Utilizing Allenic Acids and Heterocyclic Diazo Compounds in the Synthesis of Polysubstituted Spirocyclic Butenolides and ß-Methylidene 2-Furanones.

Herein, we report a novel approach for the assembly of spirocyclic Δα,ß-butenolides and ß-methylidene 2-furanones via Rh(II)-catalyzed O-H insertion of heterocyclic diazo compounds into allenic acids followed by base-promoted cyclization. Utilizing various diazo heterocycles, including α-diazo homophthalimides, 3-diazo tetramic acids, and diazo oxindoles, diverse spirocyclic scaffolds were produced. The research revealed that the allenic acid substitution pattern is decisive for the product type, enabling extraordinary target compound switching between two types of spirocyclic 2-furanones with exo- and endocyclic C═C bonds.

Access to Spiro Bis-ß-lactams via a Metal-Free Microwave-Assisted Wolff Rearrangement/Staudinger [2+2] Cycloaddition Cascade Involving 3-Diazotetramic Acids and Imines.

Herein, we report the study of the thermally promoted reaction of 3-diazotetramic acids with imines as a rapid route to a novel spiro heterocyclic scaffold, spiro bis-ß-lactams (2,6-diazaspiro[3.3]heptane-1,5-diones). The transformation proceeds via metal-free microwave-assisted Wolff rearrangement of the diazo reagent followed by Staudinger [2+2] cycloaddition of the heterocyclic ketenes with Shiff bases. This methodology enables the preparation of diastereomerically pure spiro bis-ß-lactams in high yields and provides an avenue for exploring new versions of the privileged ß-lactam core for drug design.

Phosphorescent Cyclometalated Palladium(II) and Platinum(II) Complexes Derived from Diaminocarbene Precursors.

Metal-mediated self-assembly of isocyanides and methyl 4-aminopyrimidine-5-carboxylate leads to luminescent PdII and PtII complexes featuring C,N-cyclometalated acyclic diaminocarbene (ADC) ligands. The solid-state luminescent properties of these diaminocarbene derivatives are attributed to their triplet-state metal/metal-to-ligand charge-transfer (3MMLCT) nature, which is driven by attractive intermolecular M···M interactions further reinforced by the intramolecular π-π interactions even in the structure of the Pd compound, which is the first Pd-ADC phosphor reported.

Imines with rare α-heteroatom substituted amine components generated in situ via the Staudinger/aza-Wittig tandem reaction and their application in multicomponent reactions.

A series of structurally diverse α-heteroatom substituted methyl azides (XCH2N3, where X = phthalimidoyl, benzotriazolyl, arylsulfanyl, aryloxy, alkoxy) have been prepared and evaluated for the in situ generation of imines via the Staudinger/aza-Wittig tandem reaction with aldehydes and triphenylphosphine. The obtained imines were successfully introduced into four types of multicomponent reactions: the Staudinger ß-lactam synthesis with diazo carbonyl compounds, the Castagnoli-Cushman reaction with cyclic anhydrides, and the Ugi and azido-Ugi reactions with isocyanides and carboxylic acids or TMS-azides. These transformations allowed the preparation of four-to-seven-membered lactams, acyclic bisamides and 5-(aminomethyl)-1-alkyltetrazoles with a complex and previously poorly accessible periphery. Moreover, it was demonstrated that phthalimide derivatives can be deprotected to afford medicinally relevant N-aminomethyl lactams.

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O-H insertion/base-promoted cyclization involving diazoarylidene succinimides.

A facile approach to novel medicinally relevant spiro heterocyclic scaffolds (namely furan-2(5H)-ones, tetrahydrofurans and pyrans spiro-conjugated with the succinimide ring) has been developed. The protocol consists of Rh(II)-catalyzed insertion of heterocyclic carbenes derived from diazoarylidene succinimides (DAS) into the O-H bond of propiolic/allenic acids or brominated alcohols, followed by base-promoted cyclization to afford the target spirocyclic compounds in good to high yields.

Diazo Tetramic Acids Provide Access to Natural-Like Spirocyclic Δα,ß-Butenolides through Rh(II)-Catalyzed O-H Insertion/Base-Promoted Cyclization.

