Amino Acid-Derived Bifunctional Phosphines for Enantioselective

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Amino Acid-Derived Bifunctional Phosphines for Enantioselective Transformations Tianli Wang,† Xiaoyu Han,‡ Fangrui Zhong,§ Weijun Yao,† and Yixin Lu*,† †

Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, P. R. China § Key Laboratory for Large-Format Battery Materials and System, Ministry of Education, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, P. R. China ‡

CONSPECTUS: 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-metalmediated 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 carbonates by phthalides, and enantioselective γ-additions of prochiral 3-substituted oxindoles, 5H-thiazol-4-ones, 5H-oxazol-4-ones, and oxazol-5-(4H)-ones to 2,3-butadienoates. Bifunctional modes of action in our reported reactions have been supported by experimental results and theoretical studies. With the establishment of the new families of powerful amino acid-derived bifunctional phosphines, the discovery of new modes of phosphine activation, unknown reactions, and more enantioselective processes are well-anticipated. reported their seminal findings on the [3 + 2] annulation reaction and “umpolung” addition, and ever since, the great potential of phosphine-catalyzed reactions in organic synthesis has been recognized, and many synthetic groups have been joining adventures in this dynamic and promising research field. There

1. INTRODUCTION Maelstroms of synthetic challenges arising from the high demand of enantiomerically pure substances in the pharmaceutical industry and life sciences have been stimulating the development of asymmetric catalytic methods.1 Even though landmark discoveries by Price, Rauhut and Currier, and Morita were reported in the 1960s,2 phosphine catalysis remained dormant for the next few decades. In the mid-1990s, Lu3 and Trost4 © XXXX American Chemical Society

Received: March 31, 2016

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DOI: 10.1021/acs.accounts.6b00163 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research were only two examples of phosphine-catalyzed asymmetric reactions prior to the year 2000: in 1996 Vedejs utilized chiral phosphines for enantioselective acylation of secondary alcohols,5 and in 1997 Zhang documented the first enantioselective [3 + 2] cycloaddition catalyzed by a bicyclic monodentate chiral phosphine.6 Major advances in asymmetric phosphine catalysis came in the mid-2000s, and we shall mention these literature reports in subsequent sections. Phosphine catalysis has been intensively reviewed, especially in recent years.7 In this Account, we shall crystallize and highlight our own contributions over the past few years in designing amino acid-based bifunctional phosphines and applying them to enantioselective organic reactions, in the context of major discoveries reported by others.

Scheme 2. Bifunctional Phosphines: Working Hypothesis

advanced intermediates by too-acidic H-bond donors must be avoided. At the time we initiated this research, the structures of chiral phosphine catalysts were quite limited, and there existed a need for the development of efficient phosphine catalysts that are capable of promoting a wide variety of asymmetric processes. It was with this in mind that we embarked on our journey to develop versatile bifunctional phosphines.

2. AMINO ACID-BASED BIFUNCTIONAL PHOSPHINES 2.1. Phosphine Activation and Bifunctional Catalysis

The most commonly employed reaction partners activated by phosphines and key modes of phosphine activation are illustrated in Scheme 1. Catalytic events typically start with addition of the

2.2. Bifunctional Phosphines Derived from Amino Acids

There are a few reports on bifunctional phosphine catalysis. In 2003, Shi designed a series of BINOL-based bifunctional phosphines for an asymmetric aza-MBH reaction of Nsulfonated imines with methyl vinyl ketone and phenyl acrylate.8 Miller disclosed an alanine-derived multifunctional phosphinepromoted enantioselective [3 + 2] cycloaddition of allenoates to enones in 2007.9 A few years later, Zhao reported an asymmetric [3 + 2] cycloaddition between allenoates and dual-activated olefin, catalyzed by bifunctional N-acyl amino phosphines.10 Jacobsen devised cyclohexane-based bifunctional phosphines with a thiourea moiety to promote allene−imine annulation.11 At the very beginning, we set our goal to develop a family of easily derived bifunctional phosphines that are efficient in asymmetric induction for a wide range of phosphine-mediated processes. Moreover, powerful phosphines will allow us to explore and discover unknown enantioselective reactions. Ultimately, we hope to establish asymmetric phosphine catalysis as a privileged strategy for the construction of chiral molecules. The following criteria for catalyst design were considered: (i) ready availability of chiral scaffolds at low cost, preferentially in each enantiomeric form, which is of crucial importance in consideration of practical aspects of any synthetic method; (ii) tunability of catalyst structures for asymmetric induction, given that there is no one “magic” catalyst, and tunable structures make it possible to search for the best catalyst for different enantioselective processes; and (iii) stability of bifunctional phosphines, as again for practicality it is certainly more appealing to handle bench-stable catalysts. We have been actively investigating amino catalysis in the past decade, especially those enantioselective processes catalyzed by primary amino acid-derived organic catalysts.12 It was thus natural for us to first look into the possibility of devising novel bifunctional phosphines from amino acids, which are arguably the most abundant, readily available, and economical chiral building blocks available to chemists. Our design principle is illustrated in Scheme 3. Phosphines can be prepared from αamino acids via a few trivial functional group transformations. To render the catalysts bifunctional, the amino group can be derivatized (e.g., amide). We expected that H-bond donors will interact with substrates/advanced intermediates, and thus, the strength of the H-bond donor may be crucial for catalyst performance. In this regard, conversion of the amino group into a variety of amine-based functional groups with different Hbonding capabilities precisely serves this purpose. We reasoned

