Synthesis of BC ring-systems of taxol by ring-closing metathesis

Article abstract of DOI:10.1055/s-2000-6263

Highly functionalized BC ring-systems of Taxol having the required chemistry for the C1, C2 and C8 centers have been synthesized using a ring- closing metathesis (RCM) reaction as the key step. Silylene 26 and acetonide 27 were obtained in excellent yields with Schrock's and our recently reported catalyst. In the case of carbonate 23, a trans cyclooctene was formed when using Grubbs' catalyst, indicating that RCM does not always proceed to completion of thermodynamic equilibrium.

Full text of DOI:10.1055/s-2000-6263

SPECIAL TOPIC
869
Synthesis of BC Ring-Systems of Taxol by Ring-Closing Metathesis
Damien Bourgeois,a Jacqueline Mahuteau,b Ange Pancrazi,c Steven P. Nolan,*d Joëlle Prunet*a
a Laboratoire de Synthèse Organique, associé au CNRS, Ecole Polytechnique, DCSO, F-91128 Palaiseau, France
Fax +33(1)69333010; E-mail: Joelle.Prunet@polytechnique.fr
b Service de RMN, UPRESA 8076, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France
c Laboratoire de Synthèse Organique Sélective et Chimie Organométallique, UCP-ESCOM, 13 Bd de l'Hautil, F-95092 Cergy-Pontoise,
France
d Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, USA
Received 3 February 2000; revised 2 March 2000
Abstract: Highly functionalized BC ring-systems of Taxol® having
the required chemistry for the C1, C2 and C8 centers have been syn-
thesized using a ring-closing metathesis (RCM) reaction as the key
H
step. Silylene 26 and acetonide 27 were obtained in excellent yields
with Schrock’s and our recently reported catalyst. In the case of car-
bonate 23, a trans cyclooctene was formed when using Grubbs’cat-
alyst, indicating that RCM does not always proceed to completion
of thermodynamic equilibrium.
TrisHNN
R
R
OP
O
R'
R'
5
6
7
Scheme 2
Key words: cyclooctenes, cyclization, metathesis, olefin, Taxol,
ruthenium, molybdenum
Two substituted hex-4-enals were selected. Aldehyde 10
was synthesized in four steps from commercially avail-
able 2,2-dimethylpent-4-enal (8) by conversion to ketone
9 (Scheme 3). Cyanohydrin homologation and DIBALH
reduction of the nitrile gave 10 in 57% yield for the two
steps, along with 15-20% of the corresponding a-hy-
droxy aldehyde. Compound 12 (Scheme 4) has been re-
ported by Pattenden.8
In spite of numerous synthetic approaches towards Taxol®
(1)1 and Taxotere® (2),2 including six total syntheses,3
these two antitumor agents still constitute a remarkable
challenge for organic chemists (Scheme 1). In the course
of our studies towards the total synthesis of Taxol,4 a con-
vergent approach with a key coupling reaction between
the A- and C-rings, where all the taxol functionalities
were potentially present was envisaged. A metathesis re-
action was planned for the final B-ring closure. This route
proved to be too ambitious and we designed the synthesis
plan outlined below, where the metathesis reaction would
form the BC ring-system of the target molecule by creat-
ing the C9-C10 bond (Scheme 1).
Shapiro coupling was first tested with pentenal 8. The de-
sired alcohol was obtained in 77% yield when the inter-
mediate vinyllithium was formed with t-BuLi (Scheme
1) TMSCN
1) BuLi
ZnI2
When we began this work, only a few cyclooctenes had
been formed by ring-closing metathesis (RCM).5 We
therefore decided to check the feasibility of this route with
model compounds.6 Metathesis precursors 5 could be syn-
thesized by Shapiro coupling between aldehydes 6 and tri-
sylhydrazone 7, which was prepared in one step from the
known 2-methyl-2-vinylcyclohexanone7 (Scheme 2).
O
2) Jones
83%
2) DIBALH
57%
H
O
H
O
OTMS
10
8
9
Scheme 3
R2O
O
OP
9
PO
10
OH
OP
C
OP
10
9
7
10
9
R1NH
Ph
C
O
C
3
5
B
2
O
B
13
A
1
A
O
D
O
H
O
OP
OP
HO
OAc
PO
OP
OBz
OH
4
3
1 Taxol® (paclitaxel)
2 Taxotere® (docetaxel)
R1 = C6H5CO, R2 = Ac
1 = tBuOCO, R2 = H
R
Scheme 1
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

870
D. Bourgeois et al.
SPECIAL TOPIC
4).4e Similarly, reaction of hydrazone 7 with aldehydes 12 RCM reaction, we first focused our study on the RCM of
and 10 furnished compounds 13 and 14 in 72 and 85% alcohol 11, which would lead to a seven-memberd ring.
yield, respectively. Since the two coupling partners are ra-
cemic, the adducts are produced as 1:1 mixture of diaste-
reomers, even in the case of 14 where the addition is
Compound 11, when submitted to Grubbs’ catalyst, fur-
nished the seven-membered ring 16 in 51% isolated yield
(Scheme 5). The remaining material was a complex mix-
ture of 11 and oligomers. When the alcohol function of 11
totally stereoselective at the diol level, producing only the
trans diastereomer.9
was protected as a triethylsilyl ether (TES), the yield of
the RCM increased to 93%. Both reactions were slow and
required two days to proceed to completion. In each case
(11 Æ 16 and 15 Æ 17), the two diastereomeric dienes cy-
clized at a comparable rate, and the products were formed
t-BuLi
+
as a 1:1 mixture of diastereomers.13 The Thorpe-Ingold
77%
H
TrisHNN
effect of an alcohol protecting group (OTES vs OH) is
noteworthy and a similar example has been recently re-
ported for a RCM reaction leading to a hydroxyoxocene.14
1:1
OH
O
7
11
8
t-BuLi
H
O
72%
10% [Ru], 0.02 M
OH
13
1:1
Benzene, 60 °C, 2 d
12
51%
OH
OH
1:1
1:1
11
96%
16
1) t-BuLi
2) TFA
81%
TESCl, Im
O
H
OH 1:1
OH
OTMS
7% [Ru], 0.02 M
10
14
Benzene, 60 °C, 2 d
93%
Scheme 4
1:1
1:1
OTES
OTES
15
17
Scheme 5
The RCM catalysts used in this work are presented in Fig-
ure 1: Grubbs’ruthenium complex [Ru],10 Schrock’s mo-
lybdenum compound [Mo],11 and our recently reported
catalyst [RuIm].12 Schrock’s catalyst was not employed
with substrates with free OH groups, as it is known to be
incompatible with this functional group.
Having established that the neopentylic position was not
deleterious to the RCM, we turned our attention to the for-
mation of cyclooctenes. No reaction occurred at 60 °C,
which is the temperature generally recommended for sub-
strates which are not very reactive towards olefin metathe-
sis. The following general conditions were used: RCM
with [Ru] or [Mo] were performed in benzene (0.02 M) at
80 °C for several days (8 days for [Ru], 3 days for [Mo])
and fresh catalyst was added every 24 hours.15 In the case
of [RuIm], which is a more active catalyst and which is
also thermally stable, RCM reactions were complete in 12
hours at 80 °C in 1,2-dichloroethane without any further
catalyst addition.
Figure Catalysts used for RCM reactions
Alcohol 13, when submitted to Grubbs' catalyst [Ru], only
led to polymers. With [RuIm], traces of a cyclized product
were found in the 1H NMR spectrum of the unpurified re-
action mixture. Metathesis of triethylsilyl ether 18 with
Grubbs' catalyst furnished, after deprotection of the TES
ether,16 11% of cyclooctene 1917 as a single diastereomer
with the b-configuration at C8.18 The mass balance con-
sisted of starting diene 18. On the other hand, excellent
yields were obtained for the RCM reactions with catalysts
[Mo] and [RuIm], which gave both the diastereomers of
The closure of the B-ring of Taxol between C9 and C10 by
RCM presents two separate difficulties: the unfavorable
formation of an eight-membered ring has to be overcome
and the neopentylic position at C8 adjacent to one of the
olefinic partners might prevent the formation of the inter-
mediate metallacyclobutane, which is already fused to a
highly substituted eight-membered ring. In order to assess
rapidly the influence of the steric hindrance at C8 on the
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of BC Ring-Systems of Taxol by Ring-Closing Metathesis
871
19 (Scheme 6). Here also, a Thorpe-Ingold effect could um derivatives at high temperature: Grubbs observed
explain the difference in yields between the RCM with the isomerization of RCM products during distillation when
free alcohol and the TES ether.
residual amounts of the catalyst were present.20 Both
products 24 and 25 have the b-configuration at C8.21 In
the case of [RuIm], the yield was slightly better but the in-
triguing feature was the stereochemical outcome of the
cyclization: a-24 was the only observed cyclooctene. We
are unable at this time to explain why only one diastere-
omer undergoes RCM in each case.
1) [Ru]
2) TBAF, 50°C, 2 h
11%
OTES
OH
OH
18
β-19
1) [Mo]
10
9
85%
2) TBAF, 50°C, 2 h
1) [Ru]
8
11
8
18
+
1) [RuIm], 20h
or
90%
2) TBAF
12 h
2) TBAF, 50°C, 2 h
OH
OH
OH
OTES
OH
OH
19
20
1:1
β-24
6%
25 7%
Scheme 6
1) [RuIm]
8
The following metathesis precursors contain most of the
substituents found in compound 4. Only the acetal on the
side-chain and the protected alcohol at C7 are missing.
The secondary alcohol present in 14 was protected as its
TES ether to give 20 in excellent yield. Cyclic protecting
groups were also installed to lead to silylene 21,19 ace-
tonide 22 and carbonate 23 in 84, 92 and 91% yields, re-
spectively (Scheme 7).
2) TBAF
12 h
OH
OH
α-24
27%
Scheme 8
Cyclic protecting groups for the diol moiety were the next
logical step. A poor conversion of silylene 21 to cy-
clooctene b-2622 was obtained with Grubbs’ catalyst.
However, we were gratified to discover that catalysts
[Mo] and [RuIm] led to excellent yields of 26 (Scheme 9).
Contrary to the case of 20, both diastereomers of 21 un-
derwent cyclization.
88%
91%
84%
92%
OTES
O
O
OH
20
Si
TESOTf
Et3
BuLi
21
t-Bu t-Bu
N
(t-Bu)2SiHCl
14
NaH
1,2-Dimethoxypropane
cat CSA
Im2CO
[Mo]
96%
91%
[RuIm]
20 h
O
O
O
O
Si
O
O
O
O
Si
t-Bu t-Bu
26
1:1
t-Bu t-Bu
23
22
O
21
1:1
Scheme 7
Scheme 9
We were disappointed by the outcome of RCM reaction of Similar results were obtained with acetonide 22: no no-
compound 20 with catalyst [Ru]: the desired product 24 ticeable reaction occurred with catalyst [Ru], whereas
was obtained in only 6% yield, along with 7% of cy- RCM with [Mo] and [RuIm] furnished the bicyclo com-
clooctene 25 where the double bond had migrated to the pound 27 in 93 and 86% yield, respectively (Scheme 10).
C10-C11 position (Scheme 8). A similar isomerization
We next examined the olefin metathesis of carbonate 23.
Choice of this derivative was prompted by Nicolaou’s
finding that it makes a convenient protecting group for the
has been reported by Taylor.14 The authors invoke an acid
catalysis due to the use of dichloromethane as solvent,
since the presence of triethylamine inhibits the formation
C1-C2 diol of Taxol. When phenyllithium was added to a
of the isomerized product. Here, the isomerization might
carbonate derivative of an ABC ring-system of this mole-
result from prolonged exposure of the product to rutheni-
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

872
D. Bourgeois et al.
SPECIAL TOPIC
trans b-28 to cis b-28 in the presence of (bis)allyl ether
(an easily measurable source of ethylene)27 presumably
through a ring-closing/ring-opening process, effectively
proving that RCM with this catalyst proceeds under ther-
modynamic control.
[Mo]
[RuIm] 86%
93%
O
O
O
O
A complexation of the catalyst by the carbonyl moiety
might be invoked to explain the formation of a trans cy-
clooctene, although the involved chelate would be an
eight-membered ring.28 To clarify this point, a metathesis
reaction was performed in the presence of 1 equivalent of
titanium isopropoxide, according to the work of Fürstner
and Langemann.29 In this instance, only the b-epimer cy-
clized, as above, but this time cis b-28 was produced,
along with cis b-30 where the olefin has migrated to the
C10-C11 position (Scheme 12). The a-diastereomer did
not undergo metathesis, but a similar isomerization of the
double bond led to a-29. Two aspects of this reaction de-
serve comments. First, no trans cyclooctene is produced.
