Novel synthetic strategy towards taxol by macrocyclization reaction - Conformational requirement of ring A

Article abstract of DOI:10.1002/ejoc.200600284

The synthesis of a completely substituted ring A of Taxol is reported and it is shown that the C¹³-OP group must have a β configuration to succeed in the formation of 12-membered rings, a requisite for the construction of the B and C rings of T

Full text of DOI:10.1002/ejoc.200600284

FULL PAPER
DOI: 10.1002/ejoc.200600284
Novel Synthetic Strategy Towards Taxol by Macrocyclization Reaction –
Conformational Requirement of Ring A
Sylvain Canesi,[a] Gilles Berthiaume,[a] and Pierre Deslongchamps*[a]
Keywords: Carvone / Conformation / Epimer / Macrocyclization / Taxane
The synthesis of a completely substituted ring A of Taxol is
reported and it is shown that the C13-OP group must have a
β configuration to succeed in the formation of 12-membered
rings, a requisite for the construction of the B and C rings of
Taxol by a macrocyclization step.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Our laboratory is involved in the development of novel chain at C1 and a steric effect of that magnitude is absent
and powerful synthetic strategies based on transannular in A. On the other hand, the side chain at C1 in the more
processes on macrocycles.[1] We are planning to use such a stable conformer A is oriented equatorially and the RЈ
strategy for the construction of Taxol[2] starting from a fully group takes a direction far away from the R group. It thus
substituted ring A to which a 12-membered ring would be appears difficult to approach these two alkyl groups close
incorporated, being confident that an appropriate transan- enough for a successful macrocyclization and polymeriza-
nular reaction would then lead to the Taxol skeleton (Fig- tion would likely occur.
ure 1). In this paper, we wish to report the synthesis of a
fully substituted chiral ring A and a study which indicates
that the OP group at C13 must have β configuration in order
to successfully construct 12-membered macrocyclic rings.
Scheme 1. Stability of half chair of ring A with Taxol stereochemis-
try.
However, if a ring A intermediate epimeric at C13 is con-
Figure 1. Taxol.
templated, the most stable conformation should now be re-
versed (Scheme 2). The half chair D is now more stable as
Results and Discussion
C has a severe 1,3-diaxial steric interaction between the OP
group at C13 and the tertiary oxygen atom at C1. In ad-
dition, in the more stable conformation D, the side chain at
C1 is oriented axially and has the RЈ group approaching the
direction of the R group. Their relative proximity could
thus ease macrocyclization in preference to oligomerization.
We have first theoretically examined the influence of an
α-oriented OP group at C13 on the A ring conformation
and its effect on a subsequent macrocyclization reaction.
Molecular models indicate that such intermediate will pref-
erentially exist in the half-chair conformer A rather than B
(Scheme 1). In half chair B, there is a severe 1,3-diaxial ste-
ric interaction between the OP group at C13 and the side
[a] Laboratoire de synthèse organique, Département de chimie,
Institut de pharmacologie de Sherbrooke, Université de
Sherbrooke,
Sherbrooke, Québec J1H 5N4, Canada
Pierre.Deslongchamps@USherbrooke.ca
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 2. Stability of half chair of ring A with Taxol epimeric
stereochemistry.
Eur. J. Org. Chem. 2006, 3681–3686
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Canesi, G. Berthiaume, P. Deslongchamps
FULL PAPER
In any event, we decided to construct ring A intermedi-
ates 23 and 23Ј, which are epimeric at C13 (Scheme 7) in
order to verify their conformational preference and their
ease of macrocyclization.
(–)-(R)-Carvone,[3] which is an abundant chiral natural
product, was first transformed in two steps into the known
compound 4[4] (Scheme 3).
Scheme 4. (a) O3, MeOH, –78 °C, Cu(OAc)2, FeSO4, 77%; (b) allyl
Grignard reagent, THF, 0°C; (c) Ac2O, NEt3, CH2Cl2, 90% over 2
steps; (d) SOCl2, CH2Cl2, –20 °C; (e) Al2O5, 71% over 2 steps.
It is also possible to convert epimer 16Ј into 16 under
Mitsunobu conditions in 52% overall yield as shown in
Scheme 5. The O-Boc derivative 17 was prepared from 16
and NMR study[7] indicated that 17 exists preferentially in
the desired half-chair conformation D (Schemes 3 and 5).
Scheme 3. (a) Tetravinyltin, BuLi, THF, –78 °C, 96%; (b) VO-
(acac)2, tBuOOH, CH2Cl2; (c) Jones reagent, acetone, 60% over 2
steps; (d) K2CO3, PhSH, CH3CN, 91%; (e) PhCH(OMe)2, NSA,
CH2Cl2, 92%; (f) tBuOK, MeI, THF, 97%; (g) NaIO4, MeOH,
94%; (h) (CF3CO)2O, pyridine, THF, 0 °C; (i) K2CO3, H2O; (j)
LiAlH(OCMe3)3, THF, 0 °C, 81% overall.
Addition of vinyllithium to 4 at low temperature oc-
curred with complete selectivity providing 5 in 96% yield.
Epoxidation with VO(acac)2 and tBuOOH followed by
Jones oxidation of the resulting secondary alcohol gave 7
after recrystallization in 60% yield. Epoxide opening with
thiophenolate led to diol 8 in 91% yield and this structure
was confirmed by X-ray diffraction analysis.