Scheme 1. Phosphine Activations: Key Zwitterion Intermediates and Reactions

phosphorus atom to an electron-deficient substrate, resulting in the formation of various zwitterionic intermediates. Different reaction pathways may occur, hinging on the nature of the other reaction partners. The use of suitable electrophiles may lead to various annulation reactions or (aza)-Morita−Baylis−Hillman (MBH) reaction, while γ- and Michael additions can take place if pronucleophiles are utilized in the reaction. To design catalytic systems that are broadly applicable to different asymmetric processes, we believed that bifunctional phosphines containing a nucleophilic phosphine moiety and a properly installed hydrogen bond (H-bond) donor could be a good choice. We envisioned that hydrogen-bonding interactions between the H-bond donor of the bifunctional phosphine and electrophiles may facilitate the formation of well-defined transition states, which is the key to high enantioselectivity. Zwitterionic intermediates generated upon phosphine addition have a few resonance forms, which naturally will lead to the creation of different regioisomers if no controlling element is placed. We reasoned that the inclusion of a bulky group in the catalyst to exert further stereochemical differentiation may be a good solution (Scheme 2). Notably, the basic nature of zwitterionic intermediates poses an extra difficulty in the design: H-bond donor groups need to favorably interact with advanced species, and at the same time, quenching or overstabilization of B


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Accounts of Chemical Research

different silyl groups; (ii) tunable steric effects; (iii) potential aromatic interactions if proper silyl ethers are chosen; and (iv) the excellent stability of silyl ethers in general. To turn the above hypothesis into reality, we needed to first work out a viable synthetic route to access different phosphine structures. Commercially available threonine was converted to advanced phosphine intermediate A in good overall yield through a few trivial steps, and further elaborations to give different types of phosphines were straightforward. The establishment of the above synthetic protocols paved the way to the development of families of threonine-based bifunctional phosphines for asymmetric nucleophilic catalysis. Over the past few years, we have disclosed a wide range of amino acid-based bifunctional phosphines, and some selected phosphine architectures are shown in Scheme 5. These catalysts

Scheme 3. Amino Acid-Based Bifunctional Phosphines

that the side chains of amino acids could be utilized for stereochemical control, through either steric or electronic effects. Bearing in mind our ultimate goal of developing families of catalysts to enable a broad spectrum of enantioselective reactions, we suspect that mono(amino acid)-derived phosphines may not always ensure sufficient interactions with substrates/intermediates. To best accommodate a broader scope of substrates/intermediates, we decided to also develop dipeptide-based phosphines. In consideration of practicality, we limited our synthetic efforts to dipeptides. The key distinct features of dipeptide phosphines are their tunability and modular assembly: different backbones could be selected, either the L or D forms of the amino acids could be employed, and different protective groups at the N-terminus could be utilized. The nucleophilicity of a phosphine is determined by the nature of the groups connected to the phosphorus, and such nucleophilicity is closely correlated to the catalytic activity. With the phosphorus atom attached to a primary carbon, it is anticipated that such amino acid-derived phosphines will possess high nucleophilicity. To have a good balance between nucleophilicity and stability, we intended to attach two aryl groups to the phosphorus center. In principle, any amino acid structure can be chosen as the starting point for catalyst development; one can even take a combinatorial approach to make derivatizations from all chiral amino acids. We opted to take more “rational” approach by riding on our previous success in enamine catalysis. In our early studies,13 we found that simple threonine-derived organic catalysts are capable of promoting highly enantioselective processes. The discovery that a simple amino acid backbone like threonine is remarkable in stereochemical control was truly exciting, and the implication was that taking advantage of that finding may result in the development of other simple yet powerful catalysts, thus significantly contributing to practical organic synthesis. As shown in Scheme 4, threonine14 can be converted to mono(amino acid)-based or dipeptide-derived phosphine catalysts. We intended to choose silyl ethers to block the free OH for a number of reasons: (i) the availability of

Scheme 5. Amino Acid-Derived Bifunctional Phosphines

are the optimal catalysts utilized for the studies that will be described in detail in the following sections. It is noteworthy that all of the amino acid-derived phosphines described in our studies possess superb stability in air at ambient temperature. The shelf life of our phosphines is at least a few months, which makes their applications in asymmetric catalysis highly attractive and practical. In what follows, we shall describe in detail how we applied our amino acid-based bifunctional phosphines to a range of enantioselective organic reactions.

