Synthetic pathways to create asymmetric center at C1 position of 1-substituted-tetrahydro-β-carbolines - a review

Abstract

The 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles or tetrahydro-β-carbolines (THβCs) are tricyclic compounds that are found in various natural sources that exhibit a wide range of important pharmacological activities. Chiral 1-substituted-THβCs, which have an asymmetric center at C1, have attained significant interest due to their possible Monoamine Oxidase (MAO) inhibitory activity, benzodiazepine receptor binding activity, and antimalarial effectiveness against chloroquine-resistant Plasmodium falciparum. This review highlights and summarizes various novel stereoselective approaches to introduce chirality at the C1 position of 1-substituted-THβCs in good yield and enantiomeric excess (ee) or diastereomeric excess (de). These methods include the Pictet-Spengler reaction, chiral auxiliary, Asymmetric Transfer Hydrogenation (ATH) with chiral catalysts, asymmetric addition reaction, and enzymatic catalysis. The syntheses of chiral THβCs are reviewed comprehensively, emphasizing their role in drug development from 1977 to 2024.

Fig. 1. Structures of important chiral 1-substituted-THβCs.

Scheme 1. Representative examples of asymmetric methods for synthesizing chiral 1-substituted-tetrahydro-β-carbolines.

Scheme 2. Asymmetric formal syntheses of (−)-koumine, (−)-taberpsychine, and (−)-koumidine intermediates from l-tryptophan methyl ester.

Scheme 3. Asymmetric formal syntheses of (−)-suaveoline, (−)-raumacline, and (−)-N^b-methylraumacline intermediates from l-tryptophan.

Scheme 4. Tryptamine failed to produce any 1-substituted-THβC by Pictet–Spengler reaction but diethyl 2-amino-2-(1H-indol-3-ylmethyl)propanedioate was able to produce diethyl 1-ethyl-1,2,4,9-tetrahydropyrido[3,4-b]indole-3,3-dicarboxylate.

Fig. 2. Chiral organic Brønsted acid for catalytic asymmetric Pictet–Spengler reaction.

Scheme 5. Screening of chiral organic Brønsted acid for catalytic asymmetric Pictet–Spengler reaction.

Scheme 6. Screening of diethyl 2-amino-2-(1H-indol-3-ylmethyl)propanedioate derivatives.

Scheme 7. Screening of aldehydes.

Scheme 8. Synthesizing Friedel–Crafts/Henry adducts from 1H-indole and their reduction.

Scheme 9. Protecting the OH group with TES group, Pictet–Spengler reaction, and removing the OH-protection.

Scheme 10. Screening of aldehydes.

Scheme 11. Synthesizing prop-2-ynyl ester of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid, removing Fmoc protection group, followed by Pictet–Spengler reaction.

Scheme 12. Synthesizing methyl ester of l-tryptophan, then l-tryptophan hydrazide, and Pictet–Spengler reaction.

Scheme 13. Synthesizing (1S)-1-methyl-THβC and (1S)-1-phenyl-THβC with (2R)-2-amino-2-phenylethanol as chiral auxiliary.

Scheme 14. Synthesizing (R)-tetrahydroharman with chiral acetylenic sulfoxides as chiral auxiliary.

Scheme 15. Synthesis of (S)-pyroglutamic acid derivatives.

Scheme 16. N9 addition of chiral auxiliary to the β-carboline, C1 addition of allyltributyltin and N2 protecting, then ultimately removal of the chiral auxiliary.

Scheme 17. N2 protecting, C1 addition of silyl enol ether, and then ultimately removal of the chiral auxiliary.

Scheme 18. Reducing to THβC and removing N9 protection.

Scheme 19. Addition of chiral auxiliary, Bischler–Napieralski cyclization, and reduction to THβC.

Scheme 20. Addition of chiral auxiliary, base-catalyzed cyclization to THβC and removal of the chiral auxiliary.

Scheme 21. Removal of chiral auxiliary and protecting N-2, cyclization of the fourth ring, removal of N-9 protection.

Fig. 3. Chiral catalysts for ATH.

Scheme 22. Synthesizing N-[2-(1H-indol-3-yl)ethyl]amides from tryptamine, then 1-substituted-DHβCs, and ultimately ATH to get 1-substituted-THβCs with chiral catalysts.

Scheme 23. Synthesizing N-[2-(1H-indol-3-yl)ethyl]hydroxamides from tryptamine, then 1-substituted-DHβCs, and ultimately ATH to get 1-substituted-THβCs with chiral catalysts.

Scheme 24. ATH with chiral catalysts to synthesize HCl salt of (R)-trypargine.

Scheme 25. Asymmetric synthesis of eudistomidin B and it's diastereomer.

Fig. 4. (S)-BINOL, VAPOL, and SPINOL derived chiral phosphoric acid.

Scheme 26. Synthesis of hydroxylactams from tryptamine and its derivatives.

Scheme 27. Screening of chiral phosphoric acid catalysts for the acid catalyzed ATH of hydroxylactam.

Scheme 28. Screening of additive for the acid catalyzed ATH of hydroxylactam.

Scheme 29. Acid catalyzed ATH reaction of hydroxylactams by (S)-35g under the optimized conditions.

Fig. 5. 1° amine catalysts for coupling of 7-methoxy-9-tosyl-DHβC.

Scheme 30. Total synthesis of (+)-reserpine by primary amine catalysts and [Ir(COD)(PCy₃)(py)]BAr_F.

Scheme 31. Screening of solvent, temperature, and time.

Scheme 32. Screening of ketones.

Scheme 33. Synthesis of the precursor of yohimbine and deserpidine.

Scheme 34. Generating three chiral centers in a single step (S)-proline catalyzed asymmetric addition reaction.

Scheme 35. Synthesizing enantiomer of dihydrocorynantheol by (S)-proline catalyzed asymmetric addition reaction in four steps.

Fig. 6. (R)-H8-BINOL derived chiral phosphoric acid.

Scheme 36. Catalytic asymmetric (3 + 3) cycloaddition of two different 2-indolylmethanols.

Scheme 37. Reduction of 1-substituted-DHβC with fresh or 24 hours old aliquot of AoIRED variants.

Scheme 38. Reduction of 1-substituted-DHβC with D-type IREDs e.g., IRED-A–IRED-H, and Y-type IREDs e.g., IRED-I–IRED-N.

Scheme 39. Stereoselective condensation of tryptamine and secologanin with CrSTR.

Scheme 40. Stereoselective condensation of tryptamine and small aliphatic aldehydes with CrSTR, OpSTR, RsSTR, and RvSTR.

Scheme 41. Asymmetrically synthesizing fused-ring THβCs by imine reductases.

Scheme 42. Reduction of 1-substituted-DHβC with IRED-G, IRED-I–IRED-M.

Scheme 43. Reduction of 1-substituted-DHβC with AtIRED mutants.