A novel approach to the Taxol A-ring synthetic equivalents

Article abstract of DOI:10.1016/j.tet.2005.08.061

A novel short approach to the A-ring synthetic equivalents of Taxol was described. Oxabicyclic ketone 3 served as a versatile template for selective functionalization leading to oxabicyclic vinylic ether 6 in two steps, which was hydrolyzed under mild aci

Full text of DOI:10.1016/j.tet.2005.08.061

Tetrahedron 61 (2005) 10734–10737
A novel approach to the Taxol A-ring synthetic equivalents
Zhang-Hua Gao,a Bing Liua and Wei-Dong Z. Lia,b,
*
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
bState Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
Received 14 June 2005; revised 17 August 2005; accepted 18 August 2005
Available online 16 September 2005
Abstract—A novel short approach to the A-ring synthetic equivalents of Taxol was described. Oxabicyclic ketone 3 served as a versatile
template for selective functionalization leading to oxabicyclic vinylic ether 6 in two steps, which was hydrolyzed under mild acidic
conditions to afford the hydroxy aldehyde derivative 7. Synthetic equivalents 2 of Taxol A-ring were thus, accessible from hydroxy
aldehyde 7.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
these densely functionalized intermediates 2 en route to
Taxol, including various cationic cyclization protocols
(pathways a2, b3 or c4) from geraniol-derived precursors,
Diels–Alder cycloaddition approach (pathways d5 and d0),6
intramolecular nitrone [3C2] cycloaddition (pathway e),7
and conventional multi-step transformation of a cyclo-
hexdione derivative (pathway f),8 as depicted in Figure 1,
respectively.9 In connection with our ongoing program on
the development of novel synthetic strategies based on the
use of oxabicyclic ketone 3 as a stereocontroling template,
herein we report an alternative novel approach for the facile
and general synthesis of this type of multi-functionalized
cyclohexene derivatives.
Substituted cyclohexene derivatives 2 (Fig. 1) have been
devised as common A-ring synthetic equivalents (synthons)
in various total synthetic studies of paclitaxel (1, Taxol),1 a
clinically proven effective antitumor chemotherapeutics
bearing a unique 6-8-6 carbocyclic ring system (ABC). A
number of synthetic entries2–9 have been developed for
We have recently developed10a,b a general quasi-biomimetic
strategy for the stereocontrolled synthesis of naturally
occurring eudesmane sesquiterpenoids from functionalized
oxabicyclic templates 4, derived from readily available
oxabicyclic ketone 3, as illustrated in a concise stereo-
controlled total synthesis of balanitol and the first total
synthesis of gallicadiol (Fig. 2).
As shown in Scheme 1, oxabicyclic ketone 3 was
bismethylated with excess methyl iodide in a mixture of
DMSO–THF (1/1) by using potassium tert-butoxide as a
base to give gem-dimethyl oxabicyclic ketone 5 in 92%
yield.11 (Methoxy)vinylation of ketone 5 was performed
smoothly by employing Magnus protocol12 as described
previously10b to afford a mixture of geometric isomers of
methoxy vinylic ethers (E/Z 3:4, determined by analysis of
1H NMR spectrum of the product mixture), which without
further purification, was subjected to acidic hydrolysis by
exposing to 90% (aqueous) acetic acid to furnish the
hydroxy a,b-unsaturated aldehyde 7 in 68% overall yield
Figure 1. Syntheses of Taxol A-ring equivalents 2.
Keywords: Taxol; Diels–Alder cycloaddition; Oxabicyclic template.
*
Corresponding author. Tel./fax: C86 22 23494613;
e-mail: wdli@nankai.edu.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.061

Z.-H. Gao et al. / Tetrahedron 61 (2005) 10734–10737
10735
in good yield. Alternatively, Luche reduction16 of 7
followed by selective O-silylation with tert-butyldimethyl-
silyl chloride (TBSCl) in the presence of imidazole in DMF
furnished the allylic silyl ether 113 in 79% overall yield
from 7, which was subsequently oxidized with PCC
(suspended on silica gel) to afford the known5 siloxy ketone
12 in 87% yield.