Scheme 4. Threonine Core for Phosphine Development

3. ENANTIOSELECTIVE ANNULATION REACTIONS Ring structures are omnipresent in natural products and bioactive molecules; in particular, chiral cyclic architectures are predominant structural motifs that have stimulated generations of chemists to pursue their efficient enantioselective syntheses. Ever since Lu’s seminal discovery of phosphine-catalyzed annulation between allenes and alkenes to create functionalized cyclopentenes in 1995,3 the great potential of phosphine catalysis for the construction of ring systems has been recognized, and C


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Accounts of Chemical Research many new and creative annulation reactions have been developed in the past two decades. A few common modes of phosphine-catalyzed ring formation are illustrated in Scheme 6.

Scheme 7. Enantioselective [3 + 2] Cycloaddition of Allenes to Acrylates Catalyzed by Amino Acid-Derived Phosphines

Scheme 6. Common Modes of Phosphine-Catalyzed Ring Cyclization

The cyclizations between activated allenes and suitable alkenes/ imines are the most classical [3 + 2] annulations (eq 1). With effective activations by phosphines, MBH adducts can also serve as C3 synthons in cycloadditions (eq 2). The Kwon [4 + 2] annulations make use of α-substituted allenoates as C4 synthons (eq 3), and Tong utilized β′-acetate allenoates as electrophilic C4 synthons in [4 + 1] annulations (eq 4). Our subsequent discussion will focus on these modes of cyclization.

moieties and the N-terminal groups, O-TBDPS-D-Thr-L-tertLeu-based P-1 was found to be the optimal catalyst. To further increase the stereoselectivity, the ester groups of the acrylates and allenoates were subsequently varied, and the winning combination comprised 9-phenanthryl acrylates and tert-butyl allenoate. Under the optimal conditions, different α-aryl-substituted acrylates could be used, and the [3 + 2] cycloaddition products were obtained in high yields with excellent ee values (Scheme 8).

3.1. [3 + 2] Annulations of Allenes

Scheme 8. Reaction Scope: Selected Examples

Among various [m + n] annulation processes, the Lu [3 + 2] cycloadditions involving allenes and activated alkenes have been particularly well studied. Two years after Lu’s initial disclosure, Zhang reported the first enantioselective variant.6 In 2006, Fu utilized a binaphthyl-based C2-symmetric phosphine for an asymmetric cyclization of allenoates and enones.15 Similar types of annulations were also reported by Miller,9 Marinetti,16 and Zhao.10 To test the effectiveness of our amino acid-based phosphines, we chose to investigate their catalytic effects in the [3 + 2] cycloaddition of allenes to α-substituted acrylates.17 The use of elusive substituted acrylate substrates for the construction of challenging functionalized cyclopentenes with a quaternary stereogenic center made it ideal to evaluate our novel phosphine catalysts. We mainly utilized bifunctional dipeptide phosphines in this study, anticipating that dipeptidic motifs may have better chiral communication with the substrates. We fixed the first amino acid to threonine for the reasons we elaborated in the earlier sections. To deal with the high flexibility of dipeptide structures, we hypothesized that judicious selection of suitable amino acid residues may add rigidity to the dipeptide structure, helping the catalyst to adopt a specific conformation favoring its interactions with substrates/intermediates. The screening of the catalysts was interesting and intriguing (Scheme 7). L-Threonine-derived P-15 was a poor catalyst, and dipeptide-based phosphines were more effective. L-Thr-L-Val-derived P-4 was a good catalyst. The configurations of amino acid residues in the dipeptide were found to be important, and L-Thr-D-Val-based P-16 further improved the enantioselectivity. Changing the second amino acid residue to tert-leucine was crucial, and D-Thr-L-tert-Leu-derived P-17 offered better results. Eventually, by tuning the silyl ether

A reaction mechanism and transition state were proposed, and the key point in the proposal was that the phosphonium enolate intermediate interacts with the acrylate through hydrogen bonding (Scheme 9). Theoretical studies to obtain a deep understanding of this reaction mechanism are currently ongoing. Scheme 9. Mechanism and Proposed Transition State

