Total synthesis of didmolamides A and B

Article abstract of DOI:10.1016/j.tetlet.2005.02.097

The first total synthesis of didmolamides A (1) and B (2) has been accomplished by the solid phase assembly of thiazole-containing amino acids and commercially available Fmoc-protected amino acids. The synthesis of didmolamide B was also achieved in high

Full text of DOI:10.1016/j.tetlet.2005.02.097

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2567–2570
Total synthesis of didmolamides A and B
Shu-Li You and Jeffery W. Kelly*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, BCC265, La Jolla, CA 92037, USA
Received 3 January 2005; revised 11 February 2005; accepted 16 February 2005
Abstract—The first total synthesis of didmolamides A (1) and B (2) has been accomplished by the solid phase assembly of thiazole-
containing amino acids and commercially available Fmoc-protected amino acids. The synthesis of didmolamide B was also achieved
in high yield using solution phase peptide synthesis. The thiazole-containing amino acid composing 1 and 2 was synthesized by a
MnO2 oxidation of a thiazoline, prepared from an Ala-Cys dipeptide using bis(triphenyl)oxodiphosphonium trifluoromethanesulf-
onate. The final macrolactamization was accomplished efficiently by PyBOP and DMAP in solution.
Ó 2005 Elsevier Ltd. All rights reserved.
Many oxazole and/or thiazole-containing macrolactams
have been recently isolated from marine organisms.1
Their activities, including cytotoxicity, multiple drug
resistance pump inhibition, as well as their metal bind-
ing, and transport properties, have led to much synthetic
interest.2,3 Didmolamides A and B (Fig. 1), isolated
from the marine ascidian Didemnum molle collected in
Madagascar, were shown to be mildly cytotoxic with
IC50 values of 10–20 lg/mL.4 Recently, we reported a
facile and efficient biomimetic synthesis of thiazolines
accomplished by treating N-acylated cysteine substrates
with bis(triphenyl)oxodiphosphonium trifluorome-
thanesulfonate.5 Thiazoles can in turn be obtained by
oxidation of the thiazolines. Dendroamide A,6 bistrat-
amides E–J,7 tenuecyclamides A–D8 and their analogs
have been efficiently synthesized by taking advantage
of this methodology. In this letter, we report the total
synthesis of didmolamides A (1) and B (2).
The retrosynthetic analysis for didmolamide A (1) is
shown in Figure 2. Disconnections at the amide bonds
and oxazoline ring result in two commercially available
amino acids and two identical thiazole-based amino
acids (3).
The thiazole-containing amino acid (3) was synthesized
as shown in Scheme 1. The synthesis commences with
the protection of the carboxylic acid of N-Fmoc-S-tri-
tyl-L-cysteine as an allyl ester. Fmoc deprotection allows
the resulting amine to be coupled with an active ester of
N-Fmoc-L-alanine to afford the fully protected dipeptide
4 (84% overall, three steps). Bis(triphenyl)oxodiphos-
phonium trifluoromethanesulfonate was utilized to con-
vert the trityl protected cysteine-containing dipeptide 4
into thiazoline 5 (92%). Thiazoline 5 was oxidized to
O
O
S
S
N
HO
N
H
H
O
N
NH
NH
N
N
O
Ph
Ph
NH
O
HN
O
HN
O
N
N
O
O
O
S
N
N
S
S
FmocNH
OH
H
O
N
N
S
Didmolamide A (1)
Didmolamide B (2)
3
Ph
NH
O
HN
+
Figure 1. Line drawings of didmolamides A (1) and B (2).
N
O
Fmoc-allo-Thr-OH
S
+
Keywords: Didmolamides; Bis(triphenyl)oxodiphosphonium trifluoro-
methanesulfonate; Thiazoline; Thiazole.
Fmoc-Phe-OH
Didmolamide (1)
*
Corresponding author. Tel.: +1 858 784 9880; fax: +1 858 784
9899; e-mail: jkelly@scripps.edu
Figure 2. Retrosynthetic analysis for didmolamide A (1).
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.097