In view of the ready accessibility of the chiral oxabicyclic
ketone 3 via optical resolution,17 the enantioselective
synthesis of the general Taxol A-ring equivalents 2 would
be achievable via the above described approach. Further-
more, this approach would also be applicable in principle to
the synthesis of unsymmetrically substituted (instead of
gem-dimethyl) analogs of 2 as the building blocks in natural
product synthesis (cf. 4 in Fig. 2), that is, coincidentally
Taxol C-ring equivalents (Fig. 3) as devised by Takahashi
Figure 2. General synthesis of eudesmanoids from oxabicyclic ketone 3
(Ref. 10).
3
et al. and Monti et al.9c
Scheme 1. A short synthesis of Taxol A-ring equivalent 7.
Figure 3.
(two steps from ketone 5). The structure of 7 was confirmed
spectroscopically and unambiguously ensured by sub-
sequent conversion to known Taxol A-ring equivalents,
that is, functionalized cyclohexene derivatives 9 and 12
(Scheme 2), respectively.13
In short summary, a general and alternative synthesis of the
functionalized cyclohexene derivatives 2, the classical
A-ring moiety of Taxol synthesis, was realized from readily
available oxabicyclic template 3 in a short and convenient
synthetic sequence. This application further demonstrated18
the versatility of the oxabicyclic templates 3 (and 4) in
organic synthesis, and they (and their variants) would find
other useful applications in the stereocontrolled synthesis of
various types of natural products.19
2. Experimental
2.1. General
For product purification by flash column chromatography,
silica gel (200–300 mesh) and light petroleum ether (bp
30–60 8C) were used. All solvents were purified and dried
by standard techniques, and distilled prior to use. All
organic extracts were dried over Na2SO4, unless otherwise
noted. IR spectra were recorded on a Nicolet FT-170SX
Scheme 2. Facile synthesis of Taxol A-ring equivalents.
Thus, silylation of hydroxy aldehyde 7 with tert-butyl-
dimethylsilyl trifluoromethanesulfonate (TBSOTf) in the
presence of triethylamine (K65/ K10 8C, 1 h) in
methylenechloride (DCM) produced a bis-O-silylated
conjugated silyl dienol ether 8 in good yield,14 which was
then selectively protonated by treatment with a slurry
mixture of 90% aqueous acetic acid and normal chromato-
graphic silica gel (200–300 mesh) under ultrasonic
irradiation conditions (water bath, 20 kHz, 250 W,
25–30 8C, 12 min),15 to give the known7 siloxy aldehyde 9
1
spectrometer as liquid film. H and 13C NMR spectra were
taken on a Varian mercury 300 MHz spectrometer with
TMS as an internal standard and CDCl3 as solvent unless
otherwise noted. EI-MS spectra were obtained on HP-
5988A GC/MS instrument. HRMS were determined on a
Bruker Daltonics APEXII 47e FT-ICR spectrometer. All air
and moisture-sensitive reactions were performed in a flame-
dried glassware under a stream of nitrogen. Other
commercially available chemical reagents and solvents

10736
Z.-H. Gao et al. / Tetrahedron 61 (2005) 10734–10737
were used as received without further purification unless
indicated otherwise.
155.1, 192.3 ppm; EIMS (m/z, %) 168 (MC, 26), 150 (16),
125 (100), 109 (93), 81 (82); HRMS (ESI) m/z obsd
169.1221 ([MCH]C, calcd for C10H17O2 169.1223).
2.1.1. 1,3,3-Trimethyl-7-oxabicyclo[2.2.1]heptan-2-one
(5). To a mixture of ketone 3 (1.26 g, 10 mmol) and methyl
iodide (1.50 mL, 24.0 mmol) in 5 mL of anhydrous DMSO
and 30 mL of THF was added a solution of potassium tert-
butoxide (2.69 g, 24.0 mmol) in 25 mL of DMSO at room
temperature. The mixture was stirred for 20 min at ambient
temperature and extracted with petroleum ether (bp 30–
60 8C, 3!100 mL), successively washed with water (5!
