Stereocontrolled total synthesis of amphidinolide X via a silicon-tethered metathesis reaction

Article abstract of DOI:10.1021/ol8021676

(Chemical Equation Presented) Two esterifications and an RCM to create the challenging trisubstituted C12-C13 double bond were required in the total synthesis of amphidinolide X (1) reported here. Assembling the three fragments in this order, no RCM occurred or the process yielded mainly isomer Z However, generating the E double bond first, by a new variant of a Si-tethered metathesis (using Schrock's catalyst), and carrying out the esterification and macrolactonization steps later, 1 was obtained exclusively.

Full text of DOI:10.1021/ol8021676

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5191-5194
Stereocontrolled Total Synthesis of
Amphidinolide X via a Silicon-Tethered
Metathesis Reaction
Carles Rodr´ıguez-Escrich, Fe`lix Urpí,* and Jaume Vilarrasa*
Departament de Química Orga`nica, Facultat de Química, UniVersitat de Barcelona,
AV. Diagonal 647, 08028 Barcelona, Catalonia, Spain
jVilarrasa@ub.edu
Received September 17, 2008
ABSTRACT
Two esterifications and an RCM to create the challenging trisubstituted C12-C13 double bond were required in the total synthesis of
amphidinolide X (1) reported here. Assembling the three fragments in this order, no RCM occurred or the process yielded mainly isomer Z.
However, generating the E double bond first, by a new variant of a Si-tethered metathesis (using Schrock’s catalyst), and carrying out the
esterification and macrolactonization steps later, 1 was obtained exclusively.
Among the long series of cytotoxic macrolides isolated from
Amphidinium dinoflagellates,1 amphidinolide X (1) is re-
Scheme 1. Retrosynthetic Analysis of 1
markable for its unusual nonsymmetric diolide structure,2
which has attracted the attention of synthetic groups3 since
its discovery in 2003. We report a total synthesis of 1, based
on a Si-tethered metathesis reaction and a suitable macro-
lactonization. Our initial retrosynthetic analysis4 is shown
in Scheme 1. Three fragments (2-4) resulted from the
disconnections of the ester groups and the C12-C13 double
bond.
(1) Recent reviews: (a) Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007,
70, 451. (b) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.
(2) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.; Kawabata,
J.; Katsumata, K.; Horiguchi, T.; Kobayashi, J. J. Org. Chem. 2003, 68,
5339.
(3) First total synthesis of 1: (a) Fu¨rstner, A.; Kattnig, E.; Lepage, O.
J. Am. Chem. Soc. 2006, 128, 9194. Preliminary communication: (b) Lepage,
O.; Kattnig, E.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 15970. For
tetrahydrofuran-containing fragments, see: (c) Chen, Y.; Jin, J.; Wu, J.; Dai,
W.-M. Synlett 2006, 1177. (d) Rodríguez-Escrich, C.; Olivella, A.; Urpí,
F.; Vilarrasa, J. Org. Lett. 2007, 9, 989. (e) Doan, H. D.; Gallon, J.; Piou,
A.; Vate`le, J.-M. Synlett 2007, 983. During the preparation of this paper, a
different total synthesis of 1 has appeared: (f) Dai, W.-M.; Chen, Y.; Jin,
J.; Wu, J.; Lou, J.; He, Q. Synlett 2008, 1737.
We describe here efficient syntheses of 2 and 3 and the
problems encountered during the assembly of 2-4. The
challenge was the generation of a trisubstituted E alkene by
a ring-closing metathesis (RCM) reaction.
Fragment 2 was built from aldehyde 6 (Scheme 2) arising
from ethyl acetoacetate in three steps.5 The reaction of 2
with the crotyltitanium reagent 7, obtained from TADDOL,6
(4) As planned in 2004. The strategy had to be modified in 2007:
Rodr´ıguez-E., C. Ph.D. Thesis, Universitat de Barcelona, 2008.
10.1021/ol8021676 CCC: $40.75
Published on Web 10/18/2008
2008 American Chemical Society

