Phosphine-Catalyzed Asymmetric Organic Reactions - Chemical

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Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

Phosphine-Catalyzed Asymmetric Organic Reactions Huanzhen Ni, Wai-Lun Chan, and Yixin Lu*

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Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543 Singapore ABSTRACT: Asymmetric phosphine catalysis showcasing remarkable progress over the past two decades has emerged as a key synthetic platform for the creation of molecular frameworks encountered in medicinal chemistry and materials science. Different types of novel chiral phosphine catalysts have been developed and employed in cornucopias of organic transformations, such as annulation, addition, Morita− Baylis−Hillman, and Rauhut−Currier reactions, among others. This review summarizes all of the literature examples from late 1990s to the end of 2017, alongside their mechanistic insights whenever possible, with a very aim to trigger more intensive research in the future to render asymmetric phosphine catalysis one of the most common and reliable tools to organic chemists.

CONTENTS 1. Introduction 1.1. Chiral Phosphine Catalysts 1.2. Common Reaction Partners in Phosphine Catalysis 1.2.1. Allenes in Phosphine Catalysis 1.2.2. Alkynes in Phosphine Catalysis 1.2.3. MBH Adducts in Phosphine Catalysis 1.2.4. Activated Alkenes in Phosphine Catalysis 2. Annulation Reactions Utilizing Allenes and Alkynes 2.1. [3 + 2] Annulations of Allenoates and Alkynes 2.1.1. [3 + 2] Annulations of Allenoates with Activated Alkenes 2.1.2. [3 + 2] Annulations of Allenoates with Imines 2.1.3. Intramolecular [3 + 2] Annulations of Allenes 2.1.4. [3 + 2] Annulations of Alkynes 2.2. [4 + 2] Annulations of α-Substituted Allenoates 2.2.1. [4 + 2] Annulations of α-Substituted Allenoates with Activated Alkenes 2.2.2. [4 + 2] Annulations of α-Substituted Allenoates with Activated Imines 2.3. [4 + 2] Annulations of α-Substituted Allenic Ketones 2.4. Annulations of Acetate-Substituted Allenoates 2.4.1. [4 + 1] Annulations of β′-AcetateSubstituted Allenoates 2.4.2. [3 + 2] Annulations of δ-Acetoxy Allenoates © XXXX American Chemical Society

2.5. [4 + 3] and [4 + 4] Annulations for the Construction of Medium-Sized Rings 2.6. Summary of Annulation Reactions Employing Allenes and Alkynes 3. Annulation Reactions Employing the MBH Adducts 3.1. [3 + 2] Annulations of the MBH Adducts 3.2. [4 + 1] Annulations of the MBH Adducts 3.3. [3 + 3] Annulations of the MBH Adducts 3.4. Summary of the Use of the MBH Adducts in Annulations 4. Addition Reactions 4.1. Umpolung γ-Additions to Allenoates and Alkynes 4.2. Allylic Substitution of the MBH Adducts 4.3. Michael Addition and Mannich Reaction 5. Rauhut−Currier Reactions 5.1. Intramolecular Rauhut−Currier Reactions 5.2. Intermolecular Rauhut−Currier Reactions 6. Morita−Baylis−Hillman Reactions 6.1. Intermolecular (aza)-Morita−Baylis−Hillman Reactions 6.2. Intramolecular (aza)-Morita−Baylis−Hillman Reactions 7. Other Reactions 7.1. [2 + 2] Annulation of Ketenes 7.2. Kinetic Resolution of Alcohols 7.3. Miscellaneous Reactions 8. Summary and Perspective Author Information Corresponding Author ORCID

B B D D E E F G G G O Q R T U W X Y

AB AC AC AC AG AG AI AI AI AN AQ AS AT AV AX AY BA BB BB BC BC BF BG BG BG

Z Received: April 22, 2018

AB A

DOI: 10.1021/acs.chemrev.8b00261 Chem. Rev. XXXX, XXX, XXX−XXX

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resolution of secondary alcohols7 and Zhang’s bicyclic monodentate chiral phosphine-catalyzed enantioselective [3 + 2] cycloaddition reaction.8 Since then, it is the past decade that has observed numerous significant advances that asymmetric phosphine catalysis has become a common tool in asymmetric synthesis. A good number of excellent reviews and accounts on phosphine catalysis have been published, especially in recent years.9−34 However, to give impetus to this fascinating field, an updated and comprehensive review on asymmetric phosphine catalysis is still highly desirable. In this review, we compile exhaustively the chiral phosphine-catalyzed asymmetric organic reactions in the literature, from late 1990s all the way to the end of 2017, and attempt to provide a critical, panoramic picture, as well as an outlook of this dynamic research field. Examples on asymmetric catalysis employing chiral substrates and achiral phosphines are not covered here. We hope this review can give our readers a most updated overview of asymmetric phosphine catalysis, offering insights, inspiring and intriguing more deep thinking, which eventually can drive this promising field to a much higher height with more, broader practical applications.

BG BG BH BH BH

1. INTRODUCTION The dramatic renaissance of asymmetric phosphine catalysis, where chiral phosphine is no longer a ligand in metal catalysis but a catalytic center, lends itself to a powerful methodology to access chiral molecules. The past two decades have witnessed different types of chiral phosphine catalysts which were innovatively developed and strategically applied to a wide spectrum of organic transformations. Despite the enormous Scheme 1. Seminal Reports on Phosphine Catalysis

1.1. Chiral Phosphine Catalysts

Phosphine catalysts generally undergo n → π* donor− acceptor interactions in terms of HOMO and LUMO between the Lewis basic phosphine and the Lewis acidic substrates. Typically, the catalytic cycle involves the initial nucleophilic attack of the phosphine on an activated electrophilic substrate to generate a key active zwitterionic intermediate. Subsequent reactions can then occur, hinging on the nature of different reaction partners, with such key intermediate going through a wide variety of diverse reaction pathways and giving rise to the products. As far as the design of a chiral phosphine catalyst is concerned, two of the most important factors need to be considered. First, the nucleophilicity of the phosphorus center in the catalyst is of pivotal importance, which determines whether the zwitterionic species could be efficiently formed. Another consideration is the chiral scaffold of the catalyst structure, which will be responsible for inducing asymmetry. Therefore, electronically altering the substituents on the phosphorus centers of phosphines, in combination with introducing different chiral scaffolds to the catalysts, could lead to the creation of a wide range of chiral phosphine catalysts. In what follows, we summarize all of the chiral phosphine catalysts that have been developed to date and elaborate their applications in asymmetric phosphine catalysis in subsequent sections. The past few decades have witnessed tremendous advancement of transition metal-mediated asymmetric catalytic processes, which rely heavily on the chiral ligands for stereochemical differentiation. In this context, chiral phosphine ligands are certainly one of the most important ligand classes in metal catalysis.35,36 Therefore, it is not surprising that many chiral phosphine catalysts in asymmetric phosphine catalysis were previously used as phosphine ligands in metal catalysis or derived from known phosphine ligands. Chiral phosphine catalysts covered in this review are organized into two main categories: monofunctional phosphines and multifunctional phosphines. The former could be further divided into cyclic phosphines and acyclic phosphines. Monofunctional cyclic chiral phosphines are summarized in Figure 1. Many catalysts are C2-symmetric in structure, and almost all of the catalysts in this category have at least two alkyl

success of amine-based catalysts, the utilization of more nucleophilic phosphines, another type of Lewis base catalysts, lags far behind.1 From a historical perspective, three landmark discoveries in phosphine catalysis can be traced back to 1960s. Price reported the first triphenylphosphine-catalyzed carbon− carbon bond formation via hexamerization of acrylonitrile in 1962 (Scheme 1, eq a).2 Shortly after, Rauhut and Currier disclosed a more widely recognized example on the preparation of dialkyl 2-methyleneglutarates, which was later commonly referred as the Rauhut−Currier reaction (Scheme 1, eq b).3 In 1968, Morita discovered a tertiary phosphinecatalyzed reaction of acrylic compounds with aldehydes, now known as the Morita−Baylis−Hillman reaction (Scheme 1, eq c).4 The above pioneering findings did not draw much attention from the synthetic community, and the field of phosphine catalysis remained virtually dormant for the next few decades. It is only when two landmark reports were divulged in the mid-1990s that this promising research field was refueled: Lu’s discovery on phosphine-catalyzed [3 + 2] annulation5 and Trost’s disclosure of phosphine-triggered “umpolung” addition.6 Ever since, the unique properties and great potentials of phosphines in catalysis had finally received due recognition, and numerous research groups embarked on this exciting journey. To date, far more reports on phosphine catalysis have been focused on achiral phosphine-triggered racemic reactions rather than asymmetric variants. Prior to 2000, there were only two examples on asymmetric phosphine catalysis: Vedejs’s utilization of chiral phosphines for kinetic B


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Figure 1. Monofunctional cyclic chiral phosphines.

groups on the phosphorus center, thereby demonstrating higher stability but lower nucleophilicity. Given that the efficiency of monofunctional phosphines in asymmetric induction depends entirely on the structural motifs of the catalysts, the known privileged structures were commonly used as the starting point to develop this type of catalysts.

groups on the phosphorus center, anticipated to be highly nucleophilic. The drawbacks of such phosphines are their instability, often air-sensitive, and relatively narrow scope in terms of structural variation. Moreover, their preparations can be synthetically challenging in some cases. Monofunctional acyclic chiral phosphines are shown in Figure 2. The catalysts listed here are small in number, which often have two aryl C


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pathways to provide an overall broad picture, before we zoom in on specific examples of phosphine-catalyzed asymmetric reactions. 1.2.1. Allenes in Phosphine Catalysis. The most commonly employed substrates in phosphine-catalyzed reactions are various electron-deficient allenes, usually activated by an ester or a ketone group. The popularity of allenes in phosphine catalysis is due to their high reactivity toward phosphine attack, and more importantly, the zwitterionic intermediates generated upon phosphine addition have versatile reactivities. Different substituents and activating groups in allene structures, if carefully designed and installed, are of vital importance in generating specific target molecules and inventing novel reactions. In a typical phosphine-catalyzed reaction of activated allenes, the β-carbon of allenes is electrophilic in nature and thus prone to nucleophilic attack by the phosphorus, resulting in the formation of zwitterionic intermediates (Scheme 2). The zwitterionic species contains a phosphonium, a carbon−carbon double bond, and an anion, truly rich in functionalities within a packed structure. The negative charge of the zwitterions is delocalized over the α-carbon and γ-carbon, making these two positions nucleophilic. All of the above features could be utilized in designing specific reactions, by carefully modulating the reactivities, varying the active intermediate structures, and selecting suitable reaction partners. The most common reactions of allenoates are [3 + 2] annulations for the construction of five-membered ring structures, if activated alkenes are rendered (eq a). If appropriate groups are installed at the α-position of allenoates, a [4 + 2] cycloaddition reaction would take place to generate six-membered cyclic structures (eq b). In addition to the activated alkenes, sufficiently activated imines were also found to be suitable for the above [3 + 2] and [4 + 2] annulations, leading to the creation of nitrogen-containing ring structures. Esters are not the only activating groups in allene structures; allenic ketones could render completely different reactivities. Another type of [4 + 2] annulation in which allenes serve as a C2-synthon is an excellent example (eq c). The key zwitterionic intermediates generated upon phosphine additions to allenes are basic in nature. In the presence of pronucleophiles, deprotonation and subsequent reactions would take place, yielding the so-called γaddition products (eq d). With the installation of β′-acetate group in allene structures, the electronic properties of the

Figure 2. Monofunctional acyclic chiral phosphines

The development of multifunctional phosphine catalysts is a more recent adventure. For this type of catalysts, additional functional groups are installed at the neighborhood of the phosphorus atom, resulting in multifunctional phosphines. The stereochemical differentiations are achieved via interactions of the functional group moieties of phosphine catalysts with substrates, most commonly via hydrogen bonding interactions. Therefore, chiral structural scaffolds of the catalysts, together with hydrogen bonding interactions between active intermediates and the substrates, play synergistic roles in asymmetric induction. Given more latitudes in catalyst design and relative ease in preparation, multifunctional chiral phosphines have witnessed remarkable progress in recent years. Figure 3 is a collection of multifunctional phosphines derived from BINOL. Figure 4 collates all the amino acidderived multifunctional phosphine catalysts. All of the other multifunctional phosphines are summarized in Figure 5. In the following sections, we will describe in detail how the above mono- and multifunctional chiral phosphines are utilized in asymmetric catalytic reactions. 1.2. Common Reaction Partners in Phosphine Catalysis

Phosphine-catalyzed reactions are triggered by the addition of the phosphorus atom to various electron-deficient substrates to form structurally distinct zwitterionic intermediates, which then proceed via different mechanistic pathways, leading to diverse sets of molecular architectures. We will describe common reaction partners in phosphine catalysis in the following sections, highlighting their various mechanistic

Figure 3. Multifunctional chiral phosphines derived from BINOL. D


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Figure 4. Multifunctional chiral phosphines derived from amino acids.

active intermediate could be switched totally; a dielectrophilic intermediate could be created upon phosphine addition, which can react with dinucleophilic partners, generating new sets of ring structures (eq e). 1.2.2. Alkynes in Phosphine Catalysis. Activated alkynes were shown to be suitable reaction partners in phosphine catalysis. However, due to their intrinsic electronic properties, alkynes are less electrophilic than their allene analogues, and hence their activations are more difficult. For alkyne substrates of type A, the zwitterionic intermediate generated upon phosphine addition undergoes a proton transfer process to yield α- or γ-anionic active species, hinging on the subsequent reaction partners. Either with activated alkenes or pronucleophiles, [3 + 2] cycloaddition or γ-addition may take place (Scheme 3, eq a). For alkyne substrates of type B, phosphine-

triggered tautomerization to allenes is observed, and the subsequent reactions are all well-anticipated (eq b). The third unique alkyne of type C has different reactivities. The initial αanionic zwitterion is transformed to an α′-anion, which then reacts with suitable activated alkenes to form [3 + 2] cyclization products (eq c). 1.2.3. MBH Adducts in Phosphine Catalysis. In comparison to most commonly employed allene substrates in phosphine catalysis, the Morita−Baylis−Hillman (MBH) adducts are readily accessible, with good chemical stability and great structural diversity; therefore, they hold enormous potentials for practical asymmetric catalysis and synthesis. The MBH carbonates are by far the most commonly used MBH adducts in phosphine catalysis. Nucleophilic attack of the phosphorus on the MBH carbonates yields phosphonium E


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Figure 5. Other multifunctional chiral phosphines.

Scheme 2. Main Reaction Modes of Allenes in Phosphine Catalysis

salts, and in situ generates a tert-butoxide anion. The subsequent deprotonation gives rise to the formation of ylide species, which can undergo annulation reactions with appropriately designed reaction partners (Scheme 4, eq a and b). Another common reaction for the MBH adducts is allylic substitution, generally believed to proceed via a cascade SN2′−SN2′ pathway, which is initiated by a nucleophilic phosphine attack (eq c). 1.2.4. Activated Alkenes in Phosphine Catalysis. The seminal report by Morita in the 1960s, later known as the MBH reaction, is an example of phosphine-catalyzed reaction utilizing activated alkenes. When practicality is concerned, the

readily available and structurally diverse activated alkenes are the very ideal substrates in phosphine catalysis, provided they can be activated efficiently in a synthetically useful manner. Currently, examples of using alkenes in asymmetric phosphine catalysis are rather limited (Scheme 5). The reaction mechanism starts with a phosphine addition to activated alkenes to afford an advanced phosphonium anion intermediate, which can condense with an aldehyde or an imine, leading to the eventual formation of the MBH or aza-MBH adducts (eq a). If the electrophilic partner is activated alkenes, Rauhut−Currier reaction would then take place (eq b). In the presence of pronucleophiles, the basic nature of zwitterionic F


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Scheme 3. Reaction Modes of Alkynes in Phosphine Catalysis

Scheme 4. Reaction Modes of the MBH Adducts in Phosphine Catalysis

Scheme 5. Reaction Modes of Activated Alkenes in Phosphine Catalysis

intermediates could be utilized to deprotonate the pronucleophile, leading to the Michael addition product (eq c). It is self-evident that the recent marvelous achievements in asymmetric phosphine catalysis can be attributed to the emergence of a wide range of chiral phosphine catalysts, and the discovery of fundamental modes of activations illustrated above. We will give a full account in the following sections, and our classification is based on the reaction types and the substrates in use, in a chronological manner.

Scheme 6. Mechanism of [3 + 2] Annulation between Allenoates and Activated Alkenes

2. ANNULATION REACTIONS UTILIZING ALLENES AND ALKYNES 2.1. [3 + 2] Annulations of Allenoates and Alkynes

2.1.1. [3 + 2] Annulations of Allenoates with Activated Alkenes. One of the most investigated phosphine catalyzed reactions is the [3 + 2] cycloaddition of allenoates to activated alkenes, which was first reported by Lu and coworkers in 1995 and marked the beginning of a new era of phosphine catalysis.5 A widely accepted reaction mechanism of this [3 + 2] annulation is depicted in Scheme 6. The addition G


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Scheme 7. [3 + 2] Annulation of Allenoates with Activated Alkenes (Zhang, 1997)

Scheme 8. [3 + 2] Annulation between Allenoates and Enones (Fu, 2006)

Scheme 9. [3 + 2] Annulation of an Allenoate with Exocyclic Enones (Miller, 2007)

Scheme 10. [3 + 2] Annulation of Allenic Ketone with Cyclic Enones (Wallace, 2007)

catalyst P1 or P2 (Scheme 7). While regioselectivities and enantioselectivities of the reaction were reasonably good, the substrate scope was narrow, limited to only ester activated olefins, and the chemical yields were also inconsistent. After Zhang’s first report on asymmetric [3 + 2] annulation, the field remained unexplored for almost another decade. In 2006, Fu and co-workers40 disclosed an asymmetric [3 + 2] annulation between ethyl allenoate 1a and enones 5, which marked the beginning of recent surge of asymmetric phosphine catalysis (Scheme 8). In the presence of binaphthyl-based cyclic phosphine (R)-P8, a range of aryl-substituted enantiomerically enriched cyclopentenes 6 with two adjacent tertiary or quaternary stereogenic centers was readily synthesized, and excellent selectivities for the formation of γadducts were attainable. The Miller group was the first to report41 the utilization of an alanine-derived multifunctional chiral phosphine P56 to

of phosphine to allenoate creates an active zwitterionic intermediate; the negative charge of which is delocalized on the α- (Int-1α) and the γ-carbon (Int-1γ), making these two positions nucleophilic. The [3 + 2] cycloaddition of the anion to activated alkenes then generates the five-membered cyclic ylides (Int-3α or Int-3γ). Subsequent proton transfer, followed by the elimination of the phosphine catalyst, affords the final cycloaddition products (α- or γ-adducts). Since Lu’s seminal report, the mechanism of this [3 + 2] annulation between allenoates and activated alkenes was investigated by the groups of Kwon and Yu through computational studies.37−39 A noteworthy finding of their theoretical investigations is that the proton shift process described in the above mechanism may be assisted by water, and such beneficial effects of water were also found in experimental applications by other researchers.68,76 Shortly after Lu’s initial disclosure, Zhang et al. reported8 the first asymmetric variant by employing bridged cyclic phosphine H


