Studies towards the synthesis of the bicyclic 3,8-secotaxane diterpenoid system using a ring closing metathesis strategy

Article abstract of DOI:10.1016/j.tet.2006.10.058

Molecular modelling studies on the interations between taxanes and tubulins, developed by us, revealed that modified Taxuspines U and X could adopt a conformation similar to that of the bioactive conformation of paclitaxel and could be well accommodated within the proposed model. Accordingly, simplified Taxuspine U and X analogues have been rationally designed and their bicyclic 3,8-secotaxane diterpenoids intermediates have been synthesized through an approach that involves ring closing metathesis (RCM) as the key step for the macrocycle formation. Extensive studies on RCM have been performed using chemically diverse substrates, outlining the influence in the macrocyclization of the presence and position of functionalities, the molecular constraints and the importance of the site of ring closure.

Full text of DOI:10.1016/j.tet.2006.10.058

Tetrahedron 63 (2007) 497–509
Studies towards the synthesis of the bicyclic 3,8-secotaxane
diterpenoid system using a ring closing metathesis strategy
Michela L. Renzulli,a Luc Rocheblave,b Stanislava I. Avramova,a Elena Galletti,a
Daniele Castagnolo,a Andrea Tafi,a Federico Corellia and Maurizio Bottaa,
*
aDipartimento Farmaco Chimico Tecnologico, Universitaꢀ degli Studi di Siena, 53100 Siena, Italy
b
´
´
´
´ ˆ
Laboratoire de Stereochimie Dynamique et Chiralite, Faculte des Sciences de Saint Jerome, avenue Escadrille Normandie Niemen,
13397 Marseille cedex 20, France
Received 12 May 2006; revised 28 September 2006; accepted 19 October 2006
Available online 9 November 2006
Abstract—Molecular modelling studies on the interations between taxanes and tubulins, developed by us, revealed that modified Taxuspines
U and X could adopt a conformation similar to that of the bioactive conformation of paclitaxel and could be well accommodated within the
proposed model. Accordingly, simplified Taxuspine U and X analogues have been rationally designed and their bicyclic 3,8-secotaxane
diterpenoids intermediates have been synthesized through an approach that involves ring closing metathesis (RCM) as the key step for the
macrocycle formation. Extensive studies on RCM have been performed using chemically diverse substrates, outlining the influence in the
macrocyclization of the presence and position of functionalities, the molecular constraints and the importance of the site of ring closure.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In particular, compound 5 is predicted to be as active as
TaxolÒ, while natural Taxuspine U (3) is predicted by the
model to be less active. The similarity between the macro-
cycle conformation of 5 and its orientation inside the binding
site suggested us that compound 5 might mimic the ABC
ring system of TaxolÒ. Compound 5 is structurally simpler
and synthetically more accessible than paclitaxel and it
could be an interesting alternative to the tricyclic taxanes,
as a novel lead compound for new microtubule-stabilizing
agents (Fig. 1).
The remarkable therapeutic potential and challenging struc-
tural complexity of taxane diterpenoids have stimulated con-
siderable synthetic efforts worldwide. In spite of numerous
synthetic approaches towards TaxolÒ and TaxotereÒ (1 and
2), including six total syntheses,1 not enough attention has
been paid to bicyclic 3,8-secotaxane diterpenoids Taxuspine
U (3) and X (4). These natural products, whose skeleton has
been proposed as biogenetic precursor for taxanes, were iso-
lated from the Japanese yew Taxus Cuspidata in very poor
yield.2
O
OAc
OAc
R1O
O
R2 NH O
OH
AcO
OAc
Based on our efforts to find a theoretical quantitative model
describing the relationships between the structure and bio-
logical activity of microtubules stabilizing anticancer agents
(MSAAs), an atomic pseudoreceptor model has been pro-
posed in our previous studies.3,4 These computational stud-
ies have revealed that modified Taxuspines U and X can
adopt a shape similar to that of the bioactive conformation
of paclitaxel and can be well accommodated within the
pseudoreceptor model proposed to predict the micro-
tubule-stabilizing activity for taxanes.
AcO
Ph
O
R1
OAc
OH
O
H
H
HO
OAc
OCOPh
1 R1 = Ac;
2 R1 = H;
R2 = Ph
3 R1 = Acetyl
4 R1 = trans-cinnamoyl
R2 = t-BuO
O
OAc
OH
RO
OR
Ph NH O
Ph
O
OH
OAc
H
H
OR
OH
OH
Keywords: Microtubules-stabilizing anticancer agents (MSAAs); Taxus-
pines U and X; Minireceptor model; Ring closing metathesis.
* Corresponding author. Tel.: +39 0577 234306; fax: +39 0577 234333;
e-mail: botta@unisi.it
5
6
Figure 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.058

498
M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
RCM
site a
OH
OH
9
8
1
st route
OMEM
8
esterification
OAc
simplified model
R2O
O
OR
OR
OH
10
7
Ph NH O
12
13
6
site b
Ph
O
OH
2nd route
5
H1
OR
OR
OAc
OH
RCM
H
OR1
OR
OH
9
5
7
simplified model
oxygenation
3rd route
R2O
OR2
R2O
OR2
3
3
4
4
H
H
OR1
OR1
site c
site c
RCM
RCM
11
10
simplified model
simplified model
Scheme 1. Retrosynthetic analysis.
On the other hand, if a trans-cinnamoyl moiety is introduced
on the C-5 oxygen and the b-phenyl isoserine side chain is
removed from C-13, 5 could in principle be transformed
into Taxuspine X (4) analogues, potentially interesting as
multidrug resistance (MDR) reversing agents.5 Accordingly,
our project opens a pathway to a variety of taxoids to be
tested as anticancer and MDR reversing agents, and repre-
sents a preliminary study for the synthesis of Taxuspine U
and X analogues.
deoxygenation at the C-13 position afforded the naked car-
bocyclic core 7, which was further simplified, leading to
models 8–11. All these compounds could in principle be
obtained by RCM, as outlined in Scheme 1.
Three main routes for the macrocyclization were initially
considered. Compound 8 could be obtained from an allylic
alcohol precursor, in which the double bonds are activated
towards RCM, while the precursor of 9 would display two
sterically unencumbered double bonds to be involved in
the complexation with ruthenium catalyst. Finally, com-
pound 10 (or 11) should be obtained from more constrained
precursors bearing substituents that in some cases may help
the RCM.8
In our recent communication,6 we reported the methodology
for the synthesis of bicyclic 3,8-secotaxane diterpenoids, in-
volving ring closing methatesis (RCM) as the key step for
the macrocycle formation.7 We now report a full account of
oureffortstowardsthesynthesisof 6, thecommon bicyclic in-
termediate of Taxuspine U and X analogues, via RCM; all the
trials to obtain the constrained 12-membered macrocyclewill
be discussed herein, because there is a little information avail-
able concerning RCM on related systems. It has been shown,
in fact, that RCM works very well when applied to substrates
devoid of any conformational constraints and it must be con-
sidered to be among the most efficient entries into macro-
cycles if the sites of ring closure are properly chosen.8
Disconnection at site a identified as synthetic precursor the
tetraene intermediate 12, which was readily prepared as
described in Scheme 2.
Hydrozirconiation of 13 with the Schwartz reagent
(Cp2ZrHCl)10a,b gave the intermediate vinylzirconocene,
which was reacted with aldehyde 14 and catalytic silver per-
chlorate (AgClO4) to afford the secondary alcohol 15 as
a mixture of diastereoisomers (syn–anti 3:1 ratio, according
to the HPLC analysis and confirmed by precedent literature
data),10c in 80% yield. The mixture of diastereoisomeric
alcohols 15 was in turn protected on the secondary alcohol
as a methoxyethoxymethyl ether and deprotected at the
primary alcohol groups, leading to the diol 16.
2. Results and discussion
Compound 5 is a challenging target for an original synthesis
and no procedures for its preparation have been reported in
the literature so far.9 In the retrosynthetic analysis, 5 offers
several points for disconnection; thus, appropriate pro-
tections and removal of the phenylisoserine chain and
11,12
Oxidation with Dess–Martin periodinane provided the
corresponding dialdehyde, which was converted into 12 by

M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
499
OAc
O
HO
OTBDMS
OTBDMS
i
ii, iii, iv
O
OH
OAc
i
3
4
OH
13
14
15
HO
OMEM
18
OMEM
12
O
OH
(ii)
+
OH
OH
v, vi
O
O
O
O
O
O
OMEM
12
OMEM
+
+
16
OMEM
20
OMEM
21
OMEM
19
Scheme 2. Synthesis of 12. Reagents, conditions and yields: (i) Cp2ZrHCl,
14, AgClO4, CH2Cl2, 0 ꢀC, 80%; (ii) MEMCl, DIPEA, DMAP, CH2Cl2,
95%; (iii) TBAF, THF, 90%; (iv) LiOH$H2O, CH3OH/H2O, 85%; (v)
Dess–Martin periodinane, CH2Cl2 and (vi) vinylmagnesium bromide,
THF, 56% (over two steps).
22
Scheme 4. Oxidation of allyl alcohols and RCM of 18. Reagents, conditions
and yields: (i) Dess–Martin periodinane, CH2Cl2, 75% and (ii) Grubbs’ II
cat., CH2Cl2, rt to reflux, 13% (overall yield).
treatment with vinylmagnesium bromide. The diastereo-
isomeric ratio was not calculated and 12 was used as a
mixture of isomers.
carbene exchange between 18 and the benzylidene ligand
of the catalyst as outlined in Scheme 4; compound 21 and
cyclopentenone 22, arising from intramolecular ring closing
metathesis between C3–C4 and terminal double bonds.
Attempts to perform the RCM reaction on 12 after protection
of the allylic alcohol groups as silyl ether or acetate did not
afford better results, as only the cyclopentene derivatives and
products of fragmentation of type 21 were obtained.
When 12 was treated with Grubbs’ catalyst in order to per-
form a macrocyclization,13,14 only the methyl ketone 17
was obtained instead of the expected macrocycle 8 (Scheme
3). It is clear that the ruthenium carbene species, coming
from the Grubbs’ catalyst, was consumed by this side reac-
tion: the use of only 10 mol % and 20 mol % of ruthenium
catalyst results in low conversion of 12 and all the 1H
In the meantime, the second route was also explored and the
new u–u0-diolefin triene 23 was prepared from the aldehyde
2417 in an overall yield of 82% (Scheme 5). Treatment of 24
with a small excess of 4-pentenylmagnesium bromide in di-
ethyl ether at room temperature led to a diastereoisomeric
mixture of alcohols 25, which on selective oxidation with
TPAP-NMO 18 was then converted into the ketone 26. After
hydrolysis of the acetal group of 26 with CSA in THF/H2O,
the aldehyde 27 was submitted to Grignard reaction with
3-butenylmagnesium bromide in diethyl ether at 0 ꢀC.
Oxidation of the resulting mixture of alcohols 28 with
TPAP-NMO furnished the diketone 23.
NMR spectroscopic resonances due to the catalyst disap-
that the
15,16
peared. It has been suggested in similar cases
initial metal-complexed carbene A (Scheme 3) undergoes
tautomerization to the enolyl ruthenium hydride species B,
which can further undergo reductive elimination, either
before or after tautomerization to the oxoalkyl ruthenium
hydride C, to produce the methyl ketone.
In order to circumvent this side reaction, 12 was subjected to
oxidation with Dess–Martin periodinane, affording the
ketone derivative 18, which was treated with 20 mol % of
Grubbs’ ruthenium catalyst in dry and degassed dichloro-
methane at room temperature and then at reflux (Scheme 4).
Triene 23 was submitted to RCM and different results were
obtained, according to the reaction conditions (Scheme 6).
Thus, a 3 mM solution of 23 in 1,2-dichloroethane (DCE)
was treated with 20 mol % of Grubbs’ I catalyst at room
However, only traces of the expected macrocycle 19 were
detected, together with compound 20, resulting from
HO
O
OH
O
GrubbsII catalyst
CH2Cl2
rt to reflux
OMEM
OMEM
17
12
H
H
R
R
R
R
RCM
RuLn
RuLn
RuLn
O
O
C
OH
OH
B
A
Ln = Ligand
Scheme 3. Attempted ring closing metathesis of 12.

