The first total synthesis of (-)-tamandarin A.

Article abstract of DOI:10.1021/ol9910058

[formula: see text] Tamandarin A (1), a newly isolated natural product similar in structure to didemnin B (2), was shown to be somewhat more active in vitro than 2 against pancreatic carcinoma with an ED50 value 1.5 to 2 ng/mL. We report here the first total synthesis of 1. The key steps include a practical stereoselective synthesis of the Hiv-isostatine unit, high-yielding linear precursor formation, a successful macrocyclization, and coupling of the macrocycle with the side chain to afford tamandarin A (1).

Full text of DOI:10.1021/ol9910058

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1319-1322
The First Total Synthesis of
(−)-Tamandarin A
Bo Liang, Padma Portonovo, Matthew D. Vera, Dong Xiao, and
Madeleine M. Joullie´*
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
mjoullie@sas.upenn.edu
Received September 2, 1999
ABSTRACT
Tamandarin A (1), a newly isolated natural product similar in structure to didemnin B (2), was shown to be somewhat more active in vitro than
2 against pancreatic carcinoma with an ED value 1.5 to 2 ng/mL. We report here the first total synthesis of 1. The key steps include a
50
practical stereoselective synthesis of the Hiv-isostatine unit, high-yielding linear precursor formation, a successful macrocyclization, and
coupling of the macrocycle with the side chain to afford tamandarin A (1).
Tamandarin A (1), a mewly isolated natural product similar
in structure to didemnin B (2), was shown to be somewhat
more active in vitro than 2 against pancreatic carcinoma with
an ED50 value of 1.5-2 ng/mL. We report here the first total
synthesis of 1. The key steps include a practical stereo-
selective synthesis of the Hiv-isostatine unit, high-yielding
linear precursor formation, a successful macrocyclization,
and coupling of the macrocycle with the side chain to afford
tamandarin A (1).
Tamandarin A (1) is a cyclic depsipeptide recently isolated
from an unidentified Brazilian ascidian of the family Di-
demnidae (Figure 1).1 The structure of 1 is similar to that of
didemnin B (2), a potent antiviral, immunosuppressive, and
antitumor agent.2 The macrocyclic core of tamandarin A
contains the simpler R-hydroxyisovaleryl (Hiv) isostatine
unit, rather than the more complex R-(R-hydroxyisovaleryl)-
propionyl (Hip) isostatine subunit of didemnin B. The
remainder of the tamandarin A structure is identical to that
of didemnin B.
Beyond the structural homology, 1 seems to exhibit much
of the same biological activity as 2. It retains similar levels
of in vitro antitumor activity in clonogenic assays (1-2 ng/
mL) as well as protein biosynthesis inhibition properties.1
The limited supply of 1 from its natural source has prevented
its full biological characterization. In particular, it has not
been established whether tamandarin A is a fully competent
mimic of didemnin B in vitro and in vivo, and screening for
antiviral and immunosuppressive activity has not been
reported. A viable synthetic route to tamandarin A will allow
such an investigation to proceed. Since tamandarin A is
considerably easier than other didemnins to access syntheti-
cally, the process of analogue preparation and screening
should be accelerated. Such analogues could enhance the
still-unfolding research directed at untangling the molecular
mechanism(s) by which didemnins and related compounds
exert their multifaceted cytotoxic and cytostatic effects.3
(1) Vervoort, H.; Fenical, W. J. Org. Chem. 1999, submitted for
publication.
10.1021/ol9910058 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/16/1999

isostatine unit 6. Compound 5 is an advanced intermediate
used in our previous synthesis of 2.2d
The synthesis of the target molecule (1) begins with the
(2S)-Hiv-isostatine unit 6 (Scheme 1). The (3S,4R,5S)-
Scheme 1a
a Reagents and conditions: (a) Cbz-succinimide, Et3N, CH2Cl2,
0 °C to rt (99%); (b) pentafluorophenol, EDAC‚HCl, DMAP,
CH2Cl2, 0 °C to rt; (c) LiCH2CO2Me, THF, -78 °C (80% two
steps); (d) KBH4, MeOH, -30 to 0 °C; de 91% (99%); (e)
TIPSOTf, 2,6-lutidine, CH2Cl2, rt (94%); (f) 1 M NaOH, MeOH:
THF:H2O (1:1:1), 0 °C to rt (95%).
Figure 1. Structures of tamandarin A (1) and didemnin B (2).
The retrosynthetic analysis of 1 is shown in Figure 2. The
macrocyclic core of the target molecule is disconnected into
two fragments, the tetrapeptide portion 5 and the Hiv-
isostatine portion 13 can be prepared from the noncoded
R-amino acid D-alloisoleucine (7) on a multigram scale,
which we accomplished in four steps from commercially
available (S)-2-methylbutanol.4 The amino function of 7 was
protected as its benzyloxycarbonyl (Cbz) derivative 8.
Activation of the carboxylic functionality of 8 as its
pentafluorophenol ester,2f,5 followed by condensation with
the lithium enolate of the methyl acetate, gave the â-ketoester
10.6 Stereoselective reduction of 10 with KBH4 gave 11 as
(2) (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. (c) Sakai, R.; Rinehart, K. L.; Kishore, V.; Kundu, B.;
Faircloth, G.; Gloer, J. B.; Carney, J. R.; Namikoshi, M.; Sun, F.; Hughes,
R. G., Jr.; Gravalos, G.; de Quesada, T. G.; Wilson, G. R.; Heid, R. M. J.
Med. Chem. 1996, 39, 2819-2834. (d) Li, W.-R.; Ewing, W. R.; Harris,
B. D.; Joullie´, M. M. J. Am. Chem. Soc. 1990, 112, 7659-7672. (e) Li,
W.-R.; Joullie´, M. M. In Studies in Natural Products Chemistry, Vol. 10,
StereoselectiVe Synthesis (Part F); Atta-ur-Rahman, Ed.; Elsevier: Am-
sterdam, 1992; pp 241-302. (f) Schmidt, U.; Kroner, M.; Griesser, H.
Tetrahedron Lett. 1988, 29, 4407-4408. (g) Wipf, P. Chem. ReV. 1995,
95, 2115-2134.
(3) (a) Crews, C. M.; Collins, J. L.; Lane, W. S.; Snapper, M. L.;
Schreiber, S. L. J. Biol. Chem. 1994, 269, 15411-15414. (b) Crews, C.
M.; Lane, W. S.; Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1996, 93,
4316-4319. (c) Meng, L.; Sin, N.; M., C. C. Biochemistry 1998, 37, 10488-
10492. (d) SirDeshpande, B. V.; Toogood, P. L. Biochemistry 1995, 34,
9177-9184.
(4) Portonovo, P.; Liang, B.; Joullie´, M. M. Tetrahedron: Asymmetry
1999, 10, 1451-1455.
Figure 2. Retrosynthesis of tamandarin A (1).
1320
Org. Lett., Vol. 1, No. 8, 1999