Scheme 5. Conversion of 16Ј into 16 and formation of 17. (a) PPh3,
DIAD, PhCOOH, THF; (b) K2CO3, MeOH; (c) Ac2O, NEt3,
CH2Cl2, 52% overall; (d) DMAP, Boc2O, CH3CN, 61%.
For synthetic convenience, we have preferred to work
with O-TBS-protected products (Scheme 6).
Diol 8 was converted into benzylidene acetal 9 (92%)
The following chemical transformations were carried out
which was monomethylated using tBuOK and MeI in THF on the two epimers 16 and 16Ј, respectively (Scheme 6). The
to produce 10 in 97%. The thioether was transformed into secondary alcohol in 16 was protected as a TBS ether and
the corresponding sulfoxide 11 in 94% yield using NaIO4. reductive ozonolysis with Ph3P gave aldehyde 19 in 88%
A Pummerer reaction was then achieved with trifluoro- yield. Addition of isopropenylmagnesium bromide to 19
acetic anhydride, which was followed by treatment with a followed by methanolysis (K2CO3, MeOH), oxidation
saturated solution of K2CO3. This sequence provides first (Dess–Martin periodinane) and Wittig reaction [(for-
the corresponding aldehyde, which is then isomerized into mylmethyl)triphenylphosphonium chloride and Et3N] af-
the more stable epimeric aldehyde. Being somewhat un- forded the doubly conjugated compound 20 in 55% overall
stable, this aldehyde was selectively reduced with a hindered yield. Selective reduction of the aldehyde with LiAlH(O-
hydride to give the hydroxy ketone 12 in 81% overall yield. CEt3)3 gave allylic alcohol 21 (87%), and dimethyl malon-
Compound 12 was treated with ozone in MeOH and the ate Michael addition gave an epimeric mixture of 22 in 86%
[5]
resulting peroxide was treated with Cu(OAc)2 and FeSO4
yield. Finally, the corresponding mixture of epimeric chlo-
to give the enone 13 in 77% yield (Scheme 4).
rides 23 was obtained in 91% yield by a mild efficient
Addition of allyl Grignard reagent at 0 °C followed by method using 1-chloro-N,N,2-trimethyl-1-propenylamine.[8]
protection of the primary alcohol as an acetate produced in A mixture of epimeric chlorides 23Ј was also obtained from
90% yield a 2.5:1 mixture (S)/(R) of tertiary alcohol 14. By 16Ј in similar yields for each step.
treatment of this mixture with SOCl2 at –20 °C, an SN2Ј
At this stage, we were ready to test the macrocyclization
reaction with retention of configuration yielded 15 and SN2 step (Scheme 7). Treatment of allylic chlorides 23Ј with
[6]
on Al2O5 provided a mixture of epimeric alcohols 16 and Cs2CO3 and TBAI in acetonitrile led only to oligomeric
16Ј in a 4:1 ratio and with 71% overall yield. These two material which remained at the base line on TLC. On the
epimers can be easily separated by chromatography.
other hand, we were pleased to see that treatment of β iso-
3682
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3681–3686

Novel Synthetic Strategy Towards Taxol by Macrocyclization Reaction
FULL PAPER
investigating the formation of various macrocycles which
can lead to the basic tricyclo[6.8.6] framework of Taxol by
a subsequent transannular reaction. Work is now in pro-
gress in these directions.
Experimental Section
General: Unless otherwise indicated, 1H and 13C NMR spectra
were recorded at 300 and 75 MHz, respectively, in CDCl3 solutions.
Chemical shifts are reported in ppm on the δ scale. Multiplicities
are described as s (singlet), d (doublet), dd, ddd, etc. (doublet of
doublets, doublet of doublets of doublets, etc.), t (triplet), q (quar-
tet) m (multiplet), and further qualified as app (apparent), b
(broad), c (complex). Coupling constants, J, are reported in Hz.
Specified IR spectra were recorded with a Perkin–Elmer 1600
FTIR spectrometer. Absorbance frequencies are given at maximum
of intensity in cm–1.Mass spectra (m/z) were measured in the chemi-
cal ionization (CI, ammonia as the reagent gas) or in the electronic
impact (EI) mode.
Scheme 6. Synthesis of 23 and 23Ј. (a) TBDMSCl, imidazole,
DMF, 92%; (b) O3, MeOH, PPh3, –78 °C, 88%; (c) CH2=C(CH3)-
MgBr, THF, –78 °C; (d) K2CO3, MeOH; (e) Dess–Martin
periodinane, CH2Cl2; (f) PPh3=CH(CHO), toluene, 55% overall;
(g) LiAlH(OCEt3)3, THF, –78 °C, 87%; (i) dimethyl malonate,
Cs2CO3, CH3CN, 86%; (j) (CH3)2NCCl=C(CH3)2, CH2Cl2, 91%.
