Enantioselective synthesis of a taxol C ring

Article abstract of DOI:10.1135/cccc2011039

An enantioselective synthesis of a C ring of taxol has been accomplished. The key step is an oxidative cleavage of a derivative of the Wieland-Miescher ketone. A first attempt of a Shapiro reaction modelling the coupling of the C ring with the A fragment of taxol was also successful.

Full text of DOI:10.1135/cccc2011039

Synthesis of a Taxol C Ring
1579
ENANTIOSELECTIVE SYNTHESIS OF A TAXOL C RING
a2
b,
Cong MAa1, Stéphanie SCHILTZ and Joëlle PRUNET *
a
Laboratoire de Synthèse Organique, CNRS UMR 7652, Ecole Polytechnique, DCSO,
1
2
F91128 Palaiseau, France; e-mail: ma@dcso.polytechnique.fr, schiltz@dcso.polytechnique.fr
WestCHEM, School of Chemistry, University of Glasgow, Joseph Black Building,
University Avenue, Glasgow G12 8QQ, UK; e-mail: joelle.prunet@glasgow.ac.uk
b
Received February 10, 2011
Accepted July 1, 2011
Published online December 23, 2011
Dedicated to Professor Pavel Kočovský on the occasion of his 60th birthday.
An enantioselective synthesis of a C ring of taxol has been accomplished. The key step is an
oxidative cleavage of a derivative of the Wieland–Miescher ketone. A first attempt of a
Shapiro reaction modelling the coupling of the C ring with the A fragment of taxol was also
successful.
Keywords: Taxol; Wieland–Miescher ketone; Shapiro reaction; Synthesis design; Ozonolysis;
Terpenoids.
Taxol (paclitaxel) and taxotere (docetaxel) (Scheme 1) are the highest-
selling anticancer drugs of all time, with sales of over 3 billion USD/year for
all the taxane market. They are used mainly against ovarian and breast can-
cers, and have also found use against non-small cell lung cancer1. In spite
of numerous synthetic approaches, including six total syntheses2 and a
formal synthesis3, they still constitute a remarkable challenge for organic
chemists because of their densely functionalized structure, which encom-
passes an eight-membered ring.
The retrosynthesis that we envisioned for taxol is delineated below
(Scheme 1). The primary target is an intermediate in Holton’s synthesis of
taxol, which contains the ABC tricyclic scaffold with all the required
functionalities. The A ring would be installed at a late stage by an intra-
molecular aldol reaction on diketone 1 at C11 and C13 4. Bicycle 2, avail-
able from compound 1 by a few functional group interconversions, would
be formed by a ring-closing metathesis that would close the B ring between
C10 and C11. The metathesis precursor 3 would be prepared by a Shapiro re-
action between the vinyllithium derived from hydrazone 4 and aldehyde 5.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594
© 2011 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2011039

1580
Ma, Schiltz, Prunet:
SCHEME 1
We have successfully synthesized model BC ring systems of taxol corre-
sponding to compound 2 (with no protected hydroxy group at C7 and no
ketal at C13)5. We planned an enantioselective synthetic route of the C ring
inspired by the synthesis of the 7-deoxy C ring we previously reported5k.
The target hydrazone 4 would be formed from the corresponding ketone 6,
which would be obtained from keto ester 7 (Scheme 2). This keto ester
would be formed by oxidative cleavage of the derivative 8 of the Wieland–
Miescher ketone6.
SCHEME 2
Wieland–Miescher ketone (WMK) was synthesized under Hajos–Parrish
conditions in the expected 70% ee 7. Recrystallization was low yielding in
our hands, so we adapted a procedure reported by Toda and co-workers for
the chemoselective and enantioselective reduction of the saturated ketone
function8 in order to obtain the next intermediate in our synthesis in an ef-
ficient manner (Scheme 3). Reduction of WMK (70% ee) in 1:1 dichloro-
methane/MeOH at –78 °C in the presence of one equivalent of (–)-taddol
led to enantiopure alcohol 9 (Scheme 3). In accord with literature prece-
dent, 9 was formed in 99% ee (determined by comparing the optical rota-
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

Synthesis of a Taxol C Ring
1581
tions). The undesired enantiomer decomposed during the reaction, and no
reduction of the unsaturated ketone was observed. Since our target is the
advanced intermediate in Holton’s synthesis, protection of the hydroxy
group as the BOM ether was chosen at first, and compound 10 was formed
in 78% yield. When we used ruthenium trichloride and oxone, the oxida-
tive cleavage of enone 10 led to the desired product in less than 10% con-
version9, but ozonolysis of 10 in methanol furnished acid 11. In this
reaction, some decomposition was always observed, probably due to partial
oxidation of the BOM ether by ozone. These results are in stark contrast
with the observations of Cravero et al.10, who showed that oxidation of a
compound similar to 10 could be performed with ruthenium dioxide and
sodium periodate, but not with ozone. Reduction of keto acid 11 with
LiAlH4 gave diol 12 as a 1:1 mixture of diastereomers. Selective protection
of the primary alcohol as the trityl ether 13 followed by oxidation of the
secondary alcohol with iodoxybenzoic acid (IBX)11 afforded ketone 14 in
good overall yield.
SCHEME 3
Unfortunately, transformation of the carbonyl group of 14 to the hy-
drazone performed with catalytic HCl led to removal of the trityl group,
and the BOM ether was also not stable under these conditions. This side re-
action was not observed in our previous studies on the 7-deoxy C ring5k. No
reaction occurred under the conditions Smith and co-workers used in his
approach to spongistatin 1, which transformed a ketone to the correspond-
ing hydrazone without HCl in excellent yield12.
Since HCl was necessary for the formation of the hydrazone, we thought
of realizing this step before protection of the diol group of the target mole-
cule. In other words, the hydrazone moiety must tolerate reduction condi-
tions under which the diol function would be obtained. Reduction assays of
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

1582
Ma, Schiltz, Prunet:
model hydrazone 15 5k with dimethyl sulfide borane and DIBAL-H, that are
normally unreactive towards imines, were performed. Only the latter did
not reduce the hydrazone group (Scheme 4).
SCHEME 4
The synthesis plan for the C ring was thus slightly modified: hydrazone
formation would be realized after the ozonolysis and esterification of the
corresponding product, and formation and protection of the diol group
would be carried out at a later stage. A benzoate was selected to protect
temporarily the alcohol function of 9, because this protecting group would
be removed during the reduction of the ester. Benzoate 16 was produced in
73% yield from alcohol 9 (Scheme 5). Ozonolysis of 16 gave the corre-
sponding carboxylic acid, which was directly submitted to SOCl2 in MeOH
to afford methyl ester 17. Transformation of the carbonyl group of 17 to
the hydrazone led to compound 18. Unfortunately, reduction of 18 with
four equivalents of DIBAL-H did not furnish the desired hydrazone but led
to hemiacetal 19 in 49% yield. When only three equivalents of DIBAL-H
were added to the reaction, the aldehyde peak was observed in 1H NMR
spectrum of the crude extract, but this compound could not be isolated.
Subsequent treatment of hemiacetal 19 with 4-dimethylamino-N-triphenyl-
methylpyridinium chloride afforded the corresponding trityl acetal 20 in
61% yield13.
SCHEME 5
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

