Nucleophilic Chiral Phosphines: Powerful and Versatile Catalysts for Asymmetric Annulations

Abstract

Recent advances in chiral-phosphine-catalyzed asymmetric annulation reactions; including annulations of allenes, alkynes, Morita–Baylis–Hillman (MBH) carbonates, and ketenes; and their applications in the synthesis of bioactive molecules and natural products are reviewed.

1. Introduction

A wide variety of nucleophilic phosphine-catalyzed annulation reactions have been established as reliable and powerful tools for the synthesis of carbo- and heterocycles from simple starting materials.¹ Asymmetric variants, including [2 + 2], [3 + 2], [3 + 3], [4 + 1], and [4 + 2] annulations, have also been achieved,¹ and demonstrated in dozens of applications in organic synthesis.^2,3 A few phosphine-catalyzed annulations serve as key steps in the total synthesis of several bioactive natural products such as (+)-ibophyllidine, hirsutine, ricciocarpin-A, hirsutene, alstonerine, and macroline.² In addition, a variety of novel heterocyclic compounds have also been synthesized using phosphinecatalyzed [3 + 2] and [4 + 2] annulations as important reaction steps. Some of these compounds show diverse bioactivities and potential as drug candidates (Figure 1).³

Figure 1.

Examples of Bioactive Compounds Synthesized with Phosphine-Catalyzed Annulations as Key Reaction Steps. (Ref. 3a,f)

Typically, the catalytic cycle is initiated by addition of the Lewis basic phosphine to the electrophilic center of the allene, MBH carbonate, alkyne, or alkene, leading to the formation of a zwitterionic intermediate.¹ The zwitterionic intermediate reacts with a variety of electrophilic reagents, resulting in a number of phosphine-catalyzed annulation reactions (Scheme 1). It is worth noting that the phosphonium intermediates from 1-acetoxy-2,3-butadiene act as 1,4-bis-electrophilic acceptors of nucleophilic reagents. Moreover, in the past three decades, hundreds of chiral phosphines have been designed and prepared for use in asymmetric catalysis, and most were utilized as chiral ligands of metal catalysts. Normally, all chiral tertiary phosphines could be employed as chiral catalysts for nucleophilic phosphine catalysis. However, most chiral phosphines that were originally designed as ligands for metal-catalyzed reactions are triarylphosphines which are weak nucleophiles. Furthermore, these phosphines are acyclic and without a rigid structure, and thus result in poor stereoselectivity in nucleophilic organocatalytic reactions. Therefore, only a very limited number of commercially available chiral phosphines could be used in asymmetric nucleophilic phosphine catalysis. In most of the chiral-phosphine-catalyzed asymmetric annulation reactions, cyclic and multifunctional chiral phosphines displayed better catalytic activity and stereoselectivity than acyclic chiral phosphines. Consequently, the design and synthesis of cyclic and multifunctional chiral phosphines have become a key target in the development of phosphine-catalyzed asymmetric reactions. Such chiral phosphines, developed in the past decade and exhibiting excellent catalytic activity in annulation reactions, are shown in Figures 2 and 3. Some of these chiral phosphines such as A1–A5, C2–C4, C16–C18 and M6 are commercially available.

Scheme 1.

Principal Modes of Nucleophilic Phosphine Catalysis.

Figure 2.

Chiral Phosphines Exhibiting Excellent Activity in Asymmetric Nucleophilic Phosphine Catalysis.

Figure 3.

Additional Chiral Phosphines Exhibiting Excellent Activity in Asymmetric Nucleophilic Phosphine Catalysis.

Herein, the applications of chiral phosphines in asymmetric organocatalytic annulation reactions will be highlighted according to the type of annulation reaction and phosphine acceptor. The application of chiral phosphines in other types of reaction such as allylic substitution, Michael addition, γ-umpolung addition, and acylation of alcohols, will not be included in this review.

