Stereogenic S‑Induced Generation of Axially Chiral Cyclic Vinyl Sulfinamides and Serendipitous Diastereomeric Enrichment

Abstract

Despite significant advances in the synthesis of axially chiral compounds, the development of alkene-based atropisomers remains challenging due to their inherently low rotational energy barriers and configurational instability. Herein, we describe a novel radical-mediated strategy for constructing axially chiral scaffolds based on five-membered cyclic vinyl sulfinamides. This transformation proceeds through a photoinduced difunctionalization of chiral propargyl sulfinamides, followed by cyclization, under catalyst-free conditions. Stereocontrol is achieved through chirality transfer from the sulfur stereocenter during radical homolytic substitution (S_Hi) and is further enhanced by a spontaneous diastereomeric enrichment process. Density functional theory calculations provide mechanistic insights into the origin of these serendipitous findings. The resulting product can be readily transformed into a novel class of axially chiral P,S-ligands, which demonstrate promising catalytic activity.

Introduction

The past few decades have witnessed significant advances in the chemistry of axially chiral compounds, driven by their prevalence in natural products, pharmaceutical agents and functional materials, as well as their essential roles as chiral ligands and catalysts in asymmetric synthesis. While biaryl atropisomers represent the most well-established structural motif, the development of diverse axially chiral scaffolds remains a longstanding objective in synthetic chemistry. In recent years, atropisomeric alkene-aryl systemsfeaturing sterically hindered tri- or tetra-substituted olefinshave attracted considerable attention, particularly due to their potential applications in enantioselective catalysis. Although acyclic and six-membered ring-based alkene atropisomers have been extensively explored, , the synthesis of their five-membered cycloalkene analogues presents a formidable challenge (Figure a). This stems from the greater spatial separation between the aryl group and the rigid cycloalkene unit, which lowers the rotational energy barrier and compromises configurational stability. Li et al. and Shi et al. employ transition-metal catalysis and organocatalysis (Figure b), respectively, and both rely on extended ring systems fused to the cycloalkene core to enhance conformational restraint and stabilize the axial chirality. Yan et al. successfully obtained axially chiral alkenyl products via kinetic resolution; however, the reaction required very low temperature and provided yields below 50%.

1.

(a) State-of-the-art of the synthesis of alkene-based axially chiral compounds. (b) Three existing strategies for the synthesis of five-membered cyclic alkene atropisomers. (c) This work: radical approach for the synthesis of axially chiral cyclic vinyl sulfinamides.

The integration of multiple stereogenic elements into a single molecular framework can impart unique stereoelectronic properties and expand potential functional applications. Sulfur-stereogenic molecules are widely employed in drug development and asymmetric catalysis. , Although significant advances have been made in the construction of stereogenic sulfur centers, their incorporation into atropisomeric systems remains underdeveloped. The key challenge lies in achieving simultaneous control over both axial chirality and the pre-existing sulfur-stereogenic center during the radical-mediated cyclization, while maintaining high diastereospecificity throughout the transformation. We envisioned a new photochemical strategy for constructing axially chiral scaffolds based on five-membered cyclic vinyl sulfinamides (Figure c). Our design employs a radical-mediated difunctionalization of chiral propargyl sulfinamides, which are readily accessible from inexpensive and commercially available tert-butanesulfinamide (Ellman’s reagent). We hypothesized that the addition of a bulky radical to the alkynyl moiety would generate a vinyl radical intermediate, followed by cyclization via intramolecular homolytic substitution (S_Hi) at the tert-butanesulfinamide group. It is proposed that the alkene-based axially chiral scaffold is established during this cyclization event, wherein axial chirality is transferred from the pre-existing chirality of the sulfinamide moiety.

Herein, we present experimental evidence in support of this hypothesis. The axially chiral cyclic vinyl sulfinamides are successfully constructed under photochemical conditions, as envisioned, without the use of additional photocatalysts. However, chirality transfer from the sulfur stereocenter to the axial motif is found to be inefficient, leading to unsatisfactory diastereocontrol. Intriguingly, the final products are obtained with good diastereoselectivities through an unprecedented sulfur-induced diastereomeric enrichment process. Density functional theory (DFT) calculations provide insight into the origin of these serendipitous findings. Furthermore, the product can be readily transformed into a novel class of axially chiral P,S-ligands, which exhibit promising catalytic activity in palladium-catalyzed allylic alkylation reactions.

