Synthesis of a simplified sarcodictyin analogue which retains microtubule stabilising properties

Article abstract of DOI:10.1016/S0040-4039(01)02045-7

A strategy featuring ring-closing metathesis as key reaction is applied to the synthesis of the sarcodictyin analogue 15. The precursor diene is accessed via a brief and efficient protocol, employing multiple stereoselective allylations. Simplified analog

Full text of DOI:10.1016/S0040-4039(01)02045-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9187–9190
Synthesis of a simplified sarcodictyin analogue which retains
microtubule stabilising properties
Joachim Telser,a Raphael Beumer,a Andrew A. Bell,a Simona M. Ceccarelli,a Diego Montib and
Cesare Gennaria,b,
*
aDipartimento di Chimica Organica e Industriale, Universita` di Milano, via G. Venezian 21, I-20133 Milan, Italy
bCentro CNR per lo Studio delle Sostanze Organiche Naturali, via G. Venezian 21, I-20133 Milan, Italy
Received 9 October 2001; accepted 23 October 2001
Abstract—A strategy featuring ring-closing metathesis as key reaction is applied to the synthesis of the sarcodictyin analogue 15.
The precursor diene is accessed via a brief and efficient protocol, employing multiple stereoselective allylations. Simplified
analogue 15 retains microtubule stabilising properties. © 2001 Elsevier Science Ltd. All rights reserved.
Sarcodictyins A (1a) and B (1b) (Fig. 1) were isolated in
1987 by Pietra et al. from the Mediterranean
stoloniferan coral Sarcodictyon roseum,1 while their
antitumour activity was recognised about a decade
later, and their paclitaxel-like mechanism of action
uncovered (1996).2 In the meantime, the diterpene gly-
coside eleutherobin (2) was reported by Fenical et al.
from an Eleutherobia species of Australian soft coral,
accompanied by disclosure of its potent cytotoxicity
(1995).3 Two years later, in 1997, it was shown that
eleutherobin, similarly to sarcodictyins, acted by
mitotic arrest through induced tubulin polymerisation.4
Both sarcodictyins and eleutherobin (the ‘eleutheside’
family of microtubule-stabilising drugs) are character-
ised by an activity profile different from that of pacli-
taxel; in particular, they are active against paclitaxel
resistant tumour cell lines and therefore hold potential
as second generation microtubule-stabilising anticancer
agents.4,5 The scarce availability of 1 and 2 from natu-
ral sources (e.g. eleutherobin amounts to 0.01–0.02% of
dry weight of the rare alcyonaceans of the Eleutherobia
species) makes their total synthesis vital for further
biological investigations.5 To date, sarcodictyins A and
B have been synthesised successfully by Nicolaou et
al.,6 who have also exploited a similar route for access-
ing eleutherobin.7 A subsequent report by Danishefsky
and co-workers details an elegant alternative access to
eleutherobin.8 A number of partial syntheses and alter-
native strategies have also been described.9 The total
syntheses of eleuthesides have generated very limited
diversity in the diterpenoid core, with major variations
reported only in the C-15 functionality.5–8 However,
there is a general agreement that the (E)-N-methyluro-
canic side chain, the C-4/C-7 ether bridge, and the
cyclohexene ring are important determinants of antimi-
totic activity.5
O
O
O
O
O
NMe
NMe
9
H
H
7
H
N
N
8
3
6
5
10
O
1
H
4
OMe
OH
CO2R
2
O
15
OAc
O
OH
1a; R = Me
1b; R = Et
2
OH
As a part of our ongoing programme aimed at the
synthesis of simplified analogues of the eleutheside nat-
ural products, ideally showing improved synthetic
accessibility and retaining microtubule stabilising prop-
erties, we describe in this letter a brief and efficient
synthesis of the 6–10 fused-ring system of the
Figure 1. Marine diterpenoids sarcodictyin A (1a), B (1b) and
eleutherobin (2).
Keywords: allylation; antitumour compounds; metathesis; stereocon-
trol.
* Corresponding author. Tel.: +39-025835.4091; fax: +39-025835.
4072; e-mail: cesare.gennari@unimi.it
eleuthesides via
a ring-closing metathesis (RCM)
reaction.10
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02045-7

