New entries in Lewis acid-Lewis base bifunctional asymmetric catalyst: catalytic enantioselective Reissert reaction of pyridine derivatives

The first catalytic enantioselective Reissert reaction of pyridine derivatives that affords products with excellent regio- and enantioselectivity is described. The key for success is the development of new Lewis acid-Lewis base bifunctional asymmetric catalysts containing an aluminum as a Lewis acid and sulfoxides or phosphine sulfides as a Lewis base. These reactions are useful for the synthesis of a variety of chiral piperidine subunits, and catalytic enantioselective formal synthesis of CP-293,019, a selective D4 receptor antagonist, was achieved. Preliminary mechanistic studies indicated that both sulfoxides and phosphine sulfides can activate TMSCN as a Lewis base. In addition, the sulfoxides with appropriate stereochemistry might stabilize a highly enantioselective bimetallic complex (a presumed active catalyst) through internal coordination to aluminum.     

Towards perfect catalytic asymmetric synthesis: dual activation of the electrophile and the nucleophile

The design and development of new high-performance catalysts for applications in asymmetric catalytic reactions is of ongoing interest in organic chemistry. The combination of a Lewis acid and a Lewis base working in concert is now considered state of the art in stereoselective syntheses. The synergistic activation by two or more reactive centers allows high reaction rates and excellent transfer of stereochemical information. Despite the self-quenching reaction between Lewis acids and Lewis bases that might lead to an inactive catalyst, considerable effort has been directed towards the development of the dual-activation concept. The ultimate goal is to mimic nature by the discovery of catalytic systems analogous to enzymatic processes that involve metal-ion cocatalysts. With this aim, the dual activation concept greatly broadens the range of artificial catalysts. The most efficient catalytic systems are reviewed, and the mechanisms of action are discussed.     

氮氧双功能salen催化剂在酮的不对称硅氰化反应中的应用

通过在催化剂的不同位置同时引入LALB（Lewis acid/Lewis base）双功能基团（包括氮氧偶极基团和金属钛中心）来改善其催化活性和立体控制能力,合成基于salen骨架结构的新型氮氧双功能催化剂.在相对温和的条件下成功的将该类双功能催化剂应用于酮的不对称硅氰化反应,表现出了中等程度的选择性和非常高的反应活性...     

Chiral Frustrated Lewis Pair@Metal-Organic Framework as a New Platform for Heterogeneous Asymmetric Hydrogenation

Asymmetric hydrogenation, a seminal strategy for the synthesis of chiral molecules, remains largely unmet in terms of activation by non-metal sites of heterogeneous catalysts. Herein, as demonstrated by combined computational and experimental studies, we present a general strategy for integrating rationally designed molecular chiral frustrated Lewis pair (CFLP) with porous metal–organic framework (MOF) to construct the catalyst CFLP@MOF that can efficiently promote the asymmetric hydrogenation in a heterogeneous manner, which for the first time extends the concept of chiral frustrated Lewis pair from homogeneous system to heterogeneous catalysis. Significantly, the developed CFLP@MOF, inherits the merits of both homogeneous and heterogeneous catalysts, with high activity/enantio-selectivity and excellent recyclability/regenerability. Our work not only advances CFLP@MOF as a new platform for heterogeneous asymmetric hydrogenation, but also opens a new avenue for the design and preparation of advanced catalysts for asymmetric catalysis.     

失配的Lewis对:非金属催化氢化的新策略

“失配的Lewis对”(Frustrated Lewis Pairs,FLPs)作为有机化学领域的新概念,在非金属活化H2,CO2和NH3等小分子方面的研究和应用格外引人注目.以“失配的Lewis对”为催化剂,直接以氢气作为氢源,非金属催化氢化还原醛、烯胺、亚胺、腈和二氧化碳等获得了很好的结果.手性“失配的Lewis对”(Chiral Frustrated Lewis Pairs,Chiral FLPs)在不对称催化氢化还原亚胺的反应中也呈现出较高的光学选择性,产物胺的对映体过量最高达83％ ee.综述了近几年“失配的Lewis对”在非金属催化氢化研究领域的进展情况.     