Results and Discussion

The reaction was conducted under visible light-irradiation using enantiopure propargyl sulfinamide (R, S _S )-1 and 4-fluorobenzenesulfonyl chloride as model substrates. Systematic optimization of the reaction conditions identified K₂HPO₄ as the optimal base, hexamethylphosphoramide (HMPA) as the preferred solvent, and 18 W LEDs as the suitable light source. Under these optimized conditions, the radical cyclization proceeded efficiently, affording the desired axially chiral cyclic vinyl sulfinamide 2 in 90% yield with 95:5 dr and 99% ee (Table , entry 1). The use of alternative solvents such as MeCN, DMF, or THF led to diminished yields and stereoselectivities (Table , entries 2–4). Similarly, variations in the photocatalyst or base resulted in reduced reaction efficiency (Table , entries 5–9). Notably, extending the reaction time further enhanced the stereoselectivity without affecting the yield, as full conversion was achieved within 2 h (Table , entries 10–12). Control experiments verified that visible-light irradiation was essential for the transformation to occur (Table , entry 13).

1. Reaction Conditions Optimization .

entry	variation from conditions	yield of 2 (%)	dr value of 2 (%)
1	none	90	95:5
2	MeCN as solvent	64	92:8
3	DMF as solvent	68	93:7
4	THF as solvent	78	90:9
5	Eosin Y as PC	87	95:5
6	fac-Ir(ppy)3 as PC	75	94:6
7	Ru(bpy)3.2PF6 as PC	25	94:6
8	KH2PO3 as base	85	94:6
9	K3PO3 as base	84	95:5
10	reaction time = 2 h	90	82:18
11	reaction time = 24 h	90	91:9
12	reaction time = 48 h	90	93:7
13	w/o hv	0	-

^aYields of isolated products.

^bDetermined by ¹⁹F NMR analysis.

^c99% ee is determined for major diastereomer.

^dEosin Y as PC. PC = photocatalyst.

^eStandard reaction conditions: (R, S _S )-1 (0.2 mmol), sulfonyl chloride (0.3 mmol), and K₂HPO₄ (0.3 mmol) in HMPA (4.0 mL) were irradiated with 18 W blue LEDs at RT under N₂ for 72 h.

With the optimized conditions in hand, we next explored the functional group tolerance and substrate scope of this transformation (Figure ). A wide range of functionalized sulfonyl chlorides reacted efficiently with (R, S _S )-1 to afford the corresponding axially chiral cyclic vinyl sulfinamides in consistently good yields with high stereoselectivities. Both electron-rich and deficient aryl sulfonyl chlorides were well tolerated, encompassing substrates containing halogens (5, 6), sulfone (11), ketone (12), amide (13), and ester (14) functional groups. The position of substituents on the aryl ring (para-, meta-, or ortho-) had minimal impact on the reaction efficiency (4, 15, and 16). Alkyl sulfonyl chlorides also participated smoothly, delivering the desired products (18–21) in comparable yields, albeit with a modest drop in diastereoselectivity. Furthermore, various heteroaryl-derived sulfonyl chloridesincluding thienyl (22), furyl (23), pyrazolyl (24), pyridyl (25), benzothienyl (26), benzothiazolyl (28), coumarinyl (29), and dibenzofuryl (31)proved to be competent substrates, undergoing smooth cyclization to afford the corresponding products in good yields with high stereocontrol. Notably, the diastereomeric products could be readily separated by silica gel chromatography, providing access to enantiopure compounds.

2.

Demonstration of functional group tolerance of the method. Standard reaction conditions: (R, S _S )-1 (0.2 mmol), sulfonyl chloride (0.3 mmol) and K₂HPO₄ (0.3 mmol) in HMPA (4.0 mL) were irradiated with 18 W blue LEDs at RT under N₂ for 72 h. The diastereomeric ratios (dr) were determined by crude ¹H NMR analysis.

