Coordination Chemistry Reviews 256 (2012) 938952

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Coordination Chemistry Reviews

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Review

Organocatalytic and metal-mediated asymmetric [3 + 2] cycloaddition reactions

Yalan Xing a , Nai-Xing Wang b,
a b

Department of Chemistry & Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China

Contents 1. 2. 3. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Copper(I)-catalyzed [3 + 2] cycloadditions of organic azides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recent progress in asymmetric 1,3-dipolar cycloaddition reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Organocatalytic metal-free and Ag(I)-mediated enantioselective [3 + 2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Organocatalytic Cu(II), Cu(I) and Au(I)-mediated enantioselective [3 + 2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Organocatalytic Ni(II) and Sc(III)-mediated enantioselective [3 + 2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Progress in asymmetric non-1,3-dipolar [3 + 2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Pd(0)-catalyzed asymmetric [3 + 2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Rh(I)-catalyzed intramolecular asymmetric [3 + 2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Sc(III), Ti(IV)-catalyzed asymmetric [3 + 2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938 939 941 941 941 944 945 945 946 948 948 951 951

4.

5.

a r t i c l e

i n f o

a b s t r a c t
This review focuses on recent progress in organocatalytic and metal-mediated asymmetric [3 + 2] cycloadditions, including click chemistry, asymmetric 1,3-dipolar and asymmetric non-1,3-dipolar [3 + 2] cycloadditions. The theoretical aspects and synthetic applications of these organocatalytic and metal-mediated asymmetric [3 + 2] cycloadditions are summarized. In addition, an understanding of the mechanistic details which lead to efcient stereoselectivity in organocatalytic and metal-mediated asymmetric [3 + 2] cycloadditions is provided. Most of the references reviewed in this paper are from 2007 upto now. 2012 Elsevier B.V. All rights reserved.

Article history: Received 4 July 2011 Accepted 1 January 2012 Available online 21 January 2012 Keywords: [3 + 2] cycloadditions 1,3-Dipolar cycloaddition reactions Asymmetric cycloadditions Asymmetric catalysis Organocatalysts

1. Introduction The synthesis of complex heterocyclic compounds in a stereospecic manner is an important area of organic chemistry. Cycloaddition reactions offer a very important strategy in the synthesis of many heterocyclic compounds. Recently, asymmetric [3 + 2] cycloaddition reactions using chiral organocatalysts mediated by different metals have provided new methods for the construction of stereochemically complex heterocyclic compounds. Specically, [3 + 2] cycloaddition is an excellent approach for the synthesis of many types of ve-membered ring system starting from a 3-atom and a 2-atom precursor. Thus, [3 + 2]

Corresponding author. Tel.: +86 10 82543575; fax: +86 10 62554670. E-mail address: nxwang@mail.ipc.ac.cn (N.-X. Wang). 0010-8545/$ see front matter 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.ccr.2012.01.002

cycloaddition is a broad concept that includes 1,3-dipolar cycloadditions which provide a very efcient way to synthesize complex natural products and medicinal molecules [1a]. Among 1,3-dipolar cycloaddition reactions, click chemistry is a popular method for the construction of triazole derivatives by the reaction of azides and acetylenes. During the past few years, the number of publications on asymmetric organocatalytic and metal mediated [3 + 2] cycloaddition reactions has increased dramatically. In this review, many important references from 2007 are analyzed. It is organized according to the use of different metal species with organocatalysts for asymmetric [3 + 2] cycloaddition reactions. Generally speaking, [3 + 2] cycloaddition is a broad concept that includes 1,3-dipolar cycloadditions which provide a very efcient way to synthesize complex natural products and medicinal molecules [1a]. In other words, cycloaddition reactions that involve 1,3-dipoles reacting with -bonds of dipolarophiles to give

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ve-membered rings are called [3 + 2] cycloaddition reactions [1b]. A 1,3-dipole usually contains heteroatoms and four -electrons which distribute over three atoms, such as azide, diazoalkane, nitrous oxide, nitrile imine, nitrile ylide, nitrile oxide, azomethine imine, azoxy compound, azomethine ylid, as well as nitrone, carbonyl oxide and ozone [2]. A 1,3-dipolar cycloaddition reaction can also be described as involving at least one mesomeric state structure that represents a charged dipole and a dipolarophile. The dipolarophiles usually are alkene or alkyne derivatives. For the mechanism of the 1,3 dipolar reaction, there is still an ongoing debate in the organic chemistry community, some researchers opt for the concerted reaction mechanism which means bonds are formed and broken at the same time, other researchers agree with the stepwise mechanism where biradical intermediates are formed in the reaction. In the early 1960, Huisgen proposed a concerted process which is supported by the observation of regioselectivity, stereospecicity and no trappable intermediates. Recently Houk reported the dynamics of 1,3-dipolar cycloadditions and established that the timing of bond formation in these reactions conrms the concerted nature of 1,3-dipolar cycloadditions [3a]. Houk also reported the dynamics of the 1,3-dipolar cycloaddition reactions of diazonium betaines with acetylene and ethylene; he believes that the concerted processes are more important than stepwise processes [3b,3c]. However, a two-step diradical mechanism of 1,3-dipolar cycloadditions was postulated by Firestone based on no solvent effect on reaction rate [4a,4b]. The diradical character of 1,3-dipoles and their reactivity toward ethylene or acetylene was also recently reported by Braida [4c]. A 1,3-dipolar molecule like the nitrile ylide Ph C N+ CH2 , has a HOMO of 6.4 eV and an electron decient alkene CH2 CHCHO has a LUMO +0.6 eV [5a], and the reaction rate for these 1,3-dipolar cycloaddition reactions is usually high. Fleming also believes some 1,3-dipoles, like diazomethane, have high-energy HOMOs, and react faster with alkenes carrying electron-withdrawing substituents in [3 + 2] reactions [5b]. Engels analyzed the reactivity of 1,3-dipolar cycloadditions and suggested that reaction rates and regioselectivities could be rationalized by means of frontier orbital theory [5c]. Engels found that the activation enthalpies of ethene and ethyne in a given 1,3-dipole are the same. On the basis of the frontier orbital theory, it would be expected that ethene would react substantially faster, as its HOMO (10.5 eV) is higher and its LUMO (1.5 eV) is lower in energy than the respective frontier orbitals of ethyne (11.5 and 2.5 eV, respectively) [5a] (CNDO/2). On the other hand, the similar reaction rates are remarkably fast also because of the thermodynamics of the ethene and ethyne additions [5c]. Among 1,3-dipolar cycloaddition reactions, click chemistry is a popular method for the construction of triazole derivatives by the reaction of azides and acetylenes. Huisgen-type 1,3-dipolar cycloadditions have a tremendously successful history of use in heterocyclic synthesis and in the synthesis of natural products [6,7], and now more and more [3 + 2] cycloadditions are utilized in organic chemistry, drug discovery and chemical biology [8]. After Sharpless reported the click chemistry of azides (N3 R) [9], a lot of papers were published that include a range of [3 + 2] cycloaddition reactions with high yields under ambient conditions. Click chemistry was introduced by Sharpless in 2001 and describes the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of combinatorial libraries through heteroatom links. The Huisgen 1,3-dipolar cycloaddition, in particular the Cu(I)-catalyzed stepwise variant, is often referred to simply as the click reaction [9a]. Click chemistry includes the copper(I)catalyzed cycloaddition reaction of azides and acetylenes with high regioselectivity together with high yield under ambient conditions

R N N N

R N N N

Scheme 1. Molecular structure of azides [11].

