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8 pages, 1822 KiB

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Copper(I)-Catalyzed Cross-Coupling of 1-Bromoalkynes with N-Heterocyclic Organozinc Reagents

by Christian Frabitore, Jérome Lépeule and Tom Livinghouse

Molecules 2022, 27(14), 4561; https://doi.org/10.3390/molecules27144561 - 17 Jul 2022

Cited by 2 | Viewed by 1791

Abstract

Nitrogen-containing heterocycles represent the majority of FDA-approved small-molecule pharmaceuticals. Herein, we describe a synthetic method to produce saturated N-heterocyclic drug scaffolds with an internal alkyne for elaboration. The treatment of N,N-dimethylhydrazinoalkenes with Et₂Zn, followed by a Cu(I)-catalyzed cross-coupling with 1-bromoalkynes, results [...] Read more.

Nitrogen-containing heterocycles represent the majority of FDA-approved small-molecule pharmaceuticals. Herein, we describe a synthetic method to produce saturated N-heterocyclic drug scaffolds with an internal alkyne for elaboration. The treatment of N,N-dimethylhydrazinoalkenes with Et₂Zn, followed by a Cu(I)-catalyzed cross-coupling with 1-bromoalkynes, results in piperidines and pyrrolidines with a good yield. Five examples are reported and a proposed mechanism for the Cu(I)-catalyzed cross-coupling is presented. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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8 pages, 1451 KiB

Open AccessArticle

A Concise Synthetic Method for Constructing 3-Substituted Piperazine-2-Acetic Acid Esters from 1,2-Diamines

by Srinivas Chamakuri, Sunny Ann Tang, Kevin A. Tran, Shiva Krishna Reddy Guduru, Peter K. Bolin, Kevin R. MacKenzie and Damian W. Young

Molecules 2022, 27(11), 3419; https://doi.org/10.3390/molecules27113419 - 25 May 2022

Cited by 5 | Viewed by 2714

Abstract

We report a short synthetic route for synthesizing 2,3-substituted piperazine acetic acid esters. Optically pure amino acids were efficiently converted into 1,2-diamines that could be utilized to deliver the title 2,3-substituted piperazines in five steps with a high enantiomeric purity. The novel route [...] Read more.

We report a short synthetic route for synthesizing 2,3-substituted piperazine acetic acid esters. Optically pure amino acids were efficiently converted into 1,2-diamines that could be utilized to deliver the title 2,3-substituted piperazines in five steps with a high enantiomeric purity. The novel route facilitated, for the first time, the synthesis of 3-phenyl substituted-2-piperazine acetic acid esters that were difficult to achieve using other methods; however, in this case, the products underwent racemization. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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23 pages, 2392 KiB

Open AccessArticle

Further Studies on the [1,2]-Wittig Rearrangement of 2-(2-Benzyloxy)aryloxazolines

by R. Alan Aitken, Andrew D. Harper and Ryan A. Inwood

Molecules 2022, 27(10), 3186; https://doi.org/10.3390/molecules27103186 - 17 May 2022

Cited by 5 | Viewed by 2183

Abstract

The behaviour of 14 ortho-functionalised 2-aryloxazolines (11 of them prepared and characterised for the first time) with butyllithium has been examined. Significant limitations to the Wittig rearrangement of such systems are revealed. In terms of asymmetric Wittig rearrangement, good diastereoselectivity is obtained with [...] Read more.

The behaviour of 14 ortho-functionalised 2-aryloxazolines (11 of them prepared and characterised for the first time) with butyllithium has been examined. Significant limitations to the Wittig rearrangement of such systems are revealed. In terms of asymmetric Wittig rearrangement, good diastereoselectivity is obtained with a valine-derived 4-isopropyl oxazoline, but this is compromised by racemisation upon hydrolysis. More encouraging selectivity is achieved in the Wittig rearrangement of an acyclic phenylalanine-derived ortho-benzyloxy benzamide. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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10 pages, 3874 KiB

Open AccessArticle

Stereoselective Synthesis of β-Glycinamide Ribonucleotide

by Lisa Ngu, Debarpita Ray, Samantha S. Watson, Penny J. Beuning, Mary Jo Ondrechen and George A. O’Doherty

Molecules 2022, 27(8), 2528; https://doi.org/10.3390/molecules27082528 - 14 Apr 2022

Viewed by 2003

Abstract

A diastereoselective synthesis of the β-anomer of glycinamide ribonucleotide (β-GAR) has been developed. The synthesis was accomplished in nine steps from D-ribose and occurred in 5% overall yield. The route provided material on the multi-milligram scale. The synthetic β-GAR formed was remarkably resistant [...] Read more.

