Enantioselective Synthesis of Aza-Flavanones with an All-Carbon Quaternary Stereocenter via NHC-Catalyzed Intramolecular Annulation

An enantioselective synthesis of functionalized aza-flavanone derivatives using the N-heterocyclic carbene-catalyzed intramolecular Stetter reaction of sulphoamido benzaldehydes has been reported. This procedure presents the first original approach for synthesizing chiral functionalized flavonoids at the 3-position, containing an all-carbon quaternary stereogenic center. This advancement significantly enriches the chemical toolbox for the preparation of complex nitrogen-containing compounds and opens up new avenues for further research and development in synthetic organic chemistry.


■ INTRODUCTION
Aza-flavanones, an intriguing class of compounds, are part of a diverse family that merges the structural features of both tetrahydroquinolines and quinolones.These remarkable molecules are characterized by an aromatic ring fused to a six-membered heterocyclic system that incorporates a nitrogen atom.This unique configuration is frequently observed in a plethora of bioactive natural products, many of which exhibit a wide range of pharmacological activities and therapeutic potential. 1The designation of these specific structural frameworks as "privileged structures" in drug development reflects their exceptional ability to modulate various biological targets.Their multifaceted nature has captured the attention of researchers in medicinal chemistry, leading to extensive studies on their structure−activity relationships (SAR) and potential applications in the treatment of various diseases. 2ver the years, aza-flavanones have emerged as promising lead compounds for the development of novel therapeutic agents, targeting an array of conditions such as inflammation, cancer, neurodegenerative disorders, and infectious diseases. 3heir versatile chemical structures have inspired the design and synthesis of numerous analogs, further expanding the possibilities for the discovery of innovative drug candidates.For instance, martinellic acid, a natural alkaloid containing a pyrroloquinoline ring system, exhibits potent antagonist activity against several G-protein coupled receptors such as bradykinin, α-1-adrenergic, and muscarinic receptors. 4Azachromanone has also been found to be an interesting inhibitor against the enzyme Human Leukocyte Elastase (HLE). 5alazoparib serves as a treatment for advanced breast cancer with germline BRCA mutations. 6Furthermore, compound L-689, 560 is a neuroprotective agent with the potential to minimize ischemic nerve damage following a stroke or heart attack. 7On the other hand, viratmycin belongs to a group of antiviral antibiotics that also possess antifungal properties (Figure 1). 8symmetric synthesis of aza-flavanones, including azachromanones, primarily revolves around several strategies.The first one involves stereoselective intramolecular 1,4conjugate addition of organometallic reagents to 4-quinolones. 9Another approach is the organocatalytic annulation of 2-aminoacetophenones and aryl aldehydes via aza-Michael additions. 10A noteworthy method consists of the direct 1,4addition of 2′-aminochalcones in the presence of chiral Bro̷ nsted acids or hydrogen bond donors. 11Recently, You demonstrated that the cross-benzoin reaction catalyzed by Nheterocyclic carbenes can be an effective tool for the synthesis of chiral hydroxy-aza-chromanones. 12 The majority of the previously mentioned methods focus on the functionalization of dihydroquinolinones at the 2-position.It is crucial to emphasize that stereodivergent strategies for the synthesis of aza-chromanones are relatively scarce, particularly when it comes to approaches that enable functionalization and the formation of stereogenic centers at position 3 within the dihydroquinolinone scaffold.A significant aspect is the synthetic complexity of the final substrate for the annulation reaction, which requires a multistep synthesis (see SI).In comparison, structurally similar chromanone derivatives can be obtained in a single step using commercially available reagents.
A primary challenge associated with NHC catalysis 13 lies in the employment of sterically hindered intramolecular β,βdisubstituted Michael acceptors, which additionally contain a weakly activating ester group. 14Moreover, the presence of a bulky N-tethered group contributes to the unfavorable spatial environment surrounding the Michael acceptor system.Taking into account these inherent obstacles and considering the extensive range of pharmacological properties displayed by aza-flavanone derivatives, herein, we present the NHCcatalyzed enantioselective synthesis of aza-flavanone derivatives bearing a sterically demanding all-carbon quaternary stereocenter by the intramolecular Stetter reaction of acyl anion equivalents with moderately weak electrophilic ester Michael acceptors.

