Chinese Chemical Letters  2017, Vol. 28 Issue (3): 493-502   PDF    
Phosphine-mediated enantioselective synthesis of carbocycles and heterocycles
Yu-Ning Gao, Min Shi     
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Abstract: Nucleophilic chiral phosphine catalysis has been prosperous in asymmetric synthesis over the past two decades. Various tunable chiral phosphines display excellent activity and selectivity in asymmetric transformations including acycloaddition reactions and cycloaddition reactions. Enantiomerically enriched cyclic compounds are ubiquitous in natural products and drug molecules. These phosphinecatalyzed reactions provide effective and extensive strategies for the synthesis of a series of complex cyclic compounds as well as the synthesis of chiral compounds which could be easily transformed to carbocycles and heterocycles. This minireview summarizes recent developments in this area and highlights meaningful breakthroughs.
Key words: Bifunctional phosphines     Asymmetric catalysis     Carbocycles     Heterocycles     Cycloaddition reactions    
1. Introduction

Developing new methods for chemo-, regio-, diastereo-and enantioselective carbon-carbon bond formation have always been significant in organic synthesis [1]. Catalytic asymmetric transformations have provided powerful means to construct carbon-carbon bond, carbon-hetero bond and further enantiomerically pure compounds [2]. Therefore design and synthesis of different effective chiral catalysts for new reactions have been pursued by chemists thus far.

Organocatalysis has been prosperous in the past decade due to the superiority of being environmentally friendly, easy to prepare and working in mild reaction conditions [3]. Brønsted acid, Brønsted base, Lewis acid and Lewis base are most frequently used organocatalysts. Trivalent phosphines, as significant Lewis base catalysts, usually show distinctive catalytic behaviors mainly because of stronger nucleophilicity and weaker basicity compared to amine catalysts [4]. Relying on the non-bonded electron pairs, trivalent phosphine catalysts attack electron-deficient π system (alkene, alkyne and allene) to form ylide type zwitterionic intermediates, which interact with various electrophile or pronuclephile to furnish the whole reaction [5].

Phosphine-triggered acycloaddition reactions can be dated back to 1960s when the Rauhut-Currier reaction [6] and the Morita-Baylis-Hillman (MBH) reaction [7] were found. The two reactions have been intensively studied up to nowadays, which reflect their significance in organic synthesis. Next, umpolung addition and isomerization of alkyne [8], and SN'2-SN'2 substitution of MBH adduct derivatives [9] as well as many other types of acycloaddition reactions mediated by phosphines were developed. Phosphine-promoted cycloaddition reactions started from [3 + 2] annulation between allene and electron-deficient alkene were then reported by Zhang and Lu [10]. Subsequently, diverse annulation modes including [3 + 3], [3 + 4], [3 + 6], [4 + 1], [4 + 2], [2 + 2] and some other types of cycloaddition reactions were explored.

Though phosphine-triggered reactions have been investigated extensively in recent years, quite a few of them were not achieved in asymmetric version. The first application of chiral phosphine catalysis can be dated back to 1996 when Vedejs et al. utilized chiral tertiary phosphines for enantioselective acylation of secondary alcohols [11]. Thus, design and synthesis of new chiral phosphine catalysts aimed at different reactions are still an enormous challenge in organic synthesis. Chiral phosphine catalysts can be divided into two types: chiral phosphines without other functionality and multifunctional chiral phosphines. The former type of phosphines rely on their steric hindrance effect when interact with substrates to achieve enantioselective synthesis. Besides steric hindrance, other effects such as hydrogen bonding interaction also play important roles in the reaction catalyzed by multifunctional chiral phosphines. By exploring different new synthetic method, chemists can regulate the nucleophilicity of phosphines, the effect of various functional groups and the number of chiral centers in multifunctional chiral phosphines [12].