50 mL), brine, dried, filtered, and concentrated. The
resulting trimethyl bicyclic ketone 5 (1.43 g, 92%)11 was
dried azeotropically with benzene and used in the next step
without further purification. IR (film) nmax 2975, 1757,
2.1.4. Preparation of dienol silyl ether 8. To a mixture of
aldehyde 7 (41 mg, 0.24 mmol) and triethylamine (0.13 mL,
0.93 mmol) in 1 mL of dry dichloromethane was added
TBSOTf (0.12 mL, 0.52 mmol) at K65 8C. The reaction
vessel was warmed gradually to K10 8C over 1 h. The
reaction mixture was quenched with 0.2 mL of water, and
diluted with petroleum ether (bp 30–60 8C). The organic
phase was successively washed with water, dried, and
concentrated. The resulting residue was filtered through a
short pad of chromatographic silica gel to give the bis-silyl
ether 8 (80 mg, 0.20 mmol, 83%) as a colorless oil. IR (film)
nmax 2956, 2931, 2890, 2858, 1612, 1468, 1254, 1159, 1092,
1
1027 cmK1; H NMR (300 MHz, CDCl3) d 1.04 (s, 3H),
1
1.20 (s, 3H), 1.44 (s, 3H), 1.50–1.70 (m, 2H), 1.90–2.05 (m,
2H), 4.26 (br s, 1H) ppm; 13C NMR (75 MHz, CDCl3) d
14.7, 20.0, 22.8, 25.5, 31.1, 48.9, 83.6, 86.0, 217.9 ppm;
EIMS (m/z, %) 154 (MC, 1.3), 139 (0.3), 126 (48), 43 (100).
1048, 882, 837, 777 cmK1; H NMR (300 MHz, CDCl3) d
0.035 (s, 6H), 0.156 (s, 6H), 0.89 (s, 9H), 0.95 (s, 9H), 1.03
(s, 3H), 1.37 (s, 3H), 1.71 (s, 3H), 2.12 (br s, 2H), 3.49 (t,
1H, JZ7.4 Hz), 5.23 (br s, 1H), 6.36 (s, 1H) ppm; 13C NMR
(75 MHz, CDCl3) d K5.5, K5.4, K4.9, K3.9, K3.0, 18.1,
18.9, 20.4, 24.8, 25.7, 25.9, 32.0, 38.8, 75.4, 119.9, 126.1,
131.2, 138.0 ppm; EIMS (m/z, %) 396 (MC, 0.9), 339 (10),
147 (23), 133 (19), 73 (100); HRMS (ESI) m/z obsd
397.2946 ([MCH]C, calcd for C22H45Si2O2 397.2953).
2.1.2.
2-Methoxymethylene-1,3,3-trimethyl-7-oxa-
bicyclo[2.2.1]-heptane (6). To a solution of (methoxyl-
methyl)trimethylsilane (93%, 1.14 mL, 7.5 mmol) in 13 mL
of THF was added sec-butyllithium (1.3 M, 5.7 mL,
7.5 mmol) at K60 8C. The resulting reaction mixture was
warmed gradually to K23 8C over 40 min, then cooled to
K78 8C, to which ketone 5 (924 mg, 6.0 mmol) in 3.2 mL
of THF was added dropwise. The reaction mixture was
stirred at K60 8C for another 1 h and powdered potassium
tert-butoxide (1.32 g, 12 mmol) was introduced in one
portion. The reaction mixture was allowed to warm to
ambient temperature over 1 h and stirred for additional
2.5 h, and then quenched with 1 mL of water. The reaction
mixture was diluted with petroleum ether (bp 30–60 8C),
successively washed with water, dried, and concentrated.
The residue was purified by flash silica gel chromatography
eluting with petroleum ether–ether (v/v 20/1) to give
926 mg (85%) of the enol ether 6 (E/Z 3:4) as a colorless
oil. IR (film) nmax 2972, 2933, 1696, 1460, 1381, 1216,
2.1.5. Preparation of siloxy a,b-unsaturated aldehyde 9.
A mixture of 8 (33 mg, 0.083 mmol), silica gel (200–300
mesh, 230 mg) in 3 mL of acetic acid and 0.3 mL of water
was immerged in a water bath (25–30 8C) and sonicated for
12 min (20 kHz, 250 W). TLC monitoring of the reaction
showed a complete disappearance of starting bis-silyl ether
8. The reaction mixture was diluted with ether, washed with
aqueous saturated NaHCO3, brine, dried, and concentrated.