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catalyst (S)-P8, the cyclization between oxindole-derived alkenes 28 and allenic esters or phosphonates furnished biologically important spirooxindole scaffolds 29 in good yields and with excellent enantioselectivities (eq d). In a related study,49 the Marinetti group prepared cyclopentene-fused chromanones in moderate yields and enantioselectivities by performing P16-catalyzed [3 + 2] annulation between chromenones and allenoates. The Marinetti group also employed dicyano-activated alkenes 30 as a C2 reaction partner in (S)-P8-promoted [3 + 2] annulation with allenoates,50 with the α-selective cycloaddition products 31 being obtained with good enantioselectivities (eq e). Zhao and co-workers reported an enantioselective [3 + 2] annulation between allenoates and dual-activated alkenes 32, employing a bifunctional N-acyl aminophosphine catalyst P65 (Scheme 13).51 In the proposed transition state, the authors suggested that the bifunctional catalyst assembles the allenoate to form a structurally defined zwitterion by a synergistic play of its two functional groups. Consequently, the dipolarophile approaches the phosphonium enolate from the Si-face to minimize steric repulsion (eq a). γ-Substituted racemic allenoate 34 could be used, and their annulation reaction with alkenes 32 proceeded smoothly to afford the desired products 35 in high yields, with moderate diastereoselectivities and decreased enantioselectivities (eq b). The Lu group introduced a new class of dipeptide multifunctional phosphine catalysts, and demonstrated their effectiveness in [3 + 2] annulation reaction.52 In the presence of D-Thr-L-tert-Leu-derived phosphine catalyst P97, the reaction of α-substituted acrylates 36 with allenoates proceeded in a regiospecific and enantioselective manner, affording functionalized cyclopentenes (S)-37 containing an all-carbon stereogenic center in high yields (Scheme 14). Mechanistically, it was proposed that the hydrogen bonding interactions between amide/carbamate moieties of the catalyst and substrate acrylates facilitate the dipeptide catalyst to adopt a desired conformation, allowing the phosphonium enolate intermediate to approach the acrylate from its Re-face to give the major (S)-stereoisomer. It was also suggested that the steric repulsions between the bulky tert-butyl group and the acrylate substrate, as well as the carbamate moiety in the catalyst, suppressed the formation of γ-isomers, accounting for the observed α-selectivity. Subsequently, the same group extended their studies and reported an enantioselective [3 + 2] annulation of acrylamides with allenoates, utilizing the same dipeptide phosphine catalyst.53 Around the same time, Fu and co-workers reported an interesting example in which they employed γ-substituted allenoates 38 and a variety of activated alkenes 39 containing heteroatom substitutions as substrates (Scheme 15).54 With the application of their newly designed binaphthyl-based cyclic phosphine (S)-P9, the [3 + 2] annulations led to the formation of a range of cyclopentenes 40 with heteroatom-substituted quaternary stereocenters in high yields, excellent enantioselectivities, and good diastereoselectivities. The preliminary mechanistic investigations, e.g. rate studies, observation of 31P NMR, and kinetic resolution of a phosphine-catalyzed allene/ alkene [3 + 2] cycloaddition, suggested that the rate determining step of this annulation is the addition of the phosphine to the allene. Marinetti and co-workers also documented an enantioselective desymmetrization process via [3 + 2] annulation of prochiral cyclic enones with allenoates, using their signature

catalyze [3 + 2] cycloaddition of allenoates 8 to exocyclic enones 9 (Scheme 9). The annulation products 10 bearing one quaternary stereogenic carbon center could be obtained in good yields and with moderate to high enantioselectivities. It is noteworthy that, when enones with exocyclic double bonds were employed, this reaction highly favored the formation of the α-adduct, and the employment of chalcones led to products with poor regioselectivity. When chalcone was exposed to racemic γ-substituted allenoates, “dynamic kinetic asymmetric transformations” were observed, and cyclopentene products were obtained in high yields and with excellent ee values, even though a stoichiometric amount of the catalyst was required. Mechanistically, the authors proposed that hydrogen bonding interaction plays a key role, forcing the tetralone to approach the zwitterion from the π-face opposite one of the phenyl rings of the catalyst, and resulting in Si-face attack from the enolate. The importance of hydrogen bonding interaction was supported by recent computational studies carried out by Houk and co-workers.42 During the same time period, Wallace and co-workers disclosed a similar [3 + 2] annulation between cyclic enones and activated allenes.43 An allenic ketone 12, rather than allene Scheme 11. [3 + 2] Annulation of TMS-Substituted Allenic Ketones (Loh, 2009)

esters, was used in their study, which underwent cyclization with exocyclic olefins 13 in the presence of bisphosphine ligand P41 to afford spirocyclopentenes 14/15 with moderate enantioselectivities (Scheme 10). Shortly after, another report utilizing allenic ketones as substrates for [3 + 2] annulation was disclosed by Loh and co-workers (Scheme 11).44 It was discovered that trimethylsilyl substitution could prevent selfcondensation of the extremely active allenic ketone 16, facilitating the reaction pathway toward [3 + 2] annulation. The authors showed that enantioselective [3 + 2] annulation in the presence of cyclic bisphosphine catalyst P23 was feasible, yielding cyclopentene products 18 with good enantioselectivities. The Marinetti group introduced a new class of planar chiral phosphine catalysts with ferrocene backbone.45 The effectiveness of such ferrocene-based catalysts was first demonstrated in [3 + 2] annulation of an allenoate with enones; in the presence of 2-phospha[3]ferrocenophane P16, functionalized cyclopentenes 20 with good γ to α selectivities were obtained with very good enantioselectivities (Scheme 12, eq a). The same group subsequently applied P16 to catalyze [3 + 2] annulation of exocyclic enones 23 with allenoates and obtained spirocyclic structural motifs 24 with good enantioselectivities (eq b).46 Allenylphosphonates 25 were next shown to be suitable reaction partners. The cycloaddition of which to enones 26 created useful phosphonate-containing cyclopentenes 27 with excellent enantioselectivities (eq c).47 The Marinetti group’s next effort was to further expand the C2 reaction partners in [3 + 2] annulation reaction.48 In the presence of either ferrocene-based P16 or binaphthyl-based I


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Scheme 12. [3 + 2] Annulation of Allenes with Enones (Marinetti, 2008−2010)

Scheme 13. [3 + 2] Annulations between Allenoates and Dual-Activated Alkenes (Zhao, 2010)

ferrocene-based catalyst P16 (Scheme 16).55 The cyclization took place readily with good diastereoselectivities and excellent enantioselectivities and furnished γ-adducts 42 in excellent yields. Different substituents were tested, and the tert-butyl group appeared to be optimal (eq a). To account for the formation of the observed stereoisomer, the authors proposed that the zwitterionic intermediate adds to enone syn to the 4tert-butyl group in order to minimize the steric hindrance with the axial H-substituent. In a following study,56 the same group further utilized heterocyclic bis-arylidene ketone substrates 43

in the desymmetrization/annulation reactions, and highly functionalized sulfur or nitrogen-containing spiranes 44 were constructed in high yields and with excellent enantioselectivities (eq b). Furthermore, it was shown that double annulation could occur when highly active bis-arylidene ketones 41a with highly electron-deficient aryl rings were utilized (eq c). Jørgensen and co-workers introduced olefinic azlactones as a C2 synthon in phosphine-catalyzed [3 + 2] annulation reaction (Scheme 17).57 Binaphthyl-based cyclic phosphine (S)-P8 efficiently catalyzed the cyclization of allenoate 1a with various J


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centers in good yields and high enantioselectivities. It was suggested that in the proposed transition state, the hydrogen bonding between dipeptide catalyst and maleimide, as well as the steric hindrance induced by the bulky groups in the catalyst, facilitates the Re-face attack of the enolate, resulting in the formation of (S,S)-stereoisomer. The impressive progress of asymmetric methodologies based on phosphine-catalyzed [3 + 2] annulation reactions had prompted synthetic chemists to explore their practical applications. Kumar and co-workers’ discovery of natural product-inspired neuritogenic compound classes is an excellent illustration of applications in medicinal chemistry and biological sciences (Scheme 19).60 By employing amino acidderived chiral phosphine catalyst P65, Kumar et al. successfully developed a [3 + 2] annulation of allenoates with cyclopentenones 54 to prepare the desired bicyclic structural motifs 55 in a highly enantioselective manner, which upon Baeyer− Villiger oxidation and further functionalization led to the formation of a wide range of novel optically enriched bicyclic scaffolds 56. The subsequent biological studies revealed two novel classes of neuritogenic compounds (55a and 56a), which may yield chemical probes for neurodevelopmental processes, leading to a better understanding of neuronal development and related neurodegenerative disorders. Another interesting application was disclosed by Martı ́n and co-workers (Scheme 20).61 The functionalized fullerene underwent a ferrocenebased cyclic bisphosphine P17-catalyzed [3 + 2] annulation with allenoates, and five-membered carbocyclic [60]fullerene derivatives (S)-58 were synthesized with good enantioselectivities but in low chemical yields. Shi and co-workers employed 4,4-dicyano-2-methylenebut3-enoates as a C2 synthon for the first time in phosphinecatalyzed [3 + 2] annulation with allenoates (Scheme 21).62 BINOL-derived bifunctional phosphine P44 efficiently promoted the cyclization, affording regiospecific [3 + 2] annulation products 60 in good yields. More recently, the Guo group utilized Boc-amino-substituted chalcones as a C2 synthon in phosphine-catalyzed [3 + 2] annulation with

Scheme 14. [3 + 2] Annulation of Allenoates with Acrylates (Lu, 2011)

olefinic azlactones 46, to afford the desired adducts 47 bearing a quaternary stereogenic center. Upon hydrolysis, various αamino esters were obtained in moderate yields, with reasonable regioselectivities and excellent enantioselectivities (eq a). Almost at the same time, Shi and co-workers reported a similar [3 + 2] annulation between allenoates and azlactone alkenes 49, catalyzed by spirocyclic phosphine (R)-P20.58 The spirocyclic annulation products 50 with adjacent quaternary and tertiary stereocenters were obtained in good yields, very high diastereoselectivities, and excellent enantioselectivities. To account for the observed stereoselectivity, the authors proposed that the active zwitterionic intermediate approaches the alkene from the Re-face due to steric hindrance imposed by the spirocyclic skeleton of (R)-P20 (eq b). Working collaboratively, Shi and Lu employed maleimides as a C2 synthon in [3 + 2] annulation reaction with allenoates (Scheme 18).59 In the presence of dipeptide-derived phosphine P97, the annulation afforded functionalized bicyclic cyclopentenes (S,S)-53 containing two tertiary stereogenic

Scheme 15. [3 + 2] Annulation of γ-Substituted Allenoates with Activated Heteroatom-Substituted Alkenes (Fu, 2011)

K


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Scheme 16. [3 + 2] Annulation of Allenoates with Bis-arylidene Ketones (Marinetti, 2011, 2012)

Scheme 17. [3 + 2] Annulation of Allenoates with Azlactones (Jørgensen, Shi, 2012)

allenoates to access optically enriched multisubstituted cyclopentenes.63 Marinetti and co-workers later introduced a new series of chiral phosphahelicenes with an isopinocampheyl group attached to the phosphorus (Scheme 22).64 One of the best phosphahelicenes, P32, was shown to effectively catalyze the [3 + 2] annulation of γ-substituted allenoates 61 with dicyanoactivated olefins 62, and the desired functionalized cyclopentenes 63 were attainable in high chemical yields and with excellent diastereo- and enantioselectivities. In phosphine-catalyzed [3 + 2] annulation between allenoates and activated alkenes, either α- or γ- regioisomers may be obtained, due to the fact that the key zwitterionic

intermediate has two resonance forms. Despite the widespread use of such cycloaddition reactions for the construction of fivemembered ring systems and the existence of numerous reports documenting regiospecific or regioselective formation of products, the regioselectivity issue was not carefully investigated. The Shi group then studied it more in detail to address the regioselectivity issue in asymmetric [3 + 2] cycloaddition reaction.65 With the employment of either γ-substituted allenoates 67 or unsubstituted allenoates 65, spirocyclic phosphine (R)-P18 promoted their cycloaddition reactions to benzofuranone-derived olefins 66 to furnish either α- or γselective functionalized 3-spirocyclopentene benzofuran-2-ones L


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Scheme 18. [3 + 2] Annulation of Allenoates with Maleimides (Shi and Lu, 2012)

Scheme 20. [3 + 2] Annulation between Allenoates and Fullerene (Martı ́n, 2013)

(64 or 68) in good yields and high enantioselectivities (Scheme 23, eq a). DFT calculations suggested that, when allenoates without γ-substituent are employed, the γ-addition intermediate is thermodynamically more stable than the αaddition analogue, making the γ-adduct as a major product. On the other hand, when allenoates with γ-substituent are utilized, because of the steric hindrance between the γ-substituent and benzofuranone, the α-addition pathway is more thermodynamically favored. Apparently, it is not ideal to employ different substrates in order to access different regioisomers, and a more general approach would be highly desirable. Very recently, the Lu group developed a catalyst-controlled regioselective approach to accessing spirocyclic benzofuranones via regiodivergent [3 + 2] annulations of aurones 70 and allenoate 1b.66 Interestingly, different regioisomers were accessed with the employment of different catalysts. When LThr-D-Thr-derived dipeptide phosphine P98 was used, αselective annulation adducts 69 were obtained in very good yields and with excellent enantioselectivities. When L-Thr-LThr-derived dipeptide phosphine P94 was employed, the γselective products 71 were obtained in good yields and with extremely high enantioselectivities (Scheme 23, eq b). DFT studies revealed that the selectivity may arise from the conformation of the dipeptide catalysts, which influences the hydrogen bonding interactions or the distortion energy, leading to subtle energy differentiation in the transition states, accounting for the observed regioselectivity.

An enantioselective [3 + 2] annulation of β,γ-unsaturated Nsulfonylimines 73 with α-substituted allenoates 72 was recently reported by the Lu group,67 which is an asymmetric variant of He and co-workers’ early report.68 In the presence of dipeptide-based phosphine P99, highly functionalized cyclopentenes 74 bearing an all-carbon quaternary center were obtained in good yields and with excellent enantioselectivities (Scheme 24). Very recently, Zhang and co-workers disclosed a phosphinecatalyzed enantioselective [3 + 2] cycloaddition of γsubstituted allenoates to β-perfluoroalkyl enones 76, for the construction of densely functionalized cyclopentenes (75 or 78) containing three contiguous stereogenic centers (Scheme 25).69 The annulation was catalyzed by either commercially available bisphosphine P37 or multifunctional phosphine P106. Good yields and excellent enantioselectivities were attainable for a wide range of allenes and fluorinated enone substrates (eq a). Preliminary studies were performed to probe the reaction mechanism. When monofunctional P37 was employed, the allenoate starting material recovered was in racemic form, suggesting that the cycloaddition went through a deracemization process. The authors believed such deracemization process is attributed to the same nucleophilic addition rates (k1 = k2) of phosphine P37 to both enantiomers of the racemic allenoate 77 (eq b). In contrast, when multifunctional catalyst P106 was utilized, allenoate could be recovered with

Scheme 19. [3 + 2] Annulation between Allenoates and Cyclopentenones (Kumar, 2013)

M


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Scheme 21. [3 + 2] Annulation of Allenoates with Activated Dienes (Shi, 2013)

Scheme 22. [3 + 2] Annulation of γ-Substituted Allenoates with Activated Olefins (Marinetti, 2015)

Scheme 23. Regioselective [3 + 2] Annulation of Allenoates (Shi, 2015; Lu, 2017)

Scheme 24. [3 + 2] Annulation of α-Substituted Allenoates with β,γ-Unsaturated N-Sulfonylimines (Lu, 2016)

interaction between N−H and the carbonyl group, and the resulting phosphonium enolate reacts further with enones, leading to the formation of the final [3 + 2] cycloaddition

certain enantioselectivity suggesting the occurrence of a kinetic resolution process. It was proposed that the nucleophilic attack of P106 to (−)-77 is facilitated by the hydrogen bonding N


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Scheme 25. [3 + 2] Annulation of γ-Substituted Allenoates with β-Perfluoroalkyl Enones (Zhang, 2017)

Scheme 26. Early Examples of Enantioselective [3 + 2] Annulation of Allenoates with Activated Imines (Marinetti, 2006/07; Gladysz, 2006)

phosphine catalysis, and they are widely used in phosphinecatalyzed [3 + 2] annulation reactions with allenes, for the construction of nitrogen-containing five-membered ring systems. The pioneering work in this field was first reported by Lu and co-workers in late 1990s,70−72 in which they elegantly demonstrated that triphenyl- or trialkylphosphines efficiently promoted [3 + 2] cyclizations between allenoates and electron-deficient imines to form nitrogen heterocycles. The first asymmetric variant of the above reaction was not reported until mid-2000s. Marinetti and co-workers73 applied chiral phosphine P38 to the [3 + 2] annulation of allenoates with naphthyl-substituted imine 79 and obtained products 80 in 32% yield and with 64% ee (Scheme 26, eq a).

products. On the other hand, the nucleophilic attack of P106 to (+)-77 is disfavored because of steric repulsion (eq c). The different nucleophilic addition rates (k3 > k4) of P106 to either enantiomers of allenoates account for the observed kinetic resolution process. 2.1.2. [3 + 2] Annulations of Allenoates with Imines. Activated alkenes represent the most commonly utilized C2 synthons in phosphine-mediated [3 + 2] cyclizations, and their reactions with allenes lead to the formation of structurally diverse and highly functionalized cyclopentene scaffolds. In order to construct heteroatom-containing ring structures via cyclization, substrates with heteroatom-containing multiple bonds are needed. Activated imines are valuable substrates in O


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Scheme 27. [3 + 2] Annulation of Allenoates with Activated Imines (Jacobsen, 2008)

Subsequently,74 the same group screened a number of chiral phosphines and discovered phosphine (S)-P7 or (S)-P8 gave the best results (eq b). Around the same time, Gladysz and coworkers reported75 that chiral phosphines P36 with transition metal−CH2−P linkage could be used for the same type of annulation, and the desired products 82 with moderate enantioselectivities could be obtained (eq c). The early research on asymmetric [3 + 2] annulation of allenoates with imines met with limited success, and the key problem is that the enantioselectivity of the reaction remained less ideal. Introduction of bifunctional thiourea phosphine catalysts by Jacobsen and co-workers marked a great breakthrough.76 Bifunctional thiourea phosphine P116 was readily derived from trans-2-amino-1-(diphenylphosphino)cyclohexane, which catalyzed [3 + 2] annulation of allenoate 1a and DPP-imines 85 to furnish a wide range of arylsubstituted dihydropyrroles 86 with very high enantioselectivities (Scheme 27). In the proposed transition state, thiourea activates the imine substrate through hydrogen bonding interactions with the oxygen atom of the phosphinoyl group. The DPP imine has a strong preference for the s-cis conformation, leading to the Re-face attack by the zwitterionic intermediate which is causative of the observed (R)-stereoselectivity. The addition of water and triethylamine was found to enhance the reaction rate, which was consistent to earlier

aromatic and aliphatic DPP-imines 87, and either aryl or alkyl substituted pyrrolines 88 were obtained in excellent yields and with excellent enantioselectivities. The authors also applied the method developed to the formal synthesis of (+)-trachelanthamidine. The bifunctional nature of the phosphine catalyst is noteworthy in the proposed transition state: hydrogen bonding interactions between N−H groups of amide and carbamate in the phosphine catalyst with the oxygen atom of DPP play a key role in substrate orientation. The preferentially formed s-cis conformation of DPP imine facilitates the intramolecular delivery of the phosphonium enolate to the imine. The importance of hydrogen bonding interaction was supported experimentally: the N-methylated catalyst yielded the product with much-decreased enantioselectivity. Guo and co-workers extended sulfamate-derived cyclic imines as suitable substrates in phosphine-catalyzed [3 + 2] annulation with allenoates.78 In the presence of amino acidbased catalyst P65, sulfamate-fused dihydropyrroles 90 were obtained in good yields and with moderate to excellent enantioselectivities (Scheme 29). The value of phosphine-catalyzed asymmetric reactions lies in their synthetic applications, in particular, efficient asymmetric synthesis of natural products and biologically significant molecules. In this context, the Kwon group reported an enantioselective total synthesis of (+)-ibophyllidine by using a phosphine-catalyzed asymmetric [3 + 2] annulation of an electron-deficient imine as the key step (Scheme 30).79 Bridged phosphine P3-catalyzed [3 + 2] annulation of γethyl-substituted allenoate 91 with indole-derived imine 92 was utilized to construct the key pyrrolidine intermediate, which was obtained in excellent yield and with nearly perfect enantioselectivity. The advanced intermediate 93 was further elaborated into (+)-ibophyllidine 94 in a number of trivial reaction steps, with a good overall yield of 13% (eq a). The Kwon group continued to strike in total synthesis. Very recently,80 they reported a catalytic asymmetric total synthesis of (−)-actinophyllic acid 97, with the key step being a chiral phosphine-triggered [3 + 2] annulation between allenoate 8 and imine 95 to create a key pyrroline intermediate 96 in 99% yield and 94% ee (eq b). Phosphine catalysts have been evolving continuously, as the field of asymmetric phosphine catalysis develops. Recently, Kwon and co-workers prepared two new pseudoenantiomeric [2.2.1] bicyclic phosphines P3 and P6 from naturally occurring trans-4-hydroxy-L-proline in six steps (Scheme 31).81 The two readily prepared and easily purified catalysts were shown to be efficient in promoting [3 + 2] annulation of γ-substituted allenoates 99 with activated imines 100, and yielded chiral pyrrolines (2S, 5S)-98 or (2R, 5R)-101 with opposite absolute configurations. DFT calculations were performed to understand the transition states for the formation of each isomer.