The nucleophilicity of phosphines can be tuned by employing different substituted phosphines from trialkylphosphines to triarylphosphines. Changing the substituents of phosphorus center could alter both steric and electronic properties of phosphines more elaborately. The introduction of other functional groups provides various steric hindrance interaction and hydrogen bonding interaction with substrates. In the next section, we will introduce the recent achievements with regard to asymmetric phosphine catalysis in the enantioselective synthesis of carbocycles and heterocycles.

2. (aza)-Morita-Baylis-Hillman and Rauhut-Currier reactions 2.1. Chiral phosphine-catalyzed (aza)-Morita-Baylis-Hillman reactions

The first MBH reaction was reported in 1972 on the reaction of acetaldehyde and ethyl acrylate (or acrylonitrile) catalyzed by 1, 4-diazabicyclo[2.2.2]octane (DABCO). Since then, a lot of MBH reactions were reported including their asymmetric version [13]. Though excellent enantioselectivities were achieved in some catalytic asymmetric MBH reactions, specialized Michael acceptors were usually required. We did a series of work to solve this problem by designing efficient chiral phosphine catalysts in asymmetric MBH reaction using simple substrates such as methyl vinyl ketone (MVK) or methyl acrylate [14]. According to our understanding and previous studies on MBH reaction, we introduced multifunctional chiral phosphine catalyst CP1 containing a hydroxyl group as Brønsted acid moiety (Scheme 1). We believed that the intermediate A generated by nucleophilic attack of CP1 to MVK could be stabilized by the hydrogen-bonding interaction between hydroxyl group and enolate moiety (Scheme 2). Next, the intermediate attacks the other substrate such as tosylated imine along with the elimination of the catalyst to form the product. The phenolic hydroxyl group working as a Brønsted acid moiety is essential for the excellent asymmetric induction in this transformation. Comprehensively considering our studies, we first introduced the concept of bifunctional organocatalysis into the field of phosphine catalysis. According to this strategy, we have designed various Lewis base Brønsted acid catalysts including thiourea-phosphine, amide-phosphine, urea-phosphine, hydroxyl-phosphine and applied them to asymmetric reactions [15].

Scheme 1. Asymmetric aza-MBH reactions catalyzed by bifunctional chiral phosphine catalyst CP1.

Scheme 2. A plausible mechanism of aza-MBH reaction catalyzed by CP1.

In 2010, Takizawa et al. designed a series of N-sulfonated imines 4 containing electron-deficient olefin moiety and applied (S)-CP1 in the reaction of 4 with MVK to furnish a cascade reaction, giving 1, 3-disubstituted isoindoline derivatives 5 (Scheme 3) [16]. This transformation experienced an aza-MBH process to form a nitrogen anionic intermediate, which reacted with the electrondeficient olefin moiety through aza-Michael addition to accomplish the cascade process. In this crucial aza-MBH process, bifunctional phosphine catalyst (S)-CP1 displayed excellent enantioselectivity.

Scheme 3. (S)-CP1-catalyzed domino process based on the aza-MBH reaction.

In recent years, we focused our attention on the application of asymmetric MBH reaction depending on the densely functionalized MBH adducts. In 2015, we synthesized allyl and propargyl protected 2-indolyl sulfonated imines 6, and applied them to the aza-MBH reaction with electron-deficient olefins 2. Further transformations were conducted to construct a series of polycyclic indole derivatives (Scheme 4) [17]. In the initial aza-MBH reaction, we found amino acid-derived bifunctional chiral phosphine catalyst CP2 was the best choice. However, through screening different electron-deficient olefins, we got the best result in the presence of 2a and CP2 perhaps due to the best match between benzhydryl-thiourea group and bis (3-chlorophenyl) methyl group. Next, allyl protected MBH adduct 7 were transformed to dihydropyrido[1, 2-a]indole derivatives using ring-closing-metathesis (RCM) strategy. The dihydropyrido[1, 2-a] indole was further used to construct polycyclic indole 8 through the following manipulations including RCM strategy again. As for propargyl protected compound 7, gold catalysis strategy was used to synthesize 9. Likewise, a few other steps were used again to obtain indole derivatives 10 and 11.

