Enzymatic Strategy for the Resolution of New 1‐Hydroxymethyl Tetrahydro‐β‐carboline Derivatives in Batch and Continuous‐Flow Systems

Abstract

Many alkaloids containing a tetrahydro‐β‐carboline skeleton have well‐known therapeutic effects, leading to increased interest in the synthesis of these natural products. Enantiomers of N‐Boc‐protected 1‐hydroxymethyl‐1,2,3,4‐tetrahydro‐β‐carboline [(±)‐7], 1‐hydroxymethyl‐6‐methoxy‐1,2,3,4‐tetrahydro‐β‐carboline [(±)‐8], and 1‐hydroxymethyl‐6‐fluoro‐1,2,3,4‐tetrahydro‐β‐carboline [(±)‐9] were prepared through enzymecatalyzed asymmetric acylation of their primary hydroxyl group. The preliminary experiments were performed in a continuous‐flow system, while the preparative‐scale resolutions were done as batch reactions. Excellent enantioselectivities (E>200) were obtained with Candida antarctica lipase B (CAL‐B) and acetic anhydride in toluene at 60 °C. The recovered alcohols and the produced esters were obtained with high enantiomeric excess values (ee≥96 %). The O‐acylated enantiomers [(S)‐10–(S)‐12)] were transformed into the corresponding amino alcohols [(S)‐7–(S)‐9)] with methanolysis. Microwave‐assisted Boc removals were also performed and resulted in the corresponding compounds (R)‐4–(R)‐6 and (S)‐4–(S)‐6 without a drop in the enantiomeric excess values (ee≥96 %).

Ingenine F: A new cytotoxic tetrahydro carboline alkaloid from the Indonesian marine sponge Acanthostrongylophora ingens

“…Due to the scarcity of the compound, C-1 relative configuration was assigned to be R -form based on the comparison 1 H and 13 C shifts and J value of H-1 as well as optical rotation of 4 with those of series of analogous compounds. [ 19 20 ] On the basis of the above evidence, 4 was identified as a THβC alkaloid substituted at C-1 by N-methylbutyramide. Thus, compound 4 was finally assigned as ( R )-N-methyl-4-(2,3,4,9-tetrahydro-1 H -pyrido [3,4- b ] indol-1-yl) butanamide and named ingenine F.…”

Lipase-Catalyzed Strategies for the Preparation of Enantiomeric THIQ and THβC Derivatives: Green Aspects

“…Enantiomeric N-Boc-protected amino alcohols ((R)-10-(R)-12) and amino esters ((S)-13-(S)-15) were prepared through CALB-catalyzed O-acylation of the hydroxy group of THβC (±)-10, (±)-11, and (±)-12 [52]. The optimization reactions were carried out in a continuous-flow system, while preparative-scale resolutions were performed as batch reactions (incubator shaker).…”

“…The synthesis of new enantiomers of 1,2,3,4-THβC derivatives through Candida antarctica lipase B-catalyzed O-acylation of N-Boc-protected 1-hydroxymethyl-1,2,3,4-THβC ((±)-10), 1-hydroxymethyl-6-methoxy-1,2,3,4-THβC ((±)-11), and 1-hydroxymethyl-6-fluoro-1,2,3,4-THβC ((±)-12) was described [52].…”

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

“…Three hydroxymethyl-substituted tetrahydro-bcarbolines (181-183) were subjected to CAL-B-catalysed kinetic resolution under similar reaction conditions, with excellent results in all cases (Table 2). 97 A particularly impressive example of a lipase-catalysed kinetic resolution of a primary alcohol constitutes the asymmetric key step in a recent synthesis of ve Aspidosperma alkaloids: 98 Lactam 184 (Scheme 22), containing a quaternary stereogenic centre in g-position of the reactive hydroxyl group, was kinetically resolved using lipase PS 37 and vinyl acetate. Although the enantioselectivity of this biotransformation was moderate (E ¼ 22), the desired enantiomer (R)-(À)-184 could be obtained in 36% yield and >98% ee at 64% conversion.…”

“…Three hydroxymethyl-substituted tetrahydro-β-carbolines (181–183) were subjected to CAL-B-catalysed kinetic resolution under similar reaction conditions, with excellent results in all cases ( Table 2 ). 97 …”