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

Abstract

The synthesis of the C 1 -N 15 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. KeywordsScleritodermin 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 (IC 50 <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 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 products 9 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 C 1 -N 15 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-*Corresponding author. Tel: + 598 2 9244856; fax: +598 2 924 19 06, email: gserra@fq.edu.uy. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Proline give the C 1 -N 15 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-hy...

Synthesis of Macrocyclic Lactams and Lactones Containing Sulfur and Nitrogen

“…Синтез блока (4S-119) из L-алло-изолейцина (122) включал взаимодействие (после защиты аминогруппы) с илидом из PPh 3 =CHCN, [69] озонолиз соединения 123 по методу Вассермана [70] и взаимодействие с HN 3 по Мицунобу [71] (Схема 32). Синтетический блок (4R-119) синтезирован из другого изомера 122.…”

“…Сложноэфирная функция в полученном тиазоле 126 переведена в карбонильную, [67] и соединение 127 вовлечено в реакцию олефинирования по Виттигу, приводящую исключительно к E-ненасыщенному альдегиду 128. Олефинирование последнего в условиях реакции Хорнера-Эммонса в модификации Стилла-Дженари [69] позволило построить (2Z,4Е)-сопряженную систему синтона (2Z-120), а олефинирование по Хорнеру-Уодсворту-Эммонсу [68] получить (2E,4Е)-олефин (2E-120) (Схема 33).…”

Preparation and biological evaluation of key fragments and open analogs of scleritodermin A

“…The synthesis of these fragments was based on the methodology previously described by us for the synthesis of ACT fragment. 9 Firstly, we obtained thiazole 4 and oxazole 5 by cyclodehydration of a b-hydroxyamide or thioamide derived from Lserine and L-tyrosine (Scheme 2). The thiolysis of oxazoline 7 in H 2 S/MeOH is high-yielding, and offers an alternative to the thionation of peptides using Lawesson's reagent.…”

“…In 2007, our group reported the preparation of the C 1 eN 15 fragment, 9 and recently, Nan et al reported the total synthesis of the originally proposed and revised structures of scleritodermin A, 1 and 2, Figure 1. 10 The present studies allowed us to obtain different key fragments that have been tested for cytotoxic and antihelminthic activity.…”

An efficient synthesis of 2,4′-bi-1,3-oxa(thia)zoles as scaffolds for bioactive products

“…As a part of our search for anticancer or antiparasitic drugs candidates employing molecular simplification [17][18][19][20][21][22], we focused on the synthesis of 2,4'-biheterocycles as scaffolds of bioactive products using Hantzsch and cyclodehydration-oxidation reactions. In the present work, we report the synthesis of biheterocycles of type 1 (Scheme 1) using commercially available starting materials: L-serine methyl ester hydrochloride, ethyl bromopyruvate, and thioacetamide.…”