[9]. Click chemistry is not a normal concerted 1,3-dipolar cycloadditions. Many earlier reports of [3 + 2] cycloaddition reactions did not involve chiral compounds. Recently many 1,3-dipolar cycloaddition reactions have been employed in asymmetric synthesis. Jrgensen reviewed the asymmetric reactions of 1,3-dipoles in 1998 [10a], Njera and Sansano also reviewed the catalytic enantioselective [3 + 2] cycloaddition reactions of azomethine ylides and alkenes in 2005 [10b]. They indicated that the chiral domain must differentiate the two enantiotopic faces of the 1,3-dipole on attack of the dipolarophile, and that solvent and temperature also play important roles for these asymmetric [3 + 2] reactions. Pellissier has also reviewed asymmetric 1,3-dipolar cycloadditions [10c], mainly citing references before 2006. Pandey reviewed the construction of enantiopure pyrrolidines via asymmetric [3 + 2] cycloaddition of azomethine ylides in 2006 [10d]. Meldal reviewed Cu-catalyzed azidealkyne cycloaddition recently, though chiral synthesis was not a topic of the review [10e]. Frhauf reviewed organotransition metal [3 + 2] cycloaddition reactions in 2002 and the reactions in this review did not include asymmetric examples [10f]. Research on 1,3-dipolar cycloaddition reactions using asymmetric catalysis has recently become a highly dynamic area in organic chemical research [10]. Yamamoto reviewed some organocatalytic enantioselective [3 + 2] cycloadditions, all of the references cited being before 2007 [10g]. In 2007, Sansano also reviewed some 1,3-dipolar cycloaddition reactions of metallo-azomethine ylides [10h]. Recently Eycken reviewed some microwave-assisted [3 + 2] cycloaddition reactions as a section [10i]. In this review, some recent advances focused on organocatalytic and metal-mediated asymmetric 1,3-dipolar cycloaddition reactions have been summarized, most references coming from top chemical journals mainly being from 2007 to August 2011. 2. Copper(I)-catalyzed [3 + 2] cycloadditions of organic azides Since some asymmetric [3 + 2] cycloadditions proceed with chiral starting materials (asymmetric reagents), some copper(I)mediated cycloadditions of azides and alkyne which show an excellent stereoselectivity are presented here. Chemists reported 1,3-dipolar cycloaddition reactions of phenyl azide with alkene and alkyne derivatives a long time ago [10,11]. Organic azides belong to the propargyl-allenyl category of dipoles (Scheme 1), and 1,3-dipolar cycloadditions of azide derivatives with alkenes and alkynes without copper(I)-catalyzed are well known [11]. Some 1,3-dipoles such as azomethine ylides, carbonyl ylides, thiocarbonyl ylides, nitrile oxides, nitrile ylides and nitrile imines, diazoalkanes, nitrones and nitronates, are widely used for synthetic applications of 1,3-dipolar cycloadditions [7c]. As described above, a new approach was given by Sharpless to the reactions of azide derivatives with unsaturated compounds in the presence of a copper catalyst; this is the best known example of click chemistry (Scheme 2) [9]. This involves stepwise Huisgen cycloaddition process [9]. Recently Fokin reviewed copper-catalyzed azidealkyne cycloaddition (CuAAC) and reported it involves multiple reversible steps on coordination complexes of copper(I) acetylides of varying nuclearity [9c]. Copper catalysts drastically change the mechanism and

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N R

N +
1

R2 click chemistry CuI

R2 1 N

N
4

R1

Scheme 4. Click strategy for the synthesis of asymmetric organocatalysts [27].

Scheme 2. Click reaction of azides and terminal alkynes [9].

N Br
9

N+ N NaN 3/DMF 48 h, 70 oC
9

N N N C18H 34 15 min RT
9

15

O Si O O 1

O Si O O 2

O Si O O 3

Scheme 3. Click reaction by CP [1]. Bromo-terminated SAM on a Si/SiO2 substrate [2]. Azido-terminated SAM [3]. Triazole SAM after CP of 1-octadecyne onto azidoterminated SAM.

the outcome of the reaction, converting it to a sequence of discrete steps culminating in the formation of a 5-triazolyl copper intermediate. The key C N bond-forming event takes place between the nucleophilic, vinylidene-like -carbon of copper(I) acetylide and the electrophilic terminal nitrogen of the coordinated organic azide. Copper-catalyzed azidealkyne cycloaddition (CuAAC) is far more complex than 1,3-dipolar cycloadditions of azide derivatives with alkene and alkyne without copper(I)-catalysis [9c]. Ravoo reported [12] an example of click chemistry which was induced without any catalyst by CP (microcontact printing) of acetylenes onto azido-terminated SAMs (self-assembled monolayers) on silicon oxide substrates. This showed that click chemistry can be applied to the microcontact printing of acetylenes onto azido-terminated SAMs (Scheme 3) [12]. 4-Substituted 1-(N-sulfonyl)-1,2,3-triazoles were prepared, and some heterocyclic compounds were obtained regioselectively by performing the reactions at low temperature and in the presence of a catalytic amount of CuI [13]. Click chemistry has led to excellent results [1425], and many triazole derivatives have been synthesized in excellent yield and regioselectivity. Some of them could be applied as potential transition metal ligands or new reagents. Kirshenbaum recently reviewed copper-catalyzed azidealkyne [3 + 2] cycloadditions and mainly discussed modications of peptidomimetic oligomers [25d]. The dicopper-substituted -Keggin silicotungstate TBA4 [-H2 SiW10 O36 Cu2 (-1,1-N3 )2 ] (TBA: tetran-butylammonium) shows high catalytic activity for the regioselective 1,3-dipolar cycloaddition of organic azides to alkynes. Kinetic, spectroscopic, mechanistic, and computational investigations showed that the reduced dicopper core plays an important role in the reaction [26a]. 1,3-Dipolar cycloadditions occur by several different reaction mechanisms. Some thermal 1,3-dipolar cycloadditions involve a