The residue was purified by silica gel column chromato-
graphy eluting with petroleum ether–ether (v/v 30/1) to give
siloxy aldehyde 9 (18 mg, 0.064 mmol, 77%).7 IR (film)
nmax 2954, 2931, 2888, 2858, 1675, 1466, 1254, 1088,
1
836 cmK1; H NMR (300 MHz, CDCl3) d 0.059 (s, 3H),
0.064 (s, 3H), 0.89 (s, 9H), 1.16 (s, 3H), 1.19 (s, 3H), 1.60–
1.78 (m, 2H), 2.09 (s, 3H), 2.10–2.25 (m, 1H), 2.36 (dt, 1H,
JZ19.5, 6.3 Hz), 3.45 (dd, 1H, JZ7.8, 3.5 Hz), 10.10 (s,
1H) ppm; 13C NMR (75 MHz, CDCl3) d K4.9, K4.2, 18.1,
19.0, 21.7, 25.8, 26.2, 32.6, 38.3, 76.1, 139.1, 154.5,
192.5 ppm; EIMS (m/z, %) 267 (MCK15, 1.3), 241 (1.7),
225 (100), 75 (98).
1119, 991, 836 cmK1 1H NMR (300 MHz, CDCl3)
;
Characteristic data for Z-isomer: d 1.03 (s, 3H), 1.11 (s,
3H), 1.65 (s, 3H), 3.49 (s, 3H), 5.55 (s, 1H) ppm; E-isomer:
d 1.18 (s, 6H), 1.53 (s, 3H), 3.50 (s, 3H), 5.72 (s, 1H); EIMS
(m/z, %) 182 (MC, 29), 113 (100); HRMS (ESI) m/z obsd
183.1376 ([MCH]C, calcd for C11H19O2 183.1380).
2.1.3. 5-Hydroxy-2,6,6-trimethylcyclohex-1-enecarbal-
dehyde (7). A mixture of the above enol ether 6 (925 mg,
5.10 mmol) in 7.2 mL of acetic acid and 0.8 mL of water
was stirred at room temperature for 15 h. It was diluted with
10 mL of water, neutralized with sodium bicarbonate and
then extracted with ether (4!30 mL). The combined
organic phases were washed with saturated aqueous sodium
bicarbonate, brine, dried, and concentrated. The residue was
purified by flash silica gel column chromatography to give
hydroxy aldehyde 7 (680 mg, 68% from 5). IR (film) nmax
2.1.6. 3-(tert-Butyldimethylsilyloxymethyl)-2,2,4-tri-
methyl-2-cyclohexen-3-ol (11). To a mixture of the
hydroxy aldehyde 7 (69 mg, 0.41 mmol) and cerium
trichloride heptahydrate (153 mg, 0.41 mmol) in 2 mL of
methanol at 0 8C was added sodium borohydride (16 mg,
0.38 mmol). The reaction mixture was stirred at 0 8C for
10 min, quenched with 3 M HCl (0.5 mL), and diluted with
3 mL of ether. The organic layer was separated and the
aqueous layer was saturated with sodium sulfate, and then
extracted with ether (3!5 mL). The combined organic
extracts were dried and concentrated in vacuo. The residue
(75 mg) was azeotropically dried with benzene and taken up
in DMF (0.5 mL) and cooled to 0 8C, to which imidazole
(63 mg, 0.93 mmol) and TBSCl (70 mg, 0.46 mmol) were
added successively at 0 8C. The resulting mixture was
stirred at 0 8C for 15 min, diluted with ether, washed with
3420, 2968, 2942, 2877, 2756, 1667, 1379, 1286, 1066 cmK1
;
1H NMR (300 MHz, CDCl3) d 1.24 (s, 3H), 1.25 (s, 3H),
1.70–1.90 (m, 2H), 2.12 (s, 3H), 2.25 (dt, 1H, JZ19.8,
6.3 Hz), 2.43 (dt, 1H, JZ19.8, 6.4 Hz), 3.51 (dd, 1H, JZ
8.1, 3.0 Hz), 10.12 (s, 1H) ppm; 13C NMR (75 MHz,
CDCl3) d 19.0, 21.0, 25.3, 25.7, 32.1, 37.6, 75.6, 138.5,

Z.-H. Gao et al. / Tetrahedron 61 (2005) 10734–10737
10737
cyclization approach mediated by Hg(O2CCF3)2 led to the
C-ring synthetic equivalent of Taxolw as shown (RZOH or
OBz) instead of A-ring equivalents, it represents an alternative
pathway to 2 in principle.
water, brine, dried, and concentrated. The residue was
purified by silica gel column chromatography to give 11
(92 mg, 79%);3 1H NMR (300 MHz, CDCl3) 0.08 (s, 6H),
0.90 (s, 9H), 1.03 (s, 3H), 1.10 (s, 3H), 1.68 (s, 3H), 1.65–
1.80 (m, 2H), 2.09 (t, 2H, JZ6.4 Hz), 3.50 (br s, 1H), 4.10
and 4.15 (ABq, 2H, JZ10.5 Hz) ppm.