A diastereoselective synthesis of the β-anomer of glycinamide ribonucleotide (β-GAR) has been developed. The synthesis was accomplished in nine steps from D-ribose and occurred in 5% overall yield. The route provided material on the multi-milligram scale. The synthetic β-GAR formed was remarkably resistant to anomerization both in solution and as a solid. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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10 pages, 1156 KiB

Open AccessArticle

Concise Syntheses of Marine (Bis)indole Alkaloids Meridianin C, D, F, and G and Scalaridine A via One-Pot Masuda Borylation-Suzuki Coupling Sequence

by Marco Kruppa, Gereon A. Sommer and Thomas J. J. Müller

Molecules 2022, 27(7), 2233; https://doi.org/10.3390/molecules27072233 - 30 Mar 2022

Cited by 12 | Viewed by 2755

Abstract

N-Protected 3-iodoindoles were reacted with (di)azine halides in a sequentially Pd-catalyzed one-pot fashion, i.e., by Masuda borylation–Suzuki coupling (MBSC) sequence. This methodology was successfully applied to the concise syntheses of marine indole alkaloids meridianin C, D, F, and G, as well as [...] Read more.

N-Protected 3-iodoindoles were reacted with (di)azine halides in a sequentially Pd-catalyzed one-pot fashion, i.e., by Masuda borylation–Suzuki coupling (MBSC) sequence. This methodology was successfully applied to the concise syntheses of marine indole alkaloids meridianin C, D, F, and G, as well as to the bisindole alkaloid scalaridine A, which were obtained in moderate to excellent yield. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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10 pages, 1138 KiB

Open AccessArticle

Synthesis of MAPA Reagents and 2-Alkyl(aryl)aminopyridines from 2-Bromopyridine Using the Goldberg Reaction

by Daniel L. Comins

Molecules 2022, 27(6), 1833; https://doi.org/10.3390/molecules27061833 - 11 Mar 2022

Cited by 2 | Viewed by 3048

Abstract

A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of [...] Read more.

A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5–3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2-N-substituted aminopyridines from various secondary N-alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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18 pages, 4632 KiB

Open AccessArticle

Completion of the Total Synthesis of Several Bioactive Sarpagine/Macroline Alkaloids including the Important NF-κB Inhibitor N₄-Methyltalpinine

by Md Toufiqur Rahman, Veera Venkata Naga Phani Babu Tiruveedhula, Michael Rajesh Stephen, Sundari K. Rallapalli, Kamal P. Pandey and James M. Cook

Molecules 2022, 27(5), 1738; https://doi.org/10.3390/molecules27051738 - 7 Mar 2022

Cited by 3 | Viewed by 2409

Abstract

The unification of the general synthetic strategy regarding the important and emerging group of C-19 methyl-substituted sarpagine/macroline alkaloids has culminated in the completion of the total synthesis of several bioactive alkaloids. Key transformations include an ACE-Cl mediated late-stage N(4)-demethylation and an anhydrous acid-mediated [...] Read more.

The unification of the general synthetic strategy regarding the important and emerging group of C-19 methyl-substituted sarpagine/macroline alkaloids has culminated in the completion of the total synthesis of several bioactive alkaloids. Key transformations include an ACE-Cl mediated late-stage N(4)-demethylation and an anhydrous acid-mediated intramolecular quaternary hemiaminal formation between a tertiary amine and an aldehyde function to allow efficient access to several biologically important alkaloids from this group. Herein, the enantiospecific total synthesis of the first known sarpagine/macroline alkaloid with NF-κB inhibitory activity, N(4)-methyltalpinine (as a chloride salt), as well as the anticancer alkaloids talpinine, O-acetyltalpinine, and macrocarpines F–G, are described. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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15 pages, 3436 KiB

Open AccessArticle

One-Pot Synthesis of Novel 2-Imino-5-Arylidine-Thiazolidine Analogues and Evaluation of Their Anti-Proliferative Activity against MCF7 Breast Cancer Cell Line

by Marian N. Aziz, Arzoo Patel, Amany Iskander, Avisankar Chini, Delphine Gout, Subhrangsu S. Mandal and Carl J. Lovely

Molecules 2022, 27(3), 841; https://doi.org/10.3390/molecules27030841 - 27 Jan 2022

Cited by 4 | Viewed by 3214

Abstract

An efficient surface-mediated synthetic method to facilitate access to a novel class of thiazolidines is described. The rationale behind the design of the targeted thiazolidines was to prepare stable thiazolidine analogues and evaluate their anti-proliferative activity against a breast cancer cell line (MCF7). [...] Read more.

