Diastereoselective Synthesis of Bridged Polycyclic Alkaloids via Tandem Acylation/Intramolecular Diels–Alder Reaction

Abstract

A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-β-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron β-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-β-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.

Convenient Synthesis of Alternatively Bridged Tryptophan Ketopiperazines and Their Activities against Trypanosomatid Parasites

“…The key step of the synthetic route was an intramolecular acidcatalyzed Pictet-Spengler condensation of aldehyde 7, proceeding through the intermediate imine 8 (Figure 2). While intramolecular Pictet-Spengler condensations have been previously reported, [14][15][16] they are typically implemented in the construction of comparatively less strained 1,2-bridged β-carboline and isoquinoline structures.…”

The Pictet-Spengler Reaction Updates Its Habits

“…The synthetic route started with the installation of a diene motif in the THBC skeleton by a P-S reaction between 5-substituted furan 2-carbaldehydes 193 (R 1 = Me, Et, Br) and L-tryptophan methyl ester. The resulting product 194ab (as a mixture of cis/trans diastereomers) that was treated with acryloyl chlorides (DCM, Et 3 N at rt) afforded the α,β-unsaturated amides 195ab, which spontaneously underwent [4 + 2] Diels-Alder cycloaddition to give the bridged indole alkaloids 196b in the exo form, while the cis-isomer 195a remained unreacted (Scheme 57) [185].…”

“…methyl ester. The resulting product 194ab (as a mixture of cis/trans diastereomers) that was treated with acryloyl chlorides (DCM, Et3N at rt) afforded the α,β-unsaturated amides 195ab, which spontaneously underwent [4 + 2] Diels-Alder cycloaddition to give the bridged indole alkaloids 196b in the exo form, while the cis-isomer 195a remained unreacted (Scheme 57) [185]. The reaction between N-Phth-2-formyl-L-Phe-OH (203a) and tryptamine 1a in the presence of propylphosphonic anhydride (T3P, 1 eq.…”

Post‐Pictet‐Spengler Cyclization (PPSC): A Strategy to Synthesize Polycyclic β‐Carboline‐Derived Natural Products and Biologically Active N‐Heterocycles

“…Chen et al. developed a two‐step strategy for the diastereoselective synthesis of bridged hexacyclic indole alkaloid by utilizing sequential Pictet‐Spengler condensation followed by N ‐acylation and cascade diastereoselective intramolecular [4+2] Diels‐Alder cycloaddition reaction (Scheme ) . The synthetic approach was also demonstrated on a soluble polymer support.…”