3-Diazotetramic acids were found to be valid substrates for the recently discovered approach toward natural-like Δα,ß-spirobutenolides via Rh(II)-catalyzed O-H insertion into propiolic acids followed by base-promoted intramolecular Michael addition. The target Δα,ß-spirobutenolides were obtained in generally high yields and, in the case of chiral 5-monosubstituted 3-diazotetramic acids, high diastereoselectivity. The synthesis of Δα,ß-spirobutenolides that we report here was virtually insensitive to the structure of the propiolic acids though it was somewhat sensitive to the structure of the 3-diazotetramic acids, thereby demonstrating quite a large scope. Thus, a new class of α-diazocarbonyl compounds suitable for the realization of the approach outlined above was identified.

Chemo- and Diastereoselective Entries into All-Carbon α-Quaternary Aldehydes via C-C Insertion of 4-Diazoisoquinolin-3-ones into C-CHO Bonds.

Herein, we describe a chemo- and diastereoselective formal C-C insertion reaction of 1,2-disubstituted 4-diazo-3(2H)-isoquinolones and 4-diazoisochroman-3-one into C-CHO bonds of aldehydes, delivering all-carbon α-quaternary aldehydes bearing medicinally important 1,4-dihydro-3(2H)-isoquinolone scaffold. Our protocol is enabled by the preferential 1,2-carbon migration over more common 1,2-H shift. The corresponding reaction tolerates a wide range of functionalities in both aldehyde and diazo components, giving the target homologated aldehydes in generally high yields. The synthetic utility of this method has been further showcased by some transformations of the formyl moiety.

Substrate-Controlled Three-Component Synthesis of Diverse Fused Heterocycles.

A chemoselective strategy toward a variety of fused heterocyclic scaffolds relying on a three-component condensation of heterocyclic ketene aminals (HKAs) or corresponding thioaminals with aryl glyoxals and cyclic 1,3-dicarbonyl compounds has been developed and explored. Depending on the applied combination of substrates, the strategy can be tuned to provide straightforward access to imidazo[1,2-a]quinoline, pyrrolo[1,2-a]imidazole, and pyrrolo[2,1-b]thiazole frameworks.

Synthetic Routes to Approved Drugs Containing a Spirocycle.

The use of spirocycles in drug discovery and medicinal chemistry has been booming in the last two decades. This has clearly translated into the landscape of approved drugs. Among two dozen clinically used medicines containing a spirocycle, 50% have been approved in the 21st century. The present review focuses on the notable synthetic routes to such drugs invented in industry and academia, and is intended to serve as a useful reference source of synthetic as well as general drug information for researchers engaging in the design of new spirocyclic scaffolds for medicinal use or embarking upon analog syntheses inspired by the existing approved drugs.

Facile access to 3-sulfonylquinolines via Knoevenagel condensation/aza-Wittig reaction cascade involving ortho-azidobenzaldehydes and ß-ketosulfonamides and sulfones.

Quinoline-based sulfonyl derivatives, and especially sulfonamides, are relevant and promising structures for drug design. We have developed a new convenient protocol for the synthesis of 3-sulfonyl-substituted quinolines (sulfonamides and sulfones). The approach is based on a Knoevenagel condensation/aza-Wittig reaction cascade involving o-azidobenzaldehydes and ketosulfonamides or ketosulfones as key building blocks. The protocol is appropriate for both ketosulfonyl reagents and α-sulfonyl-substituted alkyl acetates providing the target quinoline derivatives in good to excellent yields.

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N-H insertion reaction.

A technique has been proposed for incorporating a heterocyclic component into a glutarimide framework employing a Rh2(esp)2-catalyzed N-H insertion with the involvement of N-Boc-α-diazo glutarimide. The new diazo reagent is more stable, soluble and convenient to prepare than the previously suggested one. The approach permits the application of diverse heterocycles, including both aromatic and saturated NH-substrates. This yields structures that are appealing for generating cereblon ubiquitin-ligase ligands and for potential use in crafting PROTAC molecules.

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.

Multicomponent Assembly of Trisubstituted Imidazoles and Their Photochemical Cyclization into Fused Polyheterocyclic Scaffolds.

