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Synthesis of Oxazole, Oxazoline and Isoxazoline Derived Marine Natural Products: a Review

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Synthesis of Oxazole, Oxazoline and Isoxazoline Derived Marine Natural Products: a Review Author Version: Curr. Org. Chem., vol.20(8); 2016; 898-929 Synthesis of oxazole, oxazoline and isoxazoline derived marine natural products: A Review Supriya Tilvi,a* and Keisham S. Singha aBio-Organic Chemistry Laboratory, CSIR-National Institute of Oceanography, Dona Paula Goa 403 004, India. Correspondence Dr. Supriya Tilvi, Bio-Organic Chemistry Laboratory, CSIR-National Institute of Oceanography, Dona Paula Goa 403 004, India. E-mail: [email protected] ; Phone: + 91(0) 832-2450392 Fax: +91 (0) 832-2450 607 Abstract: Naturally occurring secondary metabolites containing oxazole, oxazoline and isoxazoline subunits, commonly derived from amino acids, are widely distributed in nature, both in marine and terrestrial organisms. These natural compounds have diverse significant biological activities, including anti- tumor, anti-bacterial, anti-viral, anti-malarial and immunosuppressive. Due to their significant biological properties, complex molecular structure and different functionalities present, synthesis of these classes of compounds continue to pay attention for natural product researcher and synthetic chemists. However, their complex nature, multifunctional substituents and often existed in diastereomers poise a major challenge and obstacles in their synthesis. In recent years, retrosynthetic analysis and total synthesis of oxazole containing marine natural products namely bengazoles, phorboxazole, pseudopteroxazoles, hennoxazole and cyclopeptide were reported by several groups. Total synthesis of a less common marine natural products containing oxazoline and isoxazoline ring such as calafianin, bistratamide E and tyrosine derived marine sponge metabolites have also been described. This review describes the isolation, biological activities and recent development on total syntheses of oxazole, oxazoline and isoxazoline derived marine natural products reported till 2014. Key words: oxazole, oxazoline, isoxazoline, marine natural products, synthesis 1 1. Introduction Marine natural products containing oxazole, oxazoline and isoxazoline skeleton have been reported from numerous marine organisms [1]. They display various biological properties including antifungal properties [2], cytotoxicity [3]. Among them, prominent examples of these classes of compounds include bengazoles, helipeptins, phorboxazole, (+)-calafianin, several cyclodepsipeptide and bromotyrosine derivatives. The burgeoning family of polyoxazole-based secondary metabolites now includes the phorboxazoles, hennoxazoles, diazonamide A, several azole-based cyclic peptides, the tetraoxazole YM-216391, and the intriguing hepta-oxazole telomestatin. This five membered heterocylic ring viz. oxazole, oxazoline and isoxazoline (Figure 1) were mainly isolated from marine sponges although a few of them have been obtained from associated microbes. Due to their interesting biological properties and diverse functional group derivatives, total synthesis of these class of compounds have paid attention for the past several years. This review, present the compilation of the total synthesis reported for these three classes of compounds of marine origin. In some cases where several synthesis methods were available only the most convenient and recent syntheses are discussed. For easy reading, the content has been divided under three categories; oxazole, oxazoline and isoxazoline containing marine natural products. N N O O O N Oxazole Isoxazoline Oxazoline Figure 1. Chemical structures of oxazole, oxazoline and isoxazoline rings 2. Oxazole: Marine natural products with oxazole skeleton are distributed in several marine organisms mainly sponges possessing a wide range of pharmacological activities. They are found as mono, bis, tris, tetra etc. oxazole ring containing compounds. Bengazoles and phorboxazole are the two widely distributed important marine natural products of this class. Bengazole A was isolated for the first time in 1988 by Crew and co-workers from a marine sponge of the genus Jaspis [4], and to date the bengazole family consists of 22 members [5]. Several marine natural products with 2,4-substituted azoles have been isolated and synthesized during the past few years[6]. Hennoxazoles (potent antiherpes virus agents and peripheral analgesics) [7] contain a bioxazole unit; muscoride A [8] (an antibacterial agent) features a bioxazole with methyl substituents at the 5-position of both oxazole rings; the macrolactams ulapualides,[9] kabiramides,[10] mycalolides,[11] and halichondramides [12] all contain a teroxazole unit; and the structurally complex diazonamides,[13] telomestatin,[14] 2 YM-216391,[15] and IB-01211 [16] all feature 2,4-substituted