Total synthesis of (+)-amphidinolide K [17]

Full text of DOI:10.1021/ja005644l

J. Am. Chem. Soc. 2001, 123, 765-766
765
Scheme 1
Total Synthesis of (+)-Amphidinolide K
David R. Williams* and Kevin G. Meyer
Department of Chemistry, Indiana UniVersity
Bloomington, Indiana 47405
ReceiVed September 26, 2000
The amphidinolides are an important family of antitumor
macrolides isolated from the marine dinoflagellate Amphidinium
sp., a symbiotic microalgae found in the Okinawan flatworm
Amphiscolops sp.1 Amphidinolides have extraordinary activity
against a variety of NCI tumor cell lines. However, extremely
limited quantities have slowed the pace of biological studies, and
in many cases hampered progress toward complete structural
assignments.2 Interestingly, amphidinolides A through V exhibit
remarkable structural diversity, ranging from 12-membered to 29-
membered systems.3 Our recent efforts have reported the first
total syntheses of amphidinolides J and P,4 and numerous reports
of continuing studies in other laboratories are evidence of
widespread interest in these metabolites.5 In 1993, amphidinolide
K was first described as the 19-membered lactone 1 with
undetermined stereogenicity at C2, C4, and C18.6 Herein, we report
the total synthesis of (+)-amphidinolide K (2), and communicate
new assignments of relative and absolute stereochemistry of the
natural product.
Scheme 2
A convergent, stereocontrolled synthesis of 1 relied on the
efficient preparation of three construction components derived
from bond disconnections at (C6-C7), (C12-C13), and (C1-O),
which would allow for a flexible plan in light of the challenging
stereochemical issues.7 The first component, optically active
aldehyde 3, was prepared via the readily accessible nonracemic
(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.
(2) (a) Amphidinolide N displays antitumor potency (IC50 ) 0.05 nM)
similar to levels reported for the spongistatins: Ishibashi, M.; Yamaguchi,
N.; Sasaki, T.; Kobayashi, J. J. Chem. Soc., Chem. Commun. 1994, 1455. (b)
Related carbenolide I shows promising in vivo potency: Bauer, I.; Maranda,
L.; Young, K. A.; Shimizu, Y.; Fairchild, C.; Cornell, L.; MacBeth, J.; Huang,
S. J. Org. Chem. 1995, 60, 1084. (c) Amphidinolide B: Bauer, I.; Maranda,
L.; Shimizu, Y.; Peterson, R. W.; Cornell, L.; Steiner, J. R.; Clardy, J. J. Am.
Chem. Soc. 1994, 116, 2657.
(3) For recent examples: (a) Kobayashi, J.; Shimbo, K.; Sato, M.; Shiro,
M.; Tsuda, M. Org. Lett. 2000, 2, 2805. (b) Tsuda, M.; Endo, T.; Kobayashi,
J. J. Org. Chem. 2000, 65, 1349. (c) Tsuda, M.; Endo, T.; Kobayashi, J.
Tetrahedron 1999, 55, 14565.
(4) (a) Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198.
(b) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett., 2000, 2, 945.
(5) (a) For recent studies directed toward the amphidinolides, see: Williams,
D. R.; Meyer, K. G. Org. Lett. 1999, 1, 1303. (b) Ohi, K.; Nishiyama, S.
Synlett 1999, 573. (c) Terrell, L. R.; Ward, J. S., III; Maleczka, R. E., Jr.
Tetrahedron Lett. 1999, 40, 3097. (d) Ishiyama, H.; Takemura, T.; Tsuda,
M.; Kobayashi, J. J. Chem. Soc., Perkin Trans. 1 1999, 1163. (e) Eng, H. M.;
Myles, D. C. Tetrahedron Lett. 1999, 40, 2275. (f) Chakraborty, T.;
Thippeswamy, D. Synlett 1999, 150. (g) Hollingworth, G. J.; Pattenden, G.
Tetrahedron Lett. 1998, 39, 703. (h) Chakraborty, T. K.; Das, S. Chem. Lett.
