Enantioselective Chan-Lam S-Arylation of Sulfenamides

Abstract

Sulfur-stereogenic molecules have a significant impact on drug development, but are underexplored largely due to our limited ability to construct such structures. Among them, sulfilimines are a class of chiral molecules bearing S(IV)-stereocenters, which exhibit great value in chemistry and biology but were synthetically intractable previously. We report a highly chemoselective and enantioselective Chan-Lam S-arylation of sulfenamides with arylboronic acids to deliver an array of thermodynamically disfavored diaryl and alkyl aryl sulfilimines containing a sulfur stereocenter. Though Chan-Lam coupling has been widely used to construct C-N, C-O and C-S bonds by coupling nucleophiles with boronic acids using copper complexes in academia and industry, control of the stereochemistry in this textbook transformation has proven to be a formidable challenge. A new copper catalyst from a 2-pyridyl N-phenyl dihydroimidazole ligand has been designed that enables effective enantiocontrol by means of a well-defined chiral environment and high reactivity that outcompetes the background racemic transformation. A combined experimental and computational study establishes the reaction mechanism and unveils the origin of chemoselectivity and stereoselectivity.

INTRODUCTION

The efficient creation of chiral molecules with defined stereogenic centers is of central relevance for synthetic chemistry and is a core goal of asymmetric catalysis. In contrast to the formation of typical carbon stereocenters, the creation of enantioenriched heteroatom stereocenters, especially sulfur-stereocenters, are significantly less studied. Both S(IV) and S(VI) oxidation state can display stable stereocenters. For sulfur(VI) centers, sulfoximines are notable pharmacophores, which are very stable and possess exploitable properties for drug discovery^{1, 2}, as exemplified by ronicilib (Scheme 1A). For sulfur(IV), S-chirality in the form of the sulfoxide functionality has a significant impact in pharmaceuticals, for example omeprazole (racemate) and esomeprazol [(S)-enantiomer] (Scheme 1A). The manifestation of this motif in pharmaceuticals has driven the development of a broad range of viable synthetic methods to selectively synthesize enantioenriched sulfoxides^{3, 4}. For sulfilimines, the aza-analogues to sulfoxides, much less is known about their selective synthesis which in turn limits exploration of their biological activity (Scheme 1A)^5–7. Recently, the sulfilimine bond has been discovered to be involved in covalent crosslinks between hydroxylysine-211 and methionine-93 in collagen IV, which represents an evolutionary adaptation to mechanical stress and plays a key role in stabilizing the basement membranes of metazoan⁸. Encouraged by this striking discovery, sulfilimines have drawn increasing attention in the field of chemical biology^9–11, and appear as a promising pharmacophore in medicinal chemistry¹², wherein chirality at sulfur^{4, 13} plays a significant role yet is long-time neglected.

Scheme 1.

Background and Conceptual Design

Conventionally, enantioenriched sulfilimines are prepared by enantioselective imination of sulfides, which predominantly relies on steric differentiation of the two S-substituents by a catalyst. Following such a strategy, chiral aryl alkyl sulfilimines as well as dialkyl sulfilimines have been prepared with high optical purity, whereas very limited success has been achieved in forming enantiopure diaryl sulfilimines presumably due to the small difference in the size of the two (hetero)aryl moieties (Scheme 1B)^14–22. Recently, Ellman and coworkers reported an elegant enantioselective Rh-catalyzed S-alkylation of sulfenamides with diazo compounds, representing a complimentary pathway to chiral alkyl sulfilimines (Scheme 1B, b)²³; however, the key rhodium carbene intermediate precludes the application of this tactic to diaryl variants. In sharp contrast to the alkyl counterparts, only three synthetic routes to diaryl sulfilimines have been disclosed to date, leveraging the stereo-induction effect of enantiopure reactants, but only poor stereocontrol has been achieved (12–47% ee) (Scheme 1B, c)^{24, 25}. Simultaneously as this work, Kano and coworker reported an elegant stereospecific oxygen-selective alkylation of enantioenriched sulfinamides followed by the nucleophilic addition of the Grignard reagents to furnish an array of chiral sulfilimines (Scheme 1B, e)²⁶. Therefore, a general, enantioselective method to directly prepare chiral arylsulfilimines with broad functional group compatibility and high levels of enantioselectivity remains an unsolved challenge.

