Ilija Čorić

Asymmetric spiroacetalization catalysed by confined Brønsted acids

Acetals are molecular substructures that contain two oxygen–carbon single bonds at the same carbon atom, and are used in cells to construct carbohydrates and numerous other molecules. A distinctive subgroup are spiroacetals, acetals joining two rings, which occur in a broad range of biologically active compounds, including small insect pheromones and more complex macrocycles. Despite numerous methods for the catalytic asymmetric formation of other commonly occurring stereocentres, there are few approaches that exclusively target the chiral acetal centre and none for spiroacetals. Here we report the design and synthesis of confined Brønsted acids based on a C2-symmetric imidodiphosphoric acid motif, enabling a catalytic enantioselective spiroacetalization reaction. These rationally constructed Brønsted acids possess an extremely sterically demanding chiral microenvironment, with a single catalytically relevant and geometrically constrained bifunctional active site. Our catalyst design is expected to be of broad utility in catalytic asymmetric reactions involving small and structurally or functionally unbiased substrates.

Activation of H2O2 by Chiral Confined Brønsted Acids: A Highly Enantioselective Catalytic Sulfoxidation

Confined chiral Brønsted acids are shown to catalyze asymmetric oxidations of sulfides to sulfoxides with hydrogen peroxide. The wide generality and high enantioselectivity of the developed method compare even to the best metal-based systems and suggest utility in other asymmetric oxidations.

N-Phosphinyl Phosphoramide — A Chiral Brønsted Acid Motif for the Direct Asymmetric N,O-Acetalization of Aldehydes

The advent of 1,1’-binaphthalene-2,2’-diol (BINOL) phosphates as powerful Brønsted acid catalysts heralded a new era in asymmetric organocatalysis. The recognition of the bifunctional mode of activation of these catalysts in reactions of imines with nucleophiles inspired organic chemists to design a variety of new asymmetric transformations. At the same time, significant effort has also been devoted to the construction of other Brønsted acid motifs such as thioureas, dicarboxylic acids, and disulfonic acids. A remarkable innovation in this area occurred when Yamamoto et al. introduced N-triflyl phosphoramides for the activation of less reactive substrates such as ketones, silyl enol ethers, and aldehydes. Our recent discovery of chiral disulfonimides and their use as Lewis acid precatalysts for the activation of aldehydes, has revealed yet another potentially important class of chiral acid catalysts. In research on BINOL-derived phosphoric acids little effort has been made towards the design of new analogues with alternative functionalities, except for certain modifications of their backbone and the above-mentioned derivatization. As theoretical studies confirm that these catalysts simultaneously activate electrophiles by protonation and nucleophiles through interaction with the basic P=O group, we are interested in exploring derivatives with alternative acidic and basic sites to further expand the utility of this fascinating type of organocatalyst. Here we introduce N-phosphinyl phosphoramides as a new motif for organocatalysis (Figure 1). We hypothesized that the additional basic P=O functionality of an N-phosphinyl phosphoramide could stabilize different transition-state geometries in the bifunctional activation of two reacting substrates. Additionally, by bringing in two new substituents, these catalysts could be easily modified and fine-tuned for a particular reaction. We now show that this new class of Brønsted acids can indeed be used in the first highly enantioselective direct N,O-acetalization of aldehydes. Cyclic N,O-acetals are a frequently encountered structural motif in natural products and in pharmaceuticals. The importance of the stereochemistry of the acetal carbon in N,O-acetal-containing drugs is illustrated by the different bioactivities of their enantiomers. In 2005, Antilla et al. reported the first catalytic asymmetric method for the synthesis of chiral aminals by the addition of sulfonamides to imines, using a VAPOL (vaulted biphenanthrol)-derived phosphoric acid. They also extended this strategy to the preparation of chiral N,O-acetals by the BINOL phosphoric acid catalyzed enantioselective addition of alcohols to Nbenzoyl imines. However, this methodology is limited to acyclic N,O-acetals and to the use of preformed imines as electrophiles. As part of our long-standing interest in the development of asymmetric acetalization reactions, we reported the direct enantioselective synthesis of cyclic aminals from aldehydes through a sequence consisting of imine formation and intramolecular amidation (Scheme 1). However, analogous N,O-acetalizations have been entirely unknown, which is unsatisfying since cyclic N,O-acetals, especially benzoxazinones, have recently gained importance because of their pharmaceutical applications. For example, chlorothenoxazine is well appreciated for its analgesic activity. So far only achiral acids or amines have been used in the preparation of benzoxazinones from substituted

