Castagnoli-Cushman Reaction Research Articles

Direct assembly of N-sulfamoyl lactam scaffolds bearing a zinc-binding group for inhibiting metalloenzymes based on desymmetrization of sulfamide and the Castagnoli-Cushman reaction

Sulfamide was desymmetrized by a reaction with aldehydes to give N-sulfamoylimines. The latter reagents were successfully introduced into diastereo- and chemoselective transformation with cyclic anhydride using the Castagnoli-Cushman reaction to give unprotected N-sulfamoyl tetrahydroisoquinolonic (THIQ) acids under simple metal-free protocol. Thereby, the first general approach to the direct assembly of six-membered N-sulfamoyl lactams was developed. The synthesized compounds belong to representative, drug-like chemotypes with their well-defined three-dimensional structures and tunable physicochemical properties. In an attempt to probe their pharmacological potential, the newly synthesized lactams were screened against therapeutically relevant human and bacterial carbonic anhydrases, with some derivatives showing low micromolar enzyme inhibitory profiles.

Identification of BACE-1 inhibitors through directed C(sp3)-H activation on 5-oxo-pyrrolidine-3-carboxylic acid derivatives.

Convenient synthesis of stereochemically dense 5-oxo-pyrrolidines was obtained from succinic anyhdride and imines by combining the Castagnoli-Cushman reaction with directed Pd-catalyzed C(sp3)-H functionalization, taking advantage of the developing carboxylic group properly derivatized with 8-aminoquinoline as a directing group. These fully substituted 5-oxopyrrolidines were found to be able to inhibit BACE-1 enzyme with sub-micromolar activity, thanks to the interaction of the key aryl appendage introduced by C(sp3)-H activation within BACE-1 S2' subsite.

One-pot Synthesis of Dihydrodibenzonaphthyridinediones through Sequential Imine Formation/Castagnoli-Cushman Reaction/Reductive Lactamization

A highly efficient telescopic synthesis of a nitrogen-fused heterocycle dihydrodibenzonapthyridinedione has been developed via imine formation, then the Castagnoli-Cushman reaction followed by nitro-reduction and intramolecular lactamization starting from 2-nitrobenzaldehyde, aliphatic/aromatic amines, and homophthalic anhydride. This one-pot stepwise synthesis strategy offers a practical and simple approach to produce structurally diverse dihydrodibenzonaphthyridinediones without isolating intermediates.

Influence of bicyclic anhydride structure on the outcome of the Castagnoli–Cushman reaction

Influence of bicyclic anhydride structure on the outcome of the Castagnoli–Cushman reaction

The Castagnoli-Cushman Reaction.

Since the first reports of the reaction of imines and cyclic anhydrides by Castagnoli and Cushman, this procedure has been applied to the synthesis of a variety of lactams, some of them with important synthetic or biological interest. The scope of the reaction has been extended to the use of various Schiff bases and anhydrides as well as to different types of precursors for these reagents. In recent years, important advances have been made in understanding the mechanism of the reaction, which has historically been quite controversial. This has helped to develop reaction conditions that lead to pure diastereomers and even homochiral products. In addition, these mechanistic studies have also led to the development of new multicomponent versions of the Castagnoli-Cushman reaction that allow products with more diverse and complex molecular structures to be easily obtained.

Synthesis of 3,4-dihydroisoquinolin-1(2H)-one derivatives and their antioomycete activity against the phytopathogen Pythium recalcitrans.

In an effort to exploit the bioactive natural scaffold 3,4-dihydroisoquinolin-1(2H)-one for plant disease management, 59 derivatives of this scaffold were synthesized using the Castagnoli-Cushman reaction. The results of bioassay indicated that their antioomycete activity against Pythium recalcitrans was superior to the antifungal activity against the other 6 phytopathogens. Compound I23 showed the highest in vitro potency against P. recalcitrans with an EC50 value of 14 μM, which was higher than that of the commercial hymexazol (37.7 μM). Moreover, I23 exhibited in vivo preventive efficacy of 75.4% at the dose of 2.0 mg/pot, which did not show significant differences compared with those of hymexazol treatments (63.9%). When the dose was 5.0 mg per pot, I23 achieved a preventive efficacy of 96.5%. The results of the physiological and biochemical analysis, the ultrastructural observation and lipidomics analysis suggested that the mode of action of I23 might be the disruption of the biological membrane systems of P. recalcitrans. In addition, the established CoMFA and CoMSIA models with reasonable statistics in the three-dimensional quantitative structure-activity relationship (3D-QSAR) study revealed the necessity of the C4-carboxyl group and other structural requirements for activity. Overall, the above results would help us to better understand the mode of action and the SAR of these derivatives, and provide crucial information for further design and development of more potent 3,4-dihydroisoquinolin-1(2H)-one derivatives as antioomycete agents against P. recalcitrans.

