Application of Pictet–Spengler Reaction to Indole-Based Alkaloids Containing Tetrahydro-β-carboline Scaffold in Combinatorial Chemistry

Abstract

Indole-based alkaloids are well-known in the literature for their diverse biological properties. Polysubstituted optically active tetrahydro-β-carboline derivatives functionalized on C-1 position are the common structural motif in most of the indole-based alkaloids, as well as highly marketed drugs. The stereoselective Pictet-Spengler reaction is one of the currently most important synthetic techniques used for the preparation of these privileged tetrahydro-β-carboline scaffolds. To date, there are numerous research reports that have been published on the synthesis of the tetrahydro-β-carboline scaffold both on solid phase, as well as in solution phase. Moreover rapid growth has been observed for the enantioselective synthesis of tetrahydro-β-carboline scaffold using chiral organocatalysts. In this Review, efforts have been taken to shed light on the latest information available on different strategies to synthesize tetrahydro-β-carboline both on solid phase and in solution phase during the last 20 years. Furthermore, we believe that the present synthetic methodologies covered in this Review will help to improve the status of this privileged tetrahydro-β-carboline scaffold in its use for drug discovery.

Gold‐Catalyzed Dual Annulation of Homopropargyl Alcohols with Nitrones: Synthesis of Tetrahydropyrano[4,3‐b]indole Scaffolds

“…These results confirmed that both 9 and 10 could contribute to the formation of final product in the absence of catalyst. Based on these results and the reported literature, [13][14][15][16]19,25] a rationalized reaction mechanism was proposed in Scheme 4. Initially, the nitrone 2 attacked the gold-activated alkyne to form a vinylgold species II, followed by a hydrolysis/protodeauration/ 3,3-sigmatropic rearrangment/cyclodehydration sequence via intermediate III to gave the indole product V, and releasing the corresponding aldehyde simultaneously.…”

“…These results consisted with general tendency of Pictet-Spengler reaction and cyclization with external aldehyde. [19] Moreover, the model reaction in the presence of p-methylaniline (Scheme 3d) [24] or imines 7 (Scheme 3e) only formed the product 3 a in comparable high yields, and no corresponding annulation product with aniline or imine was detected, which suggested that the early stage of this cascade reaction, the gold-catalyzed oxoarylation step, happened in the inner-sphere. [13,14] Intend to investigate the possible [a] Unless otherwise noted, the reaction was carried out on a 0.2 mmol scale: 1 (0.3 mmol) in 1.0 PhF was slowly added to a solution of PPh 3 AuNTf 2 (7.4 mg, 5.0 mol%), and 2 (0.2 mmol) in PhF (1.0 mL) under an argon atmosphere at 0°C, and the yields are given in isolated yields.…”

“…The formation of indole is feasible according to Zhang's protocol (Scheme 1b), and with the tethered hydroxyl group on these generated indoles, the oxa-Pictet-Spengler reaction could be enabled by recycling the leaving aldehyde species in the early step. [19] Furthermore, the tetrahydropyrano [4,3-b]indoles are privileged heterocyclic motifs that frequently occur in a plethora of bioactive molecules, such as anti-inflammatory and anti-tumor compounds. [20]…”

Water‐Promoted Synthesis of Azepino[3,4,5‐cd]indole Analogues via Pictet‐Spengler Reaction

“…Pictet‐Spengler reaction (PSR), discovered in 1911, has been providing economical and direct access to a versatile collection of compound structures, including tetrahydroisoquinoline, tetrahydro‐β‐carboline and other N‐heterocycles (Figure ) . Traditionally, Brønsted acid was used as the critical catalyst for PSR.…”

Development of the Vinylogous Pictet–Spengler Cyclization and Total Synthesis of (±)‐Lundurine A

“…The utility of this venerable transformation is highlighted in several total syntheses of indole alkaloids and other biologically active compounds. 3 …”