concerted mechanism when the dominant FMO interaction is the HOMOdipole with the LUMOalkene . When 1,2-disubstituted alkenes are involved in concerted [4s + 2s]-cycloaddition reactions with 1,3-dipoles, two new chiral centers can be formed in a stereospecic manner due to the syn attack of the dipole on the double bond. Intermolecular concerted 1,3-dipolar cycloaddition reactions of azides with alkenes are most frequently slow at room temperature and need a very long reaction time. These concerted cycloaddition reactions are powerful tools for stereospecic creation of new chiral centers in organic molecules. 1,3-Dipolar cycloaddition reactions can take place by a stepwise reaction involving an intermediate and in these cases the stereospecicity of the reaction may be destroyed [10a]. In 2002, the groups of Sharpless [9b] and Meldal [26b] independently reported that copper(I)-catalysts dramatically accelerate the reaction of regioselective 1,3-dipolar cycloadditions which is rst click reaction. The concerted 1,3-dipolar cycloaddition is a reaction in which all bond breaking and bond making occur in a single step, reactive or unstable intermediates are not involved, and the reaction rates tend not to depend on solvent polarity in the transition state. 1,3-Dipolar cycloadditions with normal dipolarophiles follow a concerted mechanism via an aromatic transition state by computational analysis, including previously reported computational data [26e]. SharplessMeldal click reactions with copper(I) catalysis are not subject to a concerted 1,3-dipolar cycloaddition because of a stepwise copper(I)-catalyzed process [26bd]. 1,3-Dipolar cycloadditions have been employed to construct a library of triazole-type asymmetric organocatalysts [27] (Scheme 4). By click chemistry with the azide chiral substrate, the product pyrrolidinetriazoles can be used as chiral organocatalysts and were used for the asymmetric Michael addition of cyclohexanone to nitrostyrenes with an excellent stereoselectivity (syn/anti up to 99:1, ee up to 96%) [27]. Click chemistry simplies the synthesis of efcient bifunctional ligands in which 1,4-disubstituted triazoles form an integral part of the metal chelating system and facilitates their incorporation into (bio)molecules [28]. This one-pot procedure represented a remarkable improvement for the synthesis of metal-labeled conjugates for diagnostic purposes (Scheme 5). An efcient synthesis of new bicyclic triazoles by sequential azidation/alkylation/1,3-dipolar cycloaddition/deprotection was described. This work involves a selective Huisgen cycloaddition, starting from a mixture of diasteroisomers and the bicyclic triazoles are obtained in their trans form in good yields and with very high diastereomeric ratios [29a] (Scheme 6). Click chemistry of biarylazacyclooctynones with azide-labeled biomolecules was also reported, such reactions are now being referred as Cu-free click chemistry [29b]. The history of Cu-free

Scheme 5. Derivatives of biomolecules functionalized via click chemistry [28].

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Scheme 7. Chiral phosphoramide-catalyzed 1,3-dipolar cycloaddition of diaryl nitrones with ethyl vinyl ether. Tf = triuoromethanesulfonyl [33a].

Azomethine ylides were proposed to be latent 1,3-dipoles: R1 R1

N OEt
Scheme 6. Synthesis of new bicyclic triazoles [29a].

N H OEt OEt O O OEt

click cycloaddition reactions in chemical biology was summarized by Bertozzi [29c]. Some of the attributes of click reactions were summarized by Finn and Fokin [29d]. The methods give efcient, simple and green routes to design dendrimer macromolecules [29e]. Polymerization by a click reaction was summarized recently, and research to incubate alkyne-azide click reactions into a versatile polymerization technique for the synthesis of poly(triazole)s with linear and hyperbranched structures was reviewed [29f].

3. Recent progress in asymmetric 1,3-dipolar cycloaddition reactions Asymmetric synthesis has become a highly dynamic area in organic chemistry [30]. The number of publications using the term organocatalysis in the title or abstract has been increasing at an impressive rate since 2000; an increasing trend in the use of metalfree catalysts is seen because of the high cost of transition metals [30,31]. Asymmetric 1,3-dipolar cycloadditions using organocatalysis occupy a prominent position in chiral synthesis because they provide some of the most efcient methods for creating chiral centers with excellent control of stereochemistry, which has permitted the preparation of a number of valuable chiral compounds and natural products. Vesterager summarized some of these reactions but the references cited were only from 1994 to 2001 [7d].

The use of a Brnsted acid as catalyst in the 1,3-dipolar cycloaddition of diaryl nitrones with ethyl vinyl ether leads to complete reaction with only 5 mol% of this air-stable catalyst [33a]. These results demonstrated the usefulness of Brnsted acid catalysts for the asymmetric 1,3-dipolar cycloadditions (Scheme 7) [33a]. Recently enantioselective [3 + 2] cycloaddition of allenes to acrylates catalyzed by dipeptide-derived phosphines was reported. A new family of these phosphines was developed in asymmetric [3 + 2] cycloaddition reactions, and functionalized cyclopentenes containing quaternary stereocenters were afforded in a regiospecic and enantioselective manner [33b]. Catalytic enantioselective 1,3-dipolar cycloaddition reactions of azomethine ylides and alkenes use a monodentate phosphoramiditesilver complex. This novel complex is a very efcient chiral catalyst for a wide range of 1,3-dipolar cycloaddition reactions between azomethine ylides and dipolarophiles [34a]. Chiral phosphoramidite catalysts are shown in Table 2.

Ph O O P N L*= O O P N Ph Monophos 14 L* AgClO 4 16 ( Sa,R,R - 15)

L2 * AgClO 4 17
Efcient chiral silver amide-catalyzed enantioselective [3 + 2] cycloaddition of -amino-phosphonates with olens was reported [34b]. A chiral silver amide catalyzes the [3 + 2] cycloaddition of aminoester Schiff bases to olens [34c]; this afforded the corresponding pyrrolidine derivatives in high yields with high exo- and enantioselectivities with several activated olens. A silver complex prepared from AgHMDS (HMDS = hexamethyldisilazide) and a chiral phosphine ligand worked as an efcient base catalyst without an additional tertiary amine [34c]. 3.2. Organocatalytic Cu(II), Cu(I) and Au(I)-mediated enantioselective [3 + 2] cycloadditions 3-Pyrrolines were synthesized by a catalytic asymmetric reaction, using highly enantioselective [3 + 2] cycloadditions based on the Fesulphos-Cu-mediated 1,3-dipolar cycloaddition of azomethine ylides with trans-1,2-bisphenylsulfonyl ethylene (Table 3) [35a]. Asymmetric endo-selective [3 + 2] cycloaddition catalyzed by chiral bis(imidazolidine)pyridine-Cu(OTf)2 was reported [35b].

