Stereochemistry of ulapualides, a new family of tris-oxazole-containing macrolide ionophores from marine nudibranchs. A molecular mechanics study

Maddock, John; Pattenden, Gerald; Wight, Paul

doi:10.1007/bf00124363

Cited by 20 publications

(13 citation statements)

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“…11 The juxtaposition of several nitrogen and oxygen ligandbinding sites in the ulapualides encouraged us earlier to carry out a molecular mechanics study of a hypothetical metal-chelated complex of ulapualide A. 12 This study led us to assign the relative stereochemistry shown in structure 8 for ulapualide A, 13 and in 1998 we described a total synthesis of this compound. Much to our chagrin, although the synthetic ulapualide A showed identical chromatographic behaviour, as well as chiroptical and 1 H NMR spectroscopic data, with those of the natural product, very small differences were observed in the 13 C NMR spectra, associated with the C32-C34 portions, of the structures.…”

Section: Introductionmentioning

confidence: 99%

Total synthesis of (−)-ulapualide A, a novel tris-oxazole macrolide from marine nudibranchs, based on some biosynthesis speculation

et al. 2008

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A new, second generation, total synthesis of ulapualide A (1), whose stereochemistry was recently determined from X-ray analysis of its complex with the protein actin, is described. The synthesis is designed and based on some speculation of the biosynthetic origin of the contiguous tris-oxazole unit in ulapualide A, alongside that of the related co-metabolites that contain only two oxazole rings, e.g. 6 and 7. The mono-oxazole carboxylic acid 67b and the mono-oxazole secondary 55b alcohol which, together, contain all of the 10 asymmetric centres in the natural metabolite, were first elaborated using a combination of contemporary asymmetric synthesis protocols. Esterification of 67b with 55b under Yamaguchi conditions gave the ester 77 which was then converted into the omega-amino acid 18a following simultaneous deprotection of the t-butyl ester and the N-Boc protecting groups. Macrolactamisation of 18a, using HATU, now gave the key intermediate macrolactam 17, containing two of the three oxazole rings in ulapualide A (1). A number of procedures were used to introduce the third oxazole ring in ulapualide A from 17, including: a) cyclodehydration to the oxazoline 78a followed by oxidation using nickel peroxide leading to 76; b) dehydration to the enamide 79, followed by conversion into the methoxyoxazoline 78b, via 80, and elimination of methanol from 78b using camphorsulfonic acid. The tris-oxazole macrolide 76 was next converted into the aldehyde 82b in four straightforward steps, which was then reacted with N-methylformamide, leading to the E-alkenylformamide 83. Removal of the TBDPS protection at C3 in 83 finally gave (-)-ulapualide A, whose 1H and 13C NMR spectroscopic data were indistinguishable from those obtained for naturally derived material. It is likely that the tris-oxazole unit in ulapualide A (1) is derived in nature from a cascade of cyclodehydrations from an acylated tris-serine precursor, e.g.9, followed by oxidation of the resulting tris-oxazoline intermediate, i.e.10. It is also plausible to speculate that the biosynthesis of metabolites related to ulapualide A, e.g. the bis-oxazole 6 and the imide 7, involve cyclisations of just two of the serine units in 9. These speculations were given some credence by carrying out pertinent interconversions involving the bis-oxazole amide 24, the enamide 25, the imide 26, the oxazoline 27 and the tris-oxazole 30 as model compounds. An alternative strategy to the tris-oxazole macrolide intermediate 76 was also examined, involving preliminary synthesis of the aldehyde 73, containing a shortened (C25-C34) side chain from 67b and 47b. A Wadsworth-Emmons olefination reaction between 73 and the phosphonate ester 74 led smoothly to the E-alkene 75, but we were not able to reduce selectively the conjugated enone group in 75 to 76 without simultaneous reduction of the oxazole alkene bond, using a variety of reagents and reaction conditions.

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Section: Introductionmentioning

confidence: 99%

Total synthesis of (−)-ulapualide A, a novel tris-oxazole macrolide from marine nudibranchs, based on some biosynthesis speculation

et al. 2008

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“…behave as ionophores, using the several oxazole nitrogen and side chain oxygen ligand binding sites present in their structures. 6 The combination of a unique chemical structure with novel biological properties encouraged us to examine a total synthesis of the founder member, ulapualide A (1), of this family of marine metabolites and to examine their ionophore properties. In the immediately preceding paper 7 we described concise synthetic routes to the tris-oxazole ring system found in the natural product, and in this paper we describe the extension of this work culminating in a total synthesis of ulapualide A, with the relative stereochemistry shown in structure 1.…”

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A total synthesis of the unique tris-oxazole macrolide ulapualide A produced by the marine nudibranch Hexabranchus sanguineus

Chattopadhyay

Pattenden

2000

J. Chem. Soc., Perkin Trans. 1

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“…Based on a molecular mechanics modeling study performed on a Co III –ulapualide A chelate and comparison with the scytophycins, Pattenden et al proposed the configurational assignment shown in Scheme (isomer‐ 13 ). 41, 42 However, recent chemical degradation and synthetic studies by Fusetani and Panek on the mycalolides have shown that the C20–C35 segment of ulapualide B has the same configuration as the corresponding C20–C35 segment of the mycalolides 16d. The full stereostructure of mycalolide A ( 12 ) has been unambiguously confirmed by Panek et al by total synthesis (Section 2.7), whereas the Pattenden group have synthesized isomer‐ 13 , which proved to be a diastereoisomer of ulapualide A.…”

Section: Total Synthesismentioning

confidence: 99%

Actin‐Binding Marine Macrolides: Total Synthesis and Biological Importance

2002

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Marine organisms produce a fascinating range of structurally diverse secondary metabolites, which often possess unusual and sometimes unexpected biological activities. This structural diversity makes these marine natural products excellent molecular probes for the investigation of biochemical pathways. Recently, a number of novel and stereochemically complex macrolides, having a large macrolactone (22- to 44-membered) ring, that interact with the actin cycloskeleton have been isolated from different marine sources. Actin, like tubulin, is a major component of the cytoskeleton and has important cellular functions. Although the details of these interactions are still under investigation, these marine macrolides are becoming increasingly important as novel molecular probes to help elucidate the cellular functions of actin. Owing to their potent antitumor activities, these compounds, for example the aplyronines, also have potential for preclinical development in cancer chemotherapy. Their appealing molecular structures, with an abundance of stereochemistry, and biological significance, coupled with the extremely limited availability from the marine sources, have stimulated enormous interest in the synthesis of these compounds. This review summarizes the biological properties of these unusual marine natural products and features the recently completed total syntheses of swinholide A, scytophycin C, aplyronine A, mycalolide A--all of these being potent cytotoxic agents that target actin--and a diastereoisomer of ulapualide A. Rather than detailing each individual step of these multistep total syntheses, the different synthetic strategies, key reactions, and methods adopted for controlling the stereochemistry are compared.

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Stereochemistry of ulapualides, a new family of tris-oxazole-containing macrolide ionophores from marine nudibranchs. A molecular mechanics study

Cited by 20 publications

References 26 publications

Total synthesis of (−)-ulapualide A, a novel tris-oxazole macrolide from marine nudibranchs, based on some biosynthesis speculation

Total synthesis of (−)-ulapualide A, a novel tris-oxazole macrolide from marine nudibranchs, based on some biosynthesis speculation

A total synthesis of the unique tris-oxazole macrolide ulapualide A produced by the marine nudibranch Hexabranchus sanguineus

Actin‐Binding Marine Macrolides: Total Synthesis and Biological Importance

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