91185-15-8

Upstream product

• 100-39-0 benzyl bromide 
• 93598-06-2 (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester 
• 63229-68-5 N_b-Benzyl tryptophan methyl ester 
• 75-07-0 acetaldehyde 

Relevant academic research and scientific papers

Highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted tetrahydro-β-carbolines into (1S,3R)-trans-1,3-disubstituted tetrahydro-β-carbolines: An improved asymmetric synthesis of tadalafil from l-tryptophan

An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-β- carbolines (THBCs) into (1S,3R)-trans-1,3-disubstituted THBCs is described. The method contains the following three steps: the enantiomerically pure (1S,3S)-cis-1,3-disubstituted THBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-1-naphthylmethylation/benzylation; (1S,3S)-cis-1,2,3-trisubstituted THBCs2 were then converted into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in high yields and with high stereoselectivities via a base-catalyzed epimerization at C-3; (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 were subsequently converted into (1S,3R)-trans-1,3-disubstituted THBCs 4 after reductive removal of the 1-naphthylmethyl/benzyl group. In addition, as an application of this method, an improved and highly stereoselective synthesis of the PDE5 inhibitor tadalafil (Cialis) starting from natural and less expensive l-tryptophan was developed.

Stereospecificity in the Pictet-Spengler reaction kinetic vs thermodynamic control

The Pictet-Spengler reaction of Nb-benzyl tryptophan methyl ester 4 with 5 in refluxing benzene yielded a mixture of cis and trans tetrahydro β-carbolines in a ratio of 7a(23)/7b(77), whereas the analogous reaction of isopropyl ester 10 with 5 provided increased trans stereoselectivity [cis(13):trans(87)]. The implications in regard to the role of intermediates 1-3 in this condensation are described. Moreover, Pictet-Spengler reaction of 4 or 10 with aldehydes (Ph, Δ) led to kinetic trapping of the cis/trans diastereomers, whereas reaction in TFA/CH2Cl2(25°C) provided tetrahydro β-carbolines via thermodynamic control and increased trans diastereoselectivity in most cases.