Mechanism and scope of salen bifunctional catalysts in asymmetric aldehyde and α-ketoester alkylation

Metal complexes of C₂-symmetric Lewis acid/Lewis base salen ligands provide bifunctional activation resulting in rapid rates in the enantioselective addition of diethylzinc to aldehydes (up to 92% ee). Further experiments probed the reactivity of the individual Lewis acid and Lewis base components of the catalyst and established that both moieties are essential for asymmetric catalysis. These catalysts are also effective in the asymmetric addition of diethylzinc to α-ketoesters. This finding is significant because α-ketoesters alone serve as their own ligands to accelerate racemic 1,2-carbonyl addition of Et₂Zn and racemic carbonyl reduction. The latter proceeds via a metalloene pathway, and often accounts for the predominant product. Singular Lewis acid catalysts do not accelerate enantioselective 1,2-addition over these two competing paths. The bifunctional amino salen catalysts, however, rapidly provide enantioenriched 1,2-addition products in excellent yield, complete chemoselectivity, and good enantioselectivity (up to 88% ee). A library of the bifunctional amino salens was synthesized and evaluated in this reaction. The utility of the α-ketoester method has been demonstrated in the synthesis of an opiate antagonist.     

Frustrated Lewis Pairs in Heterogeneous Catalysis: Theoretical Insights

Frustrated Lewis pair (FLP) catalysts have attracted much recent interest because of their exceptional ability to activate small molecules in homogeneous catalysis. In the past ten years, this unique catalysis concept has been extended to heterogeneous catalysis, with much success. Herein, we review the recent theoretical advances in understanding FLP-based heterogeneous catalysis in several applications, including metal oxides, functionalized surfaces, and two-dimensional materials. A better understanding of the details of the catalytic mechanism can help in the experimental design of novel heterogeneous FLP catalysts.     

Catalytic Biomimetic Asymmetric Reduction of Alkenes and Imines Enabled by Chiral and Regenerable NAD(P)H Models

The development of biomimetic chemistry based on the NAD(P)H with hydrogen gas as terminal reductant is a long‐standing challenge. Through rational design of the chiral and regenerable NAD(P)H analogues based on planar‐chiral ferrocene, a biomimetic asymmetric reduction has been realized using bench‐stable Lewis acids as transfer catalysts. A broad set of alkenes and imines could be reduced with up to 98 % yield and 98 % ee, likely enabled by enzyme‐like cooperative bifunctional activation. This reaction represents the first general biomimetic asymmetric reduction (BMAR) process enabled by chiral and regenerable NAD(P)H analogues. This concept demonstrates catalytic utility of a chiral coenzyme NAD(P)H in asymmetric catalysis.     

Asymmetric Michael Addition of Ketones to Alkylidene Malonates and Allylidene Malonates via Enamine-Metal Lewis Acid Bifunctional Catalysis

Novel enamine-metal Lewis acid bifunctional catalysts were successfully applied to the asymmetric Michael addition of ketones to alkylidene malonates, offering excellent stereoselectivity (up to >99% ee and >99:1 dr). The asymmetric Michael addition of ketones to allylidene malonates was also achieved.     

Highly enantioselective conjugate addition of malonate and beta-ketoester to nitroalkenes: asymmetric C-C bond formation with new bifunctional organic catalysts based on cinchona alkaloids

The development of readily accessible bifunctional chiral catalysts is a desirable yet challenging goal in catalytic asymmetric synthesis. In this communication, we describe the development of a new class of readily accessible chiral bifunctional organic catalysts that could be derived in one or two steps in high yield from either quinidine or quinine. These catalysts have been shown to catalyze a highly enantioselective conjugate addition of methyl and ethyl malonates and beta-ketoesters to a broad range of beta-substituted nitroalkenes, an synthetically important C-C bond-forming reaction utilizing readily available starting materials. This new catalytic asymmetric reaction proceeds in 91-98% ee and 71-99% yield.     

Metal-free asymmetric hydrogenation and hydrosilylation catalyzed by frustrated Lewis pairs

The activation of H₂ for the catalytic hydrogenation of unsaturated compounds is one of the most useful reactions in both academia and chemical industry, which has long been predominated by the transition-metal catalysis. However, metal-free hydrogen activation represents a formidable challenge, and has been less developed. The recent emerging chemistry of frustrated Lewis pairs (FLPs) with a combination of sterically encumbered Lewis acids and Lewis bases provides a promising approach for metal-free hydrogenation due to their amazing abilities for the challenging H₂ activation. In the past several years, the hydrogenation of a wide range of unsaturated compounds using FLP catalysts has been successfully developed. Despite these advances, the corresponding asymmetric hydrogenation is just in its start-up step. Similar to the mode of HH bond activation, SiH bond can also be activated by FLPs for the hydrosilylation of ketones and imines. But its asymmetric version is also not well-solved. This Letter will outline the recent important progress of metal-free catalytic asymmetric hydrogenation and hydrosilylation using FLP catalysts.     

