A carbonylative cross-coupling strategy to the total synthesis of the sarcodictyins: Preliminary studies and synthesis of a cyclization precursor

Article abstract of DOI:10.1016/S0040-4039(01)01608-2

Preliminary studies were conducted on the implementation of a new strategy to the total synthesis of the common diterpenoid tricyclic skeleton of sarcodictyins and eleutherobin. According to the approach presented, a key retrosynthetic disconnection is de

Full text of DOI:10.1016/S0040-4039(01)01608-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7421–7425
A carbonylative cross-coupling strategy to the total synthesis of
the sarcodictyins: preliminary studies and synthesis of a
cyclization precursor
Simona M. Ceccarelli,a,† Umberto Piarulli,b Joachim Telsera and Cesare Gennaria,*
aDipartimento di Chimica Organica e Industriale, Universita` di Milano,
Centro CNR per lo Studio delle Sostanze Organiche Naturali, via G. Venezian 21, 20133 Milano, Italy
bDipartimento di Scienze Chimiche, Fis. e Mat., Universita` dell’Insubria, via Valleggio 11, 22100 Como, Italy
Received 24 June 2001; accepted 28 August 2001
Abstract—Preliminary studies were conducted on the implementation of a new strategy to the total synthesis of the common
diterpenoid tricyclic skeleton of sarcodictyins and eleutherobin. According to the approach presented, a key retrosynthetic
disconnection is devised at the C3–C5 position, identifying a carbonylative cross-coupling reaction as the medium-sized ring
forming step. The synthesis of a fully functionalized cyclization precursor, comprising a Z vinylstannane and a carboalkoxy-sub-
stituted Z enol triflate as reactive centres, is described. © 2001 Elsevier Science Ltd. All rights reserved.
The limitations inherent in the use of the chemoter-
apeutic agent Taxol® (paclitaxel) in clinical applications
have raised interest in the identification of compounds
of comparable cytotoxicity that share the same mode of
action at the subcellular level.1 Among these are the
marine diterpenoids sarcodictyin A (1) and B (2)2 and
eleutherobin (3)3 (Scheme 1). Both sarcodictyins and
eleutherobin are characterized by an activity profile
different from that of paclitaxel; in particular, they are
active against paclitaxel resistant tumour cell lines and
therefore hold potential as second generation micro-
tubule-stabilizing anticancer agents.4–6
The challenging molecular architecture and potent bio-
logical activity of sarcodictyins and eleutherobin have
immediately elicited the interest of the synthetic com-
munity. To date, sarcodictyins A and B have been
synthesized successfully by Nicolaou et al.,7 who have
also exploited a similar route for accessing eleuther-
obin.8 A subsequent report by Danishefsky and co-
O
OR2
OR2
R3O
O
NMe
H
R3O
Me3Sn
5
N
6
6
O
5
4
C
OTf
3
4
H
OR
O
2
O
2
3
R1
CO2Me
CO2Me
1 R = H, R1 = CO2Me
2 R = H, R1 = CO2Et
3 R = Me, R1 =
4
5
O
OAc
OH
OH
O
Scheme 1. Key retrosynthetic disconnections.
Keywords: sarcodictyin; eleutherobin; total synthesis; cross-coupling.
* Corresponding author. Tel.: +39-02-2367593; fax: +39-02-2663079; e-mail: cesare.gennari@unimi.it
† Present address: Institut fu¨r Organische Chemie, RWTH-Aachen, Prof. Pirlet Strasse 1, 52056 Aachen, Germany.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01608-2

7422
S. M. Ceccarelli et al. / Tetrahedron Letters 42 (2001) 7421–7425
workers details an alternative access to eleutherobin.9 A
number of partial syntheses and alternative strategies
have also been described.10
TBDPSCl yielded intermediate 7 (86%), in which the
stability of the ‘south’ chain is secured. At this stage,
reduction of the ester to the allylic alcohol 8 (99%) and
Sharpless’ asymmetric epoxidation12 (87%; 90% consid-
ering recovered starting material) were straightforward.
