Studies directed toward the synthesis of taxanes: Construction of the tricyclo[5.3.1.01,7]undecane system

Article abstract of DOI:10.1002/(sici)1099-0690(199912)1999:12<3251::aid-ejoc3251>3.0.co;2-7

The intramolecular nucleophilic substitution of an epoxide by the anion of a nitrile was used to construct the bicyclo[3.1.0]hexane system of 9, derived from 8, and of 14, derived from 13. The intramolecular 1,3-dipolar cycloaddition of nitrile oxide 4, o

Full text of DOI:10.1002/(sici)1099-0690(199912)1999:12<3251::aid-ejoc3251>3.0.co;2-7

FULL PAPER
Studies Directed Toward the Synthesis of Taxanes: Construction of the
Tricyclo[5.3.1.01,7]undecane System
Alex Nivlet,[a] Luc Dechoux,[a] Thierry Le Gall,*[a] and Charles Mioskowski*[a,b]
Keywords: Taxol / Nitrile oxide / Cycloaddition reactions / Isoxazoline / Cyclopropane
The intramolecular nucleophilic substitution of an epoxide
by the anion of nitrile was used to construct the
bicyclo[3.1.0]hexane system of 9, derived from 8, and of 14,
derived from 13. The intramolecular 1,3-dipolar
isoxazoline 3. However, it was not possible to convert 3 into
the corresponding β-hydroxy ketone. Rearrangements of 3
were observed in the presence of dehydrating reagents
leading to compounds 19–21, which are structurally related
to 11(15Ǟ1)abeotaxanes.
a
cycloaddition of nitrile oxide 4, obtained from 14, led to
Various strategies have been employed to prepare taxol
and other taxane compounds. Convergent approaches
based on the formation of the B ring from a compound
which already has the A and C rings are handicapped by
the difficulty of cyclizing this eight-membered ring.[1] The
fragmentation of small rings to construct the A/B system
may be seen as an alternative. Several fragmentations of
cyclopropanes included in bicyclic or tricyclic systems have
been reported.[2]
Our own strategy to gain access to the taxane A/B system
is summarized in Scheme 1. The bicyclic compound 1 could
be derived from compound 2 by a process involving the
regioselective breaking of a carbon-carbon bond of the
cyclopropane ring included in the tricyclo[5.3.1.01,7]unde-
cane system, and the subsequent elimination of the tertiary
hydroxyl group to establish the double bond of the A ring.
The isoxazoline 3, which should serve as a precursor to the
β-hydroxy ketone 2, would itself arise from the intramolecu-
lar 1,3-dipolar cycloaddition of nitrile oxide 4; it was ex-
pected that the formation of a seven-membered ring by this
method would be much easier than the formation of an
eight-membered ring.
Scheme 1. Retrosynthetic analysis
cannot be easily anticipated as it should depend on the con-
formation of the compound in solution.
With respect to the fragmentation of the cyclopropane
ring and the subsequent elimination of water that would
lead to product 1 from the tricyclic compound 2, we re-
cently reported a study in which samarium(II) iodide was
used to induce such a transformation.[3] It must be pointed
out that when bicyclo[3.1.0]hexanes were employed as sub-
strates, the regioselectivity of the cyclopropane opening was
dependent on the nature of the carbonyl group present in
the molecule, aldehydes leading to cyclohexenes and ke-
tones leading to cyclopentanols (Scheme 2). However, the
result of the fragmentation of a tricyclic ketone such as 2
Scheme 2. SmI2-mediated fragmentation of bicyclo[3.1.0]hexanes
In this article, we present the synthesis of isoxazoline 3
and the results of the fragmentation of the cyclopropane
ring of this compound. A short reaction sequence that al-
lowed the formation of a model bicyclo[3.1.0]hexane system
was designed in the first place. It was based on the intra-
molecular formation of the cyclopropane ring by the nucle-
ophilic substitution of an epoxide by a nitrile anion, as de-
picted in Scheme 3. Thus, a DielsϪAlder reaction of 2,4-
dimethyl-1,3-pentadiene (5) with 2-chloroacrylonitrile (6)
afforded cyclohexene 7.[4] Epoxide 8 was then obtained, as
a mixture of diastereomers, by treatment of 7 with m-
CPBA. Dechlorination of 8 with phenyllithium produced
[a]
´
´
CEA-Saclay, Service des Molecules Marquees,
ˆ
Bat. 547, F-91191 Gif-sur-Yvette cedex, France
Fax: (internat) ϩ 33-1/6908-7991
E-mail: thierry.le gall@cea.fr
[b]
´
´
Universite Louis Pasteur, Faculte de Pharmacie, Laboratoire de
`
´
Synthese Bio-Organique associe au CNRS,
74 route du Rhin, BP 24, F-67401 Illkirch, France
Fax: (internat) ϩ 33-3/8867-8891
E-mail: mioskow@aspirine.u-strasbg.fr
Eur. J. Org. Chem. 1999, 3251Ϫ3256
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1212Ϫ3251 $ 17.50ϩ.50/0
3251

A. Nivlet, L. Dechoux, T. Le Gall, C. Mioskowski
FULL PAPER
the corresponding nitrile which was then treated with lith-
The synthesis of isoxazoline 3 from nitrile 14 was then
ium diisopropylamide to give the bicyclic compound 9 as a carried out as described in Scheme 5. Reduction of the ni-
single diastereomer. It was also possible to convert 8 to 9 trile function and conversion of the obtained aldehyde 15
in a one-pot procedure: after treatment of 8 with phenyllith- to the corresponding oxime 16 both proceeded in excellent
ium for 30 min, diisopropylamine (2 equiv.) was added and yields. Refluxing a highly diluted chloroform solution of 16
the reaction stirred at room temperature for 13 h. In this in the presence of excess NaOCl in water gave the tetracyc-
case 9 was isolated in a slightly lower yield (66%).
lic isoxazoline 3 as a 93:7 mixture of epimers in 81% yield.