We hypothesized that this class of molecules could be assembled by an enantioselective two-component coupling strategy, such as Chan-Lam coupling, wherein a chiral catalyst would allow the effective construction of sulfur stereogenic centers possessing two very similar, or even nearly identical (hetero)aryl moieties (Scheme 1C). Chan-Lam coupling has emerged as one of the most widely practiced methods in academia and industry to construct C-N, C-O and C-S bonds over the past two decades^{27, 28}, due to the mild and simple reaction conditions, inexpensive and biofriendly catalysts, among other advantages. Since the cross-coupling involves the union of two nucleophiles, oxidants are needed to facilitate the transformation of Cu(I) to Cu(II) in the catalytic cycle of both C-O^{29, 30} and C-N bond formation³¹. Koley group carried out in-depth computational investigations of Chan-Lam amination and esterification to provide interesting insights into these pathways, particularly on the denucleation of dimeric copper acetate, the disproportionation of the Cu(II) complex, and the regeneration of Cu(II) from Cu(I) intermediates^{32, 33}. In 2018, Schaper group exploited the mechanistic pathway of Chan-Lam coupling with pyridyliminoarylsulfonate as external ligand based on kinetic and spectroscopic investigations³⁴. However, no enantioselective Chan-Lam coupling has been achieved yet, as the majority of Chan-Lam protocols do not require an external ligand. Recently, our group introduced an unprecedented Chan-Lam S-arylation of sulfenamides to prepare an array of racemic diaryl sulfilimines³⁵, which features unconventional chemoselectivity favoring C-S bond formation over C-N bond, broad functional group tolerance, and mild reaction conditions. The key to success for this protocol is chelation of the carbonyl group on nitrogen to the copper center, which stabilizes the substrate adduct and controls the subsequent C-S bond formation. Moreover, to prevent this highly favorable background reaction from unliganded copper, multidentate chiral ligands are used to favor copper coordination. This scenario limits the coordination sites available for the two requisite substrates in a Chan-Lam coupling (aryl group and sulfenamide substrate). For example, bidentate sulfenamides³⁵ where facial control is more easily achieved are not accommodated when such chiral ligands are employed. However, monodentate substrates need to compete with solvent molecules, anions derived from the copper source, or bases in binding to the copper center in order to effect this process. Furthermore, S-binding needs to be realized over the normally more favorable N-binding in a suitable chiral pocket. Herein, we report an enantioselective copper-catalyzed Chan-Lam coupling S-arylation of sulfenamides with arylboronic acids that overcomes these considerable challenges to provide facile access to diverse diaryl sulfilimines with high level of chemoselectivity and stereoselectivity (Scheme 1B, f)³⁶.

Results

Reaction development.

