Enantioselective β-C(sp³)─H Nucleophilic Tosylation of Native Amides: A Synthetic Platform for Chiral Methyl Stereocenters

Abstract

Enantioselective oxygenation of unactivated C(sp³)─H bonds via asymmetric metalation remains an unsolved challenge. Herein we report the development of a Pd-catalyzed, enantioselective C(sp³)─H tosylation of native amides with NaOTs as the nucleophile, representing a rare example of enantioselective C─H functionalization with a nucleophilic coupling partner. High enantioselectivity in this reaction is achieved by chiral mono-protected amino sulfonamide (MPASA) ligands. Substantial enhancement of enantioselectivity by silver salt additives was also observed. Through desymmetrization of the readily available isopropyl moiety, structurally diverse β-tosylated amides bearing an α-methyl stereocenter were obtained with high yield and enantioselectivity, which complements current enzymatic method for making Roche ester chiral synthon. The tosylated products are highly versatile chiral building blocks for further diversifications with nitrogen, oxygen and other nucleophiles, thus providing a platform for constructing chiral methyl stereocenters.

Graphical Abstract

INTRODUCTION

The introduction of a methyl group is well known to profoundly affect the biological activity and physical properties of small molecules, including many pharmaceutical candidates.¹ Therefore, synthetic methodologies for constructing chiral centers bearing methyl groups are highly valuable in drug discovery.² However, achieving direct catalytic asymmetric C(sp³)─H methylation remains a formidable challenge for synthetic chemists.³ For instance, despite the utility of enolate and enamine intermediates for the asymmetric synthesis of α-carbonyl stereocenters with larger alkylating agents, catalytic methods for asymmetric methylation remain limited,⁴ and often alternative strategies have to be explored.⁵ In contrast, nature has evolved efficient enzymes for asymmetric hydroxylations of isobutyric acid as demonstrated by the efficient production of Roche ester, a key source of chiral methyl-containing moieties in total synthesis (Figure 1A).⁶ Inspired by this challenge, our group developed a chiral palladium catalyst based on chiral mono-protected aminomethyl oxazoline (MPAO) ligands that can enable enantioselective C─H arylation, vinylation and alkynylation of isobutyric acid in 2017.⁷ More recently, similar transformations of thioamides⁸ and amides⁹ have been disclosed by Gong, Jiao, and Shi.¹⁰ However, these reports are restricted to C─C bond formation with limited scope of electrophilic coupling partners or boronic acids.¹¹ Developing C─H activation reactions with heteroatoms-based nucleophiles could dramatically enhance the synthetic utility of this strategy, as it allows exploiting a wide range of X-based (X = N, O and S) coupling partners to construct carbon-heteroatom bonds (Figure 1B).¹²

Figure 1.

Construction of α-Methyl Stereocenters via C─H Functionalization

C─H oxygenation with O-based nucleophiles is particularly compelling, as the newly installed C─O bond could serve as a handle for subsequent diversification.¹³ For instance, utilizing economical and readily available tosylate salts could be an appealing choice, since the resulting C─OTs bond is a versatile electrophile that can be displaced by a wide range of synthetically important nucleophiles.¹⁴ Thus, the products of an enantioselective tosylation reaction could serve as valuable chiral building blocks that would provide access to a wide range of elaborated chiral compounds bearing an α-methyl stereocenter.

Considering the ubiquity of native amide and lactam motifs in organic and bioorganic chemistry, it would be highly valuable to apply this approach within these substrates.¹⁵ Here we report the first enantioselective C(sp³)─H tosylation of native amides by using NaOTs as a cheap nucleophilic tosylate source and selectfluor as a bystanding oxidant (Figure 1C). Chiral mono-protected amino sulfonamide ligands (MPASA) proved to be essential for obtaining high selectivity in the desymmetrization of the gem-dimethyl moieties. This approach is also compatible with α-dimethyl lactams bearing an α-quaternary center and the products serve as valuable chiral building blocks for subsequent C─N, C─S. C─X bonds formation.

RESULTS AND DISCUSSIONS

Ligand Screening and Condition Optimization.