The cis epoxide 11 could also be accessed via the same
route starting from the corresponding ester 10.10a By
means of a SN2 opening at the secondary position,
oxirane 11 would give the stereochemical arrangement
present in the target molecule.
All members of the sarcodictyin family are character-
ized by a fused tricyclic skeleton of terpenoid origin
comprising a six-, nine- and five-membered ring, in
which the five-membered ring is an internal hemiacetal
(or acetal in the case of eleutherobin). The most obvi-
ous retrosynthetic move is to convert the acetal into its
parent ketone, thus revealing, after removal of the
urocanic chain appendage,
(Scheme 1) featuring a six- and ten-membered ring.
a
bicyclic skeleton
4
Application of the regio- and stereoselective epoxide
opening procedure developed by Sharpless and co-
workers [carboxylic acid, Ti(Oi-Pr)4, CH2Cl2],13 did not
lead to the desired opened products. A variant to this
protocol, which involved preforming the titanium–
nucleophile complex before addition of the substrate in
chloroform,14 proved more effective, though a sharp
difference in the reactivity of the cis and trans oxiranes
was observed. In the case of cis oxirane 11, no opened
product could be detected and/or isolated in satisfying
yield, whereas epoxide 9 could be opened efficiently
with the preformed titanium complex of benzoic acid to
give 12 (66%; 86% considering recovered starting mate-
rial) (Scheme 3). In the resulting diol 12, the configura-
tion of the secondary C8‡ position is opposite to that of
the natural product, and must be redeemed at a later
stage with an inversion step.
The presence in the C2–C6 portion of target structure 4
of a substituted a-carboalkoxy-a,a%-dienone suggests
the possible use of a Stille carbonylative cross-coupling
reaction.11 Application of this reaction to the key
cyclization precursor 5, bearing a Z vinylstannane and
a carboalkoxy-substituted Z enol triflate as reactive
centres, would directly introduce the desired substruc-
tural element. The present communication describes a
synthetic approach to such a cyclization precursor.
The starting point of the synthetic pathway is ester 6,
available from our previous work on sarcodictyin syn-
thesis (Scheme 2).10a From previous experience,10a,d as
well as from model studies, we were aware that the
dimethylacetal group of 6 would interfere in reactions
featuring Lewis acids as promoters or catalysts, e.g. the
Sharpless’ asymmetric epoxidation12 or Ti(Oi-Pr)4-pro-
moted epoxide opening protocols.13,14 We decided
therefore to convert the dimethyl acetal to a less sensi-
tive functionality. The C2‡ aldehyde in 6 was set free by
acidic cleavage (99%), and subsequently reduced to a
primary alcohol with NaBH4 (93%). Protection with
Diol 12 was protected with a TES group at the primary
position, a methoxymethyl ether was introduced at the
tertiary alcohol and then the primary alcohol was
deprotected (TAS-F, 81% over three steps)15 and oxi-
dized (DMP)16 to aldehyde 14 (99%). Application of
Stork’s ylide17 led to isolation of the desired Z vinyl
iodide 15 (61%).
CO2Et
OH
d
CO2Et
OTBDPS
a,b,c
OMe
OTBDPS
OMe
6
7
8
e
OH
CO2Et
O
O
OTBDPS
OH
a-e
OMe
OMe
OTBDPS
10
11
9
Scheme 2. Reagents and conditions: (a) AcOH, THF, H2O, rt, 17 h, 99%; (b) NaBH4, EtOH, rt, 15 min, 93% (compound E), 98%
(compound Z); (c) TBDPSCl, Im, CH2Cl2, rt, 2 h, 86% (compound E), 88% (compound Z); (d) LiAlH4, Et2O, rt, 30 min, 99%
,
(compound E), 97% (compound Z); (e) TBHP, Ti(Oi-Pr)4 (10%), (+)-DET (12%), 4 A MS, CH2Cl2, −20°C, 20 h, 87% (compound
E), 55% (compound Z).
