Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides: A General Approach for the Synthesis of Drug Relevant S-Methyl and S-Cyclopropyl Sulfoximines

Abstract

Sulfoximines are increasingly utilized in pharmaceuticals and agrochemicals with all sulfoximine clinical candidates incorporating either an S-methyl or an S-cyclopropyl substituent. Here, we report on a general and efficient sequence for the asymmetric synthesis of both of these sulfoximine substitution patterns. The asymmetric synthesis of sulfilimine intermediates by the first Ru-catalyzed enantioselective alkylation of sulfenamides enables the first examples of enantioselective S-alkylation with monosubstituted diazo compounds. The reaction proceeds at ≤1 mol % Ru-catalyst loading, and for tert-butyl diazoacetate, high yields and ≥98:2 er are achieved for an exceedingly broad range of sulfenamides, including with S-(hetero)aryl, -alkenyl, -methyl, -benzyl, -branched alkyl and -tert-butyl substituents and for sterically and electronically diverse N-acyl groups. Sulfenamides derived from densely functionalized advanced drug intermediates also alkylated with 99:1 er. After oxidation of an N-pivaloyl S-tert-butyl acetate substituted sulfilimine to the corresponding sulfoximine, treatment with trifluoracetic acid in an aprotic solvent resulted in decarboxylation to the S-methyl N-pivaloyl sulfoximine, while aqueous HCl resulted in both decarboxylation and cleavage of the N-acyl group to give the S-methyl NH sulfoximine. Alternatively, sulfoximine alkylation with dibromoethane followed by acid-mediated decarboxylation provides the S-cyclopropyl sulfoximine. The efficient asymmetric synthesis of the preclinical candidate LTGO-33 and the formal asymmetric synthesis of the phase II clinical candidate ART0380 demonstrate the utility of the disclosed approach.

The sulfoximine motif is increasingly utilized in drug discovery and development due to its high aqueous solubility, metabolic stability, and potential for enhancing compound potency and selectivity.¹ Many preclinical and clinical candidates now incorporate the sulfoximine pharmacophore (Scheme 1A). For almost all of these compounds, the two carbon substituents on the tetrahedral sulfur are different, resulting in a stereogenic sulfur center that requires asymmetric synthesis. To achieve the enantioselective catalytic synthesis of sulfoximines, asymmetric catalytic oxidation² and amination³ of thioethers were first developed. Recently, we reported the asymmetric catalytic synthesis of sulfilimines^4,5 in route to sulfoximines by the first enantioselective catalytic C–S bond formation of readily available sulfenamides,⁶ which are desirable reactants for chiral discrimination because their carbon and nitrogen S-substituents have inherently different steric, electronic, and hydrogen bonding properties (Scheme 1B).⁷ In our initial publication, we used chiral dimeric Rh(II) tetracarboxylate catalysts and α-aryldiazoacetates to access S-benzyl sulfoximines and subsequently reported reactions with α-amidediazoacetates to prepare S-acetamide sulfoximines.⁸ Innovative new strategies for S-arylation⁹ and S-alkylation¹⁰ have now also been reported.¹¹

Scheme 1. Bioactive Sulfoximines and Catalytic Asymmetric Alkylation of Sulfenamides.

However, none of these approaches provide general access to the S-methyl or S-cyclopropyl sulfoximine substitution patterns present in all the clinical candidates and most of the preclinical candidates incorporating sulfoximine functionality.