Given our success in ligand-enabled enantioselective C(sp³)─H functionalizations, we initiated our efforts by focusing on chiral ligand screening with a piperidine-derived amide 1a as the model substrate and AgOTs as the tosylate source (Figure 2). While direct formation of C─OTs bonds with Pd(II) is challenging, oxidation of the metal center to Pd(IV) with a bystanding oxidant has been shown to facilitate a wide range of C─O reductive eliminations.¹⁶ Guided by our prior experience with related Pd^II/Pd^IV catalytic cycles, we chose to focus on F⁺ reagents as the oxidant since the comparatively slow reductive elimination of fluoride would suppress undesired C─F bond formation. With selectfluor as a bystanding oxidant, five major classes of chiral ligands (MPAA, MPAQ, MPAO, MPAThio and MPAAM) developed by our group over the past decade, denoted as L1~L5 were tested (Figure 2, entry 1 to 5).¹⁷ The Ac-Val-OH (L1) provided the desired product with a modest yield and enantioselectivity (entry 1). Other ligands (L2-L4) showed different reactivity yet significantly lower enantioselectivity in all cases (entry 2-5). Subsequently, we aimed to amplify stereochemical communication by replacing the carboxylic acid group in L1 with a bulkier acidic amide (L6) or N-acyl sulfonamide (L7) (entry 6 and 7). To our delight, L7, a mono-protected amino sulfonamide (MPASA) improved the enantioselectivity to 80% ee (entry 7). While altering the ligand backbone to a six- membered chelate (L8) resulted in a dramatic decrease in enantiocontrol (entry 8), we found that electronic tuning of the aryl sulfonamide in the five membered chelate could enhance enantioselectivity (See Supporting Information for detailed screening data). The cyano-substituted L24 was identified as optimal ligand, providing the desired tosylated amide product in 46% yield and 92% ee (entry 9). However, replacing the silver tosylate with much cheaper NaOTs resulted in both diminished yield and enantioselectivity (entry 10). Inspired by previous studies indicating the crucial role of Ag⁺ in C─H activation, we tested the effect of adding silver salts as additives.¹⁸ To our delight, the addition of a catalytic amount of Ag₂CO₃ improved both the yield and enantioselectivity (entry 11). With an Ag₂CO₃ loading of 0.5 equivalents, the desired product was obtained in 65% yield and 95% ee. (entry 12). Notably, CuSO₄ could be used as a cheaper alternative for Ag₂CO₃, delivering the tosylated products with high yield albeit lower enantioselectivity (entry 13). It was observed that decreasing the temperature to 40 °C while extending the reaction time further increased the yield to 88% while maintaining the same enantioselectivity (entry 14). However, further reduction of the temperature led to reduced yield (entry 15). Notably, lower catalyst loading (5 mol%) exhibited similar reactivity and enantioselectivity at 85% yield and 94% ee (entry 16), providing the optimal reaction conditions.

Figure 2.

Ligand Screening and Condition Optimization. Reaction conditions: 1a (0.05 mmol, 1.0 equiv), AgOTs (2.0 equiv), Pd(PhCN)₂Cl₂ (10 mol%), ligand (20 mol%) and Selectfluor (1.2 equiv) in HFIP (0.5 mL), 45 °C, under air, 12 h. Yield determined by ¹H NMR; CH₂Br₂ as internal standard. Enantiomeric excess (ee) determined by SFC. ^a40 °C, under air, 36 h.

Scope of the Reaction.

With the optimal ligand and reaction condition in hand, we set out to explore the substrate scope for this enantioselective C(sp³)─H tosylation of native amides (Figure 3). The effect of the amine moiety was first evaluated. Various 4- or 3-substituted piperidine amides with functional groups including phenyl (2b), ester (2c), ketone (2d), protected amine (2e), difluoro (2f) and a spiro ring (2g) were found to be compatible, delivering desired products in good yield and enantioselectivity. Cyclic amine moieties bearing heteroatoms in the ring, such as morpholine (2h) and protected piperazine(2i-2j) resulted in a slightly lower yield yet maintain excellent enantioselectivity. Notably, replacing the 4-carbon with silicon as a carbon isostere gave excellent yield and enantioselectivity (2k).¹⁹ A hexahydrooxazolo[3,4-α]pyrazin-3-one amide, which is a crucial motif ²⁰ in various bioactive molecules, could react with excellent yield and enantioselectivity (2l). Different ring sizes of the cyclic amine were also found to be compatible. While azetidine-derived amides afforded moderate levels of enantioselectivity (2m-2n), pyrrolidine (2o-2p) and azepane-derived amides (2q) reacted with high levels of enantioselectivity. Various non-cyclic amines were also well tolerated, including N-benzyl amides which can be readily deprotected to provide secondary and primary amides (2r-2v). N-phenyl amides were also effective, albeit requiring blocking of the 2,6-positions of the arene to avoid undesired C(sp²)─H activation (2w). Atropine and Risperidone derived amides were found to react in modest to good yields and high enantioselectivities (2x-2y). Secondary amide afforded the tosylation product with moderate yield but poor enantioselectivity (2z). The diastereoselective tosylation of substrates bearing a chiral center on the cyclic amine moiety was also achieved, with essentially complete catalyst control over substrate control, allowing access to either diastereomer based on the selection of the ligand enantiomers (2aa-2af).

