title: Synthetic studies toward the brasilinolides: controlled assembly of a protected C1-C38 polyol based on fragment union by complex aldol reactions.
abstract: The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic protocols were employed to assemble a series of increasingly elaborate fragments. The controlled preparation of suitable C1-C19 and C20-C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres respectively, was first achieved. An adventurous C19-C20 fragment union was then explored to construct the entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type aldol protocols proved unrewarding. A protected C1-C38 polyol 93 was subsequently prepared, setting the stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work, asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for controlled fragment assembly and coupling with predictable stereoinduction from the enolate component.
authors.affiliation: University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, UK. ip100@cam.ac.uk.
authors.forename: Ian
authors.initials: I
authors.lastname: Paterson
authors.forename: Michael P
authors.initials: MP
authors.lastname: Housden
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cordier
authors.forename: Paul M
authors.initials: PM
authors.lastname: Burton
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Mühlthau
authors.forename: Olivier
authors.initials: O
authors.lastname: Loiseleur
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D007659:Ketones / Q000737:chemistry*; D018942:Macrolides / Q000138:chemical synthesis*; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D007659:Ketones; D018942:Macrolides; D011108:Polymers; C024617:polyol; D002244:Carbon; C116609:3-hydroxybutanal