Studies directed toward the synthesis of taxanes: Evaluation of the B- ring formation by an intramolecular nitrile oxide cycloaddition

Article abstract of DOI:10.1002/(SICI)1099-0690(199912)1999:12<3241::AID-EJOC3241>3.0.CO;2-9

Several models for the formation of the 8-membered B-ring of taxanes by an intramolecular nitrile oxide [3+2] cycloaddition were prepared from the monoacetal of 2,2-dimethylcyclohexane-1,3-dione (5). The nitrile oxides were then generated under high-dilut

Full text of DOI:10.1002/(SICI)1099-0690(199912)1999:12<3241::AID-EJOC3241>3.0.CO;2-9

FULL PAPER
Studies Directed Toward the Synthesis of Taxanes: Evaluation of the B-Ring
Formation By an Intramolecular Nitrile Oxide Cycloaddition
Alex Nivlet,[a] Luc Dechoux,[a] Jean-Philippe Martel,[a] Gottfried Proess,[a]
Dietrich Mannes,[a] Lilian Alcaraz,[b] Jerry J. Harnett,[b] Thierry Le Gall,*[a]
and Charles Mioskowski*[a,b]
Keywords: Taxol / Nitrile oxide / Cycloaddition reactions / Isoxazoline / Macrocycles
Several models for the formation of the 8-membered B-ring
only oligomers were obtained. The isoxazoline 19, containing
of taxanes by an intramolecular nitrile oxide [3+2] a 9-membered ring, was formed from the nitrile oxide 17,
cycloaddition were prepared from the monoacetal of 2,2-
dimethylcyclohexane-1,3-dione (5). The nitrile oxides were
then generated under high-dilution conditions. In most cases
and a bis(isoxazoline) 21 was isolated from the reaction of
the nitro compound 16c.
The considerable interest in the synthesis of taxane diter- whether it would also allow the cyclization to the 8-mem-
penes stems from the antitumor activity of paclitaxel bered B-ring, which was thought to be the more challenging
(taxol 1), and its analogue docetaxel (taxotere ), which task.[3] We thus carried out the synthesis of several model
are now both used in the treatment of certain cancers, and nitrile oxide precursors and tested their ability to give an
also from their synthetically challenging structures.[1] intramolecular [3ϩ2] cycloaddition.[4] Several types of
Among the various strategies employed to construct the cyclizations were envisioned as described in the Scheme 2.
taxane skeleton, approaches that rely on the formation of The nitrile oxides A (in which the olefin could be included
the central B-ring from a precursor which already contains in a cyclohexene ring or not), B and C would be generated
the A and C rings are particularly appealing since they are either from the corresponding primary nitroalkanes or ox-
supposed to be more convergent. Our recently disclosed imes, which could all be derived from a single synthetic in-
strategy,[2] depicted in Scheme 1, was based on the forma- termediate, alcohol 4.
tion of the C and B rings by two consecutive intramolecular
[3ϩ2] cycloadditions involving nitrile oxides. Thus, taxol (1)
would derive from the bis(isoxazoline) 2, generated from
compound 3, containing two nitrile oxide moieties and two
double bonds acting as dipolarophiles.
Scheme 2. Strategies for the formation of the ring B of taxanes by
intramolecular nitrile oxide cycloaddition (PG ϭ protecting group)
Scheme 1. Retrosynthetic analysis (PG ϭ protecting group)
Two methods were applied to gain access to alcohol 4
(Scheme 3), both from the monoacetal of 2,2-dimethylcy-
clohexane-1,3-dione (5). Reaction of the potassium enolate
of 5 with N-phenyltrifluoromethanesulfonimide yielded the
enol triflate 6, which was converted into diene 7 by a pal-
ladium-mediated cross-coupling reaction with vinyltributyl-
stannane. A regioselective hydroboration with 9-borabicy-
clo[3.3.1]nonane (9-BBN) followed by alkaline oxidation
then afforded 4 (81% overall yield from 5). An analogous
sequence has been previously published by the Danishefsky
This approach was successful for the construction of the
6-membered C-ring. However, it remained to be seen
[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, 3241Ϫ3249
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1212Ϫ3241 $ 17.50ϩ.50/0
3241

C. Mioskowski et al.
FULL PAPER
group.[5] The second method was found to be more con- Table 1. Alkylation of ketone 9
venient to prepare large amounts of 4, and also cheaper.
Thus, treatment of 5 with para-toluenesulfonyl hydrazide
afforded the tosyl hydrazone 8 in 95% yield.[6] Conversion
of 8 to the corresponding cycloalkenyllithium compound
by reaction with excess tert-butyllithium was followed by
addition of ethylene oxide, giving rise to alcohol 4. Ketone
9 was then prepared from 4 in two high-yield steps: firstly,
an acid-catalyzed cleavage of the dioxolane ring and, sec-
ondly, the protection of the primary hydroxyl function as
its tert-butyldimethylsilyl ether (Scheme 3).
Scheme 3. Synthesis of ketone 9; reagents and conditions: (a)
KN(SiMe3)2, PhNTf2, THF, 0°C, 85%; (b) Bu3SnCHϭCH2,
Pd(PPh3)4 cat., LiCl, THF, reflux, 95%; (c) 9-BBN, THF, reflux,
then H2O2, NaOH, THF/EtOH, 100%; (d) ref.[6]; (e) tBuLi (4
equiv.), THF, Ϫ78 to 5°C, then ethylene oxide, THF, Ϫ78°C to
room temp., 5 h, 67%; (f) TsOH, THF/H2O, reflux, 15 h, 99%; (g)
tBuMe2SiCl, Et3N, DMAP cat., CH2Cl2, room temp., 1 h, 99%
Ketone 9 was used as a precursor to the series of nitrile
oxides A and B. The first step to be implemented at this
stage was the introduction, by the addition of an organome-
tallic reagent to the ketone function, of a chain containing
the olefin which would later serve as the dipolarophile in
the [3ϩ2] cycloaddition. Preliminary tests for such an ad-
dition showed that the Grignard reagent made from 3-
(bromomethyl)cyclohexene (10)[7] reacted with ketones to
yield the corresponding reduction products. In contrast, the
desired alkylated tertiary alcohol was obtained when the
Grignard reagent was added to a preformed suspension of
the ketone 5 and thoroughly dried cerium(III) chloride in
Scheme 4. Preparation of oximes 14a؊b; reagents and conditions:
(a) Bu4NF, THF, 0°C to room temp., 15 h; (b) (ClCO)2, DMSO,
CH2Cl2, Ϫ60°C, 15 min, then Et3N, Ϫ60°C to room temp.; (c)
NH2OH/HCl, Na2CO3, CH2Cl2/H2O, 5 h, room temp.
THF.[8] Such conditions were applied to the preparation of (Scheme 5). Treatment of 12aϪc with the reagent formed
compounds 11a and 11b, from the ketone 9 and the Grig- from triphenylphosphane, imidazole and iodine afforded
nard reagents derived from 10 or from 4-bromobutene, the iodides 15aϪc.[9] These were then reacted with sodium
respectively (Table 1). A Barbier-type coupling with allyl nitrite in DMF. The nitro compounds 16aϪc were obtained
bromide and a zinc/copper couple[6] was used to prepare in 45Ϫ61% yield, along with some isomeric nitrites.
the adduct 11c. All these reactions proceeded with satisfac-
Cycloaddition reactions were then performed using ox-
tory yields.
imes 14a,b and nitro compounds 16a؊c as substrates. In
The oximes 14a,b were prepared from the corresponding order to favor an intramolecular reaction, high dilution
silyl ethers 11a,b in three steps (Scheme 4): fluoride-induced conditions (2 ϫ 10Ϫ3 ) were employed in all cases. Thus,
desilylation to the primary alcohols, Swern oxidation, and solutions of oximes 14a or 14b in dichloromethane were
conversion of the aldehydes 13a,b to the corresponding ox- treated with aqueous sodium hypochlorite[10] (commercial
imes 14a,b.
bleach, 3Ϫ20 equiv.), at room temperature, in the presence
Other precursors of nitrile oxides, the nitro compounds of a catalytic quantity of tetrabutylammonium hydroxide.
16aϪc were synthesized in two steps from the diols 12aϪc No adduct resulting from the expected intramolecular
3242
Eur. J. Org. Chem. 1999, 3241Ϫ3249

Studies Directed Toward the Synthesis of Taxanes
FULL PAPER
described in Scheme 7. The relative configuration of this
compound, which derives from two successive cycload-
ditions, one intermolecular and the second one intramol-
ecular, was not established, but the molecule must be C2-
or Ci-symmetric since only half of the expected signals are
1
found in the H NMR spectrum. Mass spectrometry (CI/
NH3) indicated that the mass of this compound was twice
that of the expected isoxazoline.