[(2S,4S,5S)-7-Allyl-9-hydroxy-6,6,8-trimethyl-2-phenyl-1,3-dioxa-
spiro[4.5]dec-7-en-4-yl]methyl Acetate (16 and 16Ј): To a solution of
14 (1.16 g, 3 mmol) in dry CH2Cl2 (50 mL) at –20 °C, SOCl2
(0.71 g, 6 mmol) and pyridine (0.56 g, 7 mmol) were added. After
30 min, the reaction mixture was treated with a saturated solution
of NaHCO3 (30 mL). The mixture was diluted with ethyl acetate
(100 mL) and brine (50 mL), the aqueous solution was removed
and washed one time with ethyl acetate (50 mL). The organic layers
were collected and washed once with brine (50 mL); the organic
layer was dried with sodium sulfate and concentrated to provide a
mixture of chloro compounds percolated on Al2O3/6 % H2O
(116 g). The product was eluted slowly for 4 h and the solvents were
evaporated under vacuum, the mixture was purified on silica gel
(25:75, ethyl acetate/hexane) to afford a pale yellow oil (0.82 g,
2.1 mmol, 71% over 2 steps), (R)/(S) = 4:1. The two diastereoiso-
mers were easily separated, the minor (S) is the more polar one.
mer 23, which corresponds to the unnatural epimer at C13,
provided a mixture (1:3) of two macrocycles 24 and 25 in
47% yield, which were separated by chromatography.[9]
16: [α]2D5 = +21 (CHCl , c = 2.4). IR (neat): ν = 3350, 2975, 1742,
˜
3
1237, 1062 cm–1. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.45 (m,
2 H, C6H5), 7.37 (m, 3 H, C6H5), 6.09 (s, 1 H, PhCH), 5.75 (m, 1
H, CHCH2), 5.02 (dm, J = 17.0 Hz, 1 H, CH=CH2), 4.97 (dm, J
= 10.2 Hz, 1 H, CH=CH2), 4.45 (t, J = 5.6 Hz, 1 H, CHO), 4.29
(d, J = 12.6 Hz, 1 H, CH2OCOCH3), 4.23 (d, J = 12.6 Hz, 1 H,
CH2OCOCH3), 3.88 (dd, J = 11.6, 4.6 Hz, 1 H, CHOH), 2.96 (d,
J = 11.6 Hz, 1 H, OH), 2.88 (dd, J = 17.0, 6.0 Hz, 1 H, CH2), 2.81
(dd, J = 17.0, 5.2 Hz, 1 H, CH2), 2.41 (dd, J = 14.4, 1.4 Hz, 1 H,
CH2), 2.09 (s, 3 H, CH3), 2.02 (dd, J = 14.4, 5.0 Hz, 1 H, CH2),
1.78 (s, 3 H, CH3), 1.22 (s, 3 H, CH3), 1.05 (s, 3 H, CH3) ppm. 13
C
Scheme 7. Attempts of macrocyclization on two different diastereo-
isomers.
NMR (75 MHz, CDCl3, 21 °C): δ = 171.1, 136.5, 136.3, 135.1,
130.4, 129.7, 128.4, 127.1, 115.2, 101.5, 87.1, 77.9, 69.2, 63.9, 41.9,
32.7, 29.4, 24.7, 20.9, 20.0, 17.6 ppm. HRMS (IE): calcd. for
C23H30O5 386.2093; found 386.2084. 16Ј: [α]2D5 = –4 (CHCl3, c =
1.2). 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.45 (m, 2 H, C6H5),
7.37 (m, 3 H, C6H5), 6.01 (s, 1 H, PhCH), 5.75 (m, 1 H, CH=CH2),
5.00 (m, 2 H, CH=CH2), [4.41–4.18] (m, 4 H), 2.88 (dd, J = 16.6,
5.2 Hz, 1 H, CH2), 2.80 (dd, J = 16.6, 5.2 Hz, 1 H, CH2), 2.81 (dd,
J = 16.6, 5.2 Hz, 1 H, CH2), 2.41 (dd, J = 13.0, 6.4 Hz, 1 H, CH2),
2.08 (s, 3 H, CH3), 1.75 (dd, J = 13.0, 10.2 Hz, 1 H, CH2), 1.66 (s,
3 H, CH3), 1.18 (s, 3 H, CH3), 1.09 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, 21 °C): δ = 171.0, 136.5, 135.4, 130.8, 129.5,
128.4, 127.1, 127.0, 115.2, 101.9, 86.7, 77.5, 68.7, 64.4, 41.9, 33.1,
31.5, 25.8, 21.0, 20.2, 14.7 ppm.
Both macrocycles 24 and 25 correspond to one single
diastereoisomer, i.e., they are not a mixture of epimers due
to the presence of the secondary methyl group. A molecular
modeling study suggests that the carbon atom bearing the
secondary methyl group has the (R) configuration as
shown. In addition, it was shown that macrocycle 24 is
slowly converted into 25 upon reaction with Cs2CO3 in
CH3CN. This transformation must come from the enoliz-
ation of 24 followed by elimination of the silyl ether group.