Bifunctional asymmetric catalysis: a tandem nucleophile/Lewis acid promoted synthesis of beta-lactams

[reaction: see text]. We describe a superior procedure for the catalytic, asymmetric synthesis of beta-lactams using a bifunctional catalyst system consisting of a chiral nucleophile and an achiral Lewis acid.     

Lewis base catalyzed addition of trimethylsilyl cyanide to aldehydes

A variety of achiral Lewis bases were found to catalyze the addition of TMSCN to the aldehydes. Among them, phosphines and amines were the most efficient catalysts. In addition, several chiral amines and phosphines were examined in a catalytic, asymmetric addition of TMSCN to benzaldehyde albeit with low enantioselectivity. A mechanistic study revealed that the reaction was first order in aldehyde, first order in Lewis base, and zeroth order in TMSCN, suggesting the complex formation of TMSCN and Lewis base formation of complex i. However, there are at least two possible scenarios for this catalytic process, and in view of the low selectivities observed, it is not clear which mechanism is operative.     

Multifunctional asymmetric catalysis

Two types of general and practical enantioselective catalysts, namely, bimetallic complexes and Lewis acid-Lewis base bifunctional catalysts were developed based on the concept of multifunctional catalysis. In the first part of this review, the first example of a catalytic enatioselective nitro-Mannich reaction as well as a direct catalytic enantioselective aldol reaction of 2-hydroxyacetophenone using bimetallic complexes is discussed. The new complex, composed of ytterbium, potassium, and BINOL in a ratio of 1:1:3, promoted the nitro-Mannich reaction of nitromethane with up to 91% ee. On the other hand, second generation ALB catalyzed an enantioselective and diastereoselective nitro-Mannich reaction of nitroalkanes in up to 83% ee with a diastereomeric ratio up to 7:1. Moreover, the reaction of aldehydes with 2-hydroxyacetophenone in the presence of LLB, KHMDS, and H2O selectively gave the corresponding anti-alpha,beta-dihydroxy ketones in up to 95% ee and, in the presence of the catalyst prepared from linked-BINOL and 2 eq of Et2Zn, selectively afforded the syn-alpha,beta-dihydroxy ketones in up to 86% ee. In the second part, the development of new catalysts displaying a Lewis acidity and a Lewis basicity is described. The Lewis acid of the catalyst activates aldehydes, imines, acyl quinoliniums, and ketones. At the same time, the Lewis base activates the nucleophile (TMSCN). Catalysts of this type produced a highly enantioselective cyanation of these electrophiles. Application of the catalytic enantioselective cyanosilylation of aldehydes to a total synthesis of epothilones is also described.     

Asymmetric Catalysis with Heterobimetallic Compounds

This review focuses on a new concept in catalytic asymmetric reactions that was first realized for the use of heterobimetallic complexes. As these heterobimetallic complexes function as both a Brønsted base and as a Lewis acid, just like an enzyme, they make possible a variety of efficient catalytic asymmetric reactions. This heterobimetallic concept should prove to be applicable to a variety of new asymmetric catalyses. The first part of this review describes the development of rare-earth–alkali metal complexes such as LnM₃tris(binaphthoxide) complexes (LnMB, Ln = rare-earth metal, M = alkali metal), which are readily prepared from the corresponding rare-earth trichlorides or rare-earth isopropoxides, and their application to catalytic asymmetric synthesis. By using a catalytic amount of LnMB complexes several asymmetric reactions proceed efficiently to give the corresponding desired products in up to 98% ee: LnLB-catalyzed asymmetric nitroaldol reactions (L = Li), LnSB-catalyzed asymmetric Michael reactions (S ? Na), and LnPB-catalyzed asymmetric hydrophosphonylations of either imines or aldehydes (P ? K). Applications of these heterobimetallic catalysts to the syntheses of several biologically and medicinally important compounds are also described. Spectral analyses and computational simulations of the asymmetric reactions catalyzed by the heterobimetallic complexes reveal that the two different metals play different roles to enhance the reactivity of both reaction partners and to position them. From mechanistic considerations, a useful activation of the heterobimetallic catalyses was realized by addition of alkali metal reagents. The second part describes the development of another type of heterobimetallic catalysts featuring Group 13 elements such as Al and Ga as the central metal. Among them, the AlLibis(binaphthoxide) complex (ALB) is an effective catalyst for asymmetric Michael reactions, tandem Michael–aldol reactions, and hydrophosphonylation of aldehydes.     