The relative configuration of the major epimer could not be
determined by nOe experiments. We were unable to obtain
crystals suitable for an X-ray diffraction analysis. The result
of the cycloaddition constrasted sharply with our previous,
unfruitful attempts to construct directly the eight-mem-
bered A ring of the bicyclic A/B system of taxanes.[1]
Scheme 3. Preparation of nitrile 9; reagents and conditions: (a)
ref.[4]; (b) m-CPBA, CH2Cl2, 0°C, 26 h, 97%; (c) PhLi (2 equiv.),
THF, Ϫ78°C, 30 min, 86%; (d) iPr2NLi, THF, Ϫ78°C to room
temp., 13 h, 94%
Scheme 5. Preparation of isoxazoline 3; reagents and conditions:
(a) iBu2AlH, Et2O, 0°C, 2 h; (b) H2NOH.HCl, Na2CO3, CH2Cl2/
H2O, 99%; (c) 7% aq. NaOCl, CHCl3 (c ϭ 10Ϫ3 ), reflux, 36 h,
81%.
The same sequence was then applied to the synthesis of
the nitrile 14, which contains a 4-pentenyl chain (Scheme
4). Treatment of the alkenyllithium reagent derived from 3-
bromo-2,4-dimethylpenta-1,3-diene (10)[5] with 5-bromo-
pent-1-ene afforded the triene 11, which was converted into
diene 12 by a DielsϪAlder reaction with 2-chloroacrylon-
itrile at 120°C for 15 days. Epoxidation of diene 12 was
then performed by treatment with m-CPBA in CH2Cl2 at
0°C. A mixture of recovered 12 (32%), epoxide 13 (50%,
two diastereomers) and the product of epoxidation at the
terminal olefin (17%) was obtained when one equivalent of
reagent was used. Adding more m-CPBA did not improve
the yield of 13, but instead led to the formation of unde-
sired bis(epoxides). A one-pot conversion of epoxide 13 to
the bicyclic nitrile 14 proceeded smoothly under the same
experimental conditions as for the synthesis of 9.
The next planned step was the cleavage of the isoxazoline
ring to generate the corresponding β-hydroxy ketone 2,
which would then be treated with reagents that can frag-
ment the cyclopropane ring. Hydrogenolysis according to
the method developped by Curran (H2, Raney Ni, B(OH)3,
5:1 MeOH/H2O),[6] however, did not yield the expected ke-
tone 2. The signals corresponding to the protons on the
1
isoxazoline ring were no longer present in the H NMR
spectrum of the crude product, but no evidence of a car-
bonyl stretch was found in the IR spectrum (Scheme 6).
Instead, a band at 1621 cmϪ1 indicated the presence of an
1
imine function. According to the H NMR spectrum, the
crude product consisted of a mixture of imines 17, charac-
terized by a doublet at δ ϭ 3.72 (J ϭ 6.8 Hz, 2 H) and 18,
characterized by a doublet at δ ϭ 1.11 (J ϭ 6.8 Hz, 3 H).
Compound 18 apparently arose from the β-elimination of
the primary alcohol of 17, followed by the hydrogenation
of the formed α,β-unsaturated imine. Ketone 2 was not pro-
duced, even after prolonged reaction times. The resistance
of the imine function toward hydrolysis could be attributed
to steric congestion. Other authors have reported the iso-
lation of stable β-hydroxy imines as cleavage products of
isoxazolines, and the conditions allowing their conversion
into the corresponding β-hydroxy ketones.[7] However, in
our case, treatment of the crude mixture of imines 17 and
18 under similar conditions led only to degradation prod-
ucts. This was probably due to a facile elimination of the
tertiary hydroxyl group, followed by rearrangements.
Cleaner rearrangements were observed from 3 in the
presence of several dehydrating reagents; varying amounts
of isoxazolines 19؊21 were obtained (Table 1).
While 21 is the product of a simple dehydration of 3,
the formation of both compounds 19 and 20 involves the
fragmentation of the cyclopropane ring, probably via the
Scheme 4. Preparation of nitrile 14; reagents and conditions: (a)
tBuLi, THF, Ϫ78°C, 1 h, then 5-bromopent-1-ene, Ϫ78°C to room
temp., 15 h, 90%; (b) 6, 120°C, 15 days, 69%; (c) mCPBA, CH2Cl2,
0°C, 13 h, 50%; (d) PhLi (2 equiv.), THF, Ϫ78°C, 20 min, then
iPr2NH (2 equiv.), Ϫ78°C to room temp., 12 h, 71%.
3252
Eur. J. Org. Chem. 1999, 3251Ϫ3256

Studies Directed Toward the Synthesis of Taxanes
FULL PAPER
In conclusion, a new route to compounds with the bi-
cyclo[3.1.0]hexane system, based on the formation of the
cyclopropane ring by an intramolecular nucleophilic substi-
tution of an epoxide by a nitrile anion, was designed. The
construction of a fused seven-membered ring from a 1,3-
dipolar cycloaddition leading to isoxazoline 3 was, as ex-
pected, much easier than the direct cyclization of the eight-
membered ring of the taxane A/B bicyclic system. However,
we could not find suitable reaction conditions for the gener-
ation of the β-hydroxy ketone 2, partly because of the sta-
bility of the sterically crowded imine function toward
hydrolysis. Thus another method should be used to cyclize
the seven-membered ring. Dehydration of isoxazoline 3
gave rise to compounds that are structurally related to
11(15Ǟ1)abeotaxanes.
Scheme 6. Hydrogenolysis of isoxazoline 3
Table 1. Cleavage of the cyclopropane ring of isoxazoline 3
Experimental Section
General: All reactions were performed under an atmosphere of ar-
gon. Ϫ THF was freshly distilled from sodium benzophenone ketyl.
