ORGANIC
LETTERS
2010
Vol. 12, No. 13
2954-2957
A Formal Synthesis of the C1-C9
Fragment of Amphidinolide C Employing
the Tamaru Reaction
Mahesh P. Paudyal, Nigam P. Rath, and Christopher D. Spilling*
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis, One
UniVersity BouleVard, St. Louis, Missouri 63121
Received April 27, 2010
ABSTRACT
Homoallylation of aldehydes with isoprene and triethylborane catalyzed by Ni(acac)2 gave hydroxyalkenes in good yield with excellent regio-
and stereoselectivity. Cross metathesis of the hydroxyalkenes with methyl acrylate using second-generation Grubbs catalyst and copper(I)
iodide afforded r,ꢀ-unsaturated esters, which underwent cyclization in the presence of DBU to produce tetrahydrofurans with the correct
relative configuration for the C1-C9 fragment of amphidinolides C, C2, and F.
The symbiotic marine dinoflagellate Amphidinium sp., iso-
lated from the cells of aceol flatworms Amphiscolops sp.,
produces a structurally diverse group of macrolide natural
products.1 This group of macrolides, named amphidinolides,
contains over 30 compounds, and the majority of them
possess some level of cytotoxicity.
Amphidinolide C (1) (Scheme 1), isolated from the Y-5
strain of Amphidinium sp., is one of the most cytotoxic
members of the amphidinolide family.2 Embedded within
this macrolide are two 2,5-trans tetrahydrofuran rings and
12 stereocenters. Amphidinolide C was shown to possess
cytotoxicity against murine lymphoma L1210 (IC50 0.0058
µg/mL) and human epidermoid carcinoma KB (IC50 0.0046
µg/mL) in vitro. Interestingly, amphidinolides C2 (2) and F
(3), which vary only in the structure of the side chain, are
close to 1000-fold less active.
targets for synthesis. The syntheses of several fragments of
these molecules have been reported, but they have yet to
succumb to total synthesis.3
Our retrosynthetic analysis (Scheme 1) for amphidinolide
C divides the molecule into four different subunits; the
northern (C18-25), the southern (C1-C9), and the western
(C10-C17) subunits and the side chain (C26-C34). In this
paper, we describe the synthesis of the tetrahydrofuran (THF)
ring of C1-C9 fragment of amphidinolides C, C2, and F.
The C1-C9 fragment of amphidinolide C contains a 2,3,5-
trisubstituted tetrahydrofuran with a methyl substituent at the
3-position (4-position in amphidinolide C numbering). The
stereochemical relationship between the substituents is 2,5-
and 2,3-trans and 3,5-cis. Similar 3-methyl-substituted
tetrahydrofuran moieties are found in several other natural
products, e.g., monensin A,4 amphidinolides T15 and T3,6
tetronasin,7 gambieric acid,8 and gymnodimine.9
Due to their unique structure and noteworthy biological
activity, amphidinolides C (1), C2 (2), and F (3) have become
(3) (a) Bates, R. H.; Shotwell, J. B.; Roush, W. R. Org. Lett. 2008, 10,
4343. (b) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865. (c) Kubota,
T.; Tsuda, M.; Kobayashi, J. Tetrahedron 2003, 59, 1613. (d) Armstrong,
A.; Pyrkotis, C. Tetrahedron Lett. 2009, 50, 3325. (e) Mohapatra, D. K.;
Dasari, P. K.; Rahaman, H.; Pal, R. Tetrahedron Lett. 2009, 50, 6276. (f)
Mohapatra, D. K.; Rahaman, H.; Chorghade, M. S.; Gurjar, M. K. Synlett
2007, 4, 567. (g) Mahapatra, S.; Carter, R. G. Org. Biomol. Chem. 2009, 7,
4582.
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Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.; Kawabata, J.;
Kobayashi, J. J. Org. Chem. 2003, 68, 9109. (c) Kobayashi, J.; Tsuda, M.
Nat. Prod. Rep. 2004, 21, 77.
(2) (a) Kobayashi, J.; Ishibashi, M.; Walchli, M. R.; Nakamura, H.;
Hirata, Y.; Sasaki, T.; Ohizumi, Y. J. Am. Chem. Soc. 1988, 110, 490. (b)
Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363.
10.1021/ol100959a 2010 American Chemical Society
Published on Web 06/07/2010