Scheme 5. Preparation of nitro compounds 16a؊c; reagents and
conditions: (a) PPh3, imidazole, I2, Et2O/CH3CN, 0°C to room
temp., 4 h; (b) NaNO2, DMF, room temp.
cycloaddition was formed from oxime 14a Ϫ only oligo-
mers and furoxanes were obtained, as confirmed by 1H
NMR and mass spectroscopy. Under similar conditions ox-
ime 14b was consumed more rapidly and afforded, along
with oligomers, an intramolecular cycloadduct, the isoxazo-
line 19 (Scheme 6). This compound could not be obtained
as a pure material despite several chromatographic separ-
Scheme 7. Cycloaddition from nitro compound 16c
1
ations. The chemical shift values in the H NMR spectrum
and an HRMS exact mass determination are in agreement
with the proposed structure (see experimental section). The
regioselectivity of the cycloaddition leading to 19 is anal-
ogous to that which predominates in intermolecular reac-
tions of nitrile oxides with monosubstituted alkenes. Also,
19 contains a nine-membered ring instead of an eight-mem-
bered ring. These factors may explain why this compound
is formed, rather than the isoxazoline 18.
The nitrile oxide 28 was also tested as substrate for intra-
molecular cycloaddition. Its preparation is depicted in
Scheme 8. Alcohol 4 was converted into the bromide 22,
which was coupled with a vinyl Grignard reagent in the
presence of copper iodide[12] to afford diene 23. Acid treat-
ment then yielded ketone 24. Treatment of 24 with cyanotri-
methylsilane in the presence of zinc(II) iodide[13] led to the
protected cyanohydrin 25, which was converted into the ox-
ime 27 in two steps. This series of synthetic steps proceeded
efficiently in high yields. Oxidation of oxime 27 with bleach
in dichloromethane gave the nitrile oxide 28, which was
found to be stable in solution at room temperature; it was
even possible to purify it by chromatography.[14] This sta-
bility is probably due to the very hindered environment
around the nitrile oxide function. Concentration of a solu-
tion of 28 in vacuo afforded an oil, which after three days
at room temperature did not contain terminal alkene, as
seen from its 1H NMR spectrum: signals typical of 3,5-
disubstituted isoxazoline rings were observed at δ ϭ 4.5, 3.1
Scheme 6. Cycloaddition from oxime 14b
Reactions were then carried out with the nitro com- and 2.7 as unresolved multiplets.
pounds 16a؊c under Mukaiyama conditions,[11] with phe-
Highly diluted solutions of 28 were heated at reflux in
nyl or 4-chlorophenyl isocyanate as dehydrating agent and various solvents (dichloromethane, chloroform, benzene,
triethylamine as the base catalyst. High dilution conditions toluene). However, intractable mixtures of oligomers were
were also employed, and the solutions (in benzene or tolu- obtained in each case. It was not possible to isolate a com-
ene) were refluxed until the substrate had disappeared. The pound having the correct 1H NMR and mass spectra corre-
reactions with 16a and 16b led essentially to the same out- sponding to the desired intramolecular cycloadduct. Thus
come as the reactions with oximes 14a and 14b: mixtures it was concluded that cycloaddition occurred only in an in-
of oligomers were obtained. The isoxazoline 19 was also termolecular fashion.
obtained from 16b although the reaction was not as clean.
In conclusion, as part of a program aimed at the syn-
The alkenyl chain of 16c contains one carbon less than in thesis of taxanes, we have studied the possibility of con-
14b, and therefore an intramolecular cycloaddition proceed- structing the B-ring using an intramolecular [3ϩ2] cycload-
ing with the same regioselectivity that led to 19 should have dition. Several model nitrile oxide precursors were prepared
yielded an isoxazoline with an eight-membered ring. How- and tested in the cycloaddition step. However, no cycload-
ever, no such product was observed in this reaction which duct containing the expected eight-membered ring was ob-
afforded mainly oligomeric compounds; the bis(isoxazoline) tained using this strategy.[15] Its principal weaknesses lie
21 was also isolated, in 10% yield, under the conditions probably in the presence of the two methyl groups in the
Eur. J. Org. Chem. 1999, 3241Ϫ3249
3243

C. Mioskowski et al.
FULL PAPER
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).
5,5-Ethylenedioxy-6,6-dimethylcyclohex-1-enyl Trifluoromethanesul-
fonate (6): A solution of LiHMDS (32.6 mL, 1  in THF) was
diluted in THF (100 mL) and cooled to 0°C. Ketone 5 (4 g,
21.7 mmol) was then added dropwise. After 2.5 h, N-phenyltrifluo-
romethanesulfonimide (12.6 g, 35.2 mmol) was added. After stir-
ring for 30 min at 0°C, ether (100 mL) was added, the organic
phase was washed with brine (2 ϫ 50 mL), the aqueous phases were
back extracted with ether (2 ϫ 100 mL), and the combined organic
phases were dried over magnesium sulfate. After filtration and con-
centration in vacuo, chromatography on silica gel (petroleum ether/
dichloromethane, 9:1), afforded 5.82 g (85%) of triflate 6. Ϫ IR
(film): ν˜ ϭ 2980, 2950, 2882, 1670, 1460, 1350, 1240, 1160, 1175,
1
1050, 1025, 1175, 980, 870 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.17
(s, 6 H), 1.76 (t, J ϭ 6.6 Hz, 2 H), 2.24 (dt, J ϭ 6.6, 3.8 Hz, 2 H),
3.96 (s, 4 H), 5.68 (t, J ϭ 3.8 Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ
20.51, 20.65, 26.20, 44.12, 65.02, 110.59, 114.79, 118.11 (q, J ϭ
315.4 Hz. CF3), 152.63. Ϫ C11H15F3O5S: calcd. 316.0592; found
316.0581 (HRMS).
Scheme 8. Preparation of nitrile oxide 28; reagents and conditions:
(a) CBr4, PPh3, CH2Cl2, room temp., 100%; (b) vinylMgBr, CuI,
THF, 0°C to room temp., 95%; (c) TsOH, THF, H2O, 100%; (d)
Me3SiCN, ZnI2, CH2Cl2, 0°C to room temp., 85%; (e) DIBAL-H,
Et2O, 0°C, 70%; (f) NH2OH.HCl, pyridine/EtOH, 100%; (g)
NaOCl, H2O/CH2Cl2, 95%
Diene 7: A mixture of triflate 6 (3.01 g, 9.53 mmol), tributylvinyltin
(4.2 mL, 14.3 mmol), lithium chloride (0.55 g, 0.48 mmol) and
tetrakis(triphenylphosphane)palladium(0) in THF (60 mL) was
heated at reflux for 20 h. Then the mixture was allowed to cool
to room temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,
2.13 mL, 14.3 mmol) was added. Ether (250 mL) was added, the
space between the two components of the cycloaddition, i.
e. the nitrile oxide and alkene moieties, and also in the lack
of flexibility of the alkene chain, which is bonded to the sp2
carbon of the cyclohexene mimicking the A ring of taxanes.
organic phase was washed successively with
1  NaOH
(3 ϫ 60 mL) and brine (80 mL), and then dried over magnesium
sulfate. After filtration and concentration in vacuo, chromatogra-
Modification of the initial strategy to gain access to the phy on silica gel (petroleum ether/AcOEt, 97:3), afforded 1.74 g
(95%) of diene 7. Ϫ IR (film): ν˜ ϭ 2960, 2876 (br, CH), 1650Ϫ1600
(CϭC), 1460, 1380, 1160, 1138, 1094, 1040, 990 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 1.10 (s, 6 H), 1.75 (t, J ϭ 6.7 Hz, 2 H), 2.22 (dt, J ϭ
6.7, 3.8 Hz, 2 H), 3.99 (s, 4 H), 4.94 (dd, J ϭ 2.1, 10.9 Hz, 1 H),
5.30 (dd, J ϭ 2.1, 17.1 Hz, 1 H), 5.74 (t, J ϭ 3.8 Hz, 1 H), 6.28
(dd, J ϭ 10.9, 17.1 Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 22.53,
23.81, 26.15, 41.79, 64.77, 111.80, 113.78, 120.73, 135.87, 143.96.
Ϫ C12H18O2: calcd. 194.1307; found 194.1311 (HRMS).
A/B ring system was clearly needed. Taking these elements
into account, a modified approach, involving a presumably
more facile intramolecular cycloaddition of nitrile oxide 29
that would lead to the formation of a seven-membered ring
isoxazoline 30, and then the fragmentation of the cyclopro-
pylketone 31 to generate bicyclic ketone 32 was then stud-
ied, as described in the following paper in this journal
(Scheme 9).
Alcohol 4. ؊ Method Starting From Diene 7: A solution of 9-bora-
bicyclo[3.3.1]nonane (9-BBN, 132 mL, 0.5  in THF) was added
to a solution of diene 7 (4.3 g, 22.2 mmol) in THF (40 mL). The
mixture was refluxed for 3 h, and then cooled to room temperature.
