1-s2.0-S0010854512000033-main cicloaditii

7/27/2019 1-s2.0-S0010854512000033-main cicloaditii

1/15

Coordination Chemistry Reviews 256 (2012) 938952

Contents lists available at SciVerse ScienceDirect

Coordination Chemistry Reviews

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c c r

Review

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

Yalan Xing a, Nai-Xing Wang b,

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

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938

2. Copper(I)-catalyzed [3 + 2 ] cycloadditions of organic azides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939

3. Recent progress in asymmetric 1,3-dipolar cycloaddition reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941

3.1. Organocatalytic metal-free and Ag(I)-mediated enantioselective [3+2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941

3.2. Organocatalytic Cu(II) , Cu(I) and Au(I)-mediated enantioselective [3+2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9413.3. Organocatalytic Ni(II) and Sc(II I)-mediated enantioselective [3+2] cycloadditions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 944

4. Progress in asymmetric non-1,3-dipolar [3 + 2 ] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945

4.1. Pd(0)-catalyzed asymmetric [3 + 2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945

4.2. Rh (I)-cata lyzed in tramo lecular asymmetric [3 + 2] c yclo additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 946

4.3. Sc(III), Ti(IV)-catalyzed asymmetric [3 + 2 ] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 948

5. Summary and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 948

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951

a r t i c l e i n f o

Article history:

Received 4 July 2011

Accepted 1 January 2012Available online 21 January 2012

Keywords:

[3 + 2] cycloadditions

1,3-Dipolar cycloaddition reactions

Asymmetric cycloadditions

Asymmetric catalysis

Organocatalysts

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 andmetal-mediated asymmetric [3+ 2] cycloadditions are summarized. In addition, an understanding of the

mechanisticdetails whichlead to efficient stereoselectivityin organocatalytic and metal-mediatedasym-

metric [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.

1. Introduction

The synthesis of complex heterocyclic compounds in a stere-

ospecific manner is an important area of organic chemistry.

Cycloaddition reactions offer a very important strategy in thesynthesis of many heterocyclic compounds. Recently, asymmet-

ric [3 + 2] cycloaddition reactions using chiral organocatalysts

mediated by different metals have provided new methods for

the construction of stereochemically complex heterocyclic com-

pounds. Specifically, [3 + 2] cycloaddition is an excellent approach

for the synthesis of many types of five-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: [email protected] (N.-X. Wang).

cycloaddition is a broad concept that includes 1,3-dipolar cycload-

ditions which provide a very efficient 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 azidesand acetylenes. During the past few years, the number of publi-

cations 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 withorganocatalysts

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

efficient way to synthesize complex natural products and medic-

inal molecules [1a]. In other words, cycloaddition reactions that

involve 1,3-dipoles reacting with-bonds of dipolarophiles to give

0010-8545/$ see front matter 2012 Elsevier B.V. All rights reserved.

doi:10.1016/j.ccr.2012.01.002
http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.ccr.2012.01.002http://www.sciencedirect.com/science/journal/00108545http://www.elsevier.com/locate/ccrmailto:[email protected]://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.ccr.2012.01.002http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.ccr.2012.01.002mailto:[email protected]://www.elsevier.com/locate/ccrhttp://www.sciencedirect.com/science/journal/00108545http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.ccr.2012.01.002


2/15

Y. Xing, N.-X. Wang / Coordination Chemistry Reviews 256 (2012) 938952 939

five-membered rings are called [3 + 2] cycloaddition reactions [1b].

A 1,3-dipole usually contains heteroatoms and four -electronswhich 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, car-

bonyl 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, stereospeci-

ficity 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 confirms the con-

certed nature of 1,3-dipolar cycloadditions [3a]. Houk also reported

the dynamics of the 1,3-dipolar cycloaddition reactions of diazo-

nium 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 reactionrate [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-dipolarmoleculelikethe nitrile ylidePh C N+ CH2,has

a HOMO of6.4 eV and an electron deficient alkene CH2 CHCHO

has a LUMO +0.6eV [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 sub-

stituents in [3 + 2] reactions [5b].

