Total syntheses and biological investigations of tamandarins A and B and tamandarin A analog

Article abstract of DOI:10.1021/ja010222c

Tamandarins A (1) and B (2), two natural products similar in structure to didemnin B (3), were recently isolated from a Brazilian marine ascidian of the family Didemnidae. The cytotoxicity of 1 was reported to be somewhat more potent in vitro than that of 3 against various human cancer cell lines. The present account describes the first total syntheses of 1 and 2, and the syntheses of tamandarin A side chain analogues. The cytotoxicity data for these compounds show that the side chain modifications exhibit a parallel effect for both didemnins and tamandarins. This observation supports tamandarins' role as didemnins' mimic.

Full text of DOI:10.1021/ja010222c

J. Am. Chem. Soc. 2001, 123, 4469-4474
4469
Total Syntheses and Biological Investigations of Tamandarins A and
B and Tamandarin A Analogs
Bo Liang, David J. Richard, Padma S. Portonovo, and Madeleine M. Joullie´*
Contribution from the Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
ReceiVed January 25, 2001
Abstract: Tamandarins A (1) and B (2), two natural products similar in structure to didemnin B (3), were
recently isolated from a Brazilian marine ascidian of the family Didemnidae. The cytotoxicity of 1 was reported
to be somewhat more potent in vitro than that of 3 against various human cancer cell lines. The present account
describes the first total syntheses of 1 and 2, and the syntheses of tamandarin A side chain analogues. The
cytotoxicity data for these compounds show that the side chain modifications exhibit a parallel effect for both
didemnins and tamandarins. This observation supports tamandarins’ role as didemnins’ mimic.
Introduction
210 and tamandarin A analogues.11 With this highly efficient
approach in hand, analogue preparation and screening have been
greatly accelerated. Such analogues could enhance the still-
unfolding research directed at untangling the molecular mech-
anism(s) by which didemnins and related compounds exert their
multifaceted cytotoxic and cytostatic effects.12-17 We present
here an efficient, convergent synthetic strategy, which provides
access to both 1 and 2, as well as their analogues. The synthetic
tamandarin A analogues, 4, 5, and 6, have shown parallel
potencies to those of the side chain didemnin congeners 7, 8,
and 9. With dehydrodidemnin B (Aplidine) (7) reentering
clinical trials,18 the discovery of potent tamandarin analogues
may redefine lead compounds in clinical trials.11
Tamandarins A and B (1 and 2) are two naturally occurring
cytotoxic cyclic depsipeptides recently isolated from a Brazilian
ascidian of the family Didemnidae.1 The structures of 1 and 2
are similar to that of didemnin B (3), a potent antiviral
immunosuppressant and antitumor agent.2-8 The macrocyclic
cores of tamandarin A (1) and tamandarin B (2) contain the
R-hydroxyisovaleryl (Hiv) isostatine unit and R-hydroxyisov-
aleryl (Hiv) norstatine unit, respectively, rather than the more
complex R-(R-hydroxyisovaleryl)propionyl (Hip) isostatine
moiety of didemnin B (Figure 1).
Beyond its structural homology, 1 was reported to exhibit
much of the same biological activity as 3.1 Tamandarin A retains
similar levels of in vitro antitumor activity in clonogenic assays
(1 to 2 ng/mL) as well as protein biosynthesis inhibition
properties.1 However, no data were reported for tamandarin B
(2) due to the isolation of an insufficient quantity of this minor
metabolite.1 The limited supply of 1 and 2 from their natural
source has prevented their full biological characterization. In
particular, it was not established whether tamandarin A is a fully
competent mimic of didemnin B in vitro and in vivo, and
screening for antiviral and immunosuppressive activities has not
been reported. A viable synthetic route to tamandarins A and
B would make these investigations possible. We reported the
first total synthesis of 1 in a recent communication.9 The same
synthetic strategy was applied successfully to the syntheses of
Results and Discussion
Total Syntheses of Tamandarins A (1) and B (2). Due to
the importance of side chain structure for the biological activity
of didemnins, a synthetic scheme which involves addition of
the side chain to the macrocycle as the final step was necessary
for facilitating analogue preparation. The retrosynthetic analysis
of 1 and 2 is shown in Figure 2. The macrocyclic cores of the
target molecules are further disconnected into two fragments,
the tetrapeptide portion 13 and the Hiv-isostatine unit 14 or Hiv-
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Lett. 2000, 41, 9373-9376.
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S.; Joullie´, M. M. Abstracts of Papers; American Chemical Society National
Meeting, 2000; American Chemical Society: Washington, DC, 2000; 14-
Orgn.
(1) Vervoort, H.; Fenical, W.; de Epifanio, R. J. Org. Chem. 2000, 65,
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10.1021/ja010222c CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/14/2001