Synthesis of a Taxol C Ring
1583
At this point, we considered that the methyl acetal analogue of com-
pound 20 could be an alternative precursor for the Shapiro reaction, and
this compound became our targeted C ring. However, the reduction of di-
ester 18 to hemiacetal 19 was not satisfying, so we devised a new synthesis
for hemiacetal 19 via lactone 22 (Scheme 6). Direct ozonolysis of alcohol 9
only led to decomposition products. To avoid this decomposition, alco-
hol 9 was converted to the corresponding triethylsilyl ether 21. Ozonolysis
of 21 followed by acidic treatment of the resulting keto acid (24) furnished
lactone 22 in excellent overall yield. Transformation of ketone 22 to the
hydrazone and DIBAL-H reduction of the lactone moiety afforded lactol 19,
which was identical to the hemiacetal obtained by the previous route. Pro-
tection of the hemiacetal group as the methyl acetal was attempted using
several methods. Not surprisingly, PPTS with methyl orthoformate hydro-
lyzed the hydrazone function, but MeI in the presence of NaH or Ag2O 14
was also unsuccessful and only led to decomposition products13.
SCHEME 6
We then decided to install the hemiacetal protecting group before the
formation of hydrazone. Chemoselective reduction of carboxylic acid 24 to
the aldehyde using the Vilsmeier–Haack reagent was realized under
Lebreton’s conditions15 (Scheme 6). Vilsmeier–Haack reagent was formed
by mixing a large excess of DMF and oxalyl chloride at –20 °C, then crude
carboxylic acid 24 was added followed by the reductive reagent; finally,
acidic treatment in situ removed the TES group and furnished a 1:1 mixture
of epimeric hemiacetals 25. We then attempted to form the corresponding
methyl acetal 26. Curiously, no reaction occurred in the presence of PPTS
and methyl orthoformate, but silver(I) oxide promoted methylation of 25
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

1584
Ma, Schiltz, Prunet:
to afford methyl acetal 26 in excellent yield14. Finally, transformation of 26
to hydrazone 23 proceeded in quantitative yield.
With hydrazone 23 in hand, we then tested the Shapiro reaction on a
model aldehyde. Hydrocinnamaldehyde was added to the reaction mixture
containing the vinyl anion that was formed by treatment of 23 with two
equivalents of t-BuLi. Adduct 27 and alkene 28, formed by protonation of
the intermediate vinyl anion, were obtained in 42 and 26% respective un-
optimized yields (Scheme 7).
SCHEME 7
In conclusion, an enantiopure C ring of taxol was synthesized in six
steps from the WMK in 24% overall yield. In addition, a first attempt of a
Shapiro reaction modelling the coupling of the C ring with the A fragment
was also successful.
EXPERIMENTAL
All air and/or water sensitive reactions were carried out under an argon atmosphere with
dry, freshly distilled solvents using standard syringe-cannula/septa techniques. All corre-
sponding glassware was carefully dried under vacuum with a flameless heat gun. Tetra-
hydrofuran (THF) and diethyl ether were distilled from sodium benzophenone. Flash
chromatography was performed using silica gel 60, 230–400 mesh.
1H NMR spectra were recorded in CDCl3 on a Bruker AM 400 (400 MHz) or a Bruker
Avance 400 (400 MHz) instrument. The chemical shifts are expressed in parts per million
(δ, ppm) referenced to residual chloroform (7.27 ppm). Data are reported as follows: δ,
chemical shift; multiplicity (recorded as br, broad; s, singlet; d, doublet; t, triplet; q, quartet;
hex, hexuplet; hept, heptuplet; oct, octuplet and m, multiplet), integration and coupling
constants (J, Hz). 13C NMR spectra were recorded on the same instruments at 100.6 MHz.
The chemical shifts are expressed in parts per million (δ, ppm), reported from the central
peak of deuterochloroform (77.00 ppm). Assignments were obtained using J-mod or DEPT
experiments, and when necessary, COSY, NOESY, HSQC and HMBC experiments. Taxol
numbering is used for reporting assignments.
Infrared spectra (IR) were obtained on a Perkin–Elmer FT 1600 instrument and are re-
ported in terms of frequency of absorption (ν, cm–1).
Optical rotations were determined on a Perkin–Elmer 241-instrument operating at the
20
D-line of Na and are reported as follows: [α]D (g/100 ml, solvent).
Mass spectra (MS) were obtained on a Hewlett–Packard HP 5989B spectrometer via either
direct injection or GC/MS coupling with a Hewlett–Packard HP 5890 chromatograph. Ioniza-
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

Synthesis of a Taxol C Ring
1585
tion was obtained either by electron impact (EI) or chemical ionization with ammonia (CI,
NH3) or methane (CI, CH4). Mass spectrum data are reported as m/z. High resolution mass
spectra (HRMS) were performed with a Jeol GC Mate II apparatus, by direct introduction of
the compound, in magnet mode.
(4aS,5S)-5-Hydroxy-4a-methyl-4,4a,5,6,7,8-hexahydro-
3H-naphthalen-2-one (9)8
Acetic acid (50 µl), hydroquinone (1.8 mg, 0.16 mmol, 0.02 equiv.) and freshly distilled
methyl vinyl ketone (2.2 g, 32 mmol, 2.0 equiv.) were added to a solution of 2-methyl-
1,3-cyclohexanedione (2.0 g, 16 mmol) in distilled water (5 ml) at room temperature. The
reaction mixture was stirred for 1 h at 80 °C, then cooled to room temperature, treated with
NaCl (1.6 g) and diluted with AcOEt (6 ml). The layers were separated, and the aqueous
phase was extracted with AcOEt. The combined organic layers were washed twice with
brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude trione
was dissolved in dried DMSO (20 ml) and recrystallized L-proline (92 mg, 0.8 mmol,
0.05 equiv.) was added. The mixture was stirred at room temperature for 6 days. The solvent
was then evaporated and the residue was filtered through a pad of silica gel to give the
crude WMK. To a solution of crude WMK and (–)-taddol (7.5 g, 16 mmol, 1.0 equiv.) in
MeOH/CH2Cl2 (100 ml, 1:1) was added NaBH4 (0.61 g, 32 mmol, 2.0 equiv.) at –78 °C. The
reaction was stirred for 15 min at that temperature, then quenched with acetone, and the
resulting mixture was allowed to warm up to room temperature. Water (10 ml) was added
and the phases were separated, then the aqueous phase was extracted with dichloro-
methane. The combined organic fractions were washed with brine and dried over magne-
sium sulfate, filtered and the solvent was removed under reduced pressure. Purification of
the crude product by flash chromatography (ethyl acetate/petroleum ether 80:20) afforded 9
(1.7 g, 60% yield over three steps, in 99% enantiomeric excess according to the literature) as
a yellow oil; the (–)-taddol was also recovered in quantitative yield. 1H NMR (400 MHz,
CDCl3): 5.74 s, 1 H (H-2); 3.38 dd, 1 H, J = 11.5, 3.2 (H-7); 2.74–2.58 br s, 1 H (OH);
2.40–2.26 m, 2 H (H-4); 2.19–2.12 m, 2 H (H-10); 1.86–1.76 m, 3 H (CH2); 1.73–1.65 m, 2 H
20
(CH2); 1.43–1.34 m, 1 H (CH2); 1.16 s, 3 H (Me-8). [α]D +122.0 (c 1.50, CH2Cl2).
(4aS,5S)-5-Benzyloxymethoxy-4a-methyl-4,4a,5,6,7,8-hexahydro-
3H-naphthalen-2-one (10)
A solution of 9 (200 mg, 1.12 mmol) in dichloromethane was treated with BOMCl (1.55 ml,
11.2 mmol, 10.0 equiv.), TBAI (413 mg, 1.00 equiv.), i-Pr2NEt (2.92 ml, 15.0 equiv.) at room
temperature and the resulting mixture was stirred for 2 days, then diluted with water and
extracted with dichloromethane. The combined organic fractions were washed with brine
and dried over magnesium sulfate, filtered and the solvent was removed under reduced pres-
sure. Purification of the crude product by flash chromatography (ethyl acetate/petroleum
ether 50:50) afforded 10 (262 mg, 78% yield) as a pale yellow oil. 1H NMR (400 MHz,
CDCl3): 7.37–7.35 m, 5 H (H-Ar); 5.78 d, 1 H, J = 1.8 (H-2); 4.88 d, 1 H, J = 7.1 (BnOCH2);
4.76 d, 1 H, J = 7.1 (BnOCH2); 4.63 s, 2 H (PhCH2); 3.38 dd, 1 H, J = 11.7, 4.3 (H-7);
2.45–2.30 m, 2 H (H-4); 2.25–2.20 m, 2 H (H-10); 2.05–2.01 m, 2 H (CH2); 1.92–1.84 m, 2 H
(CH2); 1.73–1.63 m, 1 H (CH2); 1.424–1.32 m, 1 H (CH2); 1.24 s, 3 H (Me-8).
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