A straightforward route to a large and diverse library of trisubstituted imidazoles was established via a three-component reaction of 2-oxoaldehydes, 1,3-dicarbonyl compounds, and acyclic nitrogen bis-nucleophiles. The obtained products were subsequently explored in a photochemical cyclization yielding a variety of imidazole-fused polycyclic compounds.

In situ generation of imines by the Staudinger/aza-Wittig tandem reaction combined with thermally induced Wolff rearrangement for one-pot three-component ß-lactam synthesis.

A new efficient protocol for diastereoselective three-component one-pot lactam synthesis involving the in situ generation of imines via the Staudinger/aza-Wittig tandem reaction combined with the Wolff-rearrangement and ketene-imine cycloaddition was developed to produce a series of 24 novel structurally diverse ß-lactam- or 1,3-oxazine-products. It was shown that this synthesis can be performed both as a two step-procedure and true MCR with simultaneous loading of all reactants. The intramolecular version of the 1st step provided facile access to seven-membered cyclic imines, which allowed further preparation of a series of rare tricyclic ß-lactams. For the intermolecular version of the 1st step (acyclic imine generation), it was shown that the outcome of the synthesis is different from that using pre-synthesized and isolated imines. Additionally, this is the first example of the implementation of the Staudinger/aza-Wittig tandem reaction for the preparation of four-membered heterocycles.

Replacing the phthalimide core in thalidomide with benzotriazole.

The advent of proteolysis-targeting chimaeras (PROTACs) mandates that new ligands for the recruitment of E3 ligases are discovered. The traditional immunomodulatory drugs (IMiDs) such as thalidomide and its analogues (all based on the phthalimide glutarimide core) bind to Cereblon, the substrate receptor of the CRL4ACRBN E3 ligase. We designed a thalidomide analogue in which the phthalimide moiety was replaced with benzotriazole, using an innovative synthesis strategy. Compared to thalidomide, the resulting "benzotriazolo thalidomide" has a similar binding mode, but improved properties, as revealed in crystallographic analyses, affinity assays and cell culture.

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.

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.

Extending the Scope of the New Variant of the Castagnoli-Cushman Cyclocondensation onto o-Methyl Benzoic Acids Bearing Various Electron-Withdrawing Groups in the α-Position.

Based on the previously reported involvement of homophthalic acid monoesters in the Castagnoli-Cushman reaction-type cyclocondensation with imines, we tested a number of other o-methyl benzoic acids bearing various electron-withdrawing groups in the α-position. The majority of these substrates delivered the expected tetrahydroisoquinolone adducts on activation with CDI or acetic anhydride. Homophthalic acid mononitriles displayed the highest promise as substrates for the new reaction, both in terms of scope and product yields. Homophthalic acid monoamides either gave low yields or failed to react with imines. Sulfonyl-substituted substrates gave the desired (and hitherto unknown) type of tetrahydroisoquinolines. Despite the low yields, this approach to sulfonyl-substituted tetrahydroisoquinolines appears practical as alternative syntheses based on the traditional, carboxylic acid CCR adducts would presumably be cumbersome and multistep. The azido- and nitro-substituted o-methyl benzoic acids failed to react with imines.

Preparation and Synthetic Applications of Five-to-Seven-Membered Cyclic α-Diazo Monocarbonyl Compounds.

The reactivity of cyclic α-diazo monocarbonyl compounds differs from that of their acyclic counterparts. In this review, we summarize the current literature available on the synthesis and synthetic applications of three major classes of cyclic α-diazo monocarbonyl compounds: α-diazo ketones, α-diazo lactones and α-diazo lactams.

Dicarboxylic Acid Monoesters in ß- and δ-Lactam Synthesis.

A N-(2-methoxy-2-oxoethyl)-N-(phenylsulfonyl)glycine monomethyl ester of the respective dicarboxylic acid was involved in a reaction with imines promoted by acetic anhydride at an elevated temperature. Instead of the initially expected δ-lactam products of the Castagnoli-Cushman-type reaction, medicinally important 3-amino-2-azetidinones were obtained as the result of cyclization, involving a methylene group adjacent to an acid moiety. In contrast, replacing alcohol residue with hexafluoroisopropyl in the same substrate made another methylene group (adjacent to the ester moiety) more reactive to furnishing the desired δ-lactam in the Castagnoli-Cushman fashion.