Highly Enantioselective, Hydrogen-Bond-Donor Catalyzed Additions to Oxetanes

Abstract

A precisely designed chiral squaramide derivative is shown to promote the highly enantioselective addition of trimethylsilyl bromide (TMSBr) to a broad variety of 3-substituted and 3,3-disubstituted oxetanes. The reaction provides direct and general access to synthetically valuable 1,3-bromohydrin building blocks from easily accessed achiral precursors. The products are readily elaborated both by nucleophilic substitution and through transition-metal-catalyzed cross-coupling reactions. The enantioselective catalytic oxetane ring opening was employed as part of a 3-step, gram-scale synthesis of pretomanid, a recently-approved medication for the treatment of multi-drug-resistant tuberculosis. Heavy-atom kinetic isotope effect (KIE) studies are consistent with enantiodetermining delivery of bromide from the H-bond-donor (HBD) catalyst to the activated oxetane. While the nucleophilicity of the bromide ion is expected to be attenuated by association to the HBD, overall rate acceleration is achieved by enhancement of Lewis acidity of the TMSBr reagent through anion-abstraction.

Graphical abstract

Chiral anion-binding catalysis has emerged as a powerful strategy for enantioselective additions to cationic intermediates through their non-covalent association to catalyst-bound spectator anions.^1,2 In most applications identified to date, the chiral catalyst-anion complex mediates stereoinduction in the addition of an external nucleophile (Figure 1A). An interesting variation to the anion-binding catalysis concept arises when the catalyst-bound anion also acts as the nucleophile in the enantiodetermining bond construction.^3,4 At least in principle, such an approach can provide more precise control over stereoselectivity through specific association of both nucleophile and electrophile to the chiral catalyst. However, H-bonding from the catalyst would also be expected to attenuate the reactivity of the nucleophile relative to an uncatalyzed, racemic pathway.⁵ This fundamental reactivity challenge can be circumvented if the catalyst also promotes the generation of the reactive ion-pair, as demonstrated elegantly by Gouverneur^3f,g in the specific context of phase-transfer reactions of alkali metal fluorides (Figure 1B). Following the recent discovery that H-bond donors such as chiral squaramides can activate silyl triflates via anion binding to promote enantioselective transformations,⁶ we were drawn to an alternative and possibly general approach to catalysis of nucleophile delivery by applying the anion-binding principle to activation of Lewis acids bearing nucleophilic counterions. Anion abstraction from the promoter should result in enhanced Lewis acidity, providing a general platform to access highly-reactive, cationic, electrophilic intermediates ion paired with a catalyst-bound nucleophilic anion (Figure 1C).

Figure 1.

(A) Conventional approach to anion-binding catalysis in which the catalyst binds a spectator anion. (B) Alternative reactive mode in anion-binding catalysis involving delivery of the bound anionic nucleophile to a cationic electrophile. Hydrogen bonding attenuates the reactivity of the nucleophile, but rate acceleration has been achieved via phase-transfer catalysis. (C) Catalyst-promoted ionization of an anionic nucleophile from a neutral Lewis acid-nucleophile complex allows for H-bond donor catalyzed anion delivery.

We chose to explore the anion-binding effect on nucleophile-bearing Lewis acids in the context of additions of TMSBr to prochiral oxetanes (Fig. 2A). Enantioselective ring-opening of 3-substituted oxetanes provides a route to valuable 3-carbon chiral building blocks from simple, synthetically-accessible precursors.⁷ Several examples of enantioselective openings of 3-susbtituted oxetanes with intramolecular nucleophiles have been identified.^8,9 However, more generally applicable highly enantioselective reactions involving intermolecular nucleophilic addition are limited to two pioneering examples from Sun and coworkers involving chiral phosphoric acid-catalyzed addition of mercaptobenzothiazole and HCl.¹⁰ Here we report the successful application of a chiral squaramide catalyst to promote the ring-opening addition of TMSBr to prochiral oxetane substrates with unprecedented substrate scope.

