of 3a (150 mg,
purified by silica-gel chromatography (CH2Cl2/MeOH, 9:1) to af-
1
0.12 mmol) in dry DMF (2.95 mL) and the solution was stirred for ford pure 10 (6.5 mg, 42%) as a white amorphous solid. H NMR
3 h at room temperature. After standard workup, the residue was
purified by silica-gel chromatography (heptane/EtOAc, 75:25) to
afford 8 (124 mg, 83%) as a yellowish amorphous solid. H NMR
(300 MHz, CDCl3): δ ϭ 1.07 (s, 3 H, 16-H3), 1.26 (s, 3 H, 17-H3),
1.71 (s, 3 H, 19-H3), 1.87 (m, 1 H, 6-Hβ), 1.91 (s, 3 H, 18-H3),
1.98Ϫ2.31 (m, 6 H, 14-H2 and 2 CH2CH2CH2S), 2.32Ϫ2.43 (m, 4
1
(300 MHz, CDCl3): δ ϭ Ϫ0.30 (s, 3 H, CH3Si), Ϫ0.11 (s, 3 H, H, CH2COO and CH2CON), 2.46 (s, 3 H, CH3, OAc), 2.55 (m, 1
3
CH3Si), 0.61 [m, 12 H, 2 (CH3CH2)3Si], 0.78 [s, 9 H, (CH3)3CSi],
H, 6-Hα), 2.84 (m, 4 H, 2 CH2S), 3.83 (d, JH,H ϭ 7.3 Hz, 1 H, 3-
2
0.96 [m, 18 H, 2 (CH3CH2)3Si], 1.16 (s, 3 H, 16-H3), 1.18 (s, 3 H, H), 4.20 and 4.48 (qAB, JH,H ϭ 8.2 Hz, 2 H, 20-H2), 4.24 (dd,
3
17-H3), 1.62 (s, 3 H, 19-H3), 1.80 (s, 3 H, 18-H3), 1.91 (m, 5 H, 6-
3JH,H ϭ 6.4 Hz and JЈH,H ϭ 11.4 Hz, 1 H, 7-H), 4.73 (br. s, 1 H,
3
Hβ and 2 CH2CH2CH2S), 2.19 (m, 2 H, 14-H2), 2.30Ϫ2.32 (s, 6 2Ј-H), 4.96 (d, JH,H ϭ 9 Hz, 1 H, 5-H), 5.15 (s, 1 H, 10-H), 5.41
H, 2 CH3COS), 2.37Ϫ2.44 (m, 4 H, CH2COO and CH2CON), 2.41 (d, JH,H ϭ 7.3 Hz, 1 H, 2-H), 5.58 (br. d, 1 H, JH,H ϭ 9 Hz, 3Ј-
(s, 3 H, CH3, OAc), 2.49 (m, 1 H, 6-Hα), 2.94 (m, 4 H, 2 CH2S), H), 6.28 (d, JH,H ϭ 9 Hz, 1 H, NH), 6.47 (t, JH,H ϭ 9 Hz, 1 H,
Eur. J. Org. Chem. 2003, 542Ϫ550 549
3
3
3
3

´
´
O. Querolle, J. Dubois, S. Thoret, C. Dupont, F. Gueritte, D. Guenard
FULL PAPER
[2]
13-H), 7.31Ϫ7.43 (m, 5 H, 5 CH, 3Ј-Ph) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 9.4 (C-19), 14.2 (C-18), 21.5 (C-16), 22.6 (CH3, OAc),
25.4 (CH2CH2CH2S), 26.7 (C-17), 33.8 (2-OCOCH2), 34.9
(CH2CON), 36.0 (C-14), 36.8 (C-6), 38.9 and 39.0 (CH2S), 43.2 (C-
15), 46.3 (C-3), 55.3 (C-3Ј), 57.5 (C-8), 71.8 (C-13), 72.4 (C-7), 72.7
(C-2), 74.2 (C-2Ј), 74.7 (C-10), 77.3 (C-20), 79.6 (C-1), 80.6 (C-4),
84.4 (C-5), 126.7, 128.1, and 128.9 (o-, m-, p-C, 3Ј-Ph), 135.1 (C-
11), 138.1 (C-12), 138.3 (i-C, 3Ј-Ph), 170.8 (CO, Ac), 171.6 (C-1Ј),
173.2 (2-OCO), 173.8 (3Ј-NHCO), 211.5 (C-9) ppm. HRMS
(MALDI-TOF): m/z calcd. for [C39H51NO13S2 ϩ Naϩ] 828.2700,
found 828.2734 (∆ ϭ Ϫ4.1 ppm).