500
M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
HO
O
different amounts (5%, 10% and 15%) of Grubbs’ II catalyst,
higher dilutions (1 mM and 0.75 mM in DCE) and longer re-
action time, but in these cases only the acyclic dimers 29 and
30 were obtained. Conversely, after heating the reaction at
reflux temperature, even under the same conditions of dilu-
tion and catalyst, only the dimers 31 and 32 were isolated.
Finally, when the reaction was performed at higher temper-
ature (refluxing toluene) the catalyst decomposition was
competitive with the metathesis reaction and no product
was obtained. These results showed that probably, due to
both entropic and enthalpic reasons7f related to the length
of the chains as well as to the conformation of the substrate
23 and the products 31 and 32, the dimerization is favoured.
The resistance of these unfunctionalized dienes towards
cyclization confirmed that the presence of polar functional
groups is a pivotal parameter for successful RCM.8
O
O
iii
i
ii
O
O
O
O
O
24
25
26
O
O
O
iv
v
O
HO
O
27
28
23
Scheme 5. Synthesis of 23. Reagents, conditions and yields: (i) pentenyl-
magnesium bromide, diethyl ether, rt, 92%; (ii) TPAP, MNO, CH2Cl2,
molecular sieves, 58%; (iii) CSA, THF/H2O, reflux, 99%; (iv) butenyl-
magnesium bromide, 0 ꢀC to rt, 63% and (v) TPAP, NMO, CH2Cl2, molec-
ular sieves, 99%.
Following the observations described above, a third route
was devised, for which the trieneyne 34 was envisaged to
be a suitably functionalised and constrained substrate for
the key RCM. The disconnection of the B-ring of 10 or 11
(Scheme 7) at the site c (Scheme 1) leads to 34, a further
temperature and after one day the presence of four new prod-
ucts was detected, even if 70% of starting material was still
present. The HPLC–MS analysis of the crude reaction
mixture revealed the presence of two different families of
compounds, which were separated: acyclic dimers and 24-
membered macrocycles.19 Concerning the regiochemical
outcome of the metathesis, HPLC–MS–MS analysis of the
mixture of acyclic dimers revealed the presence of only
two compounds (29 and 30) instead of the expected three
dimers. The analysis of the cyclic dimers confirmed the pres-
ence of both compounds 31 and 32 in a 1:1 ratio. The anal-
ysis of the MS–MS fragmentation confirmed the structures
described in Scheme 6 (vide infra: Supplementary data).
PO
OP
PO
OP
7
9
8
3
4
H
H
OP
OP
10,11
34
OP
OP
O
H
+
Concerning the stereochemical outcome of the metathesis,
the configuration of the newly formed double bonds has
not been proved due to the symmetry of the molecules
and/or the complexity of the spectral data.
H
35
36
P = protecting groups
Scheme 7. Disconnection of 10 or 11.
In order to improve the RCM and to obtain the desired mac-
rocycle 33, this reaction was further investigated using
O
O
O
O
O
+
O
O
O
i
29
30
+
31 + 32
O
O
O
i
O
23
33
ii
O
O
O
O
O
+
O
O
O
31
32
Scheme 6. Ring closing metathesis of 23. Reagents, conditions and yields: (i) Grubbs’ I or II cat., DCE, rt, 64% and (ii) Grubbs’ I or II cat., DCE, reflux, 75%.

M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
501
diolefin intermediate, while the cis-C8–C9 double bond is
expected to result from selective reduction of the corre-
sponding triple bond. The second bond disconnection was
planned between C7 and C8 to provide a highly convergent
approach to the Taxuspine nucleus from the suitably func-
tionalized ring A building block 35 and aldehyde 36.
Scheme 9, the macrocycle precursors 45 and 46 were pre-
pared from the lithium derivative of 35 and aldehydes 43
and 44, respectively, followed by acetylation of the newly
formed alcohols 47 and 48. In both cases, HPLC analysis
revealed the presence of one major isomer. The C-7 rela-
tive stereochemistry of the major isomer 48 was tenta-
tively assigned on the basis of the NOESY analysis and
later confirmed by the analysis of the cyclized compounds
58 and 60 (vide infra) for comparison with the literature
data relative to Taxuspine U and X.2d,e,6 The C-7 relative
stereochemistry of 47 has been assumed based on very
similar spectroscopic data and chemical behaviour of the
alkynylation.24
The alkyne 35 was obtained according to Scheme 8.
Treatment of aldehyde 141b,17 with a small excess of vinyl-
magnesium bromide, led to a mixture of 37 and 38 with
high diastereoselectivity, 9:1 ratio in favour of the syn com-
pound 37, previously assigned by Fallis et al.22 and con-
firmed by us.6
OAc
OAc
OAc
AcO
AcO
OR
i
O
+
H
i
+
H
H
O
O
OH
OH
38
9 : 1
H
H
14
37
OTBDPS
OTBDPS
35
ii, iii
47 R = H
43
ii
45 R = Ac
OH
H
iv, v
vi
vii
AcO
OR
AcO
38
O
H
i
H
H
+
OTBDPS
40
OTBDPS
39
H
ii
H
OTBDPS
OTBDPS
AcO
HO
HO
48 R = H
44
35
46 R = Ac
ix
+
Scheme 9. Synthesis of macrocycle precursors. Reagents, conditions and
yields: (i) LHMDS, THF, ꢁ78 ꢀC to rt, 65–72% and (ii) Ac2O, Et3N,
DMAP, CH2Cl2, rt, quantitative.
H
H
H
OTBDPS
35
OTBDPS
41
OTBDPS
42
5 : 1
vi, viii
Conformational analysis has been performed on 46 and on
its partially hydrogenated derivative 49, in order to evaluate
possible problems in terms of hindrance and conformational
strains of the 12-membered macrocycle, that could limit the
success of RCM reaction.25,26 Calculations suggested that
both alkyne- and alkene-linked dienes should be viable sub-
strates for the RCM macrocyclization reaction (vide infra:
Supplementary data).
Scheme 8. Synthesis of alkyne 35. Reagents, conditions and yields:
(i) vinylmagnesium bromide, THF, ꢁ78 ꢀC to rt, 84%; (ii) Dess–Martin
periodinane, CH2Cl2, 90%; (iii) L-Selectride, THF, ꢁ78 ꢀC to rt, 84%;
(iv) TBDPSCl, imidazole, DMAP, DMF, rt, 85%; (v) K2CO3, CH3OH,
quantitative; (vi) TPAP, MNO, molecular sieves, CH2Cl2, rt, 91%; (vii)
ethynylmagnesium bromide, THF, ꢁ78 ꢀC to rt, 85%; (viii) 9-BBN, THF,
0 ꢀC, 90% and (ix) Ac2O, Et3N, DMAP, CH2Cl2, rt, quantitative.
The most abundant isomer 37 was converted into 38 by ox-
idation with Dess–Martin periodinane followed by reduction
with L-Selectride.21 The orthogonal protection of the allylic
alcohol 38 as TBDPS ether, followed by removal of the
O-acetyl group, produced the corresponding alcohol 39,
which was oxidized with TPAP-NMO to the aldehyde 40
in 95% yield. When the latter compound was reacted with
ethynylmagnesium bromide, a mixture of two diastereoiso-
mers 41 and 42 was obtained in a 5:1 ratio.20,22
Different RCM assays were performed on the intermediates
45 and 46 but in no case intramolecular cyclization occurred
and the starting material was consistently recovered, either
varying the RCM conditions and the ruthenium catalysts
used (Grubbs’ I or Grubbs’ II catalyst). In order to reduce
the steric hindrance of the double bond and to help the com-
plexation between the catalyst and the substrate, the silyl
ether in the allylic position was cleaved, giving the corre-
sponding alcohols 50 and 51, and another macrocycle pre-
cursor 52 was prepared as well (by protection of the
diasteromeric mixture of 47 as a TBS ether), but olefin
metathesis always failed on all these substrates (Scheme 10).
However, while 50 and 51 were recovered unaltered, com-
pound 52 underwent a smooth transformation to 53, through
intramolecular ene–yne metathesis involving the terminal
unhindered double bond and the more electron-rich alkyne
moiety, followed by elimination of acetic acid and rear-
rangement of the double bond, resulting in a more stable
conjugated system (Scheme 10).27
The resulting propargylic alcohols 41 and 42 were separated
by flash chromatography and 41 was converted into the dia-
stereoisomer 42 by oxidation with TPAP-NMO, followed
by reduction with 9-BBN.23 The propargyl alcohol 42 was
finally acetylated providing the intermediate 35.
For establishing the C7–C8 bond (numbering referred to the
target compound) we chose the commercially available 2,2-
dimethyl-4-pentenaldehyde 43 and the easily obtainable 2-
(2-methylenecyclohexyl)acetaldehyde 44.6 As outlined in