This work has established that the β configuration of the
C13-OP group is a prerequisite for a successful macrocycli-
[(2S,4S,5S)-7-Allyl-9-{[tert-butyl(dimethyl)silyl]oxy}-6,6,8-tri-
zation.[10,11] Starting from key intermediate 19, we are now methyl-2-phenyl-1,3-dioxaspiro[4.5]dec-7-en-4-yl]methyl Acetate (18
Eur. J. Org. Chem. 2006, 3681–3686
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3683

S. Canesi, G. Berthiaume, P. Deslongchamps
FULL PAPER
and 18Ј): To a solution of 16 (1.93 g, 5 mmol) in dry DMF (20 mL)
was added imidazole (0.82 g, 12 mmol) and TBDMSCl (0.9 g,
6 mmol). The reaction mixture was stirred overnight and directly
purified on silica gel (1:9, ethyl acetate/hexane) to afford a pale
yellow oil (2.3 g, 4.6 mmol, 92%). Compound 18Ј was prepared
under the same conditions and with similar yield. 18: [α]2D5 = +3
CH2), 1.60 (s, 3 H, CH3), 1.11 (s, 6 H, 2 CH3), 0.91 [s, 9 H, C(CH3)3],
0.10 (s, 3 H, CH3), 0.09 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3, 21 °C): δ = 200.7, 171.0, 137.1, 135.5, 129.7, 128.5, 128.4,
127.1, 102.1, 86.5, 77.6, 68.7, 64.3, 44.3, 41.3, 31.7, 25.9, 25.8, 25.2,
21.0, 20.5, 18.1, 15.7, –4.1, –4.7 ppm.
(2E)-3-[(2S,4S,5S)-9-{[tert-Butyl(dimethyl)silyl]oxy}-6,6,8-tri-
methyl-7-(3-methyl-2-oxobut-3-en-1-yl)-2-phenyl-1,3-dioxaspiro[4.5]-
dec-7-en-4-yl]acrylaldehyde (20 and 20Ј): To a solution of 19 (0.42 g,
0.84 mmol), in dry THF (20 mL) at –78 °C under argon, was added
a solution of isoprenyl bromide (2 mL, 1 mmol, 0.5 /L). The reac-
tion mixture was stirred for 1 h, treated with a saturated solution
of NH4Cl (10 mL), diluted with ethyl acetate (40 mL) and brine
(20 mL). The aqueous solution was removed and washed one time
with ethyl acetate (25 mL). The organic layers were collected and
dried with sodium sulfate and the solvents were evaporated. The
mixture was diluted with methanol (20 mL) and K2CO3 solid
(70 mg, 0.5 mmol) was added. The solution was stirred for 1 h, fil-
tered through silica gel and concentrated to give a mixture (1:1).
To a solution of the residue in dry CH2Cl2 (10 mL), Dess–Martin
reagent (1.28 g, 3 mmol) was added. The reaction mixture was
stirred for 1 h, diluted with ethyl acetate (30 mL) and treated with
a mixture (1:1) of Na2CO3/Na2S2O3 (20 mL) and brine (30 mL).
The organic layer was dried with sodium sulfate and the solvents
were evaporated. The corresponding aldehyde is not very stable,
and was used directly without further purification. The correspond-
ing residue was diluted with toluene (15 mL) under argon, NEt3
(0.2 g, 2 mmol) and (formylmethyl) triphenylphosphonium chloride
(340 mg, 1 mmol) were added. The reaction mixture was stirred
overnight, concentrated under vacuum and purified on silica gel
(12:88, ethyl acetate/ hexane) to afford a pale yellow oil (0.29 g,
0.55 mmol, 55% over 4 steps). Compound 20Ј was prepared under
the same conditions and with similar yield. 20: [α]2D5 = +5 (CHCl3,
(CHCl , c = 0.7). IR (neat): ν = 2955, 1738, 1462, 1234, 1076,
˜
3
1030 cm–1. H NMR (300 MHz, CDCl3, 21 °C): δ = 7.48 (m, 2 H,
1
C6H5), 7.37 (m, 3 H, C6H5), 6.06 (s, 1 H, PhCH), 5.78 (m, 1 H,
CH=CH2), 5.06 (dm, J = 16.2 Hz, 1 H, CH=CH2), 5.01 (dm, J =
10.2 Hz, 1 H, CH=CH2), 4.28 (m, 2 H, CH2OCOCH3), 4.19 (t, J
= 10.2 Hz, 1 H, CHO), 4.07 (dd, J = 6.3, 3.6 Hz, 1 H, CHOTBS),
2.88 (d, J = 5.8 Hz, 2 H, CH2), 2.28 (dd, J = 14.6, 4.4 Hz, 1 H,
CH2), 2.17 (dd, J = 14.6, 6.8 Hz, 1 H, CH2), 2.11 (s, 3 H, CH3),
1.67 (s, 3 H, CH3), 1.28 (s, 3 H, CH3), 1.07 (s, 3 H, CH3), 0.90 [s,
9 H, C(CH3)3], 0.12 (s, 3 H, CH3), 0.10 (s, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3, 21 °C): δ = 171.0, 137.6, 136.5, 136.1,
130.3, 129.1, 128.2, 127.0, 115.2, 101.4, 85.7, 77.8, 68.8, 64.2, 41.8,
33.0, 32.5, 25.9, 23.1, 22.7, 21.0, 18.0, 17.3, –3.9, –4.8 ppm. HRMS
(IE): calcd. for C29H43O5Si [M–H+] 499.2880; found 499.2871. 18Ј:
[α]2D5 = –16 (CHCl3, c = 1.3). H NMR (300 MHz, CDCl3, 21 °C):
1
δ = 7.48 (m, 2 H, C6H5), 7.37 (m, 3 H, C6H5), 5.99 (s, 1 H, PhCH),
5.78 (m, 1 H, CH=CH2), 5.00 (m, 2 H, CH=CH2), 4.35 (m, 3 H),
4.18 (dd, J = 12.2, 9.2 Hz, 1 H, CH2OCOCH3), 2.89 (dd, J = 16.2,
5.4 Hz, 1 H, CH2), 2.79 (dd, J = 16.2, 5.4 Hz, 1 H, CH2), 2.29 (dd,
J = 13.0, 6.0 Hz, 1 H, CH2), 2.11 (s, 3 H, CH3), 1.79 (dd, J = 13.0,
9.6 Hz, 1 H, CH2), 1.68 (s, 3 H, CH3), 1.19 (s, 3 H, CH3), 1.12 (s,
3 H, CH3), 0.90 [s, 9 H, C(CH3)3], 0.12 (s, 3 H, CH3), 0.11 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3, 21 °C): δ = 171.0, 137.4,
136.8, 134.0, 132.0, 129.6, 128.4, 127.1, 115.1, 102.0, 86.8, 77.5,
68.9, 64.5, 41.7, 33.3, 31.7, 25.9, 25.6, 21.0, 20.2, 18.1, 15.2, –4.1,
–4.7 ppm.