9188
J. Telser et al. / Tetrahedron Letters 42 (2001) 9187–9190
Despite its effectiveness in the synthesis of rings of all
sizes, two factors still limit the scope of the RCM
reaction: (a) in ring sizes ]8, no control over the E/Z
stereochemistry of the double bond generated is possi-
ble. Stereochemical control is mostly determined by the
substrate structure and is probably of thermodynamic
origin;11 (b) the reports that describe application of the
RCM to medium sized—particularly 10-membered—
rings, are still very rare, especially when dense function-
ality close to the reaction centre is involved.12
single Z stereoisomer in ]80% yield. As expected,
entropic support (by virtue of the cis fusion to the
cyclohexyl ring) made ring closure of diene 9 extremely
smooth. Luckily, and delightfully, the stereochemistry
of the double bond created by the RCM reaction was
fully controlled in the desired sense (100% Z) by the
structure of the new 10-membered ring.11 The Z stereo-
chemistry of the double bond was unequivocally
3
assigned by detection of the olefinic Jcis coupling con-
stant (11.5 Hz between the protons at l 5.51 and 5.86
ppm, respectively) by a 400 MHz H,H-COSY experi-
ment, and by detection of a NOE contact between these
protons in a 400 MHz NOESY experiment.
Aldehyde 3, previously synthesised in our labora-
tory,9a,g was prepared on a multigram scale and submit-
ted to the allyl borane derived from (−)-a-pinene,13
generating the C-8 oxygenated stereocentre (Scheme 1).
Although compound 10 does not possess the correct
functionality for accessing the eleuthesides, it represents
the first successful synthesis of the 6–10 fused-ring
system via a 100% Z selective RCM, and can be
exploited for accessing analogues and mimetics of the
natural products, e.g. 15 (Scheme 2).16
The allylation reaction proceeded with complete stereo-
control in favour of the desired stereoisomer
(diastereomeric purity >95% by 1H and 13C NMR).
After standard alcohol protection, an efficient and well
established sequence of steps8c led to the homologated
aldehyde 7, on which the same allylation procedure
described above was applied. Addition of the allyl
borane derived from (−)-a-pinene to aldehyde 7 was
again completely stereoselective (diastereomeric purity
of 8 >95%). Homoallylic alcohol 8 was acetylated to 9,
and this compound was subjected to RCM using a
variety of catalysts. After a number of attempts, the
recently developed Nolan and Grubbs’ catalysts 1114
and 1215 gave the desired ring-closed product 10 as a
Within the framework of a European collaboration
(research training network: ‘Design and synthesis of
microtubule stabilising anticancer agents’), the drug-
like compound 15 was investigated by the Botta group
(Siena, Italy) using the tubulin minireceptor binding-
site model described by Snyder and co-workers in
1999.17 The model predicts for 15 a tubulin affinity
(predicted dissociation constant Kpred.=24 mM) only
slightly weaker than paclitaxel (Kpred.=11 mM, Kexpt.
=
RO
TBDPSO
7
7
8
8
lIpc2B
CHO
c
a
OMe
CHO
OMe
4; lIpc from (−)-α-pinene
OMe
5; R = H
OMe
3
7
b
6; R = TBDPS
TBDPSO
TBDPSO
OTBDPS
7
7
lIpc2B
8
8
e
d
f
4; lIpc from (−)-α-pinene
3
3
4
4
OAc
OAc
OH
8
9
10
PCy3
Ru
PCy3
Ru
Cl
Cl
Cl
Cl
Ph
N Mst
Ph
N Mst
Mst
N
Mst
N
12; Mst = C6H2-2,4,6-(CH3)3
11; Mst = C6H2-2,4,6-(CH3)3
Scheme 1. Reagents and conditions: (a) (i) THF, −78°C to rt, 6 h, (ii) H2O2, 6N NaOH, rt, 15 h, 77% (>95% diastereomeric
purity); (b) TBDPS-Cl, excess imidazole, CH2Cl2, rt, 16 h, 98%; (c) (i) AcOH:THF:H2O (3:1:1), rt, 16 h, 99%, (ii) NaBH4, EtOH,
rt, 15 min, 98%, (iii) Ms-Cl, Et3N, CH2Cl2, 0°C to rt, 1 h, 98%, (iv) KCN, 18-crown-6, MeCN, 80°C, 5 h, 95%, (v) DIBAl-H,
hexane–toluene (2:1), −78°C, 40 min, 98%; (d) (i) THF, −78°C, 2 h, (ii) H2O2, 6N NaOH, rt, 15 h, 55% (>95% diastereomeric
purity); (e) Ac2O, cat. DMAP, Py, rt, 90%; (f) 11 (20% mol), CH2Cl2, rt, 24 h, 80% (100% Z), or 12 (7% mol), CH2Cl2, rt, 168
h, 88% (95% after recovering starting material, 100% Z).