Herein, we report the first Ru-catalyzed asymmetric alkylation of sulfenamides with diazo compounds (Scheme 1C). Not only is ruthenium approximately 10-fold less expensive than rhodium but also Iwasa’s Ru-Pheox catalyst¹² enables asymmetric sulfenamide S-alkylation with monosubstituted diazo compounds for the first time. For alkylation with diazoacetates, high enantioselectivity is achieved for an exceedingly broad range of sulfenamides with different S-substituents and N-acyl groups, including sulfenamides derived from densely functionalized advanced drug intermediates. After oxidation of the sulfilimine to the sulfoximine, facile decarboxylation is achieved by treatment with TFA in an aprotic solvent to provide the N-pivaloyl (Piv) protected S-methyl sulfoximine, and upon treatment with aqueous HCl, decarboxylation with concomitant cleavage of the N-Piv group affords the S-methyl NH sulfoximine, the form most commonly found in drug candidates. Additionally, alkylation of the sulfoximine with dibromoethane prior to decarboxylation provides rapid entry to the S-cyclopropyl sulfoximine. The utility of the disclosed enantioselective catalytic approach is demonstrated by the efficient asymmetric synthesis of LTGO-33,¹³ a preclinical candidate for the treatment of pain, and by the asymmetric formal synthesis of ART0380, a phase II clinical candidate for the treatment of cancer.¹⁴ Notably, the reported syntheses of enantiomerically pure LTGO-33 and ART0380 utilized racemic sulfoximines along with supercritical fluid chromatographic (SFC) separation.

We had previously investigated asymmetric catalytic alkylation of sulfenamides with diazoacetates utilizing commercially available chiral dimeric Rh(II) tetracarboxylate catalysts but observed disappointing enantioselectivities (data not shown). This outcome is not surprising given that this class of catalysts is most effective for asymmetric transformations with aryldiazoacetates and select other disubstituted diazo compounds.¹⁵ We therefore investigated alternative catalysts and identified the Ru-Pheox class of catalysts developed by Iwasa for asymmetric cyclopropanation of alkenes with monosubstituted diazo compounds¹² as a particularly promising catalyst system. After optimization of the reaction parameters (Table S1), we established that asymmetric catalytic alkylation of S-phenyl sulfenamide 1a with tert-butyl diazoacetate (2a) with only 1 mol % of Ru(II)-(S)-Pheox in CH₂Cl₂ at −22 °C provided complete conversion within one hour to sulfilimine 3a in 99% yield and with a 99:1 er (Scheme 2). Reaction temperatures of 0 °C and rt resulted in 98:2 and 97:3 er, respectively (entries 2 and 3). A Pheox catalyst with a tert-butyl in place of the phenyl group resulted in a slight reduction in selectivity to 98:2 er (entry 4). Although high yields and enantioselectivities were obtained in a range of solvents (entries 5 to 14), CH₂Cl₂ provided the highest selectivity. A 99:1 er was maintained at higher concentrations of 0.2 and 0.4 M (entries 15 and 16), which is desirable for large scale reactions (vide infra).

Scheme 2. Ru-Catalyzed S-Alkylation Substrate Scope^a.

^aReactions performed at 0.2 or 0.3 mmol scale of 1 and isolated yields are reported. Enantiomeric ratios determined by chiral HPLC or SFC analysis. ^b5 min reaction time. ^c4 h reaction time. ^d2 h reaction time. ^e24 h reaction time at rt. ^f20 h reaction time at −40 °C with Ru(II)-(S)-tBu-Pheox. ^g4 h reaction time at −40 °C. ^hIsolated yield and enantiopurity after recrystrallization.

We first explored scope for the sulfenamide S-substituent (Scheme 2). Electron-rich and -deficient S-aryl inputs provided sulfilimine products 3b and 3c, respectively, in high yields and with 99:1 er. Sulfilimines incorporating electrophilic ester (3d) and aldehyde (3e) as well as metal coordinating nitrile (3f) functionality were also obtained in excellent yield and 99:1 er. Sulfilimine 3g, with a meta-bromo substituent, a useful handle for further elaboration by cross-coupling reactions, was obtained in near quantitative yield. Sulfilimine 3h, which features a more sterically demanding ortho-chloro substituent, was obtained with only a minimal reduction in selectivity (98:2 er), and the β-naphthyl sulfilimine 3i was obtained without any loss of selectivity (99:1 er). Furthermore, thienyl (3j), pyridyl (3k), and alkenyl (3l) sulfilimines could all efficiently be synthesized in ≥98:2 er.

