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Photoredox catalysis enables distinctive and broadly applicable chemical reactions, but controlling their selectivity has proven to be difficult. The pursuit of enantioselectivity is a particularly daunting challenge, arguably because of the high energy of the activated radical (ion) intermediates, and previous approaches have invariably required pairing of the photoredox catalytic cycle with an additional activation mode for asymmetric induction. A potential solution for photoredox reactions proceeding via radical ions would be catalytic pairing with enantiopure counterions. However, although attempts toward this approach have been described, high selectivity has not yet been accomplished. Here we report a potentially general solution to radical cation–based asymmetric photoredox catalysis. We describe organic salts, featuring confined imidodiphosphorimidate counteranions that catalyze highly enantioselective [2+2]-cross cycloadditions of styrenes.

Nitronate anions, formally generated by α-deprotonating the corresponding nitroalkanes, are highly nucleophilic and versatile intermediates in many carbon–carbon bond-forming reactions. In contrast, the corresponding silyl nitronates are ambiphilic and react, at the same carbon atom, with both electrophiles and nucleophiles. However, while their nucleophilicity has been well exploited in catalytic enantioselective reactions with imines and aldehydes, utilizing the electrophilicity of silyl nitronates in asymmetric synthesis has remained elusive. Here we report the facile, efficient and general reactivity of readily available silyl nitronates with silyl ketene acetals, catalysed by highly Lewis-acidic and confined silylium imidodiphosphorimidate catalysts. The products of this reaction, so-called nitroso acetals, are obtained in excellent enantioselectivity and can be easily converted into N-Boc-β3-amino acid esters in a single step. Utilizing the electrophilicity of ambiphilic silyl nitronates in asymmetric synthesis has remained elusive. Now, silylium-based Lewis acids are used for their activation, achieving the catalytic asymmetric nucleophilic addition of silyl ketene acetals to silyl nitronates for the synthesis of β3-amino acids.

Enzymatic stereoselectivity has typically been unrivalled by most chemical catalysts, especially in the conversion of small substrates. According to the ‘lock-and-key theory’1,2, enzymes have confined active sites to accommodate their specific reacting substrates, a feature that is typically absent from chemical catalysts. An interesting case in this context is the formation of cyanohydrins from ketones and HCN, as this reaction can be catalysed by various classes of catalysts, including biological, inorganic and organic ones3–7. We now report the development of broadly applicable confined organocatalysts for the highly enantioselective cyanosilylation of aromatic and aliphatic ketones, including the challenging 2-butanone. The selectivity (98:2 enantiomeric ratio (e.r.)) obtained towards its pharmaceutically relevant product is unmatched by any other catalyst class, including engineered biocatalysts. Our results indicate that confined chemical catalysts can be designed that are as selective as enzymes in converting small, unbiased substrates, while still providing a broad scope.

We have designed and realized an efficient and operationally simple single-flask synthesis of imidodiphosphate-based Brønsted acids. The methodology proceeds via consecutive chloride substitutions of hexachlorobisphosphazonium salts, providing rapid access to imidodiphosphates (IDP), iminoimidodiphosphates (iIDP), and imidodiphosphorimidates (IDPi). These privileged acid catalysts feature a broad acidity range (pKa from ∼11 to 95:5 er) sulfoxidation of methyl n-propyl sulfide. Furthermore, the methodology delivers a novel, rationally designed super acidic catalyst motif, imidodiphosphorbis(iminosulfonylimino)imidate (IDPii), the extreme reactivity of which exceeds commonly employed super-Brønsted acids, such as trifluoromethanesulfonic acid. The unique reactivity of one such IDPii catalyst has been demonstrated in the first α-methylation of a silyl ketene acetal with methanol as the electrophilic alkylating reagent.