502
M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
AcO
To test this hypothesis, the fully acetylated compound 54
OAc
was treated with cobalt dicarbonyl (Scheme 11). Complex
formation proceeded readily at room temperature in DCM
even if the reaction did not go to completion, probably be-
cause of the steric hindrance around the triple bond. The
complexation provided the stable compound 55, which
was isolated after silica gel chromatography in 70% yield.
ii
no reaction
H
OR
45 R = TBDPS
50 R = H
i
OAc
Unfortunately, when 55 was subjected to the conditions of
RCM with 10% and 15% Grubbs’ II catalyst in DCM and
high dilution, no cyclization reaction occurred and starting
compound was largely recovered. Also 50 was subjected
to the complexation with cobalt dicarbonyl under the same
conditions, to afford 56 (Scheme 11). When this cobalt-
complexed diolefin was treated with Grubbs’ catalyst,
a smooth reaction occurred, providing the methyl ketone
57, instead of the desired 12-membered macrocycle, in anal-
ogy to our previous data observed for the metathesis on
substrate 12.
AcO
ii
no reaction
H
OR
46 R = TBDPS
51 R = H
i
OTBDMS
OAc
OTBDMS
iii
Subsequently, the conversion of the triple bonds of 45 and 46
to the corresponding cis-alkenes was investigated. Hydroge-
nation of 45 and 47 to the corresponding cis-alkenes with
Lindlar/quinoline was unsatisfactory,32 while the use of
Rosenmund’s catalyst/quinoline did afford the cis-C8–C9 al-
kene derivatives of 45 and 47, but with concomitant hydro-
genation of the u–u0-double bonds. Conversely, the partial
hydrogenation of 46 to the corresponding cis-alkene, in the
presence of Lindlar catalyst and quinoline proved to be ef-
fective and the new macrocycle precursor 49 was obtained
in high yield, as outlined in Scheme 12.
H
H
OTBDMS
OTBDMS
53
52
Scheme 10. Studies of RCM. Reagents, conditions and yields: (i) TBAF,
THF, 40 ꢀC, 62%; (ii) RCM conditions and (iii) Grubbs’ II ruthenium
cat., CH2Cl2, 66%.
We reasoned that the alkyne function could affect the cata-
lyst, interfering our plan of RCM. Aside from the undesired
ene–yne metathesis, the cyclization could be further compli-
cated by the linear character of the acetylene group and by
the non-productive coordination of the triple bond to the
RCM catalytic machinery.28 To the best of our knowledge,
in fact, no example of carbo-macrocycle bearing an endo-
cyclic triple bond has been obtained by olefin RCM.
Finally, RCM using 10% Grubbs’ II catalyst in dry and de-
gassed DCM at room temperature, starting from the u–u0-
diolefin 49 gave in 20% yield the desired macrocycle 58, a
3,8-secotaxane diterpenoid, simplified analogue of taxus-
pine U and the first target of this work (Scheme 12). Similar
result was obtained in the macrocyclization of 59, the fully
deprotected derivative of 49, and 60 was isolated in the
same yield. NOESY correlation peaks of H7/H318 and
H10/H318 revealed that H7 and H10 have the same relative
configuration.2d,e It was not possible to determine the geom-
etry of the C3–C4 double bond on the basis of the NMR data
Accordingly, we thought that protection of the alkyne might
be necessary. It is well known that reactions of dicobalt car-
bonyl with acetylene can lead to stable complexes.28–30
Moreover, the geometry of these cobalt-complexed alkynes
optimizes at approximately 140ꢀ and such a departure from
linearity could well favour cyclization.31
(OC)3Co
Co(CO)3
OAc
OAc
AcO
AcO
ii
iii
no reaction
H
H
OR
50 R = H
54 R = Ac
OAc
55
(OC)3Co
AcO
i
(OC)3Co
Co(CO)3
Co(CO)3
OAc
AcO
OAc
ii
iv
50
H
H
O
OH
56
57
Scheme 11. Protection of the alkyne moiety with cobalt complex and RCM. Reagents, conditions and yields: (i) Ac2O, Et3N, DMAP, CH2Cl2, rt, quantitative;
(ii) Co2(CO)8, CH2Cl2, rt, 65–70%; (iii) 15% Grubbs’ II cat. CH2Cl2 (1 mM), rt or reflux; (iv) 15% Grubbs’ II cat. CH2Cl2 (1 mM), rt, 55%.

M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
503
R1O
OR1
ACO
R1O
OR1
OAc
18
7
i
ii
3
4
H
H
H
OTBDPS
46
OR
OR
49 R = TBDPS; R1 = Ac
59 R = H; R1 = H
58 R = TBDPS; R1 = Ac
60 R = H; R1 = H
iii
Scheme 12. Synthesis of the target compounds. Reagents, conditions and yields: (i) H2, Lindlar cat., quinoline, petrol ether, 90%; (ii) Grubbs’ II ruthenium cat.,
CH2Cl2, 20 and 25% and (iii) a: TBAF, THF, 40 ꢀC, 75%; b: K2CO3, CH3OH, quantitative.
available. However, MM (Molecular Mechanic) calculations
revealed that the E isomer is the most stable one.
A 50%, B 50%; method 2: 25 min, flow rate 1 mL/min, A
15%, B 85% (solvents were HPLC grade; A: water; B: meth-
anol). FTIR spectra were recorded on a Perkin–Elmer 1600
spectrophotometer. Elemental analyses (C, H and N) were
performed in house. All the analytical and spectral data are
referred to the major isomer.
Attempts to increase the efficiency of the RCM reaction met
with little success due to the formation of intractable side
products. The macrocycles 58 and 60 represent the first ex-
amples of a highly constrained 6/12 bicyclic system obtained
by RCM.
4.1.1. [5-((E)-6-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-1-
hydroxy-2-hexenyl)-2,6,6-trimethyl-1-cyclohexenyl]-
methyl acetate (15). To a cooled (0 ꢀC) solution of 4-(tert-
butyldimethylsilyloxy)-1-pentyne (13) (1.35 g, 6.8 mmol)
in dichloromethane (13 mL), the freshly prepared Schwartz
reagent (1.75 g, 6.3 mmol), in three portions during 20 min,
was added. The ice bath was removed, the flask protected
from light, and the mixture was stirred for 15 min. After
10 min the complete dissolution of the reagent was ob-
served. The solution was recooled to 0 ꢀC, before adding
the aldehyde 14 (1.27 g, 5.67 mmol), dissolved in dichloro-
methane (2 mL), and then AgClO4 (36 mg, 0.175 mmol).
After 30 min the brown mixture was treated with saturated
aqueous NaHCO3. The aqueous phase was separated and ex-
tracted three times with ethyl acetate. The combined organic
layers were washed with brine, dried over anhydrous
Na2SO4 and evaporated. The resulting residue was purified
by flash chromatography (light petroleum ether/ethyl ace-
tate, 9:1), affording the two diastereoisomers of 15 as colour-
less oils (1.91 g, 80% overall yield) in a ratio of 3:1. The
1H NMR spectral data are referred to the major isomer. IR
3. Conclusions
In conclusion, as part of a wider project aimed at the design
and synthesis of new antimitotic agents stabilizing micro-
tubules and MDR reversing agents, we have set up a new
methodology for the synthesis of simplified Taxuspines U
analogues. This synthetic pathway involves macrocycliza-
tion via RCM to give fused 6/12 bicyclic 3,8-secotaxane
diterpenoids, the first examples of a highly constrained
macrocycle prepared via metathesis. Extensive studies to-
wards RCM have been performed using chemically different
substrates. These experiments outlined the influence on the
macrocyclization of several different factors, such as the
presence and position of functionalities as well as molecular
constraints.33 Although the target compounds have been
obtained in low to moderate yield, this route led to an
interesting and important result in the synthesis of highly
functionalized and complex macrocycle and represents an
example of a systematic approach to constrained and hin-
dered systems.
(film): n 3502, 1736, 1250 cmꢁ1 1H NMR (200 MHz,
.
CDCl3) d 5.64–5.57 (m, 2H, CH]CH), 4.58 (s, 2H,
CH2OAc), 4.20 (pseudo t, J¼5.60 Hz, 1H, H-2), 3.60 (t,
J¼6.6 Hz, 2H, H-7), 2.09–1.97 (m, 2H, H-14, H-5), 2.02
(s, 3H, COCH3), 1.77–1.51 (m, 6H, H-13, H-5, C]CCH3),
1.37–1.22 (m, 4H, H-1, H-14, H-6), 1.19 (s, 3H, CH3CCH3),
1.14 (s, 3H, CH3CCH3), 0.87 (s, 9H, (CH3)3C), 0.03 (s,
6H, Si(CH3)2). ESIMS (m/z): 447 [M+Na]+. Anal. Calcd
for C24H44O4Si: C, 67.87; H, 10.44. Found: C, 67.89; H,
10.54.
4. Experimental section
4.1. General methods
Unless otherwise stated, all reactions were carried out under
nitrogen or argon atmosphere. Reagents were obtained from
commercial suppliers and used without further purifications.
Merck silica gel 60 was used for both column chromato-
graphy (70–230 mesh) and flash chromatography (230–400
mesh). NMR spectra were recorded on a Bruker AC200
(200 MHz) or Bruker Avance DPX400 (400 MHz). The
numbers for the peak assignments are referred to the
bicyclic systems, described in Scheme 1. The HPLC analysis
was recorded by reverse phase liquid chromatography on
Agilent series 1100 LC/MSD with an UV detector at
l¼254 nm and an electrospray ionization source (ESI)
with an electron beam of 70 eV. The LC elution methods (us-
ing Zorbax Eclipse XDBÒ, 4.6ꢂ150 mm, 5 mm C8 column)
were as following: method 1: 25 min, flow rate 1.15 mL/min,
4.1.2. (6E)-8-[3-(1-Hydroxyallyl)-2,2,4-trimethyl-3-cy-
clohexenyl]-8-[(2-methoxyethoxy)methoxy]-1,6-octa-
dien-3-ol (12). Compound 16 (79 mg, 0.22 mmol) in dry
CH2Cl2 at 0 ꢀC was treated with Dess–Martin periodinane
(DMP, 328 mg, 0.77 mmol). The mixture was stirred at
0 ꢀC for 5 min and for further 1 h at room temperature. Pen-
tane was then added, the mixture was stirred for 10 min and
then filtered through a pad of silica gel (diethyl ether 100%)
affording the dialdehyde, as revealed by HPLC–MS analy-
sis, which was used directly without further purification.
The dialdehyde was dissolved in dry THF and the mixture
was cooled at 0 ꢀC; vinylmagnesium bromide (0.54 mL of