Scheme 4. Aza-MBH reaction catalyzed by amino acid-derived chiral phosphine CP2 and its application.

In 2016, our group developed a relay catalysis by merging chiral phosphine and gold catalysis to give enantiomerically enriched dihydroisoquinoline derivatives (Scheme 5) [18]. The corresponding products could be achieved by using a sequence of aza-MBH reaction and hydroamination under gold catalysis. In this asymmetric aza-MBH reaction, bifunctional chiral phosphine catalyst CP3 derived from an axially chiral binaphthyl scaffold was found to be effective. Hydroxyl group also played a key role in the control of hydrogen-bonding interaction. Modification of substituents on phosphorus center for better suitable for different reaction systems is a meaningful work. The electronic property, steric hindrance and amount of substituents on benzene rings could influence the enantioselectivity ranging from 85% to 97% ee values. In this reaction, chiral phosphine CP3, bearing a methoxy group on the 4-position of benzene ring gave the best result.

Scheme 5. Relay catalysis for synthesis of dihydroisoquinolines based on aza-MBH reaction.

In most MBH reactions, the β-position of electron-deficient olefins are unsubstituted because sterically highly demanding β, β-disubstituted enones are difficult to be activated under phosphine catalysis. Satpathi and Ramasastry have developed an intramolecular MBH reaction of 14 to solve this problem (Scheme 6) [19]. PMe3, with high nucleophilicity and small steric hindrance, promoted the reaction under mild conditions within a short time in good yields. The asymmetric version of this reaction was also investigated and enantiomerically enriched cyclopenta[b] annulated arenes and heteroarenes were obtained. Amino acidderived bifunctional chiral phosphine catalyst CP4 was the most effective one and the use of 1, 1, 1, 3, 3, 3-hexafluoroisopropanol (HFIP) displayed unique solvent effect in this reaction.

Scheme 6. Intramolecular MBH reaction of substituted enones.

2.2. Chiral phosphine-catalyzed Rauhut-Currier reactions

In 2012, we reported an asymmetric intramolecular RC reaction to construct enantiomerically enriched cyclopentene and cyclohexene derivatives (Scheme 7) [20]. As mentioned before, the existence of a substituent at β-position of Michael acceptor increased the difficulty on the initiation of reaction due to steric hindrance. Most multifunctional chiral phosphine derived from binaphthyl scaffold was not suitable for this kind of substrates. A highly nucleophilic chiral phosphine CP5 was developed and successfully applied in this reaction. The phenol group in CP5 also displayed crucial hydrogen-bonding interaction with substrates because dimethylated chiral phosphine CP6 showed no enantioselectivity in this reaction.

Scheme 7. Intramolecular RC reaction catalyzed by highly nucleophilic chiral phosphine CP5.

Chiral β-aminophosphines, as an important kind of chiral phosphines, which have been usually prepared from natural or unnatural chiral amino acids, have displayed extensive applications in asymmetric phosphine catalysis [21]. In 2015, Zhang et al. developed a new kind of chiral sulfinamide phosphines (XiaoPhos). The Xiao-Phos series, bearing hydrogen bonding site, two chiral stereocenters and nucleophilic phosphine, were synthesized from chiral sulfonamide. This kind of chiral phosphines (R, Rs)-CP7 or (S, Rs)-CP7 efficiently promoted the intramolecular RC reaction, leading to a-methylene-g-butyrolactones 21 in high yields (76%-95% yield) and excellent enantioselectivities (81%-99% ee) under mild conditions (Scheme 8) [22]. The hydrogen-bonding effect offered by amino-group and steric hindrance offered by sulfinyl group and silyl moiety played key roles in the enantioselective process. In recent years, Takizawa et al. [23] and Scanes et al. [24] also reported different intramolecular RC reactions for enantioselective synthesis of g-butyrolactone derivatives and chromanone derivatives.