Ϫ TLC: Silica Gel 60F254 plates (Merck), with detection by UV
light or with a solution of phosphomolybdic acid in EtOH. Ϫ Col-
umn chromatography: 40Ϫ63 µm Merck Silica Gel. Ϫ IR: PerkinϪ
Elmer 2000. Ϫ Melting points (uncorrected): Büchi 535. Ϫ NMR:
Bruker AM 300 (300.13 and 75.47 MHz for 1H and 13C, respec-
tively). Ϫ MS: Finnegan-Mat 4600 (70 eV).
[a]
The product of this reaction was not further purified.
3-Chloro-2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptane-3-carbo-
nitrile (8): m-Chloroperbenzoic acid (3.39 g, 19.7 mmol) was added
portionwise to a solution of alkene 7 (3.0 g, 16.4 mmol) in dichloro-
methane (109 mL) cooled to 0°C. The reaction was allowed to
warm to room temperature. After stirring for 14 h, the reaction was
incomplete. A further portion of m-chloroperbenzoic acid (850 mg)
was added at this time, and then again after 2 h (1 g). Stirring was
continued for 10 h. The reaction mixture was then concentrated in
vacuo. Chromatography on silica gel (hexane/AcOEt, 9:1) afforded
3.26 g (97%) of epoxide 8 as a 55:45 mixture of diastereomers;
samples of each one were separated. Ϫ Less polar diastereomer
(minor): IR (film): ν˜ ϭ 2998, 2935, 2878, 2240, 1471, 1458, 1425,
1384, 1370, 1322, 1234, 1085, 1038, 1020, 1002, 948, 939, 894, 874,
814, 778, 590 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 2.70 (s, 1 H),
1.88Ϫ2.22 (m, 4 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.18 (s, 3 H). Ϫ
13C NMR (CDCl3): δ ϭ 117.7, 65.4, 64.4, 58.9, 38.2, 30.8, 28.8,
24.8, 22.3, 19.8. Ϫ More polar diastereomer (major): IR (film): ν˜ ϭ
2977, 2931, 2876, 1469, 1449, 1389, 1217, 1090, 1018, 984, 937,
cationic intermediates 22 and 23 (Scheme 7), which, de-
pending on the nature of the solvent, can lose a proton to
yield alkene 20 or react with water, affording alcohol 19.
These two compounds are structurally related to
11(15Ǟ1)abeotaxanes, such as brevifoliol (24)[8] and taxchi-
nin A (25) (Figure 1).[9]
1
916, 895, 834, 819 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 2.63 (s, 1 H),
Scheme 7. Formation of compounds 19, 20, 21 from isoxazoline 3
1.95Ϫ2.21 (m, 4 H), 1.34 (s, 9 H). Ϫ 13C NMR (CDCl3): δ ϭ
118.0, 64.4, 64.2, 58.0, 38.3, 30.0, 25.6, 25.0, 22.9, 22.6.
2,2,6-Trimethyl-7-oxabicyclo[4.1.0]heptane-3-carbonitrile:
A solu-
tion of phenyllithium (94 mL, 1.6  in cyclohexane/ether 70:30,
15.1 mmol) was added dropwise to a solution of epoxide 8 (1.5 g,
7.54 mmol) in THF (75 mL) cooled to Ϫ78°C. After stirring for
30 min at this temperature, saturated aqueous ammonium chloride
(10 mL) was added. The organic layer was separated, the aqueous
phase extracted with ether (3 ϫ 100 mL) and then the combined
organic phases were dried over magnesium sulfate. After filtration
and concentration in vacuo, chromatography on silica gel (hexane/
ether, 7:3) afforded 1.13 g (86%) of the title compound as a 51:49
mixture of diasteromers; samples of each one were separated. Ϫ
Less polar diastereomer: Ϫ IR (film): ν˜ ϭ 2966, 2936, 2876, 2238,
1466, 1389, 1381, 1370, 1030, 927, 888, 794 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 2.64 (s, 1 H), 2.49 (dd, J ϭ 3.9, 10.2 Hz, 1 H),
Figure 1. Molecular structures of 24 and 25
The treatment of compound 3 with other reagents known
to cleave isoxazoline rings, such as ozone[10] or molyb-
denum hexacarbonyl[11] was not successful. Reaction with
samarium(II) iodide in THF left compound 3 unchanged,
although a decoloration of the solution from blue to yellow
was observed.
Eur. J. Org. Chem. 1999, 3251Ϫ3256
3253

A. Nivlet, L. Dechoux, T. Le Gall, C. Mioskowski
FULL PAPER
1
1.59Ϫ1.90 (m, 4 H), 1.29 (s, 3 H), 1.19 (s, 3 H), 1.18 (s, 3 H) Ϫ 13C
993, 913, 871, 735 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 5.79 (ddt, J ϭ
NMR (CDCl3): δ ϭ 120.6, 69.9, 58.4, 33.5, 32.8, 26.3, 25.4, 23.8, 16.8, 9.9, 6.9 Hz, 1 H), 5.01 (d, J ϭ 16.8 Hz, 1 H), 4.97 (d, J ϭ
21.2, 20.7. Ϫ MS (CI, NH3); m/z (%):183 (100) [Mϩ ϩ NH4]. Ϫ
More polar diastereomer: Ϫ IR (film): ν˜ ϭ 2966, 2931, 2875, 2238,
9.9 Hz, 1 H), 2.1Ϫ2.35 (m, 4 H), 2.06 (dt, J ϭ 7.5, 6.9 Hz, 2 H),
1.99 (dt, J ϭ 8.1, 17.1 Hz, 2 H), 1.62 (s, 3 H), 1.46 (tt, J ϭ 7.5,
1469, 1452, 1428, 1389, 1380, 1370, 1092, 1023, 918, 890, 814, 734 8.1 Hz, 2 H), 1.36 (s, 3 H), 1.22 (s, 3 H). Ϫ 13C NMR (CDCl3):
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 2.61 (s, 1 H), 2.13 (dd, J ϭ 3,
11.1 Hz, 1 H), 1.97Ϫ2.04 (m, 1 H), 1.60Ϫ1.75 (m, 3 H), 1.31 (s, 3
δ ϭ 138.0, 133.7, 126.1, 118.9, 114.7, 67.3, 43.4, 34.0, 32.6, 29.4,
28.7, 28.6, 24.4, 23.4, 19.3. Ϫ MS (CI, NH3); m/z (%): 269 (100)
H), 1.20 (s, 3 H), 1.19 (s, 3 H) Ϫ 13C NMR (CDCl3): δ ϭ 120.1, [Mϩ ϩ NH4].