504
M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
a 1 M solution in THF) was added dropwise and the mixture
was stirred at room temperature for 1 h. The reaction was
quenched with NH4Cl and the aqueous phase was extracted
twice with diethyl ether. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4 and con-
centrated. The resulting residue was purified by chromato-
graphy (diethyl ether/light petroleum ether 2:1), affording
the mixture of diasteroisomers of 12, as colourless oils
(50 mg, 56%, two steps). IR (film): n 3502, 1250,
1.75–1.70 (m, 1H, H-5), 1.46 (s, 3H, C]CCH3), 1.41–1.16
(m, 4H, H-1, H-14, H-13), 1.07 (s, 3H, CH3CCH3), 0.96 (s,
3H, CH3CCH3). 13C NMR (50 MHz, CDCl3) d 202.2,
195.0, 153.1, 141.3, 138.6, 137.9, 136.9, 134.2, 128.8,
127.9, 94.1, 82.0, 73.9, 66.7, 60.8, 54.7, 40.2, 31.70, 29.5,
26.8, 26.4, 26.3, 17.5, 17.0. ESIMS (m/z): 427 [M+Na]+.
Anal. Calcd for C24H36O5: C, 71.26; H, 8.97. Found: C,
71.12; H, 8.79.
1
890 cmꢁ1. H NMR (200 MHz, CDCl3) d 6.09–5.78 (m,
4.1.5. Compounds 19 and 20. Compound 18 (30 mg,
0.07 mmol) was dissolved in 7 mL of dry and degassed
CH2Cl2 and the mixture was heated at reflux. Grubbs’ cata-
lyst (20 mol %) was added via syringe pump over 5 h. After
12 h the mixturewas cooled, the solvent was removed and the
crude reaction mixture was purified by flash chromatography
(diethyl ether/light petroleum ether 1:3), affording 21 (2 mg)
and 20 (4 mg), 22 and traces of 19. Overall yield: 13%.
2H, COHCH]CH2, COHCH]CH2), 5.66–5.47 (m, 3H,
H-3, H-4, CCHOHCH), 5.40–5.02 (m, 4H, COCH]CH2,
C(OMEM)CH]CH2), 4.78–4.76 (m, 1H, CH2CHOHCH),
4.72 (d, J¼6.4 Hz, 1H, OHCHO), 4.56 (d, J¼6.4 Hz, 1H,
OHCHO), 4.08 (d, J¼7.4 Hz, 1H, H-2), 3.71–3.49 (m, 4H,
(CH2O)2), 3.35 (s, 3H, OCH3), 2.14–1.84 (m, 2H, H-14, H-
5), 1.71 (s, 3H, C]CCH3), 1.63–1.52 (m, 3H, H-13, H-5),
1.29 (s, 3H, CH3CCH3), 1.23 (s, 3H, CH3CCH3), 1.20–
1.08 (m, 4H, H-1, H-14, H-6). ESIMS (m/z): 431 [M+Na]+.
Anal. Calcd for C24H40O5: C, 70.55; H, 9.87. Found: C,
70.67; H, 9.78.
4.1.5.1. (3Z,8E)-10-((2-Methoxyethoxy)methoxy)-14,
15,15-trimethylbicyclo[9.3.1]pentadeca-1(14),3,8-triene-
2,5-dione (19). IR (film): n 1665, 1250, 890 cmꢁ1. 1H NMR
(200 MHz, CDCl3) d 6.77 (d, J¼11.7 Hz, 1H, CH]CH),
6.36 (d, J¼11.7 Hz, 1H, CH]CH), 5.64–5.36 (m, 2H, H-3,
H-4), 4.79 (d, J¼6.4 Hz, 1H, OHCHO), 4.64 (d, J¼6.4 Hz,
1H, OHCHO), 4.11–4.08 (m, 1H, H-2), 3.60–3.46 (m, 4H,
(CH2O)2), 3.37 (s, 3H, OCH3), 2.65 (t, J¼7.3 Hz, 2H, H-6),
2.17 (m, 2H, H-14, H-5), 2.01–1.95 (m, 1H, H-5), 1.71 (s,
3H, C]CCH3), 1.83–1.58 (m, 4H, H-1, H-14, H-13), 1.08
(s, 3H, CH3CCH3), 0.98 (s, 3H, CH3CCH3). ESIMS (m/z):
399 [M+Na]+. Anal. Calcd for C22H32O5: C, 70.18; H,
8.57. Found: C, 70.05; H, 8.44.
4.1.3. (E)-7-(3-Acetyl-2,2,4-trimethyl-3-cyclohexenyl)-7-
[(2-methoxyethoxy)methoxy]-5-hepten-2-one (17). Com-
pound 12 (20 mg, 0.049 mmol) was dissolved in 5 mL of
dry and degassed CH2Cl2 and the mixture was heated at re-
flux. Grubbs’ catalyst (30 mol %) was added via syringe
pump over 5 h. After 12 h the mixture was cooled, the sol-
vent was removed and the crude product was purified by
flash chromatography (diethyl ether/light petroleum ether
1:3), affording 17 (3.7 mg, 0.0098 mmol). The unreacted
starting material was recovered. IR (film): n 1670, 1250,
1
890 cmꢁ1. H NMR (200 MHz, CDCl3) d 5.57–5.42 (m,
4.1.5.2. (6E)-8-[(2-Methoxyethoxy)methoxy]-8-2,2,4-
trimethyl-3-[(E)-3-phenyl-2-propenoyl]-3-cyclohexenyl-
1,6-octadien-3-one (20). IR (film): n 1665, 1250, 890,
2H, H-3, H-4), 4.86 (d, J¼6.4 Hz, 1H, OHCHO), 4.64 (d,
J¼6.4 Hz, 1H, OHCHO), 4.04–3.99 (m, 1H, H-2), 3.70–
3.66 (m, 4H, (CH2O)2), 3.35 (s, 3H, OCH3), 2.67 (m, 2H,
H-6), 2.32 (m, 2H, H-14, H-5), 2.20 (s, 3H, CH2COCH3),
1.93 (s, 3H, CCOCH3), 1.83–1.67 (m, 1H, H-5), 1.52 (s,
3H, C]CCH3), 1.50–1.29 (m, 4H, H-1, H-14, H-13), 1.10
(s, 3H, CH3CCH3), 0.99 (s, 3H, CH3CCH3). 13C NMR
(50 MHz, CDCl3) d 139.3, 136.5, 133.9, 132.4, 128.2,
126.0, 116.1, 116.0, 92.5, 80.8, 73.2, 71.8, 66.5, 61.0,
58.3, 54.0, 38.5, 37.7, 30.7, 28.4, 26.3, 26.2, 17.5, 17.4.
ESIMS (m/z): 403 [M+Na]+. Anal. Calcd for C24H36O5: C,
69.44; H, 9.54. Found: C, 69.35; H, 9.41.
1
810 cmꢁ1. H NMR (400 MHz, CDCl3) d 7.57–7.36 (m,
5H, Ph), 7.44 (d, J¼16.0 Hz, 1H, PhCH]CH), 6.7 (d, J¼
16.0 Hz, 1H, COCH]CHPh), 6.33 (dd, J¼17.5, 10.6 Hz,
1H, COCH]CH2), 6.7 (d, J¼17.5 Hz, 1H, COCH]CH2),
5.90 (d, J¼10.6 Hz, 1H, COCH]CH2), 5.67–5.41 (m, 2H,
H-3, H-4), 4.70 (d, J¼6.8 Hz, 1H, OHCHO), 4.53 (d,
J¼6.8 Hz, 1H, OHCHO), 4.19–4.14 (m, 1H, H-2), 3.70–
3.40 (m, 4H, (CH2O)2), 3.34 (s, 3H, OCH3), 2.73 (t,
J¼7.6 Hz, 2H, H-6), 2.40 (m, 2H, H-14, H-5), 2.04–1.97
(m, 1H, H-5), 1.47 (s, 3H, C]CCH3), 1.36–1.15 (m, 4H,
H-1, H-14, H-13), 1.09 (s, 3H, CH3CCH3), 0.99 (s, 3H,
CH3CCH3). 13C NMR (100 MHz, CDCl3) d 202.2, 195.0,
153.1, 152.8, 141.3, 138.6, 136.9, 135.5, 134.2, 129.3,
129.1, 128.8, 128.7, 128.2, 126.7, 126.6, 94.1, 82.0, 73.9,
66.7, 60.8, 54.7, 40.2, 31.70, 29.5, 26.8, 26.4, 26.3, 17.5,
17.0. ESIMS (m/z): 530 [M+Na]+. Anal. Calcd for
C30H40O5: C, 74.97; H, 8.39. Found: C, 74.88; H, 8.24.
4.1.4. (6E)-8-(3-Acryloyl-2,2,4-trimethyl-3-cyclohex-
enyl)-8-[(2-methoxyethoxy)methoxy]-1,6-octadien-3-one
(18). Compound 12 (50 mg, 0.12 mmol) in dry CH2Cl2 at
0 ꢀC was treated with Dess–Martin periodinane (DMP,
182 mg, 0.42 mmol). The mixture was stirred at 0 ꢀC for
5 min and for further 1 h at room temperature. Pentane was
then added, the mixture was stirred for 10 min and then fil-
tered through a pad of silica gel (diethyl ether/light petro-
leum ether 1:1) affording 18 (colourless oils 36.4 mg,
75%), as mixture of diasteroisomers. IR (film): n 1665,
4.1.6. 1-[5-(1-Hydroxy-4-pentenyl)-2,6,6-trimethyl-1-cy-
clohexenyl]-5-hexen-1-one (28). Magnesium turnings
(44 mg, 2.16 mmol) in 5 mL of dry diethyl ether were
treated with 1-butenyl bromide (243 mg, 1.8 mmol). The
mixture was refluxed for 30 min and then cooled to 0 ꢀC.
The aldehyde 27 (224 mg, 0.9 mmol) in 5 mL of ether was
added dropwise to the clear solution of the Grignard’s re-
agent and the mixture was stirred at room temperature over-
night. The mixture was cooled to 0 ꢀC and 5 mL of saturated
NH4Cl solution was added. The aqueous phase was
1
1250, 890 cmꢁ1. H NMR (200 MHz, CDCl3) d 6.30–6.20
(m, 2H, CCOCH]CH2, CH2COCH]CH2), 6.12–5.76 (m,
4H, CCOCH]CH2, CH2COCH]CH2), 5.64–5.36 (m, 2H,
H-3, H-4), 4.67 (d, J¼6.6 Hz, 1H, OHCHO), 4.53 (d,
J¼6.6 Hz, 1H, OHCHO), 4.14 (dd, J¼2.5, 7.5 Hz, 1H,
H-2), 3.59–3.43 (m, 4H, (CH2O)2), 3.32 (s, 3H, OCH3),
2.63 (t, J¼7.4 Hz, 2H, H-6), 2.35 (m, 2H, H-14, H-5),

