Synthesis and evaluation of a novel series of indoloisoquinolines as small molecule anti-malarial leads

Horrocks, Paul; Fallon, Samantha; Denman, Laura; Devine, Oliver; Duffy, Liam J.; Harper, Anthony; Meredith, Emma-Louise; Hasenkamp, Sandra; Sidaway, Adam; Monnery, Daniel; Phillips, Theresa R.; Allin, Steven M.

doi:10.1016/j.bmcl.2011.12.071

Cited by 18 publications

(5 citation statements)

References 15 publications

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“…The chiral aryl lactam core is a prevalent motif in many natural products and biologically active compounds. For example, the NK1 receptor antagonist ( 1 , Figure 1) is used in the treatment of nausea and vomiting associated with chemotherapy, [1] and the chiral lactam 2 bearing an indole moiety possesses antimalarial activity [2] . Derivatives of the chiral aryl lactams are equally important appearing as subunits in drugs and bioactive natural products such as carmegliptin ( 3 ) used in the treatment of type 2 diabetes, and emetine ( 4 ), a natural product used as an antiparasitic agent [3] …”

Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of α,β‐Unsaturated Aryl Lactams by Heck‐Matsuda and Heck‐Mizoroki Arylations of Enelactams

et al. 2022

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The chiral aryl lactam nucleus is a common motif present in many bioactive natural products and the development of effective enantioselective methodologies for its preparation is of great interest. In this work, we report the synthesis of several enantioenriched aryl lactams in good yields and enantiomeric ratios using a combined strategy employing arenediazonium salts bearing electron-withdrawing substituents, aryl iodides with electron-donating substituents, and chiral N,N-ligands. The chiral α,β-unsaturated aryl lactams were obtained in yields of up to 78 % and enantiomeric ratios up to 95 : 5. Furthermore, this work demonstrates the use of chiral N,N-ligands as a viable alternative to the phosphine-based ligands in the enantioselective Heck-Mizoroki reactions using aryl iodides. The origins of the enantioselectivity and the full catalytic cycle for the Heck-Matsuda arylation of the enelactams were investigated through DFT calculations.

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Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of α,β‐Unsaturated Aryl Lactams by Heck‐Matsuda and Heck‐Mizoroki Arylations of Enelactams

et al. 2022

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“…Following the general procedure, and starting from lactam 10 (0.07 g, 0.19 mmol) and 1.25 M HCl in EtOH (1.3 mL). Reaction time: 20 h. Recrystallized from EtOAc/n-hexane to yield a white solid 11 (0.056 g, 80%): 1 H-NMR was found to be identical to that described in the literature [30]; Anal. calcd.…”

Section: Methodsmentioning

confidence: 63%

“…( L )-tryptophanol [( S )-tryptophanol] was bought from Sigma-Aldrich (Schnelldorf, Bavaria, Germany). Bicyclic lactams 5a – c [19,22] and δ-oxo-esters 9a – c [30,31] were synthesized as described in the literature. Methyl 4-oxobutanoate ( 9d ) was synthesized using the method described for the synthesis of methyl 5-oxopentanoate ( 9a ) but starting from γ-butyrolactone.…”

Section: Methodsmentioning

confidence: 99%

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

et al. 2016

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Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl D-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)-or (R)-tryptophanol with appropriate racemic δ-oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.

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“…As an example, Macmillan reported a singular case of a conjugate addition reaction of C2‐bearing indole potassium trifluoroborate salts to enals using secondary amine catalysis . Given that many natural products and pharmaceutically relevant core structures contain a stereocenter adjacent to the C2 position (Scheme B), we considered strategies to apply a redox‐relay Heck type reaction using an appropriately functionalized indole starting material for the purposes of enantioselective indole C2 functionalization. By coupling this starting material with a diverse selection of alkene coupling partners, we would be able to streamline access to a wide variety of enantioenriched molecular scaffolds.…”

Section: Methodsmentioning

confidence: 99%

Enantioselective C2‐Alkylation of Indoles through a Redox‐Relay Heck Reaction of 2‐Indole Triflates

Race

Yuan

Sigman

2018

Chemistry A European J

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A palladium-catalyzed enantioselective redox-relay Heck reaction of 2-indole triflates and disubstituted alkenes is reported. This process combines readily-available indole triflates with a variety of alkenes to afford a range of indole derivatives bearing a stereocenter adjacent to C2. Enantioselectivity is achieved through use of a simple pyridine-oxazoline ligand. Tuning the electronics of the indole, through judicious choice of N-protecting group, is required to ensure selective β-hydride elimination away from the indole core. Utility of this method is highlighted in a modular formal synthesis of an S1P1 agonist precursor developed by Merck.

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Synthesis and evaluation of a novel series of indoloisoquinolines as small molecule anti-malarial leads

Cited by 18 publications

References 15 publications

Enantioselective Synthesis of α,β‐Unsaturated Aryl Lactams by Heck‐Matsuda and Heck‐Mizoroki Arylations of Enelactams

Enantioselective Synthesis of α,β‐Unsaturated Aryl Lactams by Heck‐Matsuda and Heck‐Mizoroki Arylations of Enelactams

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

Enantioselective C2‐Alkylation of Indoles through a Redox‐Relay Heck Reaction of 2‐Indole Triflates

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