65.9, 58.6, 37.3, 31.6, 29.4, 27.6, 22.7, 20.83, 20.77. Ϫ MS (CI,
Epoxide 13: m-Chloroperbenzoic acid (80%, 808 mg, 4 mmol) was
added to a solution of alkene 12 (997 mg, 4 mmol) in dichlorometh-
NH3); m/z (%):183 (100) [Mϩ ϩ NH4].
4-Hydroxy-4,4,6-trimethylbicyclo[3.1.0]hexane-1-carbonitrile
(9): ane (40 mL) cooled to 0°C. The reaction was allowed to warm to
Butyllithium (4.1 mL, 6.55 mmol, 1.6  in hexanes) was added to a
solution of diisopropylamine (919 mL, 6.55 mmol) in THF (10 mL)
cooled to 0°C. After stirring for 20 min at this temperature, the
solution of lithium diisopropylamide was cooled to Ϫ78°C and
was then added via a cannula to a solution of 2,2,6-trimethyl-7-
oxabicyclo[4.1.0]heptane-3-carbonitrile (541 mg, 3.28 mmol) in
THF (10 mL), at Ϫ78°C. The reaction mixture was allowed to
warm to room temperature and stirred for 13 h. Saturated aqueous
ammonium chloride (10 mL) was then added. The organic layer
was separated and the aqueous phase extracted with ether
room temperature with vigorous stirring. After 13 h, water (10 mL)
was added The organic layer was then separated and the aqueous
phase extracted with ether (3 ϫ 20 mL). The combined organic
phases were washed successively with saturated aqueous NaHCO3
(10 mL) and brine (10 mL), then dried over magnesium sulfate.
After filtration and concentration in vacuo, the residue obtained
was chromatographed on silica gel (hexane containing increasing
amounts of ether: from 0.5% to 15%). Unreacted alkene 12
(330 mg, 32%), the two diastereomers of epoxide 13 (less polar iso-
mer: 240 mg, 23%; more polar isomer: 250 mg, 27%) and the prod-
(3 ϫ 20 mL). The combined organic phases were washed to neu- uct of epoxidation at the monosubstituted double bond (178 mg,
trality with saturated aqueous ammonium chloride, then dried over
magnesium sulfate. After filtration and concentration in vacuo,
chromatography on silica gel (hexane/AcOEt, 8:2), afforded 509 mg
17%) were successively eluted. Ϫ Less polar diastereomer: 1H
NMR (CDCl3): δ ϭ 5.75 (ddt, J ϭ 6.9, 10.2, 17.1 Hz, m, 1 H),
5.01 (d, J ϭ 17.1 Hz, 1 H), 4.96 (d, J ϭ 10.2 Hz, 1 H), 1.5Ϫ2.3 (m,
(94%) of nitrile 9. Ϫ 1H NMR (CDCl3): δ ϭ 2.22 (dt, J ϭ 14.1, 10 H), 1.18 (s, 3 H), 1.35 (s, 3 H), 1.49 (s, 3 H). Ϫ 13C NMR
9.9 Hz, 1 H), 2.10 (ddd, J ϭ 14.1, 9.9, 2.1 Hz, 1 H), 1.90 (ddd, J ϭ
14.1, 9.9, 2.1 Hz, 1 H), 1.70 (dt, J ϭ 14.1, 9.9 Hz, 1 H), 1.68 (s, 1
(CDCl3): δ ϭ 137.5, 118.1, 115.2, 68.1, 63.6, 66.2, 42.7, 34.0, 31.7,
30.8, 30.7, 25.6, 25.1, 20.3, 19.8. Ϫ MS (CI, NH3); m/z (%): 268
H), 1.48 (s, 3 H), 1.37 (s, 3 H), 1.27 (s, 3 H). Ϫ 13C NMR (CDCl3): (20) [Mϩ ϩ H], 285 (100) [Mϩ ϩ NH4]. Ϫ C15H22ClNO (267.8):
δ ϭ 121.7, 79.7, 48.6, 39.5, 31.3, 29.4, 27.2, 26.8, 26.7, 15.7.
calcd. C 67.28, H 8.28, N 5.23; found C 67.27, H 8.45, N 5.01. Ϫ
More polar diastereomer: IR (film): ν˜ ϭ 3077, 2960, 2929, 2241,
Triene 11: To a solution of vinyl bromide 10 (10.3 g, 58.7 mmol) in
THF (125 mL) cooled to Ϫ78°C was added dropwise a solution of
tert-butyllithium (725 mL, 1.7  in pentane, 123 mmol). After stir-
ring for 1 h at this temperature, 5-bromopent-1-ene (8.34 mL,
70.5 mmol) was added dropwise. The reaction mixture was stirred
for 2 h at Ϫ78°C, then allowed to warm to room temperature and
stirred for 15 h. Water (100 mL) was then added. The organic layer
was separated and the aqueous phase extracted with pentane
(3 ϫ 100 mL). The combined organic phases were washed to neu-
trality with saturated aqueous ammonium chloride, then with brine
(100 mL), and dried over magnesium sulfate. After filtration and
concentration in vacuo, 8.6 g (90%) of nitrile 9 was obtained as an
oil; it was used in the next step without further purification. Ϫ IR
1641, 1477, 1456, 1444, 1394, 1373, 1120, 1022, 993, 914, 854 cmϪ1
.
