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.