‡ Sarcodictyin numbering.

S. M. Ceccarelli et al. / Tetrahedron Letters 42 (2001) 7421–7425
7423
OTES
O
OH
OH
MOMO
BzO
BzO
BzO
OMOM
OMOM
BzO
8
b,c
d,e
f
a
I
9
OTBDPS
OTBDPS
OTBDPS
OTBDPS
13
12
15
14
Scheme 3. Reagents and conditions: (a) Ti(Oi-Pr)4, BzOH, then 9, CHCl3, rt, 8 h, 66% (+23% recovered starting material); (b)
TESCl, Im, CH2Cl2, rt, 2 min; (c) MOMCl, DIPEA, CH2Cl2, 50°C, 8 h; (d) TAS-F, DMF, H2O, rt, 40 min, 81% over three steps
(b, c, d); (e) DMP, CH2Cl2, rt, 1 h, 99%; (f) Ph3PCHI, NaN(TMS)2, then 14, −78°C, 3 h, 61%.
At this stage, we turned our attention to elaboration of
the ‘south’ chain. Deprotection of the silyl ether at the
C2‡ position with the HF·Py complex18 led to the
primary alcohol 16 (97%) (Scheme 4).
was best achieved with Comins’ reagent.20 Selective
formation of the Z enol triflate 23 from the model
ketone could be achieved (50%) by employing a slightly
substoichiometric amount (0.95 equiv.) of base, an
expedient reported to favour formation of the thermo-
dynamic enolate.21
This was oxidized (DMP)16 to aldehyde 17 (99%),
which was homologated to silyl enol ether 19 in good
yield (87%) by application of the phosphonate reagent
18, bearing a silyl protected alkoxy group in the a-posi-
tion. This reagent was developed by a minor modifica-
tion of other known a-alkoxyphosphonate reagents.19
Removal of the silicon group from 19 with HF·Py18
afforded, as before for the model compound, a mixture
of tautomers 24 (72%) (Scheme 6). We decided to
perform iodine to tin exchange before the triflate form-
ing step, to avoid exposure of the delicate vinyl iodide
to the strong base required for enolate formation.
Treatment with Pd2dba3 and hexamethylditin gave Z
vinylstannane 25 in disappointingly low yield (26%,
63% considering recovered starting material) for such a
late stage transformation, which could not be improved
by any variation of the experimental protocol.22 The
a-enol ester mojety of 25 (a single enol form was
detected) could be converted with Comin’s reagent20 to
the carboalkoxy-substituted enol triflate, which was
isolated as a single Z isomer 26 (75%).
The a-alkoxy-a,b-unsaturated ester 21, prepared in an
analogous way (78%) from aldehyde 20,10a was initially
used as a model compound for the conversion of the
silyl enol ether moiety to a Z enol triflate (Scheme 5).
Deprotection of the triethylsilyl group with HF·Py18
proceeded smoothly to give product 22 (70%), which
was isolated as a mixture of tautomeric forms, compris-
ing the keto form and the two isomeric enol forms. The
stereoselective conversion of a-keto ester 22 to the Z
enol triflate, which would serve as the coupling partner
of the ‘north’ chain vinylstannane in the synthetic plan,
MOMO
BzO
MOMO
BzO
MOMO
BzO
a
b
c
I
I
I
15
CO2Me
OTES
O
OH
O
O
MeO P
MeO
OMe
17
16
19
OTES
18
Scheme 4. Reagents and conditions: (a) HF·Py, THF/Py, 55°C, 8 h, 97%; (b) DMP, CH2Cl2, rt, 1 h, 99%; (c) 18, LiN(TMS)2, then
17, THF, −78°C to rt, 1.5 h, 87%.