3.1. Organocatalytic metal-free and Ag(I)-mediated enantioselective [3 + 2] cycloadditions Most asymmetric organocatalysts are composed of two parts: one is a chiral organic molecule (ligand); the other is metal ion. These as well as the reactants can play an important part in setting up a very complex transition state with high stereospecicity. Usually coordination between the metal and the chiral ligand should be stronger than the metal and reactants resulting in high enantioselectivity. In these different transition states, the metal ion is usually at the core of the complex. However, some organocatalytic reactions are metal free. Vicario reported the organocatalytic enantioselective [3 + 2] cycloaddition reaction between ,-unsaturated aldehydes and azomethine ylides. This reaction proceeds with complete regioselectivity and high diastereo- and enantioselectivity to furnish almost stereoisomerically pure functionalized polysubstituted pyrrolidines (Table 1) [32].

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Table 1 [3 + 2] Cycloaddition reaction of 4 and crotonaldehyde [33a]a .

Ph

CO 2Et CO2Et 4

O H

Catalyst (20 mol%)

OHC CO2Et Ph N H 5 O CO 2Et

R Ph N H COOH N H 9 Ph N N H 10

Ar N H

Ar

Ph

OR

6 R=H 7 R=OH 8 R=OTBS

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13

11 Ar=Ph, R=H 12 Ar=Ph, R=TMS 13 Ar=3,5-(CF3)2C6H3 , R=H

T ( C) 30 30 30 30 30 30 30 30 4 4 4 4 4 Yield (%)b 77 60 44 86 <5 58 <5 56 67 65 89 55 79 Endo/exoc >95:5 >95:5 90:10 60:40 n.d. >95:5 n.d. >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 ee (%)d 72 82 84 5 n.d. >99 n.d. >99 98 98 98 97 98

Catalyst 6 7 8 9 10 11 12 13 11 11 11 11 11

Solvent DMF DMF DMF DMF DMF DMF DMF DMF DMF THF THFe THFe , f THFe , g

DMF, N,N-dimethylformamide; TBS, tert-butyldimethylsily; TMS, trimethylsilyl; n.d., not determined. a Reactions were carried out with 4 (0.75 mmol), crotonaldehyde (0.70 mmol), and the catalyst (0.14 mmol) in the indicated solvent (6 mL). The reaction mixture was stirred for 72 h at the temperature indicated. b Yield of the isolated product. c Determined by 1 H NMR spectroscopic analysis of the crude reaction mixture. d Determined by HPLC analysis of the corresponding alcohol on a chiral phase. e H2 O (4.0 equiv) was used as an additive. f PhCO2 H (0.14 mmol) was used as an additive. g Catalyst: 10 mol%.

Arai developed a new bis(imidazolidine)pyridineCu(II) complex for the highly endoselective [3 + 2] cycloaddition of imino esters to nitroalkenes. The unique reaction sphere produced by pyridine has the potential to furnish highly efcient asymmetric catalysis [35b]. A general procedure for the catalytic asymmetric 1,3-dipolar cycloaddition of (Z)-sulfonyl acrylates with azomethine ylides was reported [35c]. The regioselectivity is mainly controlled by the sulfonyl group, and provides 2,3-dicarboxylic ester substituted pyrrolidines with very high exo selectivity and

enantioselectivity (8099% ee) using CuI/DTBM-segphos as the catalyst system [35c]. Interestingly, in this process the phenylsulfonyl group works as a temporal regiochemical controller actually [35c]. Sibi recently reported a method for exo and enantioselective cycloaddition of azomethine imines with pyrazolidinone acrylates with high enantioselectivity (Table 4) [36]. The -bond activation by Au(I) catalysts to other reaction manifolds was evident in the 1,3-dipolar cycloaddition of mnchnone

Table 2 Enantioselective 1,3-DC of iminoglycinate 18 and tert-butyl acrylate by using several chiral phosphoramidites/Ag(I) salts [35a].

CO 2t Bu chiral ligand (5 mol%) Ag 1 salt (5 mol%) Ph N 18 CO 2Me Et3N (5 mol%) toluene, RT, 8h
Ag1 salt AgClO4 AgClO4 AgClO4 AgOAc AgOTf AgF AgBF4 AgClO4

tBuO 2C Ph CO2Me N H endo-19

Ligand 14 15 15b 15 15 15 15 15c Conv. (%) 98 98 95 98 98 90 95 98 e.r.a 76:24 85:15 74:26 80:20 84:16 76:24 60:40 90:10

Entry 1 2 3 4 5 6 7 8
a b c

Determined by chiral HPLC analysis (Daicel, Chiralpak AS), more than 98:2 endo/exo ratio (1 H NMR). 10 mol% of the ligand was added. Reaction performed at 20 C.

Y. Xing, N.-X. Wang / Coordination Chemistry Reviews 256 (2012) 938952 Table 3 Reaction conditions for the [3 + 2] cycloadditions [35a].

943

CO 2Me N Ph 20
Entry 1 2 3 4 5
a b c

SO 2Ph + PhO 2S 21
X (mol%) 10 10 10 3 1

(R)- 22 (x mol%) Cu(MeCN)4PF6 (x mol%) Et3N (20 mol%) Solvent, 5h, rt

PhO 2S MeO2C N H exo -23

Solvent CH2 Cl2 Toluene THF THF THF

SO2Ph Ph Fe

S- t-Bu PPh2

(R- 22) Fesulphos

Yield (%)a 85 83 90 90 (88)c 65 ee (%)b 93 96 98 98 (94)c 90

Isolated yield after column chromatography. By HPLC. Reaction from N-benzylidenglycine ethyl ester.

Table 4 Copper(II)-catalyzed exo and enantioselective cycloadditions of azomethine iminesa [36].