Figure 2.

A) Model reaction: enantioselective opening of oxetanes with TMSBr. B) Catalyst screening data for a series of arylpyrrolidino squaramides.

The addition of TMSBr to 3-phenyloxetane (1a) was selected as a model reaction.¹¹ Squaramide hydrogen-bond-donor catalysts^6,12 bearing a 2-arylpyrrolidino amide were identified as particularly effective, with the the aryl substituent having a marked effect on enantioselectivity and reproducibility (Fig. 2B). Systematic reaction and catalyst development (Fig. S1-S5) led to the identification of 9-phenanthryl squaramide 3a as the optimal catalyst for the synthesis of silylated bromohydrin 2a, catalyzing its formation in quantitative yields and with 96-98% e.e. over >20 runs.¹³

Squaramide 3a was found to catalyze the opening of a broad range of 3-subsituted and 3,3-disubstituted oxetanes in high levels of e.e. (Figure 3). With 3-aryl oxetanes, both electron donating and withdrawing substituents could be introduced, with only ortho substitution impacting enantioselectivity adversely (1a–h). Weakly Lewis basic functional groups such as nitriles (1f) and esters (1g) had no deleterious effect on the reaction, and aryl ether spectator groups remained intact (1h). Oxetanes bearing protected alcohol and amine functionality (1i–m) as well as simple saturated alkyl groups (1n-p) all underwent reaction with high enantioselectivity. The reaction could even be extended successfully to certain 3,3'-disubstituted oxetane substrates, which underwent stereoselective ring opening to provide products bearing fully substituted stereocenters (1q–v) with moderate-to-high enantioselectivity.

Figure 3.

Isolated yield and enantiomeric enrichments measured for the asymmetric oxetane opening at 0.4 mmol scale. See SI for details on methods for e.e. determination, reproducibility studies, and the assignment of absolute configuration. ^a Isolated as a 12.5 : 1 ratio of ROTMS to ROH product. ^b 48-hr reaction time. ^c −25 °C. ^d 72-hr reaction time. ^e 7.5 mol% 3a. ^f −65 °C.

Alkyl bromide 2a was examined as a model substrate for potential product derivatizations (Fig. 4A) and was found to undergo facile substitution with azide, cyanide, and thiophenolate nucleophiles. Recent advances in transition-metal-catalyzed cross-coupling chemistry¹⁴ provide further opportunities for product elaborations; for example, we found that 2a engaged effectively in cobalt-catalyzed arylations.¹⁵ Moreover, the polarity of the electrophilic alkyl bromide could be inverted either by copper-catalyzed borylation,¹⁶ or through metal-halogen exchange, allowing 2a to function as the nucleophilic partner in a C(sp²)–C(sp³) cross coupling.¹⁷ Overall, the diverse range of products that can be accessed directly from 2a illustrates the synthetic versatility of these chiral bromohydrin building blocks.

Figure 4.

A) Product elaborations: all reported yields are for the entire sequence of reactions starting from 1a a) standard reaction conditions with 0.4 mmol 1a; b) NaCN; c) NaN₃; d) NaSPh; e) p-TolMgBr, Co(acac)₃, TMEDA; f) B₂Pin₂, CuCl, Xantphos, t-BuOK; g) NaI in MeCN then solvent swap to Et₂O, t-BuLi, ZnCl₂, Pd(dppf)Cl₂, R-I. See SI for detailed procedures. B) Glycidol- and oxetane-based strategies to C3 chiral derivatives. C) Gram-scale synthesis of pretomanid: Ar = 4-(trifluoromethoxy)phenyl h) 4-(trifluormethoxy)benzyl bromide (1.2 equiv.), NaH (1.2 equiv.), 2-Me-THF (1.0 M), 60 °C, 12 hr; i) 3a (2 mol%), TMSBr (1.1 equiv.), t-BuOMe (0.25 M), −80 °C, 24 hr; j) 2-chloro-4-nitroimidazole (2.0 equiv.), Et₃N (2.1 equiv.), NaI (1.0 equiv.) DMF (0.25 M), 115 °C, 24 hr, then cool to 23 °C and add MeOH (1.0 M) and NaOH (5.0 equiv.), 30 min.