Control of the copper coordination sphere is the key to realizing ligand-controlled enantioselective Chan-Lam coupling. Reasoning, that a chelating substrate combined with a bidentate ligand would likely inhibit transmetallation from the aryl boronic acid, chelating N-groups such as acyl, carbamoyl, etc. were not employed. Rather, we strategically chose a sulfenamide bearing a phenyl group on nitrogen (1a) as model substrate, along with 4-tert-butyl phenylboronic acid (2a), for examination of the process. While N-aryl sulfenamides have been used as substrates in other processes, the arylation of sulfenamides encountered an N:S chemoselectivity issue³⁷. Initially, a series of privileged nitrogen-based ligands were surveyed in the presence of a copper catalyst and amine base to quench the boronic acid byproduct (Table 1, Table S1 and Table S5). Among the chiral scaffolds tested, 2-pyridyl oxazolidine ligand L4 outperformed by delivering the desired product 3aa in 43% ee (Table 1, entry 4). Further optimization of the other parameters with this ligand (see Tables S2–4) revealed that ⁱPr₂NEt (2.0 equiv) as base, dimethoxyethane (DME) as solvent, and copper(I) thiophene-2-carboxylate (CuTc, 10 mol %) as catalyst improved the outcome forming 3aa with 50% yield and 58% ee (entry 5). Modifying the ligand to a slightly nonplanar geometry by incorporation of an aryl group in L5 (entry 6) improved the assay yield (60%) and enantiomeric excess (71%) of 3aa. Permutation of this substitution to the dihydroimidazole moiety (L6) leads to superior enantiocontrol (80% ee) albeit with slightly diminished assay yield (44%, entry 7). Installation of a further ortho-fluoro group on the pyridine (L7) led to much lower yield and ee values (entry 8). Consequently, further modification of the ligands focused on the dihydroimidazole portion. In addition, introduction of CsF (50 mol %) enhanced turnover by activation of the boronic acid³⁸. In line with this hypothesis, the yield was doubled while retaining the same enantioselectivity (entry 9 vs entry 7). As such, CsF was employed in all further trials. Addition of an ethyl group to the 5-position of the dihydroimidazole ring would further constrain the geometry and shift the ^tBu closer to bound substrates. Indeed, this modification resulted in excellent catalytic activity (85–86% assay yield) with the trans position in L9 giving the higher enantioselectivity (90% ee; compare entry 11 with 10). Further increasing the steric effect from the 5-position by employing a benzyl group in place of the ethyl group (L10) resulted in improved enantioselectivity (92% ee) while maintaining the high efficiency of the transformation. Ultimately, changing the base from ⁱPr₂NEt to Na₂CO₃ afforded 3aa in 88% assay yield, 83% isolated yield, with 92% ee (entry 13). When the oxygen atmosphere was replaced by air atmosphere, 3aa was only obtained in 40% assay yield (entry 14). Thus, the optimal conditions for enantioselective Chan-Lam coupling of sulfenamide were determined to be: 1a as limiting reagent, 2a (2.0 equiv) as coupling partner, CuTc (10 mol %)/L10 (15 mol %) as catalyst system, Na₂CO₃ (2.0 equiv) as base, CsF (50 mol %) as additive, in DME under an O₂ atmosphere at room temperature for 12 h. When no external ligand was employed, only trace amount of 3aa was detected due to the background reaction (entry 15), in agreement with the high level of enantiocontrol exerted by the chiral ligand L10. For a complete list of optimization conditions, see Tables S1–9 in SI for details.

Table 1.

Optimization of Enantioselective Copper-Catalyzed Chan-Lam Coupling of Sulfenamide (1a) with 4-tert-Butyl Phenylboronic Acid (2a)^a

entry	ligand	assay yieldb/%	eec/%	entry	ligand	assay yieldb/%	eec/%
1d	L1	8	18	9e,f	L6	87	80
2d	L2	11	18	10e,f	L8	85	82
3d	L3	trace	/	11e,f	L9	86	90
4d	L4	25	43	12e,f	L10	85	92
5e	L4	50	58	13e,f,g	L10	88(83h)	92
6e	L5	60	71	14i	L10	40	92
7e	L6	44	80	15	-	trace	-
8e	L7	20	13

^aReaction conditions unless stated otherwise: 1a (0.1 mmol), 2a (2.0 equiv), copper catalyst (10 mol %), ligand (15 mol %), base (2.0 equiv) and solvent (1.0 mL), at rt for 12 h under an O₂ atmosphere.

^bAssay yields determined by ¹H NMR spectroscopy of unpurified reaction mixtures using 0.1 mmol (7.0 μL) of CH₂Br₂ as internal standard.

^cEnantiomeric excess (ee) was determined by HPLC with a Daicel Chiralpak AS-H column (ⁱPrOH:hexane = 05:95, 0.3 mL/min), 254 nm, t_R (major) = 17.66 min, t_R (minor) = 20.13 min.

^dCu(OAc)₂⚫H₂O (10 mol %), Et₃N (2.0 equiv) and CH₂Cl₂ (1.0 mL).

^eCuTc (10 mol %), ⁱPr₂NEt (2.0 equiv) and DME (1.0 mL).

^fCsF (50 mol %).