CO2Me
O
CO2Me
CO2Me
OTES
CO2Me
OTf
CO2Me
H
O
a
c
CO2Me
CO2Me
H
20
21
23
22
Scheme 5. Reagents and conditions: (a) 18, LiN(TMS)2, then 20, THF, −78°C to rt, 1 h, 78%; (b) HF·Py, THF/Py, rt, 5 min, 70%,
mixture of keto and enol tautomers; (c) NaN(TMS)2 (0.95 equiv.), 2-bis-trifluoromethanesulfonyl-amino pyridine, THF, −78°C,
20 min–2 h, 50%, Z-isomer only.

7424
S. M. Ceccarelli et al. / Tetrahedron Letters 42 (2001) 7421–7425
MOMO
MOMO
BzO
MOMO
BzO
BzO
SnMe3
OH
SnMe3
OTf
b
c
a
I
19
H
O
CO2Me
CO2Me
CO2Me
H
24
25
26
Scheme 6. Reagents and conditions: (a) HF·Py, THF/Py, rt, 4.5 h, 72%; (b) Pd2dba3, hexamethylditin, NMP, 50°C, 6 h, 26%; (c)
NaN(TMS)2, 2-bis-trifluoromethanesulfonyl-amino pyridine, THF, −78°C, 1.5 h, 75%, Z-isomer only.
Previous studies from our group explored the
behaviour of simple carboalkoxy-substituted enol tri-
flates, such as that present in 26, towards the palla-
dium-catalyzed Stille carbonylative coupling with
vinylic stannanes, resulting in the identification of opti-
mal reaction conditions [CO (1 atm), Pd2dba3 (5%),
CuI (20%), As(Ph)3 (40%), LiCl (3 equiv.), NMP, rt].11d
Preliminary attempts to use this protocol for the ten-
membered ring closure of cyclization precursor 26 were
not rewarding. Work is in progress in our laboratories
to complete the synthetic sequence.
sive review on the chemistry and biology of the sarcodic-
tyins, see: Nicolaou, K. C.; Pfefferkorn, J.; Xu, J.;
Winssinger, N.; Ohshima, T.; Kim, S.; Hosokawa, S.;
Vourloumis, D.; van Delft, F.; Li, T. Chem. Pharm. Bull.
1999, 47, 1199.
7. Nicolaou, K. C.; Xu, J.-Y.; Kim, S.; Ohshima, T.;
Hosokawa, S.; Pfefferkorn, J. J. Am. Chem. Soc. 1997,
119, 11353.
8. Nicolaou, K. C.; Ohshima, T.; Hosokawa, S.; van Delft,
F. L.; Vourloumis, D.; Xu, J. Y.; Pfefferkorn, J.; Kim, S.
J. Am. Chem. Soc. 1998, 120, 8674.
9. Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge,
C. E.; Pettus, T. R. R.; Danishefsky, S. J. J. Am. Chem.
Soc. 1999, 121, 6563.
Acknowledgements
10. (a) Ceccarelli, S.; Piarulli, U.; Gennari, C. Tetrahedron
Lett. 1999, 40, 153; (b) Rainier, J. D.; Xu, Q. Org. Lett.
1999, 1, 27; (c) Baron, A.; Caprio, V.; Mann, J. Tetra-
hedron Lett. 1999, 40, 9321; (d) Carter, R.; Hodgetts, K.;
McKenna, J.; Magnus, P.; Wren, S. Tetrahedron 2000,
56, 4367.
11. (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508; (b) For an example of application to total synthesis,
see: Gyorkos, A. C.; Stille, J. K.; Hegedus, L. S. J. Am.
Chem. Soc. 1990, 112, 8465; (c) Stille, J. K.; Su, H.; Hill,
D. H.; Schneider, P.; Tanaka, M.; Morrison, D. L.;
Hegedus, L. S. Organometallics 1991, 10, 1993; (d) Cecca-
relli, S.; Piarulli, U.; Gennari, C. J. Org. Chem. 2000, 65,
6254.