Bifunctional Gyroidal MOFs: Highly Efficient Lewis Base and Lewis Acid Catalysts

A family of gyroidal metal–organic frameworks (STUs) composited with transition metal ions and bi‐imidazolate ligands (BIm) were prepared and applied as both Lewis base and acid catalysts. Benefiting from the intrinsic basicity of the ligands and the Lewis acidic sites of the open metal centres, the STUs materials show excellent catalytic activities as Lewis base for the Knoevenagel condensation reaction between various aldehydes and malononitrile, and as Lewis acid for cyanosilylation reactions. Among these STUs, STU‐4 (Ni(BIm)) shows the best catalytic efficiency (conversions >99 %) in both Knoevenagel condensation and cyanosilylation reactions under mild conditions, providing thus an advanced material for both Lewis base and Lewis acid catalysis.     

Asymmetric Hydrogenation of Ketones and Enones with Chiral Lewis Base Derived Frustrated Lewis Pairs

The concept of frustrated Lewis pairs (FLPs) has been widely applied in various research areas, and metal‐free hydrogenation undoubtedly belongs to the most significant and successful ones. In the past decade, great efforts have been devoted to the synthesis of chiral boron Lewis acids. In a sharp contrast, chiral Lewis base derived FLPs have rarely been disclosed for the asymmetric hydrogenation. In this work, a novel type of chiral FLP was developed by simple combination of chiral oxazoline Lewis bases with achiral boron Lewis acids, thus providing a promising new direction for the development of chiral FLPs in the future. These chiral FLPs proved to be highly effective for the asymmetric hydrogenation of ketones, enones, and chromones, giving the corresponding products in high yields with up to 95 % ee. Mechanistic studies suggest that the hydrogen transfer to simple ketones likely proceeds in a concerted manner.     

金/钯双金属纳米颗粒协同催化酰胺和醇间氢自转移反应中路易斯酸驱动反应路径

金属纳米颗粒,特别是金和它的双金属纳米颗粒作为强大的绿色催化剂广泛用于有机合成反应中。在一个反应体系中使用2个不同催化剂(如协同催化),在均相催化中是一个很好的策略。然而,这种方法仍在发展中。最近我们发现,金/钯双金属纳米颗粒与路易斯酸的协同催化体系可用于伯胺的N-烷基化：即酰胺与醇之间的氢自转移反应。我们详细报道了路易斯酸对该氢自转移反应的影响。结果表明,所选的路易斯酸不仅影响生成目标产物的反应路径,而且影响生成多个中间体和副产物的反应路径。弱的路易斯酸,如三氟甲磺酸碱土金属盐,非常适合酰胺的N-烷基化反应。     

Asymmetric catalytic aza-Morita-Baylis-Hillman reaction using chiral bifunctional phosphine amides as catalysts

The asymmetric catalytic aza-Morita-Baylis-Hillman reaction of N-sulfonated imines with α,β-unsaturated ketones has been successfully conducted by using chiral bifunctional phosphine amides as catalysts. A series of new chiral bifunctional phosphine amides were designed, synthesized, and systematically studied for this asymmetric reaction. The corresponding aza-MBH adducts were obtained in good yields (75-99%) and up to very good enantiomeric excesses (51-95% ee) under mild conditions.     

Investigation of Lewis Acid versus Lewis Base Catalysis in Asymmetric Cyanohydrin Synthesis

The asymmetric addition of trimethylsilyl cyanide to aldehydes can be catalysed by Lewis acids and/or Lewis bases, which activate the aldehyde and trimethylsilyl cyanide, respectively. It is not always apparent from the structure of the catalyst whether Lewis acid or Lewis base catalysis predominates. To investigate this in the context of using salen complexes of titanium, vanadium and aluminium as catalysts, a Hammett analysis of asymmetric cyanohydrin synthesis was undertaken. When Lewis acid catalysis is dominant, a significantly positive reaction constant is observed, whereas reactions dominated by Lewis base catalysis give much smaller reaction constants. [{Ti(salen)O}₂] was found to show the highest degree of Lewis acid catalysis, whereas two [VO(salen)X] (X=EtOSO₃ or NCS) complexes both displayed lower degrees of Lewis acid catalysis. In the case of reactions catalysed by [{Al(salen)}₂O] and triphenylphosphine oxide, a non‐linear Hammett plot was observed, which is indicative of a change in mechanism with increasing Lewis base catalysis as the carbonyl compound becomes more electron‐deficient. These results suggested that the aluminium complex/triphenylphosphine oxide catalyst system should also catalyse the asymmetric addition of trimethylsilyl cyanide to ketones and this was found to be the case.