This may be explained by complexation of the titanium by
the carbonyl moiety, which prevents complexation of the
ruthenium catalyst. The transition state would not adopt
the rigid conformation leading to the trans double bond
any longer. The second matter is the double bond migra-
tion to the C10-C11 position, that occurs both in the cy-
clized product (formation of cis b-30)30 and in the starting
material (formation of a-29).31 This migration was also
observed with the more active [RuIm] catalyst: during the
isomerization of trans b-28 with [RuIm] in 1,2-dichloro-
ethane, cis b-28 was contaminated with 20% of the
D-10,11 isomer cis b-30. In the case of [RuIm], when the
metatheses were conducted in benzene, isomerization of
the starting diene was also observed and the results were
not reproducible. For example, RCM of carbonate 23 in
benzene only produced 50% of cyclooctene cis -28, along
with 50% of isomerized starting material 29. Performing
22
1:1
27
1:1
Scheme 10
cule, the C2 benzoate was directly formed.23 Moreover, it
has also been shown that the corresponding acetonide was
not easily hydrolyzed.24 Treatment of a diastereomeric
mixture of carbonate 23 with Grubbs’ or Schrock’s cata-
lyst led to a surprising result: only the C8 b-diastereomer
of 23 cyclized, and the a-diastereomer was recovered al-
most quantitatively (Scheme 11). For the first time with
[Ru], the conversion was complete (for one diastereomer),
and no polymeric side products were formed. The totally
unexpected feature of this reaction was the trans geometry
of the C9-C10 olefin in trans b-28.25 No trace of cis b-28
was observed, even when the reaction was performed with
1 equivalent26 of [Ru] in C6D6 and monitored by 1H NMR.
On the contrary, both epimers at C8 underwent cycliza-
tion with [RuIm], giving a 86% yield of cis-28 as a 1:1
mixture of diastereomers. This result was confirmed by
independent RCM of a-23 with [RuIm] which led to cis a-
28 in 96% yield. It appears that olefin metathesis of 23
does not proceed to complete thermodynamic equilibrium
with catalysts [Ru] and [Mo]. To check the stability of the
trans cyclooctene, we attempted to convert trans b-28 to
cis b-28 with classical reagents (cat. I2/CDCl3, cat. CSA/
CDCl3, CSA/benzene/reflux/15 h), to no avail. On the
other hand, catalyst [RuIm] is capable of isomerizing
[Ru]
+
or
[Mo]
O
O
O
O
O
[RuIm]
O
O
O
O
O
trans β-28
1:1
23
α-23
[Ru]
[Mo]
34%
41%
42%
32%
[RuIm]
86%
[RuIm]
96%
67%
O
O
O
O
O
O
O
cis β-28
1:1
cis 28
cis α-28
O
O
Scheme 11
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of BC Ring-Systems of Taxol by Ring-Closing Metathesis
873
[Ru]
+
8 days
Ti(Oi-Pr)4
O
O
O
O
O
O
23
α-23
1:1
α-29
O
O
O
+
O
O
O
O
O
O
cis β-28
1:2
cis β-30
Scheme 12
the catalysis using 1,2-dichloroethane solved the problem were separated by flash chromatography. Compound b-24
for all substrates except carbonate 23, where 10% of 29 was identical to the RCM product of 20 with [Ru] fol-
1
was detected in the H NMR of the unpurified reaction lowed by TBAF deprotection (cf. Scheme 8). Finally, the
mixture. It seems that isomerization becomes a non-negli- unpurified mixture containing b-26 was treated with
gible side reaction with active catalysts (according to TBAF for 2 days and only b-24 was found in the 1H NMR
Fürstner and Langemann, titanium isopropoxide activates of the resulting mixture of products, with no trace of a-24.
[Ru]) in the case of unreactive metathesis precursors like Diastereomers of silylene 26 and acetonide 27 were sepa-
carbonate 23.
rated by flash chromatography and their stereochemistry
was assigned by extensive NMR studies (COSY, NOE-
SY, HMBC, HMQC).
Determination of the stereochemistry of the metathesis
products was based on the X-ray structure of trans b-28.
First, the trans configuration of the C1-C2 diol was estab- In conclusion, we have synthesized elaborate BC ring-
lished. The C8 configuration of cis a-28 was then estab- systems of Taxol in very good yields using RCM to form
lished, since this compound is derived from the unreacted the eight-membered ring. These model compounds pos-
epimer recovered from metathesis of 23 with [Ru] or [Mo] sess the required configuration for the C1, C2 and C8 ste-
(Scheme 11). Compound cis a-28 was deprotected to fur- reogenic centers of the target molecule. We have tested
nish diol a-24 (Scheme 13), which is identical to the com- three different catalysts, [Ru], [Mo], and [RuIm], on sev-
pound resulting from RCM of 20 with [RuIm] followed eral substrates and we have shown that catalyst [RuIm]
by fluoride treatment (cf. Scheme 8).
was the most active in all cases. During this study, we
have uncovered a specific case where a trans cyclooctene
was formed, proving that olefin metathesis does not al-
ways proceed to completion of thermodynamic equilibri-
um with [Ru] and [Mo], contrary to RCM [RuIm] which
gave the expected cis product.
2N aq. NaOH
Dioxane, 2 d
96%
O
O
OH OH
All air and/or water sensitive reactions were carried out under argon
with, freshly distilled anhydrous solvents using standard syringe-
cannula/septa techniques. THF and Et2O were distilled from sodi-
um-benzophenone, MeOH from Mg(OMe)2. Petroleum used had bp
40-65 °C. All corresponding glassware was oven dried (110 °C)
and/or carefully dried in line with a flameless heat gun, unless oth-
erwise stated.
O
cis α-28
α-24
2N aq. NaOH
8
Dioxane, 2 d
94%
1
2
1H NMR spectra were recorded in CDCl3 on a Bruker WP 200 (200
MHz) or on a Bruker AM 400 (400 MHz) instrument. The chemical
shifts are expressed in parts per million (ppm) referenced to residual
CHCl3 (7.27 ppm). Data are reported as follows: d, chemical shift;
multiplicity (recorded as s, singlet; d, doublet; t, triplet; q, quadru-
plet and m, multiplet), coupling constants (J in Hertz), integration
and assignment. H,H-COSY and H,H-NOESY experiments were
routinely carried out to ascertain H-H connections and configura-
tion assignments, respectively. 13C NMR spectra were recorded on
O
O
OH OH
O
cis 28 1:1
24 1:1
Scheme 13
The two epimers of cis -28, resulting from cyclization of
23 with [RuIm], were unseparable but the carbonate moi-
ety could be hydrolyzed to furnish both epimers of 24 that
the same instruments at 50.3 MHz and 100.6 MHz respectively. 13
NMR chemical shifts are expressed in parts per million (ppm), re-
C
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

874
D. Bourgeois et al.
SPECIAL TOPIC
ported from the central peak of CDCl3 (77.14 ppm). J-modulated
spin-echo technique (J-mod) experiments were used for evaluating
CH multiplicities.
1H NMR (CDCl3, 400 MHz): d = 5.71-5.61 (m, 1 H, H-2), 5.04-4.99
(m, 2 H, H2-1), 2.45 (t, 2 H, J = 7.3 Hz, H2-6), 2.25 (d, 2 H,
J = 7.3 Hz, H2-3), 1.55-1.48 (m, 2 H), 1.32-1.22 (m, 2 H), 1.11 (s, 6
H, 2CH3-4), 0.89 (t, 3 H, J = 7.3 Hz, H3-9).
13C NMR (CDCl3, 100.6 MHz): d = 215.4 (5), 134.1 (2), 117.7 (1),
47.4 (4), 43.9 (3), 36.7 (6), 25.8, 22.3 (7, 8), 24.0 (CH3-4), 13.9 (9).
Mass spectra (MS) were obtained on a Hewlett-Packard HP 5989B
spectrometer via either direct introduction (CI, NH3) or GC/MS
coupling with a Hewlett-Packard HP 5890 chromatograph. IR spec-
tra were obtained on a Perkin-Elmer FT 1600 instrument using
NaCl salt plates (thin film) and are reported in terms of frequency
of absorption (n, cm-1). Microanalyses were performed by the Ser-
vice de Microanalyse, Institut de Chimie des Substances Naturelles,
C.N.R.S., F-91198, Gif sur Yvette. Flash chromatography was per-
formed on E. Merck silica gel Si 60 (40-63 mm, Ref. 9385).
IR (film): n = 3077, 2960, 2873, 1705, 1640, 1467, 1365, 1120,
1039, 995, 916 cm-1.
+
MS (CI, NH3): m/z = 186 (MNH4 ), 169 (MH+), 153, 139, 126.
(2R*/S*)-2-Butyl-3,3-dimethyl-2-trimethylsilyloxyhex-5-enal
(10) and (2R*/S*)-2-Butyl-3,3-dimethyl-2-hydroxyhex-5-enal
(10a)
Taxol numbering was used for assignment on all compounds en-
compassing the BC skeleton of Taxol.
To a solution of ketone 9 (1.2 g, 7.1 mmol) in anhyd CH2Cl2 (20
mL) at 25 °C was added a pinch of ZnI2 and then trimethylsilylcya-
nide (1.4 mL, 10.5 mmol, 1.5 equiv). The resulting mixture was
heated at reflux for 2 h, then cooled to r.t. and concentrated in vacuo
(with a NaOCl/NaOH trap). The crude product was filtered on a pad
of silica gel, and the silica gel was washed three times with Et2O/
petroleum ether (1:1, 50 mL). The cyanohydrin thus obtained was
concentrated in vacuo and used as such for the following step. It was
diluted with Et2O (25 mL), and the resulting solution was cooled to
-78 °C. A solution of DIBALH (1 M in hexanes, 15.0 mL,
1.5 mmol, 2.2 equiv) was added, and the reaction mixture was
stirred at -78 °C for 2 h, then 30 min at 0 °C, and finally quenched
with EtOAc (2 mL). The mixture was then diluted with Et2O (100
ml), warmed to r.t. and silica gel (20 g) was added. The resulting
suspension was vigorously stirred for 6 h, and then filtered and con-
centrated in vacuo. Purification by flash chromatography on silica
gel (Et2O/petroleum ether, 2:98) yielded 1.1 g (57%) of aldehyde 10
along with 200 mg (14%) of deprotected aldehyde 10a as colorless
oils.
(6R*/S*)-N-2,4,6-Triisopropylbenzenesulfonyl,N’-(6-methyl-6-
vinylcyclohex-1-en-1-yl)hydrazine (7)
To a suspension of (±)-2-methyl-2-vinylcyclohexan-1-one7 (3.2 g,
2.3 mmol) and N-2,4,6-triisopropylbenzenesulfonylhydrazine
(6.6 g, 2.2 mmol, 0.96 equiv) in Et2O (15 mL) was added dropwise
concd HCl (10 drops) at 25 °C until complete dilution of the solid.
The reacting mixture was stirred for 10 min until the appearance of
a white precipitate, and then allowed to stay for a further 15 min.
The suspension was filtered and the solid washed with Et2O/petro-
leum ether (10:90) (2 ¥ 10 mL) to yield 6.1 g (63%) of hydrazone
7 as a white solid. The mother liquors were concentrated, and anoth-
er 1.15 g (12%) of 7 was recovered after recrystallization from
Et2O/petroleum ether (1:1); mp 145-146 °C.
1H NMR (CDCl3, 200 MHz): d = 7.53 (br s, 1 H, NH), 7.16 (s, 2 H,
H-Ar), 5.75 (dd, 1 H, J = 17.6, 10.7 Hz, H-1’), 4.88 [dd, 1 H,
J = 10.7, 1.0 Hz, H-2’ (cis)], 4.58 [dd, 1 H, J = 17.6, 1.0 Hz, H-2’
(trans)], 4.20 (sept, 2 H, J = 6.7 Hz, CH-Ar), 2.90 (sept, 1 H,
J = 6.7 Hz, CH-Ar), 2.51-2.28 (m, 1 H), 2.05-1.90 (m, 1 H),
1.84-1.72 (m, 2 H, CH2), 1.62-1.40 (m, 4 H, 2 CH2), 1.28 [d, 6 H,
10
1H NMR (CDCl3, 400 MHz): d = 9.68 (s, 1 H, H-1), 5.78 (ddt, 1 H,
J = 17.5, 10.0, 7.4 Hz, H-5), 5.05 [br d, 1 H, J = 10.0 Hz, H-6 (cis)],
5.01 [br d, 1 H, J = 17.5 Hz, H-6 (trans)], 2.14 (dd, 1 H, J = 13.4,
7.4 Hz, H-4), 2.07 (dd, 1 H, J = 13.4, 7.4 Hz, H-4), 1.88-1.81 (m, 1
H), 1.68-1.61 (m, 1 H), 1.43-1.23 (m, 3 H), 0.98-0.96 (m, 1 H), 0.93,
0.92 (2 s, 6 H, 2 CH3-3), 0.89 (t, 3 H, J = 7.1 Hz, CH2CH3), 0.16 (s,
9 H, CH3Si).
J = 6.4 Hz, (CH3)2CH-Ar], 1.26 [d, 12 H, J = 6.9 Hz,
(CH3)2CH-Ar], 1.02 (s, 3 H, CH3-6).
