Novel stereocontrolled syntheses of tashiromine and epitashiromine

Abstract

SummaryA novel stereocontrolled approach has been developed for the syntheses of tashiromine and epitashiromine alkaloids from cyclooctene β-amino acids. The synthetic concept is based on the azetidinone opening of a bicyclic β-lactam, followed by oxidative ring opening through ring C–C double bond and reductive ring-closure reactions of the cis- or trans-cyclooctene β-amino acids.

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

“…This was confirmed in the case of the reduced ester 12b , which was obtained in a good yield of 72% and a diastereomeric ratio of 85:15. The NMR spectroscopic data for the two diastereomers (8 R *,8a R *)- 12b' and (8 R *,8a S *)- 12b" , pure samples of which could be obtained for characterisation by careful chromatography, agreed with those reported for the same isomers by Kiss et al [9]. …”

“…1). To date this natural product and its unnatural epimer 2 have been the targets of numerous enantioselective and racemic syntheses [4–9]. Typical approaches to accessing the alkaloid’s indolizidine skeleton have included a key cyclisation onto the nitrogen atom of either a piperidine or a pyrrolidine-based precursor, with few reports of alternative approaches.…”

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols

“…The strategy for the synthesis of tashiromine and epitashiromine alkaloids started from bicyclic β‐lactam (±)‐82 and was based on the ring opening of the azetidinone skeleton followed by the ring cleavage of the olefin double bond of cyclooctene derivative (±)‐84 . The resulting crude dialdehyde (±)‐86 was submitted to catalytic hydrogenolysis and after N ‐deprotection a reduction via double intramolecular cyclization gave the desired alkaloid (±)‐88 (Scheme ) …”

“…The 1 : 1 diastereoisomer mixture formed in OsO 4 /NMO dihydroxylation of (±)‐89 could not be purified and next it was used in the ring‐opening oxidation and reductive cyclization steps. After the reduction of the ester with LiAlH 4 , epitashiromine (±)‐93 was isolated (Scheme ) …”

“…In the development of new pharmaceuticals three‐dimensional, functionalized scaffolds with saturated building blocks, especially saturated N ‐heterocycles, are used preferably . Figure shows some representative N ‐heterocyclic structures with biological relevance …”