Scheme 28. [3 + 2] Annulation of Allenoates with Alkyl/ Aryl Substituted Imines (Lu, 2012)

theoretical findings on the mechanism of phosphine-catalyzed [3 + 2] annulations.37−39 The employment of aliphatic imines in phosphine-catalyzed [3 + 2] cyclization remained elusive until Lu’s report on broadspectrum utilizations of activated imines (Scheme 28).77 It was shown that dipeptide-based phosphine P95 efficiently catalyzed [3 + 2] annulations of allenoate 1b with both P


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Scheme 29. [3 + 2] Annulation of Allenoates with Cyclic Imines (Guo, 2013)

Scheme 30. Applications of Allene−Imine [3 + 2] Annulations in Total Synthesis (Kwon, 2012, 2016)

Scheme 31. [3 + 2] Annulation of γ-Substituted Allenoates with Imines Catalyzed by Novel Bicyclic Phosphines (Kwon, 2014)

P70, the annulation reactions between allenoate 8 and ketimines 102 proceeded smoothly, leading to the formation of a wide range of spirooxindoles. It is noteworthy that enantiomeric excesses were very high, mostly >99% ee (eq a). γ-Substituted allenes 104 were also employed, and highly substituted 3,2′-pyrrolidinylspirooxindoles 105 were obtained in good yields, and with high diastereoselectivities and excellent enantioselectivities (eq b). A similar reaction was reported by the Kumar group,83 in which P65 was employed as the catalyst, paired with allenic ketones 106 in their report, in addition to the common allenoate substrates (eq c). The Kumar group discovered an interesting reaction pattern between α-substituted allenoates and isatin-derived ketimines.84 In the presence of spirocyclic phosphine (R)-P18 or (S)-P18, α-substituted allenoates 108 unprecedentedly acted as a C3 synthon in their [3 + 2] annulation with ketimines 109, rather than serving as a C4 synthon in an anticipated [4 + 2] annulation. A range of highly substituted 3,2′-pyrrolidinyl spirooxindoles 110 were obtained with excellent enantioselectivities, which is suitable for quick construction of natural product-based compound library (Scheme 33). 2.1.3. Intramolecular [3 + 2] Annulations of Allenes. Compared with the widespread applications of phosphinecatalyzed intermolecular [3 + 2] annulations of allenes for the synthesis of five-membered cyclic structures, their intramolecular counterparts were very rare, and notwithstanding intramolecular reactions can often offer quick access to challenging structural motifs. Examples of intramolecular racemic [3 + 2] annulations catalyzed by achiral phosphines were reported in early 2000s (Scheme 34). Krische and coworkers documented the first intramolecular [3 + 2] annulation of electron-deficient 1,7-enynes 111 for diastereoselective synthesis of diquinanes 112 (eq a).85 The same group subsequently developed a concise total synthesis of

There are two stabilizing factors: (i) the hydrogen bonding between imine N-sulfonyl oxygen and a hydrogen atom of the catalyst and (ii) the preferable Coulombic interaction between the phosphorus atom and the allenoate carbonyl group. These interactions facilitate the phosphine catalysts to adopt different orientations; catalyst P3 blocks the Si-face of the phosphonium enolate intermediate, while catalyst P6 blocks the Re-face, resulting in the formation of products with opposite absolute configurations. While phosphine-catalyzed [3 + 2] asymmetric cyclizations of aldehyde-derived aldimines are well-established, the employment of ketimines for similar type of reactions was very rare. Very recently, the Lu group disclosed the first highly enantioselective [3 + 2] annulation of isatin-derived ketimines (Scheme 32).82 In the presence of L-Thr-derived phosphine Q


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Scheme 32. [3 + 2] Annulation of Allenoates with Ketimines (Lu, Kumar, 2016)

Scheme 33. [3 + 2] Annulation between α-Substituted Allenoates and Ketimines (Kumar, 2016)

organize phosphine-triggered, highly crowded intermediates in a well-defined manner, which is essential for effective chiral communication. The first enantioselective intramolecular [3 + 2] annulation between allenes and alkenes was reported by Fu and co-workers (Scheme 35).88 Binaphthyl-based chiral phosphines were shown to efficiently catalyze annulations of allene−olefins 118, and bicyclic diquinanes 119 were obtained in good yields and with excellent enantioselectivities (eq a). When 2-styrenyl allenes 120 were employed, quinolin-2-ones 121 were derived in high yields and with good enantiomeric excesses (eq b). Very recently, the Lu group disclosed a highly enantioselective intramolecular [3 + 2] annulation of chalcones 122 bearing an allene moiety for the construction of dihydrocoumarin scaffolds 123 (Scheme 36).89 It is interesting to note that the catalytic system contains a chiral bifunctional phosphine P75 plus achiral benzoic acid, and the cooperation of P75 with the latter led to enhanced enantioselectivity. Theoretical studies via DFT calculations revealed that the hydrogen bonding network formed between benzoic acid and the amide N−H of the catalyst and the ester group of chalcone leads to better differentiation of two competing enantioselective pathways, thus resulting in enhanced enantioselectivity. 2.1.4. [3 + 2] Annulations of Alkynes. In Lu’s initial report,5 it was shown that alkynes could be activated by phosphines and displayed reaction profiles similar to those of allenes. The common mechanistic pathways of phosphinecatalyzed [3 + 2] annulations of alkynes are illustrated in Scheme 37. Phosphine addition to γ-substituted activated alkyne of type A generates Int-5, and subsequent proton transfer yields Int-6, which has two resonance forms (Int-6α

Scheme 34. Early Reports on Racemic Intramolecular [3 + 2] Annulations (Krische, 2003; Kwon, 2007)

(±)-hirsutene based on phosphine-catalyzed intramolecular [3 + 2] annulation of 2-alkynoates 113 containing an enone moiety (eq b).86 Shortly after, Kwon et al. reported an intramolecular [3 + 2] annulation of 116 containing allene and alkene moieties for the construction of functionalized coumarins 117 (eq c).87 To date, there are only two reports on phosphine-catalyzed enantioselective intramolecular [3 + 2] annulations, unlike multitudinous known intermolecular variants. The paucity of such reactions may be partly due to the inherent challenge to R


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Scheme 35. Intramolecular [3 + 2] Annulation of Allenoates/Allenamides and Olefins (Fu, 2015)

and Int-6γ). Internal alkynes of type B undergo phosphinetriggered isomerization to form corresponding allenoates, which upon phosphine attack creates zwitterionic Int-6α and Int-6γ. The [3 + 2] cycloaddition of either zwitterionic intermediate to alkenes leads to the formation of fivemembered ring systems. Ynones of type C are alkynes possessing unique reaction patterns. As depicted in Scheme 38, addition of phosphine to ynone C generates zwitterionic intermediate Int-10. Subsequent intramolecular proton transfer from the α′ position then affords phosphonium anion Int-11. The [3 + 2] cycloaddition of Int-11 to activated alkenes, followed by proton transfer, then furnishes the [3 + 2] annulation product with an exocyclic double bond. In comparison to the well-established applications of allenes in phosphine-catalyzed asymmetric [3 + 2] cycloaddition

Scheme 36. Intramolecular [3 + 2] Annulation to Access Dihydrocoumarin (Lu, 2017)

Scheme 37. Mechanism of [3 + 2] Annulation between Alkynes and Activated Alkenes

S


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asymmetric reaction was also attempted with the employment of chiral phosphine (S)-P8, and bicyclic product 134 was obtained with moderate enantioselectivity (Scheme 41). The Shi group reported an enantioselective [3 + 2] annulation of but-3-yn-2-one and isatins, in which a commercially available P41 was found to be a suitable catalyst.94 A variety of substituted isatins 136 were well tolerated, furnishing spiro[furan-2,3′-indoline]-2′,4(5H)-diones 137 bearing a tertiary stereogenic center in reasonable yields and with good enantioselectivities (Scheme 42). Around the same time, the Huang group developed a racemic [3 + 2] annulation by employing phenyl-substituted ynone 138, and isatins or activated olefins as reaction partners.95,96 They also attempted an enantioselective version of the reaction; however, the products (139 and 141) were obtained with poor enantioselectivities (Scheme 43, eqs a and b). Very recently, Guo and co-workers employed barbituratederived alkenes 142 in the [3 + 2] annulation with ynone 138.97 While the racemic reactions worked well, utilization of bifunctional phosphine P65 for asymmetric reactions only led to product 143 with moderate enantioselectivity (eq c).

Scheme 38. Mechanism of [3 + 2] Annulation of Ynones with Activated Alkenes

2.2. [4 + 2] Annulations of α-Substituted Allenoates

reactions, the employment of activated alkynes for similar annulation processes is rather limited, with only a handful of enantioselective examples to date. In their early report on (S)P7 or (S)-P8-catalyzed [3 + 2] annulation between allenoates and imines,74 Marinetti and co-workers also examined butynoates 124 as a potential C3 synthon (Scheme 39, eq a). The Marinetti group subsequently further investigated the same reaction and discovered that employment of DPP imines led to the formation of cyclopentenes 129 with up to 92% ee (eq b).90 The Loh group disclosed a highly enantio-, regio-, and diastereo-selective one-pot [3 + 2] annulation between 3butynoates and enones.91 Phosphine P37 catalyzed isomerization of 3-butynoates 130 to γ-substituted allenoates, and the subsequent [3 + 2] annulation furnished the desired products 132 as single regio- and diastereo-isomers in excellent yields and enantioselectivities (Scheme 40). In a control experiment, the authors confirmed isomerization of 3-butynoates and isolated the corresponding γ-substituted allenoates. In 2003, Tomita reported an intramolecular cyclization of diyne−diones or yne−diones catalyzed by tri-n-butylphosphine,92 which illustrated the distinct reactivity of ynones in phosphine-catalyzed annulations. Fu and co-workers then developed a tri-n-butylphosphine-catalyzed intramolecular annulation between the ynone and alkene moieties for the preparation of highly functionalized diquinanes.93 The

With the firm establishment of phosphine-mediated [3 + 2] annulations as a powerful tool to access five-membered ring systems, it is intriguing yet natural to consider the construction of six-membered cyclic structures via phosphine catalysis. In 2003, Kwon and co-workers explored α-substituted allenoates in phosphine-catalyzed reactions and observed an unprecedented [4 + 2] annulation between α-substituted allenes with N-tosylaldimines in which allenoates served as C4 synthons.98 This discovery was striking as α-unsubstituted allenoates used previously in phosphine catalysis all led to [3 + 2] annulation reactions. The feasibility of uncovering novel reaction modes through carefully design and employment of new allene reaction partners is truly exciting. In 2007, the Kwon group further extended their [4 + 2] annulation to include activated alkenes as a reaction partner, allowing expedient synthesis of functionalized cyclohexenes.99 The mechanism100,101 for the Kwon [4 + 2] annulation of αsubstituted allenoates and activated alkenes/imines is illustrated in Scheme 44. Phosphine adds to allenoates and generates zwitterionic intermediate Int-14, which has two resonance forms. Less sterically hindered Int-14γ is predominant for the subsequent reaction with activated alkene/imine, forming adduct Int-15. With R1 being electron-withdrawing group or aryl group, the adjacent acidic proton facilitates a proton transfer process to form Int-16a, which has a resonance

Scheme 39. [3 + 2] Annulation of 2-Butynoates with Imines (Marinetti, 2007, 2009)

T


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Scheme 40. [3 + 2] Annulation between 3-Butynoates and Enones (Loh, 2010)

Scheme 41. Intramolecular [3 + 2] Annulation of Ynone− Alkene 133 (Fu, 2010)

Scheme 44. Mechanism of Phosphine-Catalyzed [4 + 2] Annulation between α-Substituted Allenoates and Activated Alkenes/Imines

Scheme 42. [3 + 2] Annulation between But-3-yn-2-one and Isatins (Shi, 2012)

form Int-16b. Another proton shift affords Int-17, which is poised for intramolecular ring closure to furnish six-membered annulation product, while regenerating the catalyst at the same time. 2.2.1. [4 + 2] Annulations of α-Substituted Allenoates with Activated Alkenes. The first highly enantioselective variant of Kwon’s [4 + 2] annulation between allenoates and activated alkenes was reported by Lu and co-workers (Scheme

45).102 L-Thr-derived phosphine P73 efficiently catalyzed the reaction between allenoate 144 and dicyano-activated alkenes 145, furnishing functionalized cyclohexenes 146 bearing a quaternary carbon center in excellent yields, good diastereoselectivities, and excellent enantioselectivities (eq a). Isatin-

Scheme 43. [3 + 2] Annulations of Ynone 138 with Isatins or Activated Alkenes (Huang, 2012, 2014; Guo, 2017)

U


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Scheme 45. [4 + 2] Annulation of α-Substituted Allenoates with Cyano-activated Alkenes (Lu, Zhao, 2012)

Scheme 46. [4 + 2] Annulations of α-Substituted Allenoates with Various Activated Alkenes (Guo, 2015; Kumar, 2016)

150 and prepared various spiropyrazolones 154 in moderate to excellent yields, low diastereoselectivities, and high enantioselectivities (Scheme 46, eq a). The same group next expanded the scope of the [4 + 2] annulation by employing barbituratederived alkenes 156 as a C2 synthon,105 which provided quick access to biologically important spirobarbiturate−cyclohexenes 157 (eq b). Notably, the α-substituted allenoates employed in the reaction had a broader scope as compared with those reported previously, and the use of aromatic moieties with different electronic properties at the α-position of allenoates was well tolerated. More recently, Kumar and co-workers developed a P74-catalyzed annulation reaction of allenoates 158 and cyano-activated alkenes 159, obtaining a variety of optically enriched tetrahydroxanthones 160 bearing three consecutive chiral centers in good yields and excellent enantioselectivities (eq c).106

derived activated alkenes 148 were subsequently found to be suitable substrates, and a wide diversity of spirocyclic oxindoles 149 with high diastereoselectivities and excellent enantioselectivities were readily prepared by employing dipeptide catalyst P95 (eq b). Control experiments concerning dipeptide catalysts with methylated amide or carbamate were performed. The results suggested that the amide N−H is crucial for both reaction rate and enantioselectivity, whereas the carbamate N− H has more influence on the reaction rate and less on the stereoselectivity. Around the same time, Zhao and co-workers reported a similar [4 + 2] cyclization by reacting 2-cyano acrylates 151 with α-substituted allenoates 150. The annulation products 152 were obtained with high diastereoselectivities and excellent enantioselectivities (eq c).103 Guo and co-workers introduced unsaturated pyrazolones 153 as a C2 synthon104 in the [4 + 2] annulation with allenoate V


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Scheme 47. Novel Mode [4 + 2] Annulation of α-Substituted Allenoates with Enones (Guo, 2016, 2017)

Scheme 48. [4 + 2] Annulation of α-Substituted Allenoates with N-Tosylaldimines (Fu, 2005; Zhao, 2011)

A novel reactivity of α-substituted allenoates was recently reported by the Guo group, which represents a different reaction pattern for the [4 + 2] annulation of allenoates (Scheme 47).107,108 When reacting with α,β-unsaturated ketones 162 or 164, allenoates 161 served as a C2 synthon; the unsaturated ketones acted as a four-atom synthon, forming six-membered heterocyclic rings. It is noteworthy that the benzyl substitution at the α-position of the allenoates was crucial, since allenoate with a methyl group at the α-position yielded trace amounts of product. In the presence of either commercially available P5 or the multifunctional catalyst P95, a series of dihydropyran derivatives were synthesized in good yields and high enantioselectivities (eqs a and b). In the proposed mechanism, the conjugate addition of advanced phosphonium zwitterionic intermediate Int-18 to enone leads to the formation of Int-19. Subsequent addition of oxygen anion to the β-carbon of the allenoate, followed by the regeneration of phosphine catalyst, furnishes the final annulation product.