The oxetane-opening methodology presents an interesting alternative to well-established synthetic strategies for accessing three-carbon chiral building blocks based on glycidol or epichlorohydrin derivatives (Figure 4B).¹⁸ In particular, the identity of the C2 group can be set in the prochiral oxetane substrate, thereby avoiding potentially multi-step late-stage functional-group manipulations required in routes involving epoxide ring-opening. This advantage is illustrated in the synthesis of the recently approved tuberculosis drug pretomanid¹⁹ (Figure 4C), which was prepared previously by Reider, Sorensen and coworkers in an elegant 5-step route from enantioenriched (R)-3-chloro-1,2-propanediol.^20a Readily accessible oxetane 1w underwent highly enantioselective ring-opening to yield TMS-protected bromohydrin 2w in 98% e.e.²¹ Gratifyingly, 2-chloro-4-nitroimadzole, which was identified in the Reider and Sorensen synthesis as a non-explosive alternative to 2,4-dinitroimidazole,^20a underwent alkylation by 2w with complete regioselectivity followed by S_NAr annulation to yield the desired product. Both intermediates were formed in sufficient purity to be carried forward without purification, and only a recrystallization of the final product was required to access analytically-pure pretomanid (10) in >99% e.e. The synthetic route avoids protecting-group manipulation steps and provides access to pretomanid in just 3 steps.

As an initial step toward establishing the basis for exquisite enantiocontrol in oxetane ring-opening reactions with squaramide 3a, we endeavored to determine whether bromide delivery was indeed the enantiodetermining step as proposed at the outset of reaction development. To address this question, the ¹²C / ¹³C KIE at the site of bromide attack was determined through analysis of starting material recovered at partial conversion from a one-pot competition between doubly labeled oxetane ¹³C₂-1a and unlabeled isotopologue 1a (Fig. 5).²² If bromide-promoted ring opening were substrate-committing, and thus, enantiodetermining, a primary KIE consistent with C─O bond cleavage would be expected. In contrast, if a step preceding ring opening such as oxetane silylation were irreversible then only a small, secondary KIE would be anticipated. Irreversible silylation would not necessarily preclude enantiodetermining bromide delivery, but it would allow for the possibility that silylation of 1a was enantiodetermining.²³ Subjection of a mixture of 1a and ¹³C₂-1a to the catalytic reaction conditions led to the observation of a large, primary KIE (k₁₂/k₁₃ = 1.126(9)), fully consistent with reversible silylation and enantioselectivity-determining bromide delivery (see SI for full details of the KIE studies).

Figure 5.

One-pot competition KIE between 1a and ¹³C₂-1a. A primary KIE of 1.126(9) was measured, indicating that oxetane silylation must be reversible, supporting enantiodetermining bromide delivery.

In conclusion, the chiral squaramide-catalyzed addition of TMSBr to 3-aryl, 3-alkyl, and 3-heteroatom substituted oxetanes as well as certain 3,3-disubstituted oxetanes provides a general enantioselective synthesis of protected 1,3-bromohydrin derivatives. The products of these reactions can be elaborated through a variety of nucleophilic substitution reactions, and the utility of the method is illustrated in the 3-step, gram-scale synthesis of the TB drug pretomanid. Heavy-atom KIE studies are consistent with enantiodetermining bromide delivery by the catalyst to an activated oxetane. This strategy overcomes the intrinsic deactivation of nucleophiles that accompanies association with an H-bond donor and holds promise as a broadly applicable approach to asymmetric catalysis of addition reactions.