4470 J. Am. Chem. Soc., Vol. 123, No. 19, 2001
Liang et al.
Figure 1. Structures of didemnins, tamandarins, and analogues.
Scheme 1a
Figure 2. Retrosynthesis of tamandarins A (1) and B (2).
norstatine unit 15. Compound 13 is an advanced intermediate
used in our previous synthesis of 3.5
a Reagents and conditions. 16 to 28: (a) Z-succinimide, Et3N,
CH2Cl2, 0 °C to room temperature (99%); (b) PFPOH, EDAC•HCl,
DMAP, CH2Cl2, 0 °C to room temperature; (c) LiCH2CO2Me, THF,
-78 °C (80% two steps); (d) KBH4, MeOH, -30 to 0 °C (99%); (e)
TIPSOTf, 2,6-lutidine, CH2Cl2, room temperature (94%); (f) 1 M
NaOH, MeOH:THF:H2O (1:1:1), 0 °C to room temperature (95%). 17
to 29: (a) Z-Cl, saturated NaHCO3, 0 °C to room temperature (93%);
(b) PFPOH, EDAC‚HCl, DMAP, CH2Cl2, 0 °C to room temperature
(95%); (c) LiCH2CO2Me, THF, -78 °C (83%); (d) KBH4, MeOH, -30
to 0 °C (77%); (e) TIPSOTf, 2,6-lutidine, CH2Cl2, room temperature
(82%); (f) 1 M NaOH, MeOH:THF:H2O (1:1:1), 0 °C to room
temperature (81%).
The syntheses began with the lower portions of the macro-
cycle (Figure 2), (2S)-Hiv-isostatine unit (Hiv-Ist) 14 or (2S)-
Hiv-norstatine unit (Hiv-Nst) 15. The (3S,4R,5S)-isostatine
portion 28 may be prepared from the noncoded R-amino acid,
D-alloisoleucine (16), which was prepared in four steps from
affordable and commercially available (S)-2-methyl butanol on
a multigram scale.19 D-Valine was employed as the starting
material for the synthesis of the analogous norstatine acid 29
(Scheme 1). The amino functions of 16 and 17 were protected
as benzyloxycarbonyl (Z) derivatives 18 and 19. Activation of
the carboxylic functionalities of the resulting compounds (18
and 19) by formation of their PFP esters (20 and 21),7,20
followed by condensation with the lithium enolate of methyl
acetate, afforded the â-ketoesters 22 and 23, respectively.21 The
stereoselective reduction with KBH4 gave a diastereomeric
mixture (11:1),22 which provided the diastereomerically pure
(20) Schmidt, U.; Kroner, M.; Griesser, H. Synthesis 1989, 832-835.
(21) Harris, B. D.; Bhat, K. L.; Joullie´, M. M. Tetrahedron Lett. 1987,
28, 2837-2840.
(19) Portonovo, P.; Liang, B.; Joullie´, M. M. Tetrahedron: Asymmetry
1999, 10, 1451-1455.