Vetiver oil, produced on a multiton‐scale from the roots of vetiver grass, is one of the finest and most popular perfumery materials, appearing in over a third of all fragrances. It is a complex mixture of hundreds of molecules and the specific odorant, responsible for its characteristic suave and sweet transparent, woody‐ambery smell, has remained a mystery until today. Herein, we prove by an eleven‐step chemical synthesis, employing a novel asymmetric organocatalytic Mukaiyama–Michael addition, that (+)‐2‐epi‐ziza‐6(13)en‐3‐one is the active smelling principle of vetiver oil. Its olfactory evaluation reveals a remarkable odor threshold of 29 picograms per liter air, responsible for the special sensuous aura it lends to perfumes and the quasi‐pheromone‐like effect it has on perfumers and consumers alike., Despite the advance of modern analytic techniques, the smelling principle of vetiver oil is still unknown owing to its extremely complex matrix of over 150 compounds. A concise stereoselective total synthesis proves (+)‐2‐epi‐ziza‐6(13)en‐3‐one to be the key to the quasi‐pheromone‐like aura of vetiver that magically resembles the effect of Iso E Super.

Carbocations can be categorized into classical carbenium ions and non-classical carbonium ions. These intermediates are ubiquitous in reactions of both fundamental and practical relevance, finding application in the petroleum industry as well as the discovery of new drugs and materials. Conveying stereochemical information to carbocations is therefore of interest to a range of chemical fields. While previous studies targeted systems proceeding through classical ions, enantiocontrol over their non-classical counterparts has remained unprecedented. Here we show that strong and confined chiral acids catalyse enantioselective reactions via the non-classical 2-norbornyl cation. This reactive intermediate is generated from structurally different precursors by leveraging the reactivity of various functional groups to ultimately deliver the same enantioenriched product. Our work demonstrates that tailored catalysts can act as suitable hosts for simple, non-functionalized carbocations via a network of non-covalent interactions. We anticipate that the methods described herein will provide catalytic accessibility to valuable carbocation systems. In 1949, Winstein and Trifan proposed that the 2-norbornyl cation adopts a bridged, non-classical structure. Now, the generation of an asymmetric environment around the three-centre two-electron bond of such an ion has been reported, enabling highly enantioselective catalytic addition reactions to a simple, non-functionalized non-classical cation.

The chemical synthesis of organic molecules involves, at its very essence, the creation of carbon–carbon bonds. In this context, the aldol reaction is among the most important synthetic methods, and a wide variety of catalytic and stereoselective versions have been reported. However, aldolizations yielding tertiary aldols, which result from the reaction of an enolate with a ketone, are challenging and only a few catalytic asymmetric Mukaiyama aldol reactions with ketones as electrophiles have been described. These methods typically require relatively high catalyst loadings, deliver substandard enantioselectivity or need special reagents or additives. We now report extremely potent catalysts that readily enable the reaction of silyl ketene acetals with a diverse set of ketones to furnish the corresponding tertiary aldol products in excellent yields and enantioselectivities. Parts per million (ppm) levels of catalyst loadings can be routinely used and provide fast and quantitative product formation in high enantiopurity. In situ spectroscopic studies and acidity measurements suggest a silylium ion based, asymmetric counteranion-directed Lewis acid catalysis mechanism.

In 1949, S. Winstein and D. Trifan proposed that the 2-norbornyl cation adopts a bridged, non-classical structure with a 3-center, 2-electron unit much like the bonding in diborane. While some embraced this proposal, others firmly refuted it, giving rise to the vituperative 2-norbornyl cation controversy. After 60 years of debate, the long-sought crystallographic proof was eventually collected in 2013. Several decades after the first non-classical formulation, we became interested in imparting stereocontrol over the 2-norbornyl cation, a positively charged, simple hydrocarbon that, due to its structural features, offers a major challenge to asymmetric catalysis. Our investigation began by reversing the original experiment by Winstein. Specifically, we found that IDPi catalysts are competent chiral acids for carrying out a diastereo- and enantioselective C-C bond forming reaction between racemic exo- and endo-norbornyl trichloroacetimidates and 1,3,5-trimethoxybenzene to exclusively deliver the exo-product with excellent enantioselectivities. We also found that several structurally-different substrates can be converted to the same product with good to excellent enantioselectivities, pointing to the existence of a common cationic intermediate. Mechanistic and kinetic studies were conducted to elucidate relevant aspects of the reaction.