For most catalytic asymmetric C–S bond forming reactions, S-alkyl sulfenamides provided significantly lower enantioselectivies than S-aryl derivatives.^7–9 In marked contrast, the Ru-Pheox-catalyzed alkylation of S-alkyl sulfenamides proceeded with ≥98:2 er regardless of the steric parameters of the S-alkyl group (3m–3s), including for the smallest S-methyl (3m) and the very bulky S-tert-butyl (3p). The tetrahydropyranyl (3r) and N-Boc piperidinyl (3s) derivatives established the successful incorporation of drug relevant saturated heterocycles.

We also varied the N-acyl group. Sulfilimines with drastically different steric environments provided by the N-acetyl (3t), -isobutyryl (3u), and -diethylbutanoyl groups (3v), were all obtained in ≥98:2 er. Moreover, high selectivities were maintained for N-aroyl derivatives (3w–3z), including for electron-rich para-methoxy (3x), electron-poor para-trifluoromethyl (3y), and more sterically demanding ortho-methyl (3z) substituents. All the N-acyl sulfilimine products were obtained in >95% yield except for sulfilimine 3y, which was obtained in 70% yield.

We next assessed the reaction scope of the diazo coupling partner 2 (Scheme 2). Broad scope for diazo esters was observed, with the isopropyl ester 3aa obtained in 99:1 er and the unbranched ethyl (3ab) and benzyl (3ac) esters obtained with slightly lower selectivities of 98:2 and 97:3 er, respectively. Our study was directed at catalytic asymmetric alkylation with monosubstituted diazo compounds. However, given the successful application of chiral dimeric Rh(II) tetracarboxylates as catalysts for asymmetric transformations with aryldiazoacetates,^7,15 we also evaluated methyl phenyl-diazoacetate as a reactant, but 3ad was obtained in only 39% yield and with very poor stereoselectivity. This result highlights the complementarity of Ru(II)-Pheox and chiral dimeric Rh(II) tetracarboxylate catalysts for different classes of diazo coupling partners.

Monosubstituted diazo compounds with other electron withdrawing groups were also evaluated. Diethyl diazomethyl-phosphonate provided 3ae in an 86% yield but with a moderate selectivity of 88:12 er. For this reactant, the tert-butyl derivative of Ru(II)-Pheox and a −40 °C reaction temperature were employed. Diazomethylsulfonyl reactants also coupled at −40 °C in near quantitative yields to give 3af and 3ag with 91:9 er. As demonstrated for phosphonate 3ae and sulfone 3af, recrystallization provided considerable enrichment in enantiopurity. The unstabilized diazo compound trimethylsilyldiazomethane was also examined, but sulfenamide S-alkylation was not observed.

The developed method is applicable to the late-stage functionalization of advanced drug derivatives (Scheme 3A). Sulfilimine 3ah was prepared in 89% yield and 99:1 er from a precursor to apixaban, a blockbuster drug for the treatment of stroke, and sulfilimine 3ai was prepared in 76% yield and 99:1 er from a derivative of the cancer drug trametinib. These examples showcase the broad functional group tolerance of the reaction, with amide, indazole, and ester groups present in 3ah and multiple basic sites and acidic N–H functionality present in 3ai.

Scheme 3. Applications to Complex Molecule Synthesis and Conversion to Sulfoximines^a.

^aIsolated yields reported, with enantiomeric ratios determined by chiral HPLC or SFC analysis.

To enhance the practicality of the reaction at larger scale, a gram-scale reaction was performed with a reduced catalyst loading of 0.2 mol % and with the reaction concentration increased to 0.4 M (Scheme 3B). Under these conditions, 3a was isolated in 97% yield and with a 99:1 er. The stereospecific oxidation of sulfilimines to sulfoximines is well-precedented,^7,8,16 and as expected, oxidation of 3a to sulfoximine 4 occurred in high yield without racemization.

