Efficient Syntheses of (±)-Cherylline and Latifine Dimethyl Ether

A concise route for the syntheses of (±)-cherylline and latifine dimethyl ether is reported. The key steps involved are Michael addition of veratrole with p-methoxy nitrostyrene (for cherylline), anisole with 2,3-dimethoxy nitrostyrene (for latifine), and reduction of nitro intermediate, followed by Pictet–Spengler cyclization.     

Highly efficient, multigram and enantiopure synthesis of (S)-2-(2,4′-bithiazol-2-yl)pyrrolidine

(S)-2-(4-Bromo-2,4′-bithiazole)-1-(tert-butoxycarbonyl)pyrrolidine ((S)-1) was obtained as a single enantiomer and in high yield by means of a two-step modified Hantzsch thiazole synthesis reaction when bromoketone 3 and thioamide (S)-4 were used. Further conversion of (S)-1 into trimethyltin derivative (S)-2 broadens the scope for further cross-coupling reactions.     

Diastereoselective Synthesis of Camptothecin-like Scaffolds: Construction of a New Class of Pseudo-natural Products

The discovery of novel small molecules endowed with high 3D-content remains a powerful tool for interrogating underrepresented biological space. To this end, the pseudo-natural products (pseudo-NP) strategy has become one of the most important tools to deliver biologically significant chemical probes. In this article, we describe the development of a new class of pseudo-NP collection, through connecting tryptamines with a furanose derivative followed by subjecting the product from this operation to a ring distortion strategy that led to diastereoselective synthesis of camptothecin-like compounds. This process is driven by a cascade that unites Pictet–Spengler reaction with Michael addition reaction, followed by oxidative-ring enlargement and subsequent transannular aldol cyclization delivering camptothecin-like architectures. The obtained diastereoselectivity was verified using density functional theory (DFT) calculations.     

Expeditious One-Pot,Four-Step Preparation of 2-t-Butoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline and an Improved Conversion to Its 6-Cyano Derivative

3-Methoxy-phenethylamine was subjected to a sequential imination/Pictet–Spengler/demethylation/Boc protection sequence that allowed a one-pot preparation of N-Boc-6-hydroxy-1,2,3,4-tetrahydroisoquinoline 1. This intermediate was elaborated almost quantitatively via an improved triflation/cyanation procedure to its 6-cyano analog 2.     

Total Synthesis of (±)-Armepavines and (±)-Nuciferines From (2-Nitroethenyl)benzene Derivatives

A concise route to armepavine 1 and nuciferine 2 and 3, which can be isolated from the leaves of Nelumbo nucifera (Nymphaceae), has been achieved in which the longest linear sequence is only six steps from commercially available benzaldehyde in 28%, 21%, and 20% overall yield, respectively. The key transformations in the synthesis are the radical cyclization of aryl bromide with Bu₃SnH and the Pictet–Spengler reaction of N-substituted amine with aldehyde.     

Total Syntheses of (−)-Strictosidine and Related Indole Alkaloid Glycosides

A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler reaction with α-cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (−)-strictosidine, which is an important intermediate in biosynthesis. This two-step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet–Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (−)-strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (−)-strictosamide, (−)-neonaucleoside A, (−)-cymoside, and (−)-3α-dihydrocadambine.     

Divergent Asymmetric Total Synthesis of (−)-Voacafricines A and B

A divergent asymmetric total synthesis of voacafricines A and B, hexacyclic monoterpene indole alkaloids, has been accomplished featuring the following key steps: a) a catalyst-controlled asymmetric Pictet–Spengler reaction of 6-methoxytryptamine with a chiral α-ketoester affording a 1,1-disubstituted tetrahydro-β-carboline in excellent yield and diastereoselectivity; b) oxidative cleavage of a 3,5-disubstituted cyclopentene furnishing a dialdehyde intermediate, which was effectively differentiated through spontaneous cyclization with the neighboring hydroxy and secondary amine functions; c) intramolecular nucleophilic addition of a tertiary amino nitrogen atom to the in situ generated oxonium species generating stereoselectively an unprecedented 8-alkyl octahydro-2H-5,8-methanofuro[2,3-b]azepin-8-ium motif bearing five contiguous stereocenters. The synthesis confirmed the absolute configuration of these two natural products.     

Asymmetric Biocatalytic Synthesis of 1-Aryltetrahydro-β-carbolines Enabled by “Substrate Walking”

Stereoselective catalysts for the Pictet–Spengler reaction of tryptamines and aldehydes may allow a simple and fast approach to chiral 1-substituted tetrahydro-β-carbolines. Although biocatalysts have previously been employed for the Pictet–Spengler reaction, not a single one accepts benzaldehyde and its substituted derivatives. To address this challenge, a combination of substrate walking and transfer of beneficial mutations between different wild-type backbones was used to develop a strictosidine synthase from Rauvolfia serpentina (RsSTR) into a suitable enzyme for the asymmetric Pictet–Spengler condensation of tryptamine and benzaldehyde derivatives. The double variant RsSTR V176L/V208A accepted various ortho-, meta- and para-substituted benzaldehydes and produced the corresponding chiral 1-aryl-tetrahydro-β-carbolines with up to 99 % enantiomeric excess.     