[Image: see text] We report a catalytic asymmetric Nazarov cyclization of simple, acylic, alkyl-substituted divinyl ketones using our recently disclosed strong and confined imidodiphosphorimidate Brønsted acids. The corresponding monocyclic cyclopentenones are formed in good yields and excellent regio-, diastereo-, and enantioselectivities. Further, the chemical utility of the obtained enantiopure cyclopentenones is demonstrated.

The development of a highly enantioselective catalytic oxa-Pictet-Spengler reaction has proven a great challenge for chemical synthesis. We now report the first example of such a process, which was realized by utilizing a nitrated confined imidodiphosphoric acid catalyst. Our approach provides substituted isochroman derivatives from both aliphatic and aromatic aldehydes with high yields and excellent enantioselectivities. DFT calculations provide insight into the reaction mechanism.

Chiral non-racemic analogues of cyclam were prepared via reaction of (1R, 2R)-cyclohexane-1,2-diamine with appropriately substituted malonyl dichlorides. Larger macrocycles are formed as by-products in some cases. All new macrocycles were characterised by X-ray crystallography.

The design and five-step synthesis of chiral tetrakis(pentafluo­rophenyl) borate analogues from commercially available enantiopure BINOL is described. The chiral anions have been tested in a catalytic asymmetric Mukaiyama aldol reaction.

A Brønsted acid catalyzed kinetic resolution of primary amines is described that is based on the condensation between an amine and a carbonyl compound. 1,3-Diketones react with racemic α-branched amines to furnish the corresponding enantioenriched enaminone and recovered starting material. Good to excellent enantioselectivity was observed with both aromatic and aliphatic primary amines. This process represents the first small-molecule catalyzed kinetic resolution of aliphatic amines.

The development of a highly enantioselective catalytic oxa-Pictet–Spengler reaction has proven a great challenge for chemical synthesis. We now report the first example of such a process, which was realized by utilizing a nitrated confined imidodiphosphoric acid catalyst. Our approach provides substituted isochroman derivatives from both aliphatic and aromatic aldehydes with high yields and excellent enantioselectivities. DFT calculations provide insight into the reaction mechanism.

A dual-catalysis approach, namely the combination of an achiral nucleophilic catalyst and a chiral anion-binding catalyst, was applied to the Steglich rearrangement to provide α,α-disubstituted amino acid derivatives in a highly enantioselective fashion. Replacement of the nucleophilic co-catalyst for isoquinoline resulted in a divergent reaction pathway and an unprecedented transformation of O-acylated azlactones. This strategy provided highly substituted α,β-diamino acid derivatives with excellent levels of stereocontrol.

Aminobenzaldehydes react with indoles in an unprecedented cascade reaction. This acid-catalyzed redox-neutral annulation proceeds via a condensation/1,5-hydride shift/ring-closure sequence. Polycyclic azepinoindoles and related compounds are obtained in a single step with good to excellent yields.

1,4-Diketones bearing an all-carbon quarternary stereocenter are synthesized via asymmetric dearomatizing redox cross-coupling reaction between aryl hydrazines and cyclic ketones in the presence of a SPINOL-derived phosphoric acid as chiral catalyst.

