Spirocyclic Motif Research Articles

Base-Mediated Divergent Synthesis of Spiro-heterocycles Using Pronucleophiles and Ethylene via Thianthrenation.

Spirocyclic compounds are abundant in biologically active products. However, the divergent synthesis of spirocyclic compounds using low-cost and abundant available starting materials remains a challenge. Herein, we report an effective method for producing spirocyclic motifs using a cyclic β-carbonyl ester or amide and ethylene via thianthrenation. This strategy highlights the exciting possibility of utilizing abundant ethylene as a C-2 synthon and allows regulating the core structure of the spirocyclic compound by simply altering the base type.

Isolable Spirocyclic Silylone: π-Delocalized Spiro[3.3]heptasila-2,6-diylidone.

Strained cyclic tetrylones are important synthons due to various synthetic applications. Connecting two cyclic tetrylone rings through a single shared quaternary group 14 element atom to form a spirocyclic molecule has been unexplored both theoretically and experimentally. The formation of a spirocyclic motif has been a synthetic challenge. In contrast, the reaction of amidinato disilicon(I) 1, (Me3P)2SiCl4, and KC8 afforded π-delocalized spiro[3.3]heptasila-2,6-diylidone2 and tetrasilacyclobutadiene byproducts 3 and 4. Compound 2 is the smallest spirocyclic tetrylone derivative, which is composed of a σ-type lone pair and delocalized π bond in each all-silicon spirocyclic ring. The electronic property is supported by its coordination with a W(CO)5 moiety.

Enantioselective Phase-Transfer-Catalyzed Synthesis of Spirocyclic Azetidine Oxindoles.

Spiro-3,2'-azetidine oxindoles combine two independently important pharmacophores in an understudied spirocyclic motif that is attractive for medicinal chemistry. Here, the enantioselective synthesis of these structures is achieved in up to 2:98 er through intramolecular C-C bond formation, involving activation of the substrate with a novel SF5-containing chiral cation phase-transfer (PT) catalyst. The products are readily elaborated/deprotected to afford medicinally relevant enantioenriched compounds. Control experiments suggest an interfacial PT mechanism, whereby catalytic asymmetric induction is achieved through the activation of the chloride leaving group.

Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 2.

Applications of piperazine and homopiperazine in drug design are well-established, and these heterocycles have found use as both scaffolding and terminal elements and also as a means of introducing a water-solubilizing element into a molecule. In the accompanying review (10.1021/acs.jafc.2c00726), we summarized applications of piperazine and homopiperazine and their fused ring homologues in bioactive compound design along with illustrations of the use of 4-substituted piperidines and a sulfoximine-based mimetic. In this review, we discuss applications of pyrrolidine- and fused-pyrrolidine-based mimetics of piperazine and homopiperazine and illustrate derivatives of azetidine that include stretched and spirocyclic motifs, along with applications of a series of diaminocycloalkanes.

Asymmetric Organocatalytic Synthesis of aza‐Spirocyclic Compounds from Isothiocyanates and Isocyanides

AbstractThe spirocyclic motif is present in natural products, chiral ligands, and compounds of pharmacological interest. Isothiocyanates as well as isocyanides bearing electron‐withdrawing groups in the α‐position can be deprotonated and react as formal dipoles on account of the presence of a nucleophilic carbanion and an electrophilic atom in the isothiocyanate or isocyanide functional groups. In the last years a number of procedures involving the formal [3+2] cycloaddition reaction of isothiocyanates or isocyanides with cyclic compounds bearing electrophilic exocyclic double bonds have been developed for the enantioselective synthesis of aza‐spirocyclic compounds. Among them, organocatalysis has played a predominant role in the development of asymmetric versions for these reactions. The synthesis of spirooxindoles by using this methodology has received especial attention, although other spirocyclic scaffolds are available depending on the structure of the dipolarophiles and the formal isothiocyanate and isocyanide dipoles.

Synthetic Strategies to Access Heteroatomic Spirocentres Embedded in Natural Products

AbstractThe spirocyclic motif is abundant in natural products and provides an ideal three-dimensional template to interact with biological targets. With significant attention historically expended on the synthesis of flat-heterocyclic compound libraries, methods to access the less-explored three-dimensional medicinal-chemical space will continue to increase in demand. Herein, we highlight by reaction class the common strategies used to construct the spirocyclic centres embedded in a series of well-studied natural products.1 Introduction2 Cycloadditions3 Palladium-Catalysed Coupling Reactions4 Conjugate Additions5 Imines, Aminals, and Hemiaminal Ethers6 Mannich-Type Reactions7 Oxidative Dearomatisation8 Alkylation9 Organometallic Additions10 Conclusions

Recent Advances in Stereoselective Ring Expansion of Spirocyclopropanes: Access to the Spirocyclic Compounds.

Spirocyclopropane represents a privileged structural scaffold for accessing synthetic libraries of densely functionalized spirocarbo- and heterocyclic compounds. Due to the ubiquity of spirocyclic motifs as a potent pharmacophore in natural products and pharmaceuticals, recent years have witnessed significant advances in developing synthetic strategies that exploits carbon–carbon bond scission in spirocyclopropanes. This paper summarizes the recent developments in stereoselective ring expansion of spirocyclopropanes in diversity-oriented synthesis and highlights the synthetic as well as mechanistic rationale of those methodologies. This review also encompasses the applicability of the protocols in bioactive natural product syntheses.