1586
Ma, Schiltz, Prunet:
3-((1R,2S)-2-Benzyloxymethoxy-1-methyl-6-oxocyclohexyl)propionic Acid (11)
A stream of ozone was passed for 2 h through a solution of 10 (2.00 g, 6.06 mmol) in
methanol/dichloromethane (20 ml, 4:1) at –78 °C. The reaction was monitored by TLC.
Upon completion, the solvent was evaporated under reduced pressure to give crude 11 as a
colorless oil. The crude product was used for the following step without further purification.
1H NMR (400 MHz, CDCl3): 7.38–7.29 m, 5 H (H-Ar); 4.84 d, 1 H, J = 7.2 (BnOCH2); 4.72 d,
1 H, J = 7.2 (BnOCH2); 4.62 d, 2 H, J = 2.6 (PhCH2); 3.76 dd, 1 H, J = 6.9, 3.0 (H-7); 2.40 t,
2 H, J = 6.8 (H-4); 2.35 dd, 1 H, J = 11.0, 5.3 (H-10); 2.29 dd, 1 H, J = 11.0, 5.3 (H-10);
2.19–2.06 m, 2 H (CH2); 2.05–2.00 m, 2 H (CH2); 1.71–1.60 m, 2 H (CH2); 1.15 s, 3 H (Me-8).
(2S,3S)-3-Benzyloxymethoxy-2-(3-hydroxypropyl)-2-methylcyclohexanol (12)
A solution of the ketocarboxylic acid 11 in THF (10 ml) was added dropwise at 0 °C to a sus-
pension of LiAlH4 (0.58 g, 15.2 mmol, 2.50 equiv.) in THF (50 ml). The resulting mixture
was then allowed to warm slowly to room temperature, and stirred for 7 h. After cooling to
0 °C, water (2 ml), aqueous NaOH (6 M, 2 ml) and water (6 ml) were added, then the mix-
ture was stirred for 45 min. The aluminum salts were filtered off under reduced pressure
through a pad of celite, then the organic phase was dried over magnesium sulfate, filtered
and the solvent was removed under reduced pressure. The crude product was purified by
flash chromatography to afford 12 (1.62 g, 79% yield over two steps) as a colorless oil as
a 1:1 mixture of diastereomers. 1H NMR (400 MHz, CDCl3): 7.36–7.32 m, 5 H (H-Ar); 4.84 d,
1 H, J = 7.1 (BnOCH2); 4.73 d, 1 H, J = 7.1 (BnOCH2); 4.64 d, 2 H, J = 3.0 (PhCH2);
3.61–3.57 m, 2 H (H-7, H-3); 3.51–3.47 m, 2 H (H-1); 1.84–1.68 m, 3 H (CH2); 1.61–1.53 m,
5 H (CH2); 1.30–1.24 m, 2 H (CH2); 1.01 s, 3 H (Me-8).
(2S,3S)-3-Benzyloxymethoxy-2-methyl-2-(3-trityloxypropyl)cyclohexanol (13)
4-Dimethylamino-N-triphenylmethylpyridinium chloride (2.07 g, 3.90 mmol, 1.20 equiv.)
was added at room temperature to a solution of diol 12 (1.00 g, 3.25 mmol) in dichloro-
methane (10 ml). The resulting mixture was refluxed overnight. After cooling, diethyl ether
(20 ml) was added, and the white salts were filtered off. The solution was dried over magne-
sium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude
product was purified by flash chromatography (diethyl ether/petroleum ether 30:70 then
40:60) to give 13 (1.48 g, 83% yield) as a colorless oil as a 1:1 mixture of diastereomers.
1H NMR (400 MHz, CDCl3): 7.46–7.43 m,
6 H (H-Ar); 7.33–7.27 m, 11 H (H-Ar);
7.24–7.21 m, 3 H (H-Ar); 4.83 d, 1 H, J = 7.1 (BnOCH2); 4.73 d, 1 H, J = 7.1 (BnOCH2);
4.61 s, 2 H (PhCH2); 3.55 d, 1 H, J = 4.9 (H-3); 3.48 dd, 1 H, J = 7.3, 3.1 (H-7); 3.06 t, 2 H,
J = 6.4 (H-1); 1.78–1.72 m, 3 H (CH2); 1.64–1.59 m, 3 H (CH2); 1.47–1.42 m, 2 H (CH2);
1.31–1.25 m, 2 H (CH2); 1.04 s, 3 H (Me-8).
(2R,3S)-3-Benzyloxymethoxy-2-methyl-2-(3-trityloxypropyl)cyclohexanone (14)
A solution of IBX (154 mg, 0.55 mmol, 1.20 equiv.) in DMSO (15 ml) was added slowly at
room temperature to a stirred solution of 13 (200 mg, 0.36 mmol) in THF (15 ml). The re-
sulting mixture was stirred at room temperature overnight. When the reaction had gone to
completion, water (20 ml) was added and the organic phase was diluted with diethyl ether
(10 ml). The biphasic system was stirred for 3 h. The white salts were then filtered off on a
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