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their ease of isomerization and relative instability. Our amino acid-based phosphines had displayed high nucleophilicity in previous studies, and we reasoned that the use of such highly reactive phosphines may provide a solution to this challenging problem, as fast phosphine activation of the alkylimine substrates may simply outpace their decomposition. Indeed, dipeptide phosphine P-2 promoted a highly enantioselective [3 + 2] annulation of aliphatic imines and allenoates.21 It is noteworthy that the reaction went to completion within an hour even with a catalyst loading of 1 mol %. A wide range of alkylimines and various arylimines were well-tolerated for the reaction. In addition, a facile formal synthesis of (+)-trachelanthamidine was also demonstrated (Scheme 13). Mechanistically, it was

We subsequently developed a P-1-catalyzed [3 + 2] annulation reaction in which acrylamides were used as C2 synthons for the first time. The cyclization between allenoate 2b and pyrazolederived acrylamides 4 proceeded efficiently, creating cyclopentenes 5 in good yields with moderate enantioselectivity.18 Notably, 3,5-dimethyl-1H-pyrazole-derived acrylamides were specifically designed for the reaction, with the methyl groups providing steric differentiation and nitrogen atoms providing hydrogen bonding (Scheme 10). The power of dipeptide Scheme 10. [3 + 2] Annulation of Acrylamides with Allenoates

Scheme 13. Enantioselective [3 + 2] Annulation of Aliphatic Dipeptide Phosphine Imines

phosphine catalysts was further demonstrated in the [3 + 2] annulation of maleimides 6 with electron-deficient allenes 7.19 In the presence of P-1, functionalized bicyclic cyclopentenes containing two tertiary stereogenic centers were obtained in high yields with excellent ee values (Scheme 11). Scheme 11. [3 + 2] Annulation of Maleimides proposed that catalyst P-2 works in a bifunctional mode. When N-methylated P-2′ was utilized, the reaction became much slower and the product ee dropped drastically. Interestingly, a dipeptide phosphine with a thiourea moiety turned out to be completely ineffective, which may be attributed to thiourea stabilization of the phosphonium enolate intermediate rather than the dipeptide phosphine imine (Scheme 14).

Very recently, we developed an enantioselective [3 + 2] annulation of α-substituted allenoates with β,γ-unsaturated Nsulfonylimines for the synthesis of functionalized cyclopentenes bearing an all-carbon quaternary center (Scheme 12).20 Notably,

Scheme 14. Mechanistic Hints: P-2′/P-18-Catalyzed Formation of 13a

Scheme 12. [3 + 2] Annulation of α-Substituted Allenoates with β,γ-Unsaturated N-Sulfonylimines

sulfonylimine substrates have rarely been utilized in phosphine catalysis, and the winning catalyst P-7′ has a quite different dipeptide backbone, reinforcing the versatility of our catalyst system. All of the C2 synthons of the [3 + 2] cycloadditions discussed so far are activated alkenes. Imines are another class of common C2 synthons. Phosphine-catalyzed allene/alkyne−imine [3 + 2] cyclization is one of the most powerful methods for constructing pyrrolines and pyrrolidines. In 2008 Jacobsen reported an enantioselective imine−allene [3 + 2] cyclization promoted by phosphinothiourea catalysts.11 However, aliphatic imines remained elusive substrates in phosphine catalysis because of

3.2. [3 + 2] Annulations of MBH Carbonates

The perspective of using MBH adducts in phosphine catalysis is very attractive, given the tremendous applications of MBH adducts in organic synthesis.22 In the presence of a phosphine catalyst, MBH carbonates can be activated, and the in situgenerated tert-butoxide then serves as a base to create the key phosphonium enolate intermediate B, which can be trapped by suitable electrophiles to form cyclization products (Scheme 15). The low reactivity of MBH carbonates posed a key challenge in phosphine catalysis, and we envisioned that the high nucleophilicity of amino acid-based phosphines may overcome E


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Accounts of Chemical Research Scheme 15. Activation of MBH Carbonates in PhosphineCatalyzed Cycloadditions

Scheme 18. Synthesis of Functionalized Cyclohexenes and 3Spirocyclohexene-2-oxindoles via [4 + 2] Annulation

this difficulty. By employing isatin-derived tetrasubstituted activated alkenes, we uncovered an enantioselective [3 + 2] annulation of MBH carbonates for the creation of 3spirocyclopentene-2-oxindoles containing two consecutive quaternary centers.23 Interestingly, the H-bonding interactions between the thiourea moiety of the catalyst and the isatin are crucial for the asymmetric induction, as phosphine−thiourea P19 and methylated P-19′ displayed a marked difference in inducing enantioselectivity (Scheme 16). Notably, Barbas also