J. Telser et al. / Tetrahedron Letters 42 (2001) 9187–9190
9189
OH
OTBDPS
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15
Scheme 2. Reagents and conditions: (a) TBAF, THF, rt, 94%;
(b) 14 (Ref. 6b), Et3N, DMAP, CH2Cl2, 59% (87% after
recovering starting material).
15 mM) and sarcodictyin B (Kpred.=11 mM, Kexpt.=11
mM).18 The experimental tubulin polymerising ability
was tested at Pharmacia (Nerviano, Italy): although 15
was shown to be less potent (ED90=10 mM) than
paclitaxel (ED90=0.5 mM), which was used as a refer-
ence,19 it is interesting to note that this simplified
analogue of the natural product (lacking inter alia the
C-4/C-7 ether bridge) retains microtubule stabilising
properties.
Using Brown’s oxyallylation methodology [(Z)-g-
(methoxymethoxy)allyldiisopinocampheylborane from
either (−)- or (+)-a-pinene]13d in one or both the allyla-
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good stereoselectivity all possible compounds with R,R
or S,S relative stereochemistry at the two oxygenated
stereocentres formed in the reaction (7S,8S; 7R,8R;
3S,4S; 3R,4R). We are actively pursuing the use of
these new substrates for the synthesis of structurally
more related sarcodictyin analogues and for a total
synthesis of the natural products (starting from
3S,4S,7S,8S or 3R,4R,7S,8S).
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Acknowledgements
A graduate fellowship is gratefully acknowledged by S.
Ceccarelli (Pharmacia, Nerviano, Italy). We thank the
European Commission for financial support (IHP Net-
work grant ‘Design and synthesis of microtubule stabil-
ising anticancer agents’ HPRN-CT-2000-00018) and for
postdoctoral fellowships to R. Beumer (IHP Network
HPRN-CT-2000-00018), A. A. Bell (‘Marie Curie’ fel-
lowship ERB FMB ICT 98 2891) and J. Telser (‘Marie
Curie’ fellowship HPMFCT 1999 00001). We would
also like to thank Merck (Merck’s Academic Develop-
ment Program Award to C. Gennari, 2001), and
MURST COFIN 2000 (MM03155477) for financial
support.

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16. All compounds described in the present paper gave spec-
troscopic data completely in accordance with their
assigned structures. Details will be provided in a subse-
quent full paper. Final compound 15 was obtained as a
clear oil; Rf=0.25 (hexane/EtOAc 1:4); 1H NMR
(CDCl3, 400 MHz): l 0.70 (d, J=6.7 Hz, 3H), 0.87 (d,
J=6.7 Hz, 3H), 1.26–2.05 (m, 12H), 2.07 (s, 3H), 2.18–
2.23 (m, 1H), 2.25–2.40 (m, 2H), 2.77–2.88 (m, 2H), 3.72
(s, 3H), 5.18–5.24 (m, 1H), 5.34 (br s, 1H), 5.39–5.45
(m, 1H), 5.55–5.62 (m, 1H), 5.66–5.74 (m, 1H), 6.54 (d,
J=15.6 Hz, 1H), 7.09 (s, 1H), 7.47 (s, 1H), 7.55 (d,
J=15.6 Hz, 1H); 13C NMR (CDCl3, 50.3 MHz): l
15.11, 20.88, 21.17, 24.22, 24.34, 26.22, 26.88, 29.18,
29.59, 31.61, 32.71, 33.49, 34.60, 37.31, 37.49, 72.51,
73.57, 116.35, 121.02, 122.20, 126.39, 127.92, 135.85,
137.93, 138.41, 166.72, 170.37; IR (CCl4): w 2960, 2850,
1745, 1705, 1640, 1450, 1440, 1380, 1345, 1295, 905
cm−1; [h]2D0=−29 (c 0.7, EtOAc); HRMS [EI (30 eV)]
calcd for [C27H38N2O4]+: 454.2832. Found: 454.2802.
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eleutherobin in the training set (unpublished results and
personal communication by Professor M. Botta, Univer-
sity of Siena).
19. ED90=effective dose that induces 90% tubulin polymeri-
sation (see Ref. 2b). These data were kindly provided by
Dr. Nicola Mongelli and Dr. Sylvie Ducki (Pharmacia,
Nerviano).
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