title: Total synthesis of (-)-ulapualide A, a novel tris-oxazole macrolide from marine nudibranchs, based on some biosynthesis speculation.
abstract: 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.
authors.affiliation: School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, England.
authors.forename: Gerald
authors.initials: G
authors.lastname: Pattenden
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Ashweek
authors.forename: Charles A G
authors.initials: CA
authors.lastname: Baker-Glenn
authors.forename: James
authors.initials: J
authors.lastname: Kempson
authors.forename: Gary M
authors.initials: GM
authors.lastname: Walker
authors.forename: James G K
authors.initials: JG
authors.lastname: Yee
mesh_terms: D000818:Animals; D032701:Biomimetics; D002247:Carbon Isotopes; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008958:Models, Molecular; D008968:Molecular Conformation; D008974:Mollusca / Q000737:chemistry*; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D012015:Reference Standards; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D002247:Carbon Isotopes; D010080:Oxazoles; C085516:ulapualide A