Total synthesis of amphidinolide J

Article abstract of DOI:10.1021/ol801708x

(Chemical Equation Presented) The marine natural product amphidinolide J has been synthesized according to a convergent strategy. The key steps of this synthesis include a B-alkyl Suzuki-Miyaura coupling and the addition of an alkynyllithium reagent to a Weinreb amide to build the C4-C5 and C12-C13 bonds, respectively, and a Yamaguchi macrolactonization.

Full text of DOI:10.1021/ol801708x

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4489-4492
Total Synthesis of Amphidinolide J
Marion Barbazanges, Christophe Meyer,* and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin, 75231
Paris Cedex 05, France
christophe.meyer@espci.fr; janine.cossy@espci.fr
Received July 25, 2008
ABSTRACT
The marine natural product amphidinolide J has been synthesized according to a convergent strategy. The key steps of this synthesis include
a B-alkyl Suzuki-Miyaura coupling and the addition of an alkynyllithium reagent to a Weinreb amide to build the C4-C5 and C12-C13 bonds,
respectively, and a Yamaguchi macrolactonization.
The extracts from the marine dinoflagellate Amphidinum sp.
have provided an impressive number of structurally diverse
potent cytotoxic macrolides named amphidinolides.1 Am-
phidinolide J, first isolated in 1993, is a 15-membered
macrolactone polyketide bearing six stereocenters (C3, C9,
C10, C13-C15), three disubstituted double bonds of E
configuration (C7-C8, C11-C12, and C16-C17) as well
as a methylene unit (at C4), which is a structural feature
encountered in almost all amphidinolides.2 Its absolute
stereochemistry was ascertained by ozonolysis and stereo-
selective synthesis of the resulting degradation products.2
Amphidinolide J exhibits cytotoxic activity against L1210
murine leukemia (IC50 ) 2.7 µg/mL) and KB human
epidermoid carcinoma cells (IC50 ) 3.9 µg/mL).2 In 1997,
amphidinolides S and R, two minor congeners of amphidi-
nolide J differing by the presence of a carbonyl group at C9
or from the size of the macrolactone (14-membered ring),
were also isolated (Figure 1).3
Figure 1. Structures of amphidinolides J, R, and S.
To date, only one total synthesis of amphidinolide J has
been accomplished by Williams and Kissel in 19984 using
a Negishi cross-coupling and a vinylzincate addition to an
aldehyde to build the C6-C7 and C12-C13 bonds, respec-
(1) (a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77–93
(b) Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451–460.
(2) Kobayashi, J.; Sato, M.; Ishibashi, M. J. Org. Chem. 1993, 58, 2645–
2646.
(3) Ishibashi, M.; Takahashi, M.; Kobayashi, J. Tetrahedron 1997, 53,
7827–7832.
(4) Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198–
11199.
10.1021/ol801708x CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society