Racemic benzylic amines undergo kinetic resolution via benzoylation with benzoic anhydride in the presence of a dual catalyst system consisting of a readily available amide-thiourea catalyst and 4-dimethylaminopyridine (DMAP). An evaluation of various experimental parameters was performed in order to derive a more detailed understanding of what renders this process selective. The catalyst’s aggregation behavior and anion-binding ability were evaluated in regard to their relevance for the catalytic process. Alternate scenarios, such as catalyst deprotonation or the in situ formation of a neutral chiral acylating reagent were ruled out. Detailed computational studies at the M06/6-31G(d,p) level of theory including solvent modeling utilizing a polarized continuum model provide additional insights into the nature of the ion pair and reveal a range of important secondary interactions that are responsible for efficient enantiodiscrimination.

o-Aminobenzaldehdye o-Nitrobenzaldehyde Iron powder Pyrrolidine 1,2,3,3a,4,9-Hexahydropyrrolo[2,1-b]quinazolin-9(1H)-one,2,3-dihydro- Deoxyvasicinone Potassium permanganate Keywords: Cyclization; Redox-neutral aminal formation; Deoxyvasicinone; Quinolines; Friedlander condensation; Aminobenzaldehydes; Natural products; Safety; Waste disposal

Electronically and structurally diverse axially chiral binaphthyldiamine derivatives are synthesized by the developed title rearrangement.

An efficient kinetic resolution of primary propargylic amines with s-factors of up to 56 is reported. The strategy is based on a dual catalytic approach, namely the use of a newly developed and easy-to-make thiourea-amide anion binding catalyst in combination with 4-(dimethylamino)pyridine (DMAP), both employed at a 5 mol % catalyst loading. Benzylic amines are also resolved with s-factors of up to 38.

A combination of achiral N,N-dipropylaminopyridine with a chiral 1,2-cyclohexanediamine derivative is tested as a catalytic system for the kinetic resolution of diamines (I).

Electronically and structurally diverse axially chiral binaphthyldiamine derivatives are synthesized by the developed title rearrangement.

O-acylated azlactones (I) can be efficiently rearranged to the corresponding C-acylated products (II) by using the combination of a chiral hydrogen-bonding catalyst and a simple nucleophilic catalyst.

The desymmetrization of meso-diamines was accomplished via enantioselective monobenzoylation facilitated by the cooperative action of two small-molecule catalysts. A chiral acyl-transfer reagent is formed in situ through the interplay of benzoic anhydride, 4-(dimethylamino)pyridine as a nucleophilic catalyst, and a chiral amide-thiourea cocatalyst.

A variety of indoles reacts with aminobenzaldehydes under microwave-assisted conditions to form indole-fused benzazepines in good yields.

A new concept for asymmetric nucleophilic catalysis is presented. Acyl pyridinium salts derived from 4-(dimethylamino)pyridine (DMAP) and benzoic anhydride are rendered chiral via interaction with a chiral thiourea anion receptor. The power of this concept is demonstrated in the context of kinetic amine resolution.

Aromatic aminoaldehydes react with cyclic amines to produce ring-fused aminals under thermal conditions. This process is applied to two-step syntheses of the quinazolinone alkaloids deoxyvasicinone and rutaecarpine.

The kinetic resolution of racemic C(2)-symmetric 1,2-diaryl-1,2-diaminoethanes was accomplished for the first time through application of a dual-catalysis approach.

We describe a highly enantioselective Diels–Alder reaction of cross‐conjugated cyclohexadienones with cyclopentadiene, in which five stereocenters are effectively controlled by a strongly acidic and confined imidodiphosphorimidate catalyst. Our approach provides tricyclic products in excellent stereoselectivity. We also report methods to convert the obtained products into useful intermediates and a computational study that aids in gaining deeper insight into the reaction mechanism and origin of stereoselectivity., A highly enantio‐ and diastereoselective Diels–Alder reaction of cross‐conjugated dienones containing electronically unbiased quaternary centers with cyclopentadiene has been developed. The chiral microenvironment and greater acidity of the imidodiphosphorimidate (IDPi) Brønsted acid motif control the desired outcome. The resulting cycloaddition adducts contain up to five stereogenic centers.