Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters.

Molecules that contain a stereogenic phosphorus atom are crucial to medicine, agrochemistry and catalysis. While methods are available for the selective construction of various chiral organophosphorus compounds, catalytic enantioselective approaches for their synthesis are far less common. Given the vastness of possible substituent combinations around a phosphorus atom, protocols for their preparation should also be divergent, providing facile access not only to one but to many classes of phosphorus compounds. Here we introduce a catalytic and enantioselective strategy for the preparation of an enantioenriched phosphorus(V) centre that can be diversified enantiospecifically to a wide range of biologically relevant phosphorus(V) compounds. The process, which involves an enantioselective nucleophilic substitution catalysed by a superbasic bifunctional iminophosphorane catalyst, can accommodate a wide range of carbon substituents at phosphorus. The resulting stable, yet versatile, synthetic intermediates can be combined with a multitude of medicinally relevant O-, N- and S-based nucleophiles.

Bifunctional Iminophosphorane-Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,ß-Unsaturated Esters.

Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,ß-unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ-nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including ß-(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)-rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results.

Synthesis and structure-activity relationship of berkeleylactone A-derived antibiotics.

Berkeleylactone A is a potent 16-membered macrolactone antibiotic, recently isolated from a coculture of Berkeley Pit Lake fungi. Although its antimicrobial activity has already been investigated, little is known about the structure-activity relationship. Based on our previous synthetic studies, a series of berkeleylactone A derivatives were synthesized and evaluated for their in vitro antimicrobial activities against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA) strains. Our data confirmed the essential role of the embedded conjugated system and suggest a reversible sulfa-protection of the Michael acceptor as a viable option. Structurally simplified achiral macrolactam 8 showed the best inhibitory activity against S. aureus L12 (MRSA) with MIC50 values of 0.39 µg mL-1, 8-fold lower than those of berkeleylactone A. These studies may be of value in the development of more advanced candidates for antibiotic applications.

Imitation of ß-lactam binding enables broad-spectrum metallo-ß-lactamase inhibitors.

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-ß-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential ß-lactamase stable ß-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.

Structural Basis of Metallo-ß-lactamase Inhibition by N-Sulfamoylpyrrole-2-carboxylates.

Metallo-ß-lactamases (MBLs) can efficiently catalyze the hydrolysis of all classes of ß-lactam antibiotics except monobactams. While serine-ß-lactamase (SBL) inhibitors (e.g., clavulanic acid, avibactam) are established for clinical use, no such MBL inhibitors are available. We report on the synthesis and mechanism of inhibition of N-sulfamoylpyrrole-2-carboxylates (NSPCs) which are potent inhibitors of clinically relevant B1 subclass MBLs, including NDM-1. Crystallography reveals that the N-sulfamoyl NH2 group displaces the dizinc bridging hydroxide/water of the B1 MBLs. Comparison of crystal structures of an NSPC and taniborbactam (VRNX-5133), presently in Phase III clinical trials, shows similar binding modes for the NSPC and the cyclic boronate ring systems. The presence of an NSPC restores meropenem efficacy in clinically derived E. coli and K. pneumoniae blaNDM-1. The results support the potential of NSPCs and related compounds as efficient MBL inhibitors, though further optimization is required for their clinical development.

Bifunctional Iminophosphorane Superbase Catalysis: Applications in Organic Synthesis.

To improve the field of catalysis, there is a substantial and growing need for novel high-performance catalysts providing new reactivity. To date, however, the set of reactions that can be reliably performed to prepare chiral compounds in largely one enantiomeric form using chiral catalysts still represents a small fraction of the toolkit of known transformations. In this context, chiral Brønsted bases have played an expanding role in catalyzing enantioselective reactions between various carbon- and heteroatom-centered acids and a host of electrophilic reagents. This Account describes our recent efforts developing and applying a new family of chiral Brønsted bases incorporating an H-bond donor moiety and a strongly basic iminophosphorane, which we have named BIMPs (Bifunctional IMinoPhosphoranes), as efficient catalysts for reactions currently out of reach of more widespread tertiary amine centered bifunctional catalysts. The iminophosphorane Brønsted base is easily generated by the Staudinger reaction of a chiral organoazide and commercially available phosphine, which allows easy modification of the catalyst structure and fine-tuning of the iminophosphorane pKBH+. We have demonstrated that BIMP catalysts can efficiently promote the enantioselective addition of nitromethane to low reactivity N-diphenylphosphinoyl (DPP)-protected imines of ketones (ketimines) to access valuable chiral diamine and α-quaternary amino acid building blocks, and later extended this methodology to phosphite nucleophiles. Subsequently, the reaction scope was expanded to include the Michael addition of high pKa alkyl thiols to α-substituted acrylate esters, ß-substituted α,ß-unsaturated esters, and alkenyl benzimidazoles as well as the challenging direct aldol addition of aryl ketones to α-fluorinated ketones. Finally, BIMP catalysts were shown to be used in key steps in the synthesis of complex alkaloid natural products (-)-nakadomarin A and (-)-himalensine A, as well as in polymer synthesis. In most cases, the predictable nature of the BIMP promoted reactions was demonstrated by multigram scale-up while employing low catalyst loadings (down to 0.05 mol%). Furthermore, it was shown that BIMP catalysts can be easily immobilized onto a solid support in one-step for increased catalyst recycling and flow chemistry applications. Alongside our own work, this Account also includes elegant work by Johnson and co-workers utilizing the BIMP catalyst system, when alternative catalysts proved suboptimal.

