Effects of allylic and homoallylic substituents on the ring closing metathesis reaction used to synthesise simplified eleuthesides

Article abstract of DOI:10.1016/j.tetlet.2003.09.010

During the course of our synthetic studies towards simplified eleuthesides, we have found that p-methoxyphenyl (PMP) protected allylic alcohols are compatible with the RCM reaction and can give better yields than the corresponding free allylic alcohols.

Full text of DOI:10.1016/j.tetlet.2003.09.010

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7913–7919
Effects of allylic and homoallylic substituents on the ring closing
metathesis reaction used to synthesise simplified eleuthesides
Lorenzo Caggiano, Damiano Castoldi, Raphael Beumer,† Pau Bayo´n,‡ Joachim Telser§ and
Cesare Gennari*
Dipartimento di Chimica Organica e Industriale, Centro di Eccellenza C.I.S.I., Universita’ di Milano, Istituto CNR di Scienze e
Tecnologie Molecolari, via Venezian 21, I-20133 Milano, Italy
Received 10 July 2003; revised 24 August 2003; accepted 3 September 2003
Abstract—During the course of our synthetic studies towards simplified eleuthesides, we have found that p-methoxyphenyl (PMP)
protected allylic alcohols are compatible with the RCM reaction and can give better yields than the corresponding free allylic
alcohols.
© 2003 Elsevier Ltd. All rights reserved.
Sarcodictyins A and B 1 and eleutherobin 2 (the
‘eleutheside’ family of microtubule-stabilising agents,
Scheme 1) have been found to possess potent activities
against paclitaxel-resistant tumour cell lines.1–3 We have
recently shown that simplified analogues of the natural
products (lacking inter alia the C4/C7 ether bridge)
retain potent microtubule-stabilising activity whilst
being more easily accessible by total synthesis.4
The synthesis of these simplified analogues was
achieved starting from commercially available (R)-car-
vone. Using standard chemistry already reported,3a,g
the first key aldehyde intermediate 3 was generated on
multigram scale. The diene cyclisation precursors were
then synthesised using either Brown’s isopinocampheyl-
borane-mediated asymmetric allylation reactions5 or,
more recently, Hafner–Duthaler enantioselective allylti-
Scheme 1. Structures of sarcodictyins A, B and eleutherobin.
Keywords: ring closing metathesis; protective groups; p-methoxyphenyl (PMP); antitumour compounds.
* Corresponding author. Tel.: +39-025031-4091; fax: +39-025031-4072; e-mail: cesare.gennari@unimi.it
† Present address: Roche Vitamins Ltd., VFK R&D Actives, CH-4070 Basel, Switzerland.
‡ Present address: Dept. de Qu´ımica, Unitat Qu´ımica Orga`nica, Universitat Auto`noma de Barcelona, 08193 Cerdanyola del Valle`s, Spain.
§ Present address: Medicinal Chemistry PH-R EU CR MC6, Bayer AG, Pharma Research, D-42096 Wuppertal, Germany.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.010

