Toward the total synthesis of Scleritodermin A: preparation of the C1-N15 fragment

Article abstract of DOI:10.1016/j.tetlet.2007.01.034

The synthesis of the C₁-N₁₅ fragment of the marine natural product Scleritodermin A has been accomplished through a short and stereocontrolled sequence. Highlights of this route include the synthesis of the novel ACT fragment and the formation of the α-keto amide linkage by the use of a highly activated α,β-ketonitrile.

Full text of DOI:10.1016/j.tetlet.2007.01.034

Tetrahedron Letters 48 (2007) 1827–1830
Toward the total synthesis of Scleritodermin A:
preparation of the C1–N15 fragment
Diver Sellanes, Eduardo Manta and Gloria Serra*
Ca´tedra de Quı´mica Farmace´utica, Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, UDELAR,
Av. General Flores 2124, C. C. 1157, Montevideo, Uruguay
Received 24 November 2006; revised 22 December 2006; accepted 4 January 2007
Available online 10 January 2007
Abstract—The synthesis of the C1–N15 fragment of the marine natural product Scleritodermin A has been accomplished through a
short and stereocontrolled sequence. Highlights of this route include the synthesis of the novel ACT fragment and the formation of
the a-keto amide linkage by the use of a highly activated a,b-ketonitrile.
Ó 2007 Elsevier Ltd. All rights reserved.
Marine sponges of the order Lithistida are excellent
sources of bioactive metabolites.1 They produce cyclic
peptides with non-proteinogenic amino acids and poly-
ketide moieties, such as Cyclotheonamides,2 Oriamide,3
and Keramamides.4 Recently, another macrocyclic com-
pound, Scleritodermin A (1), was isolated by Schmidt
et al. from the sponge Scleritoderma nodosum.5 It shows
significant cytotoxic activity against a panel of human
tumor cells lines (IC50 <2 lM). The structure of Sclerito-
dermin A incorporates a novel conjugated thiazole
moiety 2-(1-amino-2-p-hydroxyphenylethane)-4-(4-carb-
oxy-2,4-dimethyl-2Z, 4E-propadiene)-thiazole (ACT),
L-proline, L-serine, and the unusual amino acids keto-
allo-isoleucine and O-methyl-N-sulfo-D-serine.
sis of this compound and its analogs. We describe, here-
in, the synthesis of the ACT fragment and its coupling to
the a,b-ketonitrile derived from L-allo-Ile to obtain the
key intermediate C1–N15 fragment.
Our retrosynthetic analysis of Scleritodermin A is shown
in Scheme 1. Disconnection at the ester group of the
macrolactone and cleavage of the amide bond between
keto-allo-Ile and L-proline give C1–N15 fragment (2).
This fragment contains a conjugated thiazole and the
a-ketoamide moiety, also found in other marine natural
products like Oriamide and Keramamides. The discon-
nection of the amide bond in fragment 2 produces the
ACT derivative, which could be obtained from thiazole
6. We propose to synthesize this compound (6) by cy-
clodehydration of a b-hydroxy thioamide derived from
L-serine and L-tyrosine.
It has been suggested that the a-keto amide function of
the Cyclotheonamides is involved in the deactivation of
a protease.6,7 The same function, is presented in immuno-
supressants such as rapamycin and FK-506.8
For synthesizing the ACT derivative we began by pro-
tecting the amino group of the O-benzyl-L-tyrosine with
Boc. Then, a coupling reaction with L-serine methyl es-
ter provided product 3 in a 96% yield,10 Scheme 2. When
the corresponding b-hydroxy thioamide 5 was obtained
by using the Lawesson’s reagent (after protection of the
alcohol group), the reaction proceeded in a poor yield.
In contrast, 5 was obtained in a high yield using Wipf’s
procedure by cyclodehydration of the b-hydroxy amide
with DAST,11 giving oxazoline 4 (87%) and then thioly-
sis using H2S,12 (92%). For the synthesis of the thiazole
rings our group had reported the use of Deoxo-Fluor
and in situ oxidation,9c but no reports were found in
the literature using DAST and BrCCl3/DBU. To
produce the desired thiazole 6 from thioamide 5, we
In spite of such an interesting biological activity, the
synthetic challenge defined by the assemblage of the thi-
azole ring, the polyketide chain, and the a-keto amide
function in the macrocycle, has not been described in
the literature up to date.
Our interest on the synthetic studies of marine natural
products9 stimulated us to embark upon a total synthe-
Keywords: Scleritodermin A; Thiazole; a-Ketoamide; Wittig.
*
Corresponding author. Tel.: + 598 2 9244856; fax: +598 2 924 19
06; e-mail: gserra@fq.edu.uy
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.034