tively, as well as a Yamaguchi macrolactonization. Herein,
we would like to report a new convergent total synthesis of
amphidinolide J and its formation from amphidinolide R by
intramolecular transesterification.
Scheme 2. Synthesis of the C1-C4 Subunit
In our retrosynthetic analysis of amphidinolide J, the
formation of the macrolactone was envisaged from a seco-
acid which was disconnected at the C4-C5 and C12-C13
bonds. The formation of the C4-C5 bond would be achieved
by a B-alkyl Suzuki-Miyaura cross-coupling between the
alkenyl iodide A (C1-C4 subunit) and a boronate generated
from the primary alkyl iodide B (C5-C12 subunit).5 The
C12-C13 bond would be created by the addition of an
alkynyllithium reagent, generated from the alkynylsilane at C12,
to the Weinreb amide C (C13-C20 subunit) (Scheme 1).
alcohol 7 (96%, ee ) 92%, dr > 99/1) was obtained.9,10
Protection of the secondary alcohol at C9 as a bulky
triisopropylsilyl ether (96%) allowed a chemoselective di-
hydroxylation of the terminal alkene leading to the 1,2-diol
8 (72%, dr ) 85/15).11,12 After oxidative cleavage with
NaIO4, the resulting sensitive aldehyde was converted to the
gem-dibromoolefin 9 (77%, two steps from 8) and subsequent
treatment with n-BuLi (THF, -78 °C), followed by silylation
of the resulting alkynyllithium intermediate, provided alky-
nylsilane 10 (87%).13 The alcohol at C5 was then depro-
tected14 and converted to alkyl iodide 11 (92%).15 The
preparation of the C5-C12 fragment of amphidinolide J was
therefore achieved in nine steps from homoallylic ether 5,
in 36% overall yield (Scheme 3).
The synthesis of the C13-C20 fragment was carried out
from the acetylenic ketone 1216 which underwent enantio-
selective reduction catalyzed by ruthenium complex
(R,R)-Ru-II in i-PrOH.17 The corresponding propargylic
alcohol (97%, ee ) 95%)18 was condensed with (4-methoxy-
benzyloxy)acetic acid (93%) followed by semihydrogenation
of the triple bond to provide the (Z)-allylic glycolate 13
(93%). The latter compound was converted to the corre-
sponding (Z)-silylketene acetal which underwent [3,3]-
glycolate-Claisen rearrangement.19 After hydrolysis, the
resulting carboxylic acid was treated with trimethylsilyldia-
Scheme 1. Retrosynthetic Analysis of Amphidinolide J
The synthesis of the C1-C4 fragment was first carried
out. The lithium enolate generated from (1S,2S)-pseudoephe-
drine propionamide 1 underwent a diastereoselective alky-
lation with the THP ether derived from 2-iodoethanol and
the resulting amide (98%, dr g 95/5)6,7 was subsequently
converted to methyl ketone 2 by treatment with MeLi (96%).
Ketone 2 was condensed with trisylhydrazide and trisylhy-
drazone 3 (81%) underwent a Shapiro reaction followed by
iodinolysis of the alkenyllithium intermediate to afford
alkenyl iodide 4 (87%). Thus, the C1-C4 subunit of
amphidinolide J was prepared in four steps from amide 1,
in 66% overall yield (Scheme 2).
The preparation of the C5-C12 fragment started with a
cross-metathesis between homoallylic ether 5 and acrolein
in the presence of Hoveyda-Grubbs catalyst H-II to provide
the R,ꢀ-unsaturated aldehyde 6 (89%).8 To introduce the two
stereogenic centers at C9 and C10, aldehyde 6 was involved
in an enantio- and diastereoselective crotyltitanation, with
the (E)-crotyltitanium complex (S,S)-Ti-I, and homoallylic
(9) (a) Hafner, A.; Duthaler, R. O.; Mari, R.; Rihs, J.; Rothe-Streit, P.;
Scharzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321–2336. (b) Cossy, J.;
BouzBouz, S.; Pradaux, F.; Willis, C.; Bellosta, V. Synlett 1992, 1595–
1606
.
(10) The ee of the homoallylic alcohol 7 was determined by supercritical
fluid chromatography and comparison with a racemic sample prepared by
addition of a crotylchromium reagent to aldehyde 6
(11) Andrus, M. B.; Lepore, S. D.; Sclafani, J. A. Tetrahedron Lett.
1997, 38, 4043–4046
.
.
(5) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(b) Chemler, S. R.; Trauner, D.; Danishefsky, S. Angew. Chem., Int. Ed.
2001, 40, 4544–4568.
(12) Franc¸ais, A.; Bedel, O.; Haudrechy, A. Tetrahedron 2008, 64, 2495–
2524
.
(13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–3772.
(14) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885–888.
(6) Myers, A. G.; Yang, B. H.; Chen, H.; Mc Kinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511
.
(7) The diastereoselectivity, with respect to the newly formed stereo-
center (C3), could not be accurately evaluated because of the presence of
the THP and amide rotamers. The ee of trisylhydrazone 3 was later checked
(ee > 90%) by supercritical fluid chromatography, see Supporting Informa-
(15) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866–2869. (b) Lange, G. L.; Gottardo, C. Synth. Commun. 1990,
20, 1473–1479.
(16) Verkruijsse, H. D.; Heus-Kloos, Y. A.; Brandsma, L. J. Organomet.
Chem. 1988, 338, 289–294.
tion
.
(8) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370. (b) Cossy, J.; BouzBouz, S.;
Hoveyda, A. H. J. Organomet. Chem. 2001, 634, 216–221.
(17) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738–8739
.
(18) For the ee determination, see Supporting Information
.
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Org. Lett., Vol. 10, No. 20, 2008

