Synthesis of Phthalideisoquinoline and Protoberberine Alkaloids and Indolo[2,1-a]isoquinolines in a Divergent Route Involving Palladium(0)-Catalyzed Carbonylation¹

Abstract

6,7,3',4'-Alkoxy-substituted 1-(2'-bromobenzoyl)-3,4-dihydroisoquinoline methiodides 17 were treated with sodium borohydride in methanol or acetic acid to give erythro-1-(2'-bromo-alpha-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolines 19. Treatment of 17 with lithium aluminum hydride in tetrahydrofuran gave the threo-isomer 20 in preference to the erythro 19. On the basis of studies on palladium(0)-catalyzed carbonylation of 2-bromo-3,4-dimethoxybenzyl alcohol to 6,7-dimethoxyphthalide, amino alcohol 19 or 20 was treated with a catalytic amount of palladium(II) acetate and triphenylphosphine in an atmosphere of carbon monoxide in the presence of chlorotrimethylsilane and potassium carbonate in boiling toluene to give the corresponding erythro- or threo-types of phthalideisoquinoline alkaloids 1 or 2, respectively. One-pot cyclization of the erythro-amino alcohols 19 was achieved by heating in N,N-dimethylformamide containing potassium carbonate to give 2,3,8,9- or 2,3,9,10-alkoxy-substituted 5,6-dihydroindolo[2,1-a]isoquinolines 3, which have a unique tetracyclic skeleton characteristic of dibenzopyrrocoline alkaloids. Similarly, palladium(0)-catalyzed carbonylation of 1-(2'-bromobenzyl)tetrahydroisoquinolines 21 in the presence of excess potassium carbonate was found to give 8-oxoberbines 22, which on reduction with lithium aluminum hydride can be converted to protoberberine alkaloids 4.

1H and 13C NMR signal assignment of benzylisoquinoline alkaloids from Fumaria officinalis L. (Papaveraceae)

“…Signal assignments for sinactine (7), protopine (8) and cryptopine (9) are also in good agreement with published NMR data sets. In the case of 7 only proton NMR data are available, 20,21 whereas more complete data have been presented for 8.…”

“…In the case of (C)-corlumine (1), (C)-adlumine (2) and ( )--hydrastine (3), the optical rotations and a recent synthetic approach to phthalide-isoquinoline derivatives 9 allowed the diastereomers to be distinguished unambiguously. Neither this nor previous contributions 10 -12 provided complete 1 H and 13 C NMR signal assignments.…”

A General, Concise Strategy that Enables Collective Total Syntheses of over 50 Protoberberine and Five Aporhoeadane Alkaloids within Four to Eight Steps

“…This highly efficient assembly of tetrahydroisoquinolines (THIQs, 1a-b), 2bromobenzaldehydes (2a-d)a nd trimethylsilylacetylene (3) through the redox-A 3 reactiona nd palladium-catalyzed reductive carbocyclization allowed an expedient access to the tetracyclic framework (5a-h)f or elaboration to three major types of protoberberine alkaloids (e.g.,8 -oxyberberines, tetrahydroprotoberberines, and quaternary protoberberine salts) within four or five steps. Notably,o ur unified general strategy was superior to most prior routes tailoredf or specific protoberberines of potent biological activity and intensive synthetic interest, for example, stylopine, [32] coptisine, [33] xylopine, [34] sinactine, [32] and palmatine. [35] Finally,w ew ould like to explore the possibility of synthesis of aporhoeadane naturalp roductsb yt aking advantage of the isolated prechilenine (9a)f rom oxidation of 5a,a sd epicted in Scheme3.T his idea was primarily inspired by the biogenetic connectiono fc hilenine with protoberberine (13 a)v ia prechilenine (9a)( Scheme 3a).…”

Construction of the Six‐ and Five‐Membered Aza‐Heterocyclic Units of the Isoindoloisoquinolone Nucleus by Parham‐Type Cyclization Sequences –Total Synthesis of Nuevamine

“…The bromobenzoyl chloride 7e was obtained from 2-bromo-3,4-dimethoxybenzoic acid synthesized according to a reported procedure. [19] General Procedure for the Synthesis of the Brominated (Arylalkyl)-amine Derivatives 10c,d: A solution of para-anisaldehyde (18 mmol, 2.45 g) and amine 11c or 11d (18 mmol) in toluene (60 mL) was refluxed in a Dean-Starck apparatus for 3 h. After removal of toluene in vacuo, the N- [2-(bromoaryl)ethyl]-N-(4-methoxybenzylidene)amine derivative was used directly in the next step without further purification. NaBH 4 (35 mmol, 1.33 g) was added portionwise to a solution of the previously obtained Schiff base in MeOH (70 mL) at room temperature.…”