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L. Caggiano et al. / Tetrahedron Letters 44 (2003) 7913–7919
tanation chemistry.6 The key-step of the syntheses is the
formation of the 6–10 fused bicyclic ring-system using
ring closing metathesis (RCM)7 (Schemes 2 and 3).
RCM has been used to great effect in the formation of
many medium ring systems. The influence of concentra-
tion, temperature and catalyst structure has been the
subject of much investigation, however the effects of
the allylic and homoallylic substitution is still not com-
pletely understood.
Scheme 3. RCM catalyst structures and terms used.8
The most simplified analogue, with only substitution at
C3 and C8 (using the eleutheside numbering), could be
obtained from the diene precursor 4 using the robust
second generation ‘Grubbs-II’ RCM catalyst9 in an
excellent 88% isolated yield, solely as the Z stereoiso-
mer (Scheme 4).4,10 This stereochemical course, which
was found to be common to all the substrates reported
in the present letter (vide infra), is likely to reflect
thermodynamic control.11 No reaction was observed
with the first generation ‘Grubbs-I’ catalyst.
cyclised, compared to the allylic methyl ether 5, to
afford the corresponding ‘south trisubstituted’ 6–10
fused bicyclic framework in good yields (Scheme 6).4
These results are in accordance with the observations of
Hoye and others: allylic ethers were found to retard the
RCM reaction while a rate acceleration was associated
with allylic alcohols.12,13 The lack of reactivity of the
allylic diol 9 could be attributed to the dense function-
ality at the reaction site.
Following the above rationale, diene 13a was chosen as
the cyclisation precursor since a free allylic alcohol,
together with pivaloyl- and TBDPS-protected homoal-
lylic alcohols, were shown to be compatible with the
RCM reaction (for comparison see Scheme 6 and the
failed cyclisation of the allylic methyl ether 6 in Scheme
4). Formation of the diene 13a was accomplished using
Brown’s chemistry, which established the syn relation-
ship at C7–C8. Submission of the allylic alcohol 13a to
the RCM reaction conditions, however, failed to afford
any of the cyclised material. Protection of the C8
alcohol as the acetate (13b) or oxidation to the ketone
(13c) did not aid cyclisation. Attempts to cyclise the
acetonide diene 14 also failed.14 Interconversion of the
C3 and C8 protective groups of the diene 13a gave the
allylic alcohol 15 which did undergo cyclisation, albeit
in a disappointing 24% yield (Scheme 7).
Attempts to generate ‘trisubstituted’ analogues were
made using the dienes 5 and 6 (Scheme 4). These RCM
precursors were prepared from successive asymmetric
allylation and methoxyallylation reactions using
Brown’s methodology. Treatment with the Grubbs-II
or Nolan catalysts,9 however, gave only decomposition
in the case of 5 and possible dimerisation with 6.
Changing catalyst loading and reaction times still gave
no observable product. Similarly, attempted RCM reac-
tion of the tetrasubstituted diene 7, obtained from two
successive Brown methoxyallylations, also gave none of
the desired cyclised tetrasubstituted framework (Scheme
4).
A similar lack of reactivity in the RCM reaction was
observed with the tetrasubstituted dienes 8 possessing
two MOM protected allylic alcohols (Scheme 5).
Deprotection of the allylic O-MOM groups to reveal
free allylic alcohols (9) did not aid reactivity in the
RCM reaction. Using a silyl bridge (10) to add a
conformational constraint also failed to improve
reactivity.
The rationale for this interconversion was that although
the substitution pattern in compound 13a is the same as
that shown by the successful cyclisation precursors 11
and 12 (allylic alcohol, homoallylic OPiv and OTBDPS,
Scheme 6), it is not the same with respect to the
relationship between the groups [OH adjacent to OTB-
DPS (13a) versus OH adjacent to OPiv (11 and 12)].
Again this observation demonstrates the importance of
fine tuning the allylic and homoallylic alcohol protec-
tive groups for a successful RCM reaction.
The allylic alcohols 11 and 12 were prepared in a
similar fashion (Brown’s allylation and MOM-oxyallyl-
ation followed by O-MOM deprotection) and subjected
to the RCM reaction.4 The precursors were smoothly
Scheme 2. General synthetic strategy to the simplified eleutheside analogues.

L. Caggiano et al. / Tetrahedron Letters 44 (2003) 7913–7919
7915
Scheme 4. Attempted RCM reactions with various allylic and homoallylic substituents.8
The formation of the ‘north trisubstituted’ diene 16
with C7–C8 anti stereochemistry was accomplished
using
alcohol and a PMP-protected allylic alcohol with the
Grubbs-II catalyst gave the desired 6–10 fused bicycle
in 80% yield (Scheme 8).
a
stereoselective oxyallyltitanation reaction.6
Using PMPOallyl as the reagent, the product obtained
was the PMP protected allylic alcohol (PMP=p-
methoxyphenyl). Using Brown’s allylation chemistry,5
the second olefin fragment was stereoselectively inserted
in the south chain to give diene 18. Protective group
manipulations transformed diene 18 into the desired
cyclisation precursor 16 which had the same substitu-
tion pattern as shown in diene 15. Reaction with
Grubbs-II catalyst gave a mixture of compounds, from
which the desired product could be isolated in a simi-
larly poor yield (21%, Scheme 8). No significant differ-
ence was observed in the reactivity of the two
diastereomers (15 and 16) in the RCM reaction.15
At present, the reasons why the allylic OPMP group
facilitates the RCM reaction are not completely under-
stood. Sterically, the PMP can be considered relatively
small, even smaller than a Me group (effective Van der
,
Waals radius of Ph=1.62 A compared to Me=1.80
16
,
A).
The C8 methyl substituted dienes 19 and 20 with C7-C8
anti stereochemistry were prepared by stereoselective
crotyltitanation.6 Treatment with the Grubbs-II catalyst
in toluene at 80°C gave the desired cyclised products in
good yields. These results demonstrate that the RCM
reaction is compatible with both the allylic methyl and
homoallylic MOM-protected alcohol functionalities.
Again the stereochemistry at C3 appears not to have a
dramatic effect on the reaction, as similar yields were
achieved (Scheme 9).
It was noted, however, that if the RCM reaction was
performed with the precursor PMP-protected allylic
alcohol (17), higher yields could be obtained under
similar reaction conditions. This is, for the first time, a
result in disagreement with the ‘free allylic alcohol’
effect.12,13 Given the success of the diene 17 in the
reaction, attempts were made to cyclise the precursor
18. Reaction of the diene 18 with a free homoallylic
In conclusion, our observations demonstrate the impor-
tance of fine tuning the allylic and homoallylic alcohol