Ethanol (45 mL), 6  NaOH (16 mL), and dropwise 30% H2O2
(14.7 mL) were successively added. The mixture was refluxed for
1 h, and then cooled to room temperature. Ether (400 mL) was ad-
ded and the organic phase was washed with brine (2 ϫ 200 mL),
the aqueous phases were back extracted with ether (3 ϫ 100 mL),
and the combined organic phases were dried over magnesium sul-
fate. After filtration and concentration in vacuo, chromatography
on silica gel (petroleum ether/AcOEt, 1:1), afforded 4.7 g (100%)
of alcohol 4.
Scheme 9. Modification of the strategy planned
Method Starting From Tosylhydrazone 8: To a solution of tosylhyd-
razone 8[6] (2 g, 5.68 mmol) in THF (120 mL) cooled to Ϫ78°C was
added a solution of tert-butyllithium (1.7  in pentane, 13.4 mL,
22.7 mmol). After stirring for 15 min at Ϫ78°C, the solution was
placed in a bath at 0°C for 5 min, then again cooled to Ϫ78°C.
Ethylene oxide (1.14 mL, 22.8 mmol) was added. The reaction mix-
ture was allowed to warm to room temperature over 5 h. Water
(200 mL) and then brine (200 mL) were added, The organic phase
was separated and the aqueous phase was extracted with ether
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 (4 ϫ 200 mL). The combined organic phases were successively
3244 Eur. J. Org. Chem. 1999, 3241Ϫ3249

Studies Directed Toward the Synthesis of Taxanes
FULL PAPER
washed with water (3 ϫ 200 mL) and brine (200 mL), and then
dried over magnesium sulfate. After filtration and concentration in
15 h, a 5% aqueous AcOH solution (5 mL) was added. The organic
phase was separated and the aqueous phase was extracted with
vacuo, chromatography on silica gel (petroleum ether/AcOEt, 1:1), ether (5 ϫ 2 mL). The combined organic phases were successively
afforded 0.81 g (67%) of alcohol 4. Ϫ IR (film): ν˜ ϭ 3400 (br, OH), washed with brine (2 mL), saturated aqueous NaHCO3 (5 ϫ 2 mL)
2936 (CH), 1460, 1380, 1130, 1082, 1040, 1020, 840 cmϪ1. Ϫ 1H and brine (2 mL), and then dried over magnesium sulfate. After
NMR (CDCl3): δ ϭ 1.06 (s, 6 H), 1.74 (t, J ϭ 6.9 Hz, 2 H), 1.85 filtration and concentration in vacuo, chromatography on silica gel
(broad s, 1 H, OH), 2.16 (dt, J ϭ 3.3, 6.9 Hz, 2 H), 2.26 (t, J ϭ (petroleum ether/AcOEt, 99:1 ), afforded 210 mg (73%) of the ex-
7.2 Hz, 2 H), 3.72 (t, J ϭ 7.2 Hz, 2 H), 3.98 (s, 4 H), 5.37 (t, J ϭ pected alcohol as a mixture of two diastereomers. Ϫ 1H NMR
3.3 Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 22.12, 23.56, 26.02, 34.00, (CDCl3): δ ϭ 0.93 (s, 3 H), 1.01 (s, 3 H), 1.19Ϫ1.77 (m, 13 H),
42.57, 61.47, 64.64, 111.94, 120.66, 139.90. Ϫ C12H20O3: calcd. 1.97Ϫ2.00 (m, 2 H), 2.36Ϫ2.42 (m, 1 H), 3.95Ϫ4.02 (m, 4 H),
212.1412; found 212.1419 (HRMS).
5.50Ϫ5.90 (m, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 14.81, 17.93, 21.16,
21.43, 24.85, 29.84, 30.57, 31.20, 31.55, 41.91, 45.87, 63.93, 65.36,
73.69, 113.56, 125.63, 133.72. Ϫ MS (CI, NH3); m/z (%): 263 (100)
[Mϩ Ϫ OH], 280 (6) [Mϩ], 298 (33) [Mϩ ϩ NH4].
3-(2-Hydroxyethyl)-2,2-dimethylcyclohex-3-en-1-one: A solution of
ketal 4 (5.9 g, 27.8 mmol) and para-toluenesulfonic acid (266 mg,
1.4 mmol) in 1:1 THF/water (400 mL) was refluxed for 18 h. After
cooling to room temperature, ether (400 mL) was added and the
organic phase was successively washed with saturated aqueous
NaHCO3 (100 mL), water (2 ϫ 100 mL) and brine (200 mL), then
dried over magnesium sulfate. After filtration and concentration in
vacuo, 4.6 g (99%) of the title compound were obtained; it was used
in the next reaction without further purification. Ϫ IR (film): ν˜ ϭ
3360 (broad, OH), 2920, 1670 (CO), 1010 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 1.17 (s, 6 H), 2.29 (t, J ϭ 7.2 Hz, 2 H), 2.39 (m, 2
H), 2.44 (t, J ϭ 7.1 Hz, 2 H), 2.51 (s, 1 H, OH), 3.76 (t, J ϭ 7.2 Hz,
2 H), 5.61 (t, J ϭ 3.9 Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 23.87,
24.66, 33.45, 35.40, 47.76, 61.72, 121.38, 140.66, 214.99. Ϫ
C10H16O2 [Mϩ]: calcd. 168.1150, found 168.1163 (HRMS).
Alcohol 11a: Prepared as described above from ketone 9 (237.5 mg,
0.84 mmol) and 3-(bromomethyl)cyclohexene (10) (294 mg,
1.68 mmol). Chromatography on silica gel (petroleum ether/Ac-
OEt, 98:2 ), afforded 375 mg (83%) of alcohol 11a as a 6:4 mixture
of two diastereomers. Ϫ IR (film): ν˜ ϭ 3500 (broad, OH), 2950,
2924, 2860, 1640, 1380, 1358, 1250 (δSiϪCH3), 1090, 830 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.05 (s, 6 H), 0.89 (s, 9 H), 0.97 (s, 3 H),
1.05 (s, 3 H), 1.25Ϫ2.07 (m, 13 H), 2.19 (t, J ϭ 7.7 Hz, 2 H), 2.33
(m, 1 H), 3.66 (t, J ϭ 3.0 Hz, 1 H), 5.32 (t, J ϭ 7.7 Hz, 2 H), 5.50
(dd, J ϭ 1.6, 9.9 Hz, 1 Hmajor), 5.58Ϫ5.71 (m, 1 H), 5.92 (dd, J ϭ
1.85, 11.1 Hz, 1 Hminor). Ϫ 13C NMR (CDCl3): δ ϭ 0.14 (CH3Si),
18.12 (CMe3Si), 21.15, 21.66, 22.54, 24.85, 25.75 ((CH3)3CSi),
27.37, 30.78 (minor), 30.80 (major), 30.93 (major), 31.46 (minor),
34.74, 40.44 (major), 40.63 (minor), 42.70, 63.48, 75.16, 121.05,
125.90 (minor), 126.49 (major), 133.14 (minor), 133.60 (major),
140.34. Ϫ C23H42O2Si (378.67): calcd. C 72.95, H 11.18; found C
72.94, H 11.07. Ϫ C19H33O2Si [Mϩ Ϫ tBu]: calcd. 321.2250; found
321.2248 (HRMS).
Ketone 9: To a solution of 3-(2-hydroxyethyl)-2,2-dimethylcyclohex-
3-en-1-one (3 g, 17.9 mmol), triethylamine (3 mL, 21.5 mmol) and
DMAP (0.22 g, 1.8 mmol) in dichloromethane (90 mL) at 0°C was
added dropwise a solution of tert-butyldimethylsilyl chloride
(2.97 g, 19.7 mmol) in dichloromethane (50 mL). The reaction mix-
ture was then allowed to warm to room temperature. After stirring
for 15 h, the organic phase was successively washed with 5% aque-
ous NaHCO3 (250 mL) and brine (250 mL). The combined aque-
ous washings were extracted with dichloromethane (3 ϫ 250 mL).
