Even though seminal reports on phosphine catalysis appeared in the 1960s, in the last few decades of the past century trivalent phosphines were viewed primarily as useful ligands for transition-metal-mediated processes. The 1990s saw revived interest in using phosphines in organic catalysis, but the key advances in asymmetric phosphine catalysis have all come within the past decade. The uniqueness of phosphine catalysis can be attributed to the high nucleophilicity of the phosphorus atom. In typical phosphine-catalyzed reactions, nucleophilic attacks of the phosphorus atom on electron-deficient multiple bonds create different reactive ylide-type intermediates. When such structurally diverse zwitterionic species react with a variety of suitable substrates, new reaction patterns are often discovered and a diverse array of reactions can be developed. In recent years, substantial progress has been made in the field of asymmetric phosphine catalysis; many new reactions have been discovered, and numerous enantioselective processes have been reported. However, we felt that powerful and versatile phosphine catalysts that can work for a wide range of asymmetric reactions are still lacking. We therefore set our goal to develop a family of easily derived phosphine catalysts that are efficient in asymmetric induction for a broad range of phosphine-mediated transformations. This Account describes our efforts in the past few years on the development of amino acid-based bifunctional phosphines and their applications to enantioselective processes. Building upon our previous success in primary-amine-mediated enamine catalysis, we first established that bifunctional phosphines could be readily prepared from amino acids. In most of our studies, we chose threonine as the key backbone for catalyst development, and threonine-based monoamino acid or dipeptide bifunctional phosphines have displayed remarkable stereochemical control. We began our investigations by demonstrating the usefulness of our phosphine catalysts in aza-Morita-Baylis-Hillman (aza-MBH) and MBH reactions. We then showed the great power of amino acid/dipeptide phosphines in a wide range of [3 + 2] annulation processes, including [3 + 2] cycloaddition of allenoates to acrylates/acrylamides, [3 + 2] annulation of imines with allenoates, and [3 + 2] cyclization employing MBH carbonates and activated alkenes. By utilizing α-substituted allenoates and activated alkenes, we developed an enantioselective [4 + 2] annulation to access functionalized cyclohexenes. We also devised a novel enantioselective [4 + 2] annulation process by using α-substituted allenones for the construction of 3,4-dihydropyrans. With the use of β'-acetate allenoate, a [4 + 1] annulation process has been designed to access chiral spiropyrazolones. Another array of reactions that make use of the basicity of zwitterionic phosphonium enolate intermediates have been successfully attained, including the first phosphine-catalyzed asymmetric Michael addition, enantioselective allylic substitution of MBH carbo...

Spirocyclic oxindoles [1] are the structural motifs frequently found in many natural products and biologically active molecules.[2] Among many spirooxindole cores, the 3,3'-pyrrolidinyl spirooxindole units are well known for their strong bioactivity profiles, thus synthetic studies toward this fused heterocyclic system have been pursued intensively. Oxindoles having spiral carbocyclic rings are also important substructures that are widely present in numerous bioactive natural products. In this context, 3-spirocyclopentane-2-oxindoles containing two adjacent quaternary centers are particularly striking structural motifs [3] (Scheme 1), and their efficient asymmetric constructions are formidable synthetic tasks.[4] To the best of our knowledge, there were only two catalytic asymmetric syntheses in the literature dealing with similar structural scaffolds. Trost and co-workers reported an enantioselective construction of spirocyclic oxindolic cyclopentanes by using a palladium-catalyzed [3+2] cycloaddition of trimethylenemethane.[5] Very recently, Marinetti et al. disclosed an organocatalytic asymmetric [3+2] cyclization between 3-alkylideneindolin-2-ones and allenes for the synthesis of spirooxindoles. [6] Nucleophilic catalysis employing chiral phosphines is an intensively explored research area in asymmetric catalysis. [7] For the construction of five-membered ring systems, phosphine-mediated [3+2] annulations represents one of the most efficient approaches.[8] As part of our research program toward the development of asymmetric synthetic methods catalyzed by amino-acid-based organocatalysts, [9] we recently focused on the development of novel chiral phosphines from amino acids. We showed that dipeptide-derived novel phosphines were powerful catalysts for the enantioselective allene-acrylate [3+2] cycloadditions.[8n] More recently, we also derived a series of phosphine sulfonamide bifunctional catalysts and demonstrated their effectiveness in the enantioselective aza-Morita-Baylis-Hillman (aza-MBH) reactions.[10] We envisioned that phosphine-mediated [3+2] cyclizations may be utilized to construct spirooxindole cores (Scheme 2). The electron-deficient alkene components necessary for the annulation reactions can be conveniently derived from isatins. Notably, such tetrasubstituted activated alkenes are unexplored substrates in the asymmetric [3+2] cyclization processes, and their successful elaboration in the cycloaddition reaction may create two contiguous quaternary centers. Allenes and alkynes are commonly employed as C 3 synthons in the annulation reactions, and in this context, employment of more readily available and versatile C 3 synthons in the annulations is certainly ideal. The MBH reaction is one of the most atom-economic reactions for the construction of densely functionalized products, [11] and the Scheme 1. Spirocyclicpentane oxindole structures having two contiguous quaternary centers.Scheme 2. Construction of 3-spirocyclopentene-2-oxindoles through phosphine-catalyzed [3+2] cycloadditions of MBH add...