2
13C NMR (CDCl3, 50.3 MHz): d = 161.5 (1), 153.0, 151.2 (Ar),
145.0 (1’), 131.5, 123.4 (Ar), 113.5 (8’), 45.6 (6), 39.4 (3), 34.1,
29.7, 26.1, 25.7, 24.8, 24.7, 23.5, 21.6.
IR (film): n = 3262, 3054, 2960, 2864, 1601, 1460, 1382, 1330,
1165, 1105, 990, 934, 657 cm-1.
13C NMR (CDCl3, 100.6 MHz): d = 205.2 (1), 134.9 (5), 117.7 (6),
88.7 (2), 41.7 (4), 41.5 (3), 31.2, 26.4, 23.2 (CH2), 22.2 (CH3-3),
13.9 (CH2CH3), 2.9 (CH3Si).
+
MS (CI, NH3): m/z = 436 (MNH4 ), 419 (MH+), 375, 355, 301, 280,
251, 153, 140.
IR (film): n = 3072, 2959, 2874, 1734, 1639, 1468, 1248, 1145,
4,4-Dimethylnon-1-en-5-one (9)
1082, 840, 754 cm-1.
To a solution of 90% 2,2-dimethylpent-4-enal (8; 4.0 g, 3.2 mmol)
in anhyd THF (80 mL) was added a crystal of 2,2’-bisquinoline.
The solution was cooled to -78 °C, and then a solution of BuLi (1.5
M in hexanes) was added over a 15 min period until persistency of
a purple colour (19.4 mL, 29 mmol, 0.9 equiv). The reaction mix-
ture was then quenched with sat. aq NH4Cl solution (40 mL), dilut-
ed with Et2O (100 mL) and allowed to warm to r.t. The layers were
separated, the aqueous layer was extracted with Et2O, and the com-
bined organic layers were washed with H2O and brine, dried
(MgSO4) and concentrated in vacuo. The crude product was diluted
with acetone (60 mL), and Jones reagent (CrO3/H2SO4) was added
dropwise over a 10 min period at 0 °C until persistency of an orange
colour. The mixture was stirred for 1 h at 0 °C and then quenched
with MeOH (5 mL). After 10 min, the mixture was poured into H2O
(50 mL) at 0 °C and diluted with Et2O (100 mL). The layers were
separated, the aqueous layer was extracted with Et2O, and the com-
bined organic layers were washed with H2O and brine, dried
(MgSO4) and concentrated in vacuo. Distillation of the crude prod-
uct afforded 4.5 g (83%) of ketone 9 as a colorless oil; bp 47 °C/0.1
Torr.
MS (CI, NH3): m/z = 305, 288, 271, 253, 181, 90.
10a
1H NMR (CDCl3, 400 MHz): d = 9.76 (d, 1 H, J = 1.0 Hz, H-1),
5.79 (ddt, 1 H, J = 17.4, 10.4, 7.4 Hz, H-5), 5.06 [br d, 1 H,
J = 10.4 Hz, H-6 (cis)], 5.02 [br d, 1 H, J = 17.4 Hz, H-6 (trans)],
3.38 (s, 1 H, OH), 2.18 (dd, 1 H, J = 13.4, 7.4 Hz, H-4), 2.06 (dd, 1
H, J = 13.4, 7.4 Hz, H-4), 1.94-1.87 (m, 1 H), 1.77-1.70 (m, 1 H),
1.33-1.23 (m, 3 H), 0.97, 0.95 (2 s, 6 H, 2 CH3-3), 0.86 (t, 3 H,
J = 7.1 Hz, CH2CH3), 0.82-0.76 (m, 1 H).
13C NMR (CDCl3, 100.6 MHz): d = 206.0 (1), 134.4 (5), 118.0 (6),
84.0 (2), 41.6 (4), 40.5 (3), 29.7, 25.1, 23.1 (CH2), 21.9, 21.8
(CH3-3), 13.9 (CH2CH3).
IR (film): n = 3505, 3075, 2959, 2873, 1719, 1639, 1468, 1338,
1248, 914, 641 cm-1.
MS (CI, NH3): m/z = 220, 216, 199.
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of BC Ring-Systems of Taxol by Ring-Closing Metathesis
875
[1R*(6R*/S*)]-2,2-Dimethyl-1-(6-methyl-6-vinylcyclohex-1-en-
1-yl)pent-4-en-1-ol (11)
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 148.1 (3),
146.5 (9), 135.9 (10), 123.7, 123.6 (4), 116.7, 116.7 (10’), 112.9,
112.8 (9’), 68.1, 67.7 (2), 49.9, 49.4, 47.4, 47.3 (1, 11), 40.8 (8),
37.7, 37.6 (7), 33.5, 33.4 (15), 27.5 (CH3-8), 25.4 (5), 24.9, 24.2
(CH3-15), 18.3 (6).
To a solution of 7 (300 mg, 720 mmol) in THF (3 mL) at -78 °C was
added dropwise a 1.7 M of t-BuLi in hexanes (930 mL, 1.6 mmol,
2.2 equiv) over 5 min. The resulting red solution was stirred at
-78 °C for 30 min, during which time it turned dark red. Tempera-
ture was then quickly raised to 0 °C for 1 min causing intense bub-
bling and decoloration to light yellow, then set back down to -78 °C.
A solution of 2,2-dimethylpent-4-enal (8; 150 mL, 980 mmol,
1.5 equiv) in THF (1 mL) was then added via cannula to the vinyl
anion solution prepared above, and the resulting mixture was stirred
at -78 °C for 30 min. The reaction mixture was then quenched at
-78 °C by sat. aq NH4Cl solution (5 mL) and allowed to warm to r.t.
The layers were separated, the aqueous layer was extracted with
Et2O, and the combined organic layers were washed with H2O and
brine, dried (MgSO4) and concentrated in vacuo. The resulting
crude product was purified by flash chromatography on silica gel
(Et2O/petroleum ether, 10:90) to give 130 mg (77%) of a 1:1 mix-
ture of the two diastereomers of 11 as a colorless oil.
1H NMR (CDCl3, 400 MHz): d = 6.08 (t, 0.5 H, J = 4.0 Hz, 0.5
H-2’), 6.03 (t, 0.5 H, J = 4.0 Hz, 0.5 H-2’), 5.89 (dd, 0.5 H, J = 17.4,
10.7 Hz, 0.5 H-7’), 5.93-5.82 (m, 1 H, H-4), 5.76 (dd, 0.5 H,
J = 17.45, 10.7 Hz, 0.5 H-6’), 5.10-5.00 (m, 4 H, H2-5 + H2-8’),
3.72 (s, 0.5 H, 0.5 H-1), 3.71 (s, 0.5 H, 0.5 H-1), 2.22-1.98 (m, 4 H,
H2-3 + H2-3’), 1.64-1.45 (m, 4 H, H2-4’ + H2-5’), 1.24, 1.12, 0.98,
0.96, 0.88, 0.85 (6 s, 9 H, 2 CH3-2 + CH3-6’).
IR (film): n = 3478, 3075, 2930, 1636, 1466, 1365, 1049, 997, 911
cm-1.
MS (CI, NH3): m/z = 248, 231, 175, 149.
[1R*,2R*(6R*/S*)]-2-Butyl-3,3-dimethyl-1-(6-methyl-6-vinyl-
cyclohex-1-en-1-yl)hex-5-ene-1,2-diol (14)
To a solution of 7 (1.1 g, 2.6 mmol) in THF (10 mL) at -78 °C was
added dropwise over 10 min a 1.7 M solution of t-BuLi in hexanes
(3.4 mL, 5.8 mmol, 2.2 equiv). The resulting red solution was
stirred at -78 °C for 30 min, during which time it turned dark red.
Temperature was then quickly raised to 0 °C for 1 min causing in-
tense bubbling and decoloration to light yellow, then set back down
to -78 °C. A solution of aldehyde 10 (780 mg, 2.9 mmol, 1.1 equiv)
in THF (4 mL) was then added via cannula to the vinyl anion solu-
tion prepared above, and the resulting mixture was stirred at -78 °C
for 30 min. The reaction mixture was then quenched at -78 °C by
sat. aq NaHCO3 solution (5 mL) and allowed to warm to r.t. The lay-
ers were separated, the aqueous layer was extracted with Et2O, and
the combined organic layers were washed with H2O and brine, dried
(MgSO4) and concentrated in vacuo. The resulting crude product
was diluted with CH2Cl2 (20 mL) and treated with trifluoroacetic
acid (20 drops). The solution turned yellow and was stirred at r.t. for
5 min, after which time it was concentrated in vacuo. The resulting
crude product was purified by flash chromatography on silica gel
(Et2O/petroleum Ether, 10:90) to give 680 mg (81%) of a 1:1 mix-
ture of the two diastereomers of 14 as a colorless oil.
13C NMR (CDCl3, 100.6 MHz): d = 147.1, 146.9 (7’), 145.8, 144.9
(1’), 135.9, 135.7 (4), 128.9, 128.5 (2’), 117.0, 116.8 (5), 112.6,
111.9 (8’), 75.3, 75.2 (1), 44.9 (3), 41.2 (6’), 39.1, 38.9 (2), 38.1,
37.7 (5’), 24.0, 23.9 (3’), 23.9, 23.2, 23.2, 22.5 (CH3-6’, CH3-2),
18.3, 18.2 (4’).
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.33 (t, 0.5 H,
J = 3.8 Hz, 0.5 H-4), 6.29 (t, 0.5 H, J = 3.6 Hz, 0.5 H-4), 5.92-5.84
(m, 1.5 H, H-10 + 0.5 H-9), 5.80 (dd, 0.5 H, J = 17.6, 10.5 Hz,
0.5 H-9), 5.14-5.00 (m, 4 H, H2-9’ + H2-10’), 4.09 (d, 0.5 H,
J = 10.5 Hz, 0.5 H-2), 4.08 (d, 0.5 H, J = 10.0 Hz, 0.5 H-2), 3.07 (s,
0.5 H, 0.5 OH), 2.98 (s, 0.5 H, 0.5 OH), 2.18-2.14 (m, 2 H),
2.09-2.05 (m, 2 H), 1.70-1.49 (m, 6 H), 1.43-1.25 (m, 4 H), 1.27,
1.16 (2 s, 3 H, CH3-8), 0.92, 0.91, 0.90, 0.89 (4 s, 6 H, 2 CH3-15),
0.87-0.85 (m, 3 H, CH2CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 146.6, 146.3
(9), 145.6 (3), 136.9, 136.7 (10), 128.1, 127.3 (4), 116.6, 116.5
(10’), 112.8 (9’), 78.7, 78.4 (1), 70.5, 70.4 (2), 43.8, 43.7, 41.3, 41.0
(8, 15), 42.2, 42.1, 37.8, 37.3 (7, 11), 33.4, 33.1 (CH2), 27.1, 27.0,
25.6, 25.4, 23.7 (3C, CH2), 24.4, 24.1, 22.9, 22.6, 22.5 (4C, CH3),
18.3, 18.2 (6), 14.1 (CH2CH3).
IR (film): n = 3481, 3075, 2965, 2931, 2872, 2825, 1701, 1635,
1469, 966, 911 cm-1.
+
MS (CI, NH3): m/z = 252 (MNH4 ), 234 (M+), 217 (MH+ - H2O),
175, 151, 109.
Anal. calcd for C16H26O (234.4): C, 82.00; H, 11.18. Found C,
81.91; H, 11.13.
[1R*(6R*/S*)]-3,3-Dimethyl-1-(6-methyl-6-vinylcyclohex-1-en-
1-yl)hex-5-en-1-ol (13)
To a solution of 7 (1.8 g, 4.3 mmol) in THF (15 mL) at -78 °C was
added dropwise over 12 min a 1.7 M solution of t-BuLi in hexanes
(5.6 mL, 9.5 mmol, 2.2 equiv). The resulting red solution was
stirred at -78 °C for 30 min, during which time it turned dark red.
Temperature was then quickly raised to 0 °C for 1 min causing in-
tense bubbling and decoloration to light yellow, then set back down
to -78 °C. A solution of 3,3-dimethylhex-5-enal (12; 600 mg,
4.75 mmol, 1.1 equiv) in THF (5 mL) was then added via cannula
to the vinyl anion solution prepared above, and the resulting mixture
was stirred at -78 °C for 30 min. The reaction mixture was then
quenched at -78 °C by sat. aq NH4Cl solution (5 mL) and allowed
to warm to r.t. The layers were separated, the aqueous layer was ex-
tracted with Et2O, and the combined organic layers were washed
with H2O and brine, dried (MgSO4) and concentrated in vacuo. The
resulting crude product was purified by flash chromatography on
silica gel (Et2O/petroleum ether, 10:90) yielding 770 mg (72%) of a
1:1 mixture of the two diastereomers of 13 as a colorless oil.
IR (film): n = 3510, 3075, 2961, 1636, 1456, 1375, 1004, 911, 726
cm-1.
+
MS (CI, NH3): m/z 338 (MNH4 ), 321 (MH+), 303, 285, 221, 203.