^gNa₂CO₃ (2.0 equiv) instead of ⁱPr₂NEt.

^hIsolated yield.

ⁱAir instead of O₂.

Substrate Scope.

With the optimal conditions established, we examined the generality of this enantioselective Chan-Lam coupling reaction (Table 2). The larger naphthalene substrate (1b) was similarly effective and a crystal structure thereof permitted unambiguous assignment of the absolute (S)-configuration (see Tables S10–16 for details); the configurations of the other products in Table 2 were assigned by analogy. Electron-donating 4-OMe (1c) and 4-Me (1d) or electron-withdrawing 4-F (1a), 4-Cl (1e), 4-Br (1f), 4-CO₂Et (1g), 4-CF₃ (1h), 4-CN (1i), and 4-NO₂ (1j) aryl groups on the sulfur of the sulfenamide were all well tolerated furnishing the corresponding products in good yields with excellent enantiocontrol. Attesting to the mild conditions, various functional groups, such as aldehyde (1k), ketone (1l), ester (1g), amide (1m) and alcohol (1n) were all compatible under the optimal conditions, providing the products in 61−72% yields and 81−91% ee. Remarkably, this enantioselective Chan-Lam coupling protocol displayed excellent chemoselectivity favoring S-arylation of sulfenamide (1a) over other functional groups that typically undergo Chan-Lam coupling such as the amide N-H (1m) or alcohol O-H (1n), highlighting the unique nature of this protocol. The sterically hindered 1-naphthyl group (1o) was also tolerated, affording 3oa in 47% yield and 81% ee. The chemistry was well-accommodated with sulfenamides bearing meta-substituted aryl groups, as evidenced by the formation of 3pa and 3qa in 67% with 89% ee and 73% with 88% ee, respectively. Moreover, the newly devised method proceeded smoothly with challenging S-heterocyclic sulfenamides allowing an array of chiral S-heteroaryl sulfilimines, including pyridyl (3ra, 3sa), quinolinyl (3ta), and thienyl (3ua, 3va) to be obtained with good enantioselectivities (70–88% ee), albeit in modest yields (45–75%).

Table 2.

Scope of the Substrates

^aReaction conditions: 1 (0.1 mmol), 2 (2.0 equiv), CuTc (10 mol %), L10 (15 mol %), Na₂CO₃ (2.0 equiv), CsF (50 mol %) and DME (1.0 mL), at rt for 12 h under an O₂ atmosphere.

^b18 h.

^cCuTc (20 mol %), Na₂CO₃ replaced by ⁱPr₂NEt.

^dCsF replaced by CsI (80 mol %).

^eTetrabutylammonium iodide (20 mol %) was added.

^fCuTc (20 mol %) was used.

^gL10 replaced by L8.