Scheme 19. Use of α-Substituted Allene Ketones

Scheme 16. Enantioselective [3 + 2] Annulation Employing MBH Carbonates predominant, and it also prevents potential [3 + 2] cyclization resulting from enolate C-attack. The presence of CO in the allenone increases the electrophilicity of the neighboring CC bond, making enolate O-attack favorable. This reported protocol provides a convenient route for the enantioselective synthesis of chiral 3,4-dihydropyrans (Scheme 20). Scheme 20. Enantioselective Synthesis of 3,4-Dihydropyrans via [4 + 2] Annulation

reported very similar results around the same time. 24 Subsequently,25 we further included maleimides as suitable reaction partners to react with MBH carbonates to generate functionalized bicyclic imides. It is noteworthy that the optimal catalyst P-4 has an L,L configuration (Scheme 17). Scheme 17. Formation of Bicyclic Imides via [3 + 2] Annulation of MBH Carbonates

3.4. [4 + 1] Annulation

In 2010 Tong reported a novel [4 + 1] annulation reaction in which allenoates with a β′-acetate group were used as dielectrophiles to react with dinucleophiles to form fivemembered-ring systems.29 We employed substituted pyrazolones as dinucleophilic C1 synthons and documented the first enantioselective [4 + 1] annulation of α-substituted allenoates to afford spiropyrazolones in good yields and enantioselectivity (Scheme 21).30

3.3. [4 + 2] Annulations

In 2007 Kwon reported a [4 + 2] annulation between activated alkenes and α-substituted allenoates for the construction of sixmembered-ring systems.26 However, there was no report of an asymmetric version of this useful transformation. We demonstrated that amino acid-derived phosphines could effectively catalyze enantioselective [4 + 2] annulations between activated alkenes and allenoates to generate functionalized cyclohexenes and 3-spirocyclohexene-2-oxindoles (Scheme 18).27 Very recently, we devised a novel [4 + 2] annulation process by employing allene ketones as C2 synthons and β,γ-unsaturated αketo esters as C4 synthons.28 The presence of the α-substituent in the allene and the use of allene ketones are key to the designed process (Scheme 19). The α-substituent makes the γ-anion

Scheme 21. Enantioselective [4 + 1] Annulation

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Accounts of Chemical Research 4.3. Asymmetric γ-Umpolung Addition

4. PHOSPHINE-TRIGGERED NUCLEOPHILIC ADDITIONS Upon phosphine addition to electrophilic reaction partners (e.g., allenes) or MBH adducts, zwitterionic phosphonium enolates are created, which are basic in nature and can be utilized as a base to promote subsequent synthetic events. The enantioselective processes that will be described in the following sections share the above common feature.

Phosphine-promoted γ-umpolung addition is considered to be a classical type of reaction in phosphine catalysis. Fu and coworkers carried out systematic studies of the addition of various pronucleophiles to γ-substituted allenoates to create a range of γstereocenters.35 However, there was virtually no progress on the use of prochiral nucleophiles in phosphine-triggered γ-addition reactions. Since the newly formed stereogenic center is remote from the allene substrate, more precise stereochemical control may be required. By employing amino acid-based bifunctional phosphines, we established an enantioselective γ-addition involving prochiral 3-substituted oxindoles and 2,3-butadienoates as reaction partners (Scheme 24).36 With the use of 3-

4.1. Enantioselective Michael Addition

Phosphine-catalyzed Michael reactions were first reported in the 1970s,31 but an asymmetric version was yet to be discovered. To tackle this long-standing problem, we reasoned that the key to an enantioselective process would be how to control the addition of the ion pair consisting of the anionic form of the nucleophile and phosphonium intermediate G to the Michael acceptor. Our strategy was to use bifunctional phosphines to induce H-bonding interactions with the anion moiety, leading to a structurally better-defined ion pair, facilitating its stereochemical communication with the incoming alkene (Scheme 22). With this strategy,

Scheme 24. Enantioselective γ-Addition of Prochiral 3Substituted Oxindoles to 2,3-Butadienoates