2. Asymmetric [3 + 2] Annulations of Allenes

2.1. With Alkenes

The chiral-phosphine-catalyzed, asymmetric [3 + 2] annulation of allenoates with electron-deficient alkenes to form cyclopentenes is the most studied annulation reaction in the area of nucleophilic phosphine organocatalysis, and it provides important chiral five-membered-ring carbocycles commonly found in natural and unnatural bioactive molecules.¹ In 1995, Lu reported the first achiral phosphine-catalyzed [3 + 2] annulation of allenoates with electron-deficient alkenes.⁴ Following this pioneering contribution, Zhang and co-workers achieved the first asymmetric [3 + 2] annulation of allenes with electron-deficient alkenes by employing rigid, bicyclic chiral phosphines as catalysts. The reactions employing C1 worked efficiently under mild conditions to give chiral cyclopentene derivatives in 75–92% yields and 69–93% ee’s (eq 1).⁵ This exciting work did not, however, generate sufficient interest in chiral-phosphine-catalyzed asymmetric reactions, especially ones catalyzed by chiral cyclic phosphines, and was overlooked for nearly ten years.

Almost a decade later, Wilson and Fu disclosed the next successful example of nucleophilic-phosphine-catalyzed asymmetric annulation.⁶ Chiral cyclic phosphine C9, which incorporates a rigid binaphthyl skeleton, catalyzed the enantioselective [3 + 2] annulation of ethyl allenoate with various α,β-unsaturated enones, affording highly functionalized cyclopentenes wth two contiguous stereocenters (eq 2).⁶ In particular, C9 promoted the reaction with a trisubstituted enone to form a spirocyclic compound bearing adjacent quaternary and tertiary stereocenters in 97% yield and 89% ee. In contrast, acyclic chiral phosphine (S,S)-DIOP (A1) catalyzed the asymmetric [3 + 2] annulation of allenic ketones with a diverse array of exocyclic enones, affording the spirocyclic compounds with only moderate enantioselectivities (≤ 77% ee).⁷

eq 1 (Ref. 5)

Using 3-butynoates instead of allenoates as substrates, the commercially available acyclic, chiral catalyst (R,R)-DIPAMP (A3) catalyzed the asymmetric [3 + 2] annulation with various α,β-unsaturated enones, providing highly functionalized cyclopentenes in 66–95% yield and with 81–99% ee.⁸ Control experiments revealed that under phosphine catalysis conditions, 3-butynoate initially isomerizes to the allenoate, which subsequently undergoes the [3 + 2] annulation with the enones. Compared with Fu’s catalytic system,⁶ this system, featuring a tandem isomerization–annulation, led to better yields and ee’s. Especially interesting is the observation that this acyclic chiral catalyst, not the cyclic ones, was the best catalyst for this annulation.

Employing C12, Fujiwara and Fu achieved the asymmetric [3 + 2] annulation between a wide array of γ-substituted racemic allenes and hetroatom-substituted olefins, affording functionalized cyclopentenes with adjacent quaternary and tertiary stereocenters in satisfactory yields and with good regio- (rr = 8:1 to 50:1) and stereoselectivities (up to 98% ee) (eq 3).⁹ The catalytic system is quite versatile and compatible with various nitrogen-, phosphorus-, oxygen-, and sulfur-substituted olefins. Notably, diverse allenamides also worked well in this reaction. The authors proposed that the chiral microenvironment of C12 was amplified by its 3,3’-diphenyl substituents.

The intramolecular, enantioselective [3 + 2] annulation of various allenes, tethered with electron-deficient alkenes, was also accomplished by Fu’s group by utilizing chiral tertiary phosphines C10–C13 as catalysts. The reaction afforded bicyclic compounds with three contiguous tertiary stereocenters in good yields (56–95%) and with moderate-to-high enantioselectivities (86–98% ee).¹⁰ This method could be applied to different classes of trisubstituted olefins containing a variety of linkers between the allene and the alkene functional groups, to afford the desired products with a quaternary stereocenter. Using this protocol, many useful scaffolds—widely found in bioactive compounds, including fused pyrrolidine, benzannulated diquinane, and quinolin-2-one derivatives—were generated in very good yields and ee’s.

eq 2 (Ref. 6)

eq 3 (Ref. 9)

Besides the above-mentioned examples, a variety of activated alkenes including 2-aryl-1,1-dicyanoalkenes,^11a methyleneindolinones,^11b 4-substituted 2,6-diarylidenecyclohexanones,^11c 2,4-diarylidenebicyclo[3.1.0]hexan-3-ones,^11c olefinic azlactones,^11d [60]fullerene,^11e and 4,4-dicyano-2-methylenebut-3-enoates,^11f underwent asymmetric [3 + 2] annulation with allenes to give the corresponding cyclopentene derivatives. Interestingly, in the presence of chiral phosphine (S,S)-f-Binaphane C16, [60]fullerene underwent [3 + 2] annulation with allenoates under mild conditions, giving rise to enantiomerically pure carbocyclic fullerene derivatives in remarkably high ee’s (eq 4).^11e

