In a recent decade, various organocatalysts have been developed to be applicable to a wide range of asymmetric reactions. This review briefly summarizes the hydrogen-bonding activation by chiral noncovalent organocatalysts. First, the differences between hydrogen-bonding catalysts and Brønsted acid catalysts are addressed. Next, the effect of hydrogen-bonding interactions on the transition states is discussed. Finally, the hydrogen-bonding activations by the typical noncovalent organocatalysts, such as thiourea, diol, phosphoric acid, Brønsted acid-assisted chiral Brønsted acid, and N-triflyl phoshoramide, are shown.
- hydrogen bond
- Brønsted acid
- phosphoric acid
The hydrogen bond is the interaction between a hydrogen atom and an electronegative atom, which plays a central role in biological systems. Recently, the utility of hydrogen bond in organic synthesis has been widely investigated, leading to the discovery of novel chiral organocatalysts for the asymmetric transformations [1–3].
In contrast to the covalent organocatalysts, such as proline derivatives, DMAP derivatives, and
2. Noncovalent organocatalysts
In general, noncovalent organocatalysts can be classified into hydrogen-bonding catalysts and Brønsted acid catalysts , although these catalysts may rely on other additional noncovalent interactions at the same time. First, the differences between hydrogen-bonding catalysts and Brønsted acid catalysts are addressed.
The hydrogen-bonding catalysts play as a hydrogen bond donor toward an electronegative hydrogen bond acceptor (Figure 1). The catalysts forming a hydrogen bond complex are called hydrogen-bonding catalysts. The hydrogen bonds are flexible with regard to bond length and angle. The typical bond length of a hydrogen bond is 1.5 to 2.2 Å. The hydrogen bonds are stronger than a van der Waals interaction but weaker than covalent or ionic bonds. In general, the combination of a neutral electrophile (acceptor) and a weak acid catalyst (donor) leads to hydrogen-bonding catalysis. Therefore, the nucleophilic addition to neutral carbonyl compounds, aldehyde or ketone, takes place via a hydrogen bond complex. In the case of the hydrogen bond-catalyzed reactions, a direct proton transfer from the catalyst (donor) to the electrophile (acceptor) will not occur. In other words, the hydrogen bond-catalyzed nucleophilic addition proceeds without the formation of an ion pair.
Brønsted acid catalysts play as a proton donor toward an electronegative acceptor (Figure 2). In general, the catalysts forming an activated ion pair are called Brønsted acid catalysts. When a catalyst (donor) is a stronger acid, the proton transfer to acceptor occurs to give an ion pair via the hydrogen bond complex. In contrast to hydrogen-bonding catalysts, the combination of basic electrophile (acceptor) and stronger acid catalyst (donor) leads to Brønsted acid-catalyzed reactions. Therefore, the nucleophilic addition to basic imine is often assumed to proceed via the formation of ion pair.
These catalysts might be simply distinguished in the point of view of proton transfer from catalysts. However, it is frequently difficult to make a clear distinction between hydrogen-bonding catalysts and Brønsted acid catalysts, because there is the equilibrium between a hydrogen bond complex and an ion pair (Figure 2). Moreover, Brønsted acid-catalyzed reactions can be classified into two types based on where proton transfer occurs to the substrate or to the transition state. Particularly, the Brønsted acid-associated proton transfer in the transition state is closely related to the stabilization of the transition states by hydrogen-bonding catalysts.
Thioureas, diols, phosphoric acids,
3. Stabilization of transition states by hydrogen bond
The strength of hydrogen bond becomes larger in the charged interaction than the uncharged interaction (Figure 4) [21–23]. The hydrogen bond of a water molecule with a hydroxyl anion (negatively charged acceptor) is almost three times stronger than that with another water molecule (neutral acceptor) in gas phase. The hydrogen bond between a water molecule and a positively charged donor is also strong.
In a hydrogen bond-mediated catalysis, the functions of catalysts are both the activation of substrates and the stabilization of transition states or intermediates. Particularly, the hydrogen bonds effectively stabilize the negative charges in transition states or intermediates [24, 25], because the catalysts are bound more strongly to the charged transition states or intermediates than neutral substrates (Figure 5). Therefore, the study on the transition states or the charged intermediates stabilized by hydrogen-bonding interactions is of importance [26, 27], although the catalysts also affect the reaction rates by decreasing the LUMO level of neutral substrates such as carbonyl compounds and imines.
4. Hydrogen-bonding catalysts
Thioureas and diols are recognized as the typical hydrogen-bonding organocatalysts. This section highlights the hydrogen-bonding activation models and the mechanical investigations using hydrogen-bonding catalysts.
4.1. Thiourea derivatives
In 1990, the formation of crystals of diaryl ureas with carbonyl compounds as a hydrogen bond acceptor was reported by Etter’s group . Later, this study inspired the impressive development of thiourea catalysts. The chiral bifunctional thiourea catalyst
Takemoto’s group developed the new chiral bifunctional thiourea
Thiourea catalyst can recognize the
4.2. Diol derivatives
Diols, such as α,α,α’,α’-tetraaryl-1,3-dioxolan-4,5-dimethanol (TADDOL), form an intramolecular hydrogen bond. (
The study on p
Rawal’s group studied the Mukaiyama aldol reaction using TADDOL derivatives (Figure 10) . In the presence of chiral TADDOL
5. Brønsted acid catalysts
The stronger acids are suitable for catalyzing the nucleophilic addition to basic imines as a Brønsted acid catalyst. This section highlights the activation by Brønsted acid catalyst and the investigations into Brønsted acid-associated proton transfers.
5.1. Phosphoric acid derivatives
In general, phosphoric acid derivatives are classified into Brønsted acid catalysts. The chiral BINOL-based phosphoric acid catalysts, independently developed by Akiyama’s group and Terada’s group, are bearing both Brønsted acidic site and Lewis basic site [39, 40]. In some cases, the bifunctional interaction of electrophilic and nucleophilic components plays a crucial role in the transition state of a rate-determining step.
Akiyama’s group reported the enantioselective Mannich-type reaction using chiral phosphoric acids
The reductions of imines with Hantzsch ester
5.2. Brønsted acid-assisted chiral Brønsted acid
Ishihara’s group developed Brønsted acid-assisted chiral Brønsted acid catalyst
Yamamoto’s group studied the Diels-Alder reaction using chiral
6. Concluding remarks
The utilization of organocatalysts in organic synthesis has become a subject of recent research. Particularly, chiral hydrogen-bonding catalysts and chiral Brønsted acid catalysts have developed as the highly efficient noncovalent organocatalysts for a broad spectrum of asymmetric transformations. One of the most important features of noncovalent organocatalysts is that we can use the hydrogen bond for the stabilization of transition states or intermediates as well as the activation of C=O bond in carbonyl compounds or C=N bond in imines. Because the use of organocatalysts has many advantages in organic synthesis form both economical and environmental points of view, the research into organocatalysts continues to blossom and grow.