The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli–Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center

Novel aryl-substituted homophthalic acids were cyclodehydrated to the respective homophthalic anhydrides for use in the Castagnoli-Cushman reaction. With a range of imines, this reaction proceeded smoothly and delivered hitherto undescribed 4-aryl-substituted tetrahydroisoquinolonic acids with remarkable diastereoselectivity, good yields and no need for chromatographic purification. These findings significantly extend the range of cyclic anhydrides employable in the Castagnoli-Cushman reaction and signify access to a novel substitution pattern around the medicinally relevant tetrahydroisoquinolonic acid scaffold.

One-Pot Sequence of Staudinger/aza-Wittig/Castagnoli–Cushman Reactions Provides Facile Access to Novel Natural-like Polycyclic Ring Systems

Realization of the one-pot Staudinger/aza-Wittig/Castagnoli-Cushman reaction sequence for a series of azido aldehydes and homophthalic anhydrides is described. The reaction proceeded at room temperature and delivered novel polyheterocycles related to the natural product realm in high yields and high diastereoselectivity. The methodology has been extended to three other cyclic anhydrides. These further unravel the potential of the Castagnoli-Cushman reaction in generating polyheterocyclic molecular scaffolds.

Conjugates of Iron-Transporting N-Hydroxylactams with Ciprofloxacin.

Screening of a library of novel N-hydroxylactams amenable by the Castagnoli-Cushman reaction identified four lead compounds that facilitated 55Fe transport into P. aeruginosa cells (one of these synthetic siderophores was found to be as efficient at promoting iron uptake as the natural siderophores pyoverdine, pyochelin or enterobactin). Conjugates of the four lead siderophores with ciprofloxacin were tested for antibacterial activity against P. aeruginosa POA1 (wild type) and the ∆pvdF∆pchA mutant strain. The antibacterial activity was found to be pronounced against the ∆pvdF∆pchA mutant strain grown in CAA medium but not for the POA1 strain. This may be indicative of these compounds being ‘Trojan horse’ antibiotics. Further scrutiny of the mechanism of the antibacterial action of the newly developed conjugates is warranted.

A General Approach to Spirocyclic Piperidines via Castagnoli–Cushman Chemistry

AbstractUnsaturated spirocyclic lactams stemming from a variant of the three-component Castagnoli–Cushman reaction successfully underwent hydrogenation to enable access to fully saturated spirocyclic lactams. The subsequent lactam reduction gave rise to 2-spiro piperidine building blocks. The latter can be further elaborated in compound libraries and, on their own, show propensity to activate trace amine-associated­ receptor 1 (TAAR1), an important target for CNS disease.

Trifluoroethanol Promoted Castagnoli-Cushman Cycloadditions of Imines with Homophthalic Anhydride.

Lactams are essential compounds in medicinal chemistry and key intermediates in the synthesis of natural products. The Castagnoli–Cushman reaction (CCR) of homophthalic anhydride with imines is an exciting method for accessing cyclic densely substituted lactam products. Most CCRs need to be catalyzed or heated. Herein, we report a new, efficient, metal and catalyst-free CCR for the synthesis of poly-substituted 3,4-lactams utilizing the unique properties of trifluoroethanol (TFE). This procedure provides high-speed and smooth access to a broad range of densely substituted 3,4-lactams in good yields and a 100% atom-economical fashion.

Synthesis of γ-Sultam-Annelated δ-Lactams via the Castagnoli-Cushman Reaction of Sultam-Based Dicarboxylic Acids.

An unusual type of highly reactive sultam-based dicarboxylic acids and correscponding anhydrides was employed in the Castagnoli-Cushman reaction delivering diastereomerically pure adducts at room temperature. Due to steric congestion, the initial adducts were prone to decarboxylation affording diastereomeric mixtures of bicyclic sultam lactams, separable by HPLC. The choice of a protecting group on the sultam nitrogen atom allows liberation of the NH-sultam, which is not only suitable for further modification but represents a known pharmacophore for carbonic anhydrase inhibition.

New reagent space and new scope for the Castagnoli-Cushman reaction of oximes and 3-arylglutaconic anhydrides.

The Castagnoli-Cushman reaction of oximes, discovered originally for homophthalic anhydride, stimulated the search for other cyclic anhydrides that would be workable in that reaction. Finally, 3-arylglutaconic acid anhydrides were identified as displaying the right reactivity towards a wide range of oximes (including those which did not react with homophthalic anhydride, such as derivatives of aliphatic aldehydes or ketones and substrates with nucleophilic side groups) and delivering, after 18 h at 110 °C in DMSO, β,γ-unsaturated N-hydroxylactam products lacking the carboxylic acid functionality as the result of decarboxylation accompanying the cyclocondensation process. The reaction was found to be scalable to gram quantities of the starting anhydrides. The products were shown to be easily amenable to post-condensational double-bond transposition or reduction. As expected from cyclic hydroxamic acids, the reaction products were shown to bind Fe(III) and Cu(II) ions (selectively out of a panel of 16 metal cations) and potentially serve as fluorescent metal sensors.