M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
505
extracted three times with diethyl ether; the combined
organic phases were washed with saturated NaHCO3 and
NaCl, dried over Na2SO4 anhydrous and evaporated invacuo.
The residue was purified by flash chromatography (45% di-
ethyl ether in light petroleum ether) to give the diastereoiso-
meric mixture of alcohols 28 (171 mg, 63%) as a colourless
oil. IR (film): n 3425, 1675, 910 cmꢁ1. 1H NMR (200 MHz,
CDCl3) d 5.75 (m, 2H, CH]CH2, CH]CH2), 4.9 (m, 4H,
CH]CH2, CH]CH2), 3.87–3.82 (m, 1H, CHOH), 2.46
(m, 2H, CH2C]O), 2.2–1.8 (m, 9H, H-1, H-13, H-14,
CH2CH]CH2, CH2CH]CH2), 1.8–1.5 (m, 4H,
CH2CH2CH2, CHCH2CH2), 1.44 (s, 3H, CH3C]C), 1.04
(s, 3H, CH3CCH3), 0.92 (s, 3H, CH3CCH3). ESIMS (m/z):
305 [M+1]+, 327 [M+Na]+. Anal. Calcd for C20H32O2: C,
79.90; H, 10.59. Found: C, 79.95; H, 10.48.
4.1.9. Cyclic dimers 31 and 32. To a 1 mM solution of 23
(38 mg, 0.125 mmol) in dry dichloroethane (125 mL) was
added Grubbs’ I ruthenium catalyst (31 mg, 0.037 mmol)
or Grubbs’ II catalyst (10 mg, 0.0125 mmol). The reaction
was refluxed for 24 h, then cooled and the solvent was
removed in vacuo. Purification of the residue by flash chro-
matography (30% diethyl ether in light petroleum ether) af-
forded a non-separable mixture of dimers 31 and 32 as
colourless oil (50 mg, 75% yield). IR (film): n 1690, 1675,
883 cmꢁ1. 1H NMR (400 MHz, CDCl3) d 5.4–5.25 (m, 2H,
CH]CH, CH]CH), 2.56–2.48 (m, 5H, H-1, CH2C]O,
CH2C]O), 2.45–2.15 (m, 2H, H-13), 2.12–1.92 (m,
4H, CH2CH]CH2, CH2CH]CH2), 1.88–1.55 (m, 4H,
H-14, CH2CH2CH2), 1.52 (s, 3H, CH3C]C), 1.21 (s, 3H,
CH3CCH3), 1.07 (s, 3H, CH3CCH3). ESIMS (m/z): 297
[C18H26O2+Na]+, 379 [C24H36O2+Na]+, 571 [M+Na]+.
Anal. Calcd for C36H52O4: C, 78.79; H, 9.55. Found: C,
78.85; H, 9.42. HPLC method 1 tR¼4.98 min and 6.15 min.
4.1.7. 1-[2,6,6-Trimethyl-5-(4-pentenoyl)-1-cyclohex-
enyl]-5-hexen-1-one (23). Tetra(n-propyl)ammonium per-
ruthenate (5 mg, 0.015 mmol) was added portionwise to a
stirred suspension of the alcohol 28 (88 mg, 0.29 mmol) in
4.1.10. 1-[5-(1-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-
allyl)-2,6,6-trimethyl-1-cyclohexenyl]-2-propyn-1-ol
(41). A 0.5 M solution of ethynylmagnesium bromide in
THF (17.46 mL, 8.73 mmol) was added dropwise over
5 min to a stirred solution of the aldehyde 40 (1.3 g,
2.91 mmol) in dry THF (15 mL) at 0 ꢀC under nitrogen
atmosphere. The mixture was stirred for 45 min at 0 ꢀC,
allowed to warm to room temperature and stirred for 2 h.
The clear solution was cooled to 0 ꢀC and then quenched
with saturated aqueous NH4Cl (10 mL) and diethyl ether
(20 mL). The organic layer was separated and the aqueous
layer was re-extracted with ether (3ꢂ20 mL). The combined
organic extracts were washed with brine (20 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo to afford a yel-
low oil. Purification by chromatography on silica gel (25%
diethyl ether in light petroleum ether) gave 1.11 g (85%)
of the diastereoisomeric propargyl alcohols 42 (17%) and
˚
dry dichloromethane (5 mL), 4 A molecular sieves and
4-methylmorpholine N-oxide (41 mg, 0.348 mmol). The re-
sulting suspension was stirred for 1 h at room temperature
and then filtered through Celite. After evaporation of the
solvent in vacuo, the residue was purified directly by flash
chromatography (40% diethyl ether in light petroleum ether)
affording 86 mg (99% yield) of compound 23 as a colourless
oil. IR (film): n 1690, 1675, 883 cmꢁ1. 1H NMR (400 MHz,
CDCl3) d 5.75 (m, 2H, CH]CH2, CH]CH2), 4.96 (m, 4H,
CH]CH2, CH]CH2), 2.58 (m, 5H, H-1, CH2C]O,
CH2C]O), 2.2–1.92 (m, 4H, H-13, H-14), 1.9–1.78 (m,
4H, CH2CH]CH2, CH2CH]CH2), 1.8–1.5 (m, 2H,
CH2CH2CH2), 1.57 (s, 3H, CH3C]C), 1.09 (s, 3H,
CH3CCH3), 1.05 (s, 3H, CH3CCH3). 13C NMR (100 MHz,
CDCl3) d 214.0, 201.8, 144.6, 142.5, 134.8, 134.3, 116.7,
115.9, 63.5, 41.0, 40.7, 34.0, 30.1, 29.8, 25.6, 24.7, 24.6,
24.1, 20.3, 17.4. ESIMS (m/z): 303 [M+1]+, 325 [M+Na]+.
Anal. Calcd for C20H30O2: C, 79.42; H, 10.00. Found: C,
79.32; H, 10.18.
41 (83%). IR (film): n 3442, 3085, 2129, 1613, 979 cmꢁ1
.
1H NMR (400 MHz, CDCl3) d 7.68–7.63 (m, 5H, Ph),
7.37–7.24 (m, 5H, Ph), 5.9 (ddd, J¼17, 9.7, 6.5 Hz, 1H,
CH]CH2), 5.03–4.89 (m, 3H, CH]CH2, CHOH), 4.37
(br d, J¼6.5 Hz, 1H, CHOSi), 2.45 (d, J¼2 Hz, 1H,
C^CH), 2.03 (app t, J¼4 Hz, 2H, H-13), 1.94 (s, 3H,
CH3C]C), 1.62–1.52 (m, 1H, H-1), 1.41–1.25 (m, 2H, H-
14), 1.05 (s, 9H, (CH3)3C), 0.81 (s, 3H, CH3CCH3), 0.68
(s, 3H, CH3CCH3). ESIMS (m/z): 495 [M+Na]+. Anal. Calcd
for C31H40O2Si: C, 78.76; H, 8.53. Found: C, 78.81; H, 8.73.
4.1.8. Acyclic dimers 29 and 30. 1-[3-(5-Hexenoyl)-2,2,4-
trimethyl-3-cyclohexenyl]-9-[2,6,6-trimethyl-5-(4-pente-
noyl)-1-cyclohexenyl]-4-nonene-1,9-dione. To a 1 mM
solution of 23 (40 mg, 0.132 mmol) in dry and degassed
dichloroethane (132 mL) Grubbs’ I ruthenium catalyst
(32 mg, 0.039 mmol), or Grubbs’ II catalyst (11 mg,
0.0132 mmol), was added. The reaction was stirred for
24 h at room temperature, then the solvent was removed in
vacuo. Purification of the residue by flash chromatography
(30% diethyl ether in light petroleum ether) afforded the
non-separable mixture of acyclic dimers 29 and 30, as col-
ourless oil (48 mg, 64% yield). IR (film): n 1690, 1675,
4.1.11. 1-[5-(1-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-
allyl)-2,6,6-trimethyl-1-cyclohexenyl]-2-propyn-1-ol
(42). Tetra(n-propyl)ammonium perruthenate (33 mg,
0.095 mmol) was added portionwise to a stirred suspension
of the alcohol 41 (900 mg, 1.9 mmol) in dry dichloro-
883 cmꢁ1
.
1H NMR (400 MHz, CDCl3) d 5.9–5.62 (m,
methane (15 mL), 4 A molecular sieves and 4-methylmor-
˚
1H, CH]CH2), 5.4–5.25 (m, 1H, CH]CH), 4.98 (br d, J¼
13.9 Hz, 1H, CH]CH2), 4.92 (br d, J¼9.6 Hz, 1H, CH]
CH2), 2.56–2.48 (m, 5H, H-1, CH2C]O, CH2C]O),
2.45–2.15 (m, 2H, H-13), 2.12–1.92 (m, 4H, CH2CH]CH2,
CH2CH]CH2), 1.88–1.55 (m, 4H, H-14, CH2CH2CH2),
1.52 (s, 3H, CH3C]C), 1.07 (s, 3H, CH3CCH3), 1.04 (s,
3H, CH3CCH3). ESIMS (m/z): 599 [M+Na]+, 615 [M+K]+.
Anal. Calcd for C38H56O4: C, 79.12; H, 9.78. Found: C,
79.32; H, 9.65. HPLC method 1 tR¼7.52 min and
8.02 min.
pholine N-oxide (266 mg, 2.28 mmol). The resulting
suspension was stirred for 50 min at room temperature and
then filtered through Celite. The oil residue, obtained for
evaporation of the solvent in vacuo, was used without further
purification. To a THF (3 mL) solution of the previously de-
scribed ketone (1.9 mmol) was added 9-BBN (0.5 M in THF,
15.2 mL, 7.6 mmol). The mixture was stirred at 0 ꢀC over-
night, then 10 mL of aqueous solution of NaHCO3 and
2 mL of H2O2 (30% v/v) were added and the solution was
stirred for further 30 min. The organic layer was separated