Once the excellent catalytic capability of chiral cyclic phosphines was recognized, the design and synthesis of cyclic chiral phosphines with novel skeletons became one of most important research topics in the area of nucleophilic phosphine catalysis. Marinetti and co-workers have developed a new class of very interesting, planar chiral ferrocene-derived phosphines (e.g., C7), that possess beneficial properties such as good air-stability, ease of handling, and decent nucleophilicity.¹² These chiral phosphines displayed very broad substrate scope and could be applied in asymmetric [3 + 2] annulations of various activated alkenes—such as methyleneindolinones,^11b 4-substituted 2,6-diarylidenecyclohexanones,^11c 2,4-diarylidenebicyclo[3.1.0]hexan-3-ones,^11c fumarate esters,^12a,12b α,β-unsaturated ketones,^12a–12c exocyclic enones,^{12a–12c,12e} 2-oxo-2H-chromene-3-carboxylates^12d and 3-(2-nitrophenyl)-acrylate^12d—leading to a variety of functionalized cyclopentenes, cyclopentenylphosphonates, spirooxindoles, cyclopentene-fused chromanones, dihydroquinolinones and heterocyclic spiranes with high ee’s.

eq 4 (Ref. 11e)

eq 5 (Ref. 13)

eq 6 (Ref. 15)

More recently, Marinetti’s group designed and synthesized C8, a new helically chiral phosphine, and successfully employed it for the enantioselective [3 + 2] annulation between a wide range of γ-substituted allenoates or γ-substituted buta-2,3-dienenitriles and arylidene- or alkylidenemalononitriles, affording the corresponding cycloadducts in high yields, good regio- and diastereoselectivities, and uniformly high ee’s (82–97%) (eq 5).¹³ It is worth noting that, in the presence of 10 mol % of C8, the enantioselective [3 + 2] cyclization of cyanoallenes with arylidenemalononitriles at room temperature led to the corresponding cyclopentenes in high yields, excellent regio- and diastereoselectivities, and with 83–88% ee. The reaction represents the first example of a highly enantioselective phosphine-catalyzed cyclization of cyanoallenes. The effective stereochemical control of the organocatalytic process induced by the helically chiral phosphine demonstrated that the chiral helical structure could be a useful template for the design of chiral phosphine catalysts.

Although several cyclic phosphines displayed excellent catalytic activities and enantioselectivities, the asymmetric variants of many achiral phosphine-catalyzed annulations could not be achieved by these chiral cyclic phosphines. Inspired by multifunctional chiral organocatalysts; particularly amino acid, peptide-, and thiourea-based systems;¹⁴ multifunctional chiral phosphines were designed and constructed by attaching a nucleophilic phosphine and a hydrogen-bonding moiety onto a chiral backbone. The phosphine and hydrogen-bonding moiety synergistically activate the substrates in an assembled chiral environment, providing excellent catalytic activities and enantioselectivities that could not be accomplished by using conventional chiral phosphines lacking hydrogen-bonding moieties.^1l Interest in chiral multifunctional phosphines was sparked in 2007 by Cowen and Miller who first reported α-amino acid based phosphine catalyst, M1, for the asymmetric [3 + 2] annulation of allenoates with various cyclic and acyclic enones (eq 6).¹⁵ The corresponding cyclopentene derivatives were obtained with excellent regioselectivity and high enantioselectivities. It is worth noting that single amino acid based phosphines displayed better catalytic activities than di-, tri-, and tetrapeptide-based catalysts. The proposed transition state shows that the formation of the zwitterionic intermediate from the reaction of allenoate with the phosphine moiety, and the consequent intramolecular hydrogen bonding, exert dual control on the activity and stereoselectivity.