Scheme 8. Intramolecular RC reaction for the enantioselective synthesis of butyrolactones.

3. Phosphine-catalyzed cycloaddition reactions 3.1. Chiral phosphine-catalyzed [3 + 2] cycloaddition reactions

In 1995, Lu's group developed the first phosphine catalyzed [3 + 2] cycloaddition reaction between buta-2, 3-dienoates and electron-deficient olefins. Since then, [3 + 2] annulations have been widely used for construction of five-membered carbocycles and heterocycles. In 1997, Zhu et al. developed asymmetric version of [3 + 2] cycloaddition reaction using chiral bridged-ring monophosphine catalyst [25]. The groups of Lee et al. [26], Voituriez et al. [27], Zhao et al. [28], Xiao et al. [29] etc. developed different kind of chiral phosphine catalysts and applied them in [3 + 2] annulations. Subsequently, [3 + 2] cycloaddition reactions between Morita-Baylis-Hillman carbonates and electron-deficient olefins were also developed [30].

In 2011, our group reported a [3 + 2] annulation between MBH carbonates and isatylidene malononitriles [31]. PPh3 or 1, 4-bis (diphenylphosphino) butane (dppb) promoted this reaction very well, giving the desired products in good yields. Next, we successfully applied our multifunctional chiral thiourea phosphine CP8 derived from an axially chiral binaphthyl scaffold in this reaction (Scheme 9). The corresponding spirocyclopenteneoxindole 24 was obtained in 92% yield (isolated major product), 9:1 dr and 74% ee value.

Scheme 9. Enantioselective [3 + 2] cycloaddition reaction of isatylidene malononitriles and MBH carbonates.

In 2012, we reported a catalytic enantioselective [3 + 2] cycloaddition between Morita-Baylis-Hillman carbonates withtrifluoroethylidenemalonates [32]. The desired cyclopentenes with two tertiary stereogenic centers containing trifluoromethyl group were acquired in good yields (57%->99% yield) and excellent enantioselectivities (80%-96% ee) in the presence of 10 mol% amino-acid-derived bifunctional chiral phosphine CP2 (Scheme 10).

Scheme 10. Enantioselective [3 + 2] cycloaddition reaction of trifluoroethylidenemalonates and MBH carbonates.

In the same year, we reported an asymmetric [3 + 2] cycloaddition between MBH carbonates and maleimides (Scheme 11). We found that chiral phosphine CP2 was still the most effective one in this transformation, giving functionalized cyclopentene derivatives bearing three contiguous stereocenters in moderate to excellent yields (39->99%) along with excellent enantioselectivities (73%-98% ee) [33]. Through investigating this reaction with 31P NMR spectroscopy, we found that 28, as electron deficient olefins, could also react with CP2 to form the corresponding zwitterionic intermediates. However, this intermediate was not beneficial to form the final products. Increasing the ratio of 28 and 25 is a good choice and therefore, we adopted the ratio of 2:1 because a large amount of 28 would consume the phosphine catalyst CP2.

Scheme 11. Enantioselective [3 + 2] cycloaddition reaction of maleimides and MBH carbonates.

In 2012, we reported a chiral phosphine mediated [3 + 2] cycloaddition of alkylidene azlactones and allenoates (Scheme 12) [34]. This reaction offered an effective way to construct adjacent spiro-quaternary and tertiary stereocenters. Chiral monophosphine (CP9), promoted the cycloaddition regio-, diastereo-and enantioselectively, giving the g-attack spirocyclic products in good yields, excellent diastereoselectivities and enantioselectivities. Besides, we demonstrated the synthetic utility of this reaction by transforming the products to a amino acid derivatives 34 and 35 under simple conditions.

Scheme 12. Enantioselective [3 + 2] cycloaddition reaction of alkylidene azlactones and allenoates.