Figure 3.

Isobutyramide Substrate Scope. Reaction conditions: 1 (0.10 mmol, 1.0 equiv), NaOTs (2.0 equiv), Pd(PhCN)₂Cl₂ (5 mol%), L24 (6 mol%) and Selectfluor (1.2 equiv) in HFIP (1.0 mL), 40 °C, under air, 36 h. Isolated yield. Enantiomeric excess (ee) determined by SFC.

Given the prevalence of quaternary nitrogen-containing heterocycles, we next turned our attention to using this practical tosylation method on α-quaternary lactam substrates (Figure 4). Pleasingly, 3,3-dimethyl piperidones which are widespread functional groups in many drug and bioactive molecules, could be tosylated with excellent yield and enantioselectivity (4a-4b). Notably, a protected α,α-dimethyl tetrahydropyrimidin-4-one was tolerated (4c), which could be deprotected and hydrolyzed to provide corresponding open-chain chiral β^2,2-amino acid.²¹ A bulkier piperidine-2,4-dione could also undergo tosylation, but only with non-chiral ligand. Simple caprolactams failed to provide the desired tosylated product (4e). However, a 5,5- difluoro caprolactam could react smoothly with moderate yield and enantioselectivity (4f). In addition to the OTs group, other sulfonyloxy groups can also be installed efficiently. Use of sodium methane sulfonate gave the mesylated (OMs) product (4g) in 70% yield and 96% ee. Likewise, benzenesulfonate and 4-chloro-benzenesulfonate both coupled efficiently with lactam substrate to give the corresponding sulfonyloxylation products in good yield and enantioselective (4h-4i). Notably, these lactam products can be readily converted to chiral saturated 3,3-disubstituted N-heterocycles via amide reduction.²²

Figure 4.

Lactam Substrate Scope. Reaction conditions: 3 (0.10 mmol, 1.0 equiv), NaOTs (2.0 equiv), Pd(PhCN)₂Cl₂ (5 mol%), L24 (6 mol%) and Selectfluor (1.2 equiv) in HFIP (1.0 mL), 40 °C, under air, 36 h. Isolated Yield. Enantiomeric excess (ee) determined by SFC. ^aPd(PhCN)₂Cl₂ (10 mol%), L24 (20 mol%), Selectfluor (2.0 equiv), 80 °C, 36 h ^bno ligand, 80 °C, 36 h.

In addition to enantioselective desymmetrization of dimethyl groups, we also examined the kinetic resolution of racemic amides bearing an α-methyl stereocenter (Figure 5). Various alkyl chains and amine moieties were compatible and the chiral tosylated products were afforded in moderate yield and decent enantioselectivity (6a-6g). Moreover, structurally diverse 3- mono methyl lactams could also be tosylated smoothly with excellent yield and enantioselectivity (6h-6l). However, kinetic resolution of α-quaternary lactam was ineffective.

Figure 5.

Kinetic Resolution. Reaction conditions: 5 (0.10 mmol, 1.0 equiv), NaOTs (2.0 equiv), Pd(PhCN)₂Cl₂ (5 mol%), L24 (6 mol%) and Selectfluor (1.2 equiv) in HFIP (1.0 mL), 40 °C, under air, 24 h. Isolated Yield. Enantiomeric excess (ee) determined by SFC. Calculated conversion, $c=e{e}_{\text{SM}}∕(e{e}_{\text{SM}}+e{e}_{\text{PR}})$. Selectivity $(s)=\text{ln}[(1-c)(1-e{e}_{\text{SM}})]∕\text{ln}(1-c)(1+e{e}_{\text{SM}})]$. ^#Yield determined by 1H NMR.