506
M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
and the aqueous layer was re-extracted with ethyl acetate.
The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4 and concentrated in vacuo af-
fording a yellow oil. Purification by flash chromatography
(25% diethyl ether in light petroleum ether) gave the allyl al-
cohol 42 (807 mg, 90% over two steps). IR (film): n 3442,
To a dry CH2Cl2 (2 mL) solution of the crude alcohol deriv-
ative 47 (0.311 mmol) was added dry TEA (56 mL,
0.404 mmol), DMAP (cat.) and acetic anhydride (35 mL,
0.373 mmol). The resulting yellow solution was stirred for
45 min at room temperature, then was diluted with dichloro-
methane and washed with HCl 1 M (2 mL), water (2ꢂ
2 mL), brine (3 mL) and dried over anhydrous Na2SO4. Af-
ter evaporation of the solvent, the residue was purified by
flash chromatography (20% diethyl ether in light petroleum
ether) affording 170 mg (82% over two steps) of the acetyl-
ated product 45 as pale yellow oil. IR (film): n 3080,
1
3085, 2129, 1613, 979 cmꢁ1. H NMR (400 MHz, CDCl3)
d 7.68–7.63 (m, 5H, Ph), 7.37–7.24 (m, 5H, Ph), 5.9 (ddd,
J¼17, 9.7, 6.5 Hz, 1H, CH]CH2), 5.03–4.89 (m, 3H,
CH]CH2, CHOH), 4.37 (br d, J¼6.5 Hz, 1H, CHOSi),
2.45 (d, J¼2 Hz, 1H, C^CH), 2.03 (app t, J¼4 Hz, 2H,
H-13), 1.94 (s, 3H, CH3C]C), 1.62–1.52 (m, 1H, H-1),
1.41–1.25 (m, 2H, H-14), 1.05 (s, 9H, (CH3)3C), 0.81 (s,
3H, CH3CCH3), 0.68 (s, 3H, CH3CCH3). 13C NMR
(100 MHz, CDCl3) d 139.2, 138.8, 134.4, 134.3, 132.6
(4C), 130.8 (2C), 129.0 (4H), 127.5, 114.5, 84.0, 77.3,
71.2, 56.0, 49.7, 36.6, 32.1, 25.6 (2C), 25.3 (3H), 19.6,
17.0. ESIMS (m/z): 495 [M+Na]+. Anal. Calcd for
C31H40O2Si: C, 78.76; H, 8.53. Found: C, 78.83; H, 8.70.
1
2129, 1745, 1613, 979 cmꢁ1. H NMR (400 MHz, CDCl3)
d 7.69–7.62 (m, 5H, Ph), 7.55–7.24 (m, 5H, Ph), 6.02 (s,
1H, C]CCHOAc), 5.92–5.65 (m, 2H, CHCH]CH2,
CH2CH]CH2), 5.17 (s, 1H, (CH3)2CCHOAc), 5.04 (dd,
J¼10, 1.5 Hz, 1H, CH2CH]CHcisH), 5.02 (dd, J¼18.7,
1.5 Hz, 1H, CH2CH]CHtransH), 4.6 (d, J¼10 Hz, 1H,
CHCH]CHH), 4.51 (d, J¼17 Hz, 1H, CHCH]CHH),
4.34 (d, J¼8.5 Hz, 1H, CHOSi), 2.35–2.18 (m, 4H,
H-13, CH2]CHCH2), 2.06 (s, 3H, CH3C]O), 2.02 (s,
3H, CH3C]O), 1.87 (s, 3H, CH3C]C), 1.81–1.42 (m,
3H, H-1, H-13), 1.25 (s, 3H, (CH3)2CCH2), 1.02 (s, 3H,
(CH3)2CCH2), 0.99 (s, 9H, (CH3)3C), 0.94 (s, 3H,
CH3CCH3), 0.89 (s, 3H, CH3CCH3). 13C NMR (100 MHz,
CDCl3) d 170.1, 169.5, 139.2, 138.8, 135.1, 134.4, 134.3,
132.6 (4C), 130.8 (2C), 129.0 (4H), 127.5, 115.3, 114.5,
91.7, 89.4, 79.2, 71.2, 60.4, 56.0, 41.1, 39.8, 36.6,
32.1, 25.6 (2C), 25.3 (3C), 20.2, 20.1, 19.8 (2C), 19.6,
17.04, 16.9. ESIMS (m/z): 707 [M+K]+, 691 [M+Na]+.
Anal. Calcd for C42H56O5Si: C, 75.41; H, 8.44. Found: C,
75.35; H, 8.48.
4.1.12. 1-[5-(1-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-
allyl)-2,6,6-trimethyl-1-cyclohexenyl]-2-propynyl ace-
tate (35). To a dry CH2Cl2 (6 mL) solution of propargyl
alcohol 42 (715 mg, 1.5 mmol) was added dry TEA
(192 mL, 1.38 mmol), DMAP (cat.) and acetic anhydride
(165 mL, 1.74 mmol). The resulting yellow solution was
stirred overnight at room temperature, then was diluted
with dichloromethane and washed with HCl 1 M (4 mL),
water (2ꢂ5 mL), brine (5 mL) and dried over anhydrous
Na2SO4. After evaporation of the solvent, the residue was
purified by flash chromatography (20% diethyl ether in light
petroleum ether) affording 763 mg (99%) of desired acetyl
derivative 35 as pale yellow oil. IR (film): n 3085, 2129,
4.1.14. 1-[5-(1-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-
allyl)-2,6,6-trimethyl-1-cyclohexenyl]-4-hydroxy-5-(2-
methylenecyclohexyl)-2-pentynyl acetate (48). The alkyne
35 (250 mg, 0.486 mmol) in dry THF (3 mL) at ꢁ78 ꢀC
was treated with a 1 M solution of LiHMSA (496 mL,
0.496 mmol) and stirred at low temperature for 30 min. A
solution of the aldehyde 44 (80 mg, 0.583 mmol) in dry
THF was then added, via cannula, to the solution of the lithi-
ated alkyne at ꢁ78 ꢀC. The mixture was stirred overnight
then, after partial evaporation of the solvent, it was diluted
with diethyl ether and washed with a saturated solution of
NH4Cl (2ꢂ3 mL), H2O (2ꢂ3 mL), brine (2 mL) and dried
over anhydrous Na2SO4. After evaporation of the solvent,
the residue was purified by flash chromatography (30% di-
ethyl ether in light petroleum ether) affording two diastereo-
isomeric alcohols 48 (total yield of 75%, ratio 3:1) as yellow
pale oils. The data are referred to the major compound,
whose structure is described in Scheme 9. IR (film): n
1745, 1613, 979 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d 7.67–7.64 (m, 5H, Ph), 7.37–7.33 (m, 5H, Ph), 5.9 (ddd,
J¼17, 10.6, 6.5 Hz, 1H, CH]CH2), 5.86 (d, J¼2 Hz, 1H,
CHOAc), 5.04 (br d, J¼10.6 Hz, 1H, CH]CH2), 5 (br d,
J¼17 Hz, 1H, CH]CH2), 4.36 (br d, J¼6.5 Hz, 1H,
CHOSi), 2.44 (s, 1H, C^CH), 2.03 (s, 3H, CH3C]O),
1.92–1.8 (m, 4H, H-13, H-14), 1.87 (s, 3H, CH3C]C),
1.59–1.50 (m, 1H, H-1), 1.25 (s, 3H, CH3CCH3), 1.04 (s,
9H, (CH3)3C), 0.99 (s, 3H, CH3CCH3). 13C NMR
(100 MHz, CDCl3) d 169.3, 139.2, 138.8, 134.4, 134.3,
132.6 (4C), 130.8 (2C), 129.0 (4H), 127.5, 114.5, 84.0,
77.3, 71.2, 63.4, 56.0, 36.6, 32.1, 25.6 (2C), 25.3 (3H),
21.0, 19.6, 17.0. ESIMS (m/z): 537 [M+Na]+. Anal. Calcd
for C33H42O3Si: C, 77.00; H, 8.22. Found: C, 77.81; H, 8.73.
4.1.13. 4-(Acetyloxy)-1-[5-(1-{[1-(tert-butyl)-1,1-diphenyl-
silyl]oxy}allyl)-2,6,6-trimethyl-1-cyclohexenyl]-5,5-di-
methyl-7-octen-2-ynyl acetate (45). The alkyne 35
(160 mg, 0.311 mmol) in dry THF (2 mL) at ꢁ78 ꢀC was
treated with a 1 M solution of LiHMSA (317 mL,
0.317 mmol) and stirred at low temperature for 30 min. A
solution of the aldehyde 43 (85 mL, 0.622 mmol) in dry
THF (1 mL) was then added, via cannula, to the solution
of the lithiated alkyne at ꢁ78 ꢀC. The mixture was stirred
overnight then, after partial evaporation of the THF, it was
diluted with diethyl ether and washed with a saturated solu-
tion of NH4Cl (2ꢂ3 mL), H2O (2ꢂ3 mL), brine (2 mL) and
dried over anhydrous Na2SO4. The yellow-brown oil ob-
tained for evaporation of the solvent was acetylated, without
purification. HPLC method 2 tR¼16.23 min.
3442, 3080, 2230, 1740, 1613, 979 cmꢁ1 1H NMR
.
(400 MHz, CDCl3) d 7.65–7.55 (m, 5H, Ph), 7.48–7.32
(m, 5H, Ph), 6.06 (s, 1H, C]CCHOAc), 5.85 (ddd, J¼17,
12, 8.5 Hz, 1H, CH]CH2), 4.70–4.40 (m, 6H, CH]CH2,
CH2]C, CHOH, CHOSi), 2.35–2.18 (m, 4H, H-13,
CH2]CCH2CH2), 2.06 (s, 3H, CH3C]O), 1.97–1.87
(m, 3H, H-5, H-6), 1.85 (s, 3H, CH3C]C), 1.70–1.65 (m,
5H, H-1, H-14, CH2]CCHCH2), 1.30–1.20 (m, 4H,
CH2CH2CH2CH2), 1.1 (s, 3H, CH3CCH3), 1.02 (s, 9H,
(CH3)3C), 0.97 (s, 3H, CH3CCH3). 13C NMR (100 MHz,
CDCl3) d 170.1, 148.2, 138.8, 134.4, 134.3, 132.6 (4C),
130.8 (2C), 129.0 (4C), 127.5, 110.5, 91.7, 89.4, 79.2,
71.2, 62.0, 60.8, 56.0, 38.5, 36.8, 36.6, 35.2, 35.1, 32.1,