Scheme 22. Phosphine-Promoted Michael Addition

fluorooxindoles as pronucleophiles, we subsequently realized an enantioselective γ-addition to 2,3-butadienoates for the facile synthesis of optically enriched 3-fluoro-3-allyloxindole derivatives.37 More recently, we utilized 5H-thiazol-4-ones and 5H-oxazol4-ones as reaction partners and achieved their enantioselective γadditions of to 2,3-butadienoates.38 In the presence of amino acid-derived bifunctional phosphine P-2 or P-10, chiral thiazolones and oxazolones with a heteroatom (S or O)containing tertiary chiral center were obtained in high yields with excellent enantioselectivities (Scheme 25). Density functional theory (DFT) calculations were performed to probe the mechanism of the reaction, and the key findings included the following: the H-bonding interaction between the amino moiety of the catalyst (P-10) and the “CO” of the thiazolone serves as an activation for the Michael donor; the bulky silyloxy group may

we successfully developed the first phosphine-catalyzed asymmetric Michael addition.32 The importance of the amide NH in P-11 was experimentally demonstrated, as a much lower enantioselectivity was obtained when N-methylated P-11′ was used (13% ee vs 59% ee). 4.2. Enantioselective Allylic Substitutions

When MBH carbonates are utilized as electrophilic reaction partners in the presence of pronucleophiles, phosphine activation can lead to allylic alkylation33 of the MBH adducts via a cascade SN2′−SN2′ pathway (Scheme 23). We recently successfully developed an enantioselective and regiodivergent allylic alkylation of MBH carbonates by using phthalides as pronucleophiles; threonine-derived P-3 led to the formation of γselective products in excellent yields and ee values.34

Scheme 25. Enantioselective γ-Addition Reactions of 5HThiazol-4-ones and 5H-Oxazol-4-ones

Scheme 23. Enantioselective Regioselective Allylic Alkylation of MBH Carbonates with Phthalides

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Accounts of Chemical Research be crucial in locking the transition state geometry to differentiate two facial attacks; and the phenyl group of the thiazolone contributes to stereochemical differentiation. Oxazol-5-(4H)-ones have attracted much attention from synthetic chemists because of their importance in the synthesis of amino acid derivatives and various heterocyclic structures. Making use of the acidity of oxazolones, we devised39 regiodivergent approaches to prepare both C-2-selective and C-4-selective addition products of oxazolones, which serve as useful precursors to disubstituted N,O-acetals and α,αdisubstituted α-amino acids, respectively (Scheme 26). DFT

Scheme 27. Enantioselective aza-MBH Reaction Catalyzed by a Phosphine−Sulfonamide Catalyst

Scheme 26. Regiodivergent Enantioselective γ-Addition of Oxazolones to 2,3-Butadienoates

transformation, demonstrating again the power of our easily tunable phosphine catalytic system (Scheme 28). Scheme 28. Enantioselective MBH Reaction Catalyzed by a Phosphine−Thiourea Catalyst

calculations on these processes revealed that the regioselectivity was determined by the distortion energy resulting from the interactions between the nucleophilic oxazolide and electrophilic phosphonium intermediates, and such mechanistic insights may open up new avenues in designing other regiodivergent processes involving oxazolones and similar donors.

6. CONCLUSIONS AND OUTLOOK In this Account, we have summarized our recent progress in evolving amino acid-based bifunctional phosphines and applying them in asymmetric catalysis. Built upon readily available amino acid structural motifs, threonine in particular, families of bifunctional phosphines bearing simple H-bond donors have been conveniently prepared. The salient features of our catalyst systems are that they are versatile and tunable in regard to structure and highly efficient in asymmetric induction. To date we have demonstrated the power of our phosphine catalysts in a good range of enantioselective processes, including aza-MBH/ MBH reactions, allylic substitution of MBH adducts, Michael addition, various γ-additions, [3 + 2] annulations employing allenes/MBH carbonates, [4 + 2] annulations of α-substituted allenoates/allenones, and [4 + 1] annulation of allenes, among others. In-depth mechanistic understandings of our reported reactions still lag well behind the experimental findings. More extensive theoretical studies are currently ongoing, and we anticipate that the mechanistic insights gained will further facilitate the catalyst/reaction design as well as refine the catalytic systems, enabling us to expand the scope of phosphine-mediated enantioselective transformations and discover novel modes of phosphine activation. We are confident that more intensive research in this exciting field will establish phosphine-catalyzed asymmetric reactions as powerful and broadly applicable synthetic strategies in asymmetric synthesis.