Synthesis of a Taxol C Ring
1587
pad of celite. The phases were separated and the aqueous phase was extracted with diethyl
ether (3 × 10 ml). The combined organic fractions were washed with water (20 ml) and
brine (20 ml), dried over magnesium sulfate, filtered and the solvent was removed under re-
duced pressure. Purification of the crude product by flash chromatography (diethyl ether/
petroleum ether 20:80) afforded the desired 14 (161 mg, 81% yield) as a colorless oil.
1H NMR (400 MHz, CDCl3): 7.47–7.45 m,
6 H (H-Ar); 7.37–7.30 m, 11 H (H-Ar);
7.27–7.24 m, 3 H (H-Ar); 4.85 d, 1 H, J = 7.2 (BnOCH2); 4.74 d, 1 H, J = 7.2 (BnOCH2);
4.64 d, 2 H, J = 2.2 (PhCH2); 3.89 d, 1 H, J = 3.4 (H-7); 3.12–3.05 m, 2 H (H-1); 2.31–2.51 m,
2 H (H-4); 2.16–1.92 m, 3 H (CH2); 1.81–1.75 m, 2 H (CH2); 1.70–1.54 m, 2 H (CH2);
1.46–1.38 m, 1 H (CH2); 1.18 s, 3 H (Me-8).
(1S,8aS)-8a-Methyl-6-oxo-1,2,3,4,6,7,8,8a-octahydronaphthalen-1-yl Benzoate (16)
To a solution of 9 (2.52 g, 14.0 mmol) in dichloromethane (20 ml) was added pyridine
(2.28 ml, 28.0 mmol, 2.00 equiv.) at 0 °C, then BzCl (1.95 ml, 16.8 mmol, 1.2 equiv.) and
a catalytic quantity of DMAP were added. The resulting mixture was stirred for 12 h. The re-
action was quenched by addition of aqueous sodium hydrogencarbonate (sat., 10 ml). The
phases were separated and the aqueous phase was extracted with diethyl ether (3 × 10 ml).
The combined organic fractions were washed with brine (20 ml), dried over magnesium sul-
fate, filtered and the solvent was removed under reduced pressure. Purification of the crude
product by flash chromatography (diethyl ether/petroleum ether 50:50) afforded 16 (2.88 g,
73% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): 7.70–7.66 m, 1 H (H-Ar);
7.60–7.51 m, 2 H (H-Ar); 7.48–7.44 m, 2 H (H-Ar); 5.86 d, 1 H, J = 1.8 (H-2); 4.91 dd, 1 H,
J = 11.7, 4.5 (H-7); 2.45–2.39 m, 3 H (H-10, H-4); 2.34–2.28 m, 1 H (H-10); 2.08–2.00 m, 2 H
(CH2); 1.94–1.80 m, 2 H (CH2); 1.64–1.52 m, 2 H (CH2); 1.43 s, 3 H (Me-8).
(1S,2R)-2-(2-Carboxyethyl)-2-methyl-3-oxocyclohexyl Benzoate (16′)
A stream of ozone was passed for 2 h through a solution of 16 (1.00 g, 3.52 mmol) in meth-
anol (70 ml) at –78 °C. The reaction was monitored by TLC. Upon completion, the solvent
was evaporated under reduced pressure to give crude 16′ as a colorless oil. The crude prod-
uct was used for the following step without further purification. 1H NMR (400 MHz, CDCl3):
7.64–7.61 m, 1 H (H-Ar); 7.54–7.46 m, 2 H (H-Ar); 7.41–7.37 m, 2 H (H-Ar); 5.28–5.26 m,
1 H (H-7); 2.56–2.49 m, 1 H (H-4); 2.44–2.32 m, 3 H (H-10, H-4, H-10); 2.22–2.14 m, 2 H
(CH2); 2.10–1.80 m, 4 H (CH2); 1.11 s, 3 H (Me-8).
(1S,2R)-2-(2-Methoxycarbonylethyl)-2-methyl-3-oxocyclohexyl Benzoate (17)
To a solution of 16′ and pyridine (0.83 g, 10.6 mmol, 3 equiv.) in MeOH was added
dropwise SOCl2 (0.30 ml, 4.22 mmol, 1.20 equiv.) at 0 °C. The mixture was stirred for 1.5 h
and concentrated in vacuo with a trap of aqueous NaOH solution. Purification of the crude
product by flash chromatography (diethyl ether/petroleum ether 20:80) yielded 17 (0.83 g,
74% yield over two steps). 1H NMR (400 MHz, CDCl3): 7.99–7.97 m,
2 H (H-Ar);
7.58–7.55 m, 1 H (H-Ar); 7.45–7.42 m, 2 H (H-Ar); 5.30 dd, 1 H, J = 5.3, 2.8 (H-7); 3.65 s,
3 H (COOMe); 2.60–2.52 m, 1 H (H-4); 2.49–2.34 m, 2 H (H-10, H-4); 2.28–2.16 m, 2 H
(H-10, H-9); 2.12–1.84 m, 5 H (H-9, H-6, H-5); 1.15 s, 3 H (Me-8). IR (film): 2954, 2874,
20
1715, 1600, 1449, 1270, 1173, 1107, 848, 795, 780, 661. [α]D +36.6 (c 1.35, CH2Cl2).
HRMS calculated for C18H22O5 318.1467; found 318.1477.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

1588
Ma, Schiltz, Prunet:
(1S,2R)-2-(2-Methoxycarbonylethyl)-2-methyl-3-benzoylcyclohexyl-
N′-(2,4,6-triisopropylbenzenesulfono)hydrazone (18)
Two drops of concentrated hydrochloric acid were added to a solution of ketone 17 (158 mg,
0.50 mmol) and triisopropylbenzenesulfonyl hydrazine (149 mg, 0.50 mmol, 1.00 equiv.) in
THF (5.0 ml). The resulting solution was stirred at room temperature for 2.5 h, and the reac-
tion was quenched by addition of aqueous sodium hydrogencarbonate (sat., 5 ml). The
phases were separated and the aqueous phase was extracted with diethyl ether (3 × 10 ml).
The combined organic fractions were washed with brine (15 ml) and dried over magnesium
sulfate, filtered and the solvent was removed under reduced pressure. Purification of the
crude product by flash chromatography (diethyl ether/petroleum ether 50:50) yielded 18
(274 g, 92% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.97 s, 1 H (NH);
7.89–7.86 m, 2 H (H-Ar); 7.53–7.50 m, 1 H (H-Ar); 7.36–7.33 m, 2 H (H-Ar); 7.17 s, 2 H
(H-Ar); 5.06 dd, 1 H, J = 4.8, 2.7 (H-7); 4.23 septet, 2 H, J = 6.7 (Ar-CH); 3.58 s, 3 H
(COOMe); 2.89 septet, 1 H, J = 6.9 (Ar-CH); 2.53 dt, 1 H, J = 15.3, 5.0 (H-4); 2.21–2.01 m,
3 H (H-4, H-10); 1.89–1.82 m, 2 H (H-6); 1.80–1.66 m, 4 H (H-5, H-9); 1.26–1.21 m, 18 H
(H-iPr); 0.99 s, 3 H (Me-8). 13C NMR (100.6 MHz, CDCl3): 173.7 (C-1); 165.5 (C-3); 158.4
(C-BzC=O); 153.2 (C-Ar); 151.2 (C-Ar); 132.9 (C-Ar); 131.0 (C-Ar); 130.0 (C-Ar); 129.5 (C-Ar);
128.3 (C-Ar); 123.5 (C-Ar); 77.4 (C-7); 51.5 (COOMe); 45.8 (C-8); 34.1 (C-iPr); 31.0 (C-10);
29.8 (C-iPr); 28.1 (C-6); 25.2 (C-9); 24.8 (CH(CH3)2); 24.7 (CH(CH3)2); 23.5 (CH(CH3)2); 23.4
(CH(CH3)2); 22.2 (C-4); 19.9 (C-5); 19.3 (Me-8). IR (film): 3243, 2958, 2871, 1720, 1600,
20
1596, 1453, 1319, 1270, 1163, 1110, 1026, 871, 794, 748, 632, 525. [α]D +71.0 (c 1.35,
CH2Cl2). HRMS calculated for C33H46N2O4S 598.3077; found 598.3081.
(2S,4aR,8aS)-2-Hydroxy-4a-methyloctahydrochromen-
5-N′-(2,4,6-triisopropylbenzenesulfono)hydrazone (19)
To a solution of 18 (117 mg, 0.20 mmol) in dichloromethane (10 ml) was added dropwise
DIBALH (0.80 ml, 1 M in hexanes, 0.80 mmol, 4.00 equiv.) at –78 °C, then the temperature
was allowed to warm up to 0 °C. The reaction was stirred at that temperature for 1 h, and
quenched with MeOH and a saturated aqueous NaHCO3 solution. The two phases were sepa-
rated and the aqueous phase was extracted with diethyl ether (3 × 10 ml). The combined or-
ganic fractions were washed with brine (20 ml), dried over magnesium sulfate, filtered and
the solvent was removed under reduced pressure. Purification of the crude product by flash
chromatography (diethyl ether/petroleum ether 10:90) afforded 19 (45.0 mg, 49% yield) as
a colorless oil. 1H NMR (400 MHz, CDCl3): 7.16 s, 2 H (H-Ar); 4.19 septet, 2 H, J = 6.8
(Ar-CH); 4.11 d, 1 H, J = 9.8 (H-7); 3.22 dd, 1 H, J = 10.3, 5.8 (H-1); 2.90 septet, 1 H, J = 6.9
(Ar-CH); 2.62 dt, 1 H, J = 14.3, 7.1 (H-4); 2.18 ddd, 1 H, J = 14.3, 5.3, 1.8 (H-4); 2.00–1.92 m,
1 H (H-10); 1.78–1.65 m, 5 H (H-10, H-6, H-9); 1.54–1.44 m, 2 H (H-5); 1.26–1.22 m, 18 H
(H-iPr); 1.14 s, 3 H (Me-8). 13C NMR (100.6 MHz, CDCl3): 213.3 (C-3); 153.2 (C-Ar); 151.5
(C-Ar); 131.1 (C-Ar); 123.7 (C-Ar); 89.1 (C-1); 80.0 (C-7); 77.2, 48.6 (C-8); 36.4 (C-4); 34.1
(C-iPr); 29.8 (C-iPr); 29.6 (C-6); 25.9 (C-10); 25.2 (C-9); 24.9 (CH(CH3)2); 24.8 (CH(CH3)2);
20.7 (C-5); 16.1 (Me-8).
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