[1R*(6R*/S*)]-[2,2-Dimethyl-1-(6-methyl-6-vinylcyclohex-1-
en-1-yl)pent-4-en-1-oxy]triethylsilane (15)
To a solution of alcohol 11 (100 mg, 430 mmol) in CH2Cl2 (2 mL)
was added imidazole (87 mg, 1.28 mmol, 3 equiv), chlorotriethylsi-
lane (110 mL, 640 mmol, 1.5 eq) and a catalytic pinch of 4-dimethyl-
aminopyridine. After stirring at 25 °C for 3 h, additional imidazole
(29 mg, 430 mmol, 1.0 equiv) and chlorotriethylsilane (37 mL,
210 mmol, 0.5 equiv) were added, and the reaction mixture was
stirred 6 h at 25 °C, and then MeOH (1 mL) was added. After
10 min, the mixture was quenched with sat. aq NH4Cl solution (5
mL) and diluted with 50 ml of Et2O. The layers were separated, and
the organic layer was washed with H2O (2 × 5 mL) and brine
(5 mL), dried (MgSO4) and concentrated in vacuo. The resulting
crude product was purified by flash chromatography on silica gel
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 5.93 (t, 0.5 H,
J = 3.8 Hz, 0.5 H-4), 5.89 (t, 0.5 H, J = 3.8 Hz, 0.5 H-4), 5.90-5.80
(m, 1.5 H, H-10 + 0.5 H-9), 5.71 (dd, 0.5 H, J = 17.6, 10.6 Hz, 0.5
H-9), 5.10-4.94 (m, 4 H, H2-10’ + H2-9’), 4.20-4.14 (m, 1 H, H-2),
2.11-1.96 (m, 4 H), 1.58-1.25 (m, 6 H), 1.26, 1.11 (2 s, 3 H, CH3-8),
0.97, 0.94, 0.90 (3 s, 6 H, 2 CH3-15).
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

876
D. Bourgeois et al.
SPECIAL TOPIC
(Et2O/petroleum ether, 1:99) to give 146 mg (96%) of a 1:1 mixture
of the two diastereomers of 15 as a colorless oil.
s, 0.5 H, 0.5 OH), 3.70 (br s, 0.5 H, 0.5 OH), 2.17-2.02 (m, 4 H),
1.70-1.18 (m, 10 H), 1.29, 1.16 (2 s, 3 H, CH3-8), 0.97-0.85 (m, 9
H, 3 CH3CH2Si), 0.83 (s, 6 H, 2 CH3-15), 0.68-0.60 (m, 9 H, 3
CH2Si + CH2CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 147.2, 146.8
(9), 142.2, 141.6 (3), 136.7, 136.6 (10), 129.3, 128.4 (4), 116.5,
116.4 (10’), 112.6, 112.2 (9’), 78.7, 78.2 (1), 71.3, 71.1 (2), 43.7,
43.5 (15), 41.6, 41.3 (11), 40.7, 40.1 (8), 38.5, 37.6 (7), 33.0, 32.5
(CH2), 30.2, 25.0, 24.2, 22.5, 22.4, 22.1, 22.0 (CH3), 27.4, 27.3,
25.5, 25.0, 23.8 (CH2), 18.4, 18.1 (6), 14.3 (CH2CH3), 7.1
(CH3CH2Si), 5.8, 5.8 (CH2Si).
1H NMR (CDCl3, 400 MHz): d = 6.02-5.76 (m, 3 H, H-4 + H-2’ +
H-7’), 5.08-4.93 (m, 4 H, H2-5 + H2-8’), 3.86 (s, 0.5 H, 0.5 H-1),
3.80 (s, 0.5 H, 0.5 H-1), 2.19-1.97 (m, 4 H), 1.73-1.43 (m, 4 H),
1.25, 1.14 (2 s, 3 H, CH3-6’), 0.96-0.92 (m, 9 H, 3 CH3CH2Si), 0.85,
0.82, 0.80, 0.77 (4 s, 6 H, 2 CH3-2), 0.60-0.50 (m, 6 H, 3 CH2Si).
13C NMR (CDCl3, 100.6 MHz): d = 148.4, 147.8 (7’), 143.3, 143.1
(1’), 136.4, 136.3 (4), 128.5, 127.6 (2’), 116.5, 116.3 (5), 111.8,
110.8 (8’), 76.1 (1), 43.9, 43.8 (3), 40.4, 40.1, 39.8, 39.3 (2, 6’), 39.0
(5’), 25.7, 25.1 (3’), 25.0, 24.7, 24.3, 24.1, 23.2 (CH3), 18.4, 18.1
(4’), 7.1, 6.8 (CH3CH2Si), 6.3, 5.6 (CH2Si).
IR (film): n = 3498, 3074, 2956, 2875, 1634, 1455, 1372, 1239,
1059, 1005, 911, 740 cm-1.
IR (film): n = 3076, 2955, 2876, 1637, 1458, 1237, 1069, 1007, 910,
839, 739 cm-1.
MS (CI, NH3): m/z = 435 (MH+), 417, 392, 321, 303, 285, 221, 203.
MS (CI, NH3): m/z = 265, 234 (MNH4 - TESOH), 217 (MH+ -
Anal. calcd for C27H50O2Si (434.8): C, 74.59; H, 11.59. Found C,
74.59; H, 11.71.
+
TESOH), 175.
[1R*(6R*/S*)]-[3,3-Dimethyl-1-(6-methyl-6-vinylcyclohex-1-
en-1-yl)hex-5-en-1-oxy]triethylsilane (18)
[1R*,2R*(6R*/S*)]-[2-Butyl-3,3-dimethyl-1-(6-methyl-6-vinyl-
cyclohex-1-en-1-yl)hex-5-en-1,2-dioxy]di-tert-butylsilylene (21)
To a solution of 14 (45 mg, 125 mmol) in THF (1 mL) was added at
0 °C a 1.5 M BuLi solution in hexanes (95 mL, 125 mmol, 1.0 equiv)
and the solution was stirred for 15 min. Then di-tert-butylchlorosi-
lane (31 mL, 150 mmol, 1.1 equiv) was added, and the reaction mix-
ture was stirred at r.t. for 5 h. It was then diluted with Et2O (50 mL)
and treated with sat. aq NH4Cl solution (5 mL). The layers were
separated, and the organic layer was washed successively with H2O
(5 mL) and brine (5 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash chromatography on silica gel (Et2O/petroleum
ether, 3:97) yielded 51 mg (84%) of a 1:1 mixture of the two dias-
tereomers of 21 as a colorless oil.
To a solution of 13 (770 mg, 3.1 mmol) in anhyd CH2Cl2 (10 mL)
was added imidazole (880 mg, 12.9 mmol, 4.1 equiv) and chlorotri-
ethylsilane (1.0 mL, 6.0 mmol, 1.9 equiv). The resulting mixture
was stirred at r.t. for 4 h, and quenched with MeOH (1 mL). The or-
ganic layer was diluted with Et2O (50 mL) and treated with sat.
NH4Cl solution (5 mL). The layers were separated, and the organic
layer was washed successively with H2O (5 mL) and brine (5 mL),
dried (MgSO4) and concentrated in vacuo. Purification by flash
chromatography on silica gel (Et2O/petroleum ether, 2:98) yielded
1.1 g (98%) of a 1:1 mixture of the two diastereomers of 18 as a col-
orless oil.
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 5.98 (dd, 1 H,
J = 17.6, 10.6 Hz, H-9), 5.86-5.78 (m, 2 H, H-4 + H-10), 5.79 (dd,
1 H, J = 17.6, 10.6 Hz, H-9), 5.08-4.94 (m, 4 H, H2-9’ + H2-10’),
4.23 (br d, 1 H, J = 9.4 Hz, H-2), 2.05-1.88 (m, 4 H), 1.65-1.20 (m,
6 H), 1.24 (s, 1.5 H, 0.5 CH3-8), 1.11 (s, 1.5 H, 0.5 CH3-8),
0.97-0.90 (m, 12 H, 3 CH3CH2Si + CH3-15), 0.84 (s, 3 H, CH3-15),
0.62-0.56 (m, 6 H, 3 CH2-Si).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 147.3, 146.8
(9), 146.5 (3), 136.4, 136.2 (10), 123.6, 123.0 (4), 116.3, 116.2
(10’), 111.6, 111.5 (9’), 68.7, 68.6 (2), 52.6, 51.5, 47.6, 47.5 (1, 11),
39.8, 39.6 (8), 38.6, 38.2 (7), 33.6, 33.6 (15), 27.5, 27.3 (CH3), 25.3,
25.1 (CH2), 25.1, 23.8 (CH3), 18.6, 18.4 (6), 7.1 (CH3CH2Si), 5.4,
5.1 (CH2Si).
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.19 (t, 0.5 H,
J = 3.9 Hz, 0.5 H-4), 6.16 (t, 0.5 H, J = 3.8 Hz, 0.5 H-4), 6.05 (dd,
0.5 H, J = 17.6, 10.5 Hz, 0.5 H-9), 6.02 (dd, 0.5 H, J = 17.6,
10.6 Hz, 0.5 H-9), 5.89-5.80 (m, 1 H, H-10), 5.08-4.97 (m, 4 H,
H2-9’ + H2-10’), 4.54 (s, 0.5 H, 0.5 H-2), 4.51 (s, 0.5 H, 0.5 H-2),
2.37-2.12 (m, 3 H), 1.96-1.71 (m, 2 H), 1.66-1.49 (m, 6 H),
1.46-1.10 (m, 3 H), 1.33, 1.30 (2 s, 3 H, CH3-8), 1.06, 1.01, 0.99,
0.97 (4 s, 6 H, 2 CH3-15), 1.10, 1.10, 1.08 [3 s, 18 H, 2 (CH3)3CSi],
0.92 (t, 3 H, J = 6.8 Hz, CH2CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 148.2, 148.0
(9), 142.2, 142.1 (3), 136.5, 136.3 (10), 130.0, 128.9 (4), 116.7,
116.6 (10’), 111.9, 111.3 (9’), 88.7, 88.3 (1), 78.9, 77.7 (2), 43.1,
43.0 (11), 41.9, 41.7, 41.5 (8, 15), 39.7, 39.5 (7), 35.4 (CH2), 28.9,
28.3 ((CH3)3CSi), 28.7, 28.7, 26.4, 26.2, 23.9 (CH2), 25.2, 25.1,
24.7 (CH3), 22.0, 21.9, 20.5 (C-Si), 18.1, 18.0 (6), 14.4 (CH2CH3).
IR (film): n = 3065, 2951, 2922, 2876, 1633, 1457, 1411, 1110,
1082, 987, 868, 734 cm-1.
IR (film): n = 3076, 2934, 2860, 1824, 1635, 1478, 1387, 1364,
MS (CI, NH3): m/z = 333, 321, 291, 265, 231, 149.
1110, 969, 911, 862, 735, 640 cm-1.
MS (CI, NH3): m/z = 461, 418, 403, 379, 309, 285, 203.
[1R*,2R*(6R*/S*)]-[2-Butyl-3,3-dimethyl-1-(6-methyl-6-vinyl-
cyclohex-1-en-1-yl)hex-5-en-2-ol-1-oxy]triethylsilane (20)
To a solution of 14 (135 mg, 0.42 mmol) in anhyd CH2Cl2 (3 mL)
at -78 °C was added 2,6-lutidine (75 mL, 0.63 mmol, 1.5 equiv) and
triethylsilyl trifluoromethanesulfonate (115 mL, 0.50 mmol,
1.2 equiv). The resulting mixture was stirred at -78 °C for 2 h,
quenched with MeOH (1 mL) and allowed to warm up to r.t. The or-
ganic layer was diluted with Et2O (50 mL) and treated with sat. aq
NH4Cl solution (5 mL). The layers were separated, and the organic
layer was washed successively with H2O (5 mL) and brine (5 mL),
dried (MgSO4) and concentrated in vacuo. Purification by flash
chromatography on silica gel (Et2O/petroleum ether, 2:98) yielded
160 mg (88%) of a 1:1 mixture of the two diastereomers of 20 as a
colorless oil.
[1R*,2R*(6R*/S*)]-2-Butyl-3,3-dimethyl-1,2-O-isopropylidene-
1-(6-methyl-6-vinylcyclohex-1-en-1-yl)hex-5-ene (22)
To a solution of 14 (200 mg, 0.58 mmol) in 2,2-dimethoxypropane
(2 mL) was added a pinch of CSA, and the resulting mixture was
stirred at 25 °C for 48 h. It was then diluted with Et2O (50 mL) and
treated with sat. aq NaHCO3 solution (5 mL). The layers were sep-
arated, and the organic layer was washed successively with H2O
(5 mL) and brine (5 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash chromatography on silica gel (Et2O/petroleum
ether, 1:99) yielded 207 mg (92%) of a 1:1 mixture of the two dias-
tereomers of 22 as a colorless oil.
