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For decades, electron-deficient silicon, such as trisubstituted silicon-based positive ions, is a very powerful and universal Lewis acid catalyst, which is often used to catalyze the reaction of C-C bonds and C-heteroatom bond formation. Earlier, Vorbrgggen and Krolikiewicz teams reported on nucleoside synthesis under TMSOTf and TMSClO4 catalyzed, and Noyori's team also synthesized highly allyl ethers from acetals and allyl trimethylsilanes. Ghosez and Mikami teams independently determined the excellent Lewis acidity and catalytic activity of TMSNTf2 respectively. Later, Foropoulos and DesMarteau applied TMSNTf2 to some common reactions, including Friedel-Crafts alkylation and Diels-Alder reaction. Later studies have shown that after in situ desilicate of various nucleophilic silanes used in addition reaction with carbonyl compounds, negative ionic salts of silicon ([Si]+NTf2-) can be generated from HNTf2 in situ. Although Lewis acid catalysts that generate active silicon-based positive ions in situ in this way have very broad practical value, once they form weakly coordinated anions (X-) with another chiral Lewis acid (M), it may be detrimental to the formation of chiral silicon Lewis acid, making it difficult to achieve an asymmetric catalytic reaction (Fig. 1a). In addition, the non-stable chiral Lewis base ligand (Ln*) can reduce the acidity of the metal center by increasing the electron cloud density of the s-orbital. It is precisely for these reasons that the traditional method of Lewis acid-catalyzed "silicon migration" reaction often requires a catalyst load of up to 20 mol%. Interestingly, however, it will greatly promote such asymmetric catalytic reactions if the concept of asymmetric counter-anion-directed catalysis (ACDC) is generalized to silicon Lewis acid.
Image source: Angew. Chem. Int. Ed.
In 2009, the Benjamin List research team developed the chiral bissulfonimide (DSI) catalyst, making the formation and development of chiral silicon Lewis acid possible. Unlike the chiral phosphoric acid of the previous BINOL skeleton, DSI is strong enough to exchange hydrogen silicon with silicon precursors in situ to generate chiral silicon Lewis acid with catalytic activity. Although various nucleophilic silanes and aldehydes can be added with excellent enantioselectivity under Si-DSI catalytic action, including silyl vinyl ketal acetal, allyl silane and dialkyl silyl phosphite, there are still many chemical problems to be solved in the Si-DSI catalytic system. For example, compared with aromatic aldehydes, the conversion and enantioselectivity of fatty aldehydes with small size and no difference between the two groups have not been significantly improved. On the one hand, the reaction activity of fatty aldehydes is lower, and on the other hand, the difference between enantios is more challenging. In 2012, the List research team developed a new chiral phosphoric acid catalyst IDP. Unlike traditional chiral phosphoric acid and DSI, the catalyst carries two chiral BINOL skeletons. The two modified groups at 3,3’ positions affect each other through various weak interaction forces, making the configuration of the IDP catalyst appear to have a semi-enclosed spatial structure. The catalytic active site is "embedded" into this huge "sphere". This type of catalyst with confined spatial structure has a high three-dimensional induction effect, which can theoretically achieve asymmetric reaction of substrates modified by inactive group. However, compared with DSI (pKa = 8.4 in MeCN), the acidity of IDP is significantly lower than that of the former (pKa = 11.5 in MeCN), which limits their scope of application in Brønsted acid catalysis, and in addition, the Lewis base site of chiral phosphoric acid cannot coordinate with the silicon positive ions. Afterwards, Professor List creatively combined DSI and IDP into one, learned from each other's strengths and weaknesses, and finally obtained a super strong Brønsted acid catalyst with a confined spatial structure, named this " iminophosphorimidate (IDPi)" (Figure 2).
After analysis and testing, the acidity coefficient of the combined IDPi catalyst was greatly improved (pKa = 4.5 to ≤ 2.0 in MeCN), and the pKa of IDPii even reached 0 after modification! At this time, this type of catalyst has become the best potential stock in asymmetric organic Lewis acid catalytic reactions.Since 2016, the List research team has reported many cases of IDPi catalyzed asymmetric reactions, proposed various novel asymmetric catalytic patterns and alternative synthetic methods. The following will focus on several applications of IDPi in asymmetric catalysis.
3Creative breakthrough spanning a century: Catalysis of inert olefins asymmetric intramolecular hydrogen functionalization
Image source: Science
Hand traditionally, the activation of inert olefin substrates used for asymmetric synthesis depends largely on transition metals and photocatalysis, in contrast, with considerable intensity Bioenzymes at acidic sites can promote protonation of olefins, thereby producing carbo-positive ions for the next reaction. Although organic chemists have designed numerous chiral Brønsted acid catalysts to activate imine and carbonyl compounds, it is still a very significant synthetic challenge to simulate these enzymes protonate simple carbon-carbon double bond olefins and then participate in asymmetric catalytic reactions! Until 2018, the Benjamin List team demonstrated a class of super-chiral Brønsted acid catalysts in blocked spaces. The pKa of this protonic acid is strong enough to directly activate inert olefin molecules and achieve asymmetric intramolecular hydrogenation. It is worth mentioning that the use of super-large hindered groups here greatly limits the spatial range of substrate activity, achieving the effect of simulating enzyme catalyzing asymmetric reactions. This milestone major discovery provides considerable reference value for bionic asymmetric catalytic synthesis ( Science, 2018, 359, 1501-1505, click to read for details).
