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
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