1H NMR (CDCl3, 200 MHz, taxol numbering): d = 6.20 (q, 1 H,
J = 4.1 Hz, H-4), 5.97 (dd, 1 H, J = 17.3, 10.6 Hz, H-9), 5.86-5.76
(m, 1 H, H-10), 5.14-4.94 (m, 4 H, H2-9’ + H2-10’), 4.35 (s, 0.5 H,
0.5 H-2), 4.33 (s, 0.5 H, 0.5 H-2), 2.23-2.12 (m, 4 H), 1.91-1.78 (m,
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.04-5.93 (m, 2
H, H-4 + H-9), 5.87-5.79 (m, 1 H, H-10), 5.14-4.96 (m, 4 H, H2-9’
+ H2-10’), 4.34 (s, 0.5 H, 0.5 H-2), 4.26 (s, 0.5 H, 0.5 H-2), 3.98 (br
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of BC Ring-Systems of Taxol by Ring-Closing Metathesis
877
2 H), 1.72-1.54 (m, 4 H), 1.50-1.25 (m, 4 H), 1.45, 1.44, 1.34, 1.29,
1.27, 1.25, 0.96, 0.96 [8 s, 15 H, CH3-8 + 2 CH3-15 + (CH3)2C],
0.93-0.88 (m, 3 H, CH2CH3).
to r.t., concentrated in vacuo and purified by flash chromatography
on silica gel.
13C NMR (CDCl3, 50.3 MHz, taxol numbering): d = 147.7, 147.5
(9), 138.2 (3), 136.2, 136.1 (10), 129.8, 129.6 (4), 116.7, 116.6
(10’), 112.2, 111.0 (9’), 104.4, 104.3 [OC(CH3)2O], 89.4, 89.3 (1),
77.4, 77.2 (2), 43.0, 43.0 (11), 42.0, 41.9 (15), 40.3, 40.1 (8), 39.0,
28.7 (7), 33.5, 33.4, 28.3, 26.2, 26.1, 23.9 (CH2), 29.4, 28.1, 26.5,
26.3, 24.2, 24.0, 23.9, 23.8 (CH3), 18.1, 18.0 (6), 14.0, 13.9
(CH2CH3).
Metathesis Reactions with Nolan’s Catalyst
To a refluxing solution of the diene in dry degassed benzene or 1,2-
dichloroethane (0.02 M solution) was added 5 mol% of Nolan’s cat-
alyst, and the resulting mixture was refluxed under argon for 12 h.
The reaction mixture was cooled to r.t., concentrated in vacuo and
purified by flash chromatography on silica gel.
(5R*,9aS*,8Z)-6,6,9a-Trimethyl-1,2,3,5,6,7,9a-octahydro-1H-
benzocyclohepten-5-ol (b-16) and (5R*,9aR*,8Z)-6,6,9a-Trime-
thyl-1,2,3,5,6,7,9a-octaahydro-1H-benzocyclohepten-5-ol (a-
16)
IR (film): n = 3077, 2960, 1636, 1455, 1367, 1247, 1215, 1173,
1016, 910 cm-1.
MS (CI, NH3): m/z = 303, 285, 245, 221, 177.
A solution of 11 (35 mg, 150 mmol) and Grubbs’ catalyst (6.1 mg,
5 mol%) in anhyd benzene (5 mL) was stirred at 60 °C for 24 h un-
der argon. More catalyst (3 mg, 2.5 mol%) was added more and the
reaction mixture was further stirred at 60 °C for 24 h. The resulting
mixture was cooled to r.t. and concentrated in vacuo. Purification by
flash chromatography (Et2O/petroleum ether, 5:95) yielded 6 mg
(19%) and then 10 mg (32%) of the two separated diastereomers of
16 as colorless oils.
[1R*,2R*(6R*/S*)]-2-Butyl-1,2-carbonyldioxy-3,3-dimethyl-1-
(6-methyl-6-vinylcyclohex-1-en-1-yl)hex-5-ene (23)
To a solution of 14 (250 mg, 780 mmol) in anhyd DMF (2 mL) was
added portionwise NaH (80% in oil, 49 mg, 1.6 mmol, 2.1 equiv).
The resulting suspension was vigorously stirred at r.t. for 15 min,
and then carbonyldiimidazole (630 mg, 3.9 mmol, 5.0 equiv) was
added. The resulting mixture was stirred at r.t. for 3 h, then diluted
with Et2O (50 mL) and quenched with sat. aq NH4Cl solution
(5 mL). The layers were separated, and the organic layer was
washed successively with water (3 × 10 mL) and brine (10 mL),
dried (MgSO4) and then concentrated in vacuo. The resulting crude
product was purified by flash chromatography on silica gel (Et2O/
petroleum ether, 10:90) to yield 245 mg (91%) of a 1:1 mixture of
the two diastereomers of 23 as a pale yellow solid.
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 5.95 (t, 0.5 H,
J = 3.9 Hz, 0.5 H-4), 5.87 (t, 0.5 H, J = 3.9 Hz, 0.5 H-4), 5.81-5.67
(m, 2 H, H-9 + H-10), 5.19-5.04 (m, 4 H, H2-9’ + H2-10’), 4.88 (s,
0.5 H, 0.5 H-2), 4.83 (s, 0.5 H, 0.5 H-2), 2.37-2.05 (m, 4 H),
1.86-1.11 (m, 10 H), 1.26, 1.13 (2 s, 3 H, CH3-8), 0.93, 0.93, 0.91
(3 s, 6 H, 2 CH3-15), 0.88 (t, 3 H, J = 6.5 Hz, CH2CH3).
First Isomer
1H NMR (CDCl3, 400 MHz): d = 5.54 (ddd, 1 H, J = 11.4, 7.3,
5.8 Hz, H-8), 5.47-5.43 (m, 2 H, H-5 + H-9), 3.83 (d, 1 H,
J = 6.3 Hz, H-5), 2.13-2.04 (m, 2 H), 1.93 (dd, 1 H, J = 14.8,
7.3 Hz, H-7), 1.84 (d, 1 H, J = 6.8 Hz), 1.73-1.57 (m, 4 H),
1.48-1.43 (m, 1 H), 1.32 (s, 3 H, CH3-9a), 1.06, 0.84 (2 s, 6 H, 2
CH3-6).
13C NMR (CDCl3, 100.6 MHz): d = 141.9 (4a), 140.9 (9), 125.6,
125.2 (4, 8), 87.8 (5), 39.0 (6), 38.7, 35.5 (1, 7), 29.8, 27.7, 26.9
(CH3), 29.6 (9a), 24.9, 18.1 (2, 3).
IR (film): n = 3474, 2925, 1457, 1364, 1042, 994, 794 cm-1.
MS (CI, NH3): m/z = 206 (MH+), 189, 173, 147.
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 155.6 (C=O),
145.5, 145.0 (9), 138.7, 137.4 (3), 133.8, 133.6 (10), 131.6, 131.2
(4), 118.6, 118.4 (10’), 114.7, 114.3 (9’), 92.0, 91.9 (1), 80.1, 79.3
(2), 43.7, 43.6, 41.1, 40.5 (8, 15), 40.0, 39.8, 37.8, 37.1 (7, 11), 30.7,
30.3, 27.2, 27.0, 25.5, 25.2, 23.1 (4C, CH2), 24.6, 23.3, 20.9, 20.8,
20.6 (3C, CH3), 17.9, 17.8 (6), 13.8 (CH2CH3).
Anal. calcd for C14H22O: C, 81.50; H, 10.75. Found C, 81.31; H,
10.77.
Second Isomer
1H NMR (CDCl3, 400 MHz): d = 5.67 (t, 1 H, J = 3.6 Hz, H-4), 5.42
(ddd, 1 H, J = 10.6, 7.9, 6.3 Hz, H-8), 5.28 (dd, 1 H, J = 10.6,
1.8 Hz, H-9), 4.10 (s, 1 H, H-5), 2.14-2.07 (m, 3 H), 1.75-1.50 (m,
5 H), 1.32-1.29 (m, 1 H), 1.17, 1.08, 0.84 (3 s, 9 H, 3 CH3).
IR (film): n = 3078, 2960, 2872, 1799, 1637, 1466, 1323, 1197,
1044, 916, 770 cm-1.
+
MS (CI, NH3): m/z = 364 (MNH4 ), 347 (MH+), 303, 285, 219, 203.
13C NMR (CDCl3, 100.6 MHz): d = 145.5 (4a), 140.1 (9), 122.3,
118.4, (4, 8), 76.3 (5), 39.9 (6), 38.0, 35.8 (1, 7), 29.6 (9a), 27.7,
26.8, 20.7 (CH3), 24.5 (3), 18.3 (4).
Anal. calcd for C22H34O3: C, 76.26; H, 9.89. Found C, 76.42; H,
9.91.
IR (film): n = 3454, 2926, 1455, 1362, 1037, 737, 662 cm-1.
MS (CI, NH3): m/z = 207 (MH+), 206, 189, 173, 147, 121.
Metathesis Reactions with Grubbs’ Catalyst; General Proce-
dure
To a refluxing solution of the diene in dry degassed benzene or 1,2-
dichloroethane (0.02M) was added 2 mol% of Grubbs’ catalyst, and
the resulting mixture was refluxed under argon for 8 d, during which
time 1 mol% of catalyst was added every 24 h to the refluxing mix-
ture. The reaction mixture was cooled to r.t., concentrated in vacuo
and purified by flash chromatography on silica gel.
Anal. calcd for C14H22O: C, 81.50; H, 10.75. Found C, 81.91; H,
10.91.
(5R*,9aR*/S*,8Z)-[6,6,9a-Trimethyl-1,2,3,5,6,7,9a-octahydro-
1H-benzocyclohepten-5-oxy]triethylsilane (17)
A solution of 15 (100 mg, 285 mmol) in anhyd benzene (10 mL)
with Grubbs’ catalyst (11.7 mg, 5 mol%) was stirred at 60 °C for 24
h under argon. More catalyst (5.8 mg, 2.5 mol%) was added and the
reaction mixture was further stirred at 60 °C for 24 h. The resulting
mixture was cooled to r.t. and concentrated in vacuo. Purification by
flash chromatography (petroleum ether) yielded 85 mg (93%) the
two diastereomers of 17 as a colorless oil.
1H NMR (CDCl3, 400 MHz): d = 5.65 (t, 0.5 H, J = 3.8 Hz, 0.5
H-4), 5.45-5.34 (m, 2 H, 0.5 H-4 + H-8 + 0.5 H-9), 5.26 (dd, 0.5 H,
J = 10.7, 1.9 Hz, 0.5 H-9), 4.01 (d, 0.5 H, J = 1.1 Hz, 0.5 H-5), 3.80
Metathesis Reactions with Schrock’s Catalyst; General Proce-
dure
To a refluxing solution of the diene (dried azeotropically with 3 mL
of anhyd benzene) in anhyd degassed benzene (0.02 M solution)
was added 5 mol% of Schrock’s catalyst (weighed as quickly as
possible under argon), and the resulting mixture was refluxed under
argon for 3 d, during which time 5 mol% of catalyst was added ev-
ery 24 h to the refluxing mixture. The reaction mixture was cooled
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

878
D. Bourgeois et al.
SPECIAL TOPIC
(s, 0.5 H, 0.5 H-5), 2.66 (dt, 0.5 H, J = 15.5, 2.6 Hz, 0.5 H-7),
2.11-1.96 (m, 2.5 H), 1.74-1.47 (m, 5 H), 1.29 (s, 1.5 H, 0.5 CH3),
1.16 (s, 1.5 H, 0.5 CH3), 0.99-0.93 (m, 9 H, CH3 + 3 CH3CH2Si),
0.78, 0.75 (2 s, 3 H, CH3), 0.62-0.49 (m, 6 H, 3 CH2Si).
13C NMR (CDCl3, 100.6 MHz): d = 143.7, 140.3 (4a), 140.6, 140.1
(9), 126.7, 125.4, 122.7, 119.4 (4, 8), 90.0, 76.3 (5), 41.7, 37.6, 36.0,
34.9 (1, 7), 41.0, 39.3, 39.2, 37.0 (6, 9a), 29.7, 28.5, 28.0, 25.4, 21.4
(CH3-6 + CH3-9a), 25.9, 24.4 (3), 19.0, 18.4 (8), 7.1, 7.0
(CH3CH2Si), 6.3, 5.0 (CH2Si).