The combined organic phases were then dried over magnesium sul-
fate. After filtration and concentration in vacuo, chromatography
on silica gel (petroleum ether/AcOEt, 97:3), afforded 5.0 g (99%)
of ketone 9. Ϫ IR (film): ν˜ ϭ 2840, 1690 (CO), 1397,1370, 1240,
Alcohol 11b: Prepared as described above from ketone 9 (667 mg,
2.37 mmol) and 1-bromobut-3-ene (640 mg, 4.74 mmol). Chroma-
tography on silica gel (pentane/AcOEt, 93:7), afforded 721 mg
(90%) of alcohol 11b as a 6:4 mixture of two diastereomers. Ϫ IR
(film): ν˜ ϭ 3486 (broad, OH), 2958, 1641 (CϭC), 1472, 1387, 1361,
1255, 1098, 837 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 0.03 (s, 6 H), 0.87
(s, 9 H), 0.96 (s, 3 H), 1.04 (s, 3 H), 1.37 (s, 1 H, OH), 1.43Ϫ2.09
(m, 9 H), 2.17 (t, J ϭ 7.4 Hz, 2 H), 3.64 (t, J ϭ 7.4 Hz, 2 H), 4.92
(d, J ϭ 9.9 Hz, 1 H), 5.02 (d, J ϭ 17.1 Hz, 1 H), 5.30 (t, J ϭ
3.0 Hz, 1 H), 5.77Ϫ5.89 (m, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 0.12
(CH3Si), 16.11 (CMe3Si), 22.01, 22.11, 22.65, 25.74 ((CH3)3CSi),
26.98, 27.96, 33.32, 34.61, 42.56, 63.47, 74.47, 114.00, 120.98,
139.36, 140.33. Ϫ MS (CI, NH3); m/z (%): 338 (19) [Mϩ], 356 (100)
[Mϩ ϩ NH4]. Ϫ C16H29O2Si [Mϩ Ϫ tBu]: calcd. 281.1937; found
281.1932 (HRMS).
1
1060, 810 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.05 (s, 6 H), 0.89 (s, 9
H), 1.17 (s, 6 H), 2.23 (t, J ϭ 7.3 Hz, 2 H), 2.37 (m, 2 H), 2.51 (t,
J ϭ 6.7 Hz, 2 H), 3.70 (t, J ϭ 7.3 Hz, 2 H), 5.55 (t, J ϭ 4.0 Hz, 1
H). Ϫ 13C NMR (CDCl3): δ ϭ 0.13 (CH3Si), 16.06 (Me3CSi),
23.66, 24.78, 25.68 {(CH3)3CSi}, 33.80, 35.48, 47.67, 63.22, 121.38,
141.02, 214.57. Ϫ C16H30O2Si (282.5): calcd. C 68.03, H 10.70;
found C 67.86, H 10.54. Ϫ C15H27O2Si [Mϩ Ϫ CH3]: calcd.
267.1780; found 267.1790 (HRMS).
General Procedure for the Addition of a Grignard Reagent to a Ke-
tone in the Presence of Cerium(III) Chloride.
Alcohol 11c: To a suspension of zinc/copper couple (16 g) in THF
(240 mL) was added ketone 9 (2.77 g, 9.8 mmol). The reaction mix-
ture was refluxed, then allyl bromide (1.25 mL, 14.4 mmol) was
7-(Cyclohex-2-enylmethyl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decan-7-
ol: To a suspension of magnesium turnings (27.7 mg, 1.14 ϫ 10Ϫ3 added. After 25 min a further portion of allyl bromide (0.24 mL,
mol) in ether (0.7 mL) was added dropwise a solution of 3-(bromo-
methyl)cyclohexene (10) in ether (0.7 mL), so as to maintain a
gentle reflux. The reaction mixture was then refluxed for 15 min.
In another vessel, cerium(III) chloride heptahydrate (320 mg,
0.86 mmol) was heated at 160°C under vacuum for 6 h. After cool-
ing to room temperature, THF (3 mL) was added, and the suspen-
sion was sonicated for 2 h. A solution of ketone 5 (105 mg,
0.57 mmol) in THF (0.5 mL) was then added. After stirring for 1 h
and cooling to 0°C, the previously prepared solution of Grignard
reagent was added dropwise through a cannula. The reaction mix-
2.8 mmol) was added and the reaction mixture was refluxed for
10 min, then cooled to room temperature. Saturated aqueous
NaHCO3 (200 mL) was added, then the solid was filtered off. and
washed with ethyl acetate (2 ϫ 200 mL). The aqueous phase was
extracted with ethyl acetate (2 ϫ 200 mL). The combined organic
phases were washed with water (200 mL), then dried over mag-
nesium sulfate. After filtration and concentration in vacuo, chro-
matography on silica gel (heptane/AcOEt, 95:5), afforded 3.1 g
(97%) of alcohol 11c as a mixture of two diastereomers. Ϫ IR
(film): ν˜ ϭ 3492 (broad, OH), 3075, 1639, 1255, 1190, 1097, 1004
ture was allowed to warm to room temperature. After stirring for cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 5.95 (dddd, J ϭ 17.1, 10.2,
Eur. J. Org. Chem. 1999, 3241Ϫ3249 3245

C. Mioskowski et al.
FULL PAPER
7.8, 6.9 Hz, 1 H), 5.55 (t, J ϭ 3.6 Hz, 1 H), 5.12 (d, J ϭ 10.2 Hz, methane (3 mL) cooled to Ϫ60°C. After stirring for 15 min at
1 H), 5.10 (d, J ϭ 17.1 Hz, 1 H), 3.65 (t, J ϭ 7.8 Hz, 2 H), 2.33 Ϫ60°C, a solution of diol 12a (120 mg, 0.45 mmol) in dichloro-
(dd, J ϭ 14.1, 6.9 Hz, 1 H), 2.22 (t, J ϭ 7.8 Hz, 2 H), 2.15Ϫ2.2 methane (1 mL) was added dropwise. After stirring for 15 min, tri-
(m, 1 H), 2.0Ϫ2.1 (m, 2 H), 1.7 (dt, J ϭ 13.2, 6.6 Hz, 1 H), 1.6 (dt, ethylamine (1.4 mL) was added and the reaction mixture allowed
J ϭ 13.2, 6.6 Hz, 1 H), 1.56 (broad s, 1 H, OH), 1.00 (s, 3 H), 1.08
to warm to room temperature. Water (5 mL) was added and the
aqueous phase was extracted with ether (3 ϫ 5 mL), then the com-
(s, 3 H), 0.88 (s, 9 H), 0.05 (s, 6 H). Ϫ 13C NMR (CDCl3): δ ϭ
140.3, 134.8, 121.1, 117.9, 74.3, 63.6, 42.2, 39.1, 34.6, 27.9, 25.8, bined organic phases were successively washed with 0.1  HCl
22.5, 22.2, 18.4, 5.4. Ϫ MS (CI, NH3); m/z (%): 307 (94) [Mϩ
Ϫ
(5 mL) and brine (5 mL), then dried over magnesium sulfate. After
OH], 325 (38) [Mϩ ϩ H], 342 (90) [Mϩ ϩ NH4]. Ϫ C16H31O2Si filtration and concentration in vacuo, chromatography on silica gel
[Mϩ Ϫ CH2CHϭCH2]: calcd. 283.2093; found 283.2089 (HRMS).
(petroleum ether/AcOEt, 98:2), afforded 72 mg (61%) of aldehyde
13a. Ϫ IR (film): ν˜ ϭ 3491 (broad, OH), 2926, 1722 (CO), 1658
(CϭC) cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 0.94 (s, 3 H), 1.02 (s, 3
H), 1.15Ϫ2.23 (m, 13 H), 2.27Ϫ2.42 (m, 1 H), 3.01 (s, 2 H), 5.47
(s, 1 H), 5.51Ϫ5.54 (m, 1 Hmajor), 5.59Ϫ5.73 (m, 1 H), 5.90 (dd,
J ϭ 1.9, 8.1 Hz, 1 Hminor), 9.57 (s, 1 H). Ϫ 13C NMR (CDCl3):
δ ϭ 21.10, 21.80, 22.32, 22.87, 24.84, 27.30, 29.43 (minor), 30.72
(major), 30.92 (major), 31.39 (minor), 40.58 (major), 40.76 (minor),
42.89, 47.49, 75.13, 126.34, 126.75 (major), 127.00 (minor), 132.76
(major), 133.32 (minor), 135.49, 200.97. Ϫ MS (CI, NH3); m/z (%):
245 (18) [Mϩ Ϫ OH], 280 (100) [Mϩ ϩ NH4]. Ϫ C17H26NO2 [Mϩ]:
calcd. 262.1933; found 262.1917 (HRMS).
General Procedure for the Cleavage of tert-Butyldimethylsilyl
Ethers 11a؊c.