c = 0.8). IR (neat): ν = 2930, 2857, 1692, 1066 cm–1. 1H NMR
˜
[(2S,4S,5S)-9-{[tert-Butyl(dimethyl)silyl]oxy}-6,6,8-trimethyl-7-(2-
oxoethyl)-2-phenyl-1,3-dioxaspiro[4.5]dec-7-en-4-yl]methyl Acetate
(19 and 19Ј): Ozone was passed through a solution of 18 (0.5 g,
1 mmol) in dry methanol (50 mL) at –78 °C until the reaction be-
came lightly blue. The solution was then purged with argon for
10 min and warmed to room temperature. PPh3 (0.26 g, 1 mmol)
was added and the reaction mixture was stirred for 10 min. The
solution was concentrated under vacuum and the residue was puri-
fied on silica gel (1:4, ethyl acetate/hexane) to provide a colorless
oil (0.44 g, 0.88 mmol, 88%). Compound 19Ј was prepared under
the same conditions and with similar yield. 19: [α]2D5 = +5 (CHCl3,
(300 MHz, CDCl3, 21 °C): δ = 9.67 (d, J = 7.8 Hz, 1 H, CHO),
7.47 (m, 2 H, C6H5), 7.37 (m, 3 H, C6H5), 7.11 (dd, J = 15.6,
4.8 Hz, 1 H, CH=CH), 6.66 (ddd, J = 15.6, 7.8, 1.6 Hz, 1 H,
CH=CH), 6.12 (s, 1 H, PhCH), 6.05 (s, 1 H, C=CH2), 5.83 (d, J =
1.4 Hz, 1 H, C=CH2), 5.03 (dd, J = 5.0, 1.4 Hz, 1 H, CHO), 4.01
(t, J = 8.0 Hz, 1 H, CHOTBS), 3.61 (s, 2 H, COCH2), 2.38 (dd, J
= 13.8, 8.6 Hz, 1 H, CH2), 2.17 (dd, J = 14.2, 7.2 Hz, 1 H, CH2),
1.92 (s, 3 H, CH3), 1.51 (s, 3 H, CH3), 1.23 (s, 3 H, CH3), 1.06 (s,
3 H, CH3), 0.88 [s, 9 H, C(CH3)3], 0.05 (s, 3 H, CH3), 0.02 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3, 21 °C): δ = 199.5, 193.3,
152.8, 144.3, 137.8, 134.3, 132.8, 132.2, 129.2, 128.4, 126.4, 124.6,
101.4, 89.0, 78.8, 69.5, 40.7, 37.9, 35.2, 26.5, 25.8, 20.1, 18.0, 17.9,
17.1, –4.1, –4.8 ppm. HRMS (IE): calcd. for C31H44O5Si 524.2958;
found 524.2961. 20Ј: [α]2D5 = +33 (CHCl3, c = 0.3). 1H NMR
(300 MHz, CDCl3, 21 °C): δ = 9.67 (d, J = 7.6 Hz, 1 H, CHO),
7.48 (m, 2 H, C6H5), 7.37 (m, 3 H, C6H5), 6.81 (dd, J = 15.6,
4.4 Hz, 1 H, CH=CH), 6.56 (dd, J = 7.6, 1.6 Hz, 1 H, CH=CH),
6.03 (s, 2 H, PhCH + C=CH2), 5.78 (d, J = 1.4 Hz, 1 H, C=CH2),
4.92 (dd, J = 4.4, 1.6 Hz, 1 H, CHO), 4.42 (dd, J = 9.2, 6.2 Hz, 1
H, CHOTBS), 3.52 (d, J = 18.0 Hz, 1 H, COCH2), 3.48 (d, J =
18.0 Hz, 1 H, COCH2), 2.23 (dd, J = 13.4, 6.0 Hz, 1 H, CH2), 1.91
(s, 3 H, CH3), 1.75 (dd, J = 13.4, 9.6 Hz, 1 H, CH2), 1.51 (s, 3 H,
CH3), 1.13 (s, 6 H, CH3), 0.92 [s, 9 H, C(CH3)3], 0.08 (s, 3 H, CH3),
0.07 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 21 °C): δ =
198.3, 192.9, 152.2, 144.6, 137.2, 134.4, 133.1, 130.6, 129.6, 128.4,
126.9, 123.8, 102.4, 88.0, 78.7, 68.7, 41.2, 37.6, 33.6, 25.9, 25.8,
25.3, 20.4, 17.9, 15.8, –4.1, –4.7 ppm.