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D. Sellanes et al. / Tetrahedron Letters 48 (2007) 1827–1830
Scheme 1. Retrosynthetic analysis of Scleritodermin A (1).
Scheme 2. Synthesis of thiazole 6.
investigated both procedures. The better yield was ob-
tained using DAST/BrCCl3/DBU (80%). The issue of
potential racemization of the tyrosine stereogenic center
under the dehydration–dehydrogenation conditions was
addressed by chiral HPLC analysis of the thiazole de-
rived from dipeptide 5.13
and then activated MnO2 (80% yield two steps, Scheme
3).
The Wittig reaction between aldehyde 7 and 2-(triphe-
nylphosphoranylidene)-propianaldehyde rendered exclu-
sively E alkene (8) in a 92% yield.
For synthesizing the ACT derivative, the ester group of
6 had to be converted to the corresponding aldehyde.
Since the reduction of 6 using DIBALH rendered the
aldehyde 7 in a poor yield, we used instead LiAlH4
For the last coupling reaction of the ACT derivative syn-
thesis (9), we investigated different conditions. When the
ylide ethyl 2-(triphenylphosphoranylidene)propionate
was refluxed in benzene, the E isomer was obtained

D. Sellanes et al. / Tetrahedron Letters 48 (2007) 1827–1830
1829
Scheme 3. Synthesis of ACT derivative.
Scheme 4. Synthesis of the C1–N15 fragment.
exclusively. Then, the reaction was done in MeOH at
0 °C,14 but again only the E isomer was obtained. Final-
ly, we used the modification of Still–Gennari for the
HWE reaction,15 and the 9 fragment was obtained in
Z:E, 80:20 using K2CO3 or 97:3 using KN(TMS)2 as
the base. The configuration of the two double bonds
was confirmed by NOE correlation between: (1) H7 of
the thiazole ring and the methyl group attached to C4
and (2) H3 and the methyl group attached to C2 (see
Scheme 1). Finally, the amine 10 was obtained by cleav-
ing the Boc group of 9.
Protection of the amine group of L-allo-Isoleucine with
Boc and further reaction of its carboxylic acid with the
(triphenylphosphoranylidene)acetonitrile ylide using
the coupling reagent EDCI, allowed us to obtain cyano
keto phosporane 11 (Scheme 4). Ozonolysis of 11 gener-
ated the a,b-ketonitrile, not isolable. Finally, 10 was
added to obtain the desired C1–N15 fragment (2) in
49% yield. The structure of this product was confirmed
by the presence of a signal at 194.5 ppm (13C NMR)
assignable to the C13 (keto function).21
In conclusion, a key fragment of Scleritodermin A was
prepared in a good overall yield from readily available
starting materials. Further progress toward the total
synthesis of this natural product will be reported in
the due course.
Our synthesis of a-ketoamide 2 (C1–N15 fragment) uti-
lized the reaction of the nucleophile 10 and a highly elec-
trophilic a,b-ketonitrile derived from L-allo-Isoleucine.
This procedure was described by Wasserman and
Zhang16 for the synthesis of Cyclotheonamide E2 and
E3. The synthesis of Cyclotheonamides A and B have
been reported by Schreiber and Hagihara,17 Wipf and
Kim,18 Shioiri and co-workers,19 Maryanoff et al.6 and
Ottenheijm and co-workers.20 All of them obtained the
a-ketoamide function by the oxidation of a-hydroxy
precursors in the final steps of the procedures.
Acknowledgments
This work was supported by a grant from NIH/FIRCA
(Fogarty International Research Collaboration Award).
The authors acknowledge a doctoral fellowship from

