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. Author manuscript; available in PMC: 2008 Mar 5.
Published in final edited form as: Tetrahedron Lett. 2007 Mar 5;48(10):1827–1830. doi: 10.1016/j.tetlet.2007.01.034

Toward the Total Synthesis of Scleritodermin A: Preparation of the C1-N15 Fragment

Diver Sellanes 1, Eduardo Manta 1, Gloria Serra 1,*
PMCID: PMC1832122  NIHMSID: NIHMS18431  PMID: 18320006

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 α-keto amide linkage by the use of a highly activated α, β-ketonitrile.

Keywords: Scleritodermin A, thiazole, α-ketoamide, Wittig

Marine sponges of the order Lithistida are excellent sources of bioactive metabolites.1 They produce cyclic peptides with non-proteinogenic amino acids and polyketide moieties, such as Cyclotheonamides,2 Oriamide,3 and Keramamides.4 Recently, another macrocyclic compound, Scleritodermin A (1), was isolated by Schmidt and co-workers from the sponge Scleritoderma nodosum.5 It shows significant cytotoxic activity against a panel of human tumor cells lines (IC50 <2 μM). The structure of Scleritodermin A incorporates a novel conjugated thiazole moiety 2-(1-amino-2-p-hydroxyphenylethane)-4-(4-carboxy-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.

It has been suggested that the α-keto amide function of the Cyclotheonamides is involved in the deactivation of a protease.6,7 The same function, is presented in immunosupressants such as rapamycin and FK-506.8

In spite of such an interesting biological activity, the synthetic challenge defined by the assemblage of the thiazole ring, the polyketide chain and the α-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 synthesis of this compound and its analogs. We describe, herein, the synthesis of the ACT fragment and its coupling to the α, β -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 the C1-N15 fragment (2). This fragment contains a conjugated thiazole and the α-ketoamide moiety, also found in other marine natural products like Oriamide and Keramamides. The disconnection 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 cyclodehydration of a β-hydroxy thioamide derived from L-serine and L-tyrosine.

Scheme 1.

Scheme 1

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Retrosynthetic analysis of Scleritodermin A (1)

For synthesizing the ACT derivative we began by protecting the amino group of the O-benzyl-L-tyrosine with Boc. Then, a coupling reaction with L-serine methyl ester provided product 3 in 96 % yield,10 Scheme 2. When the corresponding β-hydroxy thioamide 5 was obtained by using the Lawesson’s reagent (after protection of the alcohol group), the reaction proceeded in poor yield. In contrast, 5 was obtained in high yield using Wipf’s procedure by cyclodehydration of the β-hydroxy amide with DAST,11 giving the oxazoline 4 (87 %) and then thiolysis 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 the thioamide 5, we investigated both procedures. The better yield was obtained 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 derived from dipeptide 5.13

Scheme 2.

Scheme 2

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Synthesis of thiazole 6

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 poor yield, we used instead LiAlH4 and then activated MnO2 (80% yield two steps, Scheme 3).

Scheme 3.

Scheme 3

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Synthesis of ACT derivative

The Wittig reaction between the aldehyde 7 and 2-(triphenylphosphoranylidene)-propianaldehyde rendered exclusively the E alkene (8) in 92% yield.

For the last coupling reaction of the ACT derivative synthesis (9), we investigated different conditions. When the ylide ethyl 2-(triphenylphosphoranylidene)propionate was refluxed in benzene, the E isomer was obtained exclusively. Then, the reaction was done in MeOH at 0 °C,14 but again only the E isomer was obtained. Finally, 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 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 cleaving the Boc group of 9.

Our synthesis of the α-ketoamide 2 (C1-N15 fragment) utilized the reaction of the nucleophile 10 and a highly electrophilic α, β-ketonitrile derived from L-allo-Isoleucine. This procedure was described by Wasserman et al.16 for the synthesis of Cyclotheonamide E2 and E3. The synthesis of Cyclotheonamides A and B have been reported by Schreiber,17 Wipf,18 Shioiri,19 Maryanoff6 and Ottenheijm.20 All of them obtained the α-ketoamide function by oxidation of α-hydroxy precursors in the final steps of the procedures.

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 the cyano keto phosporane 11 (Scheme 4). Ozonolysis of 11 generated the α, β-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

Scheme 4.

Scheme 4

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Synthesis of the C1-N15 fragment

In conclusion, a key fragment of Scleritodermin A was prepared in 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.

Supplementary Material

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Acknowledgments

This work was supported by a grant from NIH/FIRCA (Fogarty International Research Collaboration Award). The authors acknowledge a doctoral fellowship from PEDECIBA (Programa de Desarrollo de Ciencias Básicas) (Diver Sellanes).

Footnotes

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References and Notes:

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Supplementary Materials

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