An efficient surface-mediated synthetic method to facilitate access to a novel class of thiazolidines is described. The rationale behind the design of the targeted thiazolidines was to prepare stable thiazolidine analogues and evaluate their anti-proliferative activity against a breast cancer cell line (MCF7). Most of the synthesized analogues exhibited increased potency ranging from 2–15-fold higher compared to the standard reference, cisplatin. The most active thiazolidines contain a halogenated or electron withdrawing group attached to the N-phenyl ring of exocyclic 2-imino group. However, combination of the two substituents did not enhance the activity. The anti-proliferative activity was measured in terms of IC₅₀ values using an MTT assay. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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11 pages, 920 KiB

Open AccessArticle

An Oxidation Study of Phthalimide-Derived Hydroxylactams

by Bernard L. Adjei and Frederick A. Luzzio

Molecules 2022, 27(2), 548; https://doi.org/10.3390/molecules27020548 - 15 Jan 2022

Cited by 4 | Viewed by 2803

Abstract

A systematic study of the oxidation of 3-hydroxy-2-substituted isoindolin-1-ones (hydroxylactams) and their conversion to the corresponding phthalimides was undertaken using three oxidants. Of special interest was the introduction of nickel peroxide (NiO₂) as an oxidation system for hydroxylactams and comparison of [...] Read more.

A systematic study of the oxidation of 3-hydroxy-2-substituted isoindolin-1-ones (hydroxylactams) and their conversion to the corresponding phthalimides was undertaken using three oxidants. Of special interest was the introduction of nickel peroxide (NiO₂) as an oxidation system for hydroxylactams and comparison of its performance with the commonly used pyridinium chlorochromate (PCC) and iodoxybenzoic acid (IBX) reagents. Using a range of hydroxylactams, optimal conversions of these substrates to the corresponding imides was achieved with 50 equivalents of freshly prepared NiO₂ in refluxing toluene over 5–32 h reaction times. By comparison, oxidations of the same substrates using PCC/silica gel (three equivalents) and IBX (three equivalents) required oxidation times of 1–3 h for full conversion but required lengthier purification. While nominal amounts (~25 mg) of substrate hydroxylactams were used to ascertain conversion, scale-up procedures using all three methods gave good to excellent isolated yields of imides. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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13 pages, 5166 KiB

Open AccessEditor’s ChoiceArticle

Photoredox-Catalyzed Giese Reactions: Decarboxylative Additions to Cyclic Vinylogous Amides and Esters

by Kevin Dykstra, Alexei Buevich, Qi Gao, Yu-Hong Lam and Jeffrey T. Kuethe

Molecules 2022, 27(2), 417; https://doi.org/10.3390/molecules27020417 - 10 Jan 2022

Viewed by 2171

Abstract

An effective strategy has been developed for the photoredox-catalyzed decarboxylative addition of cyclic amino acids to both vinylogous amides and esters leading to uniquely substituted heterocycles. The additions take place exclusively trans to the substituent present on the dihydropyridone ring affording stereochemical control [...] Read more.

An effective strategy has been developed for the photoredox-catalyzed decarboxylative addition of cyclic amino acids to both vinylogous amides and esters leading to uniquely substituted heterocycles. The additions take place exclusively trans to the substituent present on the dihydropyridone ring affording stereochemical control about the new carbon-carbon bond. These reactions are operationally simplistic and afford the desired products in good to excellent isolated yields. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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11 pages, 1520 KiB

Open AccessArticle

Intramolecular Aminolactonization for Synthesis of Furoindolin-2-One

by Kazuhiro Higuchi, Kazunori Matsumura, Takafumi Arai, Motoki Ito and Shigeo Sugiyama

Molecules 2022, 27(1), 102; https://doi.org/10.3390/molecules27010102 - 24 Dec 2021

Cited by 1 | Viewed by 2715

Abstract

Propellanes are polycyclic compounds in which tricyclic systems share one carbon–carbon single bond. Propellane frameworks that consist of larger sized rings are found in a variety of natural products. As an approach to the stereoselective synthesis of the propellane framework, one of the [...] Read more.

Propellanes are polycyclic compounds in which tricyclic systems share one carbon–carbon single bond. Propellane frameworks that consist of larger sized rings are found in a variety of natural products. As an approach to the stereoselective synthesis of the propellane framework, one of the efficient methods is forming several rings in a single operation. Lapidilectine B (1) is composed of a propellane framework and was synthesized through the oxidative cyclization of trisubstituted alkenes. When the alkene with an ester moiety was treated with N-iodosuccinimide (NIS), iodocyclization proceeded to give the cyclic carbamate. On the other hand, when PhI(OAc)₂ was allowed to react in the carboxyl form, a furoindolin-2-one structure corresponding to the A-B-C ring of lapidilectine B (1) was produced. Furthermore, when Pd(OAc)₂ catalyst was used for cyclization under oxidative conditions, the product yield was improved. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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18 pages, 1850 KiB