Syntheses and Biological InVestigations of Tamandarins
J. Am. Chem. Soc., Vol. 123, No. 19, 2001 4471
Scheme 2
Scheme 3
allyl ester with tetrakis(triphenylphosphine)palladium(0) af-
forded the acids 14 and 15 in quantitative yield.23
With the lower fragments of 1 and 2 in hand, formation of
the macrocyclic linear precursor was the next challenge.
Tetrapeptide 13 was synthesized in multigram scale utilizing
our previous synthetic strategy (Scheme 4).5 Hydrogenolysis
of 13 provided the free amine 34, which when coupled with
the acid (32) using PyBrOP24 or HATU25-29 afforded the linear
precursor (35) in poor yield. However, reaction of the activated
PFP ester (37) provided the protected linear precursor 35 in
96% yield (Scheme 5). In like manner, the linear precursor (36)
of tamandarin B (2) was also synthesized by the analogous
reaction in good yield. Selective cleavage of the SEM ester in
the presence of Boc, TIPS, and Z protecting groups was
achieved with MgBr2‚Et2O as previously reported.30,31 The
resulting acids were converted to their free secondary amines
by hydrogenolysis. Macrocyclization with HATU then afforded
the fully protected macrocycles (39 and 40).
The tamandarin macrocycle salts were obtained by treatment
with hydrogen chloride (gas) in ethyl acetate, which successfully
removed both Boc and TIPS protecting groups. The synthesis
of the side chain 12 was accomplished by using the modified
strategy developed in our previous synthesis of 3.5,32 The X-ray
of the advanced intermediate L-Lac-L-Pro-N-Methyl-D-Leu
methyl ester (41) is shown in Figure 4. The tamandarin A
macrocycle salt was coupled with this side chain by using BOP33
to afford tamandarin A, which possessed spectral properties in
Figure 3. ORTEP drawings of compounds 24 (top) and 25 (bottom).
products 24 and 25 by recrystallization in ether/hexane. This
reducing agent was found to provide superior diastereoselectivity
in comparison to other reagents which were investigated. The
reduction of 22 with KBH4 at room temperature gave an 80%
de in 8 min. By lowering the temperature to -30 to 0 °C, the
de was 91% after 15 min. NaBH4 gave an 85% de in 15 min at
a temperature of -78 °C. The stereochemistry of the major
stereoisomer (24) was determined by the NMR coupling
1
agreement with those of the natural product (IR, H, and 13C
spectra). Although BOP was the reagent of choice in all previous
investigations,5,34-36 the analogous reaction with the tamandarin
(23) Kunz, H.; Waldmann, H. Angew. Chem., Int. Ed. Engl. 1984, 23,
71-72.
constant of the corresponding 2,2-dimethyl oxazolidine (J1,2
)
(24) Coste, J.; Fre´rot, E.; Jouin, P.; Castro, B. Tetrahedron Lett. 1991,
32, 1967-1970.
5 Hz),22 (Scheme 2) and further confirmed by X-ray analysis.
The X-ray structures of 24 and 25 are shown in Figure 3.
Conversion of the secondary hydroxyl groups to their TIPS
ethers, followed by hydrolysis of the methyl esters, produced
acids 28 and 29.
(25) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398.
(26) Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J. Chem.
Soc., Chem. Commun. 1994, 201-203.
(27) Carpino, L. A.; El-Faham, A.; Albericio, F. Tetrahedron Lett. 1994,
35, 2279-2282.
(28) Carpino, L. A.; El-Faham, A. J. Org. Chem. 1995, 60, 3561-3564.
(29) Humphrey, J. M.; Chamberlin, A. R. Chem. ReV. 1997, 97, 2243-
2266.
Elaboration of the isostatine acid was accomplished by
coupling with the SEM ester of hydroxyisovaline using various
coupling conditions (Scheme 3). Unfortunately, utilization of
this substrate resulted in the formation of the lactamized product
A as the major compound instead of the desired linear compound
B. However, use of the allyl protecting group provided esters
32 and 33 in good yield by treatment with DCC/DMAP and
EDAC•HCl/DMAP, respectively (Scheme 4). Removal of the
(30) Kim, S.; Park, Y. H.; Kee, I. S. Tetrahedron Lett. 1991, 32, 3099-
3100.
(31) Chen, W.-C.; Vera, M. D.; Joullie´, M. M. Tetrahedron Lett. 1997,
38, 4025-4028.
(32) Liang, B.; Vera, M. D.; Joullie´, M. M. J. Org. Chem. 2000, 65,
4762-4765.
(33) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett.
1975, 14, 1219-1222.
(34) Mayer, S. C.; Ramanjulu, J.; Vera, M. D.; Pfizenmayer, A.; Joullie´,
M. M. J. Org. Chem. 1994, 59, 5192-5205.
(22) Harris, B. D.; Joullie´, M. M. Tetrahedron 1988, 44, 3489-3500.