4, 4-Dicyano-2-methylenebut-3-enoates, a kind of conjugated dienes, are significant synthons in organic transformation. Our group first applied them to asymmetric annulations mediated by chiral phosphine. In 2013, we reported phosphine-catalyzed [3 + 2] cycloaddition of allenoates with 4, 4-dicyano-2-methylenebut-3-enoates (Scheme 13) [35]. (4-FC6H4)3P promoted this reaction very well, affording the highly functionalized cyclopentenes bearing one all-carbon quaternary stereogenic center in moderate to good yields (42%-87%). Our multifunctional chiral thiourea-phosphines derived from axially chiral binaphthol were also effective in the asymmetric version of this reaction. Through introducing sterically hindered phenanthryl to thiourea-phosphines, sterically hindered chiral phosphine CP10 was synthesized and applied in this reaction, giving the chiral products 37' in 56%-63% ee values.

Scheme 13. [3 + 2] cycloaddition reaction of 4, 4-dicyano-2-methylenebut-3-enoates with allenoates.

Phosphine-mediated asymmetric reactions displayed significant application in the synthesis of natural products and bioactive molecules [36]. In 2014, Henry et al. developed two diastereoisomeric 2-aza-5-phosphabicyclo[2.2.1]heptanes from naturally occurring trans-4-hydroxy-L-proline and used them in asymmetric [3 + 2] cycloaddition reaction of γ-substituted allenoates with imines, giving the corresponding pyrroline products in good yields and excellent enantioselectivities [37]. In 2016, Cai et al. further modified this kind of chiral phosphine catalyst and synthesized catalyst CP11 and applied it in asymmetric [3 + 2] annulation between indole-derived imine 38 and allenoate 39 to construction pyrroline framework (Scheme 14) [38]. Key intermediate 40 could be obtained in 99% yield and 94% ee under mild conditions. The catalytic asymmetric total synthesis of (-)-actinophyllic acid was finished in only 8 steps on the basis of 40. Other groups also reported a series of excellent [3 + 2] cycloaddition reactions in recent years [39], affording powerful methods for various cyclopentene and pyrroline derivatives.

Scheme 14. Catalytic asymmetric total synthesis of (-)-actinophyllic acid based on enantioselective [3 + 2] cycloaddition reaction.

3.2. Chiral phosphine-catalyzed [4 + 2] cycloaddition reactions

In 2003, the first phosphine-mediated [4 + 2] cycloaddition reaction of α-substituted allenoates and imines was achieved by Zhu et al. [40]. Next, the asymmetric version of this kind of reaction was reported by Wurz and Fu [41]. Besides imines, alkenes, working as common electrophiles, were also introduced in [4 + 2] cycloaddition reaction by Tran and Kwon [42]. Later, the groups of Xiao et al. [43], Zhong et al. [44] etc. reported asymmetric [4 + 2] cycloaddition reaction based on allenoates. Our group has also developed other type of [4 + 2] annulations initiated by electrondeficient olefins.

In 2013, we reported the first synthesis of isatin-based spirofused tetrahydropyridine derivatives by a chiral phosphine catalyzed [4 + 2] cycloaddition reaction (Scheme 15). The reactionwent through an aza-RC process between vinyl ketones and oxindole-derived α, β-unsaturated imines. When 4-toluenesulfonyl imides 42 were used as substrates, chiral phosphine CP12 was the best catalyst, giving the desired products 43 in good yields (44%-87%), moderate diastereoselectivities (2.3:1-8.3:1 dr) and enantioselectivities (17%-99% ee) [45]. 2, 4, 6-Triisopropylphenylsulfonyl imides 44 were synthesized and applied in this reaction in order to ameliorate the diastereoselectivities [46]. Notably, amino acid-derived chiral phosphine CP13 containing two 2, 4, 6-triisopropylphenyl steric bulky groups promoted this reaction to the best extent. Therefore, compared to substrates 42, the steric bulky group in the oxindole-derived imines 44 played a key role in diastereoselectivities and enantioselectivies. An impactful steric effect of asymmetric catalysis was displayed in this transformation.