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S.-L. You, J. W. Kelly / Tetrahedron Letters 46 (2005) 2567–2570
a, b, c
(84%)
d
Fmoc-Cys(Trt)-OH
Fmoc-Ala-Cys(Trt)-OAllyl
(92%)
4
O
O
N
N
e
FmocNH
FmocNH
OAllyl
OAllyl
(91%)
S
S
5
6
f
3
(100%)
Scheme 1. Synthesis of the thiazole-containing amino acid 3. Reagents and conditions: (a) HBTU, HOBt, DIEA, allyl alcohol; (b) diethylamine,
CH3CN; (c) HBTU, HOBt, DIEA, N-Fmoc-Ala-OH; (d) Ph3PO, Tf2O, CH2Cl2, À20 °C; (e) activated MnO2; (f) Pd(OAc)2 , PS–PPh3, PhSiH3,
CH2Cl2.
thiazole 6 employing activated manganese oxide (91%;
>97% ee). Removal of the allyl ester protecting group
using a palladium catalyst, generated from Pd(OAc)2
and polymer-supported triphenylphosphine, afforded
the amino acid 3.9
in the presence of DIEA, the terminal Fmoc group
was removed and the thiazole containing triamide was
cleaved from the Wang resin using 95% TFA in CH2Cl2.
Removal of the solvent yielded the amino acid macro-
lactamization precursor, which was transformed into
the macrolactam 7 using a combination of PyBOP (benzo-
triazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflu-
orophosphate) and DMAP (4-dimethylaminopyridine)
in CH2Cl2/DMF (v/v: 2/1). Didmolamide A (1) was ob-
tained as a white semisolid after refluxing the macrolac-
tam 7 and the Burgess reagent in THF (56%).2b,11 Its 1H
and 13C NMR spectra are identical to those reported in
the literature.4
The solid phase synthesis of 1 on Wang resin is depicted
in Scheme 2.10 The first coupling between the resin and
thiazole amino acid 3 utilizing HBTU and HOBt in the
presence of DIEA was performed for 8–12 h to ensure
completion of ester bond formation. Removal of the
Fmoc group was accomplished with 20% piperidine in
DMF (1 h). Subsequent amide bond formation between
the resin bound amine and the next thiazole-based ami-
no acid residue (3) of the growing chain was enabled
using HBTU/HOBt (2 h). After sequentially coupling
N-Fmoc-allo-threonine and N-Fmoc-L-phenylalanine
to the resin-bound peptide utilizing HBTU and HOBt
Didmolamide B (2) was synthesized utilizing the same
approach (Scheme 3), minus the treatment of the macro-
lactam with Burgess reagent. The O-trityl protecting
group on the threonine residue was removed during
O
b, c
b, d
a
N
HO
FmocNH
O
Wang resin
S
Ph
O
O
O
H
N
N
O
b, e
N
N
FmocNH
HO
N
H
O
H
S
N
S
O
HO
O
S
S
N
N
H
H
NH
h
O
N
N
O
b, f, g
(56%)
Ph
Ph
NH
O
NH
O
HN
HN
N
N
O
O
S
S
7
Didmolamide A (1)
45% yield based on resin
Scheme 2. Solid phase synthesis of didmolamide A (1). Reagents and conditions: (a) HBTU (2 equiv), HOBt (2 equiv), DIEA (3 equiv), 3 (2 equiv,
0.5 M in DMF), 8–12 h; (b) 20% piperidine in DMF, 1 h; (c) HBTU (2 equiv), HOBt (2 equiv), DIEA (3 equiv), 3 (2 equiv, 0.5 M in DMF), 2 h; (d)
HBTU (2 equiv), HOBt (2 equiv), DIEA (3 equiv), N-Fmoc-allo-Thr-OH (2 equiv, 0.5 M in DMF), 2 h; (e) HBTU (2 equiv), HOBt (2 equiv), DIEA
(3 equiv), N-Fmoc-Phe-OH (2 equiv, 0.5 M in DMF), 2 h; (f) 95% TFA in CH2Cl2, 3 h; (g) PyBOP (2 equiv), DMAP (2 equiv), DIEA (2 equiv),
CH2Cl2, DMF; (h) Burgess reagent, THF, reflux.

