Towards the synthesis of the ergot alkaloids and analogues of FK-506

Abstract

A synthesis of the ergot alkaloid skeleton was attempted from the amino acid tryptophan, the biosynthetic precursor.  We anticipated that the C ring of the skeleton would be constructed by an intramolecular Friedel-Crafts type acylation of an aziridines onto the C-4 position of the indole ring.  The more reactive C-2 position of the ring would be blocked due to the electron acceptance and steric hindrance of a pivaloyl protecting group on the indole nitrogen.  The amino acid was converted to its corresponding aziridines via a Grignard addition to the amino aldehyde, followed by a Mitsunobu reaction.  Through a sequence of protecting group manipulations, a range of precursors to the Friedel-Crafts acylation were synthesised and the cyclisations attempted, mediated by the Lewis acid CF₃^.OEt₂.

FK-506 is a powerful immunosuppressant used for the prevention and treatment of organ transplant rejection.  A synthesis of the C-26-C-34 fragment of the macrocycle was achieved from an acyclic precursor where the cyclohexyl ring was constructed via an intramolecular cyclisation.  The chirality of the molecule was set prior to ring closure using Evans aldol chemistry.  Following the boron-mediated aldol condensation the molecule was protected as a TIPS ether and the chiral auxiliary reductively removed with sodium borohydride.  Conversion of the alcohol to a tosylate was achieved to furnish the precursor to the cyclisation.  The intramolecular S_N2 displacement was optimized using microwave conditions.

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