Scheme 15. Enantioselective [4 + 2] cycloaddition reaction of oxindole-derived α, β-unsaturated imines and vinyl ketones.

In the same year, we reported a formal [4 + 2] tandem cyclization between isatylidenemalononitriles and 1, 4-dien-3-ones catalyzed by chiral hydroxyl-phosphine CP14 (Scheme 16) [47]. 1, 4-Dien-3-ones, which combines the properties of chalcone and methyl vinyl ketone due to a potentially nucleophilic carbon-carbon double bonds and an electronically poor carbon-carbon double bond, were selected as C-4 synthons. This tandem reaction included Rauhut-Currier/Michael/Rauhut-Currier sequence. The phenolic hydroxyl group in CP14 was essential because other type of chiral phosphine catalysts only led to trace products. Meanwhile, methoxy groups at the 3, 5-positions of the benzene ring of CP14 offered the most suitable electronic effect and steric effect. Cycloaddition products 48 were obtained in good yields, good diastereoselectivities and excellent enantioselectivies.

Scheme 16. Enantioselective [4 + 2] cycloaddition reaction of isatylidenemalononitriles and 1, 4-dien-3-ones.

In 2014, Yao et al. reported a [4 + 2] annulation of α-substituted allene ketones and b, g-unsaturated a-keto esters (Scheme 17) [48]. Allenes were usually served as C-4 synthons in most phosphine-mediated [4 + 2] annulation. However, the ester group increased activity of carbonyl group in substrate 50. Thus allene ketones 49 worked as C2 synthons and β, γ-unsaturated α-keto esters 50 worked as C4 synthons in this novel [4 + 2] annulation. The L-threonine-derived bifunctional chiral phosphine CP15 which contains multiple chiral centers and large steric hindrance promoted this reaction effectively, giving enantiomerically enriched 3, 4-dihydropyrans 51 in good yields and excellent enantioselectivities.

Scheme 17. Enantioselective [4 + 2] cycloaddition reaction of allene ketones and α, γ-unsaturated α-keto esters.

Besides, Zhao, Zhang, Guo et al. reported other interesting enantioselective [4 + 2] cycloaddition reactions, giving the desired cycloadducts in good yields and high ee values [49]. In these reactions, enantiomerically enriched cyclohexene derivatives and pyran derivatives were readily obtained through these novel transformations.

3.3. Chiral phosphine-catalyzed [4 + 1] cycloaddition reactions

Morita-Baylis-Hillman (MBH) adducts have been used in cycloaddition reactions after Lu's pioneering work on the intermolecular [3 + 2] annulation [50]. In this reaction, MBH carbonates served as 1, 3-dipoles with activated alkenes catalyzed by a trivalent phosphine. MBH carbonates can also serve as C-1 synthons in phosphine-mediated reactions. In 2010, Chen and Zhang have developed a [4 + 1] annulation between enones and MBH carbonates [51]. Subsequently, Xie et al. [52] and Tian et al. [53] reported other type of [4 + 1] annulations using MBH carbonates as C-1 synthons.

In 2012, we developed the first asymmetric [4 + 1] annulation using MBH carbonates and dicyano-2-methylenebut-3-enoates, which gave the functionalized cyclopentene derivatives 54 containing one all-carbon quaternary stereogenic center [54]. Sterically hindered chiral thiourea-phosphine CP16 derived from binaphthol was synthesized and used in this transformation, giving the desired products in good yields and excellent enantioselectivities (Scheme 18).

Scheme 18. Enantioselective [4 + 1] cycloaddition reaction of dicyano-2-methylenebut-3-enoates and MBH carbonates.