Next, the N-aryl substitution of the sulfenamides was examined. Both electron-donating (1w) and electron-withdrawing aryls (1x, 1y, 1z) gave the desired products (3wa-za) with 60–84% yields and 83–94% enantioselectivity. Importantly, a set of functional groups, including aldehyde (1aa), ketone (1ab), ester (1z), and even the polymerizable vinyl group (1ac), were well tolerated in the protocol to deliver the corresponding chiral diaryl sulfilimines (3za-aca) in good yields (77–89%) with good to excellent enantiocontrol (74–93% ee). These results highlight the advantages of this protocol as the aldehyde and terminal alkene are not tolerated in the previously reported route, oxidative imination of sulfides, due to the competing oxidation. Sterically hindered N-(2-Br-phenyl) sulfenamide (1ad) reacted with 2a under the optimal conditions to afford 3ada in 74% with 84% ee. meta-Substituted N-aryl sulfenamides, including 3-methoxy (1ae), 3-iodo (1af), and 3-acetamido (1ag), were competent coupling partners to deliver sulfilimines 3aea-ga in 71–81% yields with 74–91% ee. Heteroaromatic sulfenamides, such as pyridines 1ah, 1ai and pyrimidine 1aj, also proved to be potent coupling partners to furnish chiral N-heterocyclic diaryl sulfilimines 3aha-ja in satisfactory yields with good stereocontrol. Of note, S-alkyl sulfenamides were also competent coupling partners in our protocol. Sulfenamide bearing a linear ⁿbutyl group (1ak) was successfully applied in this transformation to provide the desired sulfilimine 3aka, albeit in modest yield and ee. Both ethylpropyl (1al) and cyclic alkyl substituents, including cyclohexyl (1am), tetrahydropyranyl (1an), and tosylpiperidyl (1ao) were well tolerated, delivering the corresponding sulfilimines (3ala-oa) with 48–88% yields and 85–88% ee. Unfortunately, no desired product was detected with tert-butyl or adamantly on sulfur, presumably due to the increased steric hinderance. The use of alternate arylboronic acids was next interrogated. The 2-naphthalene (2b) variant again proved effective at this position. Electron-donating substrates including 4-OBn (2c), 4-ⁿbutyl (2d), 4-TMS (2e), 4-PhO (2f), and 4-Ph (2g) and electron-neutral substrates 4-MeS (2h) and 4-H (2i) furnished the products 3ab-i in moderate to good yields while sustaining good stereoselectivities. In particular, 3ah is synthetically intractable via the classic imination of sulfides, since it contains two functionalities with different oxidation states of sulfur. Importantly, labile trimethylsilyl (2e) or vinyl (2j) groups were also amendable to the chemistry, providing a means for later modification via other orthogonal processes. An ortho-substituted arylboronic acid was also viable substrate in this transformation to furnish 3ak in 51% yield and 72% ee when L10 was replaced by L8. Moreover, meta-substituted arylboronic acids (2l-n) were effective. The heterocyclic benzofuranyl boronic acid (2o) generated 3ao with good selectivity (87% ee). Finally, the coupling with alkenylboronic acids was established as evidenced by the formation of cyclopentenyl sulfilimine 3ap in synthetically useful yield and ee (59%, 78% ee).

Synthetic Utility.

A major source of nitrogen-based chiral ligands is inexpensive and abundant natural L-amino acids, which, in turn, limits the availability of the enantiomeric congeners. In this instance, the opposite enantiomeric ligand of L10 is derived from an expensive D-amino acid. Thus, generation of both of enantiomeric products from the same, less expensive chiral ligand would be a distinct advantage. Simply exchanging the aryl groups of the sulfenamide and arylboronic acid substrates enabled such an outcome. Thus, synthesis of both enantiomers of sulfilimine 3dm was achieved by using 1d with 2m vs 1p with 2q under the identical catalytic conditions (Scheme 2A, a). A pair of enantiomeric sulfenamides [(+)1ap and (−)1ap] bearing a chiral centre adjacent to sulfur were employed to react with 2a under the optimal conditions, affording diastereomeric sulfilimines 3apa and 3apa’ with nearly identical diastereomeric ratio in the same yields. This result demonstrates that enantioselectivity of our protocol is predominantly catalyst-controlled (Scheme 2A, b). Remarkably, after treatment with MeOTf, the 2-pyridyl group on the nitrogen of 3aha could be removed by NaBH₄ to afford chiral NH-sulfilimine 4 in synthetically useful yield while retaining the enantioselectivity (Scheme 2B)³⁹. With the NH-sulfilimine in hand, versatile access to a diverse range of S(VI) and S(IV) derivatives is feasible. For example, stereospecific oxidation of NH-sulfilimine 4 provided the NH-sulfoximine 5, a prevalent scaffold in medicinal chemistry, in good yield without racemization of the sulfur stereocenter. Sulfondiimine 6, which represents a category of underexplored S(VI)-scaffold, could be prepared in 40% yield with a slight erosion in enantiopurity. Moreover, NH-sulfilimine 4 could be utilized as a nucleophile to react with 1-bromobutane or BrCN to afford the corresponding sulfilimines 7 and 8 while maintaining the enantiomeric excess. NH-Sulfilimine 4 underwent acylation and Michael-type addition smoothly to give N-functionalized sulfilimine 9 and 10 in excellent yields without detectable racemization. Next, we showed the synthetic utility of this method due to the emerging role of sulfilimines in medicinal chemistry. Inspired by the elaboration of pan-CDK inhibitor Bay1000394 from Bayer by switching the sulfonamide to a sulfoximine as the pharmocophore⁴⁰, two sulfilimine analogues of patented bioactive molecules were generated using our enantioselective Chan-Lam coupling as the key step (Scheme 2C). Sulfilimine 15, an analog of an agonist (15’) of AMP-activated protein kinase (AMPK) in the treatment of degenerative neurological diseases⁴¹, could be synthesized in three steps with 60% overall yield and 80% ee. Compound 20, an analog of the sulfoxide-based histone-lysine N-methyltransferase EZH2 Inhibitor (20’)⁴², was concisely assembled in four steps with a 28% yield and 86% ee. Remarkably, compound 18 bearing a labile activated ester group reacted efficiently with 2a to deliver the corresponding chiral sulfilimine in good stereoselectivity, underlining the broad functional group compatibility. Overall, the method described herein offers a versatile platform to afford a range of derivatives in a step-economic manner.

