Total synthesis of (-)-amphidinolide P

Article abstract of DOI:10.1021/ol0000197

(equation presented) The convergent enantiocontrolled total synthesis of the 15-membered macrolactone (-)-amphidinolide P is reported. Key transformations include a Sakurai allylation, a Stille coupling for the formation of a fully functionalized acyclic

Full text of DOI:10.1021/ol0000197

ORGANIC
LETTERS
2000
Vol. 2, No. 7
945-948
Total Synthesis of (−)-Amphidinolide P
David R. Williams,* Brian J. Myers, and Liang Mi
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
williamd@indiana.edu
Received January 31, 2000
ABSTRACT
The convergent enantiocontrolled total synthesis of the 15-membered macrolactone (−)-amphidinolide P is reported. Key transformations
include a Sakurai allylation, a Stille coupling for the formation of a fully functionalized acyclic precursor, and intramolecular transesterification.
The amphidinolides are a family of structurally related
cytotoxic natural products isolated from strains of micro-
scopic marine dinoflagellates.1 In initial studies, these
metabolites have shown extremely potent in vitro antitumor
activity in NCI screens.2 Furthermore, caribenolide I,3 a
metabolite that is closely related to amphidinolide N,2 has
displayed promising in vivo activity against murine tumor
P388,3 and amphidinolide B4 has also been shown to initiate
rabbit skeletal actomyosin ATPase activity. Although cultur-
ing of the dinoflagellates is currently underway by Shimzu
using 15 000 L tanks,5 the isolated yields of individual
amphidinolides are extremely low. Because of their diverse
structural features, notable biological activity, and limited
availability, the amphidinolides represent attractive targets
for total synthesis. Several synthetic strategies have been
reported,6 and to date, the total syntheses of two amphi-
dinolides, J7 and K,8 have been communicated. Our continu-
ing efforts have focused on amphidinolide P (1), the relative
configuration of which was deduced using 2D-NMR experi-
ments and molecular modeling studies.9 Herein, we report
the first total synthesis of (-)-amphidinolide P (1), the
enantiomer of the natural product, utilizing a highly efficient,
convergent approach. Our synthesis affirms the relative
stereochemistry and establishes the absolute configuration
of the natural macrolide.
Our retrosynthetic analysis of 1 recognized bond discon-
nections, which would provide for macrolactonization, and
installation of the C11-C12 diene as late stage events. This
strategy suggested alkenes 2 and 3 as fully functionalized
(6) (a) For synthetic studies directed toward the amphidinolides, see:
Williams, D. R.; Meyer, K. G. Org. Lett. 1999, 1, 1303-1305. (b) Ohi, K.;
Nishiyama, S. Synlett 1999, 573-575. (c) Terrell, L. R.; Ward, J. S., III;
Maleczka, R. E., Jr. Tetrahedron Lett. 1999, 40, 3097-3100. (d) Ishiyama,
H.; Takemura, T.; Tsuda, M.; Kobayashi, J. J. Chem. Soc. Perkin Trans. 1
1999, 1163-1166. (e) Eng, H. M.; Myles, D. C. Tetrahedron Lett. 1999,
40, 2275-2278. (f) Chakraborty, T.; Thippeswamy, D. Synlett 1999, 150-
152. (g) Hollingworth, G. J.; Pattenden, G. Tetrahedron Lett. 1998, 39,
703-706. (h) Chakraborty, T. K.; Das, S. Chem. Lett. 2000, 80-81.
(7) Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198-
11199.
(8) Williams, D. R.; Meyer, K. G. Total Synthesis of (+)-Amphidinolide
K. In Abstracts of Papers, 218th National Meeting of the American
Chemical Society, 1999; American Chemical Society: Washington, DC,
1999; p 578-ORGN.
(9) Ishibashi, M.; Takahashi, M.; Kobayashi, J. J. Org. Chem. 1995, 60,
6062-6066.
(1) (a) For reviews on isolation of the amphidinolides, see: Kobayashi,
J. In ComprehensiVe Natural Products Chemistry; Mori, K., Ed.; Elsevier:
New York, 1999; Vol. 8, pp 619-634. (b) Ishibashi, M.; Kobayashi, J.
Heterocycles 1997, 44, 543-572.
(2) Ishibashi, M.; Yamaguchi, N.; Sasaki, T.; Kobayashi, J. J. Chem.
Soc., Chem. Commun. 1994, 1455-1456. Amphidinolide N displays
antitumor potency (IC50 0.05 nM) at levels similar to those reported for
the spongistatins.
(3) Bauer, I.; Maranda, L.; Young, K. A.; Shimizu, Y.; Fairchild, C.;
Cornell, L.; MacBeth, J.; Huang, S. J. Org. Chem. 1995, 60, 1084-1086.
We postulate that caribenolide I is a metabolite, which may correspond to
the cyclodehydration product arising from amphidinolide N (ref 2).
(4) Matsunaga, K.; Nakatani, K.; Ishibashi, M.; Kobayashi, J.; Ohizumi,
Y. Biochim. Biophys. Acta 1998, 1427, 24-32.
(5) May, M. EnViron. Health Perspect. 1998, 106, A284-A285.
10.1021/ol0000197 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/17/2000