O N N

O + Ph 24 Ph

O N N 25

O Lewis Acid Chiral Ligand 4 A MS, CH2 Cl2 , rt Z N Ph N 26 ( exo ) O Z +

O N Ph N O

27 (endo )

O N N

O O N R 28 29 R = t -Bu 30 R = Ph 31 R = Bn
L* 28 28 28 28 28 28 28 28 28 CLA (mol%)b 30 30 30 30 30 30 30 20 10 Yield (%)c 81 85 88 75 38 84 80 83 90 Exo/endod 90:10 83:17 84:16 84:16 4:96 33:67 7:93 89:11 88:12 exo eee (%) 98 98 82 84 46 (47)f 60 (59)f 55 (85)f 98 94

O N R

Entry 1 2 3 4 5 6 7 8 9
a b c d e f

Lewis acid Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Mg(OTf)2 Zn(OTf)2 Ni(ClO4 )2 Cu(OTf)2 Cu(OTf)2

For experimental details, see the Supporting Information of [36]. CLA: chiral Lewis acid catalyst. Isolated yields. Determined by 1 H NMR. Determined by chiral HPLC. Values in parentheses are for the endo adduct.

with electron-decient alkenes. The chiral gold species was associated with the dipole of mnchnone and in turn dictated the stereochemical outcome of the reaction. In this methodology, high regio-, diastereo-, and enantioselectivity were achieved by using the (S)-Cy-SEGPHOS(AuOBz)2 catalyst (Scheme 8) [6,37a]. The gold-catalyzed cycloadditions proceed with excellent diastereoand regioselectivity. The reaction is thought to proceed through a 1,3-dipole generated by deprotonation of a gold(I)-activated azlactone. A -activation mechanism was proposed in this asymmetric catalysis with gold complexes [37a]. Recently regiospecic and diastereoselective Au(I) catalyzed 1,3-dipolar cycloaddition of 2-(1-alkynyl)-2-alken-1-ones with

nitrones was reported [37b]. This work provided a practical, regiospecic, and diastereoselective access to highly substituted fused heterobicyclic furo[3,4-d][1,2]oxazines under mild reaction conditions [37b]. This Au(I) catalyzed 1,3-dipolar cycloaddition with olen moiety is described as: R3 R3 O R5 R2 N 2 Ag[I] R COR 1 + 4 O R R4 N

R1

R5

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O NPh O + Ph O

O N Me

2 mol% (S)-Cy-SEGPHOS(AuOBz)2, PhF TMSCHN2 76% yield, 95% ee

Ph O

CO2Me Me

N Ph

HOBz

[AuL]OBz O O O N [AuL] Me NPh O [3+2] Ph O O [AuL] O N Me O

TMSCHN 2

Ph O

CO2H Me

Ph

N Ph

N Ph

Scheme 8. 1,3-Dipolar cycloadditions of mnchnone with electron-decient alkenes [37a].

Ligand (L) as:

Scheme 9. Enantioselective 1,3-dipolar cycloaddition of azomethine ylides with dimethyl maleate.

Table 5 Screening studies of the asymmetric Cu(I)-catalyzed 1,3-dipolar cycloaddition of azomethine ylide 33 with dimethyl maleate 32a [38b]. Entry 1 2 3 4 5 6 7 8 Ligand 1a 1b 1c 1d 1e 1e 1e 1e Cu/L (mol) 3 3 3 3 3 3 0.5 0.1 Time (min) 10 720 720 1440 10 10 10 60 T ( C) r.t. r.t. r.t. r.t. r.t. 0 0 0 Yield (%)b 97 96 77 64 68 97 96 85 eec (%) 88 57 8 28 97 >99 >99 97

In this asymmetric 1,3-dipolar cycloaddition, it seems that azomethine 33 is not a ylid structure, but in the course of the reaction, azomethine 33 actually can generate a ylid intermediate. Ligand (L) as Scheme 9. 1,3-Dipoles are formulated as zwitterionic (mesoionic) octet structures, allylic or propargylic species with heteroatom substitution and this zwitterionic character disappears during the course of the cycloaddition [7e]. Some of compounds such as azomethines are not themselves zwitterionic structures, but can become zwitterionic by charge separation in the reaction process. A latent 1,3-dipole may be proposed herein since azomethine does not appear to be a naked 1,3-dipole. In the catalytic enantioselective 1,3-dipolar cycloaddition reactions of azomethine with alkenes using phosphoramiditesilver(I) complexes, the azomethine actually behaves as a 1,3-dipole [34]. In [3 + 2] cycloadditions based on the highly enantioselective FesulphosCu-mediated 1,3-dipolar cycloaddition of azomethine ylides with trans-1,2-bisphenylsulfonyl ethylene, the azomethine could also behave as a 1,3-dipole [35]. The enantioselective 1,3-dipolar cycloaddition of azomethine ylides is catalyzed by copper(I)/TFbiphamphos complexes and the behaves as a 1,3-dipole [38b]. Park developed a novel regioselective synthesis of tetrasubstituted pyrroles via the classic 1,3-dipolar cycloaddition of ,-unsaturated benzofuran-3(2H)-one and azlactones followed by spontaneous decarboxylation [38c]. The head-to-tail cyclodimerization of resin-bound oligopeptides bearing azide and alkyne groups occurs readily upon treatment with Cu(I), and the process was independent of peptide sequence, sensitive to the proximity of the alkyne to the resin, and sensitive to solvent composition [38d]. 3.3. Organocatalytic Ni(II) and Sc(III)-mediated enantioselective [3 + 2] cycloadditions Asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides catalyzed by chiral binaphthyldiimineNi(II) complexes have been described. Reactions of 2-(2-alkenoyl)-3-pyrazolidinone derivatives were carried out in the presence of chiral binaphthyldiimine (BINIM)Ni(II) complexes as catalysts. By using the (R)-BINIM4(3,5-xylyl)-2QNNi(II) complex (30 mol%), good regioselectivity (4-Me/5-Me) 85:15) along with high enantioselectivity (96% ee) of the (4-Me) adduct were obtained for the reaction between isolable 2,4,6-trimethylbenzonitrile oxide and 3-crotonoyl-5,5-dimethyl2-oxazolidinone [38e] (Scheme 10). Results from Suga have contributed toward the development of chiral Lewis acid catalyzed asymmetric cycloaddition reactions of unstable 1,3-dipoles [38e]. They developed a new BINIMNi(II)

a All of the reaction were carried out with 0.33 mmol of 32 and 0.40 mmol of 33 in 2 mL of solvent. CuBF4 = Cu(CH3 CN)4 BF4 . b Isolated yield. c Determined by HPLC analysis.

The regio- and the endo/exo stereoselectivity of the 1,3-dipolar cycloaddition of methyl 2-phenylthioacrylate (dipolarophile) with nitrones (1,3-dipoles) was reported [38a]. Enantiopure N,O-psiconucleosides were synthesized by using (R)-N-phenylpantolactam as a resolution agent [38a] (Table 5). Copper(I) catalyzes an enantioselective 1,3-dipolar cycloaddition of azomethine ylides with dimethyl maleate. The Cu(I)/TFbiphamPhos complex served as a highly efcient catalyst for the asymmetric 1,3-dipolar cycloaddition reaction with good reactivity and selectivity observed for various azomethine ylides [38b] (Scheme 9).