1
Ϫ H NMR (CDCl3): δ ϭ 5.74 (ddt, J ϭ 17.1, 10.2, 6.9 Hz, 1 H),
4.99 (d, J ϭ 17.1 Hz, 1 H), 4.95 (d, J ϭ 10.2 Hz, 1 H), 1.9Ϫ2.3 (m,
6 H), 1.5Ϫ1.7 (m, 4 H), 1.39 (s, 3 H), 1.35 (s, 3 H), 1.29 (s, 3 H).
Ϫ
13C NMR (CDCl3): δ ϭ 137.6, 118.6, 115.1, 67.1, 62.5, 66.7,
42.5, 33.9, 30.2, 30.0, 27.8, 25.1, 23.0, 22.6, 20.4. Ϫ MS (CI, NH3);
m/z (%): 268 (10) [Mϩ ϩ H], 285 (100) [Mϩ ϩ NH4]. Ϫ
C15H22ClNO (267.8): calcd. C 67.28, H 8.28, N 5.23; found C
67.18, H 8.49, N 5.06.
Product of epoxidation at the monosubstituted double bond: 1H
NMR (CDCl3): δ ϭ 2.91 (m, 1 H), 2.74 (t, J ϭ 4.8 Hz, 1 H), 2.45
(dd, J ϭ 4.8, 2.7 Hz, 1 H), 2.40Ϫ2.15 (m, 4 H), 2.10Ϫ2.00 (m, 2
(film): ν˜ ϭ 3076, 2977, 2927, 2859, 1641, 1442, 1371, 1189, 1123, H), 1.62 (s, 3 H), 1.60Ϫ1.40 (m, 4 H), 1.36 (s, 3 H), 1.25 (s, 3 H).
1071, 1037, 991, 910, 894 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 5.81
(ddt, J ϭ 17.1, 10.2, 6.6 Hz, 1 H), 4.9Ϫ5.0 (m, 3 H), 4.53 (d, J ϭ
2.1 Hz, 1 H), 2.08 (t, J ϭ 7.5 Hz, 2 H), 2.04 (dt, J ϭ 6.6, 7.5 Hz,
Ϫ
13C NMR (CDCl3): δ ϭ 133.4, 133.3, 126.4, 118.5, 118.2, 67.2,
51.8, 46.7, 43.3, 32.6, 29.4, 29.1, 26.1, 24.3, 23.4, 19.3. Ϫ MS (CI,
NH3); m/z (%): 285 (100) [Mϩ ϩ NH4]. Ϫ C15H22NO [Mϩ Ϫ Cl]:
2 H), 1.74 (s, 3 H), 1.66 (s, 6 H), 1.42 (tt, J ϭ 7.5, 7.5 Hz, 2 H). Ϫ calcd. 232.1701; found 232.1733 (HRMS).
13C NMR (CDCl3): δ ϭ 146.4, 138.8, 136.3, 124.7, 114.0, 112.7,
33.4, 30.3, 27.4, 22.4, 21.4, 19.4.
Nitrile 14: A solution of phenyllithium (2.4 mL, 1.6  in 7:3 cyclo-
hexane/ether, 3.84 mmol) was added dropwise to a solution of
epoxide 13 (550 mg, 1.92 mmol) in THF (20 mL) cooled to Ϫ78°C.
After stirring at this temperature for 20 min, diisopropylamine
(0.54 mL, 3.84 mmol) was added and the reaction allowed to warm
1-Chloro-3-(pent-4-enyl)-2,2,4-trimethylcyclohex-3-ene-1-carbo-
nitrile (12): 2-Chloroacrylonitrile (2.77 mL, 34.8 mmol) and triene
11 (3.8 g, 23.2 mmol) were charged in a thick-walled tube. After
heating for 5 days at 120°C, triene was still present in the reaction to room temperature. After stirring for 12 h, saturated aqueous am-
mixture; a further amount of 2-chloroacrylonitrile (0.44 mL,
5.5 mmol) was added and heating was continued for 5 days. The
reaction mixture was then cooled to room temperature, the solution
transferred to a flask and the tarry residue was washed with di-
chloromethane. The combined organic phases were concentrated in
vacuo. Chromatography on silica gel (pentane/ether, 99:1) afforded
monium chloride (10 mL) was added. The organic layer was sepa-
rated, the aqueous phase extracted with dichloromethane
(2 ϫ 20 mL) and the combined organic phases washed to neutrality
with saturated aqueous ammonium chloride, then dried over mag-
nesium sulfate. After filtration and concentration in vacuo, chro-
matography on silica gel (hexane/ether, 7:3) afforded 330 mg (71%)
4.0 g (69%) of nitrile 12. Ϫ IR (film): ν˜ ϭ 3077, 2979, 2944, 2908, of nitrile 14. Ϫ IR (film): ν˜ ϭ 3494, 3077, 2953, 2929, 2875, 2253,
2865, 2842, 2241, 1824, 1641, 1475, 1459, 1436, 1390, 1369, 1323,
1641, 1462, 1377, 1142, 1108, 1066, 993, 968, 912 cmϪ1. Ϫ 1H
3254
Eur. J. Org. Chem. 1999, 3251Ϫ3256

Studies Directed Toward the Synthesis of Taxanes
FULL PAPER
NMR (CDCl3): δ ϭ 5.78 (ddt, J ϭ 16.8, 9.9, 6.6 Hz, 1 H), 5.03 (d, temperature, the organic phase was washed with brine (100 mL),
J ϭ 17.1 Hz, 1 H), 4.97 (d, J ϭ 9.9 Hz, 1 H), 1.7Ϫ2.3 (m, 10 H), then dried over magnesium sulfate. After filtration and concen-
1.45 (s, 3 H), 1.44 (s, 3 H), 1.35 (s, 3 H). Ϫ 13C NMR (CDCl3):
δ ϭ 137.7, 120.8, 115.0, 83.0, 47.4, 41.8, 34.0, 30.1, 29.8, 27.2,
tration in vacuo, chromatography on silica gel (hexane/AcOEt, 1:1)
afforded 265 mg (81%) of isoxazoline 3 (93:7 mixture of epimers)
26.2, 26.0, 24.9, 22.5, 18.8. Ϫ C15H23NO [Mϩ]: calcd. 233.1779; as a white solid. Ϫ m.p. 143.5Ϫ144°C. Ϫ IR (film): ν˜ ϭ 3421, 2923,
found 233.1781 (HRMS).