M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
507
30.9, 28.1, 26.0, 25.6 (2C), 25.3 (3C), 19.8, 19.6, 17.04,
16.9. ESIMS (m/z): 675 [M+Na]+. Anal. Calcd for
C42H56O4Si: C, 77.25; H, 8.64. Found: C, 77.20; H, 8.69.
HPLC method 1 tR¼9.17 min.
4.1.17. tert-Butyl[(1-5-[(E)-2-(5-[1-(tert-butyl)-1,1-dime-
thylsilyl]oxy-4,4-dimethyl-1-cyclopentenyl)-2-propenyli-
dene]-4-methyl-3-cyclohexenylallyl)oxy]dimethylsilane
(53). To a 1 mM solution of 52 (14 mg, 0.023 mmol) in dry
dichloromethane (23 mL) Grubbs’ II ruthenium catalyst
(2 mg, 0.0023 mmol) was added. The reaction was stirred
for 24 h at room temperature, then the solvent was removed
in vacuo. Purification of the residue by flash chromato-
graphy (15% diethyl ether in light petroleum ether) afforded
53, as colourless oil (8.5 mg, 66% yield). IR (film): n 3090,
4.1.15. 4-(Acetyloxy)-4-[5-(1-{[1-(tert-butyl)-1,1-diphenyl-
silyl]oxy}allyl)-2,6,6-trimethyl-1-cyclohexenyl]-1-[(2-
methylenecyclohexyl)methyl]-2-butynyl acetate (46). To
a dry CH2Cl2 (3 mL) solution of alcohol 48 (190 mg,
0.3 mmol) was added dry TEA (54 mL, 0.39 mmol),
DMAP (cat.) and acetic anhydride (34 mL, 0.36 mmol).
The resulting yellow solution was stirred for 45 min at
room temperature, then was diluted with dichloromethane
and washed with HCl 1 M (2 mL), water (2ꢂ2 mL), brine
(3 mL) and dried over anhydrous Na2SO4. After evaporation
of the solvent, the oil residue was purified by flash chroma-
tography (20% diethyl ether in light petroleum ether) afford-
ing 206 mg (99%) of the acetylated product 46 as pale
1
1655, 883 cmꢁ1. H NMR (400 MHz, CDCl3) d 5.92–5.72
(m, 4H, H-13, H-10, C]CHCH2, CHCH]CH2), 5.12–
4.93 (m, 4H, CHCH]CH2, C]CH2), 4.39 (br d,
J¼7.6 Hz, 1H, CHCHOSi), 4.16 (s, 1H, CCHOSi), 2.18–
2.03 (m, 3H, H-1, C]CHCH2), 1.66 (s, 3H, CH3C]C),
1.62–1.41 (m, 2H, H-14), 1.51 (s, 3H, CH3CCH3), 1.49 (s,
3H, CH3CCH3), 0.99 (s, 3H, (CH3)2CCH2), 0.92 (s, 3H,
(CH3)2CCH2), 0.89 (s, 9H, (CH3)3C), 0.86 (s, 9H, (CH3)3C),
0.12 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si), 0.04 (s, 3H,
CH3Si), ꢁ0.01 (s, 3H, CH3Si). 13C NMR (100 MHz,
CDCl3) d 152.7, 142.7, 135.4, 135.2, 131.8, 129.5, 116.9,
113.5, 101.6, 85.2, 73.0, 71.6, 51.4, 42.7, 39.8, 39.2, 29.7,
27.8, 26.0, 25.9 (2C), 25.8, 25.7, 24.0, 22.8, 22.7, 21.2,
18.1, 18.0, 17.4, ꢁ3.4, ꢁ4.2, ꢁ4.5, ꢁ5.2. ESIMS (m/z):
595 [M+K]+, 579 [M+Na]+, 557 [M+1]+. Anal. Calcd
for C34H60O2Si2: C, 73.31; H, 10.86. Found: C, 73.15; H,
10.92.
yellow oil. IR (film): n 3080, 2230, 1740, 1613, 979 cmꢁ1
.
1H NMR (400 MHz, CDCl3) d 7.69–7.61 (m, 5H, Ph),
7.40–7.28 (m, 5H, Ph), 6 (s, 1H, C]CCHOAc), 5.83 (ddd,
J¼17, 12, 8.5 Hz, 1H, CH]CH2), 5.44–3.99 (m, 1H,
CH2CHOAc), 4.66 (br s, 1H, CH2]C), 4.62 (br s, 1H,
CH2]C), 4.53 (br d, J¼12 Hz, 1H, CH]CHcisH), 4.49
(br d, J¼17 Hz, 1H, CH]CHtransH), 4.33 (br d, J¼8.5 Hz,
1H, CHOSi), 2.35–2.18 (m, 4H, H-13, CH2]CCH2CH2),
2.06 (s, 3H, CH3C]O), 2.02 (s, 1H, CH3C]O), 1.97–
1.87 (m, 3H, H-5, H-6), 1.85 (s, 3H, CH3C]C), 1.70–1.65
(m, 5H, H-1, H-14, CH2]CCHCH2), 1.30–1.20 (m, 4H,
CH2CH2CH2CH2), 1.1 (s, 3H, CH3CCH3), 1.02 (s, 9H,
(CH3)3C), 0.97 (s, 3H, CH3CCH3). 13C NMR (100 MHz,
CDCl3) d 170.1, 169.5, 148.2, 138.8, 134.4, 134.3, 132.6
(4C), 130.8 (2C), 129.0 (4C), 127.5, 110.5, 91.7, 89.4,
79.2, 71.2, 64.2, 63.0, 56.0, 38.5, 36.8, 36.6, 35.2, 35.1,
32.1, 30.9, 28.1, 26.0, 25.6 (2C), 25.3 (3C), 19.8 (2C),
19.6, 17.04, 16.9. ESIMS (m/z): 733 [M+K]+, 717
[M+Na]+. Anal. Calcd for C44H58O5Si: C, 76.04; H, 8.41.
Found: C, 75.95; H, 8.5.
4.1.18. (Z)-4-(Acetyloxy)-4-[5-(1-{[1-(tert-butyl)-1,1-di-
phenylsilyl]oxy}allyl)-2,6,6-trimethyl-1-cyclohexenyl]-1-
[(2-methylenecyclohexyl)methyl]-2-butenyl acetate (49).
A degassed mixture of 46 (30 mg, 0.043 mmol), Lindlar’s
catalyst (15 mg), quinoline (5 mol %) in light petrol ether
(4 mL) with few drops of ethyl acetate was shaken under
H2 for 2 h. The catalyst was filtered off through Celite and
the mixture was washed with aqueous 5% KHSO4
(2ꢂ2 mL), water (1ꢂ2 mL), brine (1ꢂ2 mL) and dried
over anhydrous Na2SO4. After evaporation of the solvent,
the oil residue was purified by flash chromatography (30%
diethyl ether in light petroleum ether) affording 29 mg
(99%) of the partially reduced product 49 as pale yellow
4.1.16. 4-(Acetyloxy)-1-[5-(1-hydroxyallyl)-2,6,6-tri-
methyl-1-cyclohexenyl]-5,5-dimethyl-7-octen-2-ynyl ace-
tate (50). A dry THF (2 mL) solution of the silyl ether 45
(33.5 mg, 0.05 mmol) was treated with a 1 M solution of
TBAF (1.5 mL, 1.5 mmol) and stirred at 40 ꢀC for 20 h.
The reaction mixture was then cooled to room temperature
and evaporated to give a yellow-brown oil. The crude mate-
rial was purified by flash chromatography (50% ethyl acetate
in light petroleum ether) affording 13.5 mg (62%) of the de-
silylated product 50 as pale yellow oil. IR (film): n 3440,
1
oil. IR (film): n 3440, 3080, 1740, 1660, 979 cmꢁ1. H
NMR (200 MHz, CDCl3) d 7.69–7.61 (m, 5H, Ph), 7.40–
7.28 (m, 5H, Ph), 6.32 (d, J¼5 Hz, 1H, C]CCHOAc),
5.82 (dd, J¼5, 11 Hz, 1H, CH]CH), 5.83 (ddd, J¼17, 12,
8.5 Hz, 1H, CH]CH2), 5.45 (dd, J¼8, 11 Hz, 1H,
CH]CH), 5.22 (dt, J¼8, 11 Hz, 1H, CH2CHOAc), 4.66
(br s, 1H, CH2]C), 4.62 (br s, 1H, CH2]C), 4.53 (br d,
J¼12 Hz, 1H, CH]CHcisH), 4.49 (br d, J¼17 Hz, 1H,
CH]CHtransH), 4.33 (br d, J¼8.5 Hz, 1H, CHOSi),
2.35–2.18 (m, 4H, H-13, CH2]CCH2CH2), 2.06 (s, 3H,
CH3C]O), 2.02 (s, 3H, CH3C]O), 1.97–1.87 (m, 3H, H-5,
H-6), 1.85 (s, 3H, CH3C]C), 1.70–1.65 (m, 5H, H-1, H-14,
CH2]CCHCH2), 1.30–1.20 (m, 4H, CH2CH2CH2CH2), 1.1
(s, 3H, CH3CCH3), 1.02 (s, 9H, (CH3)3C), 0.97 (s, 3H,
CH3CCH3). 13C NMR (50 MHz, CDCl3) d 172.5 (2C),
149.0, 138.9, 135.0 (2C), 133.7, 133.3, 132.2 (4C), 131.3,
130.3 (2C), 129.0 (4C), 127.2, 115.8, 109.9, 72.7, 59.9,
55.9, 38.4, 37.7, 37.6, 36.9, 33.8, 31.2, 28.8, 26.5 (2C),
25.6 (3C), 25.1, 21.2, 21.1 (2C), 19.6, 18.1, 17.2. ESIMS
(m/z): 735 [M+K]+, 719 [M+Na]+, 697 [M+1]+. Anal.
Calcd for C44H60O5Si: C, 75.82; H, 8.68. Found: C, 75.70;
H, 8.74.
1
3080, 2129, 1745, 1613, 979 cmꢁ1. H NMR (400 MHz,
CDCl3) d 6.01 (s, 1H, C]CCHOAc), 5.95–5.68 (m, 2H,
CHCH]CH2, CH2CH]CH2), 5.22 (br d, J¼17.5 Hz, 1H,
CHCH]CH2), 5.14 (s, 1H, (CH3)2CCHOAc), 5.11 (br d,
J¼10 Hz, 1H, CHCH]CH2), 5.03 (dd, J¼8, 1.5 Hz, 1H,
CH2CH]CH2), 4.97 (dd, J¼20, 1.5 Hz, 1H, CH2CH]
CH2), 4.46 (br s, 1H, CHOH), 2.35–2.18 (m, 4H,
H-13, CH2]CHCH2), 2.06 (s, 3H, CH3C]O), 2.02 (s,
3H, CH3C]O), 1.87 (s, 3H, CH3C]C), 1.81–1.42 (m,
3H, H-1 H-14), 1.25 (s, 3H, (CH3)2CCH2), 1.02 (s, 3H,
(CH3)2CCH2), 0.94 (s, 3H, CH3CCH3), 0.89 (s, 3H,
CH3CCH3). ESIMS (m/z): 469 [M+K]+, 453 [M+Na]+.
Anal. Calcd for C26H38O5: C, 72.53; H, 8.90. Found: C,
72.49; H, 8.96.