2.2.2. [4 + 2] Annulations of α-Substituted Allenoates with Activated Imines. Shortly after Kwon’s initial disclosure of racemic [4 + 2] annulation utilizing α-substituted allenes with imines,98 Fu and co-workers described the first asymmetric variant of such annulation.109 In the presence of binaphthyl-based (S)-P8, allenoates 166 with either aryl or ester-substituted methylene group at the α-position smoothly underwent [4 + 2] annulation with activated imines 81, furnishing nitrogen-containing cyclic structures 167 in high yields, good diastereoselectivities and excellent enantioselectivities (Scheme 48, eq a). Notably, allenoate bearing α-methyl group was well tolerated for the reaction, although both yield and enantioselectivity were decreased. A similar annulation reaction was subsequently reported by Zhao and co-workers,110 in which bifunctional P65 was selected and optically enriched tetrahydropyridines 168 were prepared via [4 + 2] annulation (eq b). Sasai and co-workers reported a cyclic phosphine (R)-P18catalyzed [4 + 2] annulation between α-methyl-substituted W


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Scheme 49. [4 + 2] Annulations of α-Substituted Allenoates with Cyclic Imines (Sasai, Guo, 2014)

philic, making the oxygen anion directly add to the β-position to yield Int-23. Subsequent regeneration of phosphine catalyst furnishes the final oxygen-containing six-membered ring structure with an exocyclic double bond. The initial disclosure by the Lu group employed L-Thr-LThr-derived phosphine catalysts, and the reaction between

allenoate 163a and cyclic ketimines 169,111 which was an asymmetric variant of Ye’s earlier disclosure.112 Enantiomerically enriched tetrahydropyridines 170 with a tetrasubstituted stereogenic carbon center were synthesized in high yields and with good enantioselectivities (Scheme 49, eq a). Almost at the same time, the Guo group reported a [4 + 2] annulation of sulfamate-derived cyclic aldimines 172 with α-substituted allenoates 171, obtaining sulfamate-fused tetrahydropyridines 173 in good yields, moderate diastereoselectivities, and decent enantioselectivities (Scheme 49, eq b).113

Scheme 51. [4 + 2] Annulation Reaction of Allenic Ketones with β,γ-Unsaturated α-Keto Esters (Lu, 2015)

2.3. [4 + 2] Annulations of α-Substituted Allenic Ketones

Given the extensive utilizations of allenic esters in phosphinecatalyzed reactions, it is somewhat surprising to note that their close structural analogs, allenic ketones, did not receive much attention. Compared to allenoates, allenic ketones are more electron-deficient and thus more reactive toward phosphine attack due to the strong electron-withdrawing ability of the ketone group. Allenic ketones without α-substitutions were reported to react with electrophiles under phosphine catalysis and undergo [3 + 2] annulations, similar to those of allenoates.43 However, when allenic ketones with α-substitutions react with unsaturated ketones or imines in the presence of phosphine catalyst, the [3 + 2] annulation pathway is suppressed, resulting in a novel mode of [4 + 2] annulation. This type of annulation was first reported by the Lu group,114 in which allenic ketones served as a C2 synthon to form sixmembered heterocycles. In the proposed reaction mechanism (Scheme 50), initial phosphine addition to the allenic ketone generates Int-21, and the less hindered Int-21γ attacks the α,βunsaturated ketone to yield Int-22. The presence of the ketone functionality makes the β-position of allene highly electro-

allenic ketones 174 and β,γ-unsaturated α-keto esters 175 was examined (Scheme 51).114 In the presence of dipeptidic phosphine P94, the [4 + 2] annulation took place smoothly, and optically enriched dihydropyrans 176 were obtained in high yields and with nearly perfect enantioselectivities (≥99% ee for most cases). As a demonstration of synthetic utility, an annulation product was elaborated to an antihypercholesterolemic agent via a few trivial reaction steps. The same group subsequently expanded the scope of this novel [4 + 2] annulation reaction and demonstrated that oxadienes 178,115 3-aroylcoumarins 181,116 and o-quinone methides 184117 are suitable C4 synthons for annulation with allenic ketones (Scheme 52). Noteworthy is the fact that o-quinone methides (o-QMs) were utilized in phosphine-catalyzed asymmetric reactions for the first time (eq c). Zhang and co-workers explored β-perfluoroalkyl enones as substrates for the [4 + 2] annulation with α-substituted allenic ketones and found ferrocene-derived bifunctional phosphine P113 was a suitable catalyst, accessing chiral perfluoroalkylated dihydropyran scaffolds (Scheme 53).118 A list of β-perfluoroalkyl enones 187 could be employed, and CF3-containg dihydropyrans 188 were formed in good yields and with excellent enantioselectivities (eq a). Furthermore, the method was applicable to a series of benzocyclic α,β-enones 189,

Scheme 50. Mechanism of [4 + 2] Annulation between Allenic Ketones and α,β-Unsaturated Ketones

X


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Scheme 52. [4 + 2] Annulation Reactions of Allenic Ketones with Various α,β-Unsaturated Ketones (Lu, 2016, 2017)

Scheme 54. Stepwise [4 + 2]/[2 + 2] Cyclizations of Allenic Ketones with α,β-Unsaturated Imines (Lu, 2017)

electrophiles such as activated alkenes or imines resulting in cyclizations. In 2010, the Tong group discovered a new mode of activation in phosphine catalysis by introducing a special type of allenoates with a β′-acetate substituent.120 Remarkably, the introduction of β′-acetate group transformed the phosphonium intermediate from a nucleophile to an electrophile, leading to a novel [4 + 1] annulation when it comes to reacting with dinucleophiles. In the proposed mechanism (Scheme 55), phosphine addition to the allenoate eliminates the OAc group to create electrophilic diene Int-24, which is ready to react with dinucleophiles. Two sets of nucleophilic attacks then furnish cyclic intermediate Int-28, which then eliminates the phosphine catalyst and forms the final annulation product. The Tong group subsequently introduced another type of allenoates, bearing an acetate group at the δ position (Scheme 56).121 Similar to β′-acetate allenoates, phosphine addition to the δ-acetoxy allenoate generates electrophilic diene Int-30, which is prone to nucleophilic attack to form Int-31. Intramolecular deprotonation followed by another nucleophilic attack then furnishes cyclic intermediate Int-33. Subsequent proton transfer and regeneration of phosphine catalyst give the final annulation product. In the above reaction pathway, δacetoxy allenoate serves as a C2 synthon. Hence, relying on the

allowing easy access to structurally diverse chiral polycyclic molecules 190 (eq b). Very recently, Lu and co-workers developed enantioselective phosphine-catalyzed [4 + 2] cyclizations of allenic ketones with 1-azadienes for the synthesis of nitrogen-containing sixmembered ring structures.119 In the presence of L-Val-derived amide catalyst P68, a cavalcade of tetrahydropyridines 193 were readily prepared in high yields and with excellent enantioselectivities (Scheme 54). The [4 + 2] annulation products were further subjected to [2 + 2] cyclization with in situ generated benzynes, leading to facile synthesis of polycyclic piperidines 194 with >99% ee value. 2.4. Annulations of Acetate-Substituted Allenoates

In the aforementioned phosphine-catalyzed [3 + 2] and [4 + 2] annulations, the advanced phosphonium zwitterionic intermediates serve as a nucleophile to react with various

Scheme 53. [4 + 2] Annulation Reaction of Allenic Ketones with Different Enones (Zhang, 2017)

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Scheme 55. Mechanism of [4 + 1] Annulation of β’-Acetate Allenoates with Dinucleophiles

nature of dinucleophiles employed, various [2 + n] annulation pathways are feasible, although only asymmetric [3 + 2] annulations have been developed to date. 2.4.1. [4 + 1] Annulations of β′-Acetate-Substituted Allenoates. After Tong’s initial racemic report of [4 + 1] annulation between β′-acetate-substituted allenoates with dinucleophiles to form cyclopentenes,120 the Lu group reported the first asymmetric variant by using their L-Thrderived catalyst P72 (Scheme 57).122 Cyclic pyrazolones 196 were utilized as a dinucleophile and served as a C1 synthon in the cyclization, and a wide range of spiropyrazolones (R)-197 with an all-carbon quaternary stereocenter were readily prepared in good yields and excellent enantioselectivities. It was proposed that the hydrogen bonding interaction between amide N−H and pyrazolone enolate is crucial for the observed stereoselectivity. When methylated catalyst P72′ was employed, the product was obtained in 36% yield and with 19% ee, as compared to 82% yield and 91% ee attainable when P72 was used under otherwise identical reaction conditions. Shortly after Lu’s report, the Fu group disclosed another example of asymmetric [4 + 1] annulation of β′-acetatesubstituted allenoates by using chiral phosphine catalysts with

Scheme 56. Mechanism of [2 + n] Annulation between δAcetoxy Allenoates and Dinucleophiles

Scheme 58. [4 + 1] Annulation of β′-Acetate-Substituted Allenoates with Dinucleophiles (Fu, 2014)

Scheme 57. [4 + 1] Annulation between β′-Acetate-Substituted Allenoates and Cyclic Pyrazolones (Lu, 2014)

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Scheme 59. [4 + 1] Annulation of β′-Acetate-Substituted Allenoates with Amines (Fu, 2015)

Scheme 60. [3 + 2] Annulation of δ-Acetoxy Allenoates and 1C,3N-Bisnucleophiles (Shi, Tong, 2017)

Scheme 61. [3 + 2] Annulation of δ-Acetoxy Allenoates and 2-Naphthols (Tong, 2017)

catalyzed [4 + 1] annulation with β′-acetate allenoates 201, and obtained dihydropyrroles 203 in high yields and good enantioselectivities (Scheme 59).124 Saliently, the γ-substituted allenes were also investigated, and such allenes were rarely utilized in phosphine-catalyzed [4 + 1] annulations. Preliminary mechanistic studies suggested that the step of adding sulfonamide 202 to the advanced phosphonium−diene intermediates may be reversible.

biaryl scaffolds (Scheme 58).123 Dinucleophiles 199 containing a cyano and another electron-withdrawing group such as ketone, ester, sulfone, or phosphonate, were utilized in the reaction, and functionalized cyclopentenes 200 bearing a fully substituted stereocenter were obtained in good yields and with excellent enantioselectivities. Notably, allenoates bearing a γor β′- substituent also led to products in high yields and good enantioselectivities. Recently, Fu and co-workers utilized amines 202 as a dinucleophile in spirophosphine (R)-P21AA


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Scheme 62. [4 + 3] Annulation of Allenoates with Azomethine Imines (Guo, 2016)

Scheme 63. [4 + 4] Annulation of α-Substituted Allenic Ketones with α,β-Unsaturated Imines (Lu, 2017)

2.4.2. [3 + 2] Annulations of δ-Acetoxy Allenoates. Very recently, Shi and co-workers disclosed a triphenylphosphine-catalyzed [3 + 2] annulation between δ-acetoxy allenoates and 1C,3N-bisnucleophiles, obtaining highly functional spirocyclic structures (Scheme 60).125 Attempts to perform the reaction in an asymmetric manner were unsuccessful, as the product 206 or 208 was obtained in low yield and with moderate enantioselectivity (eqs a and b). Almost at the same time, Tong and co-workers reported126 a similar reaction between δ-acetoxy allenoates 209 and βcarbonyl amides 210, in which asymmetric [3 + 2] annulation was realized to furnish a series of spirocyclic products 211 in good yields, high diastereoselectivities, and excellent enantioselectivities (eq c). In the proposed transition state, blockage of the Si-face of the phosphonium enolate intermediate by the phenyl group of the catalyst leads to the Re-face attack from the nucleophile, accomplishing the observed stereoselectivity. Around the same time, the Tong group disclosed another [3 + 2] annulation of δ-acetoxy allenoates utilizing 2-naphthols 212 as dinucleophiles (Scheme 61).127 In the presence of (R)P18, the reaction proceeded under mild conditions to furnish

1,2-dihydronaphtho[2,1-b]furans 213 in high yields and excellent enantioselectivities. The authors also examined 1naphthol in the reaction and observed the formation of [3 + 3] annulation product. It was therefore proposed that the αcarbon of 2-naphthol is more sterically hindered due to A1,3interactions and thus preferentially attacks the δC-position of Int-34, forming the observed products. In contrast, the βcarbon of 1-naphthol is less hindered, hence attacks both αCand δC-positions of Int-34, leading to the formation of mixed products. 2.5. [4 + 3] and [4 + 4] Annulations for the Construction of Medium-Sized Rings

Despite the firm establishment of phosphine catalyzed [3 + 2], [4 + 2], or [4 + 1] annulations to access five- or six-membered rings, the construction of medium-sized rings has lagged far behind. Due to the intrinsic ring strains and the competing reaction pathways leading to smaller rings, the formation of seven- or eight-membered cyclic structures is very challenging. In 2011, Kwon and Guo described a series of annulation reactions of α-substituted allenoates and azomethine imines, among which they also observed [4 + 3] annulation AB


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products.128 Subsequently, Guo and co-workers developed a series of achiral phosphine catalyzed [4 + 3] annulations between N,N′-cyclic or C,N-cyclic azomethine imines and αsubstituted allenoates for the construction of dinitrogen-fused seven-membered rings.129,130 More recently, the Guo group disclosed the first asymmetric [4 + 3] annulation of allenoates 214 with C,N-cyclic azomethine imines 215, providing facile access to quinazoline-based tricyclic heterocycles (Scheme 62).131 In the presence of commercially available P3, a wide range of seven-membered tricyclic rings 216 was constructed with good diastereo- and enantio-selectivities. In a comparison to very limited reports on phosphinemediated synthesis of seven-membered rings, the construction of eight-membered cyclic structures via phosphine catalysis remained unknown until 2017. Lu and co-workers discovered an unprecedented [4 + 4] annulation between α,β-unsaturated imines and α-substituted allenic ketones (Scheme 63).132 In the presence of amino acid-derived phosphine P94 or P69, allenic ketones 217 reacted with benzofuran/indole-derived α,β-unsaturated imines 218 to form eight-membered azocines 219 in a highly enantioselective manner. In this novel [4 + 4] annulation, both allenic ketones and α,β-unsaturated imines acted as a four-atom synthon. As shown in the proposed reaction mechanism, the first few steps are well anticipated and generate phosphonium intermediate Int-36. Instead of attacking on the β-carbon of the allenic ketone, which was observed for the previous [4 + 2] annulation, the steric bulkiness of the tosyl group suppresses the direct attack from the nitrogen anion. The acidic proton at the β′ position is subsequently deprotonated to yield Int-37. Proton transfer then follows, and intramolecular nucleophilic addition furnishes the final eight-membered ring product.

thanks to their ready availability, superb chemical stability, and structural diversity. All of these make them extremely attractive. The pioneering studies of phosphine-catalyzed [3 + 2] annulation of the MBH adducts with activated alkenes were conducted by Lu and co-workers in 2003.133 The proposed reaction mechanism begins with the phosphine addition to the MBH adducts, forming Int-40. This intermediate then releases one molecule of carbon dioxide and in situ generates tert-butoxide anion, which extracts the αH of the Int-40 to afford ylide Int-41. The subsequent [3 + 2] cycloaddition to electrophilic alkenes affords phosphonium anion Int-42, which undergoes elimination of the phosphine Scheme 64. Mechanism of Phosphine Catalyzed [3 + 2] Annulation of the MBH Adducts and Activated Alkenes

catalyst and delivers the final five-membered cyclization product (Scheme 64). After Lu’s original disclosure, Tang and co-workers reported the first phosphine catalyzed intramolecular [3 + 2] annulation of the MBH adducts containing an activated alkene moiety and constructed fused ring systems in high yields and good diastereoselectivities.134 Subsequently, Tang, Zhou and coworkers developed an asymmetric variant of the same intramolecular [3 + 2] annulation (Scheme 65).135 Catalyst (S)-P19 efficiently promoted the reaction and afforded the bicyclic annulation products 221 in high yields, good enantioselectivities, and moderate diastereoselectivities. It was proposed that the steric hindrance from the spirocyclic moiety of catalyst (S)-P19 facilitates the nucleophilic attack at the Reface of the alkene, thus explicating the observed stereochemistry. Shortly after Tang and Zhou’ report on asymmetric intramolecular annulation of the MBH adducts, Barbas and co-workers disclosed the first intermolecular [3 + 2] annulation between the MBH carbonates 222 and methyleneindolinones 223 (Scheme 66).136 Bisphosphine P26 was found to be an optimal catalyst for the reaction, leading to the formation of chiral spirooxindoles 224 in excellent enantiomeric excesses. It was noted that bisphosphine P26 outperformed monophosphine analogue P26′. The authors proposed that the second phosphine moiety in the catalyst interacts with the carbonyl group of the methyleneoxindolinone, making the attack through the γ-carbon favorable. Such a proposal is supported by 31P NMR studies. Concurrently, the Lu group independently reported a similar intermolecular asymmetric [3 + 2] annulation of the MBH carbonates 225 with isatin-derived α,α-dicyanoalkenes 226 (Scheme 67).137 L-Thr-derived thiourea−phosphine P78

2.6. Summary of Annulation Reactions Employing Allenes and Alkynes

To date, phosphine-catalyzed annulation reactions making use of various forms of allenes have become the most widely explored reaction type in phosphine catalysis. Different annulation modes have been successfully developed, and diverse molecular scaffolds have been created. It is noteworthy that the vast majority of examples deal with five- or sixmembered cyclic structures, whereas the methods for synthesizing medium-sized rings are still very limited. Future efforts may be devoted to the synthesis of medium or large ring structures, thus further broadening the scope of phosphinecatalyzed annulation reactions. As for alkynes, although they are synthetically more accessible and structurally analogous to allenes, their utilization in phosphine catalysis is still very limited. How to more effectively activate alkyne substrates constitutes another key challenge in this research field. It is intriguing to note that different forms of allenes often render unique and interesting reactivities in phosphine-mediated reactions; thus creative designs of novel allene or alkyne reaction partners may open the door to the discovery of novel modes of annulation/unprecedented reaction pathways.

3. ANNULATION REACTIONS EMPLOYING THE MBH ADDUCTS 3.1. [3 + 2] Annulations of the MBH Adducts

Although activated allenes are the most common reaction partners for phosphine catalysis, their relative low stability and less structural versatility indeed pose certain limitations. The MBH adducts hold great potentials in phosphine catalysis, AC


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Scheme 65. Intramolecular [3 + 2] Annulation of the MBH Adducts containing an Activated Alkene Moiety (Tang, 2010)

Scheme 66. [3 + 2] Annulation between the MBH Adducts and Methyleneindolinones (Barbas, 2011)

Scheme 67. [3 + 2] Annulation of the MBH Adducts and Isatin-Derived Activated Alkenes (Lu, 2011)

co-workers reported a racemic [3 + 2] cyclization utilizing the MBH adducts and isatin-derived activated alkenes. They showed one asymmetric example in the same study, which was promoted by BINOL-based bifunctional phosphine (R)P43.138 In a subsequent report, Lu and co-workers demonstrated that maleimides were suitable reaction partners in [3 + 2] annulation with the MBH carbonates (Scheme 68).139 In the presence of amino acid-derived P91, bicyclic imides 230 were obtained in good yields and with excellent enantioselectivities.

efficiently promoted the reaction to yield spirooxindoles 227 with excellent stereoselectivities. In the mechanistic proposal, the hydrogen bonding interaction between the thiourea moiety of the catalyst and the carbonyl group of isatin substrates is considered to be crucial for the observed stereoselectivity. The importance of the hydrogen bond was supported experimentally; the diastereoselectivity and enantioselectivity of the reaction catalyzed by methylated catalyst P78′-Me were significantly lower as compared to selectivities attainable with the utilization of L-Val-derived P78′. In the same year, Shi and AD


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Scheme 68. [3 + 2] Annulation of the MBH Adducts and Maleimides (Lu, 2012)

Scheme 69. [3 + 2] Annulations of the MBH Adducts with Various Activated Alkenes (Shi, 2012)

Scheme 70. [3 + 2] Annulation between Isatin-Derived MBH Carbonates with Maleimide (Liu, 2012)

enantioselectivities (Scheme 69, eq a). The Shi group also explored other activated alkenes as potential C2 synthons in [3 + 2] annulations with the MBH carbonates. In the presence of P59, the [3 + 2] annulation between the MBH adducts and trifluoroethylidenemalonates 234 (eq b)141 or 2-arylideneindane-1,3-diones 237 (eq c) proceeded smoothly in a highly enantioselective manner.142 The hydrogen bonding interaction between the thiourea group of the catalyst and the carbonyl groups of the substrates was believed to be crucial for inducing asymmetry. Liu and co-workers established that isatin-derived MBH adducts 239 were appropriate coupling partners in phosphine-