c = 0.7). IR (neat): ν = 2956, 2857, 1742, 1720, 1236, 1078,
˜
1
1030 cm–1. H NMR (300 MHz, CDCl3, 21 °C): δ = 9.59 (s, 1 H,
CHO), 7.46 (m, 2 H, C6H5), 7.37 (m, 3 H, C6H5), 6.02 (s, 1 H,
PhCH), 4.41 (dd, J = 8.0, 3.8 Hz, 1 H, CHO), 4.23 (m, 2 H, CH2O-
COCH3), 4.11 (dd, J = 6.6, 3.2 Hz, 1 H, CHOTBS), 3.21 (d, J =
18.6 Hz, 1 H, CH2), 3.19 (d, J = 18.6 Hz, 1 H, CH2), 2.29 (dd, J
= 14.6, 3.2 Hz, 1 H, CH2), 2.12 (dd, J = 14.6, 3.2 Hz, 1 H, CH2),
2.08 (s, 3 H, CH3), 1.69 (s, 3 H, CH3), 1.28 (s, 3 H, CH3), 1.08 (s,
3 H, CH3), 0.91 [s, 9 H, C(CH3)3], 0.14 (s, 3 H, CH3), 0.08 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3, 21 °C): δ = 200.1, 171.0,
137.4, 133.5, 130.5, 129.2, 128.2, 127.0, 101.6, 85.3, 77.8, 68.4, 64.0,
44.3, 41.3, 32.1, 25.9, 25.8, 22.9, 22.8, 21.0, 18.0, 17.7, –3.9,
–4.8 ppm. HRMS (IE): calcd. for C28H42O6Si 502.2750; found
502.2740. 19Ј: [α]2D5 = –17 (CHCl3, c = 0.9). H NMR (300 MHz,
1
CDCl3, 21 °C): δ = 9.53 (t, J = 2.4 Hz, 1 H, CHO), 7.46 (m, 2 H,
C6H5), 7.37 (m, 3 H, C6H5), 5.97 (s, 1 H, PhCH), 4.43 (dd, J =
10.0, 6.0 Hz, 1 H, CHOTBS), 4.38 (m, 2 H, CH2OCOCH3), 4.12
(dd, J = 11.5, 8.5 Hz, 1 H, CHO), 3.11 (d, J = 17.3 Hz, 1 H, CH2),
1-{(2S,4S,5S)-9-{[tert-Butyl(dimethyl)silyl]oxy}-4-[(1E)-3-hydroxy-
3.07 (dd, J = 17.3, 2.4 Hz, 1 H, CH2), 2.35 (dd, J = 13.2, 6.0 Hz, prop-1-en-1-yl]-6,6,8-trimethyl-2-phenyl-1,3-dioxaspiro[4.5]dec-7-en-
1 H, CH2), 2.08 (s, 3 H, CH3), 1.75 (dd, J = 13.2, 10.2 Hz, 1 H, 7-yl}-3-methylbut-3-en-2-one (21 and 21Ј): To a solution of 20
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Eur. J. Org. Chem. 2006, 3681–3686

Novel Synthetic Strategy Towards Taxol by Macrocyclization Reaction
FULL PAPER
(0.27 g, 0.52 mmol) in dry THF (10 mL) at –78 °C under argon
a solution of lithium tris[(3-ethyl-3-pentyl)oxy]hydridoaluminate in
THF (1.2 mL, 0.6 mmol, 0.5 mol/L) was added. After 30 min (con-
scientiously checked by TLC), the reaction mixture was treated
with a saturated solution of NH4Cl (5 mL) and the mixture was
diluted with ethyl acetate (20 mL) and brine (10 mL). The aqueous
solution was removed and washed once with ethyl acetate (15 mL).
The organic layers were collected and washed once with brine
(20 mL), the organic layer was dried with sodium sulfate and the
solvents were evaporated. The residue was purified on silica gel
(1:3, ethyl acetate/hexane) to afford a pale yellow oil (243 mg,
0.46 mmol, 89%). Compound 21Ј was prepared under the same
oxole-12,12-dicarboxylate (24) and Dimethyl (2S,3aS,7Z,10S,
14E,15aS)-6,10,16,16-Tetramethyl-9-oxo-2-phenyl-4,9,10,11,13,15a-
hexahydro-12H-3a,7-methanocyclotetradeca[d][1,3]dioxole-12,12-di-
carboxylate (25): To a refluxed suspension of Cs2CO3 (82 mg,
0.25 mmol) and TBAI (74 mg, 0.2 mmol) in dry acetonitrile
(40 mL) was added 23 (34 mg, 0.05 mmol) in dry acetonitrile
(5 mL) with a syringe pump over 6 h. After 15 h of stirring, the
solution was filtered quickly through silica gel (1:3, ethyl acetate/
hexane) and the solvents were evaporated under vacuum. The resi-
due was purified on silica gel (1:4, ethyl acetate/hexane) to afford
two colourless oils, 24 (3.8 mg, 0.0059 mmol, 12%) and 25 (8.9 mg,
0.0174 mmol, 35%). 24: [α]2D5 = +15 (CHCl , c = 0.7). IR (neat): ν
˜
3
1
conditions and with similar yield. 21: [α]2D5 = –28 (CHCl3, c = 0.5).