2871, 1602, 1455, 1372, 1302, 1185, 1150, 939, 839 cmϪ1. Ϫ 1H
NMR (CDCl3) of the major diastereomer: δ ϭ 4.37 (dd, J ϭ 8.1,
10.5 Hz, 1 H), 3.90 (dd, J ϭ 6.9, 8.1 Hz, 1 H), 3.17 (dddd, J ϭ 3.6,
6.9, 10.5, 12.3 Hz, 1 H), 2.35Ϫ2.20 (m, 1 H); 2.10Ϫ1.80 (m, 5 H),
1.65Ϫ1.20 (m, 5 H), 1.46 (s, 3 H), 1.45 (s, 3 H), 1.10 (s, 3 H);
characteristic peaks for the minor diastereomer: δ ϭ 4.53 (dd, J ϭ
8.6, 10.6 Hz, 1 H), 3.65 (dd, J ϭ 8.6, 12.1 Hz, 1 H). Ϫ 13C NMR
(CDCl3) of the major diastereomer: δ ϭ 161.7, 84.1, 74.5, 52.7,
43.6, 39.8, 35.7, 33.4, 30.6, 28.9, 27.8, 27.3, 26.1, 25.8, 18.7. Ϫ MS
(CI, NH3); m/z (%): 232 (30) [Mϩ Ϫ OH], 250 (100) [Mϩ ϩ H],
267 (80) [Mϩ ϩ NH4]. Ϫ C15H23NO2 [Mϩ]: calcd. 249.1729; found
249.1724 (HRMS).
Aldehyde 15: A solution of diisobutylaluminium hydride (4.38 mL,
1  in hexanes) was added dropwise to a solution of nitrile 14
(550 mg, 1.92 mmol) in ether (15 mL) cooled to 0°C. A solid rap-
idly precipitated. After stirring for 2 h at 0°C, methanol (2 mL)
and a 0.7  aqueous solution of potassium sodium tartrate (15 mL)
were successively added. After stirring vigorously for 12 h and de-
cantation, the organic layer was separated, the aqueous phase ex-
tracted with ether (2 ϫ 10 mL) and the combined organic phases
washed with brine (10 mL), then dried over magnesium sulfate.
After filtration and concentration in vacuo, chromatography on sil-
ica gel (hexane/ether, 4:6) afforded 334 mg (100%) of aldehyde 14.
Ϫ IR (film): ν˜ ϭ 3481, 3076, 2954, 2876, 2748, 1682, 1641, 1460,
1376, 1287, 1252, 1190, 1105, 1065, 993, 952, 929, 912 cmϪ1. Ϫ 1H
NMR (CDCl3): δ ϭ 9.42 (s, 1 H), 5.79 (ddt, J ϭ 16.8, 10.2, 6.6 Hz,
1 H), 5.02 (d, J ϭ 16.8 Hz, 1 H), 4.97 (d, J ϭ 10.2 Hz, 1 H),
2.3Ϫ2.45 (m, 1 H), 2.09 (dt, J ϭ 12.6, 6.6 Hz, 2 H), 1.7Ϫ2.0 (m, 6
H), 1.4Ϫ1.5 (m, 1 H), 1.52(s, 3 H), 1.48 (s, 3 H), 1.38 (s, 3 H). Ϫ
13C NMR (CDCl3): δ ϭ 202.8, 137.9, 114.9, 84.2, 53.6, 49.8, 41.7,
35.6, 34.1, 30.0, 26.8, 26.5, 22.0, 20.8, 19.9. Ϫ MS (CI, NH3); m/z
Imines 17 and 18: To a solution of isoxazoline 3 (51 mg, 0.2 mmol)
in methanol-water (5:1, 20 mL) were added boric acid (63 mg,
1 mmol) and Raney nickel (a spatula tip). The flask was fitted with
a 3-way tap connected to a water aspirator and to a balloon filled
with hydrogen. The flask was sequentially evacuated and filled with
hydrogen. The suspension was vigorously stirred for 3 days at room
temperature, then filtered through a short pad of celite, which was
washed with methanol (20 mL). After concentration in vacuo,
water (5 mL) and dichloromethane (15 mL) were added. After de-
cantation, the organic layer was separated and the aqueous phase
was extracted with dichloromethane (3 ϫ 10 mL). The combined
organic phases were dried over magnesium sulfate. After filtration
and concentration in vacuo 50 mg of crude product were obtained.
(%): 219 (29) [Mϩ Ϫ OH], 237 (37) [Mϩ ϩ H], 254 (2) [Mϩ
NH4]. Ϫ C15H24O2 (236.35): calcd. C 76.23, H 10.23; found C
76.43, H 10.23.
ϩ
Oxime 16: Sodium carbonate (895 mg, 8.45 mmol) and hy-
droxylamine hydrochloride (503 mg, 7.23 mmol) were successively
added to a two-phase solvent system (dichloromethane/water, 3:1,
16 mL) containing aldehyde 15 (570 mg, 2.41 mmol). The reaction
mixture was vigorously stirred for 4 days at room temperature.