Scheme 3
.
Synthesis of the C5-C12 Subunit
Scheme 4. Synthesis of the C13-C20 Subunit
Red-Al to afford the (E)-allylic alcohol 18 (84%). The
secondary alcohol at C13 was protected as an acetate and
the primary alcohol at C1 was deprotected by acid-catalyzed
methanolysis. After oxidation with Dess-Martin periodinane
and deprotection of the alcohol at C14, the seco-aldehyde
19 was obtained (83%, two steps from 18). Oxidation of the
aldehyde at C1 proceeded smoothly but afforded a mixture
of two inseparable regioisomeric seco-acids 20 and 21 (4/1
ratio) due to partial migration of the acetyl group to the
hydroxyl at C14 (Scheme 5).24
The crude mixture of seco-acids 20 and 21 was then
subjected to macrolactonization under Yamaguchi condi-
tions25 to afford the 15-membered macrolactone 22 (34%)
and the 14-membered macrolactone 23 (24%) which were
readily separated by flash chromatography. Deprotection of
the C9 hydroxyl group in compounds 22 and 23 led to
macrolactones 24 (74%) and 25 (63%), respectively. The
protecting acetyl group in the 15-membered macrolactone
24 was removed (K2CO3, MeOH, rt, 2 h) and amphidinolide
J was isolated in 61% yield. Another fraction consisting of
a 4/1 mixture of amphidinolides J and R was also isolated
(15%). Interestingly, under similar conditions (rt, 4 h), an
acyl shift took place from the 14-membered lactone 25 and
amphidinolide J was again isolated as the major product
(46%) along with a 1/1 mixture of amphidinolides J and R
(18%) (Scheme 5).26,27 The spectroscopic data of the isolated
pure amphidinolide J were in perfect agreement with those
zomethane20 and methyl ester 14 was obtained with high
diastereoselectivity (87%, dr > 95/5) as a result of a chairlike
transition state in which the propyl group preferentially
occupies an equatorial position.19 Methyl ester 14 was
converted to Weinreb amide 15 (84%)21 and the C13-C20
subunit of amphinidolide J was thus synthesized in six steps
from ketone 12, in 61% overall yield (Scheme 4).
Having synthesized the three subunits, their coupling was
then studied. Alkyl iodide 11 was converted to a B-alkyl-
boronatewhichunderwentapalladium-catalyzedSuzuki-Miyaura
coupling with the alkenyl iodide 4 to afford compound 16
in 82% yield.5,22 After removal of the acetylenic TMS group
(92%), the terminal alkyne was lithiated and condensed with
Weinreb amide 15 to provide the acetylenic ketone 17 in
quantitative yield.23 To create the C13 stereocenter, ketone
17 underwent a diastereoselective reduction catalyzed by
(S,S)-Ru-II (reagent-controlled),17 and the resulting propar-
gylic alcohol (96%, dr > 95/5) was hydroaluminated with
(19) (a) Gould, T. J.; Balestra, M.; Wittman, M. D.; Gary, J. A.; Rossano,
L. T.; Kallmerten, J. J. Org. Chem. 1987, 52, 3889–3901. (b) Burke, S. D.;
Fobare, W. F.; Pacofsky, G. J. J. Org. Chem. 1983, 48, 5221–5228.
(20) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475–1478.
(24) Similar reaction conditions as described in ref 4 were used but
transacetylation could not be avoided.
(25) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
(21) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461–5464.
(22) (a) Marshall, J. A.; Schaaf, G. M. J. Org. Chem. 2003, 68, 7428–
7432. For a recent application of those conditions, see: (b) Corbu, A.;
Aquino, M.; Pratap, T. V.; Retailleau, P.; Arseniyadis, S. Org. Lett. 2008,
(26) For an example of translactonization from a 14- to a 15-membered
ring, see: (a) Adachi, T. J. Org. Chem. 1989, 54, 3507–3510. Translacton-
ization of a 15- to a 13-membered ring has been observed, see: (b) Sarabia,
F.; Chammaa, S. J. Org. Chem. 2005, 70, 7846–7857
.
(27) The reaction presumably proceeds under thermodynamic control
but the use of longer reaction times resulted in the formation of byproducts
presumably resulting from saponification, methanolysis, and/or degradation
10, 1787–1790
.
(23) An excess of alkynyllithium was used (2 equiv) and the terminal
alkyne could be recovered (69% based on the unreacted reagent).
of the macrolactones
.
Org. Lett., Vol. 10, No. 20, 2008
4491

Scheme 5. Total Synthesis of Amphidinolide J
previously reported for the natural product (∆δ e 0.1 ppm
in 1H and 13C NMR) with a measured optical rotation slightly
higher ([R]D +6.7 (c 0.52, MeOH); lit2 [R]D +1.2 (c 0.7,
MeOH)).
In conclusion, we have reported a total synthesis of
amphidinolide J in 22 steps (longest linear sequence) from
homoallylic ether 5, in 4% overall yield. A Myers alkylation,
a Shapiro reaction, an enantioselective and diastereoselective
crotyltitanation and a glycolate-Claisen rearrangement were
utilized as key steps for the synthesis of the three subunits
which were successively assembled by using a B-alkyl
Suzuki-Miyaura cross-coupling (C4-C5 bond), the addition
of an alkynyllithium to a Weinreb amide (C12-C13 bond),
and a Yamaguchi macrolactonization.
Acknowledgment. GlaxoSmithKline and the CNRS are
gratefully acknowledged for financial support (BDI grant to
M.B.).
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR data for all compounds.This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801708X
4492
Org. Lett., Vol. 10, No. 20, 2008