5. ENANTIOSELECTIVE AZA-MBH/MBH REACTIONS The MBH and aza-MBH reactions are among the most powerful organic transformations for the conversion of simple starting materials into densely functionalized structures. Therefore, it is not surprising that enantioselective MBH reactions have been intensively investigated in the past decades. In the very beginning of our catalyst development, we chose aza-MBH reactions to test the efficiency of our amino acid-based phosphine catalysts. Even though our publication on the phosphine-catalyzed enantioselective aza-MBH reaction only appeared in 2011,40 we actually obtained good enantioselectivities (∼80% ee) in 2008, and it took almost two years to do some fine-tuning and improve the enantioselectivity to excellent levels. When threonine-derived P13 was used, the aza-MBH reaction was realized in a highly enantioselective manner. Two years after the initial disclosure, we performed DFT calculations to elucidate the origin of the enantioselectivity.41 Nucleophilic attack of phosphine P-13 on the acrylate leads to the formation of the advanced intermediate It I, which possesses a well-defined geometry due to the N−H··· O hydrogen bonding interaction. The rigid structure of It I has its bottom face blocked by the phosphonium group and allows the imine to approach only from the top face. Moreover, the presence of the bulky OTDS group forces the N-Ts to stand out of the enolate plane, providing a confined arrangement for the incoming imine. Such an explanation is consistent with the experimental findings that a lower ee was observed when the OTDS group was replaced by a less hindered OTMS group (Scheme 27). We also extended the application of our phosphine catalyst to the enantioselective MBH reaction of acrylates with aromatic aldehydes.42 It is interesting to note that phosphine−thiourea catalyst P-13 was found to be the optimal structural motif for this

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The authors declare no competing financial interest. H


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Accounts of Chemical Research Biographies

Umpolung Addition Reaction of Nucleophiles to 2,3-Butadienoates Catalyzed by a Phosphine. Synlett 1995, 1995, 645−646. (4) Trost, B. M.; Li, C.-J. Novel “Umpolung” in C−C Bond Formation Catalyzed by Triphenylphosphine. J. Am. Chem. Soc. 1994, 116, 3167− 3168. (5) Vedejs, E.; Daugulis, O.; Diver, S. T. Enantioselective Acylations Catalyzed by Chiral Phosphines. J. Org. Chem. 1996, 61, 430−431. (6) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. Asymmetric [3 + 2] Cycloaddition of 2,3-Butadienoates with ElectronDeficient Olefins Catalyzed by Novel Chiral 2,5-Dialkyl-7-phenyl-7phosphabicyclo[2.2.1]heptanes. J. Am. Chem. Soc. 1997, 119, 3836− 3837. (7) For selected reviews, see: (a) Cowen, B. J.; Miller, S. J. Enantioselective Catalysis and Complexity Generation from Allenoates. Chem. Soc. Rev. 2009, 38, 3102−3116. (b) Marinetti, A.; Voituriez, A. Enantioselective Phosphine Organocatalysis. Synlett 2010, 2010, 174− 194. (c) Fan, Y. C.; Kwon, O. Advances in Nucleophilic Phosphine Catalysis of Alkenes, Allenes, Alkynes, and MBHADs. Chem. Commun. 2013, 49, 11588−11619. (d) Wei, Y.; Shi, M. Applications of Chiral Phosphine-Based Organocatalysts in Catalytic Asymmetric Reactions. Chem. - Asian J. 2014, 9, 2720−2734. (8) Shi, M.; Chen, L.-H. Chiral Phosphine Lewis Base Catalyzed Asymmetric aza-Baylis−Hillman Reaction of N-Sulfonated Imines with Methyl Vinyl Ketone and Phenyl Acrylate. Chem. Commun. 2003, 1310−1311. (9) Cowen, B. J.; Miller, S. J. Enantioselective [3 + 2]-Cycloadditions Catalyzed by a Protected, Multifunctional Phosphine-Containing αAmino Acid. J. Am. Chem. Soc. 2007, 129, 10988−10989. (10) Xiao, H.; Chai, Z.; Zheng, C.-W.; Yang, Y.-Q.; Liu, W.; Zhang, J.K.; Zhao, G. Asymmetric [3 + 2] Cycloadditions of Allenoates and Dual Activated Olefins Catalyzed by Simple Bifunctional N-Acyl Aminophosphines. Angew. Chem., Int. Ed. 2010, 49, 4467−4470. (11) (a) Fang, Y.-Q.; Jacobsen, E. N. Cooperative, Highly Enantioselective Phosphinothiourea Catalysis of Imine-Allene [3 + 2] Cycloadditions. J. Am. Chem. Soc. 2008, 130, 5660−5661. For an excellent review, see: (b) Doyle, A. G.; Jacobsen, E. N. Small-Molecule H-Bond Donors in Asymmetric Catalysis. Chem. Rev. 2007, 107, 5713− 5743. (12) For reviews, see: (a) Xu, L.-W.; Luo, J.; Lu, Y. Asymmetric Catalysis with Chiral Primary Amine-Based Organocatalysts. Chem. Commun. 2009, 1807−1821. (b) Xu, L.-W.; Lu, Y. Primary Amino Acids: Privileged Catalysts in Enantioselective Organocatalysis. Org. Biomol. Chem. 2008, 6, 2047−2053. (13) (a) Cheng, L.; Han, X.; Huang, H.; Wong, M. W.; Lu, Y. Highly Diastereoselective and Enantioselective Direct Organocatalytic antiSelective Mannich Reactions Employing N-Tosylimines. Chem. Commun. 2007, 4143−4145. (b) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. Highly Efficient Threonine-Derived Organocatalysts for Direct Asymmetric Aldol Reactions in Water. Adv. Synth. Catal. 2007, 349, 812−816. (14) allo-Threonines were not examined in our studies, as their high costs make the potential derivatives uneconomical. (15) Wilson, J. E.; Fu, G. C. Synthesis of Functionalized Cyclopentenes through Catalytic Asymmetric [3 + 2] Cycloadditions of Allenes with Enones. Angew. Chem., Int. Ed. 2006, 45, 1426−1429. (16) Voituriez, A.; Panossian, A.; Fleury-Brégeot, N.; Retailleau, P.; Marinetti, A. 2-Phospha[3]ferrocenophanes with Planar Chirality: Synthesis and Use in Enantioselective Organocatalytic [3 + 2] Cyclizations. J. Am. Chem. Soc. 2008, 130, 14030−14031. (17) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. Enantioselective [3 + 2] Cycloaddition of Allenes to Acrylates Catalyzed by Dipeptide-Derived Phosphines: Facile Creation of Functionalized Cyclopentenes Containing Quaternary Stereogenic Centers. J. Am. Chem. Soc. 2011, 133, 1726− 1729. (18) Han, X.; Wang, S.-X.; Zhong, F.; Lu, Y. Formation of Functionalized Cyclopentenes via Catalytic Asymmetric [3 + 2] Cycloaddition of Acrylamides with an Allenoate Promoted by Dipeptide-Derivde Phosphines. Synthesis 2011, 2011, 1859−1864.