5.81 (t, 0.5 H, J = 3.8 Hz, 0.5 H-4), 5.45 (dt, 0.5 H, J = 11.8, 8.8 Hz,
0.5 H-10), 5.34 (ddd, 0.5 H, J = 11.7, 8.6, 8.0 Hz, 0.5 H-10), 5.27
(d, 0.5 H, J = 11.7 Hz, 0.5 H-9), 5.21 (dd, 0.5 H, J = 11.8, 0.5 Hz,
0.5 H-9), 4.39-4.36 (m, 0.5 H, 0.5 H-2), 4.35 (dd, 0.5 H, J = 12.3,
3.5 Hz, 0.5 H-2), 2.76 (dd, 0.5 H, J = 13.0, 8.6 Hz, 0.5 H-11), 2.66
(dd, 0.5 H, J = 13.5, 8.8 Hz, 0.5 H-11), 2.12-2.02 (m, 2 H), 1.72 (dd,
0.5 H, J = 13.5, 2.9 Hz), 1.69-1.18 (m, 7.5 H), 1.32 (s, 1.5 H, 0.5
CH3-8), 1.16 (s, 1.5 H, 0.5 CH3-8), 0.96 (s, 3 H, CH3), 0.90, 0.84 (2
s, 3 H, CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering, italicized values
correspond to the b-19 isomer): d = 150.3, 145.2 (3), 141.5, 140.2
(9), 131.2, 125.6, 124.2, 121.8 (4, 10), 78.5, 68.9 (2), 50.8, 43.3 (1),
40.6, 38.1, 35.6, 35.2 (7, 11), 39.9 (8), 33.4, 33.1 (15), 32.9, 30.0,
29.8, 28.3, 28.0, 27.3 (CH3), 27.3, 25.6 (5), 19.0, 18.8 (6).
IR (film): n = 2954, 1654, 1457, 1238, 1066, 1004, 841, 740 cm-1.
MS (CI, NH3): m/z = 320 (M+), 291, 264, 189.
(5R*,10aS*,9Z)-7,7,10a-Trimethyl-1,2,3,5,6,7,8,10a-octahydro-
1H-benzocycloocten-5-ol (b-19)
IR (film): n = 3383, 2928, 1647, 1456, 1363, 1173, 1033, 975, 719
After the usual procedure with Grubbs’ catalyst was applied to 18
(75 mg, 0.21 mmol, 11 mL of benzene, 3.4 + 6 × - 1.7 mg of cata-
lyst), the resulting crude product was dissolved in THF (1.5 mL),
and TBAF (100 mg, 0.32 mmol, 1.5 equiv) was added. The reaction
mixture was stirred for 3 h at 50 °C, cooled to r.t., diluted with Et2O
(50 mL) and treated with sat. aq NH4Cl solution (5 mL). The layers
were separated, and the organic layer was washed successively with
H2O (5 mL) and brine (5 mL), dried (MgSO4) and concentrated in
vacuo. The resulting crude mixture was purified by flash chroma-
tography on silica gel (Et2O/petroleum ether, 10:90) yielding 5 mg
(11%) of b-19 as a colorless oil.
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 5.89 (t, 1 H,
J = 3.7 Hz, H-4), 5.35 (dt, 1 H, J = 11.7, 8.7 Hz, H-10), 5.29 (d, 1
H, J = 11.7 Hz, H-9), 4.40 (br d, 1 H, J = 7.1 Hz, H-2), 2.69 (dd, 1
H, J = 13.5, 8.7 Hz, H-11), 2.12-2.04 (m, 2 H), 1.80 (dd, 1 H,
J = 13.3, 2.7 Hz), 1.76-1.56 (m, 5 H), 1.48-1.40 (m, 1 H), 1.17 (s,
3 H, CH3-8), 0.98, 0.92 (2 s, 6 H, 2 CH3-15).
cm-1.
MS (CI, NH3): m/z = 221 (MH+), 220 (M+), 203, 187.
(5R*,6R*,10aR*,9Z)-6-Butyl-7,7,10a-trimethyl1,2,3,5,6,7,8,10a-
octahydro-1H-benzocyclooctene-5,6-diol (b-24) and (5R*, 6R*,
10aR*,8Z)-6-Butyl-7,7,10a-trimethyl-1,2,3,5,6,7,10,10a-octahy-
dro-2H-benzocyclooctene-5,6-diol (25)
After the usual procedure with Grubbs’ catalyst was applied to 20
(87 mg, 0.20 mmol, 10 mL of benzene, 16.3 mg of catalyst), the re-
sulting crude product was dissolved in THF (2 mL), and TBAF
(95 mg, 0.30 mmol, 1.5 equiv) was added. The reaction mixture
was stirred for 5 h at 25 °C, diluted with Et2O (50 mL) and treated
with sat. aq NH4Cl solution (5 mL). The layers were separated, and
the organic layer was washed successively with H2O (5 mL) and
brine (5 mL), dried (MgSO4) and concentrated in vacuo. The result-
ing crude mixture was purified by flash chromatography on silica
gel (Et2O/petroleum ether, 10:90 to 20:80) yielding 3.5 mg (6%) of
b-24 and then 4 mg (7%) of 25 as a white solid.
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 150.4 (3),
140.2 (9), 125.7 (10), 121.8 (4), 69.0 (2), 50.9 (1), 39.8 (8), 38.2,
35.7 (7,11), 33.4 (15), 32.9, 28.4, 27.3 (CH3), 25.6 (5), 18.8 (6).
b-24
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.07 (t, 1 H,
J = 4.1 Hz, H-4), 5.57 (br q, 1 H, J = 11.0 Hz, H-10), 5.26 (d, 1 H,
J = 11.0 Hz, H-9), 4.43 (s, 1 H, H-2), 3.08-2.94 (m, 2 H, H-11 +
OH), 2.16-2.12 (m, 2 H), 1.99-1.87 (m, 2 H), 1.57-1.50 (m, 6 H),
1.45-1.29 (m, 3 H), 1.23 (s, 3 H, CH3-8), 1.02, 0.99 (2 s, 6 H, 2
CH3-15), 0.94 (t, 3 H, J = 7.1 Hz, CH2CH3).
IR (film): n = 3419, 2925, 1456, 1363, 1261, 1176, 1031, 972, 813,
717 cm-1.
(5R*,10aR*/S*,9Z)-7,7,10a-Trimethyl-1,2,3,5,6,7,8,10a-octahy-
dro-1H-benzocycloocten-5-ol (19)
1. After the usual procedure with Nolan’s catalyst was applied to 18
(50 mg, 0.14 mmol, 7 mL of 1,2-dichloroethane, 5.8 mg of cata-
lyst), the resulting crude product was dissolved in THF (1 mL), and
TBAF (55 mg, 0.20 mmol, 1.5 equiv) was added. The reaction mix-
ture was stirred for 3 h at 50 °C, cooled to r.t., diluted with Et2O
(50 mL) and treated with sat. aq NH4Cl solution (5 mL). The layers
were separated, and the organic layer was washed successively with
H2O (5 mL) and brine (5 mL), dried (MgSO4) and concentrated in
vacuo. The resulting crude mixture was purified by flash chroma-
tography on silica gel (Et2O/petroleum ether, 10:90) yielding 30 mg
(90%) of a 1:1 mixture of the two diastereomers of 19 as a colorless
oil.
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 145.5 (3),
140.2 (9), 126.4, 124.3 (4, 10), 80.4 (1), 73.8 (2), 44.0 (15), 41.0 (8),
38.8 (11), 34.5, 31.8, 27.0, 26.0, 23.9 (CH2), 29.0, 28.2, 23.6 (CH3),
18.4 (6), 14.2 (CH2CH3).
IR (film): n = 3481, 2929, 1654, 1636, 1457, 1379, 1262, 1001, 748
cm-1.
MS (CI, NH3): m/z = 308, 291 (MH+ - 2), 275 (MH+ - H2O), 257,
205, 189.
25
Mp 84-86 °C.
2. After the usual procedure with Schrock’s catalyst was applied to
18 (60 mg, 0.16 mmol, 8 mL of benzene, 3 × 4 mg of catalyst), the
resulting crude product was dissolved in THF (1 mL), and TBAF
(67 mg, 0.25 mmol, 1.5 equiv) was added. The reaction mixture
was stirred for 3 h at 50 °C, cooled to r.t., diluted with Et2O (50 mL)
and treated with sat. aq NH4Cl solution (5 mL). The layers were
separated, and the organic layer was washed successively with H2O
(5 mL) and brine (5 mL), dried (MgSO4) and concentrated in vacuo.
The resulting crude mixture was purified by flash chromatography
on silica gel (Et2O/petroleum ether, 10:90) yielding 31 mg (85%) of
a 1:1 mixture of the two diastereomers of 19 as a colorless oil.
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 5.96 (dd, 1 H,
J = 4.7, 2.9 Hz, H-4), 5.59 (br q, 1 H, J = 12.2 Hz, H-10), 5.35 (br
d, 1 H, J = 12.2 Hz, H-11), 4.51 (s, 1 H, H-2), 2.64-2.52 (m, 2 H,
H-1 + OH), 2.18-1.97 (m, 3 H), 1.82-1.57 (m, 5 H), 1.52-1.38 (m, 2
H), 1.34 (br s, 3 H, CH3), 1.29-1.20 (m, 3 H), 1.19, 1.15 (2 s, 6 H, 2
CH3), 0.91 (t, 3 H, J = 7.3 Hz, CH2CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 145.7 (3),
140.0 (11), 128.7, 126.4 (4, 10), 81.2 (1), 72.9 (2), 42.2 (15), 38.2
(9), 31.3 (8), 29.5, 28.0, 25.4, 23.8 (CH2), 27.6 (CH3), 18.5 (6), 14.0
(CH2CH3).
1H NMR (CDCl3, 400 MHz, taxol numbering, italicized values cor-
respond to the b-19 isomer): d = 5.88 (t, 0.5 H, J = 3.9 Hz, 0.5 H-4),
IR (film): n = 3394, 2955, 1458, 1377, 1261, 999 cm-1.
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of BC Ring-Systems of Taxol by Ring-Closing Metathesis
879
MS (CI, NH3): m/z = 310 (MH+), 293, 275.
Anal. calcd for C27H48O2Si (432.8): C, 74.94; H, 11.18. Found C,
75.16; H, 11.29.
(5R*,6R*,10aS*,9Z)-6-Butyl-7,7,10a-trimethyl-1,2,3,5,6,7,8,10a
-octahydro-1H-benzocyclooctene-5,6-diol (a-24)
b-26
Mp 129-131 °C.
After the usual procedure with Nolan’s catalyst was applied to 20
(100 mg, 0.23 mmol, 12 mL of 1,2-dichloroethane, 9.8 mg of cata-
lyst), the resulting crude product was dissolved in THF (2 mL), and
TBAF (110 mg, 0.35 mmol, 1.5 equiv) was added. The reacting
mixture was stirred for 15 h at 25 °C, cooled to r.t., diluted with
Et2O (50 mL) and treated with sat. aq NH4Cl solution (5 mL). The
layers were separated, and the organic layer was washed succes-
sively with H2O (5 mL) and brine (5 mL), dried (MgSO4) and con-
centrated in vacuo. The resulting crude mixture was purified by
flash chromatography on silica gel (Et2O/petroleum ether, 10:90)
yielding 19 mg (27%) of a-24 as a white solid; mp 63-65 °C.
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 5.74 (d, 1 H,
J = 10.6 Hz, H-9), 5.61-5.53 (m, 2 H, H-4 + H-10), 4.44 (d, 1 H,
J = 12.3 Hz, H-2), 2.48 (dd, 1 H, J = 14.1, 10.5 Hz, H-11), 2.45 (d,
1 H, J = 12.3 Hz, OH), 2.19-2.15 (m, 2 H), 1.91-1.81 (m, 2 H),
1.71-1.52 (m, 5 H), 1.49-1.31 (m, 4 H), 1.34 (s, 3 H, CH3-8), 1.04,
0.97 (2 s, 6 H, 2 CH3-15), 0.92 (t, 3 H, J = 7.1 Hz, CH2CH3).
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.06 (dd, 1 H,
J = 4.7, 2.9 Hz, H-4), 5.33 (ddd, 1 H, J = 11.8, 9.4, 8.7 Hz, H-10),
5.23 (d, 1 H, J = 11.8 Hz, H-9), 4.57 (s, 1 H, H-2), 2.51 (dd, 1 H,
J = 14.1, 9.4 Hz, H-11), 2.21 (dt, 1 H, J = 8.8, 5.3 Hz), 2.11-1.95
(m, 2 H), 1.83-1.76 (m, 1 H), 1.66-1.51 (m, 6 H), 1.42 (dd, 1 H,
J = 14.1, 8.7 Hz, H-11), 1.26-1.21 (m, 2 H), 1.22 (s, 3 H, CH3), 1.14
[s, 12 H, (CH3)3CSi, CH3], 1.11 (s, 3 H, CH3), 1.08 [s, 9 H,
(CH3)3CSi], 0.89 (t, 3 H, J = 7.3 Hz, CH2CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 142.0 (3),
139.5 (9), 125.3, 124.1 (4, 10), 86.9 (1), 76.4 (2), 40.2, 39.5 (8, 15),
36.7, 35.7, 33.4, 29.6 (CH2), 29.7 (CH3), 28.9, 28.5 [(CH3)3CSi],
24.9, 24.1 (CH2), 24.5 (CH3), 22.1, 20.7 (CSi), 18.2 (6), 14.1
(CH2CH3).
IR (film): n = 2936, 1645, 1458, 1363, 973 cm-1.
MS (CI, NH3): m/z = 434 (MH+), 417, 375, 257.
