Enantioselective Synthesis of Spiro Heterocyclic Compounds Using a Combination of Organocatalysis and Transition-Metal Catalysis.

Over the last ten years, the combination of organocatalysis with transition metal (TM) catalysis has become one of the most important toolboxes used for synthesizing optically pure compounds containing chiral quaternary centers, including spiro heterocyclic molecules. The dominant method in the enantioselective synthesis of spiro heterocyclic compounds based on synergistic catalysis includes chiral aminocatalysis and NHC catalysis, as already established covalent organocatalytic strategies. Another area of organocatalysis widely combined with TM catalysis producing enantiomerically enriched spiro heterocyclic compounds is non-covalent catalysis, dominated by chiral phosphoric acids, thiourea, and squaramide derivatives. This review article aims to summarize enantioselective methods used for constructing spirocyclic heterocycles based on a combination of organocatalysis and transition metal catalysis.

Catalytic asymmetric addition to cyclic N-acyl-iminium: access to sulfone-bearing contiguous quaternary stereocenters.

Herein, we report the first chiral phosphoric acid (CPA)-catalyzed asymmetric addition of α-fluoro(phenylsulfonyl)methane (FSM) derivatives to in situ generated cyclic N-acyliminium. This process enables metal-free expeditious access to sulfone and fluorine incorporating contiguous all substituted quaternary stereocenters ingrained in biorelevant isoindolinones in excellent stereoselectivities (up to 99% ee and up to 50 : 1 dr).

Enantioselective PCCP Brønsted acid-catalyzed aminalization of aldehydes.

Here we present an enantioselective aminalization of aldehydes catalyzed by Brønsted acids based on pentacarboxycyclopentadienes (PCCPs). The cyclization reaction using readily available anthranilamides as building blocks provides access to valuable 2,3-dihydroquinazolinones containing one stereogenic carbon center with good enantioselectivity (ee up to 80%) and excellent yields (up to 97%).

Synthesis of cis-Oriented Vicinal Diphenylethylenes through a Lewis Acid-Promoted Annulation of Oxotriphenylhexanoates.

This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoates. The reaction is a BBr3-promoted cyclization of 1,6-ketoesters (1) to five-membered diketo compounds (2). The synthesis is interesting as it constitutes one of the few examples of modular stereoselective synthesis of structures with a cis-oriented vicinal diphenylethylene. The core structure of 2 can be smoothly derivatized, which makes it a promising synthetic building block for further stereoselective synthetic applications.

Polycyclizations of Ketoesters: Synthesis of Complex Tricycles with up to Five Stereogenic Centers from Available Starting Materials.

Here we present a polycyclization of oxotriphenylhexanoates. The polycyclization is governed by electronic effects, and three major synthetic paths have been established leading to stereochemically complex tricyclic frameworks with up to five stereogenic centers. The method is compatible with an array of functional groups, allowing pharmacophoric elements to be introduced post cyclization.

Formal [3+2] cycloaddition of vinylcyclopropane azlactones to enals using synergistic catalysis.

The present study reports the asymmetric cyclization of enals with vinylcyclopropane azlactones efficiently catalyzed by the combination of achiral Pd(0) complexes and chiral secondary amines. Corresponding spirocyclic azlactones were produced in high yields with moderate diastereoselectivities and excellent enantioselectivities. This protocol provides an efficient and easily-performed route to spirocyclic scaffolds, and densely functionalized cyclopentanes containing quaternary carbon centers.

Synergistic formal ring contraction for the enantioselective synthesis of spiropyrazolones.

The rapid generation of molecular complexity from simple reactants is a key challenge in organic synthesis. Spiro compounds, underrepresented 3D motifs in chemical libraries, represent a challenge due to the creation of spiro quaternary carbon and the need to control the 3D shape in one step. Herein, we report the first ring contraction/formal [6 + 2] cycloaddition using synergistic Pd(0)/secondary amine catalysis, obtaining [5,5]-spiropyrazolone derivatives in excellent yields and stereoselectivities. We demonstrate that this reaction has a broad scope of early and late stage derivatization that will benefit the creation of highly valuable chemical libraries using spiropyrazolone motifs. We detected the key palladium activated intermediate in its protonated form by mass spectrometry and characterized its structure by infrared spectroscopy and DFT calculations, allowing us to propose a conceivable mechanistic pathway for this reaction.

IDD388 Polyhalogenated Derivatives as Probes for an Improved Structure-Based Selectivity of AKR1B10 Inhibitors.

Human enzyme aldo-keto reductase family member 1B10 (AKR1B10) has evolved as a tumor marker and promising antineoplastic target. It shares high structural similarity with the diabetes target enzyme aldose reductase (AR). Starting from the potent AR inhibitor IDD388, we have synthesized a series of derivatives bearing the same halophenoxyacetic acid moiety with an increasing number of bromine (Br) atoms on its aryl moiety. Next, by means of IC50 measurements, X-ray crystallography, WaterMap analysis, and advanced binding free energy calculations with a quantum-mechanical (QM) approach, we have studied their structure-activity relationship (SAR) against both enzymes. The introduction of Br substituents decreases AR inhibition potency but improves it in the case of AKR1B10. Indeed, the Br atoms in ortho position may impede these drugs to fit into the AR prototypical specificity pocket. For AKR1B10, the smaller aryl moieties of MK181 and IDD388 can bind into the external loop A subpocket. Instead, the bulkier MK184, MK319, and MK204 open an inner specificity pocket in AKR1B10 characterized by a π-π stacking interaction of their aryl moieties and Trp112 side chain in the native conformation (not possible in AR). Among the three compounds, only MK204 can make a strong halogen bond with the protein (-4.4 kcal/mol, using QM calculations), while presenting the lowest desolvation cost among all the series, translated into the most selective and inhibitory potency AKR1B10 (IC50 = 80 nM). Overall, SAR of these IDD388 polyhalogenated derivatives have unveiled several distinctive AKR1B10 features (shape, flexibility, hydration) that can be exploited to design novel types of AKR1B10 selective drugs.

Modulation of aldose reductase inhibition by halogen bond tuning.

In this paper, we studied a designed series of aldose reductase (AR) inhibitors. The series was derived from a known AR binder, which had previously been shown to form a halogen bond between its bromine atom and the oxygen atom of the Thr-113 side chain of AR. In the series, the strength of the halogen bond was modulated by two factors, namely bromine-iodine substitution and the fluorination of the aromatic ring in several positions. The role of the single halogen bond in AR-ligand binding was elucidated by advanced binding free energy calculations involving the semiempirical quantum chemical Hamiltonian. The results were complemented with ultrahigh-resolution X-ray crystallography and IC50 measurements. All of the AR inhibitors studied were shown by X-ray crystallography to bind in an identical manner. Further, it was demonstrated that it was possible to decrease the IC50 value by about 1 order of magnitude by tuning the strength of the halogen bond by a monoatomic substitution. The calculations revealed that the protein-ligand interaction energy increased upon the substitution of iodine for bromine or upon the addition of electron-withdrawing fluorine atoms to the ring. However, the effect on the binding affinity was found to be more complex due to the change of the solvation/desolvation properties within the ligand series. The study shows that it is possible to modulate the strength of a halogen bond in a protein-ligand complex as was designed based on the previous studies of low-molecular-weight complexes.