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L. Caggiano et al. / Tetrahedron Letters 44 (2003) 7913–7919
Scheme 5. Changes of allylic and homoallylic stereochemistry and protective groups.8
Scheme 6. RCM reactions with a free allylic alcohol.8
protective groups for a successful RCM reaction. For
the first time a substrate possessing a PMP-protected
allylic alcohol, the product of a stereoselective oxyallyl-
ation, was successfully cyclised. It is believed, on the
evidence given above, that the allylic OPMP group is
not only compatible in the RCM reaction, but may
also aid cyclisation, giving better yields than the corre-
sponding free allylic alcohol. As for the synthetic util-
ity, the PMP group could be cleaved after cyclisation
in good yield.

L. Caggiano et al. / Tetrahedron Letters 44 (2003) 7913–7919
7917
Scheme 7. Interplay of protective groups.8
Scheme 8. Successful RCM reactions with a PMP protected allylic alcohol. Reagents and conditions: (a) PivCl, DMAP, CH2Cl2,
rt, 66%; (b) CAN, MeCN/H2O 1:1, 0°C, (1) 55%, (2) 80%.8

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L. Caggiano et al. / Tetrahedron Letters 44 (2003) 7913–7919
Scheme 9. Allylic methyl substitution.8
Acknowledgements
3. Partial syntheses of the eleuthesides have also been
described, see: (a) Ceccarelli, S.; Piarulli, U.; Gennari, C.
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Tetrahedron 2000, 56, 4367; (d) Ceccarelli, S.; Piarulli, U.;
Gennari, C. J. Org. Chem. 2000, 65, 6254; (e) Xu, Q.;
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8029; (f) Ceccarelli, S.; Piarulli, U.; Telser, J.; Gennari, C.
Tetrahedron Lett. 2001, 42, 7421; (g) Ceccarelli, S.;
Piarulli, U.; Gennari, C. Tetrahedron 2001, 57, 8531; (h)
Sandoval, C.; Redero, E.; Mateos-Timoneda, M. A.;
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Kaliappan, K. P.; Kumar, N. Tetrahedron Lett. 2003, 44,
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Hiscock, S. D.; McLaughlin, E. C. Org. Lett. 2003, 5,
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We thank the European Commission for financial sup-
port (IHP Network grant ‘Design and synthesis of
microtubule stabilizing anticancer agents’ HPRN-CT-
2000-00018) and for postdoctoral fellowships to
L. Caggiano and R. Beumer (HPRN-CT-2000-00018),
P. Bayo´n (‘Marie Curie’ HPMF-CT-2000-00838) and
J. Telser (‘Marie Curie’ HPMF-CT-1999-00001). We
also like to thank Merck (Merck’s Academic Develop-
ment Program Award to C. Gennari, 2001-02),
M.U.R.S.T. COFIN 2000 (MM03155477) for financial
support, and the University of Milano for a graduate
fellowship (to D. Castoldi). We wish to thank Dr
Andrew Bell, Dr Simona Ceccarelli and Piergiuliano
Bugada for preliminary experiments related to some
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L. Caggiano et al. / Tetrahedron Letters 44 (2003) 7913–7919
7919
8. % Yields reported in brackets are calculated considering the
recoveredstartingmaterial. Cy=cyclohexyl;Mes=mesityl;
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