2000, 80.
epoxy-aldehyde 4 (Scheme 1). Lewis acid-catalyzed allylation8
of 4 with bis-stannane 59 gave alcohol 6 as the major diastereomer
(79%, 6.9:1 anti:syn), resulting from Felkin-Anh addition. After
chromatographic purification of the anti isomer 6, protection as
the triisopropylsilyl (TIPS) ether was followed by selective
removal of the primary TBDPS ether under basic conditions. No
products resulting from Payne rearrangement of the epoxide were
detected throughout the sequence, and mild oxidation10 of 8
provided aldehyde 3.
Construction of the C7-C22 segment (Scheme 2) was designed
to utilize an asymmetric allylation strategy to efficiently fuse
stereochemical features in 3 with those of stannane 14. Known
alcohol 911 incorporated C18 chirality at an early stage in the
synthesis, and the efficient eight-step conversion to allylic alcohol
12 proved uneventful. A Sharpless asymmetric epoxidation of
12 (97% de) and subsequent reductive transposition established
(6) Ishibashi, M.; Sato, M.; Kobayashi, J. J. Org. Chem. 1993, 58, 6928.
(7) We have prepared 25 distinct diastereomers of 1. Detailed proton NMR
studies were supported by MM2* force field calculations (MacroModel 7.0)
for conformational analyses of these macrocycles. A detailed discussion of
these efforts will accompany a full account of our work.
(8) (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265. (b) Howe,
G. P.; Wang, S.; Proctor, G. Tetrahedron Lett. 1987, 28, 2629.
(9) Mitchell, T. N.; Kwetkat, K.; Rutschow, D.; Schneider, U. Tetrahedron
1989, 45, 969.
(10) Boeckman, R. K.; Shao, P.; Mullins, J. J. Org. Synth. 1999, 77, 141.
10.1021/ja005644l CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/09/2001

766 J. Am. Chem. Soc., Vol. 123, No. 4, 2001
Communications to the Editor
the C15 stereochemistry, and provided pure 13 after flash
chromatography (80% yield from 12). Finally, an alkoxide-assisted
allylic deprotonation led to stannane 14.12
Scheme 3
Formation of (R)-homoallylic C12 alcohol 16 was achieved by
initial transmetalation of optically pure stannane 14 with (R,R)-
bromoborane 1513 via allylic transposition to yield an intermediate
borane. Introduction of aldehyde 3 at -78 °C provided for a facile
condensation reaction yielding 16 (72%). Stereocontrol is induced
from the 1,2-diphenylethane sulfonamide auxiliary and is pre-
dicted from a Zimmerman-Traxler model with minimized steric
repulsions.14 The high level of selectivity (17:1 dr) obtained in
this case is the result of a matched diastereomeric transition state
featuring the inherent Felkin-Anh selectivity for nucleophilic
attack in aldehyde 3, with the (S)-configuration of the C15 benzoate
of 14, as well as the (R,R)-antipode of auxiliary 15, resulting in
3-fold stereodifferentiation. Conversion of 16 to the corresponding
mesylate and methanolysis of the C15 benzoate provided for
intramolecular backside displacement at C12 to give the desired
3-methylene-cis-tetrahydrofuran 17 (82%).15 Finally, desilylation
under mild acidic conditions proceeded without significant proto-
destannylation to yield key intermediate 18.
Preparation of the C1-C6 component required an adaptable
route of high stereochemical fidelity to assess elements of
stereogenicity at C2 and C4. For this purpose, the known oxirane
1916 was transformed to the triphenylmethyl (Tr) ether 20, and
regioselective nucleophilic addition of Me2CuLi in the presence
of BF3‚OEt2 followed by deprotection gave 1,2-diol 21 as the
major isomer (10:1 ratio). Direct reaction of epoxide 20 with
AlMe3 gave 22 (20% yield) along with numerous byproducts,
whereas cuprate reactions required the sterically demanding
protecting unit to minimize competing production of the corre-
sponding 1,3-diol.4b,17 Subsequent oxidative cleavage of 21 gave
an aldehyde that was immediately converted to dibromoolefin
23 in good yield (81%, 2 steps).18 Elimination and methylation
produced a disubstituted alkyne for a regioselective (9:1 ratio)
syn hydrozirconation-iodination process affording vinyl iodide
24 (91% over 2 steps). Desilylation and oxidation of the resulting
primary alcohol with pyridinium dichromate (PDC) gave the
carboxylic acid 25.