components of a Stille coupling process (Scheme 1). Further
inspection of the â-keto ester 3 focused our attention on
formation of the C6-C7 bond via a nucleophilic allylation
reaction.
protocol14 provided the corresponding alkyne, which was
subjected to palladium-catalyzed hydrostannylation15 of the
alkyne and was followed by removal of the silyl protecting
group to give the desired (E)-vinylstannane 2 (Scheme 2).
Scheme 3 illustrates the straightforward preparation of the
appropriately functionalized coupling partner, aldehyde 12,
Scheme 1
Scheme 3
Stannane 2 was prepared from optically active epoxide
410 in eight steps (Scheme 2). Thus, a Lewis acid promoted
regioselective opening of oxirane 4 provided the desired C14
Scheme 2
for further development of the hemiketal of 1 as well as diene
formation. Thus, the readily available optically active epoxy
alcohol 716 was converted to the corresponding iodide (8),
and subsequent copper-catalyzed coupling with Grignard
reagent 9 gave vinylsilane 1017 without causing elimination
of 8 to the corresponding allylic alcohol or isomerization of
10 to the corresponding dienol. Conversion to the vinylic
bromide 11,18 and removal of the silyl ether followed by
oxidation with the Dess-Martin periodinane,19 provided
aldehyde 12 (Scheme 3).
The Sakurai20 reaction of aldehyde 12 and allylsilane 1321
provided for the facile formation of the C6-C7 bond using
(12) Although DDQ has been used for removal of acetal and PMB ether
protecting groups, removal of the MMTr protecting group using DDQ has
not been previously utilized to the best of our knowledge. See: (a) Oku,
A.; Kinugasa, M.; Kamada, T. Chem, Lett. 1993, 165-168. (b) Tanemura,
K.; Nishida, Y.; Suzuki, T.; Satsumabayashi. K.; Horaguchi, T. J. Chem.
Res., Synop. 1999, 40-41. (c) Tanemura, K.; Suzuki, T.; Horaguchi, T.
Bull. Chem. Soc. Jpn. 1994, 67, 290-292. (d) Paterson, I.; Cowden, C. J.;
Rahn, V. S.; Woodrow, M. D. Synlett 1998, 915-917.
secondary alcohol while establishing the C15 stereocenter.
The resulting alcohol was protected as a tert-butyldimeth-
ylsilyl ether. The p-methoxytrityl group (MMTr)11 in 4 served
a 2-fold purpose in this reaction sequence. First, it was used
to sterically impede nucleophilic attack at the C2 position,
thus improving the regioselectivity in formation of 5. Second,
it provided for deprotection under neutral conditions in the
presence of the secondary silyl ether, which was necessary
because the use of mildly acidic or basic conditions led to
substantial quantities of silyl migration and diol products.12
The primary alcohol was oxidized to aldehyde 6 using the
Swern procedure13 with no evidence of epimerization.
Subsequent transformation of 6 using the Corey-Fuchs
(13) Mancuso, A. J.; Haung, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2482.
(14) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
(15) Zhang, H. X.; Gruibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857-1867.
(16) Epoxy alcohol 7 was prepared from 1,4-butyne diol in three steps
(91% ee). See: Total Synthesis of (+)-Breynolide A. Jass, P. A. Ph.D.
Thesis, Indiana University, 1994. Also see ref 10.
(17) Nicolaou, K. C.; Duggan, M. E.; Ladduwahetty, T. Tetrahedron
Lett. 1984, 25, 2069-2072.
(18) Miller, R. B.; McGarvey, G. J. Org. Chem. 1979, 44, 4624-4633.
(19) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7278. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(20) (a) Sakurai, H.; Hosomi, A. Tetrahedron Lett. 1976, 16, 1295-
1298. (b) Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1976, 941-942.
(21) For the synthesis of the benzyl deravative of allylsilane 13, see:
(a) Bunnelle, W. H.; Narayanan, B. A. Org. Synth. 1990, 69, 89-95 (b)
Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew. Chem., Int. Ed. Engl.
1997, 36, 2738-2741. (c) Mickelson, T. J.; Koviach, J. L.; Forsyth, C. J.
J. Org. Chem. 1996, 61, 9617-9620.
(10) Epoxide 4 is available in a one-pot Sharpless epoxidation and
protection sequence in 82% ee. See: Gao, Y.; Hanson, R. M.; Klunder, J.
M.; Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(11) Khorana, H. G.; Goldberg, H. I.; Rammler, D. H.; Smith, M. J.
Am. Chem. Soc. 1962, 84, 430-440.
946
Org. Lett., Vol. 2, No. 7, 2000