A new family of dipeptide-based chiral phosphines was designed and prepared. D-Thr-L-tert-Leu-derived catalyst 4c promoted [3 + 2] cycloaddition of allenoates to α-substituted acrylates in a regiospecific and stereoselective manner, furnishing functionalized cyclopentenes with quaternary stereogenic centers in high yields and with excellent enantioselectivities.

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Optically pure five-membered N-heterocycles are valuable intermediates in chemical synthesis, and they are also prevalent structural motifs in bioactive molecules and natural products.[1] Over the past decade, many synthetic methods have been devised for the construction of such ring systems. [2] In this context, [3+2] cyclization of imines with allenes or alkynes is one of the most straightforward and efficient methods for the creation of pyrrolines [3] and pyrrolidines, [4] which are classes of compounds that are of synthetic and biological importance. In 1997, Xu and Lu disclosed the [3+2] cycloadditions between imines and alkynes or allenes for the synthesis of pyrroline rings.[5] However, asymmetric variants of these phosphine-catalyzed [3+2] cyclizations only appeared almost a decade later. The groups of Marinetti and Gladysz independently reported chiral-phosphine-triggered asymmetric [3+2] annulations of allenes with N-tosyl imines, thus affording functionalized 3-pyrrolines with moderate enantioselectivity.[6] The breakthrough came when Fang and Jacobsen introduced phosphinothiourea catalysis of the imine-allene cyclization; by utilizing diphenylphosphinoyl (DPP) imines, [7] substituted 2-aryl-2,5-dihydropyrroles were formed in good yields and with excellent enantioselectivities.[8] Despite all the above advances, the utilization of aliphatic imines in phosphine-catalyzed [3+2] cycloaddition reaction remains elusive.[9] Aliphatic imines are challenging substrates because of their isomerizable nature [10] and relative instability. Nonetheless, their synthetic value is remarkable. Apparently, accessing five-membered N-heterocycles through cycloaddition reactions of aliphatic imines holds significant synthetic utility. As illustrated in Scheme 1, pyrrolidines with 2-alkyl substituents are very common substructures in bioactive molecules and natural products. [11] We recently embarked on an exciting adventure of developing amino-acid-based bifunctional phosphines and their applications in asymmetric organic transformations. [12] We showed that highly enantioselective aza-Morita-BaylisHillman (MBH) and MBH reactions could be realized by using l-threonine-derived phosphine sulfonamides [13] and phosphine thioureas, [14] respectively. We also demonstrated that dipeptide-derived phosphines were powerful catalysts for promoting enantioselective [3+2] cycloadditions of allenes to acrylates or acrylamides.[15] Very recently, we discovered that l-threonine-derived phosphine thioureas were capable of promoting MBH carbonates as C 3 synthons in the [3+2] cyclization. [16] Given the relative instability of aliphatic imines, we reasoned that highly reactive phosphines are probably necessary for their effective activations in the cycloaddition reaction, since potential decomposition of imines may be avoided. It is noteworthy that our aminoacid-based phosphines possess remarkably high nucleophilicity. We hypothesized that employment of highly nucleophilic bifunctional phosphines may result in a practical asymmetric [3+...

Phthalides were used for the first time in the allylic alkylation reactions with MBH carbonates for the creation of chiral 3,3-disubstituted phthalides. Highly enantioselective regiodivergent synthesis of γ-selective or β-selective allylic alkylation products was achieved by employing bifunctional chiral phosphines or multifunctional tertiary amine-thioureas as the catalyst, respectively. It was demonstrated that proper selection of catalysts and reaction conditions would differentiate an S(N)2'-S(N)2' pathway and an addition-elimination process, yielding different regioisomers of the allylic alkylation products in a highly enantiomerically pure form.

Bifunctional phosphines derived from amino acids mediate the asymmetric Michael addition of 3‐substituted oxindoles to activated alkenes (see scheme). Biologically relevant chiral 3,3‐disubstituted oxindoles were thus prepared in high yields and with excellent enantioselectivities from 3‐aryl‐ and 3‐alkyl‐substituted oxindoles and various activated alkenes.

A series of bifunctional phosphine-thiourea organic catalysts based on natural amino acid scaffolds were designed and prepared. L-threonine-derived bifunctional phosphine catalysts were found to be very efficient in promoting asymmetric Morita-Baylis-Hillman (MBH) reaction of acrylates with aromatic aldehydes, affording the desired MBH adducts with up to 90% ee. To gain mechanistic insights into the reaction, the effects of adding various additives on the MBH reaction were investigated. We propose that the hydrogen bonding interactions between the thiourea moiety of the catalyst and the enolate intermediate are crucial for the stereochemical outcome of the reaction. The method described in this report may provide a practical solution to the enantioselective MBH reaction of simple acrylates.