Diol 12a: A solution of tetrabutylammonium fluoride (1.85 mL,
1  in THF) was added dropwise to a solution of tert-butyldimeth-
ylsilyl ether 11a (350 mg, 0.93 mmol) in THF (1.4 mL) at 0°C. The
reaction mixture was allowed to warm to room temperature. After
stirring for 15 h, dichloromethane (10 mL) was added and the or-
ganic phase washed with water (5 mL). The aqueous phase was
then extracted with dichloromethane (2 ϫ 5 mL). The combined
organic phases were washed with water (2 ϫ 5 mL), then dried over
magnesium sulfate. After filtration and concentration in vacuo,
chromatography on silica gel (petroleum ether/AcOEt, 8:2), af-
forded 174 mg (71%) of diol 12a as a 6:4 mixture of two dia-
stereomers. Ϫ IR (film): ν˜ ϭ 3380 (broad, OH), 2920, 1640 (Cϭ
Aldehyde 13b: Prepared by oxidation of diol 12b (212 mg,
0.95 mmol) by the procedure described above. Chromatography on
silica gel (pentane/AcOEt, 9:1 ), afforded 187 mg (89%) of aldehyde
13b. Ϫ IR (film): ν˜ ϭ 3451 (broad, OH), 2973, 1721 (CO), 1641
1
C), 1030 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.98 (s, 3 H), 1.24 (s, 3
1
(CϭC), 1470 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.90 (s, 3 H), 0.98
H), 1.19Ϫ2.10 (m, 14 H), 2.25 (t, J ϭ 6.8 Hz, 2 H), 2.33 (m, 1 H),
3.72 (t, J ϭ 6.8 Hz, 2 H), 5.39 (m, 1 H,), 5.50 (d, J ϭ 11.6 Hz, 1
Hmajor), 5.62Ϫ5.70 (m, 1 H), 5.91 (dd, J ϭ 10.0, 2.0 Hz, 1 Hminor).
(s, 3 H), 1.40 (s, 1 H, OH), 1.43Ϫ2.24 (m, 8 H), 2.96 (s, 2 H), 4.90
(d, J ϭ 10.8 Hz, 1 H), 5.00 (d, J ϭ 17.1 Hz, 1 H), 5.42 (t, J ϭ
3.4 Hz, 1 H), 5.74Ϫ5.85 (m, 1 H), 9.53 (s, 1 H). Ϫ 13C NMR
(CDCl3): δ ϭ 21.67, 22.13, 22.95, 26.92, 27.87, 33.39, 42.59, 47.36,
74.28, 114.20, 126.30, 135.48, 139.10, 201.01. Ϫ MS (CI, NH3); m/z
(%): 240 (100) [Mϩ ϩ NH4]. Ϫ C14H22O2 [Mϩ]: calcd. 222.1620;
found 222.1614 (HRMS).
Ϫ
13C NMR (CDCl3): δ ϭ 21.20, 21.75, 22.40, 22.59, 24.84, 27.31,
30.61 (minor), 30.81 (major), 30.92 (major), 31.44 (minor), 34.55,
40.50 (major), 40.70 (minor), 42.89, 61.70 (Cp), 75.25, 121.25,
126.09 (minor), 126.55 (major), 132.97 (minor), 133.47 (major),
139.88.
(HRMS).
Ϫ
C17H28O2 [Mϩ]: calcd. 264.2089; found 264.2082
Oxime 14a: To
a solution of hydroxylamine hydrochloride
Diol 12b: Prepared as described above from tert-butyldimethylsilyl
ether 11b (1.77 g, 5.24 mmol) and tetrabutylammonium fluoride
(10.5 mL, 1  in THF). Chromatography on silica gel (pentane/
AcOEt, 6:4 ), afforded 1.19 g (quantitative) of diol 12b. Ϫ IR (film):
ν˜ ϭ 3291 (broad, OH), 2951, 1640 (CϭC), 1470, 1447, 1135, 1039
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 0.93 (s, 3 H), 1.01 (s, 3 H),
1.41Ϫ2.09 (m, 9 H), 2.17 (t, J ϭ 7.0 Hz, 2 H), 2.61 (s, 1 H, OH),
3.62 (t, J ϭ 7.0 Hz, 2 H), 4.88 (d, J ϭ 9.8 Hz, 1 H), 4.98 (d, J ϭ
17.1 Hz, 1 H), 5.30 (t, J ϭ 3.1 Hz, 1 H), 5.73Ϫ5.85 (m, 1 H). Ϫ
13C NMR (CDCl3): δ ϭ 22.05, 22.65, 26.91, 27.89, 33.32, 34.36,
42.59, 61.62, 74.58, 114.06, 121.17, 139.22, 139.88. Ϫ C14H24O2
[Mϩ]: calcd. 224.1776; found 224.1774 (HRMS).
(34.2 mg, 0.49 mmol) in water were successively added sodium car-
bonate (26.1 mg, 0.25 mmol) and a solution of aldehyde 13a
(58.7 mg, 0.22 mmol) in dichloromethane (2 mL). After vigorously
stirring for 5 h, dichloromethane (20 mL) was added. The organic
phase was washed successively with water (2 ϫ 5 mL) and brine
(5 mL), and then dried over magnesium sulfate. After filtration and
concentration in vacuo, chromatography on silica gel (petroleum
ether/AcOEt, 85:15), afforded 62 mg (quantitative) of oxime 14a as
a 1:1 mixture of syn and anti isomers. Ϫ IR (film): ν˜ ϭ 3280 (broad,
OH), 2930, 1700 (CϭN), 1640 (CϭC), 905 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 0.96 (s, 3 H), 1.04 (s, 3 H), 1.15Ϫ2.14 (m, 13 H),
2.25Ϫ2.40 (m, 1 H), 2.83 (d, J ϭ 6.2 Hz, 2 Hsyn), 3.05 (d, J ϭ
5.4 Hz, 2 Hanti), 5.33 (t, J ϭ 3.0 Hz, 1 Hsyn), 5.38 (t, J ϭ 3.0 Hz, 1
Hanti), 5.54 (d, J ϭ 10.0 Hz, 1 Hmajor), 5.55Ϫ5.67 (m, 1 H), 5.89
(dd, J ϭ 1.6, 9.3 Hz, 1 Hminor), 6.70 (t, J ϭ 5.4 Hz, 1 Hanti), 7.37
(t, J ϭ 6.2 Hz, 1 Hsyn), 9.06 (broad s, 1 H, OHanti), 9.50 (broad s,
1 H, OHsyn). Ϫ 13C NMR (CDCl3): δ ϭ 21.19, 21.75, 22.14, 22.71,
24.85, 27.43, 28.08 (syn), 30.61 (major), 30.73 (major), 30.93
(minor), 31.40 (minor), 31.96 (anti), 40.45 (major), 40.63 (minor),
42.91, 75.38, 122.73 (syn), 123.19 (anti), 126.10 (minor), 126.62
(major), 132.99 (minor), 133.42 (major), 138.97, 151.01 (anti),
151.52 (syn). Ϫ MS (CI, NH3); m/z (%): 260 (36) [Mϩ Ϫ OH], 278
(58) [Mϩ ϩ H], 295 (100) [Mϩ ϩ NH4]. Ϫ C17H27NO2 [Mϩ]: calcd.
277.2042; found 277.2041 (HRMS).
Diol 12c: Prepared as described above from tert-butyldimethylsilyl
ether 11c (78 mg, 0.24 mmol) and tetrabutylammonium fluoride
(0.42 mL, 1  in THF). Chromatography on silica gel (pentane/
ether, 2:8), afforded 38 mg (90%) of diol 12c. Ϫ IR (film): ν˜ ϭ 3380
(broad, OH), 3070, 2970, 2950, 2900, 2850, 1640, 1470, 1440, 1360,
1
1200, 1050, 1000 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 5.95 (dddd, J ϭ
17.1, 10.2, 8.1, 6.6 Hz, 1 H), 5.4 (t, J ϭ 3 Hz, 1 H), 5.15 (d, J ϭ
10.2 Hz, 1 H), 5.1 (d, J ϭ 17.1 Hz, 1 H), 3.75 (t, J ϭ 6.6 Hz, 2 H),
2.30 (dd, J ϭ 6.9, 14.1 Hz, 1 H), 2.25 (t, J ϭ 6.6 Hz, 2 H), 2.15
(dd, J ϭ 8.1, 14.1 Hz, 1 H), 1.75 (dt, J ϭ 13.5, 6.9 Hz, 1 H), 1.70
(br. s, 1 H, OH), 1.60 (J ϭ 13.5, 6.6 Hz, 1 H), 1.01 (s, 3 H), 1.09
(s, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ 140.2, 135.0, 120.8, 117.6,
74.1, 61.7, 42.2, 39.04, 34.4, 27.76, 22.4, 21.9, 22.3. Ϫ MS (CI,
NH3); m/z (%): 193 (100) [Mϩ Ϫ OH], 228 (31) [Mϩ ϩ NH4].
Oxime 14b: Prepared from aldehyde 13b (284 mg, 1.28 mmol) by
the procedure described above. Chromatography on silica gel (pen-
tane/AcOEt, 8:2), afforded 299 mg (99%) of oxime 14b. Ϫ IR (film):
Aldehyde 13a: Dimethyl sulfoxide (160 µL, 2.25 mmol) was added
to a solution of oxalyl chloride (114 mg, 0.9 mmol) in dichloro-
ν˜ ϭ 3267 (broad, OH), 2952, 1641 (CϭC), 1470, 1450, 914 cmϪ1
.