boron trifluoride etherate, which resulted in a 2:1 mixture
of separable alcohol C7 diastereomers. The desired alcohol
14 was determined to be the major diastereomer resulting
from Felkin-Ahn addition.22 The minor isomer was con-
verted into 14 utilizing the Mitsunobu reaction,23 and
subsequent protection provided the C7 silyl ether. After
treatment with DDQ, a careful oxidation with buffered
Dess-Martin periodinane19 provided a high yield of the
sensitive aldehyde 1524 with no evidence for migration of
the â,γ-olefin into conjugation or epimerization of the
R-stereocenter. Aldehyde 15 was added to an excess of the
lithium enolate derived from methyl acetate, and the resulting
2:1 ratio of aldol adducts25 was immediately oxidized to the
â-keto ester 3 using the Dess-Martin reagent (Scheme 4).
Scheme 5
Scheme 4
carbon-carbon bond involved a coupling reaction between
stannane 2 and bromide 11, which also showed that “ligand-
less” palladium conditions (Pd(OAc)2/toluene) provided the
expected diene at room temperature, whereas the addition
of triphenylphosphine or various other phosphines and polar
solvents (DMF, THF, NMP) afforded none of the product.
Furthermore, it is surprising that the use of triphenylarsine
in these reactions resulted in none of the desired cross-
coupled product even after prolonged reaction times or
elevated temperatures.28
Intramolecular transesterification was carried out by heat-
ing the â-keto ester alcohol (16) at reflux in toluene,29 which
gave the pure macrocycle (17) in 72% yield presumably via
a ketene intermediate.30 Finally, removal of the silyl ether
protecting group gave spontaneous ring closure to a single
hemiketal isomer, which proved to be synthetic (-)-
amphidinolide P (1), isolated as a white crystalline
powder: [R]23 -30° (c 0.09, MeOH), [R]25 lit. +31°
(c 0.098, MeOH), identical in all respects, except rotation,
with detailed spectroscopic data reported for the natural
product.9
In summary, we have described the first synthetic route
to amphidinolide P (1), which establishes the absolute
configuration of the natural product as opposite to that as
depicted and developed for our synthetic material. Further-
more, we have demonstrated mild “ligandless” conditions
for a Stille coupling reaction on a highly functionalized
The critical Stille coupling26 of stannane 2 and the fully
functionalized alkenyl bromide 3 were realized only when
reactions were attempted with a palladium catalyst associated
with very labile ligands in nonpolar solvent. Thus, the
atypical conditions of Pd2dba3‚CHCl3 in CH2Cl2 at room
temperature27 provided diene 16 in 81% isolated yield
(Scheme 5) along with a small amount (5-8%) of a
presumed diastereomer arising from minor enantiomers of
epoxides 4 and 7. Our exploratory studies for making this
D
D
(22) The absolute stereochemistry of 14 was determined by Mosher ester
analysis. See: Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512-519.
(23) Mitsunobu, O. Synthesis 1981, 1.
(24) See ref 21b for an example in which the Dess-Martin periodinane
(28) We were able to couple tributylvinylstannane and bromide 3 using
Pd2dba3 and Ph3As in THF, but these conditions did not give any of the
desired product for the coupling of 2 and 3 even under prolonged reaction
times. For an example of a similar Stille coupling using a vinyl bromide,
see: Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.;
Sun, L.; Akhiezer, A.; Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237-
12254.
(29) (a) Mottet, C.; Hamelin, O.; Garavel, G.; Depre´s, J.-P.; Greene, A.
E. J. Org. Chem. 1999, 64, 1380-1382. (b) Bader, A. R.; Cummings, L.
O.; Vogel, H. A. J. Am. Chem. Soc. 1951, 73, 4195-4197. (c) Bader, A.
R.; Vogel, H. A. J. Am. Chem. Soc. 1952, 74, 3992-3994.
(30) (a) Cambell, D. S.; Lawrie, C. W. J. Chem. Soc., Chem. Commun.
1971, 355. (b) Witzeman, J. S. Tetrahedrom Lett. 1990, 31, 1401.
was used for a similar oxidation.
(25) Sato, F.; Kusakabe, M.; Kato, T.; Kobayashi, Y. J. Chem. Soc.,
Chem. Commun. 1984, 1331-1332.
(26) For reviews on the Stille reaction, see: (a) Farina, V.; Krishna-
murthy, V.; Scott, W. J. In Organic Reactions; Paquette, L. A., Ed.; John
Wiley & Sons: New York, 1997; Vol. 50. (b) Stille, J. K. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 508-524. (c) Stille, J. K. Pure Appl. Chem. 1985,
57, 1771-1780. (d) Mitchell, T. N. Synthesis 1992, 803-815.
(27) (a) This catalyst system was previously used for Stille coupling
reactions of triflates by Baker, S. R.; Roth, G. P.; Sapino. C. Synth. Comm.
1990, 20, 2185-2189. (b) For “ligandless” use of Palladium in various
couplings, see: Beletskaya, I. P. J. Organomet. Chem. 1983, 250, 551.
Org. Lett., Vol. 2, No. 7, 2000
947

substrate, which could have important ramifications for the
synthesis of complex natural products.
Supporting Information Available: Procedures and
spectral data for all compounds on the synthesis pathway
and a proton NMR spectrum of 1 (PDF). This material is
available via the Internet at http://pubs.acs.org.
Acknowledgment. The authors gratefully acknowledge
the National Institutes of Health (GM-42897) for generous
support of our work.
OL0000197
948
Org. Lett., Vol. 2, No. 7, 2000