Pyrroloiminoquinone Alkaloids: Total Synthesis of Makaluvamines A and K

An, Jason; Jackson, Richard K.; Tuccinardi, Joseph; Wood, John L.

doi:10.1021/acs.orglett.3c00350

Cited by 6 publications

(4 citation statements)

References 30 publications

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“…There have been a number of reports on the total synthesis of makaluvamines [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ], although most of them have focused on the development of synthetic methods for the characteristic tricyclic skeleton. To gather more detailed SAR information, a unified, divergent synthesis of natural makaluvamines or various analogs and their biological evaluations is required.…”

Section: Resultsmentioning

confidence: 99%

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Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs

Kiichi,

Fukuoka,

Kitano

et al. 2024

Molecules

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Makaluvamine J, a pyrroloiminoquinone alkaloid of marine sponge origin, and its analogs were synthesized and assessed for their potential to develop as a novel and selective growth inhibitor targeting human pancreatic cancer PANC-1 cells. Ts-damirone B, a common precursor featuring a pyrroloiminoquinone core structure, was synthesized through Bartoli indole synthesis and IBX-mediated oxidation. Late-stage diversification at N-5 and N-9 yielded makaluvamine J and several analogs. A structure–activity relationship (SAR) analysis highlighted the significance of the lipophilic side chain at N-9 for the growth inhibitory activity of PANC-1 cells. The modest alkyl group at N-5 was found to improve selectivity against other cancer cells. Among the prepared analogs, the tryptamine analog 24 showed potent and selective cytotoxicity (IC50 = 0.029 µM, selective index = 13.1), exceeding those of natural products.

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Section: Resultsmentioning

confidence: 99%

“…Considering these findings, we examined another synthetic route, as depicted in Scheme 4. Thus, the methylation of N-5 of 19 gave Ts-damirone B (22) in quantitative yield. Unexpectedly, the subsequent treatment of 22 with tyramine (three equiv.)…”

Section: Unified Divergent Synthesis Of Makaluvamines and Analogsmentioning

confidence: 93%

Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs

Kiichi,

Fukuoka,

Kitano

et al. 2024

Molecules

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“…Aleutianamine ( 1 ) belongs to the pyrroloiminoquinone alkaloid family of natural products defined by their conserved central planar, tricyclic ring system. These natural products have received significant attention from the synthetic community due to their complex molecular frameworks and broad biological activites . Structurally, aleutianamine ( 1 ) possesses a unique heptacyclic ring system which consists of a pyrroloiminoquinone unit, a bridged azabicyclo[3.3.1]nonane ring system substituted with a congested tertiary alkyl sulfide and an alkenyl bromide, and another bridging thioaminal linkage (Figure A). The multibridged ring system of the natural product bears three stereocenters and is highly strained due to extensive unsaturation.…”

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confidence: 99%

Total Synthesis of Aleutianamine

Yu,

Sercel,

Rezgui

et al. 2023

J. Am. Chem. Soc.

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Aleutianamine is a recently isolated pyrroloiminoquinone natural product that displays potent and selective biological activity toward human pancreatic cancer cells with an IC 50 of 25 nM against PANC-1, making it a potential candidate for therapeutic development. We report a synthetic approach to aleutianamine wherein the unique [3.3.1] ring system and tertiary sulfide of this alkaloid were constructed via a novel palladium-catalyzed dearomative thiophene functionalization. Other highlights of the synthesis include a palladium-catalyzed decarboxylative pinacol-type rearrangement of an allylic carbonate to install a ketone and a late-stage oxidative amination. This concise and convergent strategy will enable access to analogues of aleutianamine and further investigation of the biological activity of this unique natural product.

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“…Alternatively, the late-stage sulfur atom introduction strategy proved successful in their hands, resulting in the first chemical total synthesis of compound 2 . To the best of our knowledge, this is one of the two sulfur-containing N,S -acetal-bridged discorhabdin C-type molecules that have been chemically synthesized successfully in this family so far. , …”

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confidence: 99%

Construction of the Tetracyclic Framework of Sulfur-Containing Discorhabdin-Type Alkaloids

et al. 2023

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Herein, we report an efficient synthetic method for constructing the tetracyclic scaffold of sulfur-containing discorhabdin-type alkaloids. The key to success is the BF3•Et2O-promoted dienone-phenol-type rearrangement/sulfur insertion cascade reaction, which converts the common and readily available N,O-acetal-bridged tetracyclic framework to the labile and synthetically challenging N,S-acetal-bridged tetracyclic framework in a single step. Additionally, the hypervalent iodine promoted intramolecular oxidative dearomatization terminated with amide and indium(III) acetate-facilitated radical cyclization were also essential elements in this study.

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Pyrroloiminoquinone Alkaloids: Total Synthesis of Makaluvamines A and K

Abstract: Herein, an efficient, scalable, and concise approach to an advanced pyrroloiminoquinone synthetic intermediate (6b) by way of a Larock indole synthesis is reported. The synthetic utility of this intermediate is demonstrated by its ready conversion to makaluvamines A (1) and K (4).

Cited by 6 publications

References 30 publications

Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs

Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs

Total Synthesis of Aleutianamine

Construction of the Tetracyclic Framework of Sulfur-Containing Discorhabdin-Type Alkaloids

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