After decantation, the organic layer was separated and the aqueous
phase extracted with dichloromethane (3 ϫ 10 mL). The combined
organic phases were washed with saturated aqueous ammonium
chloride (10 mL), then dried over magnesium sulfate. After fil-
tration and concentration in vacuo, chromatography on silica gel
(hexane/AcOEt, 6:4) afforded 598 mg (99%) of oxime 16 as a 93:7
mixture of E and Z isomers; samples of the two isomers were sepa-
rated. Z-Isomer Ϫ IR (film): ν˜ ϭ 3267, 3075, 2925, 1729, 1641,
1
According to the H NMR spectrum, it consisted of a mixture of
imines 17 and 18. A sample of imine 18 was isolated by chromatog-
raphy on silica gel (AcOEt).
18: IR (film): ν˜ ϭ 3352, 2924, 2869, 1621, 1457, 1373, 1180, 1110,
936, 736 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 2.55Ϫ2.45 (m, 1 H), 2.21
(m, 1 H), 2.16 (m, 1 H), 2.1Ϫ1.2 (m, 9 H), 1.45 (s, 3 H), 1.44 (s, 3
H), 1.11 (d, J ϭ 6.8 Hz, 3 H), 1.03 (s, 3 H). Ϫ MS (CI, NH3); m/z
(%): 218 (80) [Mϩ Ϫ OH], 236 (100) [Mϩ ϩ H].
17: This compound could not be purified since it decomposed dur-
ing the column chromatography. It was mainly characterized owing
to the occurrence of a signal in the 1H NMR spectrum (CDCl3):
δ ϭ 3.72 (d, J ϭ 6.8 Hz, 3 H). The disappearance of this signal
when the hydrogenation was continued was correlated with the in-
crease of the intensity of the signal of the methyl group of com-
pound 18 at δ ϭ 1.11.
1
1459 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 6.55 (s, 1 H), 5.78 (ddt, J ϭ
16.8, 10.2, 6.6 Hz, 1 H), 4.99 (dd, J ϭ 16.8, 1.5 Hz), 4.93 (dd, J ϭ
10.2, 1.5 Hz, 1 H), 1.1Ϫ2.1 (m, 8 H), 1.46, (s, 3 H), 1.44 (s, 3 H),
1.13 (s, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ 153.6, 138.1, 114.7, 84.3,
41.9, 38.9, 34.2, 29.9, 29.4, 26.9, 26.6, 25.1, 20.9, 20.2. Ϫ MS (CI,
NH3); m/z (%): 234 (69) [Mϩ Ϫ OH], 252 (100) [Mϩ ϩ H], 269
(15) [Mϩ ϩ NH4]. Ϫ E-Isomer Ϫ IR (film): ν˜ ϭ 3308, 3076, 2926,
1723, 1640, 1456, 1376, 1302, 1260, 1187, 967, 910 cmϪ1. Ϫ 1H
NMR (CDCl3): δ ϭ 8.6 (s, 1 H, NOH), 7.34 (s, 1 H), 5.77 (m, 1
H), 4.99 (d, J ϭ 17.7 Hz, 1 H), 4.94 (d, J ϭ 12 Hz, 1 H), 2.2Ϫ2.3
(m, 1 H), 2.0Ϫ2.1 (dt, J ϭ 13.8, 6.6 Hz, 2 H), 1.2Ϫ2.0 (m, 7 H),
1.43, (s, 3 H), 1.38 (s, 3 H), 1.23 (s, 3 H). Ϫ 13C NMR (CDCl3):
δ ϭ 153.3, 138.1, 114.8, 84.3, 47.3, 41.8, 38.9, 34.3, 29.9, 26.9,
Isoxazoline 19: To a solution of isoxazoline 3 (22 mg, 0.09 mmol)
in THF/water (2:1, 3 mL) was added amberlyst 15 (10 balls). The
reaction mixture was stirred for 3.5 days at room temperature.The
suspension was then filtered and the solid washed with dichloro-
methane (10 mL). Water (2 mL) was added, then the organic phase
was separated and the aqueous phase was extracted with dichloro-
methane (3 ϫ 5 mL). The combined organic phases were washed
with water (2 mL), then dried over magnesium sulfate. After fil-
tration and concentration in vacuo, chromatography on silica gel
(hexane/AcOEt, 9:1) afforded 16 mg (72%) of isoxazoline 19. Ϫ IR
(film): ν˜ ϭ 3471, 2952, 2853, 1683, 1464, 1442, 1395, 1373, 1355,
1186, 1167, 953, 854, 737 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 4.15 (t,
J ϭ 8.1 Hz, 1 H), 4.11 (broad s, 1 H), 3.95 (dd, J ϭ 8.1, 3.1 Hz, 1
H), 2.98 (m, 1 H), 2.35Ϫ2.7 (m, 3 H), 2.21 (dd, J ϭ 16.2, 9.9 Hz,
1 H), 1.95 (t, J ϭ 13.2 Hz, 1 H), 1.68 (s, 3 H), 1.3Ϫ1.9 (m, 5 H),
1.37 (s, 3 H), 1.19 (s, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ 169.3, 138.0,
26.5, 25.1, 20.9, 20.2. Ϫ MS (CI, NH3); m/z (%): 234 (100) [Mϩ
OH], 252 (54) [Mϩ ϩ H].
Ϫ
Isoxazoline 3: To a solution of oxime 16 (327 mg, 1.3 mmol) in
chloroform (2 L) was added a 7% solution of aqueous sodium
hypochlorite (6.8 mL, 7.8 mmol). The reaction mixture was re-
fluxed for 24 h; at this time oxime 16 was still present, so more of
the solution of hypochlorite (3.4 mL, 3.6 mmol) was added, and
heating was continued for a further 12 h. After cooling to room 136.4, 76.1, 75.0, 50.8, 40.4, 37.0, 33.9, 33.2, 29.4, 29.1, 26.9, 25.1,
Eur. J. Org. Chem. 1999, 3251Ϫ3256 3255

A. Nivlet, L. Dechoux, T. Le Gall, C. Mioskowski
FULL PAPER
13.8. Ϫ MS (CI, NH3); m/z (%): 250 (100) [Mϩ ϩ H], 267 (18)
[Mϩ ϩ NH4]. Ϫ C12H17NO [Mϩ Ϫ C3H6O]: calcd. 191.1310, found
191.1300 (HRMS).
