Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids

Abstract

An intramolecular non-stabilized azomethine ylide dipolar cycloaddition was applied toward the first non-racemic synthesis of the fully-oxygenated bridged pyrrolizidine core (45) of (+)-stemofoline (1) in eleven steps from a commercially available starting material.

Multi-Ion Bridged Pathway of N-Oxides to 1,3-Dipole Dilithium Oxide Complexes

“…Intra- and intermolecular cyclization occur via dimerization, − Michael-type addition, − and electrocyclization, − but primarily through [3 + 2] cycloaddition with dipolarophiles. − First reported by Huisgen in the early 1960s, − [3 + 2] dipolar cycloadditions are efficient and regioselective methods for forming cyclic compounds, typically following Woodward–Hoffmann rules . Moreover, Houk’s theoretical and computational work into [3 + 2] cycloadditions has established a mechanistic framework for synthetic control. − Strategic use of 1,3-dipolar cycloadditions has been pivotal in the synthesis of several natural products (Figure ), including daphniphyllum 1 , stemofoline 2 , daphnilactone 3 , pancracine 4 , epibatidine 5 , and 5-deoxymubironine 6 . For the synthesis of the natural products in Figure , and other pyrrolidine motifs of pharmaceutical interest, it is necessary to identify and efficiently synthesize the requisite dipolar azomethine ylide.…”

Use of nitrogen and oxygen dipole ylides for alkaloid synthesis

“…The formation of the azomethine ylide 72 occurred upon exposure of pyrrolidine 71 to triflic anhydride and tetrabutylammonium triphenyldifluorosilicate (TBAT; Scheme 15). 27 Cycloaddition of the resulting dipole across the pendant vinyl sulfide furnished 73 in 71% yield. Enol triflate 73 was then reduced to give the saturated side-chain in 74 in 89% yield by the action of Pd/C under an H 2 atmosphere.…”