P. B. Schiff, J. Fant, S. B. Horwitz, Nature 1979, 277, 665Ϫ667.
E. Nogales, S. G. Wolff, K. H. Downing, Nature (London)
[3]
1998, 391, 199Ϫ202.
[4]
´
´
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Synthesis of Taxoid 11: Removal of the silyl protecting groups of
8 (30 mg, 0.024 mmol) was carried out according to the general
procedure but the solution was stirred for an additional 3 h at 0
°C. After standard workup, the residue was purified by silica-gel
chromatography (CH2Cl2/MeOH, 95:5) to afford pure 11 (13.7 mg,
64%) as a white amorphous solid. 1H NMR (300 MHz, CDCl3):
δ ϭ 1.02 (s, 3 H, 16-H3), 1.21 (s, 3 H, 17-H3), 1.70 (s, 3 H, 19-H3),
[9]
[10]
[11]
[12]
1.80 (s,
3 H, 18-H3), 1.80Ϫ2.00 (m, 5 H, 6-Hβ and 2
CH2CH2CH2S), 2.12Ϫ2.65 (m, 7 H, 14-H2, 6-Hα, CH2COO, and
CH2CON), 2.23 (s, 3 H, CH3, OAc), 2.34 (s, 6 H, 2 CH3COS),
3
2.94Ϫ3.03 (m, 4 H, 2 CH2S), 3.76 (d, JH,H ϭ 7 Hz, 1 H, 3-H),
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4.17 (m, 1 H, 7-H), 4.20 and 4.44 (qAB, JH,H ϭ 8 Hz, 2 H, 20-
3
3
H2), 4.63 (d, JH,H ϭ 2.1 Hz, 1 H, 2Ј-H), 4.93 (d, JH,H ϭ 7.9 Hz,
1 H, 5-H), 5.17 (s, 1 H, 10-H), 5.45 (d, JH,H ϭ 7 Hz, 1 H, 2-H),
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3
3
3
5.54 (dd, JH,H ϭ 9 Hz and JЈH,H ϭ 2.1 Hz, 1 H, 3Ј-H), 6.16 (t,
3JH,H ϭ 9.9 Hz, 1 H, 13-H), 6.58 (d, JH,H ϭ 9 Hz, 1 H, NH),
3
[16]
[17]
7.31Ϫ7.46 (m, 5 H, CH, 3Ј-Ph) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 9.9 (C-19), 14.4 (C-18), 20.7 (C-16), 22.7 (CH3, OAc), 24.8
(CH2CH2CH2S), 26.6 (C-17), 28.3 (CH2CH2CH2S), 30.8
(CH3COS), 33.5 (2-OCOCH2), 34.9 (CH2CON), 35.8 (C-14), 37.0
(C-6), 43.2 (C-15), 46.3 (C-3), 55.8 (C-3Ј), 57.7 (C-8), 71.9 (C-13),
72.7 (C-7), 73.1 (C-2), 74.6 (C-2Ј and C-10), 78.2 (C-20), 78.4 (C-
1), 81.0 (C-4), 84.4 (C-5), 127.2, 128.3, and 129.0 (o-, m-, p-C, 3Ј-
Ph), 136.2 (C-11), 138.3 (C-12 and i-C, 3Ј-Ph), 170.3 (CO, Ac),
171.8 (C-1Ј), 173.1 (2-OCO), 173.4 (3Ј-NHCO), 196.1and 197.0
(COS), 211.5 (C-9) ppm. HRMS (MALDI-TOF): m/z calcd. for
[C43H57NO15S2 ϩ Naϩ] 914.3067, found 914.3079 (∆ ϭ Ϫ1.3 ppm).
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Larger amounts of compound 4 have been prepared by Orga-
Acknowledgments
The authors thank Dr. Alain Commerc¸on (AventisϪPharma) for a
´
gift of docetaxel. Christiane Gaspard is acknowledged for cyto-
toxicity evaluations, Jean-Francois Gallard for performing NMR
´
´
¸
´
spectra and Vincent Guerineau for high-resolution mass spectra.
Link.
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Des. 1995, 1, 95Ϫ112.
Received September 2, 2002
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