Synthesis of a Taxol C Ring
1589
(2R,4aR,8aS)-4a-Methyl-2-trityloxyoctahydrochromen-
5-N′-(2,4,6-triisopropylbenzenesulfono)hydrazone (20)
4-Dimethylamino-N-triphenylmethylpyridinium chloride (51.0 mg, 0.13 mmol, 1.30 equiv.)
was added at room temperature to a solution of 19 (450.0 mg, 0.10 mmol) in dichloro-
methane (10 ml). The resulting mixture was refluxed overnight. After cooling, diethyl ether
(20 ml) was added, and the white salts were filtered off. The solution was dried over magne-
sium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude
product was purified by flash chromatography (diethyl ether/petroleum ether 30:70 then
40:60) to give 20 (42 mg, 61% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.98 s,
1 H (NH); 7.35–7.24 m, 15 H (H-Ar); 7.18 s, 2 H (H-Ar); 4.18 septet, 2 H, J = 6.7 (Ar-CH);
4.01 d, 1 H, J = 12.0, 4.2 (H-7); 3.22 dd, 1 H, J = 10.3, 5.8 (H-1); 2.93 septet, 1 H, J = 6.9
(Ar-CH); 2.62 m, 2 H (H-4); 2.05–1.91 m, 4 H (H-10, H-6); 1.82–1.68 m, 4 H (H-5, H-9);
1.28–1.24 m, 18 H (H-iPr); 1.03 s, 3 H (Me-8).
(4aS,5S)-4a-Methyl-5-triethylsiloxy-4,4a,5,6,7,8-hexahydro-
3H-naphthalen-2-one (21)
To a solution of 9 (4.30 g, 30.7 mmol) in dichloromethane (10 ml) was added imidazole
(5.23 g, 76.8 mmol, 2.50 equiv.) and TESCl (6.90 g, 46.1 mmol, 1.50 equiv.). The mixture
was stirred for 12 h at room temperature, then quenched with a saturated aqueous NaHCO3
solution. The two phases were separated and the aqueous phase was extracted with diethyl
ether (3 × 25 ml). The combined organic fractions were washed with brine (20 ml), dried
over magnesium sulfate, filtered and the solvent was removed under reduced pressure. Puri-
fication of the crude product by flash chromatography (diethyl ether/petroleum ether 10:90)
afforded 21 (6.32 g, 90% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): 5.76 s, 1 H
(H-1); 3.39 dd, 1 H, J = 10.6, 5.2 (H-7); 2.42–2.36 m, 2 H (H-4); 2.33–2.27 m, 1 H (H-10);
2.21–2.08 m, 2 H (H-10, CH2); 1.86–1.80 m, 1 H (CH2); 1.76–1.70 m, 2 H (CH2);
1.42–1.30 m, 2 H (CH2); 1.16 s, 3 H (Me-8); 0.95 t, 9 H, J = 7.9 (H-TES); 0.59 q, 6 H, J = 7.9
(H-TES).
3-((1R,6S)-1-Methyl-2-oxo-6-triethylsiloxycyclohexyl)propionic Acid (24)
A stream of ozone was passed for 2 h through a solution of 21 (2.0 g, 6.37 mmol) in metha-
nol (70 ml) at –78 °C. The reaction was monitored by TLC. Upon completion, the solvent
was evaporated under reduced pressure to give crude 24 as a colorless oil. The crude product
was used for the following step without further purification. 1H NMR (400 MHz, CDCl3):
10.30–10.10 br s, 1 H (COOH); 3.82 dd, 1 H, J = 6.0, 2.0 (H-7); 2.41–2.25 m, 3 H (H-4, H-10);
2.16–2.07 m, 1 H (H-10); 2.06–1.94 m, 3 H (CH2); 1.78–1.65 m, 3 H (CH2); 1.03 s, 3 H
(Me-8); 0.90 t, 9 H, J = 7.9 (H-TES); 0.54 q, 6 H, J = 7.9 (H-TES).
(4aR,8aS)-4a-Methylhexahydrochromene-2,5-dione (22)
To a solution of crude 21′ in dichloromethane (10 ml) was added a catalytic quantity of
PPTS. The mixture was stirred for 1 h at room temperature and then quenched with a satu-
rated NaHCO3 aqueous solution. The two phases were separated and the aqueous phase was
extracted with diethyl ether (3 × 25 ml). The combined organic fractions were washed with
brine (20 ml), dried over magnesium sulfate, filtered and the solvent was removed under
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