provided the desired homoallylic alcohol 2. The stereocenter
of fragment 3 was created by alkylation of the N-propanoyl
derivative of the D-Phe-derived chiral auxiliary (8) with tert-
butyl bromoacetate.7 The removal of the auxiliary with
LiBH4/MeOH8 in THF gave alcohol 9, which was converted
to 10 by a standard two-step procedure. The features of 10
allowed the selective hydrolysis of its methyl ester to furnish
carboxylic acid 3. Assembly of 4 (prepared from 5)3d with
3 and later with 2 was carried out as also indicated in
Scheme 2.
common. Actually, simple variations in ring size and/or the
number and position of substituents and characteristic groups9
may lead to success or to a disaster (in the ultimate key step
of a total synthesis!).
Unfortunately, none of our attempts to cyclize 12, its keto
derivative (C8-deprotected 12), and a diastereomer of 12
(with inverted configurations at C10 and C11) using different
amountsofthemostpromising10 GrubbsIIorHoveyda-Grubbs
II reagents were successful (>50% of unreacting starting
material was recovered in most cases). In two trials (with
the above-mentioned diastereomer), we isolated the Z isomers
in 30-40% yields, exclusively.
Therefore, an alternative strategy had to be considered
(Scheme 3). Fragment 2 was linked first to a fragment
derived from 5 to give 13. The challenging C12-C13 double
bond was then created (see 14), and finally fragment 3 was
incorporated.
Scheme 2. Synthesis and Assembly of Fragments 2-4
Scheme 3. Alternative Strategy
The hydroxy group of 5 was protected and then the cyano
group was converted into a terminal alkyne by reduction to
aldehyde 15 followed by a Corey-Fuchs homologation11
(Scheme 4) to give 16. The terminal triple bond was
hydrosilylated with dimethylchlorosilane using the Trost
catalyst,12 and the resulting chlorosilane was coupled in situ
with alcohol 2 to produce 17 (PMB-protected 13). The RCM
(10) (a) Xu, Z.; Johannes, C. W.; Salman, S. S.; Hoveyda, A. H. J. Am.
Chem. Soc. 1996, 118, 10926 (“primer” work on RCM, 14-membered
lactam, Z, Schrock catalyst). (b) Xu, Z.; Johannes, C. W.; Houri, A. F.; La,
D. S.; Cogan, D. A.; Hofilena, G. E.; Hoveyda, A. H. J. Am. Chem. Soc.
1997, 119, 10302. (c) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett.
2001, 3, 449 (14-membered lactone, E, Grubbs II-type initiator) and
references therein. (d) Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton,
J. L. J. Am. Chem. Soc. 2006, 128, 2796 (22-membered, low E/Z ratio,
dolabelide, Grubbs II, eventually 31% yield of E). (e) Smith, A. B., III;
Mesaros, E. F.; Meyer, E. A. J. Am. Chem. Soc. 2006, 128, 5292
(kendomycin, only cis, four steps to isomerize the double bond later). (f)
Jin, J.; Chen, Y.; Li, Y.; Wu, J.; Dai, W.-M. Org. Lett. 2007, 9, 2585 (17-
membered, amphidinolide Y, E, 50 mol % Grubbs II, but not H-G II and
Schrock reagents). (g) Tietze, L. F.; Brazel, C. C.; Ho¨lsken, S.; Magull, J.;
Ringe, A. Angew. Chem., Int. Ed. 2008, 47, 5246 (14-membered, terpenoid,
Z, Grubbs II). (h) Dai et al., see ref 3f (three precursors of amphidinolide
X different from ours, viz. C8-OR derivatives, and three catalysts tested;
in the best case, 19% of the desired E isomer after 6 days in refluxing
CH2Cl2). For a related case, see the coleophomones of Nicolaou et al. (ref
9d).
The resulting compound 12 was ready to be subjected to
an RCM9 that could give rise to the trisubstituted double
bond of 1. Provided that the macrocyclization took place, it
was not clear whether the desired trans (E) isomer would
predominate over the cis (Z) isomer, as there are few related
cases on which to base predictions10 and the failures are very
(5) (a) Oishi, T.; Nagai, M.; Ban, Y. Tetrahedron Lett. 1968, 9, 491.
(b) Uchino, K.; Yamagiwa, Y.; Kamikawa, T.; Kubo, I. Tetrahedron Lett.
1985, 26, 1319.
(6) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(7) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin,
D. H.; Tedrow, J. S. J. Org. Chem. 1999, 64, 6411.
(8) (a) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000. (b) Penning,
T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J. M.; Rowell,
B. W.; Yu, S. S. Synth. Commun. 1990, 307. (c) Evans, D. A.; Gage, J. R.
J. Org. Chem. 1992, 57, 1958.
(9) Very recent reviews on RCM: (a) Coquerel, Y.; Rodriguez, J. Eur.
J. Org. Chem. 2008, 1125. (b) Kotha, S.; Lahiri, K. Synlett 2007, 2767. (c)
Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243. (d) Nicolaou,
K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490. (e)
Grubbs, R. H. Tetrahedron 2004, 60, 7117.
(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(12) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726.
(b) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644.
5192
Org. Lett., Vol. 10, No. 22, 2008