Silver-Catalyzed Enantioselective Mannich Reaction of Diazoacetate Esters with N-Boc Aldimines.

The highly enantioselective Mannich reaction of diazoacetate esters with N-Boc aldimines catalyzed by silver(I) triflate in the presence of (R)-DM-SEGPHOS is reported. The reaction is broad in scope with respect to the (hetero)aromatic aldehyde-derived aldimine and tolerates significant variability of the diazoacetate ester component. Yields and enantioselectivities are good to excellent, and the reaction can be performed on a gram scale with catalyst loadings as low as 1 mol %.

Bifunctional iminophosphorane catalysed enantioselective sulfa-Michael addition of alkyl thiols to alkenyl benzimidazoles.

The first enantioselective sulfa-Michael addition of alkyl thiols to alkenyl benzimidazoles, enabled by a bifunctional iminophosphorane (BIMP) organocatalyst, is described. The iminophosphorane moiety of the catalyst provides the required basicity to deprotonate the thiol nucleophile while the chiral scaffold and H-bond donor control facial selectivity. The reaction is broad in scope with respect to the thiol and benzimidazole reaction partners with the reaction proceeding in up to 98% yield and 96 : 4 er.

Direct sulfonylation of anilines mediated by visible light.

Sulfones feature prominently in biologically active molecules and are key functional groups for organic synthesis. We report a mild, photoredox-catalyzed reaction for sulfonylation of aniline derivatives with sulfinate salts, and demonstrate the utility of the method by the late-stage functionalization of drugs. Key features of the method are the straightforward generation of sulfonyl radicals from bench-stable sulfinate salts and the use of simple aniline derivatives as convenient readily available coupling partners.

C-H Cyanation of 6-Ring N-Containing Heteroaromatics.

Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far-reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C-H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one-pot protocol is simple to perform, is applicable to a broad range of decorated 6-ring N-containing heterocycles, and has been shown to be suitable for late-stage functionalization of complex drug-like architectures.

Enantioselective bifunctional iminophosphorane catalyzed sulfa-Michael addition of alkyl thiols to unactivated ß-substituted-α,ß-unsaturated esters.

The highly enantioselective sulfa-Michael addition of alkyl thiols to unactivated ß-substituted-α,ß-unsaturated esters catalyzed by a bifunctional iminophosphorane (BIMP) organocatalyst is described. The low acidity of the alkyl thiol pro-nucleophiles is overcome by the high Brønsted basicity of the catalyst and the chiral scaffold/thiourea hydrogen-bond donor moiety provides the required enantiofacial discrimination in the addition step. The reaction is broad in scope with respect to the alkyl thiol and ß-substituent of the α,ß-unsaturated ester, affords sulfa-Michael adducts in excellent yields (up to >99%) and enantioselectivity (up to 97 : 3 er) and can operate down to 1 mol% catalyst loading.

Towards the total synthesis of keramaphidin B.

The enantio- and diastereoselective Michael addition of a δ-valerolactone-derived pronucleophile to a substituted furanyl nitroolefin catalysed by a bifunctional cinchonine-derived thiourea has been used as the key stereocontrolling step in a new synthetic strategy to the heavily functionalised piperidine core of keramaphidin B.

Bifunctional Iminophosphorane Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α-Substituted Acrylate Esters.

The highly enantioselective sulfa-Michael addition of alkyl thiols to unactivated α-substituted acrylate esters catalyzed by a bifunctional iminophosphorane organocatalyst under mild conditions is described. The strong Brønsted basicity of the iminophosphorane moiety of the catalyst provides the necessary activation of the alkyl thiol pro-nucleophile, while the two tert-leucine residues flanking a central thiourea hydrogen-bond donor facilitate high enantiofacial selectivity in the protonation of the transient enolate intermediate. The reaction is broad in scope with respect to the alkyl thiol, the ester moiety, and the α-substituent of the α,ß-unsaturated ester, affords sulfa-Michael adducts in excellent yields (up to >99%) and enantioselectivities (up to 96% ee), and is amenable to decagram scale-up using catalyst loadings as low as 0.05 mol %.

Bifunctional iminophosphorane organocatalysts for enantioselective synthesis: application to the ketimine nitro-Mannich reaction.

The design, synthesis, and development of a new class of modular, strongly basic, and tunable bifunctional Brønsted base/H-bond-donor organocatalysts are reported. These catalysts incorporate a triaryliminophosphorane as the Brønsted basic moiety and are readily synthesized via a last step Staudinger reaction of a chiral organoazide and a triarylphosphine. Their application to the first general enantioselective organocatalytic nitro-Mannich reaction of nitromethane to unactivated ketone-derived imines allows the enantioselective construction of ß-nitroamines possessing a fully substituted carbon atom. The reaction is amenable to multigram scale-up, and the products are useful for the synthesis of enantiopure 1,2-diamine and α-amino acid derivatives.