In 2010, Zhao and co-workers reported a novel single amino acid based chiral N-acyl aminophosphine M2.¹⁶ Using 10% mol of M2, the asymmetric [3 + 2] annulation of various arylidenemalononitriles with allenoate proceeded smoothly to give various chiral cyclopentene derivatives as single regioisomers in 79–99% yield 80–99% ee, and with excellent diastereoselectivities.¹⁶ In particular, with 2-cyano-3-arylacrylates bearing two different electron-withdrawing functional groups as substrates, chiral cyclopentenes bearing adjacent quaternary and tertiary stereocenters could be obtained in exclusive regioselectivity and high diastereo- and enantioselectivities. Interestingly, γ-substituted racemic allenoates underwent the catalytic [3 + 2] annulation reaction, leading to a dynamic kinetic asymmetric transformation to afford the desired products in high yields and with moderate diastereoselectivities and good enantioselectivities.

A new family of dipeptide-derived chiral phosphines has been developed by Lu and co-workers for asymmetric [3 + 2] annulation reactions.¹⁷ Among them, phosphine M7 displayed remarkably high activities, catalyzing the asymmetric [3 + 2] annulation of allenoates with acrylates in a rapid (≤0.5 h in most instances) and regiospecific manner to afford functionalized cyclopentenes containing quaternary stereocenters in 61–97% yield and 68–94% ee (eq 7).^17a A proposed transition state model reveals that the phosphonium enolate intermediate approaches the acrylate from its Re face to yield the major stereoisomer. Since this kind of chiral phosphine contains a dipeptide moiety, its structure can be easily tuned. A series of dipeptide-derived chiral phosphines with diverse structures have? been constructed and evaluated for the asymmetric [3 + 2] annulation of allenes with acrylamides and maleimides, giving rise to the desired chiral functionalized cyclopentenes.^17b,c

2.2. With Imines

Functionalized pyrrolines are important units in many bioactive compounds and natural products, and Lu and co-workers first reported the achiral phosphine-catalyzed [3 + 2] annulation of allenes with activated imines to form such pyrrolines.¹⁸ However, developing the asymmetric variant of the reaction proved quite challenging, since acyclic (A2, A6) and cyclic (C5, C10, C11) chiral phosphines—which had displayed excellent activities and enantioselectivities in asymmetric [3 + 2] annulations of allenes with activated alkenes¹⁰—delivered poor results in the annulation of allenes with imines.¹⁹

A huge leap forward in the development of enantioselective [3 + 2] annulations of allenoates with imines was achieved in 2008 by Jacobsen’s group who used a multifunctional catalyst, M9, bearing a phosphine fragment, a thiourea moiety, and an amino acid residue. In the presence of M9, a wide range of aromatic N-diphenylphosphinoylimines underwent asymmetric [3 + 2] annulations with allenoate, affording 2-aryl-2,5-dihydropyrrole derivatives in high yields (68–90%) and with excellent enantioselectivities (94–98% ee) (eq 8).²⁰ Unfortunately, aliphatic imines were unsuitable substrates since they underwent decomposition under the optimal reaction conditions. On the basis of the proposed transition state, the high enantioselectivity observed could be attributed to synergetic activation and enantioinduction of both the phosphine moiety—which accounts for activation of the allenoate and the enantioinduction—and the thiourea unit, which plays the dual roles of activating the imine and stereochemically controlling the association of the phosphoryl substituents of the imine. The catalytic amounts of triethylamine and water required were indispensable for enhancing the reaction rate. Water is believed to promote proton transfer, while triethylamine probably facilitates the regeneration of the phosphine catalyst.

The limitation of the imine scope was overcome by Lu’s team, who utilized dipeptide-derived phosphine M6 as chiral catalyst to convert a wide range of alkyl, vinyl, and aryl imines into the corresponding 3-pyrroline derivatives in good yields and with nearly perfect enantioselectivities (eq 9).²¹ With this reaction as a key step, a concise formal synthesis of the alkaloid (+)-trachelanthamidine was accomplished by the same group, highlighting the synthetic value of this methodology.

Recently, our group designed and synthesized a new class of rigid [2.2.1] bicyclic chiral phosphines, C2 and C3, from commercially available trans-4-hydroxy-l-proline.²² These chiral cyclic phosphines are highly effective catalysts for the asymmetric [3 + 2] annulation of γ-substituted allenoates with imines, providing 1,2,3,5 substitued pyrrolines in high yields and with excellent enantioselectivities (eq 10).²² Compared with the above two kinds of multifunctional chiral phosphine (M6 and M9), which only catalyzed the reaction of 2,3-butadienoate, C2 and C3 extended the scope of allenes to include γ-substituted allenoates. A demonstration of the utility of this chemistry has been the first enantioselective total synthesis (15 steps, 13% overall yield) of the indole alkaloid (+)-ibophyllidine via a C3-catalyzed asymmetric [3 + 2] annulation (93%, 99% ee) of an indole-derived N-tosylaldimine and 4-ethyl-2,3-butadienoate at rt (Scheme 2).^2h The reaction was also performed on a 30 g scale to provide the optically pure pyrroline (94%, 97% ee) without loss of activity and enantioselectivity.

eq 7 (Ref. 17a)

eq 8 (Ref. 20)

eq 9 (Ref. 21)

eq 10 (Ref. 22)

eq 11 (Ref. 23)

eq 12 (Ref. 25)

Scheme 2.