3246
Eur. J. Org. Chem. 1999, 3241Ϫ3249

Studies Directed Toward the Synthesis of Taxanes
FULL PAPER
1
Ϫ H NMR (CDCl3): δ ϭ 0.97 (s, 3 H), 1.06 (s, 3 H), 1.42Ϫ2.22 General Procedure for the Preparation of Nitro Compounds 16a؊c
(m, 9 H), 2.84 (d, J ϭ 6.0 Hz, 2 Hsyn,), 3.05 (d, J ϭ 5.1 Hz, 2 Hanti),
4.92 (d, J ϭ 10.1 Hz, 1 H), 5.02 (d, J ϭ 17.1 Hz, 1 H), 5.32 (t, J ϭ
3.0 Hz, 1 Hsyn), 5.38 (t, J ϭ 3.0 Hz, 1 Hanti), 5.76Ϫ5.90 (m, 1 H),
6.69 (t, J ϭ 5.1 Hz, 1 Hanti), 7.37 (t, J ϭ 6.0 Hz, 1 Hsyn), 9.28
(broad s, 1 H, OHanti), 9.72 (broad s, 1 H, OHsyn). Ϫ 13C NMR
(CDCl3): δ ϭ 21.82, 22.00, 22.72, 26.92, 27.69, 31.84, 33.34, 42.65,
74.73, 114.17, 122.76 (syn), 123.25 (anti), 138.98, 139.17, 151.03
From the Corresponding Iodides.
Nitro Compound 16a: A solution of iodide 15a (1.4 g, 3.74 mmol) in
DMF (100 mL) was added to a mixture of sodium nitrite (577 mg,
8.36 mmol) and urea (638 mg, 10.5 mmol) in DMF (50 mL). After
vigorously stirring for 6 h at Ϫ78°C in the dark ether (150 mL) and
water (250 mL) were added. The organic layer was separated and
the aqueous phase extracted with ether (4 ϫ 150 mL). The com-
bined organic phases were successively washed with water
(2 ϫ 100 mL), 20% aqueous sodium thiosulfate (100 mL) and brine
(100 mL), and then dried over magnesium sulfate. After filtration
and concentration in vacuo, chromatography on silica gel (pentane/
ether, 2:1), afforded 489 mg (45%) of 16a. Ϫ 1H NMR (CDCl3):
δ ϭ 1.01 (s, 3 H), 1.08 (s, 3 H), 1.21Ϫ2.32 (m, 13 H), 2.31 (m, 1
H), 2.66 (t, J ϭ 7.4 Hz, 2 H), 4.48 (t, J ϭ 7.4 Hz, 2 H), 5.32 (s,1
H), 5.47 (dd, J ϭ 1.7, 9.8 Hz, 1 Hmajor), 5.61Ϫ5.73 (m, 1 H), 5.90
(dd, J ϭ 1.9, 9.5 Hz, 1 Hminor). Ϫ 13C NMR (CDCl3): δ ϭ 21.14,
21.87, 22.20, 22.65, 24.85, 27.37, 29.05, 30.60 (minor), 30.75
(major), 30.92 (major), 31.39 (minor), 40.44 (major), 40.64 (minor),
43.03, 74.86, 75.04, 122.03, 126.34 (minor), 126.75 (major), 133.28,
138.25. Ϫ MS (CI, NH3); m/z (%): 311 (100) [Mϩ ϩ NH4].
(anti), 151.51 (syn). Ϫ MS (CI, NH3); m/z (%): 220 (16) [Mϩ
Ϫ
OH], 238 (56) [Mϩ ϩ H], 255 (100) [Mϩ ϩ NH4]. Ϫ C14H23NO2
[Mϩ]: calcd. 237.1729; found 237.1725 (HRMS).
General Procedure for the Preparation of Iodides 15a؊c From the
Corresponding Alcohols.
Iodide 15a: Iodine (290 mg, 1.14 mmol) was added portionwise to a
solution of triphenylphosphane (299 mg, 1.14 mmol) and imidazole
(77 mg, 1.14 mmol) in ether/acetonitrile (4:1, 5 mL) at 0°C. After
vigorously stirring for 20 min at 0°C, the reaction mixture was
stirred for 20 min at room temperature, then cooled to 0°C. A solu-
tion of diol 12a (100 mg, 0.38 mmol) in ether/acetonitrile (4:1,
2 mL) was added dropwise over 10 min. The reaction mixture was
vigorously stirred for 4 h at room temperature, and then filtered.
The solid residue was washed with ether (20 mL), and the filtrate
concentrated in vacuo. Ether (40 mL) was added, and the organic
phase successively washed with brine (10 mL), saturated aqueous
NaHCO3 (3 ϫ 10 mL) and brine (10 mL), then dried over mag-
nesium sulfate. After filtration and concentration in vacuo, chro-
matography on silica gel (pentane/AcOEt, 95:5), afforded 122 mg
(86%) of iodide 15a. Ϫ IR (film): ν˜ ϭ 3261 (broad, OH), 2924,
Nitro Compound 16b: Prepared as described above from iodide 15b
(805 mg, 2.41 mmol). Chromatography on silica gel (pentane/Ac-
OEt, 97:3), afforded 352 mg (58%) of 16b. Ϫ IR (film): ν˜ ϭ 3451
(broad, OH), 2956, 1640 (CϭC), 1554, 1473, 1447, 1380 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 1.02 (s, 3 H), 1.10 (s, 3 H), 1.38 (s, 1H,
OH), 1.50Ϫ2.10 (m, 8 H), 2.68 (t, J ϭ 7.2 Hz, 2 H), 4.48 (t, J ϭ
7.2 Hz, 2 H), 4.95 (d, J ϭ 9.8 Hz, 1 H), 5.04 (d, J ϭ 17.1 Hz, 1 H),
5.32 (t, J ϭ 3.0 Hz, 1 H), 5.78Ϫ5.84 (m, 1 H). Ϫ 13C NMR
(CDCl3): δ ϭ 21.87, 22.13, 22.65, 26.85, 27.89, 28.92, 33.27, 42.71,
74.34, 74.81, 114.29, 122.03, 138.26, 139.11. Ϫ MS (CI, NH3); m/z
(%): 271 (100) [Mϩ ϩ NH4]. Ϫ C13H20NO3 [Mϩ Ϫ CH3]: calcd.
238.1443; found 238.1464 (HRMS).
1
1650 (CϭC), 1170 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.97 (s, 3 H),
1.05 (s, 3 H), 1.18Ϫ2.10 (m, 13 H), 2.33Ϫ2.45 (m, 1 H), 2.56 (t,
J ϭ 7.9 Hz, 2 H), 3.21 (t, J ϭ 7.9 Hz, 2 H), 5.38 (s,1 H), 5.49 (dd,
J ϭ 1.7, 9.8 Hz, 1 Hmajor), 5.60Ϫ5.65 (m, 1 H), 5.91 (dd, J ϭ 1.8,
9.8 Hz, 1 Hminor). Ϫ 13C NMR (CDCl3): δ ϭ 5.05, 21.18, 21.91,
22.40, 22.58, 24.86, 27.31, 30.60 (minor), 30.74 (major), 30.94
(major), 31.40 (minor), 36.50, 40.42 (major), 40.62 (minor), 42.89,
75.18, 121.63, 126.22 (minor), 126.66 (major), 132.88 (minor),
Nitro Compound 16c: Prepared as described above from iodide 15c
(91.7 mg, 0.31 mmol). The crude product was chromatographed on
silica gel; elution with pentane/ether (85:15) afforded 9.5 mg (14%)
of nitrito compound, then elution with pentane/ether (60:40) af-
forded 42 mg (61%) of 16c. Ϫ IR (film): ν˜ ϭ 3480 (broad, OH),
3580, 3480, 3074, 2975, 2950, 2900, 2850, 1640, 1550, 1471, 1443,
1381, 1194, 1078, 1003 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 5.93 (ddt,
J ϭ 17.4, 10.2, 7.5, 6.6 Hz, 1 H), 5.33 (t, J ϭ 3.6 Hz, 1 H), 5.15
(d, J ϭ 10.2 Hz, 1 H), 5.12 (d, J ϭ 17.4 Hz, 1 H), 4.49 (t, J ϭ
7.5 Hz, 2 H), 2.7 (td, J ϭ 7.5, 1.5 Hz, 2 H), 2.32 (dd, J ϭ 6.6,
14.1 Hz, 1 H), 2.15 (dd, J ϭ 7.5, 14.1 Hz, 1 H), 2.05 (m, 2 H), 1.7
(m, 1 H), 1.6 (m, 1 H), 1.25 (broad s, 1 H, OH), 1.04 (s, 3 H), 1.11
(s, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ 138, 134.7, 122, 118.5, 74.8,
74, 42.3, 38.9, 28.9, 27.7, 22.5, 21.8, 22.3. Ϫ MS (CI, NH3); m/z
(%): 222 (78) [Mϩ Ϫ OH], 257 (100) [Mϩ ϩ NH4]. Ϫ C10H16NO3
[Mϩ Ϫ CH2CHϭCH2]: calcd. 198.1130; found 198.1143 (HRMS).