Interestingly, dipeptide catalyst P91 possessed an L-Lconfiguration, as opposed to the L-D-dipeptide catalysts found optimal in the previous reports, showing versatility of such amino acid-based catalytic systems. It was proposed that hydrogen bonding network brings maleimide and phosphonium enolate intermediate in close proximity, allowing γ-attack from the phosphonium enolate to form the observed stereoisomer. Coincidentally, Shi and co-workers reported the same type of reactions employing L-Phe-derived thiourea−phosphine catalyst P59140 and constructed cyclopentenes 232 bearing three contiguous stereocenters in good yields and excellent AE


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Scheme 71. [3 + 2] Annulation of the MBH Adducts and Maleimides Catalyzed by Ferrocene-Based Phosphine (Zhong, 2016)

Scheme 72. [3 + 2] Annulations of the MBH Adducts with Different Activated Alkenes (Guo, 2016)

Scheme 73. Catalyst-Controlled Diastereoselective [3 + 2] Annulations (Chen, 2016)

catalyzed asymmetric [3 + 2] annulation with maleimide 229a (Scheme 70).143 In the presence of bisphosphine Me-DuPhos P22, spirooxindoles 240 with excellent diastereoselectivities and high enantioselectivities were prepared. Mechanistically, it was proposed that the two phosphine moieties play distinct roles; one forms active allylic phosphonium ylide, whereas the other one interacts with the carbonyl of the imide to lock the two reactants in the open U-shaped cleft of the catalyst. In a related study,144 the Barbas group further expanded the scope of phosphine-catalyzed asymmetric [3 + 2] annulation of the MBH carbonates and showed that 3-substituted methylenebenzofuranone derivatives served as an appropriate C2 synthon for the construction of spirocyclopentenebenzofuranones. Zhong and co-workers developed a novel class of ferrocenebased multifunctional chiral phosphines and applied them to

the [3 + 2] annulation between the MBH carbonates and maleimides (Scheme 71).145 In the presence of P111, bicyclic products 242 were prepared in good yields and with excellent enantioselectivities. It was proposed that hydrogen bonding interaction between the catalyst amide N−H and maleimide is crucial for asymmetric induction, and the phosphonium zwitterionic intermediate attacks maleimide from its Re-face, yielding the major stereoisomer. Guo and co-workers established146 an amino acid-derived phosphine P65-catalyzed annulation between the MBH adducts 243 and barbiturate-derived alkenes 244 to access spirobarbiturate-cyclopentenes 245 in good yields and excellent diastereo- and enantioselectivities (Scheme 72, eq a). The Guo group subsequently utilized α,β-unsaturated cyclic imines 247 as a C2 component in the [3 + 2] annulation with AF


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the MBH adducts.147 Phosphine P65 catalyzed the reaction smoothly to deliver optically enriched cyclopentene derivatives 248 bearing three contiguous tertiary stereocenters in moderate to excellent yields and good enantioselectivities (Scheme 72, eq b). In 2016, Chen and co-workers established a catalystcontrolled diastereoselective [3 + 2] annulation process utilizing isatin-derived MBH adducts 250 and diketoneactivated alkenes 237.148 With the employment of either cyclic phosphine P6 or dipeptide-based multifunctional phosphine P95, different diastereomeric spirooxindoles, 249 or 249′, could be selectively obtained (Scheme 73). Notably, all of the reactions exhibited exclusive α-regioselectivity, high yields, and excellent enantioselectivities.

good yields.149 Subsequently, He and co-workers reported a similar [4 + 1] annulation utilizing α,β-unsaturated imines as four-atom synthons for the preparation of 2-pyrrolines.150 The first asymmetric [4 + 1] annulation of the MBH adducts was documented by Shi and co-workers (Scheme 75).151 Treatment of the MBH adducts 251 and activated dienes 252 with BINOL-derived bifunctional phosphine (R)-P44 furnished a range of cyclopentene derivatives 253 in high yields and excellent enantioselectivities. It is noteworthy that the MBH adducts with various aryl substituents could also be utilized, including low reactivity substrates with no or halogen substituent on the aryl ring. Shi and co-workers next explored the reaction between the MBH adducts 254 and isatin-derived enones 255 (Scheme 76).152 The use of thiourea-based catalyst (R)-P46 led to the formation of spirooxindole derivatives 256 with excellent enantioselectivities, albeit the diastereoselectivities were modest (eq a). The same group later examined isatin-derived α,β-unsaturated imines as four-atom synthons in a methyldiphenylphosphine-catalyzed annulation reaction with the MBH adduct and obtained spirooxindoles bearing dihydropyrrole scaffolds in good yields.153 An asymmetric reaction was attempted by employing catalyst P102, and the annulation product 259 was obtained in 78% yield, with 7:1 dr, and 61% ee (eq b). Very recently, Li and co-workers disclosed a cyclic bisphosphine P24-catalyzed [4 + 1] annulation between the MBH adducts 260 and enones 261 (Scheme 77).154 A variety of activated enones were tolerated regardless of the electronic nature or steric bulkiness of the substituents, and the optically enriched 2,3-dihydrofurans 262 were obtained in good yields and with excellent diastereo- and enantioselectivities. Very recently, the He group designed a novel class of hybrid P-chiral phosphine oxide−phosphines and demonstrated their utility in the [4 + 1] annulation of the MBH adducts and α,βunsaturated imines (Scheme 78).155 In the presence of P42, a good number of α,β-unsaturated imines 264 containing different aryl substitutions readily reacted with the MBH carbonate 263, furnishing polysubstituted 2-pyrrolines 265 in good yields, excellent diastereoselectivities, and high enantioselectivities. The authors proposed that the key ylide intermediate adopts a cyclic structure through intramolecular Coulombic interaction between the phosphonium group and the phosphine oxide moiety, which dictates the path of the subsequent addition to imine and accounts for the observed stereoselectivity.

3.2. [4 + 1] Annulations of the MBH Adducts

Other than serving as a C3 synthon in the [3 + 2] annulation reactions, the MBH adducts could act as a C1 synthon when reacting with activated dienes, α,β-unsaturated ketones, or imines, furnishing five-membered rings via [4 + 1] annulation. In a general reaction mechanism, phosphine first activates the MBH carbonates to form the phosphonium ylide Int-43, which then reacts with an electrophilic diene, α,β-unsaturated ketone, or imine to give Int-44. Subsequently, two proton transfer processes take place to yield Int-46, which undergoes SN2′ reaction to furnish the [4 + 1] annulation product and Scheme 74. Mechanism of [4 + 1] Annulation of the MBH Adducts with Activated Dienes, α,β-Unsaturated Ketones, or Imines

3.3. [3 + 3] Annulations of the MBH Adducts

Riding on their earlier success of utilizing azomethine imines in annulation reactions, Guo and co-workers further developed an enantioselective [3 + 3] annulation between the MBH adducts and C,N-cyclic azomethine imines (Scheme 79).156 Spirocyclic phosphine (R)-P18 effectively promoted the cycloaddition

regenerates the phosphine catalyst at the same time (Scheme 74). Zhang and co-workers disclosed the first phosphinecatalyzed [4 + 1] annulation between the MBH adducts and activated enones, obtaining functionalized 2,3-dihydrofurans in

Scheme 75. [4 + 1] Annulation of the MBH Adducts and Activated Dienes (Shi, 2012)

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Scheme 76. [4 + 1] Annulation of the MBH Adducts and α,β-Unsaturated Ketones or Imines (Shi, 2014, 2015)

Scheme 77. [4 + 1] Annulation of the MBH Adducts and Enones (Li, 2017)

Scheme 78. [4 + 1] Annulation of the MBH Adducts and α,β-Unsaturated Imines (He, 2017)

Scheme 79. [3 + 3] Annulation of the MBH Adducts with C,N-Cyclic Azomethine Imines (Guo, 2015)

Scheme 80. [3 + 3] Annulation of the MBH Adducts and Azomethine Imines (Guo, 2017)

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this is followed by a proton transfer and the regeneration of catalyst to furnish the final γ-addition product (Scheme 81). The pioneering studies of phosphine-catalyzed γ-addition to alkynes were carried out by Trost et al. in 1994.6,158 In the following year, Lu and co-workers disclosed the utilization of α-allenic esters as substrates for phosphine-promoted umpolung γ-addition.159 The first asymmetric γ-addition of dicarbonyl compounds to allenoates or alkynes was reported by Zhang and co-workers (Scheme 82).160 The reaction was effectively promoted by a cyclic bridged phosphine P1. Both alkynoates 272 and allenoates 273 were found to be suitable and various pronucleophiles 274 were employed, and the addition products 275 bearing a quaternary stereogenic center were synthesized in good yields and with moderate enantioselectivities. There was no development of phosphine-promoted asymmetric γ-additions for more than a decade, until Fu and co-workers disclosed an enantioselective cyclization of hydroxy-2-alkynoates via intramolecular γ-addition in 2009 (Scheme 83).161 Spirocyclic phosphine (S)-P18 catalyzed the intramolecular reaction of hydroxyl-containing alkynoates 276 to furnish oxygen heterocycles 277 in high enantioselectivities. The Fu group also utilized chiral phosphoramidite (S)-P11 to promote γ-addition of nitromethane to γ-substituted allenes, furnishing α,β-unsaturated carbonyl compounds with a γstereogenic center (Scheme 84).162 Notably, activated allenes with γ-substitutions were employed in this study for the creation of γ-stereocenters. Fu and co-workers then studied the employment of malonate esters in phosphine-catalyzed γaddition, for the asymmetric carbon−carbon bond formation.163 In the presence of binaphthyl-based phosphine (S)-P7, γ-addition of malonate esters 281 to various γ-substituted allenoates 280 afforded highly functionalized products 282 in good yields and excellent enantioselectivities (Scheme 85). The Fu group next examined the feasibility of using thiols as nucleophilic partners in phosphine-mediated γ-addition reaction (Scheme 86).164 It was discovered that TangPhos P27 efficiently promoted the reaction between a variety of alky/benzyl substituted thiols 284 and different γ-substituted allenoates 283, giving rise to γ-thioesters 285 with excellent enantioselectivities. However, the γ-addition of aryl thiols failed to produce γ-adducts in good yield or high ee (eq a). This problem was solved in a subsequent study carried out by the same group, in which they uncovered that binaphthylbased catalyst (S)-P9 effectively promoted the γ-addition of aryl thiols 287 to allenoates, affording a wide range of aryl alkyl sulfides 288 in good yields and excellent ee values (eq b).165 The nitrogen nucleophiles were subsequently explored by the Fu laboratory in asymmetric umpolung γ-additions to allenoates and alkynes (Scheme 87).166 The C-2 symmetric spirophosphine (S)-P18 efficiently promoted the cyclization of aminoalkynes 289 via an intramolecular γ-addition of amine to alkyne moiety, forming highly enantiomerically enriched pyrrolidines or indolines 290 (eq a). Fu and co-workers then focused on the intermolecular γ-addition of nitrogen nucleophiles to allenoates and chose trifluoroacetamide as a potential nucleophile. In the presence of (S)-P18, the reaction between trifluoroacetamide and a variety of γ-substituted allenoates 291 furnished γ-amino-α,β-unsaturated carbonyl compounds 292 in good yields and high enantioselectivities (eq b). Jacobsen and co-workers established that N-methoxy carbamates were effective reaction partners in phosphine-

reaction to deliver 1,2-nitrogen-containing heterocycles 268 in good yields and extremely high enantioselectivities (Scheme 79). Various MBH adducts 266 and azomethine imines 267 were well tolerated for the reaction, regardless of electronic properties and substitution patterns of the aryl substituents in the substrates. Very recently, the same group developed a similar [3 + 3] annulation of the MBH adducts with another type of C,Ncyclic azomethine imines (Scheme 80).157 Bridged cyclic phosphine P3 was found to be the optimal catalyst, and a catalogue of optically active quinazoline-fused heterocycles 271 was obtained in very high yields and with excellent enantioselectivities. 3.4. Summary of the Use of the MBH Adducts in Annulations

The current literature examples on the use of the MBH adducts in [3 + 2], [4 + 1], and [3 + 3] annulations were described in the previous sections. However, it should be noted that the MBH adducts are much less common substrates in phosphine-catalyzed cyclizations, compared to allenes. Not only are the cyclization modes limited but also the total number of examples employing the MBH adducts is small. How to effectively create reactive phosphonium ylides via phosphine-triggered reaction sequence poses the first challenge; specifically designed MBH adducts, other than the MBH carbonates, may offer a solution. The relative low reactivity of phosphonium ylides creates another challenging problem. Strategies to overcome this difficulty are highly desirable, which will allow the choice of different reaction partners and thus widely broaden the scope of reactions.

4. ADDITION REACTIONS 4.1. Umpolung γ-Additions to Allenoates and Alkynes

In the phosphine-catalyzed reactions of allenoates or alkynes, the initial addition of the phosphorus atom to electrondeficient multiple bonds creates the key zwitterionic intermediates, which are basic in nature. When a suitable pronucleophile is available, a process known as γ-addition reaction may take place. In a commonly accepted reaction mechanism, phosphine addition to allenoates or alkynes results in the generation of zwitterionic intermediate Int-48α or Int48γ, which deprotonates the pronucleophile to form Int-49, a reasonably active electrophile. The subsequent attack of the nucleophile anion at the γ-carbon of Int-49 yields Int-50, and Scheme 81. Mechanism of Phosphine-Catalyzed γ-Additions

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Scheme 82. First Asymmetric γ-Addition of Dicarbonyl Compounds to Allenoates or Alkynes (Zhang, 1998)

Scheme 83. Intramolecular γ-Addition of Hydroxyl Group to Alkynoates (Fu, 2009)

Scheme 84. γ-Addition of Nitromethane to γ-Substituted Allenoates (Fu, 2009)

Scheme 85. γ-Addition of Malonates to γ-Substituted Allenoates (Fu, 2010)

Scheme 86. γ-Addition of Thiols to Allenoates (Fu, 2010, 2011)

catalyzed γ-addition to propargyl esters (Scheme 88).167 In the presence of bifunctional phosphinothiourea P115, propargyl esters isomerized to the corresponding allenyl esters, and subsequent γ-addition furnished α,β-unsaturated γ-amino acid ester products 295 in good yields and excellent enantioselectivities. The hydrogen bonding interaction between the thiourea group of P115 and carbamate 294 was believed to

substantially lower the pKa value of the N−H bond, favoring the deprotonation of the carbamate. The subsequent facile nucleophilic addition from the catalyst-bound carbamate leads to the formation of the observed (S)-stereoisomers. Whereas the vast majority of reported γ-addition reactions employed γ-substituted allenes to create γ-stereogenic centers, Lu and co-workers explored the use of prochiral nucleophiles AJ


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γ-addition products were readily elaborated to known key synthetic intermediates. The amide N−H was proven to be crucial for the reaction; N-methylated catalyst P67′ led the formation of the desired product in 77% yield and 44% ee in 36 h, in comparison to 98% yield and 90% ee attainable in 15 h when P67 was employed. In their mechanistic rationale, the authors proposed that the amide N−H forms hydrogen bonds with the oxindole enolate and carbamate which directs the subsequent attack to the alkene. Zhao and co-workers also documented a similar γ-addition reaction and obtained 3,3disubstituted oxindoles with good enantioselectivities.169 The Lu group later expanded their methodology through the use of 3-fluoro-substituted oxindoles in phosphine-triggered γ-addition to allenoates, allowing quick access to biologically important chiral 3-fluoro-3-alkyl oxindole derivatives.170 The Lu group further explored other prochiral nucleophiles in phosphine-promoted γ-addition reactions and showed that 5H-thiazol-4-ones 301 and 5H-oxazol-4-ones 302 were suitable reaction partners (Scheme 90).171 Upon the optimization with amino acid-derived phosphine P76 or P95, substituted 5H-thiazol-4-ones 303 and 5H-oxazol-4-ones 304 bearing heteroatom (S or O)-containing tertiary chiral centers were constructed in high yields and with excellent enantioselectivities. The γ-addition products were readily converted to enantiomerically enriched tertiary alcohols and thioethers. The DFT calculations revealed that the observed enantioselectivity can be ascribed to a number of factors: the hydrogen bonding interaction between the sulfonamide N−H group of the catalysts and the carbonyl group of the nucleophiles; the locked conformation by hydrogen bonds and the bulky O-silyl group; the phenyl group of the thiazolone to differentiate the stereochemistry. Furthermore, structural analogues of sulfonamide P76, i.e., catalyst P76′ with a free OH and P76″ with a blockage of N−H, were also examined in the γ-additions. The resulting much reduced reactivity and enantioselectivity suggested the pivotal roles that the sulfonamide N−H and big silyl group have played in promoting the reaction and inducing asymmetry. The Fu laboratory documented phosphine-catalyzed doubly stereoconvergent γ-additions of prochiral nucleophiles to γsubstituted allenoates (Scheme 91).172 With the employment of binaphthyl-based cyclic phosphine (S)-P7, allenoates 305 with γ-alkyl substitutions reacted with 1,3-oxazol-5(4H)-ones

Scheme 87. γ-Addition of Nitrogen Nucleophiles to Allenoates or Alkynes (Fu, 2013)

Scheme 88. γ-Addition of N-Methoxy Carbamate (Jacobsen, 2014)

in phosphine-triggered γ-additions (Scheme 89).168 Treatment of 3-substituted oxindoles 297 with allenoates 296 and amino acid-derived phosphine catalyst P67 or P92 furnished a wide range of 3,3-disubstituted oxindoles 298 or 299 with an allcarbon quaternary center. The synthetic utility of the method was demonstrated in two formal total syntheses, whereby the

Scheme 89. γ-Addition of 3-Substituted Oxindoles to Allenoates (Lu, 2014)

AK


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Scheme 90. γ-Additions of 5H-Thiazol-4-ones/5H-Oxazol-4-ones to Allenoates (Lu, 2015)

Scheme 91. γ-Addition of 1,3-Oxazol-5(4H)-ones to γ-Substituted Allenoates (Fu, 2015)

Scheme 92. Regioselective γ-Addition of Oxazolones to Allenoates (Lu, 2016)

Scheme 93. γ-Addition of Alcohols to γ-Aryl-Substituted Alkynoates (Fu, 2016)

306 to furnish an array of α,α-disubstituted α-amino acid derivatives 307 with good diastereoselectivities, high yields, and excellent enantioselectivities. In comparison to previously reported γ-additions that established stereocenters either at γ or δ-positions, this report is the first example to simultaneously install two adjacent chiral centers. The authors discovered a modest kinetic resolution of racemic allenoates in the course of γ-additions, and 31P NMR studies suggested that phosphine

addition to allenoates to form zwitterionic intermediate is the turnover limiting step. Lu and co-workers recently developed phosphine-catalyzed regiodivergent enantioselective C-4- and C-2-selective γadditions of oxazolones to 2,3-butadienoates (Scheme 92).173 When 2-aryl-4-alkyloxazol-5-(4H)-ones 309 were employed, LThr-derived phosphine P76-catalyzed C-4-selective γ-addition of oxazolones took place smoothly to form adduct 310, which AL


Chemical Reviews

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Scheme 94. γ-Addition of Isatin-Derived α-(trifluoromethyl)imines to Allenoates (Shi, 2017)

