65026-49-5

Upstream product

• 111581-75-0 (11aS,11bS)-11a-Ethyl-1,2,4,5,10,11,11a,11b-octahydro-3a,9b-diaza-benzo[cd]fluoranthen-3-one 
• 56245-51-3 (-)-dehydro-1,2 aspidospermidine 
• 90475-65-3 16-acetoxy, 16-dehydrovincane 
• 473-99-4 eburnamine 
• 134287-10-8 (10bS,12aR,12bS)-12a-Ethyl-2,3,4,5,11,12,12a,12b-octahydro-1H-3a,6-diaza-indeno[7,1-cd]fluorene 
• 4880-88-0 vinburnine 
• 1617-90-9 vincamin 
• 3382-95-4 (15S,17S,19S)-15-ethyl-17-(hydroxymethyl)-1,11-diazapentacyclo[9.6.2.0^2,7.0^8,18.0^15,19]nonadeca-2,4,6,8⁽¹⁸⁾-tetraen-17-ol 
• 19877-90-8 (15S,17S,19S)-15-ethyl-1,11-diazapentacyclo[9.6.2.0^2,7.0^8,18.0^15,19]nonadeca-2,4,6,8⁽¹⁸⁾-tetraen-17-ol 
• 517-30-6 (+/-)-3-epieburnamenine 
• 675-20-7 piperidin-2-one 
• 159682-74-3 1-(2-iodoethyl)indole 
• 62937-66-0 2-[1,3]Dithian-2-ylmethyl-2-ethyl-5-hydroxy-pentanoic acid ethyl ester 
• 62937-64-8 α-ethyl-α-(1,3-dithian-2-ylmethyl)-δ-valerolactone 

Relevant academic research and scientific papers

Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity

Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.

ANALOGS OF VINCAMINE AND USES THEREOF

The present disclosure provides compounds of any one of Formulae (I'), (I), (IA), (II'), (II), (IIA), (IIIA), (III"), (III'), (III), (IIIA), (IV), (V'), (V), (VI), (VII), (VIII'), (VIII), (ΙΧ'), (IX), and (X). The compounds described herein may be useful in treating and/or preventing a broad range of diseases (e.g., proliferative disease (e.g., cancers (e.g., non-small cell lung cancer, or glioma), inflammatory diseases, autoimmune diseases), CNS disorder (e.g., drug addiction), metabolic disorder (e.g., diabetes), or infectious disease (e.g., bacterial infection or parasitic infection (e.g., malaria))). Also provided in the present disclosure are pharmaceutical compositions, methods of synthesis of a compound described herein, kits, methods, and uses including or using a compound described herein.

Cycloaddition Reaction of Mesoionic Betaines as an Approach toward Trialkylindoline Alkaloids

Intramolecular 1,4-dipolar cycloaddition of an anhydro-4-hydroxy-2-oxo-1,3-thiazium hydroxide across a tethered indole π-bond has been used for the construction of the pentacyclic skeleton of epi-16,17-dihydroeburnamenine. The reaction of 3-ethyl-3-(alkenyl)piperidinones with diketene and trimethylsilyl triflate in benzene at ambient temperature produced annulated pyridones in good yield. The initial reaction involved formation of a N-acetoacetylated amide which was further converted to the pyridone with TMSOTf. The overall process was found to proceed with complete stereospecificity. Treating a sample of 3-ethyl-3-[(E)-4-phenyl-3-butenyl]-2-piperidone with diketene and TMSOTf produced a cycloadduct in 63% yield whose stereochemistry was elucidated by a X-ray crystallographic study. The epimeric Z-isomer produced a different stereoisomer of the annulated dihydropyridone. The mechanism of the annulation involves a TMSOTf induced cyclization followed by proton removal and generation of a cross-conjugated heteroaromatic betaine. This 1,4-dipole undergoes a subsequent intramolecular dipolar cycloaddition across the neighboring π-bond, and the resulting cycloadduct is subsequently converted to the annulated lactam. A related annulation sequence leading to a key intermediate previously utilized in the synthesis of the (±)-vallesamidine has been developed which is based on the intramolecular dipolar cycloaddition of a mesoionic betaine intermediate.

An expedient synthesis of epi-eburnamenine via an intramolecular 1,4-dipolar cycloaddition reaction

The intramolecular 1,4-dipolar cycloaddition of an anhydro-4-hydroxy-2-oxo-1,3-thiazium hydroxide across a tethered indole π-bond has been used for the construction of the pentacyclic skeleton of epi-16,17-dihydroeburnamenine.

Flow Thermolysis Rearrangements in the Indole Alkaloid Series: 1,2-Dehydroaspidospermidine

Flow thermolysis of 1,2-dehydroaspidospermidine (1) at various temperatures allowed isolation of all four predictable rearrangement products, namely indolenines 2 and 3 and indoles 4 and 5.The structures of the rearranged products were confirmed by chemical and spectroscopic means, particularly HMBC and HMQC NMR techniques.

Chiral Total Synthesis of Indole Alkaloids of the Aspidosperma and Hunteria Types

Expeditious enantioselective syntheses of (+)-quebrachamine (6), (-)-aspidospermidine (7), (+)-demethoxyaspidospermine (8), and (-)-eburnamonine (9) were accomplished starting from (S)-lactone 1.The syntheses also complete formal, total syntheses of 12 other indole alkaloids of the Aspidosperma and Hunteria types.The key step in the synthesis of (+)-quebrachamine (6) was the Pictet-Spengler condensation of chiral C9 unit 10, derived from 1, with tryptamine.Another C9 unit (15) was also prepared from 1 and utilized for the syntheses of three other alkaloids, 7, 8, and 9.

STRUCTURE OF GONIOMITINE, A NEW TYPE OF INDOLE ALKALOID

The structure 1 proposed for goniomitine, an indole alkaloid isolated from the root bark of Gonioma malagasy (Apocynaceae), was inferred from an analysis of its MS, 1H and 13C NMR spectral data.A biogenetic scheme is proposed to account for the formation of 1 from vincadifformine 9.

THERMAL REARRANGEMETS OF SOME INDOLE ALKALOID DERIVATIVES

Under both static and flow thermolysis conditions, several compounds with an "aspidosperma" framework rearranged to "vinca" derivatives.Thus (-)1,2-dehydroaspidospermidine (4) rearranged to (-)aspidospermidine and compound 17 on pyrolysis (200 deg C) while flow termolysis (580 deg C) gave vincane (14).Compound 6 rearranged to vincamine (13a) and 16-epivincamine (13b) under either condition; increasing the temperature resulted in formation of apovincamine (19) (pyrolysis) or vincamone (16) (flow thermolysis).

Synthetic Approach to (+/-)- Vincamine via Cleavage of an α-Diketone Monothioacetal. Alternative Synthesis of (+/-)-Eburnamine, (+/-)-Isoeburnamine, and (+/-)-Eburnamenine

The half ester (8) prepared from cleavage of 2-(1,3-dithian-2-yl)-4-ethoxycarbonyl-4-ethylcyclohexanone (7) has been converted into (+/-)-eburnamine (20), (+/-)-isoeburnamine (21), and (+/-)-eburnamenine (22) by a stereospecific reaction sequence proceeding via the dithian intermediate (16).However an attempted conversion of (16) into (+/-)-vincamine (6) was unsuccessful.