of 20 was then cleaved with DDQ. We thus reached the E
double bond of 21 (a TBS-protected derivative of 14) in a
stereocontrolled manner, which would have been difficult
to achieve by olefination of a carbonyl compound.
Scheme 4. Synthesis of 21 via Si-Tethered RCM
Reaction of carboxylic acid 3 with alcohol 21 (Scheme
5) was carried out by activation of the carboxyl group as its
mixed anhydride, with (2,4,6-Cl3C6H2)COCl and Et3N,
followed by reaction with the alcohol in the presence of
DMAP, according to the method of Yamaguchi et al.19
Treatment of 22 with Me3SiOTf/2,6-lutidine cleaved both
the tert-butyl ester and the acetal moiety. Finally, the TBS
group was removed with aqueous HF in CH3CN to give 23,
a seco-acid ready to be subjected to macrolactonization under
high-dilution conditions.
Scheme 5. The Endgame
of this silicon-tethered diene in the presence of the Schrock
reagent13 gave the desired siloxane 18 in 78% yield.14
We examined different methods of cleaving the tether,
that is, to convert the C-Si bond to a C-Me bond, on a
model compound (3,6-diethyl-2,2-dimethyl-1-oxa-2-sila-
3-cyclohexene). In our case, Hiyama coupling15 with MeI
was unproductive. Generation of the pentacoordinate
silicon species by addition of MeLi, followed by trapping
with CuBr·Me2S16 and MeI, did not furnish the desired
compound either.
We had to rely upon a lengthier, novel sequence to add
the Me group on C13 (Scheme 4). The tether was cleaved
by addition of MeLi to give a hydroxyvinylsilane, which
was protected (TBS ether 19). The SiMe3 group was then
converted to a Me group by iododesilylation with N-
iodosuccinimide in (CF3)2CHOH17 and Negishi coupling of
the resulting iodoalkene with Me2Zn.18 The PMB-O bond
The macrocyclization of 23 to 1 was examined via the
Yamaguchi et al. procedure19 and via the Shiina et al. method
(formation of a mixed anhydride by exchange with 2-methyl-
6-nitrobenzoic anhydride, MNBA).20 The results are shown
in Table 1. Entry 3 is the protocol of choice, to date, as it
gave 1 in higher yield (42%).
In summary, a new and efficient synthesis of amphidino-
lide X (1) has been achieved that relies upon the assembly
of the fragments by means of the Shiina macrolactonization
procedure and by using a temporary Si-tether for the key
construction of the E double bond. Although it has required
three additional steps (to cleave the tether with MeLi, to
(13) It has been demonstrated that this kind of compounds cannot be
cyclized using Ru initiators: (a) Chang, S.; Grubbs, R. H. Tetrahedron Lett.
1997, 38, 4757. (b) Barrett, A. G. M.; Beall, J. C.; Braddock, D. C.; Flack,
K.; Gibson, V. C.; Salter, M. M. J. Org. Chem. 2000, 65, 6508.
(14) For related Si-tethered cyclizations, see: (a) Gaich, T.; Mulzer, J.
Org. Lett. 2005, 7, 1311 (disiloxane tether, G II and H-G II, trisubstituted
olefin, Z/E 5:1). For other temporary Si-tethered cyclizations (standard cis
double bonds), see: (b) Denmark, S. E.; Yang, S.-M. Tetrahedron 2004,
60, 9695. (c) Evans, P. A.; Cui, J.; Buffone, G. P. Angew. Chem., Int. Ed.
2003, 42, 1734, and references therein. For reviews on silicon tethers, see:
(d) Fensterbank, L.; Malacria, M.; Sieburth, S. M. Synthesis 1997, 813. (e)
Gauthier, D. R.; Zandi, K. S.; Shea, K. J. Tetrahedron 1998, 54, 2289.
(15) For a review, see: (a) Denmark, S. E.; Sweis, R. F. In Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004; Vol. 1, p 163. For a similar approach with
aryl iodides instead of MeI, see: (b) Denmark, S. E.; Yang, S.-M. Org.
Lett. 2001, 3, 1749.
(17) The solvent played a crucial role to avoid double-bond isomerization
during the iododesilylation: (a) Zakarian, A.; Batch, A.; Holton, R. A. J. Am.
Chem. Soc. 2003, 125, 7822. (b) Ilardi, E. A.; Stivala, C. E.; Zakarian, A.
Org. Lett. 2008, 10, 1727.
(18) Review: Negishi, E.; Hu, Q.; Huang, Z.; Qian, M.; Wang, G.
Aldrichim. Acta 2005, 38, 71.
(19) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989. For reviews on its use in
macrolactonization reactions, see: (b) Bartra, M.; Urpí, F.; Vilarrasa, J. In
Recent Progress in the Chemical Synthesis of Antibiotics; Lukacs, G., Ed.;
Springer-Verlag: Berlin, 1993; Vol. 2, p 1. (c) Parenty, A.; Moreau, X.;
Campagne, J.-M. Chem. ReV. 2006, 106, 911.
(16) (a) Taguchi, H.; Tsubouchi, A.; Takeda, T. Tetrahedron Lett. 2003,
44, 5205, and references therein. (b) Schmidt, D. R.; Park, P. K.; Leighton,
J. L. Org. Lett. 2003, 5, 3535.
(20) (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
Chem. 2004, 69, 1822. (b) Shiina, I.; Fukui, H.; Sasaki, A. Nature Protocols
2007, 2, 2312.
Org. Lett., Vol. 10, No. 22, 2008
5193

