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A Total Synthesis of Spirastrellolide A Methyl Ester

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons58400

Arlt,  Alexander
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons58425

Benson,  Stefan
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons58980

Schulthoff,  Saskia
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons58558

Gabor,  Barbara
Service Department Farès (NMR), Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons58380

Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Arlt, A., Benson, S., Schulthoff, S., Gabor, B., & Fürstner, A. (2013). A Total Synthesis of Spirastrellolide A Methyl Ester. Chemistry – A European Journal, 19(11), 3596-3608. doi:10.1002/chem.201203965.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-E3C0-2
Abstract
A concise total synthesis of spirastrellolide A methyl ester (1a, R1=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 (6a,R1=Me). Key to success was the masking of the signature Delta-bond of 1a 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.