1590
Ma, Schiltz, Prunet:
reduced pressure. Purification of the crude product by flash chromatography (diethyl ether/
petroleum ether 10:90) afforded the desired 22 (1.04 g, 90% yield over two steps) as a color-
less oil. 1H NMR (400 MHz, CDCl3): 4.11 dd, 1 H, J = 11.6, 4.5 (H-7); 2.61–2.45 m, 3 H (H-4,
H-10); 2.20–2.10 m, 2 H (H-10, H-6); 2.00–1.85 m, 3 H (H-5, H-6); 1.68–1.63 m, 1 H (H-9);
1.54–1.40 m, 1 H (H-9); 1.11 s, 3 H (Me-8). 13C NMR (100.6 MHz, CDCl3): 210.1 (C-3); 170.5
(C-1); 81.0 (C-7); 47.9 (C-8); 36.1 (C-9); 26.6 (C-5); 26.2 (C-6); 25.5 (C-10); 19.7 (C-4); 16.3
(Me-8). IR (film): 4197, 3465, 3059, 2963, 2883, 2306, 1743, 1454, 1425, 1380, 1216, 1184,
20
1053, 1015, 892, 821, 711, 659, 607. [α]D –41.3 (c 1.50, CH2Cl2). HRMS calculated for
C
10H14O3 182.0943; found 182.0945.
(4aR,8aS)-4a-Methylhexahydrochromene-2-one-
5-N′-(2,4,6-triisopropylbenzenesulfono)hydrazone (22′)
Two drops of concentrated hydrochloric acid were added to a solution of ketone 22 (60 mg,
0.33 mmol) and triisopropylbenzenesulfonyl hydrazine (100 mg, 0.33 mmol, 1.00 equiv.) in
THF (5.0 ml). The resulting solution was stirred at room temperature for 1 h, and the reac-
tion was quenched by addition of aqueous sodium hydrogencarbonate (sat., 5 ml). The
phases were separated and the aqueous phase was extracted with diethyl ether (3 × 10 ml).
The combined organic fractions were washed with brine (15 ml) and dried over magnesium
sulfate, filtered and the solvent was removed under reduced pressure. Purification of the
crude product by flash chromatography (diethyl ether/petroleum ether 20:80) yielded 22′
(132 mg, 87% yield). 1H NMR (400 MHz, CDCl3): 8.33 s, 1 H (NH); 7.15 s, 2 H (H-Ar);
4.17 septet, 2 H, J = 6.7 (Ar-CH); 3.99 dd, 1 H, J = 12.0, 4.2 (H-7); 2.89 septet, 1 H, J = 6.9
(Ar-CH); 2.68 dt, 1 H, J = 14.6, 5.0 (H-4); 2.56–2.51 m, 2 H (H-10); 2.00–1.88 m, 4 H (H-4,
H-9, H-6, H-7); 1.76–1.65 m, 2 H (H-6, H-7); 1.34–1.28 m, 1 H (H-9); 1.24–1.22 m, 18 H
(H-iPr); 1.01 s, 3 H (Me-8). 13C NMR (100.6 MHz, CDCl3): 171.1 (C-1); 158.4 (C-Ar); 153.2
(C-Ar); 151.0 (C-3); 130.8 (C-Ar); 123.4 (C-Ar); 82.3 (C-7); 41.4 (C-8); 33.9 (C-iPr); 29.5
(C-iPr); 28.6 (C-6); 26.9 (C-10); 26.0 (C-5); 24.7 (C-CH(CH3)2); 24.5 (C-CH(CH3)2); 23.4
(C-CH(CH3)2); 23.4 (C-CH(CH3)2); 21.7 (C-4); 20.7 (C-9); 16.8 (Me-8).
(4aR,8aS)-2-Hydroxy-4a-methyloctahydrochromen-5-one (25)
To a solution of DMF (5.88 ml, 76.5 mmol, 10.0 equiv.) in anhydrous CH2Cl2 (20 ml) was
added oxalyl chloride (2.00 ml, 23.0 mmol, 3.00 equiv.) at –20 °C. After 90 min, the mixture
was concentrated under reduced pressure. Dry acetonitrile (10 ml) and THF (25 ml) were
added at –30 °C and a solution of 24 (2.43 g, 7.65 mmol) in THF (10 ml) and pyridine
(2 ml) was added dropwise. The resulting mixture was stirred for 90 min at –30 °C, cooled to
–78 °C and a solution of copper iodide (10 mole %) and tri-tert-butoxyaluminum hydride
(3.89 g, 15.3 mmol, 2.00 equiv.) in THF (15 ml) was added. After stirring for 15 min, the re-
action was quenched with 7% aqueous HBr solution (15 ml). The resulting mixture was al-
lowed to warm up to room temperature and basified with 30% aqueous NaOH solution
(5 ml). The aqueous layer was extracted with diethyl ether. The combined extracts were
washed with saturated aqueous sodium hydrogencarbonate solution, brine, dried over
MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography
(diethyl ether/petroleum ether 20:80) to give 25 (704 mg, 50% yield) as a 1:1 mixture of
diastereomers. 1H NMR (400 MHz, CDCl3): 5.24 s, 0.5 H (H-1); 4.72 d, 0.5 H, J = 10.3 (H-1);
4.01 dd, 0.5 H, J = 12.0, 4.2 (H-7); 3.58–3.54 br s, 0.5 H (OH); 3.37 dd, 0.5 H, J = 11.6, 4.2
(H-7); 2.87–2.84 br s, 0.5 H (H-OH); 2.62 dt, 1 H, J = 14.4, 7.0 (H-4); 2.23–2.16 m, 1 H (H-4);
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

Synthesis of a Taxol C Ring
1591
2.02–1.92 m, 1.5 H (CH2); 1.91–1.77 m, 3 H (CH2); 1.74–1.68 m, 1.5 H (CH2); 1.63–1.52 m,
2 H (CH2); 1.25 s, 1.5 H (Me-8); 1.21 s, 1.5 H (Me-8).
(2S,4aR,8aS)-2-Methoxy-4a-methyloctahydrochromen-5-one (26)
A solution of 25 (515 mg, 2.8 mmol) in dichloromethane (10 ml) was treated with silver(I)
oxide (650 mg, 2.8 mmol, 1.00 equiv.) and excess methyl iodide (0.55 ml). The black sus-
pension was stirred overnight at room temperature, then filtered through a cotton plug and
concentrated in vacuo. The residue was purified by flash chromatography (diethyl ether/
petroleum ether 10:90) to give 26 (499 mg, 90% yield) as a colorless oil. 1H NMR (400 MHz,
CDCl3): 4.16 dd, 1 H, J = 9.6, 2.3 (H-1); 3.36 s, 3 H (H-OMe); 3.20 dd, 1 H, J = 11.5, 4.3
(H-7); 2.54 dt, 1 H, J = 14.5, 7.1 (H-4); 2.23–2.16 ddd, 1 H, J = 14.7, 4.9, 1.5 (H-4);
1.91–1.84 m, 1 H (C-10); 1.82–1.72 m, 2 H (C-6); 1.64–1.58 m, 3 H (C-9, C-5); 1.53–1.35 m,
2 H (C-5, C-10); 1.11 s, 3 H (Me-8). 13C NMR (100.6 MHz, CDCl3): 213.1 (C-3); 103.6 (C-1);
79.0 (C-7); 56.1 (C-OMe); 48.4 (C-8); 36.2 (C-4); 29.0 (C-9); 27.0 (C-5); 25.7 (C-6); 20.6
(C-10); 16.0 (Me-8). IR (film): 3682, 3510, 3403, 2854, 2747, 2641, 2251, 2140, 1915, 1736,
1431, 1337, 1264, 1247, 1080, 984, 953, 914, 856, 778, 730, 565. HRMS calculated for
C
11H18O3 198.1256; found 198.1255.
(2S,4aR,8aS)-2-Methoxy-4a-methyloctahydrochromen-
5-N′-(2,4,6-triisopropylbenzenesulfono)hydrazone (23)
Two drops of concentrated hydrochloric acid were added to a solution of ketone 26 (499
mg, 2.55 mmol) and triisopropylbenzenesulfonyl hydrazine (912 mg, 3.06 mmol,
1.20 equiv.) in THF (5.0 ml). The resulting solution was stirred at room temperature for 1 h,
and the reaction was quenched by addition of aqueous sodium hydrogencarbonate (sat.,
5 ml). The phases were separated, then the aqueous phase was extracted with diethyl ether
(3 × 10 ml). The combined organic fractions were washed with brine (15 ml) and dried over
magnesium sulfate, filtered and the solvent was removed under reduced pressure. Purifica-
tion of the crude product by flash chromatography (diethyl ether/petroleum ether 20:80)
yielded 23 (1.22 g, quantitative yield). 1H NMR (400 MHz, CDCl3): 7.67 s, 1 H (NH); 7.15 s,
2 H (H-Ar); 4.22–4.14 m, 3 H (Ar-CH, H-7); 3.45 s, 3 H (H-OMe); 3.11 dd, 1 H, J = 10.3, 5.6
(H-1); 2.91 septet, 1 H, J = 6.9 (Ar-CH); 2.56–2.50 m, 1 H (H-4); 2.01–1.96 m, 1 H (H-4);
1.92–1.87 m, 2 H (H-10); 1.72–1.66 m, 2 H (H-6); 1.64–1.51 m, 4 H (H-5, H-9); 1.26–1.22 m,
18 H (H-iPr); 1.01 s, 3 H (Me-8). 13C NMR (100.6 MHz, CDCl3): 161.6 (C-Ar); 153.2 (C-Ar);
151.1 (C-3); 131.2 (C-Ar); 123.5 (C-Ar); 104.0 (C-1); 79.4 (C-7); 56.3 (C-OMe); 42.0 (C-8);
34.1 (C-iPr); 31.3 (C-9); 29.8 (C-iPr); 27.5 (C-5); 26.1 (C-6); 24.8 (C-CH(CH3)2); 24.7
(C-CH(CH3)2); 23.6 (C-CH(CH3)2); 23.5 (C-CH(CH3)2); 21.6 (C-10); 21.5 (C-4); 17.3 (Me-8).
IR (film): 3240, 2954, 2872, 2836, 2752, 2635, 1712, 1629, 1596, 1550, 1453, 1384, 1326,
1252, 1203, 1160, 1067, 912, 730, 653, 584. HRMS calculated for C26H42N2O4 478.2865;
found 478.2855.
1-((2S,4aS,8aS)-2-Methoxy-4a-methyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)-
3-phenylpropan-1-ol (27) and (2S,4aS,8aS)-2-Methoxy-4a-methyl-
3,4,4a,7,8,8a-hexahydro-2H-chromene (28)
tert-Butyllithium (0.33 ml, 0.46 mmol, 2.20 equiv., titrated at 1.40 M) was added dropwise to
a solution of hydrazone 23 (100 mg, 0.21 mmol) in THF (10 ml) at –78 °C. The solution
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

