Synthesis of isoquinoline alkaloids. Total synthesis of (±)‐tetrahydroescholamine and its (±)‐threo‐ and (±)‐erythro‐α‐hydroxy analogs

Abstract

The studied tetrahydroisoquinolines 1, 2 and 3 were synthesized from a common intermediate 6, which was prepared b y addition of the lithium salt of dithiane 5 to hydrastinine chloride (4).In a previous'' paper we have described a total synthesis of secoberbine alkaloids in which 1,3-dithianes and 3,4-dihydroisoquinolinium salts are used as building blocks in the construction of the alkaloid carbon skeleton. The 1,3-dithiane masking group can then be removed either reductively with Raney nickel or by hydrolysis to afford 1 -benzyl-or 1 -benzoyltetrahydroisoquinolines, respectively. The success of this strategy has encouraged us to perform a synthesis of three other isoquinoline alkaloids, namely ( f )-tetrahydroescholamine (1) and ( f )-threo-and (+)-erythro-(a-hydroxybenzy1)tetrahydroisoquinolines 2 and 3, utilizing also a common intermediate. The latter two structures, 2 and 3, were postulated by R.-S. Xu et al.*' as (+)-decumbensine and (+)-epi-a-decumbensine, two alkaloids isolated recently from Corydalis decumbens. As we have briefly reported3', our synthetic amino alcohols 2 and 3 are not identical with the two alkaloids, but differ significantly from the latter in their spectroscopic data. This difference was unambiguously established by a comparison (TLC, Analtech silica gel GHLF, benzene/methanol, 9: 1) with an authentic sample of (+)-decumbensine. Additional structural proof for 2 and 3 is provided by converting the alcohols 2 and 3 into ( +)-tetrahydroescholamine (I), which is also prepared in the course of this study by a total synthesis.The key intermediate in this study, the addition product 6, is obtained in 89% yield by the action of lithiated 1,3-dithiane 5 on the iminium salt 4in T H F at -76°C. Its 'H-NMR spectrum reveals a NCH3 singlet at 6 = 2.58, a 1-H singlet at 6 = 3.95, one AB quadruplet centered at 6 = 5.89 ( J = 1.5 Hz) and one singlet at 6 = 5.96, both characteristic of methylenedioxy protons. Two singlets at 6 = 6.36 and 6.45 and a multiplet between 6 = 6.75-7.29 represent the five aromatic protons. The molecular ion is not detected by EI-MS; instead, we have found two fragment ions at m/z = 190 and 240 corresponding to two parts of the molecule formed by cleavage of the central bond between the two benzylic moieties.Reductive desulfurization of adduct 6 with Raney nickel in T H F at room temperature results in (&)-tetrahydroescholamine (1) in 83% yield. The general spectroscopic data of this benzyltetrahydroisoquinoline correspond to those of ( +)-tetrahydroescholamine prepared from the methoiodide of natural escholamine by reduction with zinc in hydrochloric acid4), or by the Bischler-Napieralski synthesis5). Its 'H-NMR spectrum exhibits a NCH3 singlet at 6 = 2.45, the I-H proton signal at 6 = 3.63 ist split in to a triplet ( J = 6 Hz). However, the neighboring benzylic proton signals are hidden by other methylene proton signals in a multiplet between 6 = 2.67-2.96. The protons of one of the methylenedioxy substitutents form an AB quadruplet centered at 6 = 5.86 ( J = 1.5 Hz), while...

Genome-scale cis-acting catabolite-responsive element editing confers Bacillus pumilus LG3145 plant-beneficial functions

“… 33 Isoquinoline alkaloid is a plant alkaloid derived from tyrosine metabolism (ko00350, p value = 0.01), which is involved in various biological activities. 34 N-methylnicotinate (C01004) and dihydroxy-methylcanadine (C21587) are examples of isoquinoline skeleton components upregulated in strain LG3145, 35 , 36 which also possess strong pharmacological and antibacterial properties ( Datas S15 and S16 ).

Figure 7 Metabolic changes in wheat shoots infected by F graminearum under strain LG3145 stress at the seedling stage (A) Differential metabolites analysis of wheat shoots under strain LG3145 stress using a volcano chart.

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Synthesis of Isoquinoline Alkaloids. Total Synthesis of (±)-Stylopine

“…Since that time stylopine [1] in both the racemic and the optically active S-(~) form, has been found in many different plants of the families Fumariaceae and Papaveraceae (3).The protoberberine alkaloids play an important role as precursors in the biosynthesis of a variety of related isoquinoline alkaloids, such as protopines, phthalideisoquinolines, spirobenzylisoquinolines, rhoeadines, indenobenzoazepines, secoberbines, and benzo[c]phenanthridines. The transformations between these alkaloids have been reviewed by Hanaoka (4).The protoberberine system has been synthesized in many different ways and there are several reviews that outline various approaches to the synthesis of this class of alkaloids (5,6), including syntheses of stylopine [1] itself (7-11).In this paper we report a new and convergent synthesis of the protoberberine ring system from 3,4-dihydroisoquinoline [2] (12) and 1,3-dithiane [3] (13), according to a published synthetic strategy (13)(14)(15)(16)(17)(18). This method has already been successful in the syntheses of 1,2-secobenzylisoquinolines (14,15), secoberbines (13,16), secophthalideisoquinolines (17), and benzylisoquinolines (18).…”

“…In this paper we report a new and convergent synthesis of the protoberberine ring system from 3,4-dihydroisoquinoline [2] (12) and 1,3-dithiane [3] (13), according to a published synthetic strategy (13)(14)(15)(16)(17)(18). This method has already been successful in the syntheses of 1,2-secobenzylisoquinolines (14,15), secoberbines (13,16), secophthalideisoquinolines (17), and benzylisoquinolines (18).…”