A Total Synthesis of Spirastrellolide A Methyl Ester

Abstract

A concise total synthesis of spirastrellolide A methyl ester (1 a, R(1) =Me) as the parent compound of a series of highly cytotoxic marine macrolides is disclosed, which exploits and expands the flexibility of a synthesis plan previously developed by our group en route to the sister compound spirastrellolide F methyl ester (6 a, R(1) =Me). Key to success was the masking of the signature Δ(15,16) -bond of 1 a as a C16-carbonyl group until after the stereogenic center at C24 had been properly set by a highly selective hydrogenation of the C24 exo-methylene precursor 66. Conformational control over the macrocyclic frame allowed the proper stereochemical course to be dialed into this reduction process. The elaboration of the C16 ketone to the C15-C16 double bond was accomplished by a chemoselective alkenyl triflate formation followed by a palladium-catalyzed hydride delivery. The role of the ketone at C16 as a strategic design element is also evident up-stream of the key intermediate 66, the assembly of which hinged upon the addition of the polyfunctionalized dithiane 37 to the similarly elaborate aldehyde fragment 46. Other crucial steps of the total synthesis were an alkyl-Suzuki coupling and a Yamaguchi lactonization that allowed the Northern and the Southern sector of the target to be stitched together and the macrocyclic perimeter to be forged. The lateral chain comprising the remote C46 stereocenter was finally attached to the core region by a modified Julia-Kocienski olefination. The preparation of the individual building blocks led to some methodological spin-offs, amongst which the improved procedure for the N-O-bond cleavage of isoxazolines by zero-valent molybdenum and the ozonolysis of a double bond in the presence of other oxidation-prone functionality are most noteworthy. Preliminary biological data suggest that the entire carbon framework, that is the macrocyclic core plus the lateral chain, might be necessary for high cytotoxicity.

Concise Total Syntheses of Amphidinolides C and F

“…Obviously, the bulk of the chosen KHMDS base and the differential in the acidity of the two different carbonyl groups synergized in that deprotonation of 38 at the methyl terminus was largely favored. After some optimization, this delicate transformation was well reproducible and furnished alkenyl triflate 39 in a respectable 71 % yield on a 1.2 gram scale (single largest batch) 51. The subsequent conversion into the corresponding stannane 40 was best performed with a catalyst formed in situ from [Pd 2 (dba) 3 ] and tris‐2‐furylphosphine 52.…”

“…After some optimization, this delicate transformation was well reproducible and furnished alkenyl triflate 39 in a respectable 71 % yield on a 1.2 gram scale (single largest batch). [51] The subsequent conversion into the corresponding stannane 40 was best performed with a catalyst formed in situ from [Pd 2 (dba) 3 ] and tris-2-furylphosphine. [52] Final saponification of the ester completed the preparation of the required acid building block 41.…”

Spirastrellolide E: synthesis of an advanced C(1)–C(24) southern hemisphere

“…The combination of structural complexity, biological activity, and, at the outset, unknown relative stereochemistry led to considerable interest in the synthetic community, 5–27 culminating in the first total synthesis of spirastrellolide A (2008) by the Paterson 28–31 group, and the total syntheses of spirastrellolide F (2009, 2011) 32–34 and later A (2013), 35 both by Furstner and colleagues.…”

Synthesis of a C(1)–C(23) Fragment for Spirastrellolide E: Development of a Mechanistic Rationale for Spiroketalization

“…Given both the intriguing biological profile and architectural complexity of the spirastrellolides, a number of synthetic approaches toward this family have appeared, 4 culminating in total syntheses of spirastrellolide A by the Paterson 5 and Fürstner 6 groups, as well as a total synthesis of spirastrellolide F by the Fürstner group. 7 …”

“…Successful syntheses of spirastrellolide congeners possessing this unsaturation have either masked the olefin 6 or utilized a stepwise approach to construct the southern hemisphere. 5 Given this lack of chemoselectivity, we elected to dissect spirastrellolide E at the C(23)–C(24) bond (Scheme 2 ), utilizing the C(22) hydroxyl as a directing group.…”