Scheme 95. γ-Addition of Ketimines to Allenoates (Zhang, 2017)

provides rapid access to highly enantiomerically enriched α,αdisubstituted α-amino acid derivatives. With the utilization of 2-alkyl-4-aryloxazol-5-(4H)-ones 309, L-Thr-derived phosphine P96-catalyzed C-2-selective γ-addition of oxazolones readily occurred, leading to adduct 311, which can be readily elaborated to chiral N,O-acetals and γ-lactols. Mechanism-wise, DFT calculations suggested that distortion energy resulting from the interactions between oxazolide and phosphonium intermediate played a key role for the observed regioselectivity. When 2-aryl-substituted oxazolones are employed, the conjugation effect reduces the reactivity of the C-2 position and makes the distortion of C-2 carbon unfavorable, leading to the preferable C-4 attack. In contrast, the nonconjugated alkyl group in 2-alkyl-substituted oxazolones makes the distortion at C-2 easier, which results in lower distortion energy and accounts for the observed C-2 selectivity. The Fu group described a novel approach for the synthesis of benzylic ethers via chiral phosphine catalyzed γ-additions of alcohols to γ-aryl substituted alkynoates (Scheme 93).174 In the presence of spirocyclic phosphine (S)-P18, alcohols 313 reacted with γ-aryl-substituted alkynoates 312 and formed benzylic ethers 314 with high enantioselectivities. The γadducts may be used as the final products or serve as useful synthetic intermediates. The Shi group documented γ-additions of isatin-derived α(trifluoromethyl)imines 316 to allenoates (Scheme 94).175 Thiourea−phosphine P59 was found to be the catalyst of choice, delivering isatin-derived α-(trifluoromethyl)imine

derivatives 317 in excellent yields, yet with moderate enantioselectivities. Very recently, Zhang and co-workers developed an enantioselective γ-addition of ketimines to allenoates, in which the umpolung reactivity of ketimines was utilized (Scheme 95).176 Bifunctional phosphine catalyst P108 efficiently catalyzed the addition of trifluoromethyl-substituted ketimines 318 to allenoate 8, creating enantiomerically enriched non-natural aminoesters 319 bearing a chiral trifluomethylated tertiary stereocenter (eq a). Notably, threecomponent reactions also worked efficiently, and hydrolysis of the γ-addition products yielded optically enriched α-amino esters 321 (eq b). The authors proposed that hydrogen bonding interaction between amide N−H of the catalyst and imine plays a crucial role for asymmetric induction. Such proposal was evidenced experimentally: the employment of methylated catalyst P108’ led to decreased yield and enantioselectivity (eq c). Phosphine-catalyzed enantioselective γ-additions of allenes and alkynes have gained momentous progress, especially in the past decade. However, it is noteworthy that most of the reported examples required the utilization of pronucleophiles with strongly acidic protons. Moreover, α-or γ- nonsubstituted allenes are often the necessary reaction partners. The future trajectory of research is thereby anticipated to overcome the above limitations, which undoubtedly will render phosphinecatalyzed umpolung γ-addition reactions wider applications in organic synthesis. AM


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4.2. Allylic Substitution of the MBH Adducts

N−H of the chiral phosphine was believed to form intramolecular hydrogen bonds with the carbonyl group of 324 to stabilize intermediate A, and the subsequent endoselective Diels−Alder reaction with 2-trimethylsilyloxy furan leads to intermediate B. The Grob-type fragmentation of B, which may be assisted by water through hydrogen bonding, then takes place and forms γ-butenolide. The Shi group subsequently investigated the same reaction comprehensively, and performed theoretical calculations to understand the origin of observed stereoselectivity.181 Utilizing their BINOL-derived chiral phosphines, Shi and co-workers further explored other pronucleophiles in asymmetric allylic substitution reactions. Oxazolones 327 were found to be a suitable reaction partner. Under the catalytic action of phosphine−thiourea (R)-P54, the allylic alkylation products 328 were synthesized in good yields and with excellent enantioselectivities (Scheme 99, eq a).182 It was proposed that hydrogen bonding interactions between the thiourea group and oxazolone facilitate the Re-face attack, leading to the observed stereoselectivity. The Shi group also demonstrated that phthalimide183,184 and diphenylphosphite/ phosphane oxides185 were suitable pronucleophiles for the allylic substitution reactions of the MBH adducts, with their corresponding, highly enantioselective substitution products 330 or 332 being obtained in good yields (Scheme 99, eqs b and c). The Shi group next examined 3-substituted oxindoles 334 or benzofuranones 335 in allylic alkylation of the MBH adducts (Scheme 100).186 Through using phosphine (R)-P49, 3,3disubstituted oxindoles 336 or benzofuranones 337 were obtained in good yields, with modest diastereoselectivities and excellent enantioselectivities. The Lu group, taking advantage of phthalides for the first time in asymmetric allylic alkylation of the MBH adducts, excogitated a catalyst-controlled regiodivergent approach toward the preparation of γ- or β-selective allylic alkylation products (Scheme 101).187 L-Thr-derived thiourea−phosphine P78 effectively promoted the γ-selective substitution to provide highly optically enriched 3,3-disubstituted phthalides 340. It was proposed that the hydrogen bonding interactions between the thiourea group of P78 and the ester group of phthalide are crucial for the asymmetric induction. Moreover, it was also shown in the same study that β-adducts 340′ could be selectively synthesized via a Brønsted base-initiated addition−elimination process by employing cinchona alkaloid-derived tertiary amine catalysts. Liao and co-workers developed an efficient synthesis of optically enriched functionalized dihydroquinones through allylic alkylation of the MBH adducts with the ensuing intramolecular acylcyanation of alkenes (Scheme 102).188 Treatment of the MBH carbonates 341 with 3-cyano phthalides 342 and an amino acid-derived phosphine P79 furnished 3-allylic-3-cyano-substituted phthalides 343 in high

The nucleophilic addition of the phosphine to the MBH adduct creates phosphonium intermediates, which then reacts with nucleophiles, forming allylic substitution products. This reaction pathway is mechanistically analogous to the γ-addition of allenes/alkynes. As illustrated in Scheme 96, when a Scheme 96. Mechanism of Allylic Substitution of the MBH Adducts

phosphine catalyst adds to an MBH adduct via SN2′ process, a phosphonium intermediate Int-52 bearing an activated double bond is generated, which is electrophilic in nature. If a pronucleophile is present in the system, the in situ generated base deprotonates the pronucleophile, which then undergoes Michael addition to the phosphonium intermediate Int-52 and leads to the formation of the final allylic substitution product via another SN2′ process. The first phosphine-catalyzed allylic substitution of the MBH adducts was reported by Krische and co-workers in 2004.177 In the presence of triphenylphosphine, 2-trimethylsilyloxy furan reacted with the MBH acetates to furnish γbutenolides in good yields and excellent diastereoselectivities. The Krische group next developed a triphenylphosphinecatalyzed allylic amination of the MBH adducts with phthalimide or 4,5-dichlorophthalimide. This reaction was also investigated in an asymmetric manner, but the product was only obtained with moderate enantioselectivity.178 Shortly after Krische’s initial reports, Hou and co-workers applied planar chiral [2.2]paracyclophane monophosphine P40 in the allylic substitution of the MBH adducts 322 by phthalimide, and obtained amination products 323 with ee values up to 71% (Scheme 97).179 Based on Krische’s early report,177 Shi and co-workers developed an asymmetric variant of the allylic alkylation reaction of the MBH acetates with 2-trimethylsilyloxy furan (Scheme 98).180 With the employment of BINOL-derived multifunctional phosphine catalysts (R)-P48 and (R)-P49, γbutenolides 325 were constructed in a highly enantioselective manner via asymmetric allylic alkylation reaction. The amide

Scheme 97. Allylic Amination of the MBH Adducts with a Phthalimide (Hou, 2007)

AN


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Scheme 98. Allylic Alkylation of the MBH Adducts with 2-Trimethylsilyloxyfuran (Shi, 2008)

Scheme 99. Allylic Substitutions of the MBH Adducts with Oxazolones, Phthalimide, and Diphenyl Phosphite/Phosphane Oxide (Shi, 2011, 2012)

yields and excellent enantioselectivities. The subsequent cyanide-catalyzed intramolecular acylcyanation reaction then delivered densely functionalized dihydronaphthoquinones 344 in reasonable yields. Shortly after, the same group reported the construction of sulfur-incorporated dihydronaphthoquinones, through a sulfa-Michael addition-triggered stereoselective ringexpansion reaction of 3-allylic phthalides.189 Zhong and co-workers developed a series of ferrocene-based chiral phosphine catalysts and applied them in allylic amination of the MBH adducts with phthalimide. In the presence of P111, the substitution products 346 with moderate to excellent ee values were attainable (Scheme 103).190

Mechanistically, it was proposed that the amide N−H of catalyst P111 forms a hydrogen bond with the acrylate moiety of the MBH adduct, resulting in phthalimide attack from alkene Re-face to avoid steric hindrance and leading to the formation of the observed (S)-stereoisomer. The Wu group also investigated the allylic amination of the MBH adducts with phthalimide by using chiral thiourea−phosphine catalyst. The desired chiral amines were prepared in good yields and with moderate enantioselectivities.191 Toffano, Vo-Thanh and co-workers described the utilization of thiols as nucleophiles in allylic substitution of the MBH adducts (Scheme 104).192 In the presence of a number of AO


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Scheme 100. Allylic Alkylation of the MBH Adducts with 3-Substituted Oxindoles or Benzofuranones (Shi, 2012)

Scheme 101. Allylic Substitution of the MBH Adducts with Phthalides (Lu, 2012)

Scheme 102. Allylic Substitution of the MBH Adducts with 3-Cyano Phthalides (Liao, 2014)

Scheme 103. Allylic Amination of the MBH Adducts with Phthalimide (Zhong, 2016)

novel L-Pro-derived multifunctional catalysts, P87, P88, P89, and P90, the allylic substitution products 349 were obtained with ee values up to 92% (eq a). While the use of alkyl thiols led to the formation of allylic substitution products via an

SN2′−SN2′ pathway, aromatic thiols went through only one SN2′ reaction to yield different allylic products 351 (eq b). A novel phosphine-catalyzed umpolung addition of trifluoromethyl ketimines to the MBH adducts was disclosed by the AP


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Scheme 104. Allylic Substitution of Thiols to the MBH Adducts (Toffano, Vo-Thanh, 2016)

Scheme 105. Umpolung Addition of Trifluoromethyl Ketimines to the MBH Adducts (Zhang, 2016)

Scheme 106. Allylic Substitution of MBH Adducts with mix-Indenes (Zhang, 2017)

Zhang group (Scheme 105).193 With the employment of multifunctional phosphine catalyst P107, the allylic addition of trifluoromethyl ketimines 352 to the MBH adducts 257 led to the formation of optically enriched trifluoromethyl amines 353 bearing a tertiary stereocenter. The authors proposed that hydrogen bonding interaction between amide N−H of P107 and imine is crucial for the observed stereoselectivity, which was supported experimentally; employment of N-methylated catalyst P107′ resulted in lower chemical yield and much decreased enantioselectivity, as compared to the results obtained by applying P107. Very recently, the Zhang group developed an asymmetric allylic alkylation of the MBH adducts 354 with mix-indenes 355 to access 1,1,3-trisubstituted (trifluoromethyl)indene derivatives (Scheme 106).194 The reaction was efficiently catalyzed by sulfinamide phosphine P86, and trisubstituted indene derivatives 356 having an all-carbon quaternary stereocenter were readily obtained in high yields and with

excellent enantioselectivities. Strikingly, a mixture of both isomers of the indenes could be exploited in the reaction, delivering virtually the same results as each isolated isomer. In brief, the scope for phosphine-catalyzed enantioselective allylic substitutions of the MBH adducts remains narrow; only a limited number of C-nucleophiles or heteroatom nucleophiles with sufficient acidity were exploited. How to engage a broader scope of nucleophiles with a less stringent acidity requirement in such reactions is a promising and challenging research direction, worthy of intensive future investigations. 4.3. Michael Addition and Mannich Reaction

In 1973, White and Baizer disclosed the first phosphinecatalyzed Michael addition, in which tertiary phosphines catalyzed the addition of nitromethane to activated olefins.195 The mechanism is illustrated in Scheme 107. Phosphine addition to activated alkenes such as methyl vinyl ketone (MVK) or acrylate results in the generation of zwitterionic AQ


Chemical Reviews

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359 were readily prepared in high yields and with excellent enantioselectivities (eq a). To comprehend the reaction mechanistically, the authors compared the catalytic effects of P68 with the methylated catalyst P68′; the utilization of P68′ resulted in much slower reaction and drastically decreased enantioselectivity, indicating the importance of the amide N− H group (eq b). It was proposed that hydrogen bonding interaction facilitates the formation of a structurally defined nucleophile−phosphonium ion pair, and the blockage of the Re-face by the aromatic ring of P68 leads to the Si-face attack and forms the major (R)-stereoisomer. Zhao and co-workers developed a phosphine-catalyzed Mannich-type reaction of aldimines with malonates or nitroalkanes (Scheme 109).198 In the presence of catalytic amounts of thiourea−phosphine P57 and methyl acrylate, malonates 360 efficiently reacted with Boc-protected imines 361 in a highly enantioselective manner. Mannich products (S)-362 possessing a quaternary stereocenter were obtained (eq a). Amino acid-derived phosphine P63 in combination with methyl acrylate were also found to catalyze the addition of nitroalkanes 363 to imines, and the aza-Henry products 364 were formed in high yields and with excellent enantioselectivities (eq b). In this work, not merely aromatic imines were suitable for these Mannich-type reactions, but also aliphatic imines to be good substrates. To gain insights into the reaction mechanism, the authors performed mechanistic studies, which suggested that more than one molecule of the catalyst might be involved in the transition state. Two possible asymmetric induction models were presented. It was proposed that hydrogen bonding interactions between the thiourea group of P57 and imine/malonate are crucial for asymmetric induction. Subsequently, the same group further developed phosphine-catalyzed Mannich reactions of cyclic β-ketoesters199 and isocyanoacetates,200 securing a wide range of Mannich products bearing an all-carbon quaternary center in high yields and excellent diastereo- and enantioselectivities. Zhao and co-workers next devised a dipeptidic phosphine P103-catalyzed asymmetric cyanation of imines via phosphine−methyl acrylate dual catalysis (Scheme 110).201 They proposed that the basic zwitterionic intermediate formed upon phosphine addition to methyl acrylate serves as a Lewis base for the desilylative reaction of Me3SiCN, hence releasing the cyanate anion for a nucleophilic attack to the electrophilic imines. In the presence of catalytic amounts of P103 and methyl acrylate, the cyanation of isatin-derived imines 365 with Me3SiCN led to 3,3-disubstituted oxindoles 366 in nearly quantitative yields and excellent enantioselectivities (eq a). The employment of azomethine aldimines 367 as a cyanation partner was also explored, and products 368 with excellent enantioselectivities were attainable (eq b). Interestingly, when racemic azomethine imines 369 were used, kinetic resolution was observed. Both cyanated products 370 and the starting azomethine imines 369 could be obtained in enantiomerically enriched form (eq c). In a relevant study, the Zhao group made use of azodicarboxylates for the generation of basic zwitterionic intermediate, and developed a bifunctional phosphine-catalyzed asymmetric α-amination of 3-substituted oxindoles.202 Very recently, the Zhang group developed a phosphinecatalyzed Michael addition of β-carbonyl esters to βtrifluoromethyl enones (Scheme 111).203 In the presence of dipeptide phosphine catalyst P105, Michael addition of malonates 371 to a range of enones 372 proceeded in a

Scheme 107. Mechanism of Phosphine Catalyzed Michael Addition/Mannich Reaction

intermediate Int-54, which is basic in nature and deprotonates the pronucleophile, leading to the formation of ion pair Int-55. Michael addition of the anion to activated alkenes/imines yields Int-56, and the subsequent proton transfer furnishes the final product. A key consideration for the phosphine-catalyzed Michael addition/Mannich reaction is the generation of basic phosphonium zwitterionic intermediate Int-54; the basicity of which dictates the types of pronucleophiles that are applicable for the reaction. After White and Baizer’s original report, no progress was made in phosphine-catalyzed asymmetric Michael addition for almost four decades. In 2012, the Kwon group reported a phosphine-catalyzed asymmetric double Michael addition, although the enantioselectivity of the reaction was poor.196 The first highly enantioselective phosphine-catalyzed Michael addition was disclosed by Lu and co-workers (Scheme 108).197 Amino acid-derived bifunctional catalyst P68 or P72 successfully promoted the Michael addition of 3-substituted oxindoles to MVK, and a variety of 3,3-disubstituted oxindoles Scheme 108. Michael Addition of 3-Substituted Oxindoles to Alkenes (Lu, 2013)

AR


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Scheme 109. Mannich-Type Reaction of Malonates or Nitroalkanes (Zhao, 2015)

Scheme 110. Asymmetric Cyanation of Imines (Zhao, 2016)

highly enantioselective manner. Moreover, when prochiral βcarbonyl esters were employed, the Michael products 374 bearing two contiguous chiral centers were formed efficiently. Addition of K3PO4 enhanced the reaction rate, likely due to its role as a proton shuttle to accelerate the formation of phosphonium−nucleophile ion pair and subsequent protonation of the Michael adduct. Masking the two amide groups of the catalyst resulted in much reduced reaction rate and almost eroded the enantioselectivity completely. Hydrogen bonding interactions between two amide N−H groups of the catalyst with enones and dicarbonyl compounds were proposed to correlate the observed enantioselectivity. The first phosphine-catalyzed asymmetric Michael addition emerged only almost four decades after the initial disclosure of the racemic version of the reaction, hinting an under-

developed nature of this research area. To further empower phosphine-catalyzed Michael/Mannich reactions, future efforts may be devoted to expanding the types of suitable substrates, evolving new catalytic systems for more effective substrate activations, as well as careful designing reactions accessing synthetically useful molecular architectures.