133.45 (major), 142.98. Ϫ MS (CI, NH3); m/z (%): 357 (7) [Mϩ
OH], 392 (100) [Mϩ ϩ NH4].
Ϫ
Iodide 15b: Prepared as described above from diol 12b (500 mg,
2.23 mmol). Chromatography on silica gel (pentane/AcOEt, 95:5),
afforded 700 mg (94%) of iodide 15b. Ϫ IR (film): ν˜ ϭ 3397 (broad,
OH), 2954, 1639 (CϭC), 1470, 1446, 1168, 1032 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 0.99 (s, 3 H), 1.07 (s, 3 H), 1.36 (s, 1 H, OH),
1.45Ϫ2.30 (m, 8 H), 2.53 (t, J ϭ 8.0 Hz, 2 H), 3.22 (t, J ϭ 8.0 Hz,
2 H), 4.95 (d, J ϭ 11.0 Hz, 1 H), 5.08 (d, J ϭ 17.1 Hz, 1 H), 5.38
(s, 1 H), 5.80Ϫ5.93 (m, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 4.92,
21.91, 22.07, 22.65, 27.04, 27.89, 33.33, 36.44, 42.58, 74.41, 114.14,
121.64, 139.25, 142.98. Ϫ MS (CI, NH3); m/z (%): 317 (27) [Mϩ
Ϫ
OH], 352 (100) [Mϩ ϩ NH4]. Ϫ C14H23O [Mϩ Ϫ I]: calcd.
Nitrito Compound. Ϫ 1H NMR (CDCl3): δ ϭ 5.96 (dddd, J ϭ 16.8,
10.2, 7.8, 6.9 Hz, 1 H), 5.4 (t, J ϭ 3.6 Hz, 1 H), 5.15 (d, J ϭ
10.2 Hz, 1 H), 5.12 (d, J ϭ 16.8 Hz, 1 H), 4.8 (t, J ϭ 7.2 Hz, 2 H),
2.39 (t, J ϭ 7.2 Hz, 2 H), 2.3 (dd, J ϭ 6.9, 13.8 Hz, 1 H), 2.2 (dd,
J ϭ 7.8, 13.8 Hz, 1 H), 2.05 (m, 2 H), 1.7 (m, 1 H), 1.6 (m, 1 H),
1.02 and 1.10 (2s, 6 H). Ϫ 13C NMR (CDCl3): δ ϭ 134.5, 122.0,
118.5, 75.0, 68.0, 42.0, 39.0, 27.8, 25.0, 22.5, 22.2, 22.0.
207.1749; found 207.1746 (HRMS).
Iodide 15c: Prepared as described above from diol 12c (246 mg,
1.17 mmol). Chromatography on silica gel (pentane/ether, 4:6), af-
forded 370 mg (99%) of iodide 15c. Ϫ IR (film): ν˜ ϭ 3580 (broad,
OH), 3460, 3075, 2980, 1638, 1470, 1440, 1360, 1170 cmϪ1. Ϫ H
1
NMR (CDCl3): δ ϭ 5.85 (dddd, J ϭ 17.1, 10.2, 8.4, 6.6 Hz, 1 H),
5.3 (t, J ϭ 3.6 Hz, 1 H), 5.06 (d, J ϭ 10.2 Hz, 1 H), 5.03 (d, J ϭ
17.1 Hz, 1 H), 3.15 (t, J ϭ 8.1 Hz, 2 H), 2.45 (t, J ϭ 8.1 Hz, 2 H), Isoxazoline 19: A solution of oxime 14b (22.3 mg, 0.094 mmol) was
2.25 (dd, J ϭ 14.1, 6.6 Hz, 1 H), 2.11 (dd, J ϭ 14, 8.4 Hz, 1 H), added in 1 h (with a syringe pump) to a vigorously stirred mixture
1.9Ϫ2.0 (m, 2 H), 1.6 (m, 1 H), 1.5 (m, 1 H), 0.93 (s, 3 H), 1.0 (s, of dichloromethane (50 mL), sodium hypochlorite (0.75 mL,
3 H). Ϫ 13C NMR (CDCl3): δ ϭ 142.9, 134.6, 121.8, 118.2, 74.1, 1.88 mmol, 2.5  in water) and 40% aqueous tetrabutylammonium
42.1, 38.9, 36.3, 27.8, 22.4, 21.9, 5.0. Ϫ MS (CI, NH3); m/z (%):
303 (28) [Mϩ Ϫ OH], 338 (100) [Mϩ ϩ NH4].
hydroxide solution (1 drop). After stirring for 30 min at room tem-
perature, the organic phase was washed with water (2 ϫ 15 mL)
Eur. J. Org. Chem. 1999, 3241Ϫ3249
3247

C. Mioskowski et al.
FULL PAPER
and brine (15 mL), then dried over magnesium sulfate. After fil-
tration and concentration in vacuo, the residue was chromato- purification Ϫ H NMR (CDCl3): δ ϭ 1.18 (s, 6 H), 1.74 (t, J ϭ
tained as an oil which was used in the next step without further
1
graphed on silica gel (pentane containing increasing amounts of
AcOEt, from 0% to 100%, then methanol) to give a solid (18 mg)
which was found to contain isoxazoline 19 as the major product,
as judged by the following analyses, and some oligomeric impurit-
6.7 Hz, 2 H), 1.95Ϫ2.10 (m, 2 H), 2.10Ϫ2.25 (m, 4 H), 3.97 (broad
s, 4 H), 4.93 (dd, J ϭ 10.7 Hz, 1.4 Hz, 1 H), 5.01 (dd, J ϭ 17.4 Hz,
1.7 Hz, 1 H), 5.31 (m, 1 H), 5.75Ϫ5.95 (m, 2 H). Ϫ 13C NMR
(CDCl3): δ ϭ 215.3, 143.6, 138.4, 120.1, 114.7, 48.1, 35.8, 33.1,
ies. Ϫ IR (film): ν˜ ϭ 3436 (broad, OH), 2953, 1622, 1471, 1196 29.9, 24.9, 24.1. Ϫ MS (CI, NH3); m/z (%): 196 (100) [Mϩ ϩ NH4].
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.01 (s, 3 H), 1.08 (s, 3 H),
1.42Ϫ2.07 (m, 9 H), 2.55 (m, 1 H), 2.96 (m, 1 H), 3.01 (s, 2 H),
4.46Ϫ4.64 (m, 1 H), 5.38 (s, 1 H). Ϫ MS (CI, NH3); m/z (%): 235
(67) [Mϩ], 253 (100) [Mϩ ϩ NH4]. Ϫ C14H21NO2: calcd. 235.1572;
found 235.1572 (HRMS).
Silylated Cyanohydrin 25: To a solution of ketone 24 (240 mg,
1.35 mmol) and trimethylsilyl chloride (1.5 equiv.) in dichlorometh-
ane (5 mL) cooled to 0°C was added zinc diiodide (2 mg.). The
reaction mixture was allowed to warm to room temperature. After
stirring for 1 h, the suspension was filtered and the filtrate was
concentrated in vacuo. Chromatography on silica gel (pentane) af-
forded 315 mg (85%) of silylated cyanohydrin 25. Ϫ 1H NMR
(CDCl3): δ ϭ 0.24 (s, 9 H), 1.04 (s, 3 H), 1.24 (s, 3 H), 2.0Ϫ2.15
(m, 2 H), 2.15Ϫ2.30 (m, 2 H), 2.35Ϫ2.45 (m, 2 H), 2.53 (t, J ϭ
6.5 Hz, 2 H), 4.98 (dd, J ϭ 10.5 Hz, 1.5 Hz, 1 H), 5.04 (broad d,
J ϭ 17.3 Hz, 1 H), 5.55 (m, 1 H), 5.75Ϫ5.95 (m, 1 H). Ϫ
C16H27NOSi [Mϩ]: calcd. 277.1862; found 277.1877 (HRMS).