1592
Ma, Schiltz, Prunet:
turned red and was stirred at –78 °C for 30 min until the color turned dark red, then the
temperature was allowed to warm to 0 °C. When nitrogen evolution was finished and the
color had turned to red, the solution was cooled again to –78 °C. A cooled solution of
hydrocinnamaldehyde (30.5 µl, 0.23 mmol, 1.10 equiv.) in THF (5.0 ml) was added dropwise
via cannula. The resulting mixture was stirred at –78 °C for 30 min. The reaction was
quenched by addition of aqueous sodium hydrogencarbonate (sat., 10 ml). The phases were
separated and the aqueous phase was extracted with diethyl ether (3 × 15 ml). The com-
bined organic fractions were washed with brine (20 ml) and dried over magnesium sulfate,
filtered and the solvent was removed under reduced pressure. Purification of the crude prod-
uct by flash chromatography (diethyl ether/petroleum ether 5:100) yielded 27 (27 mg, 42%
yield) and 28 (9.8 mg, 26% yield) as pale yellow oils.
Compound 27. 1H NMR (400 MHz, CDCl3): 7.30–7.26 m, 2 H (H-Ar); 7.21–7.18 m, 3 H
(H-Ar); 5.70–5.68 m, 1 H (H-4); 4.37–4.32 m, 1 H (H-1′); 4.17–4.10 m, 1 H (H-1); 3.52 s,
1.5 H (OMe); 3.51 s, 1.5 H (OMe); 3.35–3.27 m, 1 H (H-7); 2.88–2.72 m, 1 H (H-3′);
2.68–2.58 m, 1 H (H-3′); 2.25–2.18 m, 2 H (H-5); 1.95–1.82 m, 3 H (H-6, H-2′); 1.78–1.65 m,
3 H (H-10, H-2′); 1.62–1.52 m, 1 H (H-9); 1.40–1.30 m, 1 H (H-9); 1.19 s, 1.5 H (Me-8);
1.10 s, 1.5 H Me-8). 13C NMR (100.6 MHz, CDCl3): 148.2 (C-Ar); 146.8 (C-Ar); 142.0 (C-3);
141.9 (C-3); 128.4 (C-Ar); 128.4 (C-Ar); 125.8 (C-Ar); 121.4 (C-4); 121.2 (C-4); 103.9 (C-1′);
103.9 (C-1′); 78.9 (C-7); 78.7 (C-7); 69.4 (C-1); 69.0 (C-1); 56.3 (C-OMe); 56.3 (C-OMe); 39.6
(C-6); 39.3 (C-6); 36.5 (C-8); 36.2 (C-8); 32.7 (C-3); 32.5 (C-3); 32.4 (C-2′); 27.7 (C-9); 27.7
(C-9); 24.5 (C-5); 24.4 (C-5); 23.5 (C-10); 19.7 (Me-8); 19.6 (Me-8). IR (film): 3041, 2957,
2863, 1451, 1434, 1281, 1266, 1250, 1065, 936, 787, 686, 664. HRMS calculated for
C
20H28O3 316.2039; found 316.2027.
Compound 28. 1H NMR (400 MHz, CDCl3): 5.46–5.40 m, 2 H (H-3, H-4); 4.38 dd, 1 H, J =
8.4, 4.2 (H-1); 3.52 s, 3 H (OMe); 3.28 dd, 1 H, J = 11.7, 4.4 (H-7); 2.20–2.16 m, 2 H (H-5);
1.80–1.67 m, 4 H (H-6, H-10); 1.60–1.55 m, 1 H (H-9); 1.46–1.38 m, 1 H (H-9); 1.05 s, 3 H
(Me-8). 13C NMR (100.6 MHz, CDCl3): 135.5 (C-4); 124.5 (C-3); 104.4 (C-1); 78.5 (C-7); 56.4
(C-OMe); 35.0 (C-9); 34.2 (C-8); 27.9 (C-10); 25.4 (C-5); 23.7 (C-6); 19.6 (Me-8). IR (film):
3041, 2985, 2956, 2844, 1449, 1388, 1250, 1159, 1109, 1062, 1010, 949, 686, 665. HRMS
calculated for C11H18O2 182.1307; found 182.1316.
Financial support was provided by the CNRS, the Ecole Polytechnique and the University of Glasgow.
REFERENCES AND NOTES
1. Oberlies N. H., Kroll D. J.: J. Nat. Prod. 2004, 67, 129.
2. For reviews on the chemistry of taxol, see: a) Nicolaou K. C., Dai W.-M., Guy R. K.:
Angew. Chem., Int. Ed. Engl. 1994, 33, 15; b) Kingston D. G. I.: Chem. Commun. 2001,
867; For the total syntheses, see: c) Nicolaou K. C., Yang Z., Liu J. J., Ueno H., Nantermet
P. G., Guy R. K., Claiborne C. F., Renaud J., Couladouros E. A., Paulvannan, K., Sorensen
E. J.: Nature 1994, 367, 630; d) Nicolaou K. C., Nantermet P. G., Ueno H., Guy R. K.,
Couladouros E. A., Sorensen E. J.: J. Am. Chem. Soc. 1995, 117, 624; e) Nicolaou K. C.,
Liu J. J., Yang Z., Ueno H., Sorensen E. J., Claiborne C. F., Guy R. K., Hwang C. K.,
Nakada M., Nantermet P. G.: J. Am. Chem. Soc. 1995, 117, 634; f) Nicolaou K. C.,
Yang Z., Liu J. J., Nantermet P. G., Claiborne C. F., Renaud, J., Guy R. K., Shibayama K.:
J. Am. Chem. Soc. 1995, 117, 645; g) Nicolaou K. C., Ueno H., Liu J. J., Nantermet P. G.,
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