The Catalytic Asymmetric Acetalization

asymmetric Brønsted acid catalysis has recently enabled the enantioselective generation of chiral N,N-, N,O-, and N,Sacetals, either from imines or directly from aldehydes. 3] The success of these reactions is based on the well-established ability of chiral phosphoric acids to direct the enantioselective addition of nucleophiles to imines. However, the corresponding enantioselective additions to oxocarbenium ion intermediates, which are required for obtaining O,O-acetals, are much less developed. Although acetals are among the most common stereocenters in organic molecules, there are only few examples of their catalytic asymmetric synthesis. We have recently reported that chiral Brønsted acids catalyze intramolecular asymmetric transacetalizations and spiroacetalizations generating chiral acetals with high enantioselectivity. 9] However, although our laboratory has pursued the direct asymmetric acetalization of aldehydes with alcohols for many years now, and has investigated numerous chiral Brønsted acid catalysts, unfortunately, very little success towards this goal has been encountered. Here we report that a new member of our recently developed class of chiral confined Brønsted acids finally enables this elusive transformation with excellent selectivity and scope. The summary of our investigations towards asymmetric acetalization with diol 1a and aldehyde 2 a is given in Table 1. A catalytic amount of TRIP (4 a ; Scheme 1), one of the most successful phosphoric acid catalysts, catalyzes the reaction at room temperature giving cyclic acetal 3a with an e.r. (enantiomeric ratio) of 66.5:33.5 and 66 % conversion after 7 days (Table 1, entry 1). The recently developed spirocyclic analogue STRIP (5), which proved to be superior to TRIP on several occasions, gave a slightly improved e.r. of 79:21, but displayed lower reactivity (Table 1, entry 2). Catalysts 4b and 6, which provided excellent results for the related N,Nand N,O-acetalizations of aldehydes, did not give any improvement (Table 1, entries 3 and 4). This striking failure of some of the most successful phosphoric acid catalysts illustrates the general difficulty of dealing with oxocarbenium ion intermediates in Brønsted acid catalysis. Recently, our group has developed a new generation of stronger Brønsted acids, based on a C2-symmetric imidodiTable 1: Catalyst discovery.

Binding of dinitrogen to an iron–sulfur–carbon site

Nitrogenases are the enzymes by which certain microorganisms convert atmospheric dinitrogen (N2) to ammonia, thereby providing essential nitrogen atoms for higher organisms. The most common nitrogenases reduce atmospheric N2 at the FeMo cofactor, a sulfur-rich iron–molybdenum cluster (FeMoco). The central iron sites that are coordinated to sulfur and carbon atoms in FeMoco have been proposed to be the substrate binding sites, on the basis of kinetic and spectroscopic studies. In the resting state, the central iron sites each have bonds to three sulfur atoms and one carbon atom. Addition of electrons to the resting state causes the FeMoco to react with N2, but the geometry and bonding environment of N2-bound species remain unknown. Here we describe a synthetic complex with a sulfur-rich coordination sphere that, upon reduction, breaks an Fe–S bond and binds N2. The product is the first synthetic Fe–N2 complex in which iron has bonds to sulfur and carbon atoms, providing a model for N2 coordination in the FeMoco. Our results demonstrate that breaking an Fe–S bond is a chemically reasonable route to N2 binding in the FeMoco, and show structural and spectroscopic details for weakened N2 on a sulfur-rich iron site.