= 2930, 2856, 1732, 1711, 1455, 1258, 1092, 1042 cm–1. H NMR
1
IR (neat): ν = 3470, 2828, 1681, 1066 cm–1. H NMR (300 MHz,
(300 MHz, CDCl3, 21 °C): δ = 7.45 (m, 2 H, C6H5), 7.38 (m, 3 H,
˜
CDCl3, 21 °C): δ = 7.48 (m, 2 H, C6H5), 7.39 (m, 3 H, C6H5), C6H5), 6.29 (tm, J = 11.5 Hz, 1 H, CH=CH), 6.08 (s, 1 H, PhCH),
[6.14–6.02] (m, 4 H), 5.79 (d, J = 1.4 Hz, 1 H, C=CH2), 4.86 (d, J 5.39 (dd, J = 15.4, 10.2 Hz, 1 H, CH=CH), 4.42 (d, J = 10.2 Hz,
= 6.6 Hz, 1 H, CHO), 4.24 (d, J = 3.2 Hz, 1 H, CH2OH), 4.14 (t,
J = 7.8 Hz, 1 H, CHOTBS), 3.55 (d, J = 18,0 Hz, 1 H, COCH2),
3.50 (d, J = 18.0 Hz, 1 H, COCH2), 2.34 (dd, J = 13.8, 8.0 Hz, 1
1 H, CHO), 4.16 (t, J = 8.2 Hz, 1 H, CHOTBS), 3.74 (s, 3 H,
COOCH3), 3.71 (s, 3 H, COOCH3), 3.22 (d, J = 16.2 Hz, 1 H,
COCH2), 3.20 (m, 1 H, COCHCH3), 3.18 (dm, J = 15.4 Hz, 1 H,
H, CH2), 2.18 (dd, J = 13.8, 8.0 Hz, 1 H, CH2), 1.91 (s, 3 H, CH3), CH2), 2.99 (d, 1 H, COCH2), 2.81 (dd, J = 14.2, 9.0 Hz, 1 H, CH2),
1.46 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 0.93 (s, 3 H, CH3), 0.88 [s, 2.41 (t, J = 13.7 Hz, 1 H, CH2), 2.03 (m, 2 H, 2 CH2), 1.72 (d, J
9 H, C(CH3)3], 0.07 (s, 3 H, CH3), 0.04 (s, 3 H, CH3) ppm. 13C = 14.5 Hz, 1 H, CH2), 1.54 (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 1.20
NMR (75 MHz, CDCl3, 21 °C): δ = 199.3, 144.4, 137.8, 133.5, (s, 3 H, CH3), 0.91 [s, 9 H, C(CH3)3], 0.82 (d, J = 6.8 Hz, 3 H,
133.3, 133.1, 128.9, 128.2, 126.7, 126.5, 124.2, 100.8, 87.6, 80.5,
69.8, 62.9, 41.5, 37.8, 35.3, 26.2, 25.9, 20.0, 18.1, 17.9, 16.9, –4.1, (75 MHz, CDCl3, 21 °C): δ = 212.9, 171.9, 171.8, 139.9, 137.3,
CH3), 0.12 (s, 3 H, CH3), 0.08 (s, 3 H, CH3) ppm. 13C NMR
–4.7 ppm. HRMS (IE): calcd. for C31H46O5Si 526.3114; found
134.8, 131.8, 128.7, 128.4, 125.9, 124.9, 100.2, 87.9, 79.7, 69.1, 54.8,
53.0, 52.2, 43.2, 39.7, 39.3, 38.4, 36.1, 34.8, 28.9, 25.8, 21.5, 18.0,
1
526.3118. 21Ј: [α]2D5 = +29 (CHCl3, c = 2.2). H NMR (300 MHz,
CDCl3, 21 °C): δ = 7.50 (m, 2 H, C6H5), 7.36 (m, 3 H, C6H5), 6.08 17.0, 15.8, –3.9, –4.8 ppm. HRMS (IE): calcd. for C36H52O8Si
(dt, J = 16.0, 5.4 Hz, 1 H, CH=CH), 6.07 (s, 2 H, PhCH + 640.3431; found 640.3444. 25: [α]2D5 = +214 (CHCl3, c = 0.5). IR
C=CH2), 5.79 (dd, J = 16.0, 6.6 Hz, 1 H, CH=CH), 5.77 (s, 1 H, (neat): ν = 2962, 2922, 1731, 1694, 1436, 1260, 1090 cm–1. 1H NMR
˜
C=CH2), 4.68 (d, J = 6.6 Hz, 1 H, CHO), 4.50 (dd, J = 10.2,
6.0 Hz, 1 H, CHOTBS), 4.22 (d, J = 5.0 Hz, 2 H, CH2OH), 3.52
(d, J = 17,8 Hz, 1 H, CH2), 3.50 (d, J = 17.8 Hz, 1 H, CH2), 2.33
(dd, J = 13.2, 5.8 Hz, 1 H, CH2), 1.92 (s, 3 H, CH3), 1.76 (dd, J =
(300 MHz, CDCl3, 21 °C): δ = 7.45 (m, 2 H, C6H5), 7.38 (m, 3 H,
C6H5), 6.01 (s, 1 H, PhCH), 5.88 (s, 1 H, C=CHCO), 5.85 (br., 1
H, CH=CCH3), 5.59 (m, 2 H, CH=CH), 4.29 (d, J = 8.8 Hz, 1 H,
CHO), 3.72 (s, 6 H, 2 COOCH3), 2.89 (dm, J = 19.0 Hz, 1 H,
13.2, 10.4 Hz, 1 H, CH3), 1.48 (s, 3 H, CH3), 1.11 (s, 3 H, CH3), CH2), 2.82 (d, J = 8.5 Hz, 1 H, CH2), 2.68 (m, 1 H, COCHCH3),
1.04 (s, 3 H, CH3), 0.92 [s, 9 H, C(CH3)3], 0.09 (s, 3 H, CH3), 0.07 2.40 (dm, J = 19.0 Hz, 1 H, CH2), 2.16 (d, J = 14.2 Hz, 1 H, CH2),