The sulfoximine 4 served as a versatile precursor toward drug-relevant S-methyl and S-cyclopropyl sulfoximines (Scheme 3B). Treatment of sulfoximine 4 with aqueous 3 N HCl afforded concomitant decarboxylation and cleavage of the N-pivaloyl group to give the free-NH S-methyl sulfoximine 5 in 83% yield without racemization. The absolute configuration of 5 was assigned by correlation of the optical rotation and chiral HPLC retention times to those reported in the literature.¹⁷ Alternatively, upon treatment of sulfoximine 4 with TFA in CH₂Cl₂, only decarboxylation occurred to provide the N-pivaloyl protected S-methyl sulfoximine 6 in 81% yield without any racemization.

The S-cyclopropyl sulfoximine 7 was obtained from 4 by bisenolate alkylation with 1,2-dibromoethane in 85% yield (Scheme 3B).¹⁸ Treatment of 7 with TFA and subsequent heating in toluene resulted in decarboxylation to afford the N-pivaloyl S-cyclopropyl sulfoximine 8 in 79% yield.

We next demonstrated the utility of our method by the asymmetric synthesis of LTGO-33, a recently disclosed NaV1.8 inhibitor that is a preclinical candidate for the treatment of pain, and by the formal asymmetric synthesis of ART0380, an ATR inhibitor in phase II clinical trials for the treatment of cancer (Scheme 3C). Notably, the reported syntheses of both drug candidates relied on racemic sulfoximines and SFC separations.

For the asymmetric synthesis of LTGO-33 (Scheme 3C), intermediate 9 was first prepared in two steps and 70% overall yield from commercially available starting materials (see SI Section VIII). Next, Ullmann coupling of 9 with N-pivaloyl S-phenethyl sulfenamide proceeded with in situ elimination of styrene from the sulfilimine intermediate to give sulfenamide 10 in 72% yield.^6b Asymmetric alkylation then provided sulfilimine 11 in 99% yield and a 99:1 er. After oxidation to sulfoximine 12 in 95% yield, treatment with aqueous 3 N HCl resulted in decarboxylation and N-pivaloyl group cleavage to give LTGO-33 in 88% yield.

For the formal asymmetric synthesis of ART0380 (Scheme 3C), asymmetric S-alkylation with Ru(II)-(R)-Pheox provided ent-3n in 95% yield and a 98:2 er. Oxidation to the sulfoximine 14 proceeded in 80% yield. Treatment of 14 with TFA and then heating in toluene resulted in decarboxylation to afford sulfoximine 15 in 71% yield. Reductive cleavage of the N-pivaloyl protecting group with LiAlH₄^7,10b then provided 16 in 86% yield. We chose to utilize this reductive procedure rather than aqueous hydrolysis cleavage approaches due to the high aqueous solubility of 16. Given that racemic 16 was employed in the reported synthesis of ART0380,¹⁴ the sequence described here constitutes a formal synthesis of this phase II clinical candidate.

A mechanism is proposed in analogy to that reported by Iwasa for Ru(II)-Pheox-catalyzed cyclopropanation of alkenes (Scheme 4).^12,19 Reaction of the ruthenium catalyst with diazo compound 2 generates the ruthenium carbenoid I with release of nitrogen. The attack of sulfenamide 1 upon I generates ylide II with release of the catalyst. Ylide II then tautomerizes to sulfilimine 3. In ongoing work, we are investigating modifications of the Pheox ligand structure to identify those aspects that most contribute to high catalytic turnover and asymmetric induction. We intend to use this data along with supporting DFT calculations to design catalysts with enhanced selectivity for other classes of diazo compounds.

Scheme 4. Proposed Mechanism.

In summary, we report the Ru(II)-Pheox-catalyzed enantioselective S-alkylation of sulfenamides to afford sulfilimines in uniformly high yields and for most examples ≥98:2 er. Exceptionally broad scope was observed for sulfenamides with different S-substituents and N-acyl groups. Moreover, after stereospecific oxidation to the sulfoximine, the S-methyl sulfoximine could be obtained in one step and the S-cyclopropyl sulfoximine in two steps. The utility of the methodology was demonstrated by the efficient asymmetric synthesis of LTGO-33 and the formal asymmetric synthesis of ART0380.