Subsequently, we have developed another asymmetric [4 + 1] annulation between isatin-derived α, β-unsaturated ketones 55 and MBH carbonates 56. Oxindole spiro-fused dihydrofuran derivatives containing two adjacent quaternary stereocenters were obtained under mild conditions [55]. Sterically hindered chiral thiourea-phosphine CP17 derived from binaphthol was found to be the most effective catalyst to give the desired products 57 in high yields (51%-98%), moderate dr values (1:1-4:1) and excellent ee values (81%-98%) (Scheme 19).

Scheme 19. Enantioselective [4 + 1] cycloaddition reaction of isatin-derived α, β-unsaturated ketones and MBH carbonate.

In 2015, we also reported a [4 + 1] annulation between MBH carbonates and oxindole-derived α, β-unsaturated imines [56]. MBH carbonate 59, served as 1, 1-dipolar synthons, were employed to construct oxindole spiro-fused dihydropyrrole derivatives in this transformation. PPh2Me smoothly promoted this reaction and gave the desired products in 54%-95% yields and 4:1-20:1 dr. In an attempt to realizing asymmetric version of this reaction, we tested a lot of chiral phosphine catalysts and found that phenylglycine-derived dipeptide phosphine CP18, which contains two chiral centers, was the best catalyst, affording the desired product 60 in 78% yield and 7:1 dr and 61% ee as the major diastereomeric isomer (Scheme 20).

Scheme 20. [4 + 1] cycloaddition reaction of MBH carbonates and oxindole-derived α, β-unsaturated imines.

Besides MBH carbonates, allenoates were also involved in phosphine-mediated [4 + 1] cycloaddition reactions working as C-4 synthons. In 2010, Zhang et al. reported a [4 + 1] annulation between dinucleophiles and allenoates containing a leaving group at β0 position [57]. Asymmetric version of this kind of reaction was reported by Ziegler et al. [58] and Han et al. [59]. In 2015, Kramer and Fu reported this kind of [4 + 1] cycloaddition reaction between γ-substituted allenoates 61 and nitrogen dinucleophiles such as primary amines 62 (Scheme 21) [60]. In this type of reaction, the application of γ-substituted allenes is a challenging issue because of the possibility of isomerization to 1, 3-dienes. On the basis of their previous work, they modified spirocyclic-phosphine CP10 by adding methyl groups at the ortho-position of phosphine center leading to new catalyst CP20 with two more chiral centers. Different γ-substituted allenoates and sulfonamide were tested and dihydropyrroles 63 were obtained with 67%-95% yields and 83%-92% ee (Scheme 21).

Scheme 21. [4 + 1] cycloaddition reaction of g-substituted allenoates and nitrogen dinucleophiles.

Other types of chiral phosphine-mediated cycloaddition reactions have been developed such as [3 + 3] annulations and [4 + 3] annulations [61], affording new methods for the synthesis of N-containing heterocyclic compounds [62].

4. Conclusions

As demonstrated before, the development of chiral phosphine catalysis has seen significant progress in the past two decades. Chemists can easily design and synthesize powerful chiral phosphine catalysts and apply them in various asymmetric reactions. These reactions include a series of cycloaddition and acycloaddition reactions such as MBH reaction, RC reaction, umpolung addition reaction and substitution reaction etc. However, the preparation of cycloadducts with phosphine catalysis is the most attractive aspect in this field. The cycloaddition reactions have been applied in the synthesis of carbocycles and heterocycles. Acycloaddition reaction products have also been extensively used in the synthesis of cyclic compounds through further transformations. Despite the great progress, there are many unsatisfactory results in phosphine-mediated asymmetric synthesis. In the future, expanding the scope of phosphine-catalyzed reactions and exploring new modes of phosphine catalysis are still highly desirable. Meanwhile, design and exploitation of novel chiral phosphine catalysts that are suitable for these asymmetric reactions will be another significant task.


We are grateful for the financial support from the National Basic Research Program of China (973 Project, No. 2015CB856603), and the National Natural Science Foundation of China (Nos. 20472096, 21372241, 21361140350, 20672127, 21421091, 21372250, 21121062, 21302203, 20732008 and 21572052).

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