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Natural products are rich sources of interesting scaffolds possessing a plethora of biological activity. With the isolation of the martinella alkaloids in 1995, namely martinelline and martinellic acid, the pyrrolo[3,2-c]quinoline scaffold was discovered. Since then, this scaffold has been found in two additional natural products, viz. incargranine B and seneciobipyrrolidine. These natural products have attracted attention from synthetic chemists both due to the interesting scaffold they contain, but also due to the biological activity they possess. This review highlights the synthetic efforts made for the preparation of these alkaloids and formation of analogues with interesting biological activity.

An efficient ring-closing reaction was developed for the synthesis of spirocyclopropane quinolinediones from 2,2-disubstituted 2-benzoylacetamides in the presence of [bis-(trifluoroacetoxy)iodo]benzene (PIFA). This reaction proceeds at room temperature in the absence of a metal catalyst to provide spirocyclopropane quinolinediones in good to excellent yields. Furthermore, these compounds were readily converted to the corresponding pyrrolo[3,2-c]quinolinones to provide tricyclic ring structures similar to those found in the natural products martinellic acid and martinelline via an intermolecular amine ring-opening cyclization reaction.

A green and efficient solid acid catalyst (SAC) has been synthesized upon modification of F-type fly ash using ortho-phosphoric acid (35 wt. %). Catalyst characterization has been accomplished using different analytical techniques, such as FT-IR, XRD, SEM–EDS, and BET surface area analysis. SAC possessed excellent catalytic activity for Fischer esterification reaction between 4-aminobenzoic acid and methanol at 95 °C to produce methyl 4-aminobenzoate (MAB), an important precursor for the synthesis of pharmaceutical drugs, (±) martinelline, and (±) martinellic acid. This investigation suggests the utilization of fly ash to develop novel solid acid catalyst system for catalyzing industrially important esterification reaction.

An enantioselective total synthesis of martinellic acid is described. The pyrroloquinoline alkaloid core is efficiently prepared from a quinoline, employing a method which relies on a newly developed Cu-catalyzed enantioselective alkynylation using the chiral imidazole-based biaryl P,N ligand StackPhos to establish the absolute stereochemistry. The remaining carbon atoms are then installed by means of a diastereoselective Pd-catalyzed decarboxylative allylation and the synthesis is completed after straightforward functional-group manipulation. This new synthetic method enables the most concise enantioselective synthesis of this important class of molecules to date.

An enantioselective total synthesis of martinellic acid is described. The pyrroloquinoline alkaloid core is efficiently prepared from a quinoline, employing a method which relies on a newly developed Cu-catalyzed enantioselective alkynylation using the chiral imidazole-based biaryl P,N ligand StackPhos to establish the absolute stereochemistry. The remaining carbon atoms are then installed by means of a diastereoselective Pd-catalyzed decarboxylative allylation and the synthesis is completed after straightforward functional-group manipulation. This new synthetic method enables the most concise enantioselective synthesis of this important class of molecules to date.

International audience; Three become one: Phosphoric acid-catalyzed enantioselective three-component Povarov reactions of aldehydes, anilines, and endocyclic enethioureas have been developed. This process afforded hexahydropyrroloquinolines in high yields with excellent diastereo- and enantioselectivities. The presence of the thiourea functionality is crucial for the enantioselectivity of the reaction.

[EN] The feasibility of an electron transfer imino-Diels Alder reaction betweenN-benzylideneaniline and arylalkenes in the presence of a pyrylium salt as a photosensitizer has been demonstrated by a combination of product studies, laser flash photolysis (LFP), and DFT theoretical calculations. A stepwise mechanism involving two intermediates and two transition states is proposed., Financial support from the MICINN (Grants CTQ2010-14882, CTQ2009-13699, CTQ2009-11027, and JCI-2010-06204) and from the UPV (Grant No. 20100994 and MCI Program) is gratefully acknowledged. Dedicated to Prof. Dr. Jaime Primo (Universidad Politecnica de Valencia) on the occasion of his 60th birthday.

An efficient approach for the synthesis of pyrrolo[3,2-c]quinolines (the core nucleus of the natural product martinellic acid) from protected 2-alkynylanilines via the regioselective formation of pyrroles followed by Heck and intramolecular Michael addition has been described.

The martinelline chiral core 3 and its diastereomer were synthesized by using the asymmetric tandem Michael–aldol reaction as the key step from 4-methoxycarbonylanthranilaldehyde and the α,β-unsaturated aldehyde.

A concise formal synthesis of (-)-martinellic acid has been accomplished by preparing optically active dipyrroloquinoline as a key synthetic intermediate, which was prepared via the radical addition-cyclization-elimination of oxime ether carrying an unsaturated ester followed by two chemoselective reductions of the carbonyl groups.

The simple and one-pot method for the synthesis of polysubstituted tetrahydroquinolines from readily available anilines and aldehydes under reagent-free conditions has been developed. The scope of the transformation has been demonstrated. This method has been successfully applied to the rapid formal synthesis of (±)-martinellic acid and martinelline.

Asymmetric syntheses of (—)-martinellic acid (I) and (—)-4-epi-martinellic acid (II) are achieved in a multistep procedure from commercially available starting materials using a diastereodivergent strategy.

Formal [4+2] cycloaddition of cyclic enamides with imines derived from aromatic amines gave the 4-arylhexahydropyrroloquinoline skeleton in one step as mixtures of diastereoisomers. Aromatic imines derived from formaldehyde and methylglyoxalate also participated in this chemistry, with the latter favouring formation of the endo -cycloadduct. The cycloadducts derived from methylglyoxalate were unstable and fragmented to give highly substituted quinolines under both neutral and basic conditions. Imines derived from 3-cyanoacrolein also underwent cycloaddition and gave an advanced potential precursor to martinellic acid, albeit with poor diastereoselectivity.