Acknowledgments
We thank Mr. Valleix for performing the mass spectra.
Isoxazolines 20 and 21: To a solution of isoxazoline 3 (20 mg,
0.08 mmol) in benzene (0.5 mL) was added dropwise a solution of
(methoxycarbonylsulfamoyl)-triethylammonium hydroxide (Bur-
gess reagent, 23.9 mg, 0.096 mmol) in benzene (1 mL). After stir-
ring for 24 h at room temperature, more Burgess reagent (15 mg,
0.063 mmol) was added and the reaction mixture was refluxed for
2 h. After cooling to room temperature, water (2 mL) and dichloro-
methane (5 mL) were added. The organic phase was separated and
the aqueous phase was extracted with dichloromethane (3 ϫ 5 mL).
The combined organic phases were then washed with brine (5 mL)
and dried over magnesium sulfate. After filtration and concen-
tration in vacuo, chromatography on silica gel (hexane/AcOEt, 9:1)
afforded 10 mg (54%) of a 9:1 mixture of the inseparable isoxazol-
ines 20 and 21.
[1]
See preceding publication in this Journal.
[2]
[2a]
For references in the context of taxanes synthesis see:
P.
Kumar, A. T. Rao, K. Saravanan, B. Pandey, Tetrahedron Lett.
[2b]
1995, 36, 3397Ϫ3400. Ϫ
W. Thielemann, H. J. Schäfer, S.
[2c]
Kotila, Tetrahedron 1995, 51, 12027Ϫ12034. Ϫ
BouzBouz, Tetrahedron Lett. 1997, 38, 1931Ϫ1932.
A. Nivlet, V. Le Guen, L. Dechoux, T. Le Gall, C. Mioskowski,
Tetrahedron Lett. 1998, 39, 2115Ϫ2118.
J. Cossy, S.
[3]
[4]
T. Masamune, A. Fukuzawa, A. Furusaki, M. Ikura, H.
Matsue, T. Kaneko, A. Abiko, N. Sakamoto, N. Tanimoto, A.
Murai, Bull. Chem. Soc. Jpn. 1987, 60, 1001Ϫ1014.
K. J. Shea, C. D. Haffner, Tetrahedron Lett. 1988, 29,
1367Ϫ1370.
[5]
[6]
D. P. Curran, J. Am. Chem. Soc. 1983, 105, 5826Ϫ5833.
[7] [7a]
D. P. Curran, C. J. Fenk, Tetrahedron Lett. 1986, 27,
[7b]
4865Ϫ4868. Ϫ
P. G. Baraldi, A. Barco, S. Benetti, G. P.
Pollini, E. Polo, D. Simoni, J. Chem. Soc., Chem. Commun.
1986, 757Ϫ758. Ϫ [7c] M. Ihara, Y. Tokunaga, N. Taniguchi, K.
Fukumoto, C. Kabuto, J. Org. Chem. 1991, 56, 5281Ϫ5285.
20: Ϫ IR (film): ν˜ ϭ 3088, 3039, 2922, 2853, 1636, 897, 839 cmϪ1
.
1
Ϫ H NMR (CDCl3): δ ϭ 4.95 (s, 2 H), 4.40 (dd, J ϭ 7.8, 9.9 Hz,
1 H), 3.77 (dd, J ϭ 7.8, 10.8 Hz, 1 H), 3.11 (m, 1 H), 2.52 (dt, J ϭ
3.9, 12.3 Hz, 1 H), 1.5Ϫ2.3 (m, 9 H), 1.72 (s, 3 H), 1.68 (s, 3 H).
[8]
[8a] F. Balza, S. Tachibana, H. Barrios, G. H. N. Towers, Phyto-
[8b]
chemistry 1991, 30, 1613Ϫ1614. Ϫ
G. Appendino, L. Bar-
boni, P. Gariboldi, E. Bombardelli, B. Gabetta, D. Viterbo, J.
Chem. Soc., Chem. Commun. 1993, 1587Ϫ1589.
K. Fuji, K. Tanaka, B. Li, T. Shingu, H. Sun, T. Taga, J. Nat.
Prod. 1993, 56, 1520Ϫ1531.
Ϫ
13C NMR (CDCl3): δ ϭ 166.2, 146.7, 136.8, 136.6, 113.3, 74.6,
[9]
52.3, 36.1, 35.6, 30.4, 29.4, 29.0, 25.9, 19.7, 13.7. Ϫ MS (CI, NH3);
m/z (%): 232 (100) [Mϩ ϩ H], 249 (75) [Mϩ ϩ NH4].
[10]
[11]
A. P. Kozikowski, M. Adamczyk, Tetrahedron Lett. 1982, 23,
3123Ϫ3126.
1
21: Ϫ H NMR (CDCl3): δ ϭ 5.25 (br. s, 1 H), 4.25 (dd, J ϭ 8.2,
P. G. Baraldi, A. Barco, S. Benetti, S. Manfredini, D. Simoni,
Synthesis 1987, 276Ϫ278.
9.8 Hz, 1 H), 3.97 (dd, J ϭ 8.0, 10.7 Hz, 1 H), 3.0Ϫ3.15 (m, 1 H),
2.43 (br. d, J ϭ 17.9 Hz, 1 H), 2.37 (br. d, J ϭ 17.9 Hz, 1 H), 1.64
(br. s, 3 H), 0.98 (s, 3 H).
Received March 25, 1999
[O99193]
3256
Eur. J. Org. Chem. 1999, 3251Ϫ3256