Scheme 2.

Synthetic Applications

Mechanistic Studies.

To understand the factors controlling chemo- and enantioselectivity, the mechanism was probed using density functional theory (DFT) [UM06/6–311++G(d,p)-SDD(Cu)-CPCM(DME)//UB3LYP-D3/6–31G(d)-SDD(Cu)^43–51, see Supporting Information for full computational details]. Initially, Cu^II complex 1’ forms the pre-reacting complex 1 with the incoming aryl boronic acid (Figure 1a, downhill in energy by 2.0 kcal/mol). This complex then undergoes transmetalation (via [1–2], 3.9 kcal/mol) to form intermediate 2 (−25.1 kcal/mol) following dissociation of boric acid. Next, sulfenamide coordinates to 2 to form 2a’ (−20.6 kcal/mol).

Figure 1.

a) Formation of common intermediate 2a’, which can undergo N-arylation or S-arylation. b) Formation of S-arylation product 3-S via kinetic control. c) Formation of (S)-product over (R)-product, an entropically controlled process. All free energies were computed using UM06/6–311++G(d,p)-SDD(Cu)-CPCM(DME)//UB3LYP-D3/6–31G(d)-SDD(Cu).

Intermediate 2a’ can undergo kinetically controlled S-arylation (Figure 1b, blue pathway) or the higher energy N-arylation (Figure 1b, red pathway). For the S-arylation, Cu^II intermediate 2a’ first undergoes disproportionation with Cu^II intermediate 1’ to form Cu^III complex 2’ (Figure 1b, blue, −22.4 kcal/mol) and LCu^I hydroxide. Thiophene carboxylate dissociates from the inner coordination sphere of the Cu^III complex to form the square pyramidal Cu^III cationic complex 2c’. Cystallographic evidence of various square pyramidal cationic Cu^III species supports the formation of such an intermediate⁵². Furthermore, the dihydroimidazole ring of L10, a strong sigma donor, is trans to sulfur, (see Figure S1). Next, sulfur-arylation occurs via [2–3] (overall energetic span⁵³ of 8.0 kcal/mol from intermediate 2a’) to give protonated S-arylation product 3’-S. Finally, deprotonation of the nitrogen atom gives the final product 3-S and Cu^I, which is oxidized to Cu^II intermediate 1’ by dioxygen to restart the cycle.