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 144.5 (3),
140.6 (9), 128.6, 123.3 (4, 10), 80.5 (2), 76.4 (1), 42.7 (15), 37.8
(11), 37.5 (8), 33.9, 32.4 (CH2), 31.9, 29.3, 24.0 (CH3), 25.8, 23.9,
23.4 (CH2), 17.6 (6), 14.2 (CH2CH3).
Anal. calcd for C27H48O2Si: C, 74.94; H, 11.18. Found C, 74.51; H,
11.09.
(5R*,6R*,10aR*,9Z)-6-Butyl-5,6-O-isopropylidene-7,7,10a-tri-
methyl-1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene (b-27)
and (5R*,6R*,10aS*,9Z)-6-Butyl-5,6-O-isopropylidene-7,7,10a-
trimethyl-1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene (a-
27)
1. The usual procedure with Nolan’s catalyst, applied to 22 (63 mg,
175 mmol, 7 mL of 1,2-dichloroethane, 7.4 mg of catalyst), yielded
25 mg (43%) of a-27 and 25 mg (43%) of b-27 as colorless oils after
flash chromatography on silica gel (Et2O/petroleum ether, 1:99 to
2:98).
IR (film): n = 3544, 2931, 2869, 1731, 1651, 1455, 1370, 1242,
1193, 1114, 1055, 999, 875, 758 cm-1.
MS (CI, NH3): m/z = 308, 291 (MH+-2), 275 (MH+ - H2O), 257,
205, 189.
(5R*,6R*,10aR*,9Z)-[6-Butyl-7,7,10a-trimethyl-1,2,3,5,6,7,8,
10a-octahydro-1H-benzocyclooctene-5,6-dioxy]di-tert-butylsi-
lylene (b-26) and (5R*,6R*,10aS*,9Z)-6-[Butyl-7,7,10a-trimeth-
yl-1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene-5,6-
dioxy]di-tert-butylsilylene (a-26)
1. The usual procedure with Schrock’s catalyst, applied to 21
(53 mg, 0.11 mmol, 6 mL of benzene, 3 × 4 mg of catalyst), yielded
25 mg (50%) of a-26 as a white solid and 23 mg (46%) of b-26 as a
white solid after flash chromatography on silica gel (Et2O/petro-
leum ether, 2:98).
2. The usual procedure with Schrock’s catalyst, applied to 22
(46 mg, 130 mmol, 7 mL of benzene, 3 × 5 mg of catalyst), yielded
19 mg (45%) of a-27 and 20 mg (48%) of b-27 after flash chroma-
tography on silica gel (Et2O/petroleum ether 1:99 to 2:98).
a-27
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.01-5.99 (dd, 1
H, J = 5.0, 0.7 Hz, H-4), 5.71 (ddd, 1 H, J = 11.6, 9.5, 8.9 Hz,
H-10), 5.44 (d, 1 H, J = 11.6 Hz, H-9), 4.97 (q, 1 H, J = 1.7 Hz,
H-2), 2.76 (br dd, 1 H, J = 14.0, 9.5 Hz, H-11), 2.28-2.22 (m, 2 H),
1.98-1.86 (m, 1 H), 1.67-1.50 (m, 8 H), 1.46, 1.40, 1.35 [3 s, 9 H,
CH3-8, (CH3)2C], 1.31-1.23 (m, 2 H), 1.16, 1.03 (2 s, 6 H, 2
CH3-15), 0.90 (t, 3 H, J = 7.3 Hz, CH2CH3).
2. The usual procedure with Nolan’s catalyst, applied to 21 (62 mg,
0.14 mmol, 8.5 mL of 1,2-dichloroethane, 7.2 mg of catalyst),
yielded 58 mg (91%) of a 1:1 mixture of the two diastereomers a-
26and b-26 after flash chromatography on silica gel (Et2O/petro-
leum ether, 2:98).
a-26
Mp 82-84 °C
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 141.2 (3),
140.2 (9), 129.5 (10), 124.9 (4), 105.2 [OC(CH3)2O], 87.8 (1), 79.7
(2), 40.9 (15), 40.5 (11), 36.8 (7), 32.3 (CH2), 29.9 (8), 29.2, 28.1,
27.1, 24.4, 23.6 (CH3), 27.8, 23.9, 22.0 (CH2), 16.0 (6), 14.2
(CH2CH3).
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.06 (ddd, 1 H,
J = 5.9, 3.0, 2.5 Hz, H-4), 5.67 (dt, 1 H, J = 11.8, 8.8 Hz, H-10),
5.43 (d, 1 H, J = 11.8 Hz, H-9), 5.00 (d, 1 H, J = 1.5 Hz, H-2), 2.76
(dd, 1 H, J = 14.1, 8.8 Hz, H-11), 2.34-2.18 (m, 2 H), 1.97-1.83 (m,
1 H), 1.67-1.47 (m, 6 H), 1.40 (s, 3 H, CH3-8), 1.45-1.41 (m, 2 H),
1.20-1.15 (m, 2 H), 1.21 (s, 3 H, CH3-15), 1.11 (s, 3 H, CH3-15),
1.10 [s, 18 H, 2 (CH3)3CSi], 0.87 (t, 3 H, J = 7.0 Hz, CH2CH3).
IR (film): n = 2958, 1653, 1456, 1367, 1246, 1215, 1180, 1012, 912,
739 cm-1.
MS (CI, NH3): m/z = 332, 317, 292, 275, 257, 201.
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 145.1 (3),
140.0 (9), 129.6, 124.1 (4, 10), 87.0 (1), 80.2 (2), 42.9 (15), 40.9,
37.3, 34.7 (CH2), 37.7 (8), 30.2 (CH3), 28.6, 27.9 ((CH3)3CSi), 28.2
(CH2), 26.2, 23.6 (CH3-8, CH3-15), 21.5 (CH2), 20.9 (CSi), 15.7 (6),
14.2 (CH2CH3).
IR (film): n = 2937, 1478, 1382, 1039, 991, 912, 861, 823 cm-1.
MS (CI, NH3): m/z = 434 (MH+), 404, 377, 275, 257, 201.
b-27
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.13 (dd, 1 H,
J = 4.2, 3.6 Hz, H-4), 5.36 (dt, 1 H, J = 11.7, 9.2 Hz, H-10), 5.25 (d,
1 H, J = 11.7 Hz, H-9), 4.58 (s, 1 H, H-2), 2.44 (br dd, 1 H, J = 14.2,
10.0 Hz, H-11), 2.21-2.11 (m, 2 H), 1.87-1.73 (m, 2 H), 1.70-1.64
(m, 6 H), 1.49, 1.34, 1.20 [3 s, 9 H, CH3-8 + (CH3)2C], 1.42 (dd, 1
H, J = 14.2, 8.2 Hz, H-11), 1.82-1.27 (m, 2 H), 1.04, 1.03 (2 s, 6 H,
2 CH3-15), 0.93 (t, 3 H, J = 7.3 Hz, CH2CH3).
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

880
D. Bourgeois et al.
SPECIAL TOPIC
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 139.7 (9),
138.3 (3), 126.5, 124.2 (4, 10), 105.6 [OC(CH3)2O], 87.6 (1), 76.1
(2), 40.4, 37.8 (8, 15), 36.7, 34.3, 31.5 (CH2), 30.2, 29.5, 28.2, 26.3,
22.0 (CH3), 28.2, 25.0, 24.4 (CH2), 18.1 (6), 14.2 (CH2CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 154.2 (C=O),
142.3 (9), 137.5 (3), 126.7, 125.4 (4, 10), 93.2 (1), 82.7 (2), 48.2 (8),
43.6 (11), 41.8 (15), 36.2 (6), 31.7, 26.0, 24.8, 23.0 (CH2), 26.2,
22.0, 20.4 (CH3), 17.6 (6), 13.8 (CH2CH3).
IR (film): n = 2930, 1654, 1456, 1366, 1244, 1215, 1173, 1023
IR (film): n = 2931, 2871, 1798, 1455, 1376, 1321, 1242, 1048,
cm-1.
1027, 772 cm-1.
MS (CI, NH3): (m/z) 336 (MNH4 ), 319 (MH+), 303, 285, 221, 169,
+
MS (CI, NH3): m/z = 332, 317, 292, 275, 257.
151.
(5R*,6R*,10aR*/S*,9Z)-6-Butyl-5,6-carbonyldioxy-7,7,10a-tri-
methyl-1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene (cis-
28)
a-23:
mp 85-87 °C.
The usual procedure with Nolan’s catalyst, applied to 23 (70 mg,
0.2 mmol, 10 mL of 1,2-dichloroethane, 8.5 mg of catalyst), yield-
ed 55 mg (86%) of a 1:1 mixture of the two diastereomeric deriva-
tives cis-28 as a colorless oil after flash chromatography on silica
gel (Et2O/petroleum ether, 8:92).
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.10 (t, 0.5 H,
J = 3.6 Hz, 0.5 H-4), 6.02-5.97 (br s, 0.5 H, 0.5 H-4), 5.73 (dt, 0.5
H, J = 11.8, 9.2 Hz, 0.5 H-10), 5.56 (s, 0.5 H, 0.5 H-2), 5.48-5.39
(m, 1 H, 0.5 H-9 + 0.5 H-10), 5.34 (d, 0.5 H, J = 11.8 Hz, 0.5 H-9),
5.25 (s, 0.5 H, 0.5 H-2), 2.66 (dd, 0.5 H, J = 14.1, 9.2 Hz, 0.5 H-11),
2.23-2.04 (m, 3 H), 2.00-1.75 (m, 5 H), 1.72-1.58 (m, 3 H),
1.57-1.45 (m, 1.5 H), 1.43 (s, 1.5 H, CH3), 1.25 (s, 1.5 H, 0.5 CH3),
1.30-1.20 (m, 1 H), 1.16 (s, 1.5 H, 0.5 CH3), 1.11 (s, 1.5 H, 0.5 CH3),
1.09 (s, 3 H, CH3), 0.88 (t, 1.5 H, J = 7.0 Hz, 0.5 CH2CH3), 0.86 (t,
1.5 H, J = 7.1 Hz, 0.5 CH2CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 154.8, 154.0
(C = O), 140.6, 140.5 (9), 135.8, 134.7 (3), 128.8, 128.5, 126.1,
124.7 (4, 10), 92.1, 91.5 (1), 82.0, 79.8 (2), 40.9, 38.2, 35.5, 34.9 (7,
11), 39.9, 39.2, 39.1, 36.7 (8, 15), 31.7, 30.5 (CH2), 28.2, 27.1, 26.8,
25.0, 23.3, 21.7, 21.6 (CH3), 26.6, 24.8, 24.5, 23.3, 23.0, 22.3
(CH2), 17.7, 15.9 (6), 13.8 (CH2CH3).
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 5.95 (t, 1 H,
J = 3.8 Hz, H-4), 5.78 (ddt, 1 H, J = 17.0, 10.0, 7.1 Hz, H-10), 5.70
(dd, 1 H, J = 17.5, 10.5 Hz, H-9), 5.18 (dd, 1 H, J = 10.5, 1.0 Hz,
H-9’(cis)), 5.10 (br d, 1 H, J = 10.0 Hz, H-10’(cis)), 5.07 (br d, 1 H,
J = 17.0 Hz, H-10’(trans)), 5.06 (dd, 1 H, J = 17.5, 1.0 Hz,
H-9’(trans)), 4.88 (s, 1 H, H-2), 2.20-2.02 (m, 3 H), 1.80-1.69 (m,
1 H), 1.62-1.15 (m, 8 H), 1.13 (s, 3 H, CH3-8), 0.93 (s, 6 H, 2
CH3-15), 0.88 (t, 3 H, J = 7.0 Hz, CH2CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 155.6 (C=O),
145.4 (9), 137.4 (3), 133.6 (10), 131.5 (4), 118.6, 118.5 (10’), 114.6
(9’), 91.8 (1), 80.0 (2), 43.6 (15), 41.0 (8), 39.8, 37.7 (7, 11), 30.3,
27.0, 25.4, 23.0 (CH2), 24.5, 20.6, 20.5 (CH3-8, CH3-15), 17.8 (6),
13.8 (CH2CH3).
IR (film): n = 3078, 2961, 2934, 2872, 1799, 1637, 1466, 1332,
1198, 1045, 916, 770 cm-1.
(5R*,6R*,10aR*,9Z)-6-Butyl-5,6-carbonyldioxy-7,7,10a-trime-
thyl-1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene (cis b-28)
To a refluxing solution of trans b-28 (34 mg, 100 mmol) in anhyd
degassed 1,2-dichloroethane (5.5 mL) was added a 0.1 M solution
of diallyl ether in 1,2-dichloroethane (100 mL, 10 mol%), then
Nolan’s catalyst (4.5 mg, 5 mol%), and the resulting mixture was
refluxed under argon for 12 h. The reaction mixture was cooled to
r.t., concentrated in vacuo and purified by flash chromatography on
silica gel (Et2O/petroleum ether, 8:92) to yield 23 mg (67%) of a 4:1
mixture of what was assigned to be after deprotection with 2 N aq
NaOH in dioxane cis b-28 and cis b-30.