5. (a) Nicolaou, K. C.; Hwang, C.-K.; Sorensen, E. J.; Clairborne,
C. F. J. Chem. Soc., Chem. Commun. 1992, 1117–1118. (b)
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, 634–644.
6. Magnus, P.; Westwood, N.; Spyvee, M.; Frost, C.; Linnane, P.;
Tavares, F.; Lynch, V. Tetrahedron 1999, 55, 6435–6452.
7. Ishikawa, T.; Ikeda, S.; Ibe, M.; Saito, S. Tetrahedron 1998,
54, 5869–5882.
2.1.7. 3-(tert-Butyldimethylsilyloxymethyl)-2,2,4-tri-
methyl-cyclohexen-3-one (12). A mixture of alcohol 11
(8.0 mg), PCC (32.0 mg) and silica gel (ca. 60 mg) in 1 mL
of dichloromethane was stirred at room temperature for 2 h,
filtered through a pad of silica gel, concentrated and purified
by silica gel column chromatography to give ketone 125
1
(7 mg, 87%); H NMR (300 MHz, CDCl3) 0.092 (s, 6H),
0.90 (s, 9H), 1.21 (s, 6H), 1.79 (s, 3H), 2.39 (t, 2H, JZ
6.8 Hz), 2.54 (t, 2H, JZ6.8 Hz), 4.15 (s, 2H) ppm.
8. (a) Roy, O.; Pattenden, G.; Pryde, D. C.; Wilson, C.
Tetrahedron 2003, 59, 5115–5121. (b) Di Grandi, M. J.;
Jung, D. K.; Krol, W. J.; Danishefsky, S. J. J. Org. Chem.
1993, 58, 4989–4992. (c) Queneau, Y.; Krol, W. J.; Bornmann,
W. D.; Danishefsky, S. J. J. Org. Chem. 1992, 57, 4043–4047.
9. For some other methods, see: (a) Ding, Y.; Jiang, X.-R.
J. Chem. Soc., Chem. Commun. 1995, 1693–1694. (b) Audran,
G.; Uttaro, J.-P.; Monti, H. Synlett 2002, 1261–1264. (c)
Uttaro, J.-P.; Audran, G.; Monti, H. J. Org. Chem. 2005, 70,
3484–3489.
Acknowledgements
We thank the National Natural Science Foundation
(Distinguished Youth Fund 29925204 and QT 20021001)
for financial support. The Cheung Kong Scholars program
and the Outstanding Scholars program of Nankai University
are gratefully acknowledged.
10. (a) Zhang, Z.; Li, W.-D.Z.; Li, Y.-L. Org. Lett. 2001, 3,
2555–2557. (b) Li, W.-D.Z.; Gao, Z.-H. Org. Lett. 2005, 7,
2917–2920.
11. DiFazio, M. P.; Wallace, W. A.; Sneden, A. T. Heterocycles
1989, 29, 2391–2397. The methylation procedure described in
this work is suitable for scalable preparation.
Supplementary data
12. Magnus, P.; Roy, G. Organometallics 1982, 1, 553–559.
13. Further oxygenative or alkylative derivatization of compounds
7, 9 or 12 to other more densely functionalized variants of 2
would be achievable according to Refs. 5 and 8.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.08.
061
14. Mild O-silylation conditions (TBSCl, imidazole, DMF) led to
a sluggish (low yield) silyl ether formation.
15. This interesting chemoselective effect by the action of
ultrasonication implies again the selective activation of more
delocalized conjuated electronic structure by ultrasonic
irradiation, which would deserve further investigations on
the exact mode of action (activation mechanism) of the
sonochemical process. See: Wei, K.; Gao, H.-T.; Li, W.-D.Z.
J. Org. Chem. 2004, 69, 5763–5765.
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