(s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 21 °C): δ = 198.5, 1.76 (dd, J = 14.8, 11.2 Hz, 1 H, CH2), 1.70 (s, 3 H, CH3), 1.29 (s,
144.7, 138.3, 134.1, 133.9, 131.0, 129.2, 128.3, 126.9, 126.8, 123.6,
3 H, CH3), 1.20 (s, 3 H, CH3), 0.90 (d, J = 6.4 Hz, 3 H, CH3) ppm.
101.8, 87.3, 79.4, 69.2, 62.9, 41.0, 37.6, 32.9, 25.9, 25.4, 20.4, 18.2, 13C NMR (75 MHz, CDCl3, 21 °C): δ = 210.2, 171.7, 171.4, 151.0,
18.0, 15.8, –4.1, –4.7 ppm.
139.5, 133.0, 131.4, 129.0, 128.5, 128.4, 127.4, 126.1, 123.4, 101.0,
85.0, 79.3, 54.9, 53.1, 52.6, 42.0, 40.6, 35.1, 33.7, 31.2, 24.4, 23.5,
19.6, 13.5 ppm. HRMS (IE): calcd. for C30H36O7 508.2461; found
508.2449.
Dimethyl (4-{(2S,4S,5S)-9-{[tert-Butyl(dimethyl)silyl]oxy}-4-[(1E)-
3-chloroprop-1-en-1-yl]-6,6,8-trimethyl-2-phenyl-1,3-dioxaspiro[4.5]-
dec-7-en-7-yl}-2-methyl-3-oxobutyl)malonate (23 and 23Ј): To a
solution of 21 (105 mg, 0.2 mmol) in dry acetonitrile (5 mL) were
added dimethyl malonate (105 mg, 0.8 mmol) and Cs2CO3 (197 mg,
0.6 mmol). The reaction mixture was stirred overnight, concen-
trated under vacuum and directly purified on silica gel (1:4, ethyl
acetate/hexane) to afford a pale yellow oil (113 mg, 0.17 mmol,
86%) of an epimeric mixture (1:1). To the corresponding mixture
(66 mg, 0.1 mmol) in dry CH2Cl2 (5 mL) was added 1-chloro-
N,N,2-trimethyl-1-propenylamine (40 mg, 0.3 mmol). The reaction
mixture was stirred for 45 min, treated with a saturated solution of
NaHCO3 (5 mL) and diluted with ethyl acetate (15 mL) and brine
(10 mL). The aqueous solution was removed and washed once with
ethyl acetate (15 mL). The organic layers were collected and dried
with sodium sulfate and the solvents were evaporated. The residue
was purified on silica gel (15:85, ethyl acetate/hexane) to afford
a pale yellow oil (62 mg, 0.091 mmol, 91%). Compound 23Ј was
prepared under the same conditions and with similar yield. These
compounds were used immediately in the next reaction.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and data for compounds 5–14 and 17.
Acknowledgments
We wish to thank NSERC Canada for financial support, we thank
Dr. Pierre Soucy for a gift of starting material 4 and Professor Yves
Dory for a molecular modeling calculation.
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11,13,15a-octahydro-12H-3a,7-methanocyclotetradeca[d][1,3]di-
Eur. J. Org. Chem. 2006, 3681–3686
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3685

S. Canesi, G. Berthiaume, P. Deslongchamps
FULL PAPER
Biediger, P. D. Boatman, M. Shindo, C. C. Smith, S. Kim, H.
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der to form the macrocycle, but to our disapointment this
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Received: March 30, 2006
Published Online: June 19, 2006
[7] The proton at C13 in 17 is axial [δ = 5.32 (dd, J = 9.4, 6.8 Hz,
1 H) ppm] as in compound 18Ј [δ = 4.18 (dd, J = 12.2, 9.2 Hz,
1 H) ppm].
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Eur. J. Org. Chem. 2006, 3681–3686