S.-L. You, J. W. Kelly / Tetrahedron Letters 46 (2005) 2567–2570
2569
O
b, c
a
b, d
N
HO
FmocNH
Ph
O
Wang resin
S
O
O
S
O
H
N
N
S
N
b, e
N
FmocNH
N
H
O
H
S
O
O
Trt
O
HO
N
H
NH
NH
N
O
b, f, g
Ph
O
HN
N
O
S
Didmolamide B (2)
51% yield based on resin
Scheme 3. Solid phase synthesis of didmolamide B (2). Reagents and conditions: (a) HBTU (2 equiv), HOBt (2 equiv), DIEA (3 equiv), 3 (2 equiv,
0.5 M in DMF), 8–12 h; (b) 20% piperidine in DMF, 1 h; (c) HBTU (2 equiv), HOBt (2 equiv), DIEA (3 equiv), 3 (2 equiv, 0.5 M in DMF), 2 h; (d)
HBTU (2 equiv), HOBt (2 equiv), DIEA (3 equiv), N-Fmoc-Thr(Trt)-OH (2 equiv, 0.5 M in DMF), 2 h; (e) HBTU (2 equiv), HOBt (2 equiv), DIEA
(3 equiv), N-Fmoc-Phe-OH (2 equiv, 0.5 M in DMF), 2 h; (f) PhSH (1.1 equiv), 95% TFA in CH2Cl2, 3 h; (g) PyBOP (2 equiv), DMAP (2 equiv),
DIEA (2 equiv), CH2Cl2, DMF.
cleavage of the peptide from the Wang resin using TFA.
Didmolamide B (2) was obtained as a white foam. Its 1H
and 13C NMR spectra were reported in an undefined
mixture of CDCl3 and CD3OD, however, upon request
the author provided the 1H spectrum in DMSO-d6,
which is very similar to our spectra excepting the amide
O
O
a, c
a, b
(95%)
N
N
N
OAllyl
6
FmocNH
H
(91%)
S
S
8
O
O
O
a, d
N
N
FmocNH
TrtO
N
OAllyl
N
H
(94%)
H
S
S
9
Ph
O
O
O
H
N
a, e, f
(88%)
N
N
N
H
OAllyl
FmocNH
N
H
S
S
O
O
10
Trt
O
S
TrtO
N
H
NH
NH
g
N
O
Didmolamide B (2)
(96%)
Ph
O
HN
N
O
S
11
Scheme 4. Solution phase synthesis of didmolamide B (2). Reagents and conditions: (a) Diethylamine, CH3CN; (b) 3, HBTU, HOBt, DIEA; (c) N-
Fmoc-Thr(Trt)-OH, HBTU, HOBt, DIEA; (d) N-Fmoc-Phe-OH, HBTU, HOBt, DIEA; (e) Pd(OAc)2 , PS–PPh3, PhSiH3, CH2Cl2; (f) PyBOP,
DMAP, DMF/CH2Cl2 (1/2); (g) TFA, PhSH, CH2Cl2.

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S.-L. You, J. W. Kelly / Tetrahedron Letters 46 (2005) 2567–2570
resonances and the Thr hydroxyl resonance, which may
be shifted owing to the presence of H2O in their sample.4
be found, in the online version, at doi:10.1016/j.tetlet.
2005.02.097.
In order to ensure the integrity of didmolamide B (2), its
total synthesis was also accomplished in solution
(Scheme 4). The carboxylic acid 3 was coupled with
the free amine derived from 6 (generated by removing
the Fmoc group with diethylamine) utilizing HBTU
and HOBt in the presence of DIEA (Scheme 4). The
amide-linked bisheterocycle 8 was obtained in 95%
yield. Compound 8 was coupled sequentially with N-
Fmoc-O-trityl-L-threonine and N-Fmoc-L-phenylala-
nine employing HBTU/HOBt/DIEA affording 9 (91%)
and 10 (94%), respectively.
References and notes
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Boyce, R. J.; Mulqueen, G. C.; Pattenden, G. Tetrahedron
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Deprotecting the Fmoc group in 10 using diethylamine
followed by removal of the allyl ester protecting group
using a palladium catalyst, generated from Pd(OAc)2
and polymer-supported triphenylphosphine, gave the
amino acid macrolide precursor.9 The macrolactamiza-
tion was mediated by PyBOP and DMAP yielding 11
in 88% yield. After removing the trityl group from the
threonine residue in 11, didmolamide B (2) was ob-
tained. The properties of this compound were identical
to those of didmolamide B (2) synthesized using a solid
phase strategy.
2. (a) Wipf, P.; Miller, C. P. J. Am. Chem. Soc. 1992, 114,
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cles 2002, 58, 521.
In summary, the first total synthesis of didmolamides A
(1) and B (2) has been accomplished by the solid phase
assembly of thiazole-containing amino acids and
Fmoc-protected a-amino acids. The synthesis of didmo-
lamide B was also achieved using solution phase peptide
synthesis (48% overall yield). The crucial thiazole amino
acid (3) was synthesized by a MnO2 oxidation of a thiaz-
oline prepared from an Ala-Cys dipeptide using bis(tri-
phenyl)oxodiphosphonium trifluoromethanesulfonate.
The final macrolactamization was accomplished effi-
ciently by PyBOP and DMAP in all cases.
4. Rudi, A.; Chill, L.; Aknin, M.; Kashman, Y. J. Nat. Prod.
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Acknowledgements
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We gratefully acknowledge NIH grant GM63212 and
the Skaggs Institute for Chemical Biology for generous
financial support. We thank Professor Evan T. Powers
for helpful discussions and Professor Yoel Kashman
for providing the NMR spectra of didmolamides A
and B.
´
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Supplementary data
Experimental details and NMR data for compounds 1–
11. Supplementary data associated with this article can