polyoxazoles linked to other heterocycles and/or peptidic fragments (Figure 2). OH OH N O Me O OMe Me O N N N MeO O OH OH OH H O O Me Me (-)- Hennoxazole A Bengazole A MeO OH Me Br Me O Me Me N O H HN N N Cl HO N O Cl MeO OH O O O O O O NH O N HO O NH O O Diazonamide A (+)-Phorboxazole A H O O CHO O N O N N N N O N OMe O OMe O OAc Me O H O H O NH O N N O HN N HO O NH N O O N N N Ph O O N N O N N S O S Ph O Ulapualide A O YM-216391 IB-01211 Figure 2. Structures of some oxazole containing marine natural products 2.1 Monoxazole: 2.1.1 Martefragin A (I) The sea alga Martensia fragilis produces a potent inhibitor of lipid peroxidation. The active metabolite has been identified as martefragin A (I) and its first synthesis has been reported starting with R-citronellol 1[17] (Scheme 1). Removal of the hydroxy group was followed by oxidative cleavage of the double bond to produce carboxylic acid 2 which was condensed (via its acid chloride) with oxazolidine 3 to give 4. Asymmetric azidation using the Evans procedure gave azide 5 in diastereomerically pure form. Conversion of this azide into the protected (2S,4S)-homoisoleucine 6 occurred in three steps whence it was condensed with O-benzyl-L-tryptophan hydrochloride to give dipeptide 7. This dipeptide cyclised upon treatment with DDQ[†] to give ozazole 8. N,N- dimethylation and debenzylation resulted in (1S,3S)-martefragin A (I). The spectral properties of the [†] A list of abbreviations can be found at the end of the Review 3 synthetic product were in good agreement with those of the natural product thus indicating that martefragin A has either the 1S,3S or 1R,3R absolute configuration. O O O O O a-c d-e HO C O f OH 2 N N NH O O N3 1 2 Bn 34 5 BuO2C BuO C NH 2 HO C N g-i 2 jk,l O BocHN O BocHN N N H N 6 7 H 8 - O2C N m, n 1 3 O +HN N H Martefragin A (I) Scheme 1. Total synthesis of Martefrafin A. Reagents and conditions: (a) MsClEt3N; (b) LiAlH4, Et2O, 77%; (c) KMnO4, NaIO4 aq acetone, 74%; (d) SOCl2, benzene; (e) Li-(S)-4-benzyl-2-oxo-1,3-oxazolidine; (f) KN(TMS)2, THF, -78 ºC then 2,4,6-triisopropylbenzenesulfonyl azide, -78 ºC then HOAc, -78 ºC, 78%; (g) LiOH, aq THF; (h) H2, 10% Pd/C, EtOH; (i) (Boc)2O, NaOH, aq dioxane, 81%; (j) Benzyl-L-tryptophan HCl, diethyl phosphonocyanidate, Et3N, THF, 0 ºC then rt, 97%; (k) DDQ, THF, reflux; (l) CF3CO2H, CH2Cl2, 57%; (m) Formalin, AcOH dioxane, H2, 10% Pd/C; (n) H2, Pd/C, AcOEt, 47%. 2.1.2 Pseudopteroxazole (II) Pseudopteroxazole (II) was isolated along with homopseudopteroxazole, and seco- pseudopteroxazole by Rodrigues and coworkers from the sponge Pseudopterogorgia elisabethae which showed activity against Mycobacterium tuberculosis [18]. Several synthetic chemists paid attention on the synthesis of these classes of compounds mainly due to their biological activity, complex molecular structure, and functionalization of the compounds present in P. elisabethae [19]. Corey and Davidson reported a concise, enantiospecific synthesis of pseudopteroxazole (II), starting from S-(-)-limonene 9 [20] (Scheme 2). They have initiated their synthesis starting from the commercially available (S)-(-)-limonene 9 and after cyclic hydroboration and alkaline peroxide oxidation, the diol 10 was obtained which was on selective oxidation with sodium hypochlorite in aqueous acetic acid provided the diastereoisomeric mixtures of hydroxyl ketones 11. Protection of the hydroxyl as the tert-butyl-diphenylsilyl ether (TBDPS) afforded the sython 12 in 96% yield. The selective kinetic deprotonation of the intermediate was carried out using lithium diisopropylamide (LDA) and trapping chlorotrimethylsilane (TMSCl) furnishing the desired silyl enol ether, which on subsequent treatment with 1-benzyloxy-3-methyl-but-3-en-2-one and thionyl 4 chloride (SnCl4), gave the Mukaiyama-Michael adduct 13 in 61%. The α,β-enone 14 was obtained as a mixture of diastereoisomeres after cyclization of the 1,5-diketone in dilute solution of potassium hydroxide (KOH) in ethanol (83%) and elimination of the tertiary hydroxyl group in presence of SnCl4 in pyridine. The oxime pivalate 15 was obtained in 96% yield after the oxime formation using hydroxylamine followed by acylation with pivaloyl chloride. The aromatization and N-acylation of the intermediate 16 was achieved using an acetyl chloride at 80oC giving 17 in 64% yield [20]. The hydrogenolysis of the benzyl ether and cyclization of the phenol with carbonyldiimidazole, followed by mildly basic aqueous workup using NaHCO3 to remove the N-acyl group afforded the cyclic carbamate 18 in 94% yield. The diene 19 was obtained by deprotection of 18 in the presence of HF- pyridine followed by mild oxidation to the aldehyde with tetrapropylammonium perruthenate and N- methylmorpholine-N-oxide (TPAP-NMO, 82% yield) and E– selective olefination while the key intermediate was obtained in 80% yield by cationic cyclization in the presence of three
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