Synthetic Application.

Finally, the application of this enantioselective tosylation as a general platform for late-stage diversification was demonstrated using substrate 2b as an example (Figure 6A). The tosylated product can be prepared on gram scale in 52% yield and 93% ee. to serve as a common intermediate for diversification. Subsequent derivatization via S_N2 reactions provides rapid access to a variety of native amides bearing an α-chiral methyl group through C─X, C─S, and C─Nbond forming reactions. Notably, it is challenging to introduce functional groups such as azides and sulfides using common C─H activation methods because of their strong coordination to transition metals and their sensitivity to oxidants. Our tosylation approach can overcome this limitation to afford azide 7d and thioether 7e by employing the tosylated product as a key intermediate. The tosylated lactam product 4b also underwent substitution reactions smoothly to provide various chiral 3,3- disubstituted lactams (Figure 6B). These lactams can serve as precursors to access diverse C3-substituted chiral piperidines, which are otherwise difficult to synthesize.²⁰ Moreover, a hydroxylated product 9a can be prepared from substrate 1a in two steps with 41% yield and 93% ee. Subsequent amide reduction provided the chiral 1,3-amino alcohol 9c in nearly quantitative yield (Figure 6C). A cross-coupling reaction of tosylated lactam 4a with Grignard reagent was also performed, providing the β-arylated chiral lactam 10 in moderate yield while maintaining high enantioselectivity (Figure 6D).²³

Figure 6.

Product Diversification. ^#Enantiomeric excess (ee) determined by its benzyl protected derivative. (a) LiF (4.0 equiv), THF. (b) LiBr (4.0 equiv), THF. (c) NaI (4.0 equiv), acetone, 80 °C, 24 h. (d) NaOPh (2.0 equiv), THF. (e) PhSH (2.0 equiv), NaOH (2.0equiv), EtOH. (f) NaN₃ (4.0 equiv), THF (g) 5-bromoindole (2.0 equiv), NaH (2.0 equiv), EtOH.

Mechanistic Studies.

To gain further insight into this reaction, we performed deuterium incorporation experiments in HFIP-OD (Figure 7A). The absence of deuterium incorporation in both the tosylated product and the recovered substrate suggested that the C─H cleavage step is irreversible for β-C(sp³)─H tosylation. Moreover, kinetic isotope effect (KIE) studies revealed large primary KIE values (pKIE of 5.4 & cKIE of 5.7)) when using β-deuterated substrates (Figure 7B and Figure 7C). These results are consistent with the C─H cleavage being the rate- and enantio-determining step for β-C(sp³)─H tosylation.

Figure 7.

Mechanistic Studies. Yield determined by ¹H NMR; CH₂Br₂ as internal standard.

CONCLUSIONS

In summary, we have developed an enantioselective β-C(sp³)─H tosylation of native amide substrates including lactams. A bulky and electron-deficient mono-protected amino sulfonamide (MPASA) was identified as an effective ligand for the differentiation of small geminal dimethyl groups. This method provides access to synthetically valuable α-methyl stereocenters while forming a C─O bond with nucleophilic tosylate. Subsequent substitution reactions of the tosylated products were compatible with a wide range of nucleophiles, demonstrating the synthetic versatility of the products as chiral building blocks. The tosylated lactams can be transformed into diverse valuable chiral C3-quaternary N-heterocycles.

METHODS

General procedure for enantioselective β-C(sp³)─H tosylation of native amides including lactams: In air, to an oven-dried reaction tube (10 mL) equipped with a magnetic stir bar was added Pd(PhCN)₂Cl₂ (1.9 mg, 5 mol%), ligand (L24, 1.9 mg, 6 mol%), Selectfluor (42.5 mg, 1.2 equiv), NaOTs (38.8 mg, 2.0 equiv), Ag₂CO₃ (13.8 mg, 0.5 equiv) and solvent (HFIP, 1.00 mL), followed by the amide substrate (0.1 mmol, 1.0 equiv). The tube was sealed and stirred at 40 °C for 36 h under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature and the dark brown suspension was diluted with 2 mL of ethyl acetate and was passed through a pad of Celite and washed with ethyl acetate (1.0 mL × 3). The crude reaction mixture was purified by preparatory TLC using hexanes/EtOAc (2 : 1 to 1 : 10) as the eluent to afford the desired product.

Supplementary Material

The Supporting Information is available free of charge at

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