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945

O Ar C N O

(R)-BINIM-Ni(II)
Y

Ar Me

O O Y

Ar

O Me

Me O

1a
Ar=Mesityl

O Y

Y=
Ph

N N
X

N N

N N

(R)-BINIM-2QN: X=H (R)-BINIM-4Me-2QN: X=Me (R)-BINIM-4Ph-2QN: X=Ph (R)-BINIM-4(3,5-Xylyl)-2QN: X=4(3,5-Xylyl)

Structures of the BINIM ligands

Scheme 10. Asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides catalyzed by chiral binaphthyldiimineNi(II) complexes [38e].

complexes as chiral Lewis acid catalysts for the asymmetric [3 + 2] cycloadditions of nitrile oxide, and the best result in these reactions with 96% ee was achieved. Some asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides catalyzed by chiral binaphthyldiimineNi(II) complexes were described, the products being obtained with high stereoselectivity [10d].

4.1. Pd(0)-catalyzed asymmetric [3 + 2] cycloadditions Trost reported that catalytic asymmetric palladium-catalyzed [3 + 2] cycloaddition of cyano-substituted PdTMM-complexes (Pdtrimethylenemethane complex) with 35 led to spirocyclic oxindolic cyclopentanes. This reaction proceeded under mild conditions generating arrays of up to three stereogenic centers with excellent yields and enantiomeric excesses [39,40]. (Table 6)

Ph O P N O Ph N P O O N P O O

La
Sc(OTf)3 catalyzed intramolecular [3 + 2] cycloaddition of cyclopropane 1,1-diesters with carbonyls and imines is a good method for the construction of chiral bridged [n.2.1] skeletons. The reactions were carried out under the optimized reaction conditions and the chiral cycloadduct products were successfully obtained with 97% ee in 91% yield [38f] (Scheme 11). Sc(OTf)3 catalyzed intramolecular [3 + 2] cycloaddition can be used to access the compact core of platensimycin which is a complex natural product [38f]. 4. Progress in asymmetric non-1,3-dipolar [3 + 2] cycloadditions Usually the 1,3-dipoles used in 1,3-dipolar cycloadditions are azides, nitrones, nitronates, azomethine ylides, carbonyl ylides, thiocarbonyl ylides, nitrile oxides, nitrile ylides and nitrile imines, diazoalkanes [7d]. However, some [3 + 2] cycloadditions do not appear to involve 1,3-dipolar compounds. It seems that naked 1,3dipoles are not involved in these [3 + 2] cycloadditions, but high enantioselectivity and good yields were still successfully obtained.

Lb

Lc

Trost also reported a palladium-catalyzed asymmetric [3 + 2] cycloaddition of trimethylenemethane with imines; a new phosphoramidite ligand effects the palladium-catalyzed asymmetric

2
+

1 CO 2 R - CO 2 R

Lewis Acid

- + X=Y (X=N, Y=C)

1 CO 2R CO 2R X Y Fused [n.3.0]

Type I

2
+

1 CO 2 R - CO 2 R

2 Lewis Acid Y X

1 CO 2R CO 2R

- + X=Y (X=C, Y=N, O)

Type II

Bridged [n.2.1]

Scheme 11. Two types of intramolecular [3 + 2] cycloadditions of cyclo-propane 1,1-diesters [38f].

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Table 6 Initial scope of the substituted TMM [3 + 2] cycloadditiona [39].

TMS 1.5 eq. O N CO 2Me R 35

Substrate 35 (R = H) 35a (R = 6-Cl) 35b (R = 6-MeO) 35c (R = 6,7-MeO) 35d Ligand Lb Lcc Lbb Lcc Lbc Lcd Lbb Lcc
b

CN

CN

CN 36 OAc O N CO 2Me R tr ans- 37

Yield (%) 97 97 90 99 94 94 96 97

O N CO2 Me R cis-38
37/38 1:6.2 4.3:1 1:2.7 19:1 1:2.7 4:1 1.3:1 14:1 37 37a 37b 37c 37d ee (%) 96 92 99 93 95 85 >99 96 38 38a 38b 38c 38d ee (%) >99 95 92 77 99 84 99 80

2.5% Pd2 dba3 CHCl3 10% Ligand, toluene

N MeO2C

Lbb Lcc

99 99

1:2.3 15:1

37e

99 86

38e

99 76

35e

Lbb
O O

99 91

1:5.7 4.6:1

37f

>99 94

38f

>99 92

35f

Lcc

a All reactions were performed at 0.2 M in toluene and stirred for 12 h; yields were combined isolated yields; ees were determined by HPLC with a chiral stationary phase column. b At 20 C. c At 0 C. d At 23 C.

TMM reaction of imines with high ee (Table 7).

O O

P N

Ld
Enantioselective palladium-catalyzed trimethyl-enemethane [3 + 2] cycloadditions provide a new method that is very useful in the asymmetric synthesis of biologically important natural products [41] (Scheme 12).

4.2. Rh(I)-catalyzed intramolecular asymmetric [3 + 2] cycloadditions [3 + 2] Cycloadditions of cyclopropane derivatives have been widely used in recent researches. Vinylcyclopropanes without electron-withdrawing activating groups can act as three-carbon synthons in transition-metal catalyzed cycloadditions by Rh(I)catalyzed intramolecular [3 + 2] cycloadditions. This methodology provided an efcient and diastereoselective approach to fused vemembered ring systems [42a] (Table 8).

(Chiral ligand)
Scheme 12. Asymmetric palladium-catalyzed [3 + 2] cycloadditions of TMM and alkenes [41].

Y. Xing, N.-X. Wang / Coordination Chemistry Reviews 256 (2012) 938952 Table 7 Imine optimization study of [3 + 2] cycloaddition [40].

947

TMS

OAc

+ Ar 1

Ar 2

5 mol% Pd(dba)2 10 mol% Ld toluene, T C

Ar 2 Ar 1

Entry

Substrate

Product

T ( C)

Yield (%)a

ee (%)

1b

N
45 80 82

OCH 3
2

H 3CO N
45 80 84

N Cl Cl H 3CO

OCH 3 N
45 87 83

N Cl Cl F F

N F F

N
4 83 83

Table 8 Optimization studies on the [3 + 2] cycloadditiona [42a].

H TsN conditions TsN H 45

CO (atm) 0.2 1.0 0 0 0 0 0
c

TsN

44
Entry 1 2 3 4 5 6 7
a b c d e

46
T ( C) 80 80 80 80 80 110 50 Solvent Dioxane Dioxane Dioxane Dioxane Dioxane Toluene Toluene t [h] 23 17 17 23 23 5.5 10 Yield (%)b 59 28d 77 13d 21e 83 62

Catalyst (mol%) 5% [Rh(CO)2 Cl]2 5% [Rh(CO)2 Cl]2 5% [Rh(CO)2 Cl]2 10% RhCl(PPh3 )3 10% RhCl(PPh3 )3 + 10% AgOTf 5% [Rh(CO)2 Cl]2 5% [Rh(CO)2 Cl]2 + 10% AgOTf

Racemic VCP-ene 44 was used. Isolated yields. Reaction run with 0.2 atm CO + 0.8 atm N2 . Recovered 52% of 44. Recovered 31% of 44.