an 11:1 diastereomeric mixture.7 Crystallization of 11
afforded the diastereomerically pure product, whose stereo-
chemistry was determined by the NMR coupling constants
of the corresponding 2,2-dimethyloxazolidine7 and further
confirmed by X-ray crystallography (Figure 3).
Hydrogenolysis of the Cbz group of the fully protected
tetrapeptide 5 gave free amine 18 (Scheme 3). Coupling of
Scheme 3a
Figure 3. ORTEP drawing of compound 11.
Protection of the secondary hydroxyl group of 11 as the
TIPS ether afforded a separable mixure of diastereomeric
methyl esters. Purification by chromatography and hydrolysis
with 1 N NaOH solution gave the acid 13.
The Hiv (15) obtained from L-valine2d was protected as
its allyl ester (16, Scheme 2); the coupling of 16 with the
Scheme 2a
a (a) H2, Pd/C, EtOAc/MeOH (98%); (b) 19, DIEA, DMAP,
CH2Cl2, 0 °C to rt (96%); (c) MgBr2‚Et2O, CH2Cl2, -15 to 0 °C;
(d) H2, Pd/C, EtOAc/MeOH (1:1), rt; (e) HATU, DMF, DIEA, rt
(63% three steps overall); (f) HCl(g), EtOAc, -30 to 0 °C; (g) 4,
BOP, NMM, CH2Cl2, 0 °C to rt (56% two steps overall).
amine 18 with acid 6 using PyBrOP9 or HATU10 afforded
the linear precursor of 1 (20) in poor yield. However, the
coupling of the activated PFP ester 19 of acid 6 and amine
18 provided the protected linear precursor 20 in 96% yield.
Mild cleavage of the SEM ester11 with MgBr2‚Et2O was
selective in the presence of the Boc, TIPS, Cbz, and ester
functionalities, as we had demonstrated previously.12 The
resulting acid was subjected to hydrogenolysis. Macro-
cyclization using HATU afforded product 21 in good yield.
The synthesis of the side chain was accomplished using the
modified strategy developed in our previous synthesis of 2.2d
Hydrogen chloride (gas) in ethyl acetate successfully cleaved
both Boc and TIPS protecting groups on the macrocycle 21
to yield a product, which was coupled to side chain 4 using
a Reagents and conditions: (a) 1 N H2SO4, NaNO2, 0 °C to rt
(78%); (b) allyl bromide, DMF, K2CO3, Bu4NI, rt (96%); (c) 13,
DCC, DMAP, 0 °C to rt (65%); (d) Pd(PPh3)4, morpholine, THF,
rt; (e) PFPOH, EDAC‚HCl, DMAP, CH2Cl2, 0 °C to rt (83% two
steps overall).
isostatine unit (13) using DCC and DMAP afforded 17.
Removal of the allyl group of 17 using Pd(PPh3)4 gave acid
6 in quantitative yield.8
BOP,13 to afford tamandarin A {[R]20 -43.93 (c 1.05,
D
CHCl3)}, identical with the natural product (IR, 1H and 13
C
spectra).
Org. Lett., Vol. 1, No. 8, 1999
1321

In conclusion, we have achieved the first total synthesis
of (-)-tamandarin A (1) in 15 steps from D-alloisoleucine,
in 12.8% overall yield and 87.2% average yield per step.
This efficient synthetic route to tamandarins is anticipated
to accelerate SAR and mechanistic studies of this interesting
natural product.
providing the 1H and 13C spectra of the natural product and
a preprint of their manuscript.
Supporting Information Available: Experimental pro-
cedures, characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge the Na-
tional Institute of Health (CA-40081), NSF (CHE-9901449),
and the University of Pennsylvania for financial support of
this work. We thank Professor Fenical and Dr. Vervoort for
OL9910058
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