A C3-Catalyzed Asymmetric [3 + 2] Annulation as a Key Step in the First Enantioselective Total Synthesis of the Indole Alkaloid (+)-Ibophyllidine. (Ref. 2h)

In the presence of amino acid based, bifunctional chiral phosphine M2, sulfamate-derived cyclic imines undergo asymmetric [3 + 2] annulation reactions with allenoate, providing sulfamate-fused dihydropyrroles in good yields and with moderate-to-excellent enantioselectivities (≤91%, ≤98% ee) (eq 11).²³

2.3. With Azomethine Imines

In the past five years, the phosphine-catalyzed annulation of 1,3-dipoles with allenes or Morita–Baylis–Hillman (MBH) carbonates has emerged as a powerful tool for the synthesis of bioactive heterocyclic compounds.²⁴ Several asymmetric variants of the reaction have been reported. For example, the C19-catalyzed asymmetric [3 + 2] annulation of a cyclic N,N’-azomethine imine with allenoate affords a chiral tetrahydropyrazolopyrazolone in 56% yield and 89% ee.^24a The asymmetric [3 + 2] annulation of C,N-cyclic azomethine imines with γ-substituted allenoates has also been achieved in the presence of (S)-Me-f-KetalPhos (C6), providing a variety of functionalized tetrahydroisoquinoline (a moiety widely found in pharmaceutically important compounds) derivatives in good yields and with high diastereo- and enantioselectivities (eq 12).²⁵

3. Asymmetric [4 + x] Annulations of Allenes

3.1. With Bisnucleophiles (x = 1)

The phosphine-catalyzed [4 + 1] annulation reaction is an expedient alternative approach for the synthesis of five-membered-ring carbocycles and heterocycles, and has received considerable attention.¹ Based on the achiral phosphine-catalyzed [4 + 1] annulation of allenoates with bisnucleophiles developed by Tong and co-workers,²⁶ Fu’s group accomplished its asymmetric version with the biphenyl-derived phosphines C14 and C15.²⁷ In the presence of phosphine C14, the asymmetric [4 + 1] annulation of allenoate with a variety of α-cyano-substituted carbonyl compounds afforded functionalized (S)-cyclopentenes bearing an all-carbon quaternary stereocenter in high yields (61–97%) and good ee values (82–94%) (eq 13).²⁷ For α-cyano-substituted sulfones, phosphine oxides, and phosphonates, however, C15 was a more effective catalyst, enabling the efficient synthesis of the corresponding enantioenriched (R)-cyclopentene chiral spirophosphine catalyst C20, Kramer and Fu reported the [4 + 1] annulation of various sulfonamides with a wide range of γ-alkyl-substituted allenes, giving the (S)-5-alkyl-substituted dihydropyrrole products in good yields and ee’s (14 examples; 67–95%, 83–93% ee).²⁸

eq 13 (Ref. 27)

Pyrazolones are bisnucleophiles and one-carbon synthons, and 4-spiro-5-pyrazolones are a class of compounds with potential biological significance. Lu and co-workers disclosed an efficient [4 + 1] annulation for the synthesis of optically enriched pyrazolones in the presence of l-threonine-derived, O-silylated phosphine M3. A wide range of chiral spiropyrazolones were obtained at room temperature in 57−88% yield and 85−92% ee (eq 14).²⁹ The reaction also served as the key step in the synthesis of a chiral inhibitor of type-4 phosphodiesterase.