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Table 9 Effect of oxophilic Lewis acids on the efciency and diastereoselectivity of 1,2isoxazolidine formation [43].a .

Ns Ph 50
Entry 1 2 3 4 5
a b c

N O H Ph 51

Lewis acid 5 A MS toluene, 23 oC Ph

Ns O N Ph 52

cycloaddition between allenoates and doubly activated olens using novel bifunctional N-acyl aminophosphine catalysts was also reported recently [48]. In 2011, Lu reported enantioselective [3 + 2] cycloadditions mediated by l-threonine-derived phosphines [49]; Kwon also reported phosphine-catalyzed [3 + 2] cycloaddition reaction and other cycloadditions [50a]. 5. Summary and outlook

Catalyst Sc(OTf)3 BF3 Oet2 SnCl4 TiCl4 TiCl4

Loading (mol%) 20 20 20 20 10

t (h) 6 6 6 1 4

Yield (%) 23 58 80 93 95

d.r. (syn/anti) 1.2:1 >10:1 6:1 >10:1 >10:1

Ns = 4-nitrobenzenesulfonyl. Isolated yield. Diastereomer ratio determined by 1 H NMR.

Rh2 (S-DOSP)4 -catalyzed [3 + 2] annulation of indoles was described recently. Depending on the substitution pattern of the indole, two distinct regioisomeric products can be generated with high ee% [42b]. This rhodium-catalyzed [3 + 2] annulation of indoles as [42b]:

A 1,3-dipolar cycloaddition reaction is dened as a reaction involving a dipolarophile and 1,3-dipolar compounds containing one or more heteroatoms which can be described as having at least one mesomeric state structure that represents a charged dipole. Since Huisgen led to the general concept of 1,3-dipolar cycloaddition, this reaction has developed into a very useful method for ve-membered heterocyclic ring synthesis and this area has experienced strong growth. Asymmetric 1,3-dipolar cycloaddition chemistry provides very efcient methods for the synthesis of vemembered heterocyclic ring systems and is extremely useful in the synthesis of many biologically important natural products and medical molecules.

N2 Ph N CO2Me

MeO2C H + N H Ph ratio: 4/1

Ph H CO2Me

Rh2(R -DOSP)4 CH2 Cl2, -45 oC

72% yield 80% ee

17% yield > 99% ee

Generally, click chemistry mainly means the copper(I)catalyzed 1,3-dipolar cycloaddition reaction of azides and acetylenes with regioselectivity together with high yield under ambient conditions. Click chemistry is not a concerted 1,3-dipolar cycloaddition but a stepwise copper(I)-catalyzed process. A metal ion and an organocatalytic ligand as well as the reactants can set up a very complex transition state with stereospecicity; coordination between the metal and the chiral ligand should be stronger than the metal and reactants, resulting in high enantioselectivity in the asymmetric [3 + 2] cycloadditions. A further understanding of these mechanistic details could lead to efcient asymmetric cycloaddition reactions and the development of new organocatalytic and metal-mediated reagents. Recently, lots of research on asymmetric catalysis and transition-metal catalysis has been developed, enantiomeric excesses of these products mostly ranged from 90 to 98% with high yields. Sustmann introduced the FMO theory to the reactivity of concerted 1,3-dipolar cycloadditions for substituted dipolarophilies [50b,50c]. Based on the importance frontier interactions, he classied 1,3-dipolar cycloadditions to three classes, (1) dipole dipolarophile, (2) dipolarophile dipole, or (3) both. First class reactions have the smallest energy separation between the HOMO of 1,3-dipole and the LUMO of dipolarophile. Second class reactions have the opposite direction of charge-transfer. These types of dipolar cycloadditions have the smallest FMO gap between the dipole LUMO and the dipolarophile HOMO orbitals. The third class reactions include almost equivalent FMO gaps. We believe, for the organocatalytic and metal-mediated asymmetric [3 + 2] cycloaddition reactions, since the organocatalysts and metalligand complex can effect the frontier orbitals of both the transition state of 1,3-dipole and the dipolarophile, the regio-, diastereo-, and enantioselectivity can be introduced by the presence of organocatalysts or metalligand complex. Johnson proposed a mechanism on substituent and geometric effects in enantioselective [3 + 2] cycloadditions, cyclopropane

An effective Rh2 (S-DOSP)4-catalyzed asymmetric cyclopentannulation of indolyl rings has been developed by Davies et al. [42b]. 4.3. Sc(III), Ti(IV)-catalyzed asymmetric [3 + 2] cycloadditions The application of oxaziridines as latent 1,3-dipoles was reported by Yoons group. The heterocyclic product presumably arises from a rearrangement of the oxaziridine to a transient Nsulfonyl nitrone that undergoes 1,3-dipolar cycloaddition with styrene (Scheme 13) [43]. Sc(III) and Ti(IV)-catalyzed asymmetric [3 + 2] are described in Table 9. Enantioenriched tetrahydrofuran derivatives were prepared through a dynamic kinetic asymmetric [3 + 2] cycloaddition (Scheme 14) [44a]. Johnson tried to extend this methodology to other asymmetric reactions [44a]. Stereoselective synthesis of 10-hydroxy-trilobacin via a stereodivergent [3 + 2] cycloaddition also was described. This strategy provided a stereochemically diverse library of bis-THF (tetrahydrofuran) acetogenins (Scheme 15) [44b]. By utilizing nonchelate- and chelate-controlled [3 + 2] cycloaddition conditions, the synthesis of three diastereomers was achieved [44b]. Recently Zheng and She completed a platinum-catalyzed tandem reaction involving enynyl ester isomerization and subsequent intramolecular [3 + 2] cyclization [45]. This strategy provides a new approach to ve-, six-, or seven-membered cyclic compounds [45]. A synthetic access to -substituted amino acid derivatives via 1,3-dipolar cycloadditions was reported recently, and the [3 + 2] cycloaddition reactions were investigated under thermal solventfree conditions [46]. A palladium-catalyzed asymmetric addition of a carbon nucleophile to ketimines in the context of a [3 + 2] cycloaddition was also reported [47], providing highly substituted pyrrolidines, and it was possible to obtain high enantioand diastereomeric excesses by matching substrate classes with the appropriate ligand [47]. The asymmetric organocatalytic [3 + 2]

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949

Scheme 13. 1,3-Dipolar cycloaddition of transient N-sulfonyl nitrone with styrene.