5. RAUHUT−CURRIER REACTIONS In 1963, Rauhut and Currier disclosed a patent describing a phosphine-catalyzed dimerization of activated alkene, which became one of the milestones in organophosphine catalysis.3 Shortly after, McClure reported the first cross-coupling reaction between acrylonitrile and ethyl acrylate.204 Such phosphine-catalyzed reaction between activated alkenes leading to C−C bond formation was later widely recognized AS


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Scheme 111. Michael Addition of β-Carbonyl Esters to βTrifluoromethyl or β-Ester Enones (Zhang, 2017)

and obtained cyclized products 376 in reasonable yields with moderate enantioselectivities (Scheme 113).207 Scheme 113. Intramolecular Rauhut−Currier Reaction Catalyzed by Chiral Rhenium-Containing Phosphine (Gladysz, 2007)

Wu and co-workers disclosed the first highly enantioselective intramolecular Rauhut−Currier reaction catalyzed by chiral phosphines (Scheme 114).208 In the presence of thiourea− phosphine catalyst P61, intramolecular Rauhut−Currier reaction of bis(enone)s 377 furnished substituted cyclohexenes 378 in high yields and excellent enantioselectivities (eq a). Unsymmetrical bis(enone) 379 was also investigated as a reactant, and a mixture of two regioisomers (380 and 381) was obtained (eq b). In a following study, the Wu group employed a cyclohexane-based thiourea−phosphine for the same reaction, and Rauhut−Currier products in good yields and excellent enantioselectivities were obtained.209 Shi et al. also documented an enantioselective intramolecular Rauhut−Currier reaction of bis(enone)s catalyzed by BINOL-derived nonsymmetric phosphine (R)-P12 (Scheme 115).210 When bis(enone)s 382 were employed, cyclohexene derivatives 383 were obtained in high yields and with excellent enantioselectivities (eq a). The utilization of bis(enone)s 384 furnished cyclopentenes 385 with moderate enantioselectivities but in poor yields (eq b). The authors believed that the hydrogen bonding interactions between the phenolic O−H and enolate are critical for the Re-face attack and account for the formation of (R)-stereoisomers. The Sasai group reported a desymmetrization of prochiral dienones 386 via an enantioselective intramolecular Rauhut− Currier reaction (Scheme 116).211 L-Val-derived phosphine P81 catalyzed the formation of α-alkylidene-γ-butyrolactones 387 bearing a quaternary stereocenter in good yields and excellent enantioselectivities. When dienone containing two βmethyl substituents was used, the Rauhut−Currier product 388 was only attainable in 56% yield and with 70% ee. It was proposed that the NHTs of P81 stabilizes the phosphonium enolate intermediate, directs the subsequent Michael addition, and facilitates the proton transfer to furnish products with the observed stereoselectivity. Shortly after, the Zhang group designed a novel class of chiral sulfinamide phosphines, and applied them to the desymmetrization of cyclohexadienones 389 (Scheme 117).212 Catalyst P110 led to the formation of Rauhut− Currier reaction products 390 in good yields and excellent enantioselectivities (eq a). The authors observed an efficient kinetic resolution process when racemic substrate 391 was employed (eq b). Interestingly, when racemic 393 was subjected to the standard reaction conditions, a parallel kinetic resolution process occurred, resulting in the formation of two different chiral products 394 and 395 with excellent enantioselectivities (eq c). Transition state models (TS-1 and TS-2) were proposed to understand the observed

as the Rauhut−Currier reaction. Since the early reports in 1960s, Rauhut−Currier reactions were virtually unexplored for a few decades. Only until the recent decade has there been rapid progress on phosphine-catalyzed enantioselective Rauhut−Currier reactions. Both intramolecular and intermolecular Rauhut−Currier reactions were intensively explored, which will be discussed in detail in the following sections. Despite the recent success, phosphine-catalyzed asymmetric Rauhut− Currier reactions still suffer from limited reaction scope, and the requirement of highly activated alkenes, i.e., vinyl ketones in the reaction. Employing other activated alkenes with more structural diversity would be an interesting potential research direction. The mechanism of the Rauhut−Currier reaction is depicted in Scheme 112. Phosphine addition to activated alkene creates Scheme 112. Mechanism of Phosphine-Catalyzed Rauhut− Currier Reaction

Int-57, which undergoes Michael addition to another molecule of alkene to yield Int-58. A proton transfer then leads to Int59, while the subsequent elimination of phosphine catalyst furnishes the Rauhut−Currier product. 5.1. Intramolecular Rauhut−Currier Reactions

In 2002, the groups of Krische205 and Roush206 independently established trialkyl phosphine catalyzed intramolecular Rauhut−Currier reactions for the synthesis of five- or sixmembered rings. In an early study, Gladysz and co-workers utilized a rhenium-containing chiral phosphine P36 to catalyze the intramolecular Rauhut−Currier reaction of dienone 375 AT


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Scheme 114. Intramolecular Rauhut−Currier Reaction of Bis(enone)s (Wu, 2011)

Scheme 115. Intramolecular Rauhut−Currier Reaction of Various Bis(enone)s (Shi, 2012)

Scheme 116. Desymmetrization of Dienones via Phosphine Catalyzed Rauhut−Currier Reaction (Sasai, 2012)

Scheme 117. Desymmetrization of Cyclohexadienones via Enantioselective Intramolecular Rauhut−Currier Reactions (Zhang, 2015)

stereoselectivity in the parallel kinetic resolution. The hydrogen bonding interaction between sulfinamide N−H and enolate facilitates the formation of a stabilized and defined transition state, with the bulky TIPS group blocking the front site of the enolate. The steric repulsion between the methyl group and the TIPS makes the rate of nucleophilic attack to the methyl-substituted alkene much slower than to the nonsubstituted alkene, accounting for the occurrence of parallel kinetic resolution. Huang and co-workers later reported a similar intramolecular Rauhut−Currier reaction of cyclohexadienones, achieving the facile construction of nitrogen-containing hydro-2H-indole cores.213

The Chi group disclosed an intramolecular Rauhut−Currier reaction induced [4 + 2] annulation (Scheme 118).214 AU


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Very recently, Fan and co-workers described an amino acidderived bifunctional phosphine P83-catalyzed intramolecular Rauhut−Currier reaction of para-quinone methides (p-QMs; Scheme 120).216 Upon phosphine addition to the activated alkenes 400, the resulting enolate moiety underwent 1,6conjugate addition to the p-QM moiety, forming functionalized coumarins and quinolinones in high yields and excellent enantioselectivities. It was proposed that the hydrogen bonding interaction between carbamate N−H of P83 and enolate stabilizes the intermediate, and subsequent 1,6addition from the less hindered Re-face of the enolate to the Si-face of p-QM is favored, leading to products with the observed (S)-stereoselectivity.

Scheme 118. Intramolecular [4 + 2] Annulation Induced by Rauhut−Currier Reaction (Chi, 2012)

5.2. Intermolecular Rauhut−Currier Reactions

In comparison with the well-developed intramolecular Rauhut−Currier reaction, the intermolecular counterpart was investigated to a lesser extent mainly due to the difficulty in controlling reaction selectivity. The first asymmetric intermolecular Rauhut−Currier reaction was reported by Loh and Zhong when they described a [4 + 2] annulation initiated by an aza-Rauhut−Currier reaction (Scheme 121).217 With the amino acid-derived phosphine P75, vinyl ketones 402 reacted with 1-aza-1,3-dienes 403 to form six-membered heterocycles 404 in good yields, high diastereoselectivities, and excellent enantioselectivities. In the proposed transition state, the hydrogen bonding interaction between the pivaloyl amide and the 1,3-diene facilitates the Si-face attack of the enolate, accouting for the observed stereoselectivity. Shortly thereafter, the Wu group explored the same reaction by using cyclohexanediamine-based chiral phosphine catalysts.218 Very recently, Zhang and co-workers developed a similar [4 + 2] annulation of β-fluoroalkylated-α,β-unsaturated imines with vinyl ketones, to access enantiomerically enriched trifluoromethylated tetrahydropyridines.219 An enantioselective [4 + 2] annulation of vinyl ketones 405 with isatin-derived α,β-unsaturated imines 406 induced by an intermolecular Rauhut−Currier reaction was disclosed by Shi and co-workers (Scheme 122).220 Amino acid-derived thiourea−phosphine P80 efficiently promoted the annulation, furnishing 4-N-piperidine spirooxindoles 407 in good yields, with high diastereoselectivities and excellent enantioselectivities. It was proposed that hydrogen bonding interactions between thiourea and sulfonamide direct the alkene side chain outward to minimize the steric repulsions, allowing the favored Si-face attack. In a follow-up study, the Shi group further investigated the same reaction, attaining enhanced enantioselectivities.221

Through capitalizing on L-Val-derived phosphine P81, an intramolecular Rauhut−Currier reaction of substrate 396 took place, which was followed by ring closure to furnish bicyclic products 397 in good yields and excellent diastereo- and enantio-selectivities. The authors proposed that the hydrogen bonding interaction between sulfonamide N−H and imine facilitates the Re-face attack from enolate to α,β-unsaturated imines; the subsequent SN2 substitution of nitrogen anion offers the final annulation product and regenerates the phosphine catalyst. Grossman and Spring developed an intramolecular Rauhut− Currier reaction of chalcone-derived substrates 398 (Scheme 119).215 In the presence of dipeptidic phosphine P101, αScheme 119. Intramolecular Rauhut−Currier Reaction of Chalcones (Grossmann and Spring, 2015)

methylene-δ-valerolactones 399 were readily prepared in high yields and with moderate to excellent enantioselectivities. The proposed catalytic cycle follows the common mechanism for the Rauhut−Currier reaction. The authors’ preliminary mechanistic studies suggested that the intramolecular Michael addition is the rate-determining step.

Scheme 120. Intramolecular Rauhut−Currier Reaction of p-QMs (Fan, 2017)

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Scheme 121. Intermolecular Rauhut−Currier Reaction-Induced [4 + 2] Annulation of Vinyl Ketones and α,β-Unsaturated Imines (Zhong, 2012)

Scheme 122. Intermolecular Rauhut−Currier Reaction Induced [4 + 2] Annulation of Vinyl Ketones and Isatin-Derived α,βUnsaturated Imines (Shi, 2013)

The first asymmetric intermolecular cross Rauhut−Currier reaction was reported by Huang and co-workers (Scheme 123).222 With the utilization of amino acid-derived phosphine

Shortly thereafter, Zhang and co-workers designed novel chiral sulfinamide bisphosphine catalysts and successfully applied them to the intermolecular cross-Rauhut−Currier reactions (Scheme 124).223 Bisphosphine P109 efficiently catalyzed the reaction between vinyl ketones 411 and a range of enones 412 to furnish multicarbonyl products 413 in high yields and excellent enantioselectivities (eq a). The reaction

Scheme 123. Intermolecular Cross Rauhut−Currier Reaction of 3-Aroyl Acrylates and Vinyl Ketones (Huang, 2015)

Scheme 124. Intermolecular Cross Rauhut−Currier Reaction of Enones and Vinyl Ketones (Zhang, 2015)

P66, the Rauhut−Currier reaction between 3-aroyl acrylates 409 and vinyl ketones 408 furnished desired adducts 410 in very high yields and excellent enantioselectivities. In the proposed transition state, both phenolic hydroxyl group and amide N−H in the catalyst form hydrogen bonds with enolate, which dictates the attack from the Re-face, accounting for the observed stereoselectivity. AW


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Scheme 125. Cross-Vinylogous Rauhut−Currier Reaction of Vinyl Ketones with para-Quinone Methides (Zhang, Wu, 2017)

Scheme 126. Cross Rauhut−Currier of Viny Ketones with para-Quinone Methides Derived from Isatins (Zhao, 2017)

mechanism was probed by 31P NMR experiments. It was discovered that, when phosphine catalyst was mixed with MVK, two new resonances (P3 and P4) appeared, which were distinctive from the initial resonances (P1 and P2) corresponding to the phosphine catalyst, indicating the formation of phosphonium enolate zwitterionic intermediate (eq b). The authors proposed that the more nucleophilic phosphorus adds to vinyl ketones, while the other less nucleophilic phosphine moiety may play a dual roleexerting steric hindrance and acting as a Lewis base to enhance the hydrogen bond donating ability of the sulfonamide group. Subsequently, the same group further extended chiral phosphine catalyzed cross Rauhut− Currier reaction by exploring reactions between activated alkenes and acrolein.224 The Zhang group later showed that βperfluoroalkyl enones were suitable reaction partners for the cross Rauhut−Currier reaction with vinyl ketones, and gained access to enantiomerically enriched perfluoroalkyl-substituted molecules.225 Another finding by the Zhang group was the development of cross vinylogous Rauhut−Currier reaction between alkyl vinyl ketones 414 and para-quinone methides 415 (Scheme 125, eq a).226 Phosphine−amide P85 efficiently promoted the reaction, and structurally diverse diarylmethines were readily prepared in good yields and with excellent enantioselectivities. DFT calculations were performed to gain insights into the reaction mechanism. The most favored transition state suggested that the hydrogen bonding interaction between amide N−H and enolate assists the Re-face attack, leading to the formation of (R)-stereoisomer. Coincidentally, Wu and coworkers reported a very similar Rauhut−Currier reaction between methyl vinyl ketone and para-quinone methides 417 at virtually the same time (Scheme 125, eq b).227 In the

mechanistic proposal, the two Brønsted acid moieties of the catalyst were believed to interact with the enolate derived from MVK and the carbonyl group of p-QM through hydrogen bonding, attributing to the observed enantioselectivity. Very recently, Zhao and co-workers reported a cross Rauhut−Currier of viny ketones 402 with para-quinone methides 419 derived from isatins for the construction of 3,3-disubstituted oxindoles with a quaternary stereogenic center (Scheme 126).228 Amino acid-derived phosphine P58 effectively promoted the reaction, and a variety of 3,3disubstituted oxindoles 420 were obtained in good yields and with excellent enantioselectivities.

6. MORITA−BAYLIS−HILLMAN REACTIONS Being one of the earliest reported phosphine-catalyzed reactions, the Morita−Baylis−Hillman (MBH) reaction and its aza counterpart (aza-MBH reaction) are effective synthetic tools for the construction of carbon−carbon bonds. The development of enantioselective (aza)-MBH reactions flourished in the 2000s, but most of the reports involved chiral amine catalysts. Chiral phosphines, on the other hand, received much less attention. The mechanism of phosphine-catalyzed (aza)-MBH reaction is illustrated in Scheme 127. Phosphine attacks the activated alkene to produce zwitterionic intermediate Int-60, which then adds on to aldehydes/imines to yield adduct Int-61. A proton transfer takes place to form Int62, and the subsequent elimination of phosphine catalyst furnishes the final (aza)-MBH product. AX


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reaction of N-sulfonated imines with acrylates (Scheme 129).235 L-Thr-derived P77 efficiently promoted the reaction between imines 427 and 2-naphthyl acrylate 428, furnishing the aza-MBH adducts 429 in high yields and excellent enantioselectivities (eq a). To shed light on the reaction mechanism, the catalytic effects of different phosphine catalysts were examined. Methylated catalyst P77′ resulted in slower reaction and drastically decreased enantioselectivity, suggesting the importance of the sulfonamide N−H group. Notably, catalyst P82 containing N-trifluoromethanesulfonamide led to very poor results. The reason behind this may be due to the overstabilization of the enolate intermediate. Lu and Huang subsequently performed DFT calculations to elucidate the origin of enantioselectivity of the above aza-MBH reaction.236 It was found that the intramolecular hydrogen bonding interaction between the sulfonamide N−H and the oxygen atom of the enolate is of crucial importance in maintaining the structural rigidity of the phosphonium−enolate intermediate. The bulky thexyldimethylsilyl (TDS) group from the catalyst, together with the naphthyl ester group from the acrylate, directs the approach of the imine substrate, leading to the observed stereoselectivity. Lu and co-workers next reported an enantioselective MBH reaction of acrylates with aldehydes, promoted by L-Thrderived phosphine−thiourea catalysts.237 Shortly after, the He group developed new BINOL-derived bifunctional phosphines and applied them to the (aza)-MBH reaction of imines/ aldehydes with acrylates; however, only modest enantioselectivities were attainable.238 Recently, Veselý and co-workers prepared thiourea−phosphine catalysts derived from D-glucose and amino acids and demonstrated their effectiveness in promoting enantioselective MBH reaction between aromatic aldehydes and acrylates.239 Very recently, the Pfaltz group developed a mass spectrometric back-reaction screening protocol for catalyst evaluation, which successfully identified an efficient bifunctional chiral phosphine for the MBH reaction of aldehydes with acrylates.240 Sasai and co-workers designed a unique spiro-type multifunctional phosphine catalyst P121, which was shown to effectively catalyze enantioselective aza-MBH reaction of Ntosylimines 430 with vinyl ketones 402 (Scheme 130).241 The newly developed phosphine P121 was found to be superior to the known BINOL-derived catalyst (R)-P50, which may be

Scheme 127. Mechanism of (aza)-Morita−Baylis−Hillman Reaction

6.1. Intermolecular (aza)-Morita−Baylis−Hillman Reactions

In 2003, Shi and co-workers disclosed their preliminary findings on chiral phosphine-catalyzed aza-MBH reaction of N-sulfonated imines and MVK or phenyl acrylate, obtaining the MBH adducts in good yields and with moderate to high enantioselectivities.229 Shortly after, the Shi group published a detailed study of the same reaction (Scheme 128).230 Treatment of aryl aldimines 421 with vinyl ketones/acrolein 422 and BINOL-derived bifunctional phosphine (R)-P50 furnished adducts (S)-423 in high yields and good enantioselectivities (eq a). Acrylates 425 could also be utilized, although only moderate enantioselectivities were attainable (eq b). To account for the observed stereoselectivity, it was proposed that the hydrogen bonding interaction between phenolic OH of the catalyst and nitrogen anion facilitates the formation of relatively stable diastereomeric intermediates. The Shi group subsequently developed another type of BINOL-derived catalysts bearing perfluoroalkanes as “pony tails”, which efficiently catalyzed the aza-MBH reaction of Nsulfonated imines with methyl vinyl ketones.231 Shortly thereafter, the groups of Shi, Sasai, and Ito reported similar enantioselective aza-MBH reactions of N-sulfonated imines with MVK, employing structurally analogous BINOL-derived multifunctional phosphine catalysts.232−234 The Lu laboratory designed a series of amino acid-derived bifunctional phosphines and applied them to the aza-MBH

Scheme 128. Aza-MBH Reaction of N-Sulfonated Imines with Activated Olefins (Shi, 2005)

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Scheme 129. Aza-MBH Reaction of N-Sulfonated Imines and Acrylates (Lu, 2011)

Scheme 130. Aza-MBH Reaction of N-Tosylimines and Vinyl Ketones Catalyzed by Spiro-Type Multifunctional Phosphine (Sasai, 2011)

was employed, the aza-MBH product was obtained in quantitative yield and with 90% ee (eq b). Around the same time, Shi and Li applied a BINOL-derived phosphine to asymmetric aza-MBH reaction of isatin-derived ketimines with MVK, allowing for facile synthesis of enantiomerically enriched 3-substituted-3-amino-oxindoles.248 A catalytic enantioselective aza-MBH reaction of acrylates 440 with isatin-derived ketimine was reported by Wu and coworkers (Scheme 133).249 Notably, in the presence of only 2 mol % of bifunctional phosphine−squaramide P118, 3substituted-3-amino-2-oxindoles 441 were obtained in excellent yields and with high enantioselectivities. In the proposed transition state, the hydrogen bonding interactions between squaramide N−H and the nitrogen and oxygen atoms of the ketimines facilitate the enolate attack from the Si-face, forming the major product with an (S)-configuration. Shi and co-workers developed an enantioselective aza-MBH reaction between indole-derived sulfonyl imines 442 and bis(3chlorophenyl)methyl acrylate 443, catalyzed by thioureaphosphine P59 (Scheme 134).250 The functionalized indole derivatives 444 were obtained in good yields and with high enantioselectivities. Further manipulations of the MBH adducts using ring-closing-metathesis (RCM) as a key step rendered polycyclic dihydropyrido[1,2-a]indole scaffolds. The Shi group later established a one-pot enantioselective synthesis of isoquinolines from alkynyl imines 446 and vinyl ketones 402 by merging chiral phosphine and gold catalysis (Scheme 135).251 Through the formation of aza-MBH reaction intermediates, as well as the subsequent relay catalysis, dihydroisoquinoline derivatives 447 were prepared in high yields and with excellent enantioselectivities.

attributed to the more rigid spiro scaffold of the former. In related studies, the groups of Š tĕpnička and Kitagaki synthesized a series of ferrocene-based phosphines and planar chiral bifunctional phosphines, respectively, and evaluated their catalytic effects in the aza-MBH reactions of imines and vinyl ketones.242,243 Wu and co-workers described an asymmetric MBH reaction of isatins with acrylates, catalyzed by cyclohexanediaminederived bifunctional phosphine catalysts.244 In a follow-up study, the same group prepared a series of novel phosphine− squaramides and found catalyst P117 efficiently promoted the MBH reaction of isatin derivatives 432 and acrylates 433 (Scheme 131).245 Recently, Zhou and co-workers contrived a series of tunable phosphine−squaramide catalysts, whose efficiencies were demonstrated in enantioselective MBH reaction of isatins with acrylates.246 Sasai and co-workers discovered that P-chiral phosphines were efficient catalysts in promoting aza-MBH reaction of vinyl ketones with α-ester ketimines (Scheme 132).247 In the presence of P122 or P123, addition of vinyl ketones 402 to αester ketimines 435 proceeded smoothly, delivering aza-MBH adducts 436 in high yields and moderate to excellent enantioselectivities (eq a). When isatin-derived ketimine 437