mild heating at 35 °C in the presence of palladium(0) catalyst
and copper(I) thiophene-2-carboxylate (CuTC)21 to give the
desired seco-acid. Cocatalyst CuTC resulted in a dramatic
improvement compared to CuI, and no products were observed
in the absence of CuTC. In the absence of palladium(0), only
homocoupling of stannane 18 was detected. Macrolactonization
with inversion at C18 proceeded under Mitsunobu conditions,22
and deprotection of the C9 alcohol provided (+)-amphidinolide
24
K (2: [R]D +62.0° (c 0.05, MeOH)), which proved to be the
antipode of the natural macrolide.23 Furthermore, a single-crystal
X-ray diffraction study of 2 (mp 114-118 °C) has unambiguously
confirmed our stereochemical assignments.24
In summary, the execution of a highly convergent strategy has
led to completion of the first total synthesis of amphidinolide K.
These efforts have led to the establishment of the relative
stereochemistry, as well as the absolute configuration of the
natural product. Our report of the use of CuTC as a cocatalyst in
the Stille reaction is an important development for the preparation
of substituted dienes, and holds considerable potential for use in
related cross-coupling processes.
The Stille coupling of alkenylstannane 18 and 25 was a crucial
development for our synthesis. Indeed, the formation of butadienes
featuring internal (C2/C3) dialkyl substitution is particularly
challenging.19,20 Successful coupling of 18 and 25 occurred upon
Acknowledgment. The authors gratefully acknowledge the National
Institutes of Health (GM-42897) for generous support of our work.
(11) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(12) Trost, B. M.; King, S. A. J. Am. Chem. Soc. 1990, 112, 408.
(13) Corey, E. J.; Yu, G.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111,
5493, 5495.
(14) (a) Williams, D. R.; Brooks, D. A.; Meyer, K. G.; Clark, M. P.
Tetrahedron Lett., 1998, 39, 7251. (b) Williams, D. R.; Brooks, D. A.; Berliner,
M. A. J. Am. Chem. Soc. 1999, 121, 4924.
(15) For related studies of palladium-induced tetrahydrofuran formation:
Williams, D. R.; Meyer, K. G. Org. Lett. 1999, 1, 1303.
Supporting Information Available: Procedures and spectral data for
compounds 2, 3, 6-8, 13-18, and 24-26 of the synthesis pathway, tables
1
of H and 13C data for 2 and natural amphidinolide K, and data of the
X-ray crystal study of 2 (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA005644L
(16) (a) Boeckman, R. K.; Barta, T. E.; Nelson, S. G. Tetrahedron Lett.
1991, 32, 4091. (b) Marshall, J. A.; Sedrani, R. J. Org. Chem. 1991, 56, 5496.
(17) Tung, R. D.; Rich, D. H. Tetrahedron Lett. 1987, 28, 1139.
(18) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(19) Formation of similar dienes is unprecedented via the Stille coupling
process. For reviews: (a) Duncton, M. A. J.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 1999, 1235. (b) Mitchell, T. N. Synthesis 1992, 803.
(20) Our studies have shown that vinyl stannanes, such as 18, have a
propensity to undergo cine substitution rather than ipso replacement. (See:
Farina, V.; Hossain, M. A. Tetrahedron Lett. 1996, 37, 6997.) In addition,
iodide 25 was thermally unstable above 60 °C.
(21) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J.
Org. Chem. 1994, 59, 5905.
(22) Li, K. W.; Wu, J.; Xing, W.; Simon, J. A. J. Am. Chem. Soc. 1996,
118, 7237 and references therein.
(23) We gratefully acknowledge Dr. Jun’ichi Kobayashi, Hokkaido Uni-
versity, Sapporo, Japan, for providing spectral data of authentic material for
comparison.
(24) The stereochemical features of synthetic (+)-amphidinolide K (2) were
confirmed by a single-crystal X-ray diffraction study at -165 °C. Data are
available in the Supporting Information.