Bis(isoxazoline) 21: To a solution of p-chlorophenylisocyanate
(276 mg, 1.8 mmol) and triethylamine (248 µL, 1.8 mmol) in tolu-
ene (10 mL) heated to 80°C was added, with a syringe pump over
a period of 18 h, a solution of 16c (43 mg, 0.18 mmol) in toluene
(45 mL). After cooling to room temperature, methanol (5 mL) was
added. The reaction mixture was then concentrated in vacuo. The
residue was chromatographed on silica gel (hexane, then hexane
containing increasing amounts of acetone). The fraction eluted
with hexane/acetone (80:20) was again chromatographed on silica
gel (hexane/AcOEt, 1:1) to afford 4.3 mg (10%) of bis(isoxazoline)
21. Ϫ IR (film): ν˜ ϭ 3500 (broad, OH), 3000, 2975, 2920, 2850,
Aldehyde 26: A solution of diisobutylaluminium hydride (4.38 mL,
1  in toluene) was added dropwise to a solution of nitrile 25
(300 mg, 1.08 mmol) in ether (10 mL) cooled to 0°C. After stirring
for 2 h at this temperature, methanol (1 mL) and a 0.7  aqueous
solution of potassium sodium tartrate (10 mL) were successively
added. After stirring vigorously for 4 h the mixture was decanted,
the organic layer separated, the aqueous phase extracted with ether
(2 ϫ 10 mL) and the combined organic phases washed with brine
(10 mL) and then dried over magnesium sulfate. After filtration
and concentration in vacuo, chromatography on silica gel (hexane/
ether, 9:1) afforded 210 mg (70%) of aldehyde 26. Ϫ 1H NMR
(CDCl3): δ ϭ 9.76 (s, 1 H), 5.75Ϫ5.90 (m, 1 H), 5.34 (m, 1 H), 5.04
(broad d, J ϭ 17.1 Hz, 1 H), 4.96 (d, J ϭ 10.3 Hz, 1 H), 2.00Ϫ2.25
(m, 6 H), 1.80Ϫ1.90 (m, 2 H), 1.16 (s, 3 H), 0.97 (s, 3 H), 0.11 (s,
9 H). Ϫ 13C NMR (CDCl3): δ ϭ 204.8, 142.2, 138.4, 119.1, 114.4,
83.3, 41.2, 32.8, 30.4, 27.7, 23.9, 23.0, 21.0, 2.3.
1
1465, 1030 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 5.32 (t, J ϭ 3 Hz, 2
H), 4.90 (t, J ϭ 9 Hz, 2 H), 3.50 (d, J ϭ 13.8 Hz, 2 H), 3.05 (dd,
J ϭ 15.9, 9 Hz, 2 H), 2.65 (d, J ϭ 13.8 Hz, 2 H), 2.50 (d, J ϭ
15.9 Hz, 2 H), 2.30Ϫ1.70 (m, 12 H), 1.55 (broad s, 1 H, OH), 1.12
(s, 3 H), 1.05 (s, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ 159.9, 139.9,
128.0, 76.9, 73.5, 43.7, 42.9, 38.1, 32.3, 31.7, 27.0, 26.2, 23.7, 22.4.
Ϫ MS (CI, NH3); m/z (%): 407 (15) [Mϩ Ϫ 2 OH], 425 (90) [Mϩ
Ϫ OH], 443 (100) [Mϩ ϩ H], 460 (19) [Mϩ ϩ NH4].
Bromide 22: To a solution of alcohol 4 (360 mg, 1.7 mmol) cooled
to 0°C were successively added tetrabromomethane (1.25 equiv.)
and triphenylphosphane (1.5 equiv.). After stirring for 1 h at 0°C,
ether (20 mL) was added. The suspension was filtered and the fil-
trate was concentrated in vacuo. Chromatography on silica gel
(hexane/AcOEt, 95:5), afforded 470 mg (100%) of bromide 22. Ϫ
1H NMR (CDCl3): δ ϭ 1.07 (s, 6 H), 1.74 (t, J ϭ 6.6 Hz, 2 H),
2.10Ϫ2.20 (m, 2 H), 2.54 (broad t, J ϭ 7.7 Hz, 2 H), 3.45 (t, J ϭ
Hz, 2 H), 3.90Ϫ4.00 (m, 4 H), 5.36 (broad t, J ϭ 3.6 Hz, 1 H).
Oxime 27: Pyridine (0.035 mL) was added to a suspension of alde-
hyde 26 (400 mg, 1.43 mmol) and hydroxylamine hydrochloride
(150 mg, 2.14 mmol) in ethanol (0.8 mL). The reaction mixture was
heated for 5 min at 50°C and then allowed to cool to room tem-
perature. After 15 min, the reaction mixture was concentrated in
vacuo. The residue was dissolved in dichloromethane and the solu-
tion was washed with water (5 mL), then dried over magnesium
sulfate. Filtration and concentration in vacuo afforded 400 mg
(95%) of oxime 27, which was used in the next step without further
purification. Ϫ 1H NMR (CDCl3): δ ϭ 7.57 (s, 1 H), 5.75Ϫ5.90
(m, 1 H), 5.26 (m, 1 H), 5.04 (broad d, J ϭ 17.2 Hz, 1 H), 4.96
(dd, J ϭ 10.3 Hz, 1.7 Hz, 1 H), 1.90Ϫ2.20 (m, 8 H), 1.16 (s, 3 H),
0.97 (s, 3 H), 0.10 (s, 9 H). Ϫ 13C NMR (CDCl3): δ ϭ 154.1, 141.9,
138.8, 116.9, 114.3, 77.7, 42.6, 32.9, 30.6, 27.9, 23.0, 22.9, 22.4, 2.1.
Diene 23: To a solution of bromide 22 (687 mg, 2.5 mmol) in THF
(25 mL) cooled to 0°C were successively added copper(I) iodide
(25 mg, 0.0125 mmol) and vinylmagnesium bromide (3.6 mL of a
1  solution in THF). The reaction mixture was allowed to warm
to room temperature. After stirring for 1 h, saturated aqueous am-
monium chloride (15 mL) was added. The aqueous phase was ex-
tracted with ether (50 mL) and the combined organic phases were
dried over magnesium sulfate. After filtration and concentration in
vacuo, 525 mg (95%) of diene 23 were obtained as an oil which was
used in the next step without further purification. Ϫ 1H NMR
(CDCl3): δ ϭ 1.07 (s, 6 H), 1.74 (t, J ϭ 6.6 Hz, 2 H), 2.01Ϫ2.07
(m, 2 H), 2.14Ϫ2.20 (m, 4 H), 3.96 (m, 4 H), 4.91Ϫ5.04 (m, 2 H),
5.31 (m, 1 H), 5.83 (m, 1 H). 13C NMR (CDCl3): δ ϭ 22.2, 23.6,
26.1, 30.1, 32.5, 64.8, 112.1, 114.0, 118.4, 139.7.
Nitrile Oxide 28: To a solution of oxime 27 (440 mg, 0.15 mmol)
in dichloromethane (5 mL) were added a 40% solution of aqueous
tetrabutylammonium hydroxide (0.01 mL) and a 7% solution of
Ketone 24: A solution of ketal 23 (500 mg, 2.25 mmol) and p-tolu-
enesulfonic acid (20 mg, 0.112 mmol) in acetone/water (2:1, 5 mL) aqueous sodium hypochlorite (5 mL). After stirring for 24 h at
was refluxed for 5 h. The reaction mixture was concentrated in va-
cuo to eliminate acetone. The aqueous phase was extracted with
ether (2 ϫ 20 mL). The combined organic phases were successively
washed with saturated aqueous NaHCO3 (10 mL) and brine
(10 mL), and then dried over magnesium sulfate. After filtration
and concentration in vacuo, 400 mg (100%) of ketone 24 were ob-
room temperature, the two phases were separated. The organic
phase was concentrated in vacuo. Chromatography of the residue
on silica gel (pentane/ether, 97:3) afforded 417 mg (95%) of nitrile
oxide 28. Ϫ H NMR (CDCl3): δ ϭ 5.75Ϫ5.90 (m, 1 H), 5.28 (m,
1 H), 5.04 (broad d, J ϭ 17.1 Hz, 1 H), 4.96 (d, J ϭ 10.3 Hz, 1 H),
1.90Ϫ2.30Ϫ2.25 (m, 8 H), 1.16 (s, 3 H), 1.03 (s, 3 H), 0.21 (s, 9 H).
1
3248
Eur. J. Org. Chem. 1999, 3241Ϫ3249

Studies Directed Toward the Synthesis of Taxanes
FULL PAPER
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Acknowledgments
We thank Mr. Valleix for performing the mass spectra.
[5]
[6]
[7]
[8]
[9]
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[1b]
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K. C. Nicolaou,
[10]
[11]
Z. Yang, J.-J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C. F.
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Claiborne, J. Renaud, E. A. Couladouros, K. Paulvannan, E. J.
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5339Ϫ5342.
[1c]
Sorensen, Nature 1994, 367, 630Ϫ634. Ϫ
J. J. Masters, J. T.
[12]
[13]
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[1d]
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[15]
The formation of the A/B ring system by the intramolecular
cyclisation of an aromatic nitrile oxide (a FriedelϪCrafts reac-
tion rather than a [3ϩ2] cycloaddition) was recently reported:
Y. Hirai, H. Nagaoka, Tetrahedron Lett. 1997, 38, 1969Ϫ1970.
For a related approach see also: P. Magnus, N. Westwood, M.
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1999, 55, 6435Ϫ6452.
[2]
[3]
[4]
Received March 23, 1999
[O99192]
Eur. J. Org. Chem. 1999, 3241Ϫ3249
3249