Synthesis of a Taxol C Ring
1593
Yang Z., Renaud J., Paulvannan K., Chadha R.: J. Am. Chem. Soc. 1995, 117, 653;
h) Holton R. A., Somoza C., Kim H. B., Liang F., Biediger R. J., Boatman P. D.,
Shindo M., Smith C. C., Kim S., Nadizadeh H., Suzuki Y., Tao C., Vu P., Tang S.,
Zhang P., Murthi K. K., Gentile L. N., Liu J. H.: J. Am. Chem. Soc. 1994, 116, 1597;
i) Holton R. A., Kim H. B., Somoza C., Liang F., Biediger R. J., Boatman P. D., Shindo M.,
Smith C. C., Kim S., Nadizadeh H., Suzuki Y., Tao C., Vu P., Tang S., Zhang P., Murthi
K. K., Gentile L. N., Liu J. H.: J. Am. Chem. Soc. 1994, 116, 1599; j) Masters J. J., Link
J. T., Snyder L. B., Young W. B., Danishefsky S.: Angew. Chem., Int. Ed. Engl. 1995, 34,
1723; k) Wender P. A., Badham N. F., Conway S. P., Floreancig P. E., Glass T. E.,
Gränicher C., Houze J. B., Jänichen J., Lee D., Marquess D. G., McGrane P. L., Meng W.,
Mucciaro T. P., Mühlebach M., Natchus M. G., Paulsen H., Rawlins D. B., Satkofsky J.,
Shuker A. J., Sutton J. C., Taylor R. E., Tomooka K.: J. Am. Chem. Soc. 1997, 119, 2755;
l) Wender P. A., Badham N. F., Conway S. P., Floreancig P. E., Glass T. E., Houze J. B.,
Krauss N. E., Lee D., Marquess D. G., McGrane P. L., Meng W., Natchus M. G., Shuker
A. J., Sutton J. C., Taylor R. E.: J. Am. Chem. Soc. 1997, 119, 2757; m) Mukaiyama T.,
Shiina I., Iwadare H., Saitoh M., Nishimura T., Ohkawa N., Sakoh H., Nishimura H., Tani
Y.-I., Hasegawa M., Yamada K., Saito K.: Chem. Eur. J. 1999, 5, 121; n) Morihara, K., Hara
R., Kawahara S., Nishimori T., Nakamura N., Kusama H., Kuwajima I.: J. Am. Chem. Soc.
1998, 120, 12980.
3. Doi T., Fuse S., Miyamoto S., Nakai K., Sasuga D., Takahashi T.: Chem. Asian J. 2006, 1,
370.
4. Swindell C. S., Patel B. P.: J. Org. Chem. 1990, 55, 3.
5. For previous work on approaches towards taxol from our group, see: a) Muller B.,
Delaloge F., den Hartog M., Férézou J.-P., Pancrazi A., Prunet J., Lallemand J. Y., Neuman A.,
Prangé T.: Tetrahedron Lett. 1996, 37, 3313; b) Delaloge F., Pancrazi A., Prunet J.,
Lallemand J.-Y.: Tetrahedron Lett. 1997, 38, 237; c) Grimaud L., Férézou J.-P., Prunet J.,
Lallemand J.-Y.: Tetrahedron 1997, 53, 9253; d) Muller B., Férézou J.-P., Lallemand J.-Y.,
Pancrazi A., Prunet J., Prangé T.: Tetrahedron Lett. 1998, 39, 279; e) Bourgeois D.,
Lallemand J. Y., Pancrazi A., Prunet J.: Synlett 1999, 1555; f) Bourgeois D., Pancrazi A.,
Ricard L., Prunet J.: Angew. Chem. Int. Ed. 2000, 39, 725; g) Bourgeois D., Mahuteau J.,
Pancrazi A., Nolan S. P., Prunet J.: Synthesis 2000, 869; h) Bourgeois D., Prunet J.,
Pancrazi A., Prangé T., Lallemand J.-Y.: Eur. J. Org. Chem. 2000, 4029; i) Bourgeois D.,
Pancrazi A., Nolan S. P., Prunet J.: J. Organomet. Chem. 2002, 643–644, 247; j) Schiltz S.,
Ma C., Ricard L., Prunet J.: J. Organomet. Chem. 2006, 691, 5438; k) Ma C., Schiltz S.,
Le Goff X. F., Prunet J.: Chem. Eur. J. 2008, 14, 7314.
6. For previous syntheses of taxane derivatives using the Wieland–Miescher ketone, see ref.
2j and: a) Brown P. A., Jenkins P. R., Fawcett J., Russell D. R.: J. Chem. Soc., Chem.
Commun. 1984, 253; b) Bonnert R. V., Jenkins P. R.: J. Chem. Soc., Chem. Commun. 1987,
1540; c) Brown P. A., Jenkins P. R.: J. Chem. Soc., Perkin Trans. 1 1986, 1303; d) Bonnert
R. V., Jenkins P. R.: J. Chem. Soc., Perkin Trans. 1 1989, 413; e) Rubenstein S. M.,
Williams R. M.: J. Org. Chem. 1995, 60, 6215.
7. a) Wieland P., Miescher K.: Helv. Chim. Acta 1950, 33, 2215; b) Gutzwiller J.,
Buchschacher P., Fürst A.: Synthesis 1977, 167; c) Buchschacher P., Fürst A., Gutzwiller J.:
Org. Synth. 1985, 63, 37.
8. Toda F., Kiyoshige K., Yagi M.: Angew. Chem., Int. Ed. Engl. 1989, 28, 320.
9. Yang D., Zhang C.: J. Org. Chem. 2001, 66, 4814.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

1594
Ma, Schiltz, Prunet:
10. Labadie G. R., Luna L. E., Gonzalez-Sierra M., Cravero R. M.: Eur. J. Org. Chem. 2003,
3429.
11. Frigerio M., Santagostino M., Sputore S.: J. Org. Chem. 1999, 64, 4537.
12. Smith III A. B., Doughty V. A., Sfouggatakis C., Bennett C. S., Koyanagi J., Takeuchi M.:
Org. Lett. 2002, 4, 783.
13. We chose to protect the hemiacetal as a trityl acetal because of the mild conditions
required for this transformation.
14. Paquette L. A., Sturino C. F., Wang X., Prodger J. C., Koh D.: J. Am. Chem. Soc. 1996,
118, 5620.
15. Felpin F.-X., Bertrand M.-J., Lebreton J.: Tetrahedron 2002, 58, 7381.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1579–1594

Copyright of Collection of Czechoslovak Chemical Communications is the property of Institute of Organic
Chemistry & Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.