4472 J. Am. Chem. Soc., Vol. 123, No. 19, 2001
Liang et al.
Scheme 4a
a Reagents and conditions: (a) allyl bromide, DMF, K2CO3, Bu4NI, room temperature (96%). 31 to 14: (b) 28, DCC, DMAP, 0 °C to room
temperature (65%); (c) Pd(PPh3)4, morpholine, THF, room temperature. 31 to 15: (b) 29, EDAC‚HCl, DMAP, CH2Cl2, 0 °C to room temperature
(60%); (c) Pd(PPh3)4, morpholine, THF, room temperature.
Scheme 5a
a Reagents and conditions. Synthesis of 1: (a) PFPOH, EDAC‚HCl, DMAP, CH2Cl2 (83% 2 steps overall from allyl deprotection); (b) 37, DIEA,
DMAP, CH2Cl2, 0 °C to room temperature (96%); (c) MgBr2‚Et2O, CH2Cl2, -15 to 0 °C; (d) H2, Pd/C, EtOAc/MeOH (1:1), room temperature; (e)
HATU, DMF, DIEA, room temperature (63% 3 steps overall); (f) HCl(g), EtOAc, -30 to 0 °C; (g) 12, BOP, NMM, CH2Cl2, 0 °C to room
temperature (56% 2 steps overall). Synthesis of 2: (a) PFPOTf, Pyr., CH2Cl2 (64% 2 steps overall from allyl deprotection); (b) 38, DIEA, DMAP,
CH2Cl2, 0 °C to room temperature (79%); (c) MgBr2‚Et2O, CH2Cl2, -15 to 0 °C; (d) H2, Pd/C, EtOAc/MeOH (1:1), room temperature; (e) HATU,
DMF, DIEA, room temperature (23% 3 steps overall); (f) HCl(g), EtOAc, -30 to 0 °C; (g) 12, DEPBT, DIEA, CH2Cl2, 0 °C to room temperature
(85% 2 steps overall).
B macrocycle provided the final product only in 20% yield.
The yield of this coupling was dramatically improved by use
of the newly reported coupling reagent 3-(diethoxyphosphory-
loxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT).37
Tamandarin A Analogues: Design and Syntheses
Though the complete SAR profile and mechanism(s) of action
of didemnins are still evolving, it is believed that the side chains
are important in determining biological activities as illustrated
in Table 1.4 Didemnin A is the simplest member of the family,
having only N-methyl-D-leucine as its side chain. Didemnin B
(35) Pfizenmayer, A. J.; Ramanjulu, J.; Vera, M. D.; Ding, X.; Xiao,
D.; Chen, W.-C.; Joullie´, M. M.; Tandon, D.; Toogood, P. L. Bioorg. Med.
Chem. Lett. 1998, 8, 3653-3656.
(36) Pfizenmayer, A. J.; Ramanjulu, J.; Vera, M. D.; Ding, X.; Xiao,
D.; Chen, W.-C.; Joullie´, M. M. Tetrahedon 1999, 55, 313-334.
(37) Li, H.; Jiang, X.; Ye, Y.-h.; Fan, C.; Romoff, T.; Goodman, M.
Org. Lett. 1999, 1, 91-93.

Syntheses and Biological InVestigations of Tamandarins
J. Am. Chem. Soc., Vol. 123, No. 19, 2001 4473
Scheme 6
Figure 4. ORTEP drawing of L-Lac-L-Pro-N-Methyl-D-Leu methyl
ester 41.
Scheme 7
Table 1. The Importance of the Side Chain for the Biological
Activities of Didemninsa
Immunosuppressive
Activity
Cytotoxic Activity
Compound name
IC50 in MLR assay
IC50 against P388 cells
didemnin A
0.98 nM
0.42 nM
0.38 nM
11 nm
1.8 nM
0.18 nM
didemnin B (3)
dehydrodidemnin B
(Aplidine) (7)
didemnin M (8)
0.00076 nM
1.5 nM
a IC50 concentration at 50% inhibition.
(3), the first marine natural product that entered Phase I and II
clinical trials, has been the lead didemnin compound over the
past 20 years of didemnin research. Dehydrodidemnin B
(Aplidine) (7), which contains a pyruvyl residue instead of the
lactyl group of 3, exhibited a 10-fold increase in cytotoxicity.
Furthermore, the cardiotoxicity which caused didemnin B to
be discontinued in clinical trials was not observed with this
compound.18 For this reason, dehydrodidemnin B was believed
to have clinical potential and was introduced by PharmaMar
into Phase I clinical trials in January, 1999.18 Didemnin M (8),
which has an elongated side chain relative to didemnin B, has
shown exceptional immunosuppressive activity with 0.76 pM
IC50 in the mixed lymphocyte reaction assay.4 N-Prolyldidemnin
A (9),7,34 which lacks the lactyl group present in 3, has been
synthesized as a didemnin analogue and shown cytotoxicity
comparable to didemnin B.
Tamandarin A (1) has been reported to exhibit cytotoxic and
protein biosynthesis inhibition properties comparable to those
of didemnin B,1 suggesting that the macrocyclic Hip subunit
may not be required for bioactivity. However, the immunosup-
pressive activity of tamandarin-type congeners has not been
examined. Our current research effort is focused on determining
the effects of side chain structural changes on this property. To
investigate the consequences of the Hip-to-Hiv modification
present in tamandarin-type congeners for the varied biological
effects exerted by this family of natural products, analogue
synthesis was undertaken. With the synthesis of [Hiv2]didemnin
M (5) recently reported,32 we now disclose the syntheses of
dehydrotamandarin A (4) and N-prolyl [Hiv2]didemnin A (6).
These analogues, which have not been isolated as natural
products, contain the simplified tamandarin macrocycle and the
same side chains which are present in dehydrodidemnin B (7),
didemnin M (8), and N-prolyldidemnin A (9), respectively.
Biological testing of these compounds, and comparison to the
results provided by their didemnin counterparts, will establish
the relevance of both the Hiv2 residue and the effect of side
chain variations on the biological activities.
With the A tamandarin macrocycle 39 in hand, the synthesis
of dehydrotamandarin A (4) was straightforward (Scheme 6).
Dess-Martin oxidation of the secondary alcohol 41 provided
the diketone compound 42 and saponification of the methyl ester
afforded the free acid side chain 43. The synthetic tamandarin
A analogue 4 was synthesized employing the BOP mediated
coupling strategy described above.
The synthesis of N-prolyl [Hiv2] didemnin A (6) is shown in
Scheme 7. The coupling of N-methyl D-leucine methyl ester
and N-Z-proline with BOP-Cl provided the dipeptide 44 in high
yield, which was subjected to saponification to afford the
carboxylic acid 45. The two-step deprotection of the fully
protected tamandarin A macrocycle 39, followed by coupling
with the side chain 45, gave the desired product. Removal of
the Z protecting group present on the proline residue afforded
the synthetic tamandarin A analogue 6.
Biological Investigations of the Natural Products and
Synthetic Analogues
Tamandarin B (2) and the synthetic tamandarin A analogues
4, 5, and 6 were tested by the National Cancer Institute against
various cell lines in vitro.38 A representative sample of cytotoxic
activity data, derived from 48 h of continuous drug exposure
of at least five concentrations at 10-fold dilutions, is shown in
Table 2.
The cytotoxicity data show that tamandarin B (2) is more
active than didemnin B (3), dehydrotamandarin A (4) exhibits
over a 10-fold potency increase, and both [Hiv2] didemnin M
(5) and N-prolyl [Hiv2] didemnin A (6) possess comparable
cytotoxicity, though examination of the immunosuppressive
(38) Boyd, M. R.; Paul, K. D. Drug DeV. Res. 1995, 34, 91-109.