3.2. With Alkenes (x = 2)

Only limited examples of the phosphine-catalyzed [4 + 2] annulation had been reported prior to 2007, when our group disclosed the first achiral phosphine-catalyzed [4 + 2] annulation of allenoates with activated alkenes.³⁰ Five years later, Lu and co-workers reported the first highly enantioselective variant employing bifunctional phosphines derived from chiral amino acids, M4, or dipeptides, M6.³¹ Highly functionalized cyclohexenes and 3-spirocyclohexene-2-oxindoles were obtained in very high yields and with excellent diastereo- and enantioselectivities (eq 15).³¹ 3-Spirocyclohexene-2-oxindoles are biologically significant structures in natural products and therapeutically useful agents. At about the same time, Zhao and co-workers reported a highly asymmetric [4 + 2] annulation between activated alkenes and α-substituted allenoates that is catalyzed by an analogue of the bifunctional chiral phosphine M2. The reaction afforded various optically active cyclohexenes with three neighboring carbon stereocenters in high yields and with excellent enantioselectivities.³²

eq 14 (Ref. 29)

eq 15 (Ref. 31)

Very recently, Lu’s group developed another novel [4 + 2] annulation between allenones and β,γ-unsaturated α-keto esters by using dipeptide-based bifunctional phosphines as chiral catalysts (eq 16).³³ In the presence of 10 mol % of the l-threonine-derived bifunctional phosphine M8, a wide range of β,γ-unsaturated α-keto esters bearing aryl, heteroaryl, vinyl, and alkyl substituents underwent cyclizations with various allene ketones, generating the desired 3,4-dihydropyrans in good yields with nearly perfect enantioselectivities (≥99% ee in most cases). Moreover, the dihydropyran motif in the product could readily be transformed into bioactive compounds, demonstrating the significant synthetic value of the reaction.

3.3. With Imines (x = 2)

In 2003, our group reported the PBu₃-catalyzed [4 + 2] annulation of allenoates and N-tosylimines.³⁴ The asymmetric variant was disclosed two years later by Wurz and Fu who employed the binaphthyl-based chiral cyclic phosphine C9 as catalyst to generate a range of chiral functionalized tetrahydropyridines in moderate-to-excellent yields (42–99%) with excellent enantio- (ee ≤ 99%) and diastereoselectivities (dr ≤ 99:1) (eq 17).³⁵ This asymmetric [4 + 2] annulation served as the key step in the synthesis of the bridged tetracyclic framework of the Alstonia class of indole alkaloids.³⁵ Later, Zhao and co-workers also accomplished this asymmetric reaction by utilizing bifunctional N-acylaminophosphine M2.³⁶ For some activated imines, the bifunctional phosphine displayed a catalytic capability superior to that of Fu’s cyclic chiral phosphine system in terms of yield, ee, or both. In the presence of amino acid-derived thiourea-based multifunctional chiral phosphine^37a or cyclic phosphine (R)-SITCP (C18),^37b cyclic aldimines and ketimines underwent asymmetric [4 + 2] annulations with allenoates, leading to the formation of tetrahydropyridines with good enantioselectivities.³⁷

eq 16 (Ref. 33)

eq 17 (Ref. 35)

eq 18 (Ref. 40)

eq 19 (Ref. 41a)

eq 20 (Ref. 42)

4. Addition–Annulation Domino Reaction of Allenes with Enones

Most recently, Tong and co-workers developed two novel classes of phosphine-catalyzed addition–annulation domino reactions of β’-acetoxyallenoate with 2-acyl-3-methylacrylonitriles (β′-addition–[4 + 4] annulation) and 2-acyl-3-(2-pyrrole)acrylonitriles (γ-addition–[3 + 2] annulation),³⁸ affording 2-oxabicyclo[3.3.1]nonanes (e.g., ≤86%, ≤93% ee with Kwon’s phosphine C3) and cyclopenta[a]pyrrolizines (e.g., 74–82%, 83–87% ee with C3), respectively (Scheme 3).³⁸ The oxabicyclononanes and cyclopentapyrrolizines are two ubiquitous frameworks in natural products and biologically active compounds. Some preliminary results of their asymmetric variants were also reported.

Scheme 3.