■ RESULTS AND DISCUSSION
We initiated our optimization studies by evaluating various NHC precatalysts in the presence of o-sulphoamidobenzaldehyde 1a, using DIPEA as a base and o-xylene as the solvent for the reaction process.To our delight, pinene-derived NHC precatalyst A efficiently promoted this reaction, affording the desired aza-chromanone in high yield and promising stereoselectivity (Table 1, entry 1).Replacing the pinene scaffold with a camphor skeleton in the NHC structure provided the chiral product 2 with enhanced enantioselectivity, albeit in a reduced yield.Unfortunately, the spirocyclic NHC precatalyst C proved to be unsuitable for stereocontrol in this annulation process.Switching from terpene-derived NHC precatalysts to an NHC with an aminoindanol motif led to an increase in both product yield and optical purity (Table 1, entry 4).When this reaction was performed using alternative organic bases, diminished yields of 2a were observed, indicating that DIPEA is the optimal base for this reaction (entries 5−8).Importantly, the employment of strong organic bases, such as DBU and BEMP, resulted in the absence of any detectable traces of product 2a (entries 9 and 10).Although other solvents tested in place of o-xylene yielded satisfactory results, and ether solvents even exhibited high enantiomeric excesses (entries 13−15), the best combination of reactivity and selectivity was achieved using o-xylene (99 yield, 96% ee).
After establishing the optimized reaction conditions, we proceeded to investigate the reaction scope using sulfoamidobenzaldehyde substrates 1 with varying substituents and substitution patterns (Table 2).Electron-donating groups and halogen atoms were successfully introduced at position 6 of the phenyl group of 1, yielding the desired products with excellent yields and high enantioselectivities (2c-e, 2g-h).When a strong electron-withdrawing substituent (OCF 3 , 2f) was present at this position, the product yield slightly decreased, although the optical purity remained high.
Substrates with electron-withdrawing groups at the 7position of the benzene rings exhibited similar trends, producing products almost quantitatively with high optical purity.However, the fluorine substituent led to a reduced yield (2k) while maintaining a high enantiomeric excess.We found it particularly intriguing to examine the impact of the substituent at position 5 of the aromatic ring on the reactivity and selectivity of the annulation, given the close proximity of  activating and deactivating groups in ortho-orientation.The presence of electron-withdrawing or electron-donating groups at the 5-position (2m−p) resulted in lower product yields, while stereoselectivity remained constant.
The reaction involving the N-Ms-linked substrate 1b underwent the annulation reaction, yielding product 2b with a 37% yield and 64% ee.Employing a tosyl substituent instead of a mesyl was found to be crucial for achieving both high stereoselectivity and yield.The absolute configuration of the product was determined by an X-ray crystallographic analysis of an enantiopure 2i crystal, identified as R configuration.The functionalization of the synthesized benzo-fused piperidinones was successfully explored (Scheme 1).A direct reduction of both carbonyl groups, employing lithium aluminum hydride as the reducing agent, resulted in 1,3-diol 8 with moderate efficiency and selectivity.By utilizing the Luche reduction method under mild experimental conditions, we were able to synthesize hydroxy-aza-flavanone 9 in 82% yield with remarkable diastereoselectivity. Furthermore, subjecting the hydroxy-aza-flavanone to treatment with p-toluenesulfonic acid facilitated the formation of a tricyclic lactone 10, while maintaining the enantiopurity of the product.Reductive detosylation using the sodium/naphthalene system provided N−H chromanone 11 in a 30% yield.

■ CONCLUSIONS
In summary, we have successfully developed an NHCorganocatalyzed strategy for the enantioselective synthesis of functionalized aza-flavanone derivatives bearing an all-carbon quaternary stereogenic center.The reaction products were obtained with high yields and enantioselectivities. Noteworthy features of this annulation reaction include the highly enantioselective construction of biologically relevant nitrogen-containing compounds, mild reaction conditions, and a broad substrate scope.The stereoselective functionalization of position 3 in the heterocyclic flavone ring system remains a synthetic challenge.
■ EXPERIMENTAL SECTION Instrumentation.Presented reactions were carried out in dry glassware under an inert atmosphere of argon.Selected reactions were monitored by using thin-layer chromatography (TLC), which was visualized under a UV lamp (254 nm).Anhydrous solvents were prepared using an INERT PureSolv Solvent Purification System.Purification of the selected products was performed by column chromatography using a CombiFlash Rf+ Lumen system with UV−vis and ELSD detectors.RediSepRf GOLD columns were used.NMR spectra were recorded on Bruker AMX 400 [400 MHz (1H)] and Bruker AMX 700 [700 MHz (1H)] spectrometers, using CDCl 3 as a solvent, and were reported in ppm relative to the CHCl 3 residual peak (δ 7.24) for 1 H NMR and relative to the central CDCl 3 (δ 77.23) resonance for 13 C NMR. Coupling constants (J) are given in Hz.Infrared spectra were recorded on an Alpha FT-IR spectrometer from Bruker with an ATR module.Mass spectra were recorded on an Agilent 6530 Q- Unless otherwise specified, the reaction was performed on a 0.1 mmol scale in solvent (1.0 mL) at room temperature.Yields of isolated products.Ee values determined by HPLC on chiral stationary phase.

ACS Omega
TOF LC/MS system coupled to a 1290 Infinity II liquid chromatograph.Melting points of the obtained products were measured on a Stuart SMP30 melting point apparatus and an automatic SMP50.The enantiomeric excess of chiral products was determined using an HPLC Agilent Technologies 1200 Series and chiral stationary phases: Phenomenex Lux Cellulose-1 (3 μm) and Phenomenex Lux Amylose-1 (3 μm).The diffraction data of the studied compound were collected at T = 100 (2) K for the single crystal on an XtaLAB Synergy Dualflex (Rigaku) equipped with a HyPix detector and MoKα source (λ = 0.71073 Å).The specific rotation of chiral products was determined using a PolAAr 30-3000 polarimeter from Optical Activity Ltd.
Full experimental procedures, as well as the physicochemical characterization of all products, can be found in the Supporting Information.
General Procedure: Intramolecular Stetter Reaction.A round-bottom flask was charged with precatalyst D (0.2 equiv) and o-xylene (0.1 M).Then diisopropylethylamine (1 equiv) was added, and the solution was allowed to stir at ambient temperature for 10 min.The substrate 1 (1 equiv) was added, and stirring was continued at ambient temperature.The progress of the reaction was monitored by TLC.o-Xylene was evaporated, and the residue was washed with diethyl ether and petroleum ether and filtered through PTFE syringe filters with 45 μm pores.Evaporation of the solvents afforded analytically pure product 2.

Table 2 .
Substrate Scope of the NHC-Catalyzed Annulation for the Constructing of Aza-Flavanones Bearing Quaternary Carbon Stereocenter a