IR (film): n (cm-1) 2957, 1797, 1469, 1454, 1323, 1249, 1192, 1051,
1011.
MS (CI, NH3): (m/z) 336 (MNH4 ), 319 (MH+), 275, 257, 217, 201.
+
(5R*,6R*,10aR*,9E)-6-Butyl-5,6-carbonyldioxy-7,7,10a-trime-
thyl-1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene (trans b-
28) and [1R*,2R*(6S*)]-2-Butyl-1,2-carbonyldioxy-3,3-dimeth-
yl-1-(6-methyl-6-vinylcyclohex-1-en-1-yl)hex-5-ene (a-23)
1. The usual procedure with Grubbs’ catalyst, applied to 23 (80 mg,
0.23 mmol, 11 mL of benzene, 3.8 + 6 × 1.9 mg of catalyst), yield-
ed 25 mg (34%) of trans b-28 as a white solid and 34 mg (42%) of
unreacted a-23 as a pale yellow solid after flash chromatography on
silica gel (Et2O/petroleum ether, 5:95).
(5R*,6R*,10aS*,9Z)-6-Butyl-5,6-carbonyldioxy-7,7,10a-trime-
thyl-1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene (cis a-28)
The usual procedure with Nolan’s catalyst catalyst, applied to a-23
(35 mg, 95 mmol, 5 mL of 1,2-dichloroethane, 4.0 mg of catalyst),
yielded 29 mg (96%) of cis a-28 as a white solid after flash chroma-
tography on silica gel (Et2O/petroleum ether, 8:92); mp 78-80 °C.
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.03 (td, 1 H,
J = 4.5, 2.0 Hz, H-4), 5.73 (dt, 1 H, J = 11.5, 9.0 Hz, H-10), 5.56 (q,
1 H, J = 2.3 Hz, H-2), 5.47 (dd, 1 H, J = 11.8, 1.5 Hz, H-9), 2.68 (br
dd, 1 H, J = 14.3, 9.0 Hz, H-11), 2.26-2.21 (m, 2 H), 1.92-1.88 (m,
3 H), 1.82 (dd, 1 H, J = 14.3, 9.0 Hz, H-11), 1.78-1.68 (m, 2 H),
1.57-1.50 (m, 2 H), 1.46 (d, 3 H, J = 0.5 Hz, CH3-8), 1.44-1.24 (m,
3 H), 1.19, 1.12 (2 s, 6 H, 2 CH3-15), 0.89 (t, 3 H, J = 7.2 Hz,
CH2CH3).
13C NMR (CDCl3, 100.6 MHz, taxol numbering): d = 154.0 (C=O),
140.6 (9), 136.0 (3), 128.9, 126.3 (4, 10), 91.6 (1), 82.2 (2), 41.0 (7),
40.0 (15), 36.8 (8), 35.6 (11), 31.8 (CH2), 27.1, 25.1, 21.8 (CH3),
24.6, 23.1, 22.4 (CH2), 16.0 (6), 13.8 (CH2CH3).
2. The usual procedure with Schrock’s catalyst, applied to 23
(80 mg, 0.23 mmol, 11 mL of benzene, 3 × 10 mg of catalyst),
yielded 33 mg (41%) of trans b-28 and 24 mg (32%) of unreacted
a-23 after flash chromatography on silica gel (Et2O/petroleum
ether, 5:95).
trans b-28
Mp 73-75 °C.
1H NMR (CDCl3, 400 MHz, taxol numbering): d = 6.01 (ddd, 1 H,
J = 5.0, 2.5, 1.5 Hz, H-4), 5.80 (ddd, 1 H, J = 16.7, 12.0, 3.5 Hz,
H-10), 5.39 (d, 1 H, J = 16.7 Hz, H-9), 5.09 (d, 1 H, J = 2.5 Hz,
H-2), 2.27 (t, 1 H, J = 12.0 Hz, H-11), 2.25-2.18 (m, 1 H), 2.10 (dd,
1 H, J = 12.0, 3.5 Hz, H-11), 2.11-2.01 (m, 1 H), 1.88-1.81 (m, 3 H),
1.76-1.68 (m, 2 H), 1.65-1.56 (m, 2 H), 1.28 (d, 3 H, J = 0.4 Hz,
CH3-8), 1.22, 1.17 (2 s, 6 H, 2 CH3-15), 0.89 (t, 3 H, J = 7.1 Hz,
CH2CH3).
IR (film): n = 2957, 1797, 1469, 1454, 1323, 1249, 1192, 1051,
1011, 774 cm-1.
+
MS (CI, NH3): m/z = 336 (MNH4 ), 319 (MH+), 275, 257, 217, 201.
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of BC Ring-Systems of Taxol by Ring-Closing Metathesis
881
[1R*,2R*(6S*)]-2-Butyl-1,2-carbonyldioxy-3,3-dimethyl-1-(6-
methyl-6-vinylcyclohex-1-en-1-yl)hex-4-ene (a-29) and (5R*,
6R*,10aR*,8Z)-6-Butyl-5,6-carbonyldioxy-7,7,10a-trimethyl-
1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene (cis b-30)
To a refluxing solution of the diene 23 (40 mg, 115 mmol) in anhyd
degassed benzene (6 mL) was added titanium tetraisopropoxide
(34 mL, 115 mmol, 1.0 equiv) and then Grubbs’ catalyst (4.7 mg,
5 mol%), and the resulting mixture was refluxed under argon for 8
d, during which time 0.9 mg (1 mol%) of catalyst was added every
24 h to the refluxing mixture. The reaction mixture was cooled to
r.t., concentrated in vacuo and purified by flash chromatography on
silica gel (Et2O/petroleum ether, 8:92) to yield 18 mg (45%) of a 1:1
mixture of a-23 and a-29 and 10 mg (28%) of a 1:2 mixture of what
was assigned to be after deprotection with 2 N aq NaOH in dioxane
cis b-28 and cis b-30.
(4) For previous work on Taxol synthesis from our laboratory,
see:
(a) Muller, B.; Delaloge, F.; den Hartog, M.; Férézou, J.-P.;
Pancrazi, A.; Prunet, J.; Lallemand, J.-Y. Tetrahedron Lett.
1996, 37, 3313.
(b) Delaloge, F.; Prunet, J.; Pancrazi, A.; Lallemand, J.-Y.;
Neuman, A.; Prangé, T. 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.
(5) For recent reviews on RCM, see: (a) Schuster, M.; Blechert,
S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036.
(b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(c) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
For cyclooctene syntheses by RCM, see:
Hydrolysis of cis a-28; (5R*,6R*,10aS*,9Z)-6-Butyl-7,7,10a-tri-
methyl-1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene-5,6-
diol (a-24)
(d) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am.
Chem. Soc. 1995, 117, 2108.
(e) Fürstner, A.; Langemann, K. J. Org. Chem. 1996, 61,
8746.
(f) Wenz, M.; Grobbach, D.; Beitzel, M.; Blechert, S.
Synthesis 1999, 607.
(g) Paquette, L.; Méndez-Andino, J. Tetrahedron Lett. 1999,
40, 4301. In Ref. 5f, the cyclooctene is a precursor of an AB
ring-system of Taxol.
To a solution of cis a-28 (25 mg, 80 mmol) in dioxane (1 mL) was
added at 0 °C 2 N aq NaOH solution (0.2 mL). The resulting mix-
ture was stirred at r.t. for 2 d, diluted with Et2O (50 mL) and
quenched with sat. aq NH4Cl solution (5 mL). The layers were sep-
arated, and the organic layer was washed successively with H2O
(2 × 5 mL) and brine (5 mL), dried (MgSO4) and concentrated in
vacuo. The resulting crude product was purified by flash chroma-
tography on silica gel (Et2O/petroleum ether, 10:90) and yielded
22 mg (96%) of a-24 as a white solid.
(6) For preliminary results, see: Bourgeois, D.; Pancrazi, A.;
Ricard, L.; Prunet, J. Angew. Chem., Int. Ed. Engl. 2000, 39,
725.
(7) Mehta, G.; Acharyulu, P. V. R. Tetrahedron Lett. 1993, 34,
8157.
(8) Pattenden, G.; Teaque, S. J. Tetrahedron 1987, 43, 5637.
(9) Bourgeois, D.; Maiti, G.; Pancrazi, A.; Prunet, J. Synlett 2000,
323.
(10) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039.
(b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100.
Hydrolysis of cis 28; (5R*,6R*,10aS*,9Z)-6-Butyl-7,7,10a-tri-
methyl-1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene-5,6-
diol (a-24) and (5R*,6R*,10aR*,9Z)-6-Butyl-7,7,10a-trimethyl-
1,2,3,5,6,7,8,10a-octahydro-1H-benzocyclooctene-5,6-diol (b-
24)
To a solution of cis-28 (30 mg, 95 mmol) in dioxane (1 mL) was
added at 0 °C 2 N aq NaOH solution (0.5 mL). The resulting mix-
ture was stirred at r.t. for 2 d, diluted with Et2O (50 mL) and
quenched with sat. aq NH4Cl solution (5 mL). The layers were sep-
arated, and the organic layer was washed successively with H2O
(2 × 5 mL) and brine (5 mL), dried (MgSO4) and concentrated in
vacuo. The resulting crude product was purified by flash chroma-
tography on silica gel (Et2O/petroleum ether, 10:90) and yielded
13 mg (47%) of a-24 as a white solid and 13 mg (47%) of b-24 as a
colorless oil.
(11) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.;
DiMare, M.; O'Regan, M. J. Am. Chem. Soc. 1990, 112, 3875.
(12) (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J.
Am. Chem. Soc. 1999, 121, 2674.
(b) Huang, J.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P.
Organometallics 1999, 18, 5375.
(c) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247.
Acknowledgement
(d) For related catalysts, see: Ackermann, L.; Fürstner, A.;
Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett.
1999, 40, 4787.
We gratefully acknowledge the CNRS (UMR 7652), the Ecole Po-
lytechnique, the National Science Foundation and the Board of Re-
gents of the State of Louisiana for financial support.
(13) Ratio observed in the 1H NMR spectrum of the unpurified
product.
(14) Edwards, S. D.; Lewis, T.; Taylor, R. J. K. Tetrahedron Lett.
1999, 40, 4267.
References
(15) See experimental section for details.
(16) The TES ether was deprotected for purification purposes.
(17) In reference 6, we have reported a 20% yield for this reaction.
In fact, it was performed the first time on a 2:1 diastereomeric
mixture of 18. The yield discrepancy is due to the fact that
only one diastereomer cyclizes with [Ru].
(18) Proof of stereochemistry was obtained by NOESY
experiment.
(19) Tanino, K.; Shimizu, T.; Kuwahara, M.; Kuwajima, I. J. Org.
Chem. 1998, 63, 2422.
(20) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,
4137.
(1) (a) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
McPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325.
(b) ACS Symposium Series 583, Taxane Anticancer Agents:
Basic Science and Current Status; Georg, G.I.; Chen, T.T.;
Ojima, I.; Vyas, D. M., Eds.; American Chemical Society:
Washington D.C., 1995.
(2) (a) Lavelle, F.; Guéritte-Voegelein, F.; Guénard, D. Bull.
Cancer, 1993, 80, 326.
(b) Guénard, D.; Guéritte-Voegelein, F.; Potier, P. Acc. Chem.
Res. 1993, 26, 160, and references cited therein.
(3) Morihara, K.; Hara, R.; Kawahara, S.; Nishimori, T.;
Nakamura, N.; Kusama, H.; Kuwajima, I. J. Am. Chem. Soc.
1998, 120, 12980 and references therein.
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York

882
D. Bourgeois et al.
SPECIAL TOPIC
(21) Proof of stereochemistry for compound 24 will be given later
in this article and structure of compound 25 was determined
by X-ray diffraction analysis (see Ref. 6).
(27) Hoveyda, A. H. OMCOS X, Versailles, July 18-22, 1999.
(28) Fürstner, A.; Langemann, K. Synthesis 1997, 792.
(29) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130.
(22) Proof of stereochemistry for compound b-26 will be given
later in this article.
(30) Deprotection of the carbonate moiety of cis b-30 furnished a
(23) Nicolaou, K. C.; Nanternet, P. G.; Ueno, H.; Guy, R. K. J.
Chem. Soc., Chem. Commun. 1994, 295.
(24) Nicolaou, K. C.; Yang, Z.; Sorensen, E. J.; Nakada, M. J.
Chem. Soc., Chem. Commun. 1993, 1024.
compound identical to 25 (Scheme 8).
(31) a-29 was prepared independently: it is a side product of the
hydrogenation of a-23, see Ref. 9.
(25) The stucture of compound trans b-28 was determined by X-
ray diffraction analysis, see reference 6.
Article Identifier:
(26) In this case, the reaction was complete in 30 min.
1437-210X,E;2000,0,06,0869,0882,ftx,en;C01700SS.pdf
Synthesis 2000, No. 6, 869–882 ISSN 0039-7881 © Thieme Stuttgart · New York