Mechanistic Investigation of Castagnoli–Cushman Multicomponent Reactions Leading to a Three-Component Synthesis of Dihydroisoquinolones

The mechanisms for the three- and four-component variants of the Castagnoli-Cushman reaction (CCR) have been investigated. A series of crossover experiments were conducted to probe the structure and reactivity of known amide-acid intermediates for the three- and four-component variants of the CCR (3CR and 4CR, respectively). Control experiments paired with in situ reaction monitoring with infrared spectroscopy for the 4CR align with a mechanism in which amide-acids derived from maleic anhydride can reversibly form free amine and cyclic anhydride. Although this equilibrium is unfavorable, the aldehyde present can trap the primary amine through imine formation and react with the enol form of the anhydride through a Mannich-like mechanism. This detailed mechanistic investigation coupled with additional crossover experiments supports an analogous mechanism for the 3CR and has led to the elucidation of new 3CR conditions with homophthalic anhydride, amines, and aldehydes for the formation of dihydroisoquinolones in good yields and excellent diastereoselectivity. This work represents the culmination of more than a decade of mechanistic speculation for the 3- and 4CR, enabling the design of new multicomponent reactions that exploit this novel mechanism.

Rare cis-configured 2,4-disubstituted 1-alkylpiperidines: synthesized and tested against trace-amine-associated receptor 1 (TAAR1)

Rare cis-configured 2,4-disubstituted 1-alkylpyridines were envisioned as ligands for trace amine associated receptor 1 (TAAR1). They were synthesized in diastereomerically pure form with the decarboxylative Castagnoli–Cushman reac-tion followed by two reduction events. Despite showing no affinity to TAAR1 as was anticipated, these novel, druglike and CNS-focused compounds will be of much utility in sub-sequent lead generation pursuits.

Cover Feature: Three‐Component Castagnoli‐Cushman Reaction of 3‐Arylglutaconic Acid Anhydrides, Carbonyl Compounds, and Ammonium Acetate: a Quick and Flexible Way to Assemble Polysubstituted NH‐δ‐lactams (Eur. J. Org. Chem. 11/2021)

The Cover Feature shows the synthesis of NH-δ-lactams through three-component Castagnoli–Cushman reaction of 3-arylglutaconic anhydrides with carbonyl compound and ammonium acetate. The way chemical building blocks are united to form the desired heterocyclic product is compared to the famous tile-matching Tetris game. More information can be found in the Communication by M. Krasavin et al.

Microwave accelerated Castagnoli-Cushman reaction: Synthesis of novel 6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazines

The Castagnoli-Cushman reaction of various azaindole dicarboxylic acids with imines using acetic anhydride as a dehydrating agent was significantly accelerated by microwave irradiation. The reaction conditions offer a convenient preparation of novel 6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazines in moderate to good yields with good trans stereoselectivity.

Unexpected formal [4 + 2]-cycloaddition of chalcone imines and homophthalic anhydrides: preparation of dihydropyridin-2(1H)-ones.

A series of medicinally important dihydropyridin-2(1H)-ones have been prepared via a novel [4 + 2]-formal cycloaddition reaction of chalcone imines and homophthalic anhydrides, which is a rare example of lactam construction from an imine acting as a four-atom building block. In contrast to previous studies on the reactivity of homophthalic anhydrides towards similar substrates, N-tosyl chalcone imines, we found the possibility of switching chemoselectivity by changing substituents at the nitrogen atom, which leads to the formation of heterocycles instead of the expected carbocycles. This reaction is very similar in appearance to the classic 1,2-addition of cyclic anhydrides to imines, often referred to as the Castagnoli-Cushman reaction, but differs in mechanistic details (representing a 1,4-reaction of imine). The developed atom-economical, stereoselective and catalyst- and chromatography-free protocol provided facile access to 28 structurally diverse heterocyclic products (in up to 88% yield) including synthetically challenging annelated tricyclic and previously unreported pentaaryl-substituted dihydropyridin-2(1H)-ones.

Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds.

During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (trans-1). For the preparation of racemic trans-1, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans-1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-(2R,3R)-1 represents a reference compound for the configurational study of structurally related lactams.

When periphery matters: Enhanced reactivity of 8-oxa-1,4-dithiaspiro[4.5]decane-7,9-dione and 9-oxa-1,5-dithiaspiro[5.5]undecane-8,10-dione in the Castagnoli-Cushman reaction with imines

8-Oxa-1,4-dithiaspiro[4.5]decane-7,9-dione and 9-oxa-1,5-dithiaspiro[5.5]undecane-8,10-dione, cyclic anhydrides formed in situ from the respective dicarboxylic acids in the presence of acetic anhydride, possess an enhanced reactivity and display a broad substrate scope in the Castagnoli-Cushman reaction with imines.