To understand the chemoselectivity observed in this transformation, we also computed the formation of the N-aryl product. When an identical sequence of events from the S-arylation was used for the N-arylation (Figure S2), the energy span for N-arylation (21.5 kcal/mol) was significantly higher than for S-arylation (8.0 kcal/mol) indicating that reductive elimination to form the ammonium is disfavorable relative to the sulfonium such as 3’-S. Apparently, the greater polarizability of sulfur permits such a build-up of positive charge and thus avoids a disfavorable deprotonation of the neutral substrate. Thus, the order of events was changed to consider deprotonation before reductive elimination for the N-arylation (Figure 1b, red) which resulted in a pathway with a lower span (14.0 kcal/mol) albeit still higher than that for S-arylation. In this pathway, the nitrogen atom of the sulfenamide in 2a’ undergoes deprotonation with NMe₃ as the base (as a simplified model for ⁱPr₂NEt) via 2’-TS (overall energetic span of 14.0 kcal/mol) to form intermediate 2d’. Disproportionation of Cu^II species 2d’ with Cu^II intermediate 1’ yields Cu^III intermediate 2b’ and LCu^I hydroxide. From intermediate 2b’, N-arylation occurs via [2’−4], giving the thermodynamically favored product 4. Notably, S-arylation is under kinetic control as the energetic span to form the product 3’-S is lower by 6.0 kcal/mol, explaining the observed experimental chemoselectivity in this transformation. Apparently, the need to deprotonate the sulfenamide drives up the barriers toward N-arylation while the S-arylation benefits from being able to proceed without this initial deprotonation due to the greater ability of the sulfur to take on positive charge. This kinetic control overcomes the far greater stability of the N-aryl product relative to the S-aryl product³⁵.

Next, we delved further into the chemoselectivity by comparing the experimental results with different ligands to our computational results (see Figures S3–4 in the Supporting Information). Notably, ligand L47, which gives a lower ratio of S-arylation:N-arylation product, has a smaller difference between energy spans for S-arylation and N-arylation (see Table S17). This agreement of the experimental results with our computational findings provides additional support for the proposed mechanism.

Finally, the origin of enantioselectivity in this transformation was investigated. The lowest energy conformations of the S-arylation transition state leading to (S)-enantiomer and (R)-enantiomer are shown in Figure 1c (for comparison of energetics with different methods, see Tables S18–20). Upon initial inspection of the transition state geometries, it is unclear what factors control the excellent enantioselectivity observed in this transformation (see Figure S5). As a result, interaction/distortion analysis was performed as described by Morokuma⁵⁴ as well as Houk and Bickelhaupt⁵⁵ (see Figure S6 for the fragments compared) in which the favorable interaction energy between the copper-ligand (CuL) and aryl substrate is compared with the energy required to distort the intermediates into the transition state geometries (see Figure S7). The distortion in the LCu component of [2–3]_R is 27.2 kcal/mol, which is much greater than the analogous distortion in the [2–3]_S (12.0 kcal/mol). This distortion in the LCu component can be observed in the overlaid transition state and intermediate geometries given in Figure S8. However, the interaction energy between the two LCu and aryl substrate components is greater in [2–3]_R, giving an overall energy of −34.4 kcal/mol compared to −34.1 kcal/mol in [2–3]_S. This trend of a more favorable interaction energy between the fragments in [2–3]_R is also observed in energy decomposition analysis performed with the second-generation absolutely localized molecular orbitals^56–58 (ALMO-EDA) method implemented in Q-Chem 5.0⁵⁹ using HF/6–311G(d,p) in the gas phase as employed by Liu⁶⁰ (see Table S21). Based on both interaction-distortion and energy decomposition analyses, the observed enantioselectivity does not arise predominantly from the sum of the distortion and interaction energies. Instead, it is the free energy difference, with a lower energy for [2–3]_S, that drives the enantioselectivity.

