Total Synthesis of Sarpagine‐Related Bioactive Indole Alkaloids

Abstract

Extension of the asymmetric Pictet-Spengler reaction to bulkier N -alkylated tryptophan derivatives resulted in an improved stereospecific access to the key bicyclo[3.3.1]nonane core of bioactive C-19 methyl substituted sarpagine/macroline/ajmaline indole alkaloids with excellent diastereoselectivity by internal asymmetric induction. Complete stereocontrol of the C-19 methyl function in either the α- or β-configuration was achieved, which enables the total synthesis of any member from this group of thirty alkaloids. We report herein, the total synthesis of macrocarpines (A-C) 1-3, talcarpine 4, N(4)-methyl-N(4),21-secotalpinine 5, dihydroperaksine 8 and deoxyperaksine 9.

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

“…Interestingly, a Pictet–Spengler reaction is critical in the biosynthesis of indole alkaloids, which is presented in Section 3.1 (Scheme ). The Pictet–Spengler reaction has found numerous applications in natural product synthesis, including many biomimetic‐inspired routes, and drug development . The synthesis of Cialis ( 57 ), a clinical agent used to treat erectile dysfunction, involves a key stereoselective Pictet–Spengler reaction (Scheme B) …”

“…Indole heterocycles are known to engage in Pictet-Spengler reactions [6,8,21,[44][45][46] (Scheme 4B)u tilizing tryptamine derivatives (e.g., 49,54). In this reaction, at ryptamine undergoes an initial condensation reactionw ith an aldehyde/ketone to give an imine intermediate (51), which undergoes as ubsequente lectrophilica romatic substitution atC -2 of the indolen ucleus to afford tryptoline-containing compounds (53).…”

“…The Pictet-Spengler reaction has found numerousa pplications in natural product synthesis, including many biomimetic-inspired routes, and drug development. [8,21,[44][45][46] The synthesis of Cialis (57), ac linical agentu sed to treat erectile dysfunction, involves ak ey stereoselective Pictet-Spengler reaction(Scheme 4B). [8]…”

Application of the Asymmetric Pictet–Spengler Reaction in the Total Synthesis of Natural Products and Relevant Biologically Active Compounds

“…Furthermore, this route corrects the optical rotation values of (−)-macrocarpine A 114 and (+)- N (4)-methyl, N (4), 21-secotalpinine 118 demonstrated by others [ 195 ]. This route obviously demonstrates that a large group other than the benzyl on the N b -nitrogen atom of the d -(+)-tryptophan initiating precursor can still give 100% de through internal enantioselective induction ( Scheme 23 ) [ 199 ].…”

Synthesis and Evaluation of Antimicrobial Activities of Novel N-Substituted Indole Derivatives

“…Particularly, the nitrogen-containing heterocycles (Nheterocycles) have proven ubiquitous structural features and pivotal role in medicinal chemistry [5][6][7][8][9][10][11]. Amongst the various N-heterocycles, indole motifs have received significant attention due to their presence in proteins, amino acids, bioactive alkaloids, and drugs ( Figure 1) [12][13][14][15][16][17][18][19][20][21][22][23]. In this context, a large number of indole moieties have been investigated in the development of new efficient bioactive molecules with diverse pharmacological properties, such as antimicrobial, antiviral, anticancer, anti-inflammatory, inhibitors, and antioxidant .…”