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D. Sellanes et al. / Tetrahedron Letters 48 (2007) 1827–1830
13. Chiralcel OD column; k = 228 nm; 10% 2-propanol:hex-
´
PEDECIBA (Programa de Desarrollo de Ciencias Basi-
cas) (Diver Sellanes).
ane; 1.0 mL/min; tR = 14.8 min.
14. Valverde, S.; Lomas, M. M.; Herradon, B.; Ochoa, S. G.
Tetrahedron 1987, 43, 1895.
Supplementary data
15. Still, W.; Gennari, C. Tetrehedron Lett. 1983, 24, 4405.
16. Wasserman, H. H.; Zhang, R. Tetrahedron Lett. 2002, 43,
3743.
17. Hagihara, M.; Schreiber, S. L. J. Am. Chem. Soc. 1992,
114, 6570.
18. Wipf, P.; Kim, H. J. Org. Chem. 1993, 58, 5592.
19. Deng, J.; Hamada, Y.; Shioiri, T.; Matsunaga, S.;
Fusetani, N. Angew. Chem., Int. Ed. Engl. 1994, 33,
1729.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.01.034.
References and notes
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0.23 mmol) was dissolved in CH2Cl2 (2 mL) and TFA
(1 mL) was added at 0 °C. The reaction mixture was
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filtered, and concentrated to afford the nucleophile 10 as a
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A solution of 11 (126 mg, 0.24 mmol) in CH2Cl2 (5 mL)
was ozonized at À78 °C until the color of the solution
remained blue (or yellow-blue). After the solution was
purged with N2 to remove the excess O3, the nucleophile
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Compound 2: Rf = 0.45 (EtOAc/n-hexane, 1: 2); IR (film)
2926, 1716, 1699, 1508, 1248, 1016, 748; 1H NMR (CDCl3,
400 MHz) d: 0.68 (d, 3H35, J = 6.9 Hz), 1.00 (t, 3H34,
J = 6.9 Hz), 1.31 (m, 5H33, 27), 1.44 (s, 9H31), 1.96 (m,
1H32), 2.06 (s, 3H24), 2.20 (s, 3H21), 3.29 (m, 2H10), 4.23
(q, 2H26, J = 7.2 Hz), 5.03 (m, 3H28,15), 5.20 (m, 1H9),
5.50 (m, 1H5), 6.31 (s, 1H22), 6.50 (s, 1H1), 6.88 (d, 2H13,
J = 8.7 Hz), 7.03 (m, 3H12,3), 7.42 (m, 5H17,18,19), 7.67 (m,
1H6); 13C NMR (CDCl3, 100 MHz) d: 12.0 (C34), 14.1
(C35), 14.5 (C27), 17.8 (C21), 22.0 (C24), 28.6 (C31), 30.0
(C33), 36.7 (C32), 41.4 (C10), 52.5 (C5), 58.8 (C9), 61.1
(C26), 70.4 (C15), 79.9 (C30), 115.3 (C13), 117.5 (C3), 124.2
(C1), 127.8 (C18), 128.3 (C19), 128.9 (C17), 129.3 (C11),
129.6 (C23), 130.8 (C12), 136.4 (C20), 137,5 (C16),
137.9(C22), 153.6 (C2), 152.4 (C29), 158.4 (C14), 167.4
(C4), 169.2 (C25), 170.2 (C7), 194.5 (C8); HRMS m/z calcd
for C39H49N3O7S (M+) 703.3291. Found 703.3247.
´
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