508
M. L. Renzulli et al. / Tetrahedron 63 (2007) 497–509
4.1.19. (2Z)-1-(5-(1-Hydroxyallyl)-2,6,6-trimethylcyclo-
hex-1-enyl)-5-(2-methylenecyclohexyl)pent-2-ene-1,4-
diol (59). A dry THF (1.5 mL) solution of the silyl ether 49
(50 mg, 0.07 mmol) was treated with a 1 M solution of
TBAF (700 mL, 0.7 mmol) and stirred at 40 ꢀC for 20 h.
The reaction mixture was then cooled to room temperature
and evaporated to give a yellow-brown oil, which was then
dissolved in CH3OH (2 mL) and treated with K2CO3
(30 mg, 0.21 mmol). The resulting mixture was stirred for
24 h and the residue obtained after evaporation of the solvent
in vacuo was purified by flash chromatography (40% ethyl
acetate in light petroleum ether) affording 19 mg (75%
over two steps) of desired product 59 as colourless oil. IR
in light petroleum ether) afforded 60, as colourless oil
(4.5 mg, 25% yield). IR (film): n 3440, 3080, 1660,
1
979 cmꢁ1. H NMR (400 MHz, CDCl3) d 5.6 (dd, J¼5,
7 Hz, 1H, CH]CH), 5.5 (d, J¼6 Hz, 1H, CH]CH), 5.45
(dd, J¼7, 7.5 Hz, 1H, C]CCHOH), 5.15 (d, J¼10 Hz,
1H, CHCH]C), 4.45 (br d, J¼10 Hz, 1H, CHOHCH]C),
4.38 (dd, J¼6, 7.5 Hz, 1H, CH2CHOH), 2.35–2.18 (m, 4H,
H-13, CH2]CCH2CH2), 1.97–1.87 (m, 3H, H-5, H-6),
1.85 (s, 3H, CH3C]C), 1.70–1.65 (m, 5H, H-1, H-14,
CH2]CCHCH2), 1.30–1.20 (m, 4H, CH2CH2CH2CH2),
1.1 (s, 3H, CH3CCH3), 0.97 (s, 3H, CH3CCH3). 13C NMR
(100 MHz, CDCl3) d 140.1, 133.8, 133.0, 128.2, 126.4,
122.8, 68.8, 65.8, 63.9, 56.7, 40.6, 37.2, 36.5, 34.2, 31.9,
31.7, 29.1, 26.4, 26.3, 25.2, 18.0, 17.8. ESIMS (m/z): 385
[M+K]+, 369 [M+Na]+, 347 [M+H]+. Anal. Calcd for
C22H34O3: C, 76.26; H, 9.89. Found: C, 75.81; H, 10.54.
(film): n 3392, 3084, 1750, 1367, 1092, 986 cmꢁ1 1H
.
NMR (400 MHz, CDCl3) d 5.88 (ddd, J¼17, 11, 4.8 Hz,
1H, CH]CH2), 5.71–5.66 (m, 1H, CH]CH), 5.47–5.41
(m, 1H, CH]CH), 5.22 (d, J¼17 Hz, 1H, CH]CHtransH),
5.1 (d, J¼11 Hz, 1H, CH]CHcisH), 5.09 (d, J¼6.7 Hz,
1H, C]CCHOH), 4.7–4.65 (m, 3H, CH2]C, CH2CHOH),
4.45 (d, J¼3.8 Hz, 1H, CHOH), 2.30–2.1 (m, 2H,
CH2]CCH2CH2), 1.9–1.5 (m, 10H, H-1, H-5, H-6, H-13,
H-14, CH2]CCHCH2), 1.8 (s, 3H, CH3C]C), 1.43–0.8
(m, 4H, CH2CH2CH2CH2), 0.86 (s, 3H, CH3CCH3), 0.83
(s, 3H, CH3CCH3). 13C NMR (100 MHz, CDCl3) d 148.3,
139.2, 133.8, 133.0, 128.2, 126.4, 115.9, 109.4, 68.8, 65.8,
63.9, 56.7, 40.6, 37.9, 37.2, 36.5, 34.2, 31.9, 29.1, 26.4,
26.3, 25.2, 18.0, 17.8. ESIMS (m/z): 397 [M+Na]+. Anal.
Calcd for C24H38O3: C, 76.96; H, 10.23. Found: C, 76.81;
H, 10.24.
Acknowledgements
We are grateful to the Research Training Network (HPRN-
CT-2000-00018) ‘Design and Synthesis of Novel Paclitaxel
(TaxolÒ) Mimics Using a Common Pharmacophore Model
for Microtubule-Stabilizing Agents (MSAAs)’, FIRB
(RBAU01LR5P) ‘Development of a Common Pharmaco-
phore Model for Microtubule-Stabilizing Anticancer Agents
to be used to Design and Synthesize Novel Paclitaxel
Mimics’ for the financial support. One of us (M.B.) thanks
the Merck Research Laboratories for the 2002 Academic
Development Programme (ADP) Chemistry Award.
4.1.20. 3,8-Secotaxane diterpenoid 58. To a solution of
49 (35 mg, 0.05 mmol) in dry dichloromethane (15 mL),
Grubbs’ II ruthenium catalyst (4.5 mg, 0.005 mmol) was
added. The reaction was stirred for 36 h at room tempera-
ture, then the solvent was removed in vacuo. Purification
of the residue by flash chromatography (30% diethyl ether
in light petroleum ether) afforded 58, as colourless oil
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2006.
10.058.
(7 mg, 20% yield). IR (film): n 3080, 1740, 1660, 979 cmꢁ1
.
1H NMR (400 MHz, CDCl3) d 7.69–7.61 (m, 5H, Ph), 7.40–
7.28 (m, 5H, Ph), 6.32 (d, J¼5 Hz, 1H, C]CCHOAc), 5.74
(dd, J¼5, 7 Hz, 1H, CH]CH), 5.55 (dd, J¼6, 7 Hz, 1H,
CH]CH), 5.47–5.41 (m, 1H, CH2CHOAc), 5.1 (d,
J¼10 Hz, 1H, CHCH]C), 4.32 (dd, J¼2.5, 10 Hz, 1H,
CHOSi), 2.35–2.18 (m, 4H, H-13, CH2]CCH2CH2), 2.06
(s, 3H, CH3C]O), 2.02 (s, 3H, CH3C]O), 1.97–1.87 (m,
3H, H-5, H-6), 1.85 (s, 3H, CH3C]C), 1.70–1.65 (m,
5H, H-1, H-14, CH2]CCHCH2), 1.30–1.20 (m, 4H,
CH2CH2CH2CH2), 1.1 (s, 3H, CH3CCH3), 1.02 (s, 9H,
(CH3)3C), 0.97 (s, 3H, CH3CCH3). 13C NMR (100 MHz,
CDCl3) d 172.5 (2C), 140.1, 135.0 (2C), 133.7, 133.3,
132.2 (4C), 131.3, 130.3 (2C), 129.0 (4C), 127.2, 122.3,
65.5, 59.9, 55.9, 38.4, 37.6, 36.9, 33.8, 31.8, 31.2, 28.8,
26.5 (2C), 25.6 (3C), 25.1, 21.2, 21.1 (2C), 19.6, 18.1,
17.2. ESIMS (m/z): 707 [M+K]+, 691 [M+Na]+, 669
[M+H]+. Anal. Calcd for C42H56O5Si: C, 75.41; H, 8.44.
Found: C, 75.15; H, 8.76.
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