The intermolecular Pictet-Spengler condensation with chiral carbonyl derivatives in the stereoselective syntheses of optically-active isoquinoline and indole alkaloids

Abstract

The stereoselective Pictet-Spengler synthesis is one of the currently most important synthetic methodologies for the preparation of polysubstituted optically active tetrahydroisoquinolines and tetrahydro-β-carboline derivatives functionalized on C-1. The intermolecular Pictet-Spengler condensation with chiral carbonyl derivatives constitutes an interesting and useful approach towards this goal, as summarized in this review. Strategies covered, which were developed during the last 15 years, include the intermolecular Pictet-Spengler reaction with the use of carbonyl derivatives tethered to removable chiral auxiliaries and the cyclocondensation of β-arylethylamines with chiral carbonyl components. Brief mention is also made to the occurrence of asymmetric β-carbolines in foodstuffs.

Food-Derived β-Carboline Alkaloids Ameliorate Lipid Droplet Accumulation in Human Hepatocytes

“…The ion product 2b with an abundance of 38% was obtained by protonation of the hydroxy group on the furfuryl alcohol moiety, followed by elimination of H 2 O generating an ionic 2-methyl furan moiety at C-1 on 2b-1 ( Figure 2 B). The suggested mass fragmentation pathway of this β-carboline is well in agreement with similar compounds reported in literature [ 34 , 35 , 36 , 37 , 38 ]. The fragmentation behaviors of the predicted flazin derivative ( 2 ) with a piperidine ring having a furfuryl alcohol moiety at C-1 were proposed based on the observed MS 2 fragment values (m/z); I, compound 2 exact mass: 312.1110 (C 17 H 16 N 2 O 4 ); precursor ion ( 2a ), MS 1 : 313.1176 (C 17 H 17 N 2 O 4 + ); inducted ion ( 2a-1 ), MS 1 : 313.1176 (C 17 H 17 N 2 O 4 + ); product ion ( 2a-2 ) MS 2 : 240.1060 (C 15 H 14 N 2 O 4 + ); neutral loss: 75.0320 (C 2 H 5 NO 2 ).…”

Asymmetric Synthesis of a 5,6,7,8-Tetrahydro-1,6-naphthyridine Scaffold Leading to Potent Retinoid-Related Orphan Receptor γt Inverse Agonist TAK-828F

“…However, after an extensive literature search, the synthesis of tetrahydro-1,6-naphthyridines was found to still be underdeveloped despite their significant value as a scaffold of biologically active molecules. , Furthermore, to the best of our knowledge, no enantioselective synthesis of this particular ring system had been reported at that time, with only two other reports found on non-enantioselective methods. , In the original medicinal chemistry synthesis (Scheme ), the chiral center of target molecule 1 was generated by a Pictet–Spengler-type cyclization. However, enantioselective Pictet–Spengler reactions have been reported only for highly activated (hetero)­aromatic substrates, such as pyrroles or indoles, with no successful examples reported for inactivated aromatic rings, such as pyridines. Therefore, we aimed to evaluate a different chemical transformation to establish the chiral stereogenic center in an enantioselective fashion.…”

Synthesis and Characterization of N-Substituted Tetrahydroiso-quinoline Derivatives via a Pictet-Spengler Condensation

“…Pictet-Spengler reaction was used in cyclocondensation of -phenethylamine (3) with formaldehyde dimethyl acetal (4) in the presence of hydrochloric acid to give 1-methyl-1,2,3,4-tetrahydroisoquinoline (5) [22]. The reaction was later modified and subsequently intramolecular electrophilic substitution was proposed as depicted in (Scheme 2) [23].…”