Aqueous Titanium Trichloride Promoted Reductive Cyclization of o‐Nitrostyrenes to Indoles: Development and Application to the Synthesis of Rizatriptan and Aspidospermidine

Abstract

Treatment of o-nitrostyrenes with aqueous TiCl 3 solution at room temperature afforded indoles through af ormal reductive C(sp 2 )-H amination process.Arange of functions such as halides (Cl, Br), carbonyl (ester,carbamate), cyano,h ydroxy,a nd amino groups were tolerated. From b,bdisubstituted o-nitrostyrenes,2 ,3-disubstituted indoles were formed by ad omino reduction/cyclization/migration process. Mild conditions,s imple experimental procedure,r eady accessibility of the starting materials and good to excellent yields characterize the present transformation. The methodology was used as ak ey step in ac oncise synthesis of rizatriptan and aformal total synthesis of aspidospermidine.

Synthesis of indole derivatives as prevalent moieties present in selected alkaloids

“…Scheme 51 Total synthesis of festuclavine (370), pyroclavine (371), pibocin A (373), 9-deacetoxyfumigaclavine C (372), fumigaclavine G (374) and dihydrosetoclavine (369). and reduction, yielded demethoxycarbonyl dihydrogambirtannine (324) (Scheme 43).…”

“…Moreover, reduction of the intermediate 362 (using LiAlH 4 , THF at 0 C) yielded dihydrolysergol (364) (Scheme 50). 316 An efficient method for the total synthesis of eight ergot alkaloids was reported in 2017 by Jia et al 317 This method permits the rst total synthesis of pyroclavine (371), pibocin (373), 9deacetoxyfumigaclavine C (372), fumigaclavine G (374), festuclavine (370), and dihydrosetoclavine (369). The key aspect of the synthesis is the usage of a palladium-mediated intramolecular Larock indole annulation/Tsuji-Trost allylation cascade to make the tetracyclic unit in one step.…”

“…The key aspect of the synthesis is the usage of a palladium-mediated intramolecular Larock indole annulation/Tsuji-Trost allylation cascade to make the tetracyclic unit in one step. The total synthesis of festuclavine (370), pyroclavine (371), pibocin A (373), 9-deacetoxyfumigaclavine C (372), fumigaclavine G (374) and dihydrosetoclavine (369) began with bromide 365. Aer six steps, 365 gave homopropargylic amines 366a and b.…”

“…Following this, the tetracyclic basic framework 368, aer four steps, gave dihydrosetoclavine (369). 317 In addition, the total synthesis of festuclavine ( 370) and pyroclavine (371) were started from bromide 365, and aer six steps gave 366a and b. Aer reacting Pd(OAc) 2 (20 mol%) and Me-phos (40 mol%), K 2 CO 3 , and LiCl in DMF at 100 C, 366a and b afforded 367, and aer a further ve steps these gave compounds 370 and 371. In the following, this research group examined the formation of pibocin A (373), 9-deacetoxyfumigaclavine C (372) and fumigaclavine G (374) using the direct functionalization of 370 and 371.…”

“…Moreover, the chlorination of 370 with tert-butyl hypochlorite and reaction with prenyl-9-BBN using triethylamine gave 9-deacetoxyfumigaclavine C (372) in a good yield (80% yield). Similarly, pyroclavine (371) was converted to fumigaclavine G (374) in a satisfactory yield (50% yield) (Scheme 51). 317 Aspergilazine A, dimerized by two diketopiperazines cores through an unusual N-1 to C-6 linkage, was extracted in 2012 by Gu and co-workers from the marine-derived fungus Aspergillus taichungensis ZHN-7-07.…”