Acknowledgment. The Ministerio de Educacio´n y Ciencia
is acknowledged for grant SAF2002-02728 to J.V. and F.U.,
including a FPI studentship to C.R.-E. (May 2003-April
2007) and grant CTQ-2006-15393 to J.V. We are members
of the IBUB (Institut de Biomedicina de la Universitat de
Barcelona).
Table 1. Macrolactonization of seco-Acid 23 to 1
yield
concn of 1
(mM) (%)
entry
1
reagents and conditions
2,4,6-trichlorobenzoyl chloride, Et3N, THF, 1.7
1.5 h, then DMAP, toluene, rt, 16 h
20
26
42
Supporting Information Available: Experimental pro-
2
3
2,4,6-trichlorobenzoyl chloride, Et3N, THF, 1.6
1.5 h, then DMAP, toluene, 50 °C, 16 h
1
cedures for all compounds, copies of the H and 13C NMR
spectra of the new compounds involved in the second
strategy (Schemes 4 and 5), and copies of the NMR spectra
of 1. This material is available free of charge via the Internet
at http://pubs.acs.org.
MNBA, Et3N, DMAP, CH2Cl2, 40 °C,
slow addition of 23 over 12 h at 40 °C
2.7
convert the C-Si to C-I bonds, and to couple the C-I bonds
with Me2Zn/Pd), all of them have been accomplished readily
in excellent yields (93-97%). This tactic can be useful in
other challenging cases.
OL8021676
5194
Org. Lett., Vol. 10, No. 22, 2008