To further expand the structural diversity of axially chiral vinyl sulfinamide products, we investigated modifications to the propargyl sulfinamide substrates (Figure ). Substitutions at the R¹ position of the aryl ringincluding para-, ortho-, and meta- substituents (32–34), were all well accommodated. The absolute configuration of the β-naphthyl-substituted product 36 was unambiguously determined to be (R, R _S , aS) by single-crystal X-ray diffraction analysis. Substrates featuring thienyl (37) and alkyl groups (38) also underwent efficient transformation, although with moderately reduced diastereoselectivity. The unsubstituted substrates (39) reacted successfully but exhibited significantly lower diastereoselectivity, suggesting that substituent at R¹, though distal from the chiral axis, plays a crucial role in stereochemical control. N-Methyl substitution (40) resulted in slightly diminished yield and stereoselectivity, likely due to increased steric hindrance. Modifications at the R² position on the naphthyl ring were also tolerated, including bulky substituents such as phosphoryl groups (42), highlighting the potential for developing axially chiral P-ligands. Moreover, besides sulfonyl radicals, phosphoryl radical was also capable of promoting the transformation, as evidenced by the formation of product 43 in good yield.

3.

Demonstration of broad structural diversity of products. Standard reaction conditions: (R, S _S )-1 (0.2 mmol), sulfonyl chloride (0.3 mmol), and K₂HPO₄ (0.3 mmol) in HMPA (4.0 mL) were irradiated with 18 W blue LEDs at RT under N₂ for 72 h. The diastereomeric ratios (dr) were determined by crude ¹H NMR analysis. ^aPh₂P­(O)H as radical precursor and 3 mol % Eosin Y as photocatalyst.

To demonstrate the practical utility of this method, a gram-scale reaction was conducted using 2.6 mmol of the substrate, affording 1.08 g of product 4 in 85% yield with no erosion in diastereoselectivity (Figure a). The resulting axially chiral vinyl sulfinamides serve as versatile synthetic intermediates. For instance, oxidation of 4 with m-CPBA provided the corresponding axially chiral sultam 44a scaffold of potential medicinal relevance (Figure b, left). Treatment of 4 with trifluoromethanesulfonic anhydride triggered a Pummerer-type rearrangement, yielding enantioenriched axially chiral isothiazole 45 (Figure b, right). Furthermore, compound 42 was readily transformed into a novel P,S-ligand (47), representing the first axially chiral P,S-ligand reported to date (Figure c). Preliminary evaluation of 47 in a palladium-catalyzed allylic alkylation afforded product 48 in 92% yield with 76% ee, demonstrating its potential in asymmetric catalysis. These transformations highlight the value of axially chiral cyclic vinyl sulfinamides as privileged building blocks for the design of chiral ligands and functionalized architectures.

4.

(a) Gram-scale preparation. (b) Product transformations. (c) Development of new axially chiral P,S-ligand.

To gain insight into the reaction mechanism, a series of mechanistic experiments were performed. The introduction of radical scavengers, including 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), entirely inhibited the formation of product 4. The detection of radical-adduct species by high-resolution mass spectrometry (HRMS) confirmed the participation of radical species (Figure a). A quantum yield of = 39, along with the identification of tert-butyl chloride, supports the involvement of a chain-propagation process (see Supporting Information for details). UV–vis absorption studies of a mixture containing (R, S _S )-1, tosyl chloride, and K₂HPO₄ revealed no significant red shift, thereby suggesting that an electron donor–acceptor (EDA) complex is unlikely to be operative. Further investigation into radical generation pathways showed that direct irradiation of tosyl chloride and 3,4-dimethoxystyrene under blue LEDs afforded the radical adduct 49 (Figure b), confirming that sulfonyl chlorides undergo photolytic cleavage to produce sulfonyl and chlorine radicals. Time-course analysis of the diastereomeric ratio revealed that, although full conversion was achieved within 2 h, the dr value continued to increase over time (Figure c). This indicates that the initially formed productwith lower drundergoes dynamic atropisomerization, driven by intrinsic conformational stability, ultimately enriching the thermodynamically favored diastereomer. This was further corroborated by subjecting product 4 (dr = 79:21) to stirring in HMPA in the dark for 72 h, which resulted in an increased dr of 95:5 (Figure d). Notably, both the carbon and sulfur chirality are crucial for the diastereomeric enrichment, as mismatched configuration of carbon and sulfur chirality exerts a detrimental effect on the stereochemistry (for details, see the SI).

5.