Explore the limit of organic catalytic load: ppm-level catalytic asymmetry Mukaiyama-aldol synthesis
Image source: Nature Chemistry
In the past few decades, the aldol condensation reaction system of Mukaiyama enol silyl ether has tended to mature. Currently, most of the reports are asymmetric condensation reactions between nucleophilic enol silyl ethers and aldehydes. However, due to the low electrophilic activity of ketones, the reaction selectivity is poor, and even the phenomenon of reverse aldol reactions occurs. However, in only a few metal-catalyzed asymmetric condensation reactions, there are often problems such as high catalyst loading and limited substrate range, and it is not very practical. Therefore, achieving efficient catalytic asymmetric Mukaiyama condensation reaction of ketones has become the wish of every chemist. In 2018, Professor List of the MaxPak Institute made a breakthrough in applying IDPi catalysts to such reactions, successfully solving the asymmetric Mukaiyama-aldol reaction of ketones. A large range of substrates can obtain excellent enantioselective products at a catalytic amount of 50-500 ppm, which is eye-catching. It should be emphasized here that the List research team reduced the minimum load of the catalyst to the 0.9 ppm level for the first time (= 900 ppb), and obtained condensation products with up to 95/5 er and 82% yield (TON = 911000), which is also the lowest limit of catalytic load in all reports of organic catalytic asymmetric reactions (Nat. Chem., 2018, 10, 888-894, click to read for details).
One stone two birds: IDPi solves two major problems in asymmetrical aldol reactions
Image source: Science
hydroxyaldehyde condensation is one of the most basic strategies for forming C-C bonds in organic synthesis. The generated β-hydroxycarbonyl compounds are important synthetic motifs of many chemical intermediates, especially oligoketone compounds. This structure has antibiotics, anti-proliferation, antifungal and cholesterol-lowering properties.In the known asymmetric aldehyde reactions, there are two centuries-old problems. One is the synthesis of β-hydroxyaldehydes. It can be imagined that in the direct cross or indirect aldol condensation between the two aldehydes, the obtained product aldehyde is unstable and is often affected by oligomerization or polymerization; the other is how to achieve the minimum aldol condensation reaction of the enolizable donor aldehyde and regulate its stereoselectivity. Inspired by Yamamoto and Ghosh and others, the List research team reported that enol silicon ether derived from acetaldehyde is used as a nucleophilic substrate to achieve highly enantioselective Mukaiyama-aldol synthesis, effectively inhibiting the generation of polymers during the reaction. The reaction is catalyzed by the independently developed super chiral acid IDPi. It has restricted active sites like enzymes, and also has a wide range of substrates like small-molecular catalysts. It has great scientific significance for the modification of complex natural drugs and biologically active molecules ( Science, 2018, 362, 216-219, click to read more).
Carbon positive ions for the first time realizes the asymmetric rearrangement of non-classical carbon positive ions
Image source: Nature Chemistry
Carbon positive ions can be divided into classical carbon positive ions and non-classical carbon positive ions. These carbon positive ions intermediates are everywhere in basic and actual related reactions, and have been widely used in the research of the petroleum industry, new drugs and materials science. Therefore, the transfer of stereochemical information to carbo-positive ions has attracted interest in a range of chemical fields. Although several studies on classical ion and rearrangement reactions have been conducted before, the enantioselective control of its non-classical counterparts remains an unprecedented major challenge. In 2020, Professor List was inspired by the research work of Weinstein's team in 1949 and imagined whether the existing hindered space chiral superacid can be used to achieve three-dimensional control of non-classical carbon positive ion rearrangement? Subsequently, under a rational experimental design, IDPi catalyst was used to stabilize the highly active 2-norbornene cations, thereby conducting nucleophilic attack to obtain enantioselective bridge ring products. Through a large number of mechanism research and theoretical calculations, it was further proved that under the action of protonic acid, the generation of carbohydrate positive ions was "encapsulated" by IDPi negative ions. Due to the unique spatial structure of the IDPi catalyst, the nucleophilic reagent attacks from specific reaction sites and obtains enantiomer-enriched bridge ring products (Nat. Chem., 2020, 12, 1174-1179, click to read more).
Summary
Benjamin List develops iminobisphosphonomide ester (IDPi) for unprecedented reactions in the field of organic catalysis, while providing excellent stereoselective control in a series of challenging intermolecular and intramolecular C-C and C-O bond formation reactions. Through interaction with the covalent and strong non-covalent bonds (hydrogen bonds) of the reaction substrate, organic small molecules such as proline can catalyze the conversion with high enantioselectivity. In contrast, IDPi simulates the mechanism of enzyme catalysis and achieves excellent enantiospectrum subtle recognition through the chiral microenvironment of its substrate binding sites. The huge potential of IDPi catalysts has been fully reflected in just a few years. We can further look forward to the new reactions and new catalytic mechanism models in the future. I believe that Professor List will bring us more surprises in the future! Professor
Benjamin List. Image source: Mapu Coal Institute official website
Benjamin List Mapu Coal Institute research group official website:
https://www.kofo.mpg.de/en/research/homogeneous-catalysis
(This article is provided by bench )