Tianli Wang was born in Sichuan, China. She received her B.S. from Sichuan University in 2006 and her Ph.D. from the Institute of Chemistry of the Chinese Academy of Sciences in 2011 under the supervision of Professor Qing-Hua Fan. Currently she is a Research Fellow with Professor Yixin Lu at the National University of Singapore (NUS). Her research interests focus on asymmetric catalysis and synthesis, emphasizing the design and development of new chiral catalysts and asymmetric reactions. Xiaoyu Han was born in Shanxi, China. She received her Ph.D. in Organic Chemistry from NUS under the supervision of Professor Yixin Lu in 2012. She then worked as a Postdoctoral Fellow with Prof. Lu at NUS. In 2014, she began her independent research career at Zhejiang University of Science and Technology in China. Her research interests include the development of novel chiral catalysts and their applications in highly enantioselective reactions as well as the synthesis of biologically important molecules. Fangrui Zhong received his B.Sc. in 2008 from Zhejiang University. He then continued his graduate studies under the supervision of Professor Yixin Lu at NUS and obtained his Ph.D. in 2012. After an Alexander von Humboldt Research Fellowship with Professor Thorsten Bach at Technische Universität München, he joined the faculty of Huazhong University of Science and Technology as Professor of Chemistry in December 2015. His research involves the development of novel multifunctional ligands and artificial catalysts inspired by natural enzymes. Weijun Yao was born in Zhejiang, China. He received both his B.Sc. (2006) and Ph.D. (2011) from Zhejiang University. He then joined the Lu lab as a Research Fellow in 2011. His research interests involve the development of novel organocatalysts and their application in asymmetric reactions. Yixin Lu received his B.Sc. from Fudan University in Shanghai and subsequently obtained his Ph.D. in Organic Chemistry in 2000 from McGill University in Canada under the supervision of the late Prof. George Just. After postdoctoral appointments with Prof. Peter W. Schiller at the Clinical Research Institute of Montreal and Prof. Ryoji Noyori at Nagoya University, he joined NUS in 2003, where now he is a Professor. His key research interest is asymmetric catalysis and synthesis.

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ACKNOWLEDGMENTS We are deeply indebted to all of the co-workers, whose names can be found in the references, for their significant contributions to the projects described herein. We gratefully acknowledge Singapore A*STAR SERC Public Sector Research Funding (PSF; R-143-000-618-305) and the National University of Singapore (R-143-000-599-112) for generous financial support. We thank Wai-Lun Chan for proofreading.

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Amino Acid-Derived Bifunctional Phosphines for Enantioselective

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