Open AccessArticle

In Search of Small Molecules That Selectively Inhibit MBOAT4

by Emily S. Murzinski, Ishika Saha, Hui Ding, David Strugatsky, Ryan A. Hollibaugh, Haixia Liu, Peter Tontonoz and Patrick G. Harran

Molecules 2021, 26(24), 7599; https://doi.org/10.3390/molecules26247599 - 15 Dec 2021

Cited by 2 | Viewed by 3173

Abstract

Ghrelin is a 28-residue peptide hormone produced by stomach P/D1 cells located in oxyntic glands of the fundus mucosa. Post-translational octanoylation of its Ser-3 residue, catalyzed by MBOAT4 (aka ghrelin O-acyl transferase (GOAT)), is essential for the binding of the hormone to [...] Read more.

Ghrelin is a 28-residue peptide hormone produced by stomach P/D1 cells located in oxyntic glands of the fundus mucosa. Post-translational octanoylation of its Ser-3 residue, catalyzed by MBOAT4 (aka ghrelin O-acyl transferase (GOAT)), is essential for the binding of the hormone to its receptor in target tissues. Physiological roles of acyl ghrelin include the regulation of food intake, growth hormone secretion from the pituitary, and inhibition of insulin secretion from the pancreas. Here, we describe a medicinal chemistry campaign that led to the identification of small lipopeptidomimetics that inhibit GOAT in vitro. These molecules compete directly for substrate binding. We further describe the synthesis of heterocyclic inhibitors that compete at the acyl coenzyme A binding site. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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16 pages, 2621 KiB

Open AccessArticle

Total Synthesis of Decahydroquinoline Poison Frog Alkaloids ent-cis-195A and cis-211A

by Takuya Okada, Naizhen Wu, Katsuki Takashima, Jungoh Ishimura, Hiroyuki Morita, Takuya Ito, Takeshi Kodama, Yuhei Yamasaki, Shin-ichi Akanuma, Yoshiyuki Kubo, Ken-ichi Hosoya, Hiroshi Tsuneki, Tsutomu Wada, Toshiyasu Sasaoka, Takahiro Shimizu, Hideki Sakai, Linda P. Dwoskin, Syed R. Hussaini, Ralph A. Saporito and Naoki Toyooka

Molecules 2021, 26(24), 7529; https://doi.org/10.3390/molecules26247529 - 12 Dec 2021

Cited by 5 | Viewed by 4048

Abstract

The total synthesis of two decahydroquinoline poison frog alkaloids ent-cis-195A and cis-211A were achieved in 16 steps (38% overall yield) and 19 steps (31% overall yield), respectively, starting from known compound 1. Both alkaloids were synthesized from [...] Read more.

The total synthesis of two decahydroquinoline poison frog alkaloids ent-cis-195A and cis-211A were achieved in 16 steps (38% overall yield) and 19 steps (31% overall yield), respectively, starting from known compound 1. Both alkaloids were synthesized from the common key intermediate 11 in a divergent fashion, and the absolute stereochemistry of natural cis-211A was determined to be 2R, 4aR, 5R, 6S, and 8aS. Interestingly, the absolute configuration of the parent decahydroquinoline nuclei of cis-211A was the mirror image of that of cis-195A, although both alkaloids were isolated from the same poison frog species, Oophaga (Dendrobates) pumilio, from Panama. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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Review

Jump to: Research

24 pages, 3323 KiB

Open AccessEditor’s ChoiceReview

Pyrazine and Phenazine Heterocycles: Platforms for Total Synthesis and Drug Discovery

by Robert W. Huigens III, Beau R. Brummel, Srinivasarao Tenneti, Aaron T. Garrison and Tao Xiao

Molecules 2022, 27(3), 1112; https://doi.org/10.3390/molecules27031112 - 7 Feb 2022

Cited by 37 | Viewed by 6906

Abstract

There are numerous pyrazine and phenazine compounds that demonstrate biological activities relevant to the treatment of disease. In this review, we discuss pyrazine and phenazine agents that have shown potential therapeutic value, including several clinically used agents. In addition, we cover some basic [...] Read more.

There are numerous pyrazine and phenazine compounds that demonstrate biological activities relevant to the treatment of disease. In this review, we discuss pyrazine and phenazine agents that have shown potential therapeutic value, including several clinically used agents. In addition, we cover some basic science related to pyrazine and phenazine heterocycles, which possess interesting reactivity profiles that have been on display in numerous cases of innovative total synthesis approaches, synthetic methodologies, drug discovery efforts, and medicinal chemistry programs. The majority of this review is focused on presenting instructive total synthesis and medicinal chemistry efforts of select pyrazine and phenazine compounds, and we believe these incredible heterocycles offer promise in medicine. Full article

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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