Scheme 131. MBH Reaction of Isatins and Acrylates (Wu, 2012)

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Scheme 132. Aza-MBH Reaction of Vinyl Ketones with Ketimines (Sasai, 2013)

Scheme 133. Aza-MBH Reaction of Acrylates with Isatin-Derived Ketimines (Wu, 2014)

Scheme 134. Aza-MBH Reaction of Indole-Derived Sulfonyl Imines and Acrylate (Shi, 2015)

6.2. Intramolecular (aza)-Morita−Baylis−Hillman Reactions

formyl-α,β-unsaturated carbonyl compounds 452 and obtained cyclohexene derivatives 453 in good yields and ee values up to 84% (Scheme 137).253 The Wu group later enhanced the results of the same reaction by employing phosphine− squaramide catalyst P119 (Scheme 138).254 More recently, Wu and co-workers further enhanced the above intramolecular MBH reaction by using mannose-based thiourea−phosphines.255 Chen and co-workers studied the intramolecular MBH reaction of dicarbonyl compound 454 by using a ferrocenebased phosphine−squaramide P112 (Scheme 139).256 Good yields and high enantioselectivities were attainable for a wide range of substrates, except for substrates bearing 2-Br and 2-Cl on the aryl ring. It was proposed that hydrogen bond between

In a pioneering study carried out by Fráter and co-workers in early 1990s, (+)-CAMP was utilized to promote asymmetric intramolecular MBH reaction of the α,β-unsaturated-ε-keto ester, and the cyclization product with 14% ee was obtained.252 Thereafter, no progress was made until 2007 when Gladysz and co-workers reported chiral rhenium-containing phosphine P36-catalyzed intramolecular MBH reactions (Scheme 136).207 With the employment of different dicarbonyl compounds 448 or 450, enantiomerically enriched cyclopentenes 449 or cyclohexenes 451 were attainable. Wu and co-workers applied amino acid derived thiourea− phosphine P58 to the intramolecular MBH reaction of ωBA


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Scheme 135. One-Pot Enantioselective Relay Catalysis of Chiral Phosphine and Gold Catalysts (Shi, 2016)

Scheme 136. Intramolecular MBH Reaction Catalyzed by Rhenium-Containing Phosphine (Gladysz, 2007)

Scheme 139. Intramolecular MBH Reaction Catalyzed by Ferrocene-Based Phosphine−Squaramide (Chen and Jiang, 2014)

Scheme 137. Thiourea−Phosphine-Promoted Intramolecular MBH Reaction (Wu, 2010)

Scheme 140. Intramolecular MBH Reaction of β-Mono and β,β-Disubstituted Enones (Ramasastry, 2016)

Scheme 138. Phosphine−Squaramide-Promoted Intramolecular MBH Reaction (Wu, 2011)

squaramide N−H and oxygen atom of aldehyde facilitates the enolate attack from the Si-face (TS-A). When substrates bearing ortho-substitutions are used, the squaramide N−H preferentially forms hydrogen bonds with the enolate oxygen and ortho-halogen atom, resulting in poor enantioselectivity (TS-B). Very recently, Ramasastry et al. reported an intramolecular MBH reaction of enones promoted by cyclohexanediaminederived thiourea−phosphine P114 (Scheme 140).257 When βmonosubstituted enones 456 were employed, the MBH products with good E/Z ratios and high enantioselectivities were formed in excellent yields (eq a). Here, it should be noted that sterically demanding β,β-disubstituted enones 456′ were also found to be suitable substrates, and the corresponding

cyclopenta[b]annulated arenes and heteroarenes were obtained in high yields and with good enantioselectivities (eq b).

7. OTHER REACTIONS 7.1. [2 + 2] Annulation of Ketenes

Ketenes are highly electron-deficient, which makes them suitable substrates for phosphine-triggered reactions. A general mechanism of phosphine-catalyzed [2 + 2] annulation of ketenes is illustrated in Scheme 141. Nucleophilic attack of phosphine to ketene generates zwitterionic intermediate Int63, which readily reacts with electrophilic reaction partners, such as aldehyde, imine, or another molecule of ketene. The resulting adducts, Int-64 or Int-65, then undergo cyclization to BB


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The Vedejs group subsequently synthesized a series of novel bicyclic phosphines and examined their catalytic effects in acylation of secondary alcohols with anhydrides.262 Bicyclic phosphine P30 or P31 efficiently catalyzed the acylation of alcohol 471 with isopropyl anhydride, furnishing acylated products 472 with high enantioselectivities, while (S)-471 were recovered with up to 95.3% ee (Scheme 145, eq a). To circumvent problems encountered previously in the catalyst preparation, Vedejs and co-workers prepared P-aryl-2phosphabicyclo[3.3.0]octane-type phosphines via enantioselective synthesis starting from lactate esters and applied them to kinetic resolutions of secondary alcohols.263 Through the screening of different anhydrides, it was discovered that P30 functioned as an efficient catalyst for the kinetic resolution of aryl alkyl carbinols 471′ by benzoylation (Scheme 145, eq b). On the other hand, the use of catalyst P31 with more bulky aryl substitution on phosphorus atom significantly enhanced the selectivity of the acylation, thus suitable for kinetic resolutions of less hindered aryl alkyl carbinols by isobutyroylation (Scheme 145, eq c). In related studies, Vedejs and co-workers prepared a range of monocyclic and bicyclic phosphines and carried out in-depth studies of their catalytic effects in the kinetic resolution of alcohols.264−266 Woerpel and co-workers reported an interesting reductive kinetic resolution of hydroperoxide mediated by chiral phosphines.267 In the presence of stoichiometric amount of phosphine P39, kinetic resolution of hydroperoxide 473 yielded enantioenriched hydroperoxide (R)-473 and the reduced chiral alcohols 474 (Scheme 146).

Scheme 141. Mechanism of [2 + 2] Annulation of Ketenes

furnish the final four-membered ring structures and regenerate phosphine catalyst at the same time. In 2009, Kerrigan and co-workers disclosed a trialkylphosphine-catalyzed homodimerization of ketenes.258 The same group subsequently established an asymmetric version using Josiphos as the catalyst and obtained highly substituted ketoketene dimer β-lactones (S)-459 in good yields and excellent enantioselectivities (Scheme 142).259 In the proposed enantioselection model, Josiphos blocks the Si-face of the enolate and makes the Re-face relatively open for the key nucleophilic attack to take place. The Kerrigan group next explored the [2 + 2] annulations of ketenes with aldehydes 461 and N-sulfonyl imines 430 (Scheme 143).260,261 In the presence of bisphosphine P15, a variety of highly diastereoselective β-lactones 462 and βlactams 464 bearing an all-carbon quaternary center were obtained in good yields and with moderate to excellent enantioselectivities.

7.3. Miscellaneous Reactions

Sasai and co-workers discovered a domino reaction between activated alkenes 475 and N-tosylimines 476 (Scheme 147).268 In the presence of BINOL-derived bifunctional phosphine (S)P50, an aza-MBH/intramolecular aza-Michael domino process furnished 1,3-disubstituted isoindolines 477 in high yields and with ee values up to 93%. The Shi group documented a three-component asymmetric formal [4 + 2] tandem annulation of isatin-derived dicyano alkenes 478 with arylpenta-1,4-dien-3-one 479 (Scheme 148).269 When BINOL-derived bifunctional phosphine (R)P52 was employed, a Rauhut−Currier/Michael/Rauhut− Currier reaction sequence engendered the formation of spirocyclic oxindoles 480 in high yields and excellent enantioseletivities. Allenes are important molecules in organic chemistry; therefore, developing efficient asymmetric synthetic methods to access chiral allenes is an interesting topic. In 2014, Shi and co-workers discovered that racemic mono- or multisubstituted allenoates could be readily prepared via a triphenylphosphinecatalyzed reaction of cyclopropenones with water/methanol.270 The same group subsequently performed a thorough

7.2. Kinetic Resolution of Alcohols

Kinetic resolution of alcohols is a powerful approach to accessing enantiomerically enriched alcohols from racemic mixtures. The most common approach for kinetic resolution is through acylation, and tertiary amine catalysts are often used. Owing to their high nucleophilicity, phosphines certainly represent another interesting class of catalysts for kinetic resolution processes. In 1996, the Vedejs group disclosed the first phosphine-catalyzed enantioselective acylation of alcohols (Scheme 144).7 In the presence of cyclic phosphine P28, desymmetrization of diols 465 produced acetylated products with moderate enantioselectivities. Benzoylation of mesohydrobenzoin 467 also proceeded smoothly with the use of P28. Furthermore, alcohol 469 was acylated to yield product 470 with 81% ee at 25% conversion. Scheme 142. Homodimerization of Ketenes (Kerrigan, 2010)

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Scheme 143. [2 + 2] Annulations of Ketenes with Aldehydes and Imines (Kerrigan, 2010, 2012)

Scheme 144. Acylation of Secondary Alcohols via Phosphine-Catalyzed Kinetic Resolution (Vedejs, 1996)

Scheme 146. Kinetic Resolution of Hydroperoxides (Woerpel, 2007)

investigation and developed an asymmetric variant to access enantiomerically enriched allenoates (Scheme 149).271 In the presence of amino acid-derived bifunctional phosphine P62, the reaction between cyclopropenones 481 and a range of alcohols delivered trisubstituted chiral allenoates 483 in good yields and moderate enantioselectivities. The mechanistic proposal starts from the phosphine addition to cyclopropenone

to form phosphonium anion Int-66, the ring of which is then opened to afford Int-67. The subsequent alcohol attack at the ketene and the expelling of the OAc group then generate Int68. The product allenic ester is formed upon regeneration of phosphine. A unique asymmetric [4 + 2] annulation employing cyclobutenenone as a new type of 1,4-dipole C4 synthon was recently disclosed by Zhang and co-workers (Scheme 150).272 With the use of amino acid-derived phosphine−thiourea catalyst P58, an intermolecular 1,4-diploar spiroannulation between cyclobutenone 484 and isatin-derived activated alkenes 485 took place to deliver 3-spirocyclohexenone 2oxindoles 486 in excellent yields and good enantioselectivities. In the mechanistic rationale, the authors reasoned that the hydrogen bonding interactions between thiourea N−H of the catalyst and the carbonyl group of the isatin are crucial for

Scheme 145. Acylation of Secondary Alcohols with Bicyclic Phosphines (Vedejs, 1999)

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Scheme 147. Domino aza-MBH/Intramolecular aza-Michael Reaction of Activated Olefins with N-Tosylimines (Sasai, 2010)

diastereoselective bicyclic products 489 in moderate yields and excellent enantioselectivities. Huang et al. developed a phosphine-catalyzed sequential [2 + 3]/[3 + 2] annulations between γ-benzyl-substituted allenoates 490 and cyclic ketimines 491 (Scheme 152).274 Amino acid-derived bifunctional phosphine P84 led to the formation of polycyclic products 492 in good yields and excellent enantioselectivities. The key to this unique reaction pattern is the generation of aryl-stabilized anion intermediate Int-76, derived from phosphonium zwitterionic intermediate Int-75 via a proton transfer process. The δ-addition of Int-76 to ketimine then generates Int-77. The subsequent proton shift, followed by a Michael addition, forms Int-80; another aza-Michael takes place, and the final proton shift then furnishes the polycyclic products, regenerating the phosphine catalyst. In a related study, the Shi group also made use of the unique reactivity of the δ-benzyl substituted allenoates. They reported an atypical [3 + 2] annulation between such allenoates and azomethine imines, in which the δ,γ-C−C bond of the allenoates participated in the annulation and served as a C2 component.275 Very recently, Shi and co-workers developed276 a phosphinemediated dimerization of conjugated ene-yne ketones 493 (Scheme 153). In the presence of a stoichiometric amount of bisphosphine (S)-P35’, the reaction proceeded via a 1,6addition/cyclization/Michael addition/Wittig reaction cas-

Scheme 148. Three-Component Formal [4 + 2] Annulation (Shi and Wei, 2014)

asymmetric induction. This novel reaction mode is originated from the 1,2-nucleophilic addition of phosphine to cyclobutenone to form zwitterionic intermediate Int-69, which undergoes 4π ring-opening to yield the key 1,4-dipolar intermediate Int-70. The subsequent Michael addition to activated alkene then gives Int-72, and intramolecular cyclization affords the spirocyclic oxindole product. Sasai and co-workers established a phosphine catalyzed enantioselective β,γ-umpolung domino reaction of allenoates leading to desymmetrization of prochiral dienones (Scheme 151).273 In the presence of spirocyclic phosphine (R)-P18, γaddition of dienone 488 to allenoates furnished the intermediate Int-74. Subsequently, an intramolecular Michael addition took place, leading to the formation of highly

Scheme 149. Lewis Base-Catalyzed Synthesis of Allenic Esters from Cyclopropenones (Shi, 2015)

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Scheme 150. [4 + 2] Annulation Utilizing Cyclobutenone (Zhang, 2015)

Scheme 151. β,γ-Umpolung Domino Reaction of Allenoates (Sasai, 2015)

cade, affording dihydrobenzofurans 494 in reasonable yields and good enantioselectivities.

On the catalyst development frontier, more nucleophilic phosphines with sufficient stability are to be developed. This is particularly pressing should one aim for practical large-scale production of optically enriched molecules. In essence, efficient activations and better stereochemical controls are the key to the development of asymmetric variants of many known racemic processes promoted by phosphines. Welldesigned and judiciously employed chiral phosphines could provide a viable solution. Currently, allenes have gained the ascendancy over the substrate menu in most known phosphine-catalyzed reactions. We foresee that multifaceted applications of alkynes, the MBH adducts, activated alkenes, and other novel suitable reaction partners in asymmetric phosphine catalysis are the next strides, which may entail the emergence of novel catalysts, the discovery of new modes of activation, and the invention of currently unknown mechanistic pathways. In short, the scope

8. SUMMARY AND PERSPECTIVE Even though the first report of asymmetric phosphine catalysis appeared in late 1990s, it was only in the past decade that we have witnessed tremendous advancement of this vibrant research field. The recent upsurge can be attributed to the development of numerous powerful chiral phosphine catalysts, the establishment of new modes of phosphine activations, as well as the design of novel asymmetric catalytic processes that make full use of new catalytic systems via unprecedented mechanistic pathways. In order to move the promising field to a greater height, many long-standing challenges are to be addressed. Here we attempt to offer our own opinions on some future directions. BF


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Scheme 152. Sequential Annulation of Allenoates and Ketimines (Huang, 2016)

AUTHOR INFORMATION

Scheme 153. Phosphine-Mediated Dimerization of Conjugated Ene-Yne Ketones (Shi, 2017)

Corresponding Author

*E-mail: [email protected]. ORCID

Yixin Lu: 0000-0002-5730-166X Notes

The authors declare no competing financial interest. Biographies Huanzhen Ni was born in 1992 in Anhui province, China. She received her B.Sc. (Hons) degree from National University of Singapore (NUS) in 2014 and then continued her Ph.D. studies under the supervision of Prof Yixin Lu at NUS as an NGS Scholar. Her research interests include the design and development of novel chiral phosphine catalysts and their application to organic synthesis. Wai-Lun Chan was born in Hong Kong SAR, China. He received his B.Sc. (Hons.) in Chemistry (2014) and M.A. in Communication (2015) from Hong Kong Baptist University (HKBU). He worked as a research assistant in Prof. Ka-Leung Wong’s group (HKBU), concentrating on luminescent lanthanide−organic materials for biomedical and photonic applications. He is now pursuing his Ph.D. in Organic Chemistry under the supervision of Prof. Yixin Lu in NUS, applying novel chiral phosphine catalysts to asymmetric natural product synthesis.

of asymmetric phosphine-catalyzed reactions needs to be broadened. The significance of exploring new asymmetric processes to the continuous advancement of this active and dynamic research area cannot be overstated. Despite the immense number of reports on synthetic methodologies based on phosphine catalysis, the real demonstrations of phosphine catalysis in natural product synthesis and for the preparation of biologically important molecules in pharmaceutical industry are still very limited. The evolution of asymmetric phosphine-based catalytic methods into the practical/novel synthesis of complex molecules is expected to catch up in the future.

Yixin Lu was born in China. He studied chemistry and received his B.Sc. from Fudan University and then obtained his Ph.D. from McGill University, Montreal, Canada, under the supervision of the late Professor George Just in 2000. He was a postdoctoral fellow working with Professor Peter W. Schiller at the Clinical Research Institute of Montreal and subsequently joined Professor Ryoji Noyori’s group at Nagoya University as an RCMS fellow. In September 2003, He started his independent career at NUS where he is now a professor. He is the recipient of a number of awards, including Singapore National Research Foundation (NRF) Investigatorship Award BG


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Thr = threonine TIPS = triisopropysilyl TMS = trimethylsilyl TS = transition state Ts = para-toluenesulfonyl PMB = para-methoxybenzyl PMP = para-methoxyphenyl PNB = para-nitrobenzoate o-QM = ortho-quinone methide Rr = regioisomeric ratio Val = valine

(2018); Asian Core Program (ACP) Lectureship awards to China, Japan, Korea, and Taiwan (2009−2016); Young/Outstanding Scientist Award from Faculty of Science, NUS (2009, 2013); GSK−SNIC Award in Organic Chemistry (2013); and Dean’s Chair Professorship (2013). He is an Editorial Advisory Board Member for Accounts of Chemical Research, and Editorial Board Member for Asian Journal of Organic Chemistry. His key research interest is asymmetric catalysis and synthesis, and his group is particularly interested in practical enantioselective processes promoted by amino acid-derived organic catalysts.

ACKNOWLEDGMENTS Y.L. thanks the Singapore National Research Foundation (NRF) (NRF Investigatorship Grant: R-143-000-A15-281), the National University of Singapore (R-143-000-695-114 and C-141-000-092-001), and the National Natural Science Foundation of China (21672158) for generous financial support.

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ABBREVIATIONS Ac = acetyl Alloc = allyloxycarbonyl Ar = aryl Bn = benzyl Boc = tert-butoxycarbonyl Bu = n-butyl s-Bu = sec-butyl t-Bu = tert-butyl Bz = benzoyl BINOL = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (+)-CAMP = (R)-(+)-cyclohexyl(2-anisyl)methyl-phosphine Cbz = carboxybenzyl CPME = cyclopentyl methyl ether Cy = cyclohexyl DFT = density functional theory DPP = diphenylphosphinoyl Et = ethyl EWG = electron-withdrawing group Hex = hexyl HFIP = hexafluoroisopropanol Leu = leucine LG = leaving group Me = methyl MOM = methoxymethyl MS = molecular sieve MVK = methyl vinyl ketone NMP = N-methyl-2-pyrrolidone Ns = para-nitrophenylsulphonyl Nu = nucleophile Ph = phenyl Phe = phenylalanine PMB = para-methoxybenzyl Pr = propyl i-Pr = isopropyl TBACN = tetrabutylammonium cyanide TBDPS = tert-butyldiphenylsilyl TBME = tert-butyl methyl ether TBS = tert-butyldimethylsilyl TDS = thexyldimethylsilyl Tf = triflyl THF = tetrahydrofuran BH


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