Hindered guanidines can be prepared by reaction of cyanamides with amines in hexafluoroisopropanol at 90–120°C. This sequence was used for preparing guanidinium acid 21 as a model for martinellic acid.

A simple method is elaborated for the preparation of tetrahydroquinolines (III) from anilines (I) and aldehydes (II).

The tricyclic core of the martinellines has been synthesised stereoselectively in two steps, using 1,3-dipolar cycloaddition of azomethine ylides as a key step.

The tricyclic triamine core27 of martinellic acid (2) has been prepared stereospecifically in eight steps from 2-hydroxymethylaniline in 11% overall yield. The key steps are the addition of 2-hydroxymethylaniline to vinylcyclopropane14 to prepare cycloaddition precursor19 in only two steps and an intramolecular [3+2] azomethine ylide cycloaddition reaction to produce tetracycle20 with>9:1 diastereoselectivity. Download : Download full-size image

An expedient method for the assembly of the pyrroloquinoline skeleton found in the martinelline alkaloids using a [3+2] cycloaddition of an azomethine ylide and an alkene has been developed.

Herein, we describe the first asymmetric total synthesis of (-)-martinelline ((-)-2) and the second total synthesis of (-)-martinellic acid ((-)-1) by employing a tandem Mukaiyama-Mannich reaction/aminal cyclization as the key step.

Radical cyclisation of the N-(2′-iodophenyl)pyrrole-3-carboxamides 5 and 6 gave the tricyclic pyrrolo [3,2-c]quinolone ring system found in the recently isolated martinelline 1 and martinellic acid 2.

[reaction: see text] The first total synthesis of martinellic acid, a naturally occurring bradykinin receptor antagonist, via a CuI-catalyzed coupling reaction of beta-amino ester 6 with 1,4-diiodobenzene and a guanylation reaction of secondary amine 3 under mild conditions as key steps, is described.

Radical cyclisation of the N-(2′-iodophenyl)pyrrole-3-carboxamides 5 and 6 gave the tricyclic pyrrolo [3,2-c]quinolone ring system found in the recently isolated martinelline 1 and martinellic acid 2.

An expedient method for the assembly of the pyrroloquinoline skeleton found in the martinelline alkaloids using a [3+2] cycloaddition of an azomethine ylide and an alkene has been developed.

The tricyclic triamine core27 of martinellic acid (2) has been prepared stereospecifically in eight steps from 2-hydroxymethylaniline in 11% overall yield. The key steps are the addition of 2-hydroxymethylaniline to vinylcyclopropane14 to prepare cycloaddition precursor19 in only two steps and an intramolecular [3+2] azomethine ylide cycloaddition reaction to produce tetracycle20 with>9:1 diastereoselectivity. Download : Download full-size image

Hindered guanidines can be prepared by reaction of cyanamides with amines in hexafluoroisopropanol at 90–120°C. This sequence was used for preparing guanidinium acid 21 as a model for martinellic acid.

Formal [4+2] cycloaddition of cyclic enamides with imines derived from aromatic amines gave the 4-arylhexahydropyrroloquinoline skeleton in one step as mixtures of diastereoisomers. Aromatic imines derived from formaldehyde and methylglyoxalate also participated in this chemistry, with the latter favouring formation of the endo -cycloadduct. The cycloadducts derived from methylglyoxalate were unstable and fragmented to give highly substituted quinolines under both neutral and basic conditions. Imines derived from 3-cyanoacrolein also underwent cycloaddition and gave an advanced potential precursor to martinellic acid, albeit with poor diastereoselectivity.

Arylthio-substituted succinic anhydrides undergo cycloaddition reactions with imines to produce gamma-lactams in high yield and with high diastereoselectivity. The origin of the selectivity is proposed to result from anion-pi repulsion in the transition state. The utility of this technique is demonstrated in a synthesis of the carbon framework common to the alkaloids martinellic acid and martinelline in five steps.

A concise formal total synthesis of the pyrrolo[3,2-c]quinoline containing natural product, martinellic acid, has been achieved from a pyrroloquinol-2-one through addition of a copper acetylide to an iminium ion. Global deprotection and alkyne reduction then provides the tricyclic triamine, which can be converted to martinelline and martinellic acid.

[reaction: see text] A concise synthesis of the guanidine alkaloids, (+/-)-martinelline and (+/-)-martinellic acid, using a protic acid catalyzed 2:1 hetero Diels-Alder coupling reaction between N-Cbz 2-pyrroline and methyl 4-aminobenzoate, is described. Protic acid catalysis, rather than Lewis acid catalysis, was necessary to achieve the desired sense of diastereocontrol in the coupling reaction.

Background Candida susceptibility commonly occurs in breast cancer patients. Of which, Candida albicans is considered as a common pathogen causing candidiasis. Martinella iquitosensis (Bignoniaceae) is one of the species belonged to Martinella, distributed widely in Amazon basin. Its root extract yielded two complex substituted tetrahydroquinolines, Martinelline and Martinellic acid which were the first natural non-peptide bradykinin receptor antagonists identified. Findings In this study, a novel martinelline type analogue, named 2,3,3a,4,5,9b-hexahydro-8-phenoxy-4-(pyridin-2-yl)furo[3,2-c]quinoline, was synthesized and its preliminary anticancer activity and antifungal potential were investigated. This compound showed potential anticancer activity against MDAMB-231 breast cancer cells. Meanwhile it could enhance the fungistatic activity of miconazole against Candida albicans. Conclusions These findings provide an implication for the continue investigation and development of martinelline type analogues as therapeutic agents in the future.