Thus, the difference in free energy between [2–3]_R and [2–3]_S was further explored. Since [2–3]_S is favored by 2.9 kcal/mol in free energy, but only by 0.3 kcal/mol in enthalpy, we attributed much of the enantioselectivity to entropic differences. On further examination of the transition state geometries (Figure 1c), the S-arylation transition state [2–3]_S leading to the (S)-enantiomer has an 8-membered ring involved in the bond formation whereas [2–3]_R has a 6-membered ring. This difference arises from different orientations of the NHPh group as the S-Ar bond forms that are controlled by the shape of the chiral cavity. For the [2–3]_S transition state, the pro-(S) enantiotopic lone pair on sulfur is involved in this bond forming process and the chiral cavity then disposes the NH to engage in a hydrogen bond with carboxylate of the thiophenecarboxylate ligand, thus creating the 8-membered ring transition state. On the other hand, when the pro-(R) enantiotopic lone pair on sulfur of [2–3]_R approaches to generate the bond, the NH cannot reach the thiophenecarboxylate within the chiral cavity. Instead, the NH makes a stronger hydrogen bond with the dihydroimidazole nitrogen of the ligand that is offset by greater overall distortion and a more rigid 6-membered ring transition state. In particular, the rigid non-chair conformation of this transition state possesses a disfavorable ΔS‡ (–5.5 cal/mol•K). Since the 8-membered ring is less rigid, it is more entropically favorable in accord with Hutchinson and coworkers⁶¹ and even has a favorable ΔS‡ (+3.4 cal/mol•K). The increased conformational entropy associated with the larger ring contributes to a favorable free energy for [2–3]_S. To validate our prediction that the ring size in [2–3]_R and [2–3]_S is responsible for the free energy difference, we computed the transition states leading to the R- and S-products for a truncated system with limited side chain conformations. The entropic differences persist in the model system, providing further evidence that the entropic factors derive in part from the ring sizes (Figure S9).

Finally, the decrease in the observed experimental enantioselectivity when the substrate is changed from the unsubstituted phenyl substrate (left, Figure S10) to the p-NO₂ substituted substrate (right, Figure S10) was computed with L10 ligand. In agreement with the observed experimental decrease in enantioselectivity (from 92% ee to 56% ee), the free energy difference also decreases (from 2.9 kcal/mol to 0.7 kcal/mol).

CONCLUSION

In summary, we have introduced a highly chemoselective and enantioselective Chan-Lam coupling of sulfenamides with arylboronic acids to synthesize a diverse range of diaryl and alkyl aryl sulfilimines containing a stereogenic sulfur center. A copper catalyst generated from the newly developed 2-pyridyl N-phenyl dihydroimidazole ligand enables effective enantiocontrol by means of a well-defined chiral environment and high reactivity that outcompetes the background racemic transformation. With this strategy, a single chiral ligand can deliver either enantiomeric product by exchanging the aryl groups of the sulfenamide and arylboronic acid substrates, thereby circumventing the need to prepare the enantiomeric ligands from the unnatural D-amino acids. The 2-pyridyl protecting group could be removed from the product which, in turn, could be readily transformed to S(IV) and S(VI) derivatives with retained enantiopurity. In addition, the synthetic utility of this unprecedented asymmetric coupling was underscored by synthesis of two sulfilimine-analogs of patented bioactive molecules. In concert with experimental data, computational studies reveal the unconventional chemoselectivity favoring C-S bond over C-N bond was enabled by disproportionation of Cu(II) complexes prior to deprotonation of sulfenamides. Furthermore, the excellent enantioselectivity arises from the difference of entropy between the transition states. The protocol described herein represents the first enantioselective Chan-Lam coupling, which is anticipated to serve as a powerful tool to prepare chiral scaffolds in medicinal chemistry and organic synthesis.

Methods

General Procedure for Catalysis.

To an oven-dried microwave vial equipped with a stir bar was added sulfenamide 1 (0.10 mmol), arylboronic acid 2 (0.2 mmol, 2.0 equiv), CuTc (1.9 mg, 0.01 mmol), L10 (5.5 mg, 0.015 mmol), CsF (7.6 mg, 0.05 mmol), and Na₂CO₃ (21.2 mg, 0.2 mmol). Then, the microwave vial was sealed with a cap. Oxygen was purged/vacuumed three times through a three-way valve, and the microwave tube turned to an oxygen atmosphere. DME (1.0 mL) was added into the reaction vial via syringe, and the reaction solution was stirred at room temperature under the oxygen atmosphere for 12 h. Upon completion of the reaction, the vial was opened to air, and the solution was concentrated under reduced pressure. The crude product was purified by flash chromatography, as outlined below, to afford the pure product.

Data availability

Detailed experimental procedures, characterization data, NMR spectra of new compounds, detailed computational results, and calculated structures are available within Supplementary Information. The X-ray crystallographic coordinates for structure reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition number CCDC 2215359 (for 3ba). These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service. Any further relevant data are available from the authors upon reasonable request.