J. Appl. Cryst.の発刊に際して

Organosulfur compounds have long played a vital role in organic chemistry and in the development of novel chemical structures and architectures. Prominent among these organosulfur compounds are those involving a sulfur(IV) center, which have been the subject of countless investigations over more than a hundred years. In addition to a long list of textbook sulfur-based reactions, there has been a sustained interest in the chemistry of organosulfur(IV) compounds in recent years. Of particular interest within organosulfur chemistry is the ease with which the synthetic chemist can effect a wide range of transformations through either bond formation or bond cleavage at sulfur. This review aims to cover the developments of the past decade in the chemistry of organic sulfur(IV) molecules and provide insight into both the wide range of reactions which critically rely on this versatile element and the diverse scaffolds that can thereby be synthesized.

Bond-Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides, Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts.

To the Editor.— The editorial by Samuel Vaisrub, MD, "To the Best of Our Knowledge, Which Is Limited at Best" (241:278, 1979), was delightful, and its point was unhappily correct. It brought to my mind that demolisher of analytical studies, "to the best of our knowledge," or "as far as we know." It goes like this: We treated so many people, and we know this many are well, and so many have died; and this many,from whom we have not heard, are alive and well,as far as we know. Someone from whom you have not heard is more likely to be dead than alive.

To the Best of Our Knowledge

The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.

Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds.

Redox processes are at the heart of synthetic methods that rely on either electrochemistry or photoredox catalysis, but how do electrochemistry and photoredox catalysis compare? Both approaches provide access to high energy intermediates (e.g., radicals) that enable bond formations not constrained by the rules of ionic or 2 electron (e) mechanisms. Instead, they enable 1e mechanisms capable of bypassing electronic or steric limitations and protecting group requirements, thus enabling synthetic chemists to disconnect molecules in new and different ways. However, while providing access to similar intermediates, electrochemistry and photoredox catalysis differ in several physical chemistry principles. Understanding those differences can be key to designing new transformations and forging new bond disconnections. This review aims to highlight these differences and similarities between electrochemistry and photoredox catalysis by comparing their underlying physical chemistry principles and describing their impact on electrochemical and photochemical methods.

Photons or Electrons? A Critical Comparison of Electrochemistry and Photoredox Catalysis for Organic Synthesis.

The design, synthesis, and development of a new class of modular, strongly basic, and tunable bifunctional Bronsted base/H-bond-donor organocatalysts are reported. These catalysts incorporate a triaryliminophosphorane as the Bronsted 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 β-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.

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

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 Bronsted 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,β-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 %.

http://pubs.acs.org/doi/pdf/10.1021/jacs.5b10226

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

The highly enantioselective sulfa-Michael addition of alkyl thiols to unactivated β-substituted-α,β-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 Bronsted 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 β-substituent of the α,β-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.

/pdf/enantioselective-bifunctional-iminophosphorane-catalyzed-167x9egm2i.pdf

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

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.

/pdf/direct-sulfonylation-of-anilines-mediated-by-visible-light-41evja7fnl.pdf

Direct sulfonylation of anilines mediated by visible light.

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.

/pdf/bifunctional-iminophosphorane-catalysed-enantioselective-vcqg6v9zty.pdf

Alistair J. M. Farley

Papers

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

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

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

Direct sulfonylation of anilines mediated by visible light.

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