ORGANIC
LETTERS
Total Synthesis of Lys3 Tamandarin M:
A Potential Affinity Ligand
2010
Vol. 12, No. 22
5306-5309
Kenneth M. Lassen and Madeleine M. Joullie´*
Department of Chemistry, UniVersity of PennsylVania, 231 South 34th Street,
Philadelphia, PennsylVania 19104, United States
Received October 7, 2010
ABSTRACT
The synthesis of Lys3 tamandarin M is described. This analogue can be used as a protein affinity ligand to probe the mechanism of action
of this unique class of molecules.
The didemnins are a family of marine natural products that
were isolated by Rinehart in 1984.1 They consist of a 23-
membered depsipeptide macrocycle with a side chain at-
tached to the threonine nitrogen of the macrocycle. The
didemnins (Figure 1) have been the subject of many
syntheses.2 Didemnin B (2) was the first marine natural
product to enter into phase II clinical trials, but the trials
were terminated due to toxicity issues associated with dosing
levels,3 and didemnin M (3) was later reported by Rinehart
in 1994.4 The difference between didemnins B and M is that
the side chain of didemnin M is extended by two additional
amino acid residues. It is one of the most potent immuno-
suppressive reagents known. In 2000, Fenical and Vervoort
reported the structure of the structurally related tamandarins
A and B5 (Figure 1) and both molecules were subsequently
synthesized.6 The main difference between didemnins and
tamandarins is that tamandarins A and B possess a structur-
ally simpler hydroxyisovaleryl (Hiv) fragment within a 21-
membered ring instead of the R-(R-hydroxyisovaleryl)pro-
pionyl fragment within a 23-membered ring. This structural
distinction results in minor differences in biological activity,
but the absence of the highly epimerizable stereocenter
present in the didemnins makes the tamandarins a more
accessible synthetic target. Although these compounds have
been extensively studied, their mechanism of action remains
unclear.
(1) (a) Rinehart, K. L., Jr.; Gloer, J. B.; Hughes, R. G., Jr.; Renis, H. E.;
McGovren, J. P.; Swynenberg, E. B.; Stringfellow, D. A.; Kuentzel, S. L.;
Li, L. H. Science 1981, 212, 933–935. (b) Rinehart, K. L., Jr.; Gloer, J. B.;
Cook, J. C., Jr.; Mizsak, S. A.; Scahill, T. A. J. Am. Chem. Soc. 1981, 103,
1857–1859.
(2) (a) Rinehart, K. L., Jr.; Kishore, V.; Nagarajan, S.; Lake, R. J.; Gloer,
J. B.; Bozich, F. A.; Li, K. M.; Maleczka, R. E., Jr.; Todsen, W. L.; Munro,
M. H. G.; Sullins, D. W.; Sakai, R. J. Am. Chem. Soc. 1987, 109, 6846–
6848. (b) Schmidt, U.; Kroner, M.; Griesser, H. Tetrahedron Lett. 1988,
29, 3057–3060, and 4407-4408. (c) Schmidt, U.; Kroner, M.; Griesser, H.
Tetrahedron Lett. 1988, 29, 4407–4408. (d) Hamada, Y.; Kondo, Y.; Shibata,
M.; Shioiri, T. J. Am. Chem. Soc. 1989, 111, 669–673. (e) Li, W.-R.; Ewing,
W. R.; Harris, B. D.; Joullie´, M. M. J. Am. Chem. Soc. 1990, 112, 7659–
7672.
(4) Sakai, R.; Stroh, J. G.; Sullins, D. W.; Rinehart, K. L. J. Am. Chem.
Soc. 1995, 117, 3734–3748.
(5) Vervoort, H.; Fenical, W.; de A. Epifanio, R. J. Org. Chem. 2000,
65, 782–792.
(6) (a) Liang, B.; Portonovo, P.; Vera, M. D.; Xiao, D.; Joullie´, M. M.
Org. Lett. 1999, 1, 1319–1322. (b) Joullie´, M. M.; Portonovo, P. S.; Liang,
B.; Richard, D. J. Tetrahedron Lett. 2000, 41, 9373. (c) Liang, B.; Richard,
D. J.; Portonovo, P.; Joullie´, M. M. J. Am. Chem. Soc. 2001, 123, 4469–
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(3) Vera, M. D.; Joullie´, M. M. Med. Res. ReV. 2002, 22, 102–145.
10.1021/ol1024212 2010 American Chemical Society
Published on Web 10/29/2010