A graduate fellowship is gratefully acknowledged by
S.C. (Pharmacia, Nerviano, Italy). We thank the
European Commission for financial support (IHP Net-
work grant ‘Design and synthesis of microtubule stabi-
lizing anticancer agents’ HPRN-CT-2000-00018) and
for a postdoctoral fellowship to J.T. (‘Marie Curie’
fellowship HPMFCT 1999 00001). We would also like
to thank Merck (Merck’s Academic Development Pro-
gram Award to C.G., 2001), and MURST COFIN
2000 (‘Sintesi di mimetici e analoghi di sostanze natur-
ali biologicamente attive’ MM 03155477) for financial
support.
12. (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765; (b) Katzuki, T.; Sharpless, K. B. J. Am. Chem.
Soc. 1980, 102, 5974.
References
13. Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50,
1557.
14. (a) Raifeld, Y. E.; Nikitenko, A.; Arshava, B. Tetra-
hedron: Asymmetry 1991, 2, 1083; (b) Raifeld, Y. E.;
Nikitenko, A.; Arshava, B. M. Tetrahedron 1993, 49,
2509.
1. For a comprehensive review on the chemistry and biology
of Taxol® (paclitaxel), see: Nicolaou, K. C.; Dai, W.-M.;
Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15.
2. D’Ambrosio, M.; Guerriero, A.; Pietra, F. Helv. Chem.
Acta 1988, 71, 964.
3. Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.;
Casazza, A. M.; Carboni, J.; Fairchild, C. R. J. Am.
Chem. Soc. 1997, 119, 8744.
4. Ciomei, M.; Albanese, C.; Pastori, W.; Grandi, M.;
Pietra, F.; D’Ambrosio, M.; Guerriero, A.; Battistini, C.
Proc. Am. Assoc. Cancer Res. 1997, 38, Abstract 30.
5. Long, B. H.; Carboni, J. M.; Wasserman, A. J.; Cornell,
L. A.; Casazza, A. M.; Jensen, P. R.; Lindel, T.; Fenical,
W.; Fairchild, C. R. Cancer Res. 1998, 58, 1111.
6. (a) Hamel, E.; Sackett, D. L.; Vorloumis, D.; Nicolaou,
K. C. Biochemistry 1999, 38, 5490; (b) for a comprehen-
15. tris(Dimethylamino)sulfonium
difluorotrimethylsilicate
(TAS-F): Scheidt, K. A.; Chen, H.; Follows, B. C.;
Chemler, S. R.; Coffey, D. S.; Roush, W. R. J. Org.
Chem. 1998, 63, 6436.
16. Dess Martin Periodinane (DMP): (a) Dess, D. B.; Mar-
tin, J. C. J. Am. Chem. Soc. 1991, 113, 7277; (b) Ireland,
R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
17. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
18. Corey, E. J.; Venkateswawarlu, A. J. Am. Chem. Soc.
1972, 94, 6190.

S. M. Ceccarelli et al. / Tetrahedron Letters 42 (2001) 7421–7425
7425
19. (a) Horne, D.; Gaudino, J.; Thompson, W. J. Tetra-
hedron Lett. 1984, 25, 3529; (b) Grell, W.; Machleidt, H.
Liebigs Ann. Chem. 1966, 699, 53.
20. (a) Comins, D. L.; Dehgani, A.; Foti, C. J.; Joseph, S. P.
Org. Synth. 1997, 74, 77; (b) Comins, D. L.; Dehgani, A.
Tetrahedron Lett. 1992, 33, 6299.
21. Fataftah, Z. A.; Kopka, I. E.; Rathke, M. W. J. Am.
Chem. Soc. 1980, 102, 3959.
22. (a) Farina, V.; Hauck, S. I. J. Org. Chem. 1991, 56, 4317;
(b) Smith, III, A. B.; Ott, G. R. J. Am. Chem. Soc. 1998,
120, 393; (c) Paterson, I.; Lombart, H.-G.; Allerton, C.
Org. Lett. 1999, 1, 19.