Intramolecular Formal Aza-[3 + 3] Cycloaddition Approach to Indoloquinolizidine Alkaloids. A Stereoselective Total Synthesis of (±)-Tangutorine

Abstract

[reaction: see text] A 19-step stereoselective total synthesis of (+/-)-tangutorine is described here. The total synthesis features an intramolecular aza-[3 + 3] formal cycloaddition strategy and also a Heck coupling for constructing the C2-C3 bond. This work provides a novel approach toward the indoloquinolizidine family of alkaloids.

Domino or Single‐Step Tsuji–Trost/Heck Reactions and Their Application in the Synthesis of 3‐Benzazepines and Azepino[4,5‐b]indole Ring Systems

“…Functionalisation at this position, through intermolecular cross coupling, has recently been observed by Hsung [26] and Chu, [27] and compound 20, bearing a bromine atom at C-2, was considered an ideal precursor for such cross couplings. This compound was prepared from tryptamine (18) through protection and bromination, [27] in 70 and 83 % yield, respectively (Scheme 4).…”

Asymmetric electrocyclic reactions

“…The major diastereomer is formed from an upward rotation of the inward methyl group; downward rotation is apparently disfavoured due to severe close interactions with the metal and its ligands. [144][145][146][147][148][149][150][151][152] In situ generated 1-azatrienes undergo efficient electrocyclization en route to 1,2-dihydropyridines, and chiral subsituents on the azatriene nitrogen or the C-terminus of the triene are effective in controlling the stereochemistry of the electrocyclic process (Scheme 30).…”

A Formal [3 + 3] Cycloaddition Approach to Natural‐Product Synthesis

“…[112] (Ϯ)-Tangutorine (253 in Scheme 55) was first isolated from the leaves of Nitraria tangutorum by Che and co-workers. [113] It possesses a novel benz[f]indolo[2, 3-a]quinolizidine skeleton and, to date, is the only known β-carboline natural product of this type, [114] although it is related to well-known monot- Scheme 55 erpenoid indole alkaloids such as (ϩ)-geissoschizine (254) [115,116] and (ϩ)-deplancheine (255).…”

“…Subsequent NaBH 4 reduction, elimination, and LAH reduction furnished (Ϯ)-tangutorine (253) in 61% overall yield. [112,113] Scheme 57…”