CO 2 Me CO 2 Me + MeO X L1: L2: L3: L4: L5: L6: X= X= X= X= X= X= H MeO F3C Ph Mes N3 O H Ph MgI2 (0.10 eguiv) ligand (0.12 equiv), CCl4, rt, 48h MeO 2 C R O CO 2 Me Ph

dr>50:1 [a] R = 4-MeOPh L7: X = N N N L8: X = Cl L9: X = Br

O N
tBu

N N

O
tBu

Ph

Scheme 14. Preparation of enantioenriched tetrahydrofuran derivatives through an asymmetric [3 + 2] cycloaddition. [a] Determined by 1 H NMR spectroscopy of the unpuried product. [b] Determined by 1 H NMR spectroscopy using a mesitylene internal standard. [c] Determined by chiral SFC analysis. [e] Average isolated yield of two trials. [f] With CH2 Cl2 as the solvent. [g] With C7 H8 as the solvent.

Scheme 15. Asymmetric [3 + 2]-annulation reactions [44b].

MeO CO 2Me CO 2Me LA* H R

K int'

O O OMe
K int

LA*

R CH=N-PG k (S)

CO 2Me CO 2 Me R N PG R1

(S)

(R)

CO 2Me CO 2Me

LA*

MeO R H

O O OMe

LA*

R CH=N-PG k (R) R N

CO 2Me CO 2 Me R1

PG

Scheme 16. Summary of observed substituent and geometric effects in enantioselective cyclopropane/aldehyde annulation [50d].

substituent effects was researched [50d] (PG is protecting group) (Scheme 16). Gong reported organocatalytic asymmetric [3 + 2] cycloaddition reaction of isocyanoesters to nitroolens leading to highly optically active dihydropyrroles catalyzed by cinchona alkaloid derivatives to yield 2,3-dihydropyrroles with high diastereoand enantioselectivities (up to >20:1 d.r., >99% ee) [50e]. The proposed mechanism for this asymmetric [3 + 2] cycloaddition

reactions catalyzed by quinidine (QD) derivatives is shown below [50e] (Scheme 17). This review focused on recent advances in the organocatalytic and metal-mediated asymmetric [3 + 2] cycloadditions, including asymmetric 1,3-dipolar and non-1,3-dipolar [3 + 2] cycloaddition reactions. Click chemistry and the development of the 1,3-dipolar cycloaddition reactions as well as other theoretic aspects are elucidated. 1,3-Dipolar cycloadditions will be extremely useful in the

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synthesis of many biologically important natural products and medicinal molecules. Some new developments are emphasized herein with the use of asymmetric [3 + 2] cycloadditions in natural product synthesis. In 2009, Pandey and coworkers reported the synthesis of natural maritidine using intramolecular [3 + 2] cycloaddition as key transformation. The challenging vicinal quaternary and tertiary stereocenters of the 5,10b-ethanophenanthridine skeleton are established in a single step by intramolecular [3 + 2] cycloaddition

MeO

OH

1,3-dipolar cycloaddition of a cyclic formyl-carbonyl ylide. Retrosynthetically, they envisioned that natural product E could be established from protected 8-oxabicyclo[3.2.1]oct-6-en-2-ones F, Rh2 (S-TCPTTL)4 -catalyzed reaction of tert-butyl 2-diazo-5-formyl3-oxopentanoate H with phenylacetylene derivative G could provide coupling product compound F. This work demonstrated the utility of the enantioselective intermolecular 1,3-dipolar cycloaddition of a six-membered cyclic formyl-carbonyl ylide with phenylacetylene dipolarophiles under the inuence of Rh2 (STCPTTL)4 in the synthesis of natural product [52]. OMe MeO OR OR

H O

OH

H O

CO2t Bu

Rh CO2t Bu O

enantioselective 1,3-diapolar cycloaddition

Rh

OMe OR G +

N2 H O CO 2t Bu O

of nonstabilized azomethine ylide. From the retrosynthetic analysis, we could see that natural product maritidine could be prepared by intermediate B which could be synthesized from the AgF catalyzed intramolecular [3 + 2] cycloaddition of compound D [51]. O

MeO H MeO A N

MeO MeO

MeO 2C H N B

MeO2 C MeO H MeO C O N O AgF MeO

MeO2 C O O MeO N TMS

Pyrroloindoline alkaloids are an important class of natural products. In 2010, Reisman group described a convergent method to prepare enantioenriched pyrroloindolines by [3 + 2] cycloaddition. The skeletons of pyrroloindolines could be established in a single step by intermolecular [3 + 2] cycloaddition with excellent yield and high ee value by employing (R)-BINOL as a catalyst in the presence of stoichiometric SnCl4 [53]. O O OR2 1 R N OR 2 H O (R)-BINOL N R1 N H N SnCl4 (1.2 equiv) O o solvent, 23 C Research on the metal-mediated asymmetric cycloaddition reactions are also proceeding in our group [54].

TMS D Very recently, Hashimoto and coworkers published an asymmetric total synthesis of endo-6-aryl-8-oxabicyclo[3.2.1]oct-3-en2-one natural product E from Ligusticum chuanxing Hort using
NO 2 * * N R1 H 3

R 2O 2C R1

C 1

R3

NO 2 2

chiral base(B*)

R3 R 2 O2C

B* B* H R 2 O2C R1 N C R3 C N R1 * R 2O 2C * R3 NO 2

B*- H

NO 2

- B*-H

R3 R 2O 2C

NO 2 * * N R1

Scheme 17. Proposed mechanism for the asymmetric cycloaddition reactions of isocyanoesters to nitroolens catalyzed by a chiral base [50e].

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Acknowledgments We thank the National 973 Program Foundation (No. 2010CB732202) and the Natural Science Foundation of China (21172227) for nancial support. References
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Y. Xing, N.-X. Wang / Coordination Chemistry Reviews 256 (2012) 938952 1996, and in October of the same year he was invited from Sweden to Clemson University and University of Nebraska-Lincoln in USA to continue the postdoctoral research until 1998. In June 1998, he was selected for a Robert A. Welch Foundation Postdoctoral Fellowship in Department of Chemistry at Rice University in USA from June 1998 to May 2000. In May 2000 he returned to Beijing and was appointed Professor at Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, and has been awarded by the Hundred Talent Program of the Chinese Academy of Sciences.

Nai-Xing Wang obtained his MSc from Xian Modern Chemistry Research Institute in 1990 and Ph.D. from Beijing Institute of Technology in 1993. He was appointed as postdoctoral fellow at Institute of chemistry, Chinese Academy of Sciences in 1993, he completed the postdoctoral research in 1995 and was promoted to associate professor there. He moved to Department of Organic Chemistry at Chalmers University of Technology in Sweden and pursued postdoctoral studies in January