β′-Addition–[4 + 4] Annulation and γ-Addition–[3 + 2] Annulation of Allenes with Enones. (Ref. 38)

5. Asymmetric Annulations of MBH Carbonates

5.1. [3 + 2] Annulation with Alkenes

Besides activated allenes and alkynes, Morita–Baylis–Hillman (MBH) carbonates are often employed as versatile substrates for the phosphine-catalyzed annulations.^1,39 Tang, Zhou, and co-workers have found that spirocyclic chiral phosphines can efficiently promote the intramolecular asymmetric [3 + 2] cyclization of MBH carbonates and electron-deficient alkenes (eq 18).⁴⁰ In the presence of 10 mol % (S)-DMM-SITCP C21, a variety of α,β-unsaturated carbonyl compounds were transformed in toluene at −5 °C into the optically active benzobicyclo[4.3.0] products A in 76–98% yield with 77–95% ee. Interestingly, the addition of 20 mol % of Ti(O-i-Pr)₄, under otherwise identical conditions, inhibited the isomerization process, leading to the regioisomeric benzobicyclo[4.3.0] compounds B as major products in almost identical optical purities (77–92% ee) to those of A.

In 2011, aiming to develop new, highly enantioselective methods for the direct construction of the spirocyclopenteneoxindole scaffold, Barbas and co-workers discovered a novel highly efficient asymmetric [3 + 2] annulation between methyleneindolinones and MBH carbonates.^41a In the presence of 10 mol % (+)-Ph-BPE (C4), the annulation between a wide range of Boc- and carbamoyl-protected methyleneindolinones and various MBH carbonates occurred readily, yielding polyfunctionalized spirocyclopenteneoxindoles in moderate-to-excellent yields (63–85%) and good ee’s (91–99%) (eq 19). Aryl-substituted MBH carbonates reacted much better than methyl-substituted ones. Following this study and using the same catalytic system, the same group achieved the asymmetric [3 + 2] annulation of MBH carbonates with methylene benzofuranone derivatives, affording a wide range of polysubstituted spirocyclopentenebenzofuranones in high yields and with good-to-excellent enantioselectivities.^41b

Lu and co-workers synthesized biologically important 3-spirocyclopentene-2-oxindoles with two contiguous quaternary centers by employing asymmetric [3 + 2] annulations between MBH carbonates and activated isatin-based alkenes catalyzed by amino acid derived chiral phosphines.⁴² In the presence of catalyst M11, the reactions proceeded in very high yields and with good enantioselectivities. This reaction is synthetically appealing, since it can be conveniently and equally effectively performed in a one-pot manner. For example, simply mixing the isatin, malononitrile (precursors of activated alkene), and MBH carbonate produces the corresponding spirooxindole with the same enantioselectivity as that acquired in the reaction between activated alkenes and MBH adducts, albeit in slightly diminished yields (eq 20). Shi and co-workers found that chiral bifunctional thiourea-based phosphine catalyst M12 could catalyze the same reaction, giving the corresponding cycloadduct as the major product in 92% yield and with a 9:1 diastereomeric ratio and 74% ee.⁴³

The asymmetric [3 + 2] annulation between MBH carbonates and maleimides, giving functionalized bicyclic imides, has been achieved with the amino acid derived chiral phosphine catalyst M5 in excellent yields and with high enantio- and diastereoselectivities.⁴⁴ With the versatile and powerful thiourea-based chiral phosphine M10 as catalyst, Shi’s group effected asymmetric [3 + 2] annulations of MBH carbonates with various activated alkenes, including maleimides,^45a trifluoroethylidenemalonates,^45b and 2-arylideneindane-1,3-diones,^45c providing the functionalized cyclopentenes in moderate-to-excellent yields, diastereoselectivities, and enantioselectivities.

5.2. [4 + 1] Annulation with Dienes

While allenes function as four-carbon synthons in the [4 + 1] annulation under phosphine catalysis, MBH carbonates serve as one-carbon synthons in the same reaction. In the presence of 20 mol % of the bifunctional phosphine M13 and 4 Å molecular sieves, the asymmetric [4 + 1] annulation of MBH carbonates with activated dienes proceeded smoothly in toluene at room temperature. A wide range of functionalized cyclopentenes bearing quaternary carbon stereocenters were thus prepared in 29–92% yield with 66–98% ee, albeit requiring very long reaction times (up to 7 days) (eq 21).⁴⁶ Those substrates bearing bulky substituents were not compatible with the reaction conditions, leading to low yields or ee’s.