(a) Radical trap experiments. (b) Photolytic experiment. (c) Time-course analysis of the dr values of 2 by ¹⁹F NMR. (d) Diastereomeric enrichment experiment.

A plausible reaction mechanism is proposed in Figure . Upon visible-light irradiation, the sulfonyl chloride undergoes photoinduced homolytic cleavage to generate a sulfonyl radical. This radical adds regioselectively to the propargyl sulfinamide substrate (S), affording vinyl radical intermediate (Int), which then cyclizes asymmetrically through an intramolecular homolytic substitution pathway. This step yields axially chiral cyclic vinyl sulfinamide (P) with moderate initial diastereoselectivity, along with a tert-butyl radical. The resulting tert-butyl radical subsequently abstracts a chlorine atom from another molecule of sulfonyl chloride, thereby regenerating the sulfonyl radical and propagating the chain cycle. The initially formed cyclic vinyl sulfinamide product (P) subsequently undergoes spontaneous atropisomerization, induced by the sulfur-stereogenic center, ultimately leading to the final product with high diastereo- and enantioselectivity.

6.

Proposed reaction mechanism.

The proposed mechanism was further evaluated through DFT calculations, as illustrated in Figure . For diastereomers 2 and 2’, the pathways diverge upon addition of the sulfonyl radical to the propargyl sulfinamide substrate (R, S _s )-1, forming intermediates IM1 and IM1’ with minor free energy changes of – 0.7 kcal/mol and +0.7 kcal/mol, respectively. The free energy barrier via TS1-major, leading to product 2, is 1.1 kcal/mol lower than that of TS1 minor, which leads to diastereomer 2’. Subsequent intramolecular cyclization via TS2-major and TS2 minor proceeds through S_Hi pathways to afford 2 and 2’, respectively, with an energy barrier difference of 0.5 kcal/mol. Although the pathway to 2 is kinetically favored, the energy advantages of neither TS1-major nor TS2-major are sufficient to account for the high diastereoselectivity observed between 2 and 2’. However, when explicit solvation effects are consideredwith a DMF molecule adsorbed via hydrogen bondingthe free energy of 2 becomes 1.7 kcal/mol lower than that of 2’. This enhanced thermodynamic stability of 2 aligns with the experimental observation of improved diastereoselectivity (up to 93:7 in DMF; see Supporting Information) achieved simply by stirring the product in solvent under dark conditions. Atropisomerization of 2’ to 2 proceeds via a rotational transition state TS-3 with a barrier of 22.4 kcal/mol. While high, this barrier remains surmountable under prolonged reaction conditions (up to 72 h). The overall free energy change from (R, S _s )-1 to 2 is −1.1 kcal/mol. Although this value is small, the reaction is rendered irreversible by the subsequent engagement of the tert-butyl radical in regenerating the sulfonyl radical, thereby propagating the chain process.

7.

Energy profile calculated at the M06–2X/Def2-TZVP-SMD­(DMF)//M06–2X-Def2-SVP-SMD­(DMF) level of theory.

Conclusions

We have developed an efficient strategy for constructing novel five-membered cyclic alkene atropisomers by incorporating cyclic vinyl sulfinamide motifs into axially chiral scaffolds. The reaction is operationally simple, proceeding under visible-light irradiation without the requirement for an external photocatalyst. Utilizing readily accessible starting materials, the transformation occurs through a sequential process involving intramolecular homolytic substitution followed by diastereomeric enrichment. This approach enables the synthesis of a diverse array of axially chiral cyclic vinyl sulfinamides with broad functional group compatibility and high levels of diastereo- and enantioselectivity. The practical utility of these products is demonstrated by the conversion into a novel axially chiral P,S-ligand, which exhibits promising performance in asymmetric catalysis. The observed diastereomeric enrichment, discovered serendipitously, has been rationalized through DFT calculations.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01695.

• Supplementary tables and figures, experimental procedures, characterization, spectra of all materials, and DFT calculations (PDF)

‡.

Y.C. and T.W. contributed equally to this work. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors are grateful for the financial support from the National Natural Science Foundation of China (22371185 and 22571194), the Fundamental Research Funds for the Central Universities (23X010301599 and 24X010301678), and the Program of Shanghai Academic/Technology Research Leader (23XD1421900).

The authors declare no competing financial interest.