Three-Component Reaction of Homophthalic Anhydride with Carbonyl Compounds and Ammonium Acetate: New Developments

The earlier described reaction of homophthalic anhydrides with aromatic ketones and ammonium acetate was tested for cyclic ketones (yielding spirocyclic motifs) and aliphatic aldehydes. In contrast to previous findings, the reaction was found to require no catalyst at all and to be applicable, in the non-catalyzed format, to these new carbonyl substrates as well as aromatic ketones. The reaction typically proceeds with high diastereoselectivity; if not, the initial diastereomeric mixture can be quantitatively equilibrated into a single, trans-diastereomer on treatment with aqueous base.

Spirocyclic Motifs in Natural Products.

Spirocyclic motifs are emerging privileged structures for drug discovery. They are also omnipresent in the natural products domain. However, until today, no attempt to analyze the structural diversity of various spirocyclic motifs occurring in natural products and their relative populations with unique compounds reported in the literature has been undertaken. This review aims to fill that void and analyze the diversity of structurally unique natural products containing spirocyclic moieties of various sizes.

Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold.

With the discovery that serine hydroxymethyltransferase (SHMT) is a druggable target for antimalarials, the aim of this study was to design novel inhibitors of this key enzyme in the folate biosynthesis cycle. Herein, 19 novel spirocyclic ligands based on either 2-indolinone or dihydroindene scaffolds and featuring a pyrazolopyran core are reported. Strong target affinities for Plasmodium falciparum (Pf) SHMT (14-76 nm) and cellular potencies in the low nanomolar range (165-334 nm) were measured together with interesting selectivity against human cytosolic SHMT1 (hSHMT1). Four co-crystal structures with Plasmodium vivax (Pv) SHMT solved at 2.2-2.4 Å resolution revealed the key role of the vinylogous cyanamide for anchoring ligands within the active site. The spirocyclic motif in the molecules enforces the pyrazolopyran core to adopt a substantially more curved conformation than that of previous non-spirocyclic analogues. Finally, solvation of the spirocyclic lactam ring of the receptor-bound ligands is discussed.

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long-chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly’s drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC50=55nM) was reached. Four lead compounds (EC50 range 55–410nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F=10.3%) and plasma levels achieved on oral administration.

Spirocyclic chromanes exhibit antiplasmodial activities and inhibit all intraerythrocytic life cycle stages

We screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile. We have performed a limited structure-activity-relationship study with commercially available chromanes preserving the spirocyclic motif. Our evaluation of stage specificities of UCF 201 indicated that the compound is early-acting in blocking parasite development at ring, trophozoite and schizont stages of development as well as merozoite invasion. SPC is an attractive lead candidate scaffold because of its ability to act on all stages of parasite's aexual life cycle unlike current antimalarials.

ChemInform Abstract: Diastereoselective Synthesis of Quinolizidin‐4‐one and Indolizidin‐3‐one Derivatives with a Spirocyclic Motif via Cascade Cyclization Using a Gold(I)/Broensted Acid Relay Catalysis.

ChemInform Abstract: Diastereoselective Synthesis of Quinolizidin‐4‐one and Indolizidin‐3‐one Derivatives with a Spirocyclic Motif via Cascade Cyclization Using a Gold(I)/Broensted Acid Relay Catalysis.

Diastereoselective synthesis of quinolizidin-4-one and indolizidin-3-one derivatives with a spirocyclic motif via cascade cyclization using a gold(I)/Brønsted acid relay catalysis

Functionalized quinolizidin-4-ones and indolizidin-3-ones were synthesized from mixed N,O-acetals with a terminal alkyne unit and nucleophiles with two reactive sites by a gold(I)/Brønsted acid relay catalysis with 40–90% yield. The reactions are proposed to proceed through gold-catalyzed carboalkoxylation of the alkynes with the internal mixed N,O-acetals, giving the corresponding cyclic enols, which are transformed to spirocyclic compounds by a Brønsted acid catalyst. The latter spirocyclization process occurs under thermodynamic control, providing polycyclic quinolizidin-4-one and indolizidin-3-one derivatives diastereoselectively.

Chemoenzymatic route to various spirocyclic compounds based on enantiomerically enriched tertiary allylic, homoallylic, and homopropargylic alcohols

A ring closing metathesis (RCM) reaction of dienes and an intramolecular Pauson–Khand (PKR) reaction of enynes derived from tertiary allyl, homoallyl, and homopropargyl alcohol backbones to afford the corresponding spirocyclic dihydrofuran and dihydropyrans and spirocyclic cyclopentenone pyrans, respectively, are described. Cyclopent-2-ene anchored tertiary allyl, homoallyl, and homopropargyl alcohols 1a–c have been efficiently resolved via enzymatic resolution with high ee (up to 90%) with 44%, 40%, and 43% chemical yields, respectively. Moreover, the cyclohex-2-ene anchored tertiary allyl, homoallyl, and homopropargyl alcohols 3a–c have also been resolved in the same manner with high ee (up to 97%) and in 42%, 45%, and 49% chemical yields. Enantiomerically enriched dienes derived from tertiary homoallyl alcohols yield the corresponding enantiomerically enriched spirocyclic dihydropyran derivatives via RCM with 74% and 78% chemical yields and with 90% and 97% ee, respectively. Moreover, enantiomerically enriched enynes derived from tertiary homoallyl alcohols afford the corresponding enantiomerically enriched cyclopentenone pyrans with spirocyclic motifs via PKR with 80% and 81% chemical yields, respectively, and as single diastereomers.