5.3. [3 + 3] Annulation with Azomethine Imines

The phosphine-catalyzed [3 + 3] annulation is a very useful alternative to the [4 + 2] annulation for the synthesis of biologically important six-membered-ring carbocycles and heterocycles. However, this type of reaction, especially the asymmetric variant, has met with limited success.¹ Most recently, the first phosphine-catalyzed asymmetric [3 + 3] annulation of MBH carbonates with C,N-cyclic azomethine imines was achieved using the commercially available spirocyclic chiral phosphine C18 as catalyst under mild conditions.⁴⁷ The reaction yielded a novel class of pharmaceutically interesting 4,6,7,11b-tetrahydro-1H-pyridazino[6,1-a]isoquinoline derivatives in high yields and with good-to-excellent diastereoselectivities and outstanding enantioselectivities (98 to >99% ee) (eq 22). Moreover, the reaction could be scaled up without significant loss of diastereoselectivity, enantioselectivity, or yield.

6. Asymmetric [2 + 2] Annulation of Ketenes

Ketenes, analogues of allenes, can also undergo phosphine-catalyzed annulations, whereby they generally function as binary synthons. In the presence of 10 mol % of (R)-binaphane (C17), disubstituted ketenes underwent asymmetric [2 + 2] annulations with N-tosyl arylimines in dichloromethane or tetrahydrofuran, giving the corresponding trans-β-lactams in moderate-to-excellent ee’s (≤98%), diastereoselectivities (dr ≤ 99:1), and yields (up to >99%) (eq 23).⁴⁸ Very interestingly, with (S,Rp)-JosiPhos A4 or A5 as chiral catalyst, ketenes underwent asymmetric homodimerization, namely formal [2 + 2] annulations, affording chiral β-lactones in high yields (≤99%) with good-to-excellent ee’s (≤96%).⁴⁹

7. Miscellaneous Annulations through Domino Reactions

In addition to the annulations employing allenes, alkynes, MBH carbonates, and ketenes described in the preceding sections, phosphine-catalyzed asymmetric annulations can also be achieved by domino reactions. These transformations allow the rapid construction of carbocyclic and heterocyclic molecules from readily available starting materials in two or more steps in a single operation. By utilizing acyclic, cyclic, and multifunctional chiral phosphines as catalysts, several asymmetric annulations have been accomplished through domino aza-MBH–Michael,⁵⁰ tandem RC–Michael,⁵¹ double-Michael,⁵² and tandem Michael addition–Wittig olefination.⁵³ These asymmetric annulations are described in the cited references, and will not be discussed in this review.

8. Conclusions and Outlook

In summary, nucleophilic chiral phosphines—including acyclic, cyclic, and multifunctional phosphines—especially the latter two types, display powerful and versatile catalytic capabilities. Under catalysis by these phosphines, various asymmetric annulations have been developed, which serve as very valuable tools in the synthesis of a significant number of bioactive molecules and natural products. Although huge strides in the area of nucleophilic chiral-phosphine-catalyzed asymmetric annulations have been made, many challenges still remain, necessitating a continued vigorous research effort in the design and synthesis of chiral phosphines with novel skeletons.

eq 21 (Ref. 46)

eq 22 (Ref. 47)

eq 23 (Ref. 48)

Biographies

Dr. Y. Xiao

Yumei Xiao received her Ph.D. degree in 2003 from China Agricultural University, and is currently an associate professor of chemistry at that institution. In 2013, she worked as a visiting scholar at the National Institutes of Health, Bethesda, Maryland. Her current research interests include organocatalysis, organic synthesis, and bioorganic chemistry.

Prof. H. Guo

Hongchao Guo received his B.S. degree in 1997 and his Ph.D. degree in 2002 both from China Agricultural University, Beijing, China. After spending several years performing chemical research at the Shanghai Institute of Organic Chemistry, Max-Planck-Institut für Kohlenforschung (Mülheim), the University of California at Los Angeles, and the University of Illinois at Urbana-Champaign, he joined China Agricultural University in 2010 as an associate professor, and was promoted to Professor in 2011. His research focuses on organo- and metal-catalyzed cycloadditions and annulations and their applications in organic synthesis.

Prof. O. Kwon

Ohyun Kwon, Professor of Chemistry and Biochemistry at UCLA, received her B.S. and M.S. degrees in 1991 and 1993, respectively, from Seoul National University. After receiving her Ph.D. degree in 1998 from Columbia University and, following a postdoctoral stint at Harvard University, Kwon started her independent career in 2001 at UCLA. She has played key roles in establishing phosphinocatalysis as one of the main areas of organocatalysis research, and is recognized as one of the leaders in the field.