钙拮抗剂普拉地平合成的改进

普拉地平 (Pranidipine ,1 ,4 二氢 2 ,6 二甲基 4 (3 硝基苯基 ) 3 ,5 吡啶二羧酸甲酯肉桂醇酯 ,1 ) ,属于 1 ,4 二氢吡啶类钙拮抗剂。化合物 1具有钙通道拮抗作用 ,能缓解抑制钙通道 ,阻滞钙离子内流 ,并能抑制细胞内钙离子的释放 ,起长效降压作用[1 ] 。化合物 1降压作用优于硝苯地平和氨氯地平等钙拮抗剂[2 ] ,处于临床Ⅲ期研究[3] 。专利[4] 报道了 3 氨基 2 丁烯酸甲酯 (2 )和 2 (3 硝基亚苄基 )乙酰乙酸肉桂醇酯 (3 )发生Hantzsch环化反应合成普拉地平 (1 )。本文以双乙烯酮为原料 ,经与肉桂醇酯化制备乙酰乙酸肉桂醇酯 (4…     

Organocatalytic Enantioselective Pictet–Spengler Reaction of α-Ketoesters: Development and Application to the Total Synthesis of (+)-Alstratine A

We report herein an asymmetric Pictet–Spengler reaction of α-ketoesters. In the presence of a catalytic amount of simple alanine-derived squaramide and p-nitrobenzoic acid, reaction of tryptamines with methyl 2-oxoalkanoates afforded the corresponding 1-alkyl-1-methoxycarbonyl tetrahydro-β-carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2-deteurium-labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro-β-carbolinium ion could be the rate- and enantioselectivity-determining step. A concise enantioselective total synthesis of (+)-alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]_D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper.     

Microwave‐Assisted One‐Pot Preparation of Tetrahydro‐β‐carboline Hydrochlorides under Solvent‐Free Conditions

An efficient and environmentally friendly synthesis of tetrahydro‐β‐carboline hydrochlorides via Pictet–Spengler reaction was described. Tryptamine hydrochlorides were used as the reactant and no additional acid catalyst was needed. This reaction was completed within 2.5–9 min in good yield.     

Synthetic routes to thiazoloindoles

Several structural types of thiazoloindoles can be distinguished with regard to the position of the fusion between the thiazole, benzene, and pyrrole rings. The present review describes the synthetic routes to five selected types of thiazoloindole derivatives with [3,2-a], [3,4-a], [5,4-b], [5,4-e], and [4,5-e] fusion. These compounds are useful for the discovering of future targets and the development of new drug molecules.     

Carbopyronine荧光染料中间体的有效合成方法

在非质子路易斯酸的辅助下高收率的合成了Carbopyronine荧光染料中间体2,7-双二甲氨基-9,10-二氢-9,9-二甲基蒽环。反应关键步骤是路易斯酸辅助下的环化反应,考查了几种路易斯酸的效果。确立了环化反应的最佳条件为： 2.5mol的路易斯酸与1mol的叔醇2在0 ˚C反应6 h,再于室温下反应10 h。     

Microwave-accelerated Synthesis of Some (±)-1-Aryl-5-chloroisochromans

Solventless one-pot synthesis of some new (±)-1-aryl-5-chloroisochromans by cyclocondensation of 2-(2-chlorophenyl)ethanol with aromatic aldehydes via an acid catalyzed oxa-Pictet-Spengler reaction under microwave irradiation is described.     

InCl3‐Driven Regioselective Synthesis of Functionalized/Annulated Quinolines: Scope and Limitations

The efficient, regioselective synthesis of functionalized/annulated quinolines was achieved by the coupling of 2‐aminoaryl ketones with alkynes/active methylenes/α‐oxoketene dithioacetals promoted by InCl₃ in refluxing acetonitrile as well as under solvent‐free conditions in excellent yields. This transformation presumably proceeded through the hydroamination–hydroarylation of alkynes, and the Friedländer annulation of active methylene compounds and α‐oxoketene dithioacetals with 2‐aminoarylketones. In addition, simple reductive and oxidative cyclization of 2‐nitrobenzaldehyde and 2‐aminobenzylalcohol, respectively, afforded substituted quinolines. Systematic optimization of the reaction parameters allowed us to identify two‐component coupling (2CC) conditions that were tolerant of a wide range of functional groups, thereby providing densely functionalized/annulated quinolines. This approach tolerates the synthesis of various bioactive quinoline frameworks from the same 2‐aminoarylketones under mild conditions, thus making this strategy highly useful in diversity‐oriented synthesis (DOS). The scope and limitations of the alkyne‐, activated methylene‐, and α‐oxoketene dithioacetal components on the reaction were also investigated.     

Synthesis of substituted quinolines by the electrophilic cyclization of n-(2-alkynyl)anilines

A wide variety of substituted quinolines are readily synthesized under mild reaction conditions by the 6-endo-dig electrophilic cyclization of N-(2-alkynyl)anilines by ICl, I₂, Br₂, PhSeBr, and p-O₂NC₆H₄SCl. The reaction affords 3-halogen-, selenium- and sulfur-containing quinolines in moderate to good yields in the presence of various functional groups. Analogous quinolines bearing a hydrogen in the 3-position have been synthesized by the Hg(OTf)₂-catalyzed ring closure of these same alkynylanilines.