The Catalytic Asymmetric α-Benzylation of Aldehydes

The first aminocatalyzed α-alkylation of α-branched aldehydes with benzyl bromides as alkylating agents has been developed. Using a sterically demanding proline derived catalyst, racemic α-branched aldehydes are reacted with alkylating agents in a DYKAT process to give the corresponding α-alkylated aldehydes with quaternary stereogenic centers in good yields and high enantioselectivities.

Brønsted Acid Catalyzed Asymmetric SN2‐Type O‐Alkylations

Asymmetric Brønsted acid catalysis has flourished in recent years especially in the context of nucleophilic additions to carbon-based electrophiles. These reactions generally involve the formal approach of nucleophiles at the p* orbital of an sp-hybridized carbon atom of electrophiles, typically imines, but also aldehydes, ketones, or certain Michael acceptors. In contrast, substitution reactions involving nucleophilic attack at the s* orbital of an sp-hybridized carbon atom are underexplored in this context. The bifunctional nature of chiral phosphoric acids could offer unique opportunities for catalyzing such reactions. We hypothesized that these acids could bridge the trigonal bipyramidal transition state of an SN2 reaction, to simultaneously activate both the leaving group and the nucleophile.

Resolution of diols via catalytic asymmetric acetalization.

A highly enantioselective kinetic resolution of diols via asymmetric acetalization has been achieved using a chiral confined imidodiphosphoric acid catalyst. The reaction is highly efficient for the resolution of tertiary alcohols, giving selectivity factors of up to >300. Remarkably, even in cases where the selectivity factors are only moderate, highly enantioenriched diols are obtained via a stereodivergent resolution to diastereomeric acetals.

Insight into the Iron–Molybdenum Cofactor of Nitrogenase from Synthetic Iron Complexes with Sulfur, Carbon, and Hydride Ligands

Nitrogenase enzymes are used by microorganisms for converting atmospheric N2 to ammonia, which provides an essential source of N atoms for higher organisms. The active site of the molybdenum-dependent nitrogenase is the unique carbide-containing iron-sulfur cluster called the iron-molybdenum cofactor (FeMoco). On the FeMoco, N2 binding is suggested to occur at one or more iron atoms, but the structures of the catalytic intermediates are not clear. In order to establish the feasibility of different potential mechanistic steps during biological N2 reduction, chemists have prepared iron complexes that mimic various structural aspects of the iron sites in the FeMoco. This reductionist approach gives mechanistic insight, and also uncovers fundamental principles that could be used more broadly for small-molecule activation. Here, we discuss recent results and highlight directions for future research. In one direction, synthetic iron complexes have now been shown to bind N2, break the N-N triple bond, and produce ammonia catalytically. Carbon- and sulfur-based donors have been incorporated into the ligand spheres of Fe-N2 complexes to show how these atoms may influence the structure and reactivity of the FeMoco. Hydrides have been incorporated into synthetic systems, which can bind N2, reduce some nitrogenase substrates, and/or reductively eliminate H2 to generate reduced iron centers. Though some carbide-containing iron clusters are known, none yet have sulfide bridges or high-spin iron atoms like the FeMoco.

Developing Catalytic Asymmetric Acetalizations

Acetals are among the most common stereocenters in Nature. They form glycosidic bonds that link together essential molecules of life, carbohydrates, including starch and cellulose, the most abundant organic material on Earth. Stereogenic acetals are also common motifs in other natural products, from small insect pheromones to highly complex spiroacetal polyketides. Although far less common than O,O-acetals, chiral N,N-, N,O-, and N,S-acetals are structural motifs also found in a number of natural products and pharmaceuticals. Here, recent progress towards chiral acetals using asymmetric Bronsted acid catalysis is summarized, with particular emphasis on O,O-acetalizations. In this context the development of novel catalyst classes, namely spirocyclic phosphoric acids and confined Bronsted acids, proved crucial and is also presented.