4474 J. Am. Chem. Soc., Vol. 123, No. 19, 2001
Liang et al.
Table 2. NCI-60 Mean Data from the NCI-60 Tumor Cell Screena
Conclusion
Growth Inhibition 50% Cell Kill
Compound
didemnin B (3)
tamandarin B (2)
dehydrotamandarin A (4)
[Hiv2] didemnin M (5)
N-prolyl [Hiv2] didemnin A (6)
(GI50)
(LC50)
We have completed the first total syntheses of the tamandarin
natural products, as well as some of their synthetic analogues.
Biological studies indicate that tamandarin A is a competent
mimic of didemnin B. These investigations should greatly
enhance the still-unfolding research on the mechanism(s) of
action of the family of didemnidae ascidian metabolites.
13 nM
2.3 nM
1 nM
4 nM
16 nM
3.8 µM
1.4 µM
2.7 µM
7.6 µM
10.2 µM
a Preliminary results from the NCI-60 tumor cell screen. Concentra-
tions for 50% growth inhibition (GI50) and 50% cell kill (LC50) are
based upon the mean-graph midpoint across all cell lines.
Acknowledgment. We gratefully acknowledge the National
Institute of Health (CA-40081), National Science Foundation
(CHE-9901449), and the University of Pennsylvania for finan-
cial support of this work. We thank Dr. William Fenical and
activity of 5 is still in progress. The side chain modifications
of tamandarin A provide strong evidence that tamandarins do
mimic the biological activities of the didemnins. To target the
localization properties of these compounds, coumarin-labeled
fluorescent didemnins39 and tamandarins11,40 have been syn-
thesized. The two probes were shown to share the same
localization pattern in predators (fish) and to behave similarly.
These results further indicate that tamandarin A (1) is a
competent mimic of didemnin B (3).
1
Dr. He´le`ne Vervoort for providing the H and 13C spectra of
the natural products, an authentic sample of tamandarin B, and
a preprint of their original manuscript.
Supporting Information Available: All experimental pro-
cedures, X-ray data of compounds 24, 25, and 41, and copies
of IR, 1H, and 13C NMR spectra of all new compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(39) Portonovo, P.; Ding, X.; Leonard, M. S.; Joullie´, M. M. Tetrahedron
2000, 56, 3687-3690.
(40) Joullie´, M. M.; Leonard, M. S.; Portonovo, P.; Liang, B.; Ding, X.;
La Clair, J. J. 2001, manuscript in preparation.
JA010222C