A Five-Step Synthesis of (±)-Tylophorine via a Nitrile-Stabilized Ammonium Ylide

Abstract

The Stevens rearrangement of a nitrile-stabilized ammonium ylide is the key step of a very short and practical synthesis of the phenanthroindolizine alkaloid (±)-tylophorine. The method requires only five linear steps and is devoid of any protecting group manipulations.

Heterocycles from α‐Aminonitriles

“…Deprotonation with KHMDS was followed by Stevens rearrangement even at temperatures as low as 0 °C to furnish compounds 129 after reductive decyanation of intermediates 128 (Scheme ). With only five linear steps, this represents the shortest route to the phenanthroindolizidine alkaloid (±)‐tylophorine ( 129 a ) known so far 66. Similarly, the tetrahydroprotoberberine alkaloid (±)‐xylopinine was synthesized in three steps from 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline‐1‐carbonitrile ( 18 ) and 1,2‐bis(bromomethyl)‐4,5‐dimethoxybenzene 67…”

“…[64] Starting from similar tetrahydroiso- www.chemeurj.org 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim quinolinium salts 121 in combination with dimethyl acetylenedicarboxylate, the same authors achieved a ring enlargement by three carbon atoms under formation of 2,3,6,7-tetrahydro-1H-benz[d]azonines 124 (Scheme 25). [66] Similarly, the tetrahydroprotoberberine alkaloid (AE)-xylopinine was synthesized in three steps from 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (18) and 1,2-bis(bromomethyl)-4,5-dimethoxybenzene. Starting from simple cyclic a-aminonitriles 125, the salts 127 were prepared by double N-alkylation with readily available dibromide 126 (two steps from veratrol and diacetyl).…”

“…With only five linear steps, this represents the shortest route to the phenanthroindolizidine alkaloid (AE)-tylophorine (129 a) known so far. [66] Similarly, the tetrahydroprotoberberine alkaloid (AE)-xylopinine was synthesized in three steps from 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (18) and 1,2-bis(bromomethyl)-4,5-dimethoxybenzene. [67]…”

Rearrangements of Nitrile-Stabilized Ammonium Ylides

“…sodium borohydride gave benz [4,5]azepino[2,1-a]isoindole 16 in 72% yield over two steps (Scheme 5). The phenanthroindolizidine alkaloid tylophorine 20 and its non-natural higher homologue 7methoxycryptopleurine 18 were prepared in high yields (Scheme 6). Precursor 17 is available in two steps from vetratrol and diacetyl, which makes tylophorine available in multigram quantities in only five linear steps.…”

A Formal Synthesis of (±)-Tylophorine Based on an Atom Transfer Radical Addition Reaction

“…Epoxide 6 would be assembled from iodoacetonitrile (7) and allyl alcohol 8, derived from a phenanthrene ester. (1) Our synthesis started with known allyl alcohol 8, 13,15 prepared in six steps from commercially available homoveratric acid (9). The originally established conditions for the epoxidation reaction, which employed triethylborane as the radical initiator, resulted in low yields and incomplete reactions.…”