Engels analyzed the reactivity of 1,3-dipolar cycloadditions andsuggested that reaction rates and regioselectivities could be ratio-

nalized by means of frontier orbital theory [5c]. Engels found that

the activation enthalpies of etheneand ethyne in a given 1,3-dipole

are the same. Onthe 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 (1.5eV) is lower in energy than

the respective frontier orbitals of ethyne (11.5 and 2.5eV, respec-

tively) [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 inheterocyclic 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 (N3R) [9], a lot

of papers were published that include a range of [3 + 2] cycload-

dition 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 partic-

ularthe Cu(I)-catalyzed stepwise variant,is oftenreferredto simply

as the click reaction [9a]. Click chemistry includes the copper(I)-

catalyzedcycloaddition reaction of azides and acetylenes withhigh

regioselectivity together with high yield under ambient conditions

N N N

R

N N N

R

Scheme 1. Molecular structure of azides [11].

[9]. Click chemistry is not a normal concerted 1,3-dipolar cycload-

ditions.

Many earlier reports of [3 + 2] cycloaddition reactions did not

involve chiral compounds. Recently many 1,3-dipolar cycload-dition 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 enan-

tioselective [3 + 2] cycloadditionreactions 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

importantroles for these asymmetric [3 + 2] reactions. Pellissierhas

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] cycloaddi-

tion reactions in 2002 and the reactions in this review did not

include asymmetric examples [10f].

Researchon 1,3-dipolar cycloaddition reactions usingasymmet-

ric 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 thisreview, some recent advancesfocused on organocatalytic

and metal-mediated asymmetric 1,3-dipolar cycloaddition reac-

tions have been summarized, most references coming from topchemical 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

(Scheme1), and1,3-dipolarcycloadditionsof azidederivativeswith

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,nitronesand 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 cycload-

dition (CuAAC) and reported it involves multiple reversible steps

on coordination complexesof copper(I)acetylides of varying nucle-

arity [9c]. Copper catalysts drastically change the mechanism and


3/15

940 Y. Xing, N.-X. Wang / Coordination Chemistry Reviews 256 (2012) 938952

N N N

R 2

R 1

+click chemistry

CuI

NN

NR2

R 1

1

4

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

NaN3/DMF

48 h, 70oC

C18

H34

15 min

1 2 3

O

Si OO

Br

O

Si OO

N

N+N

O

Si OO

N

N

N

15

9 9 9

RT

Scheme 3. Click reaction byCP [1]. Bromo-terminated SAMon a Si/SiO2 substrate

[2]. Azido-terminated SAM [3]. Triazole SAM after CP of 1-octadecyne onto azido-

terminated SAM.

the outcome of the reaction, converting it to a sequence of discrete

steps culminating in the formation of a 5-triazolyl copper interme-

diate. The key C N bond-forming event takes place between the

nucleophilic, vinylidene-like -carbon of copper(I) acetylide andtheelectrophilic terminalnitrogenof thecoordinatedorganicazide.

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) ofacetylenes onto azido-terminated SAMs (self-assembled monolay-

ers) on silicon oxide substrates. This showed that click chemistry

can be applied to the microcontact printing of acetylenes ontoazido-terminated SAMs (Scheme 3) [12].

4-Substituted1-(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. Kirshen-

baum recently reviewed copper-catalyzed azidealkyne [3 + 2]

cycloadditions and mainly discussed modifications of pep-

tidomimetic oligomers [25d]. The dicopper-substituted -Kegginsilicotungstate TBA4[-H2SiW10O36Cu2(-1,1-N3)2] (TBA: tetra-n-butylammonium) shows high catalytic activity for the regios-

elective 1,3-dipolar cycloaddition of organic azides to alkynes.

Kinetic, spectroscopic, mechanistic, and computational investiga-

tions 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

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

concerted mechanism when the dominant FMO interaction is the

HOMOdipole with the LUMOalkene. When 1,2-disubstituted alkenesare involved in concerted [4s +2s]-cycloaddition reactions with1,3-dipoles, two new chiral centers can be formed in a stereospe-

cific 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

reactionsare powerfultools for stereospecificcreationof newchiral

centers in organic molecules.

1,3-Dipolar cycloadditionreactions can take place by a stepwise

reaction involving an intermediate and in these cases the stere-

ospecificity 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 first click reac-tion.

The concerted 1,3-dipolar cycloaddition is a reaction in which

all bond breaking and bond making occur in a single step, reac-

tive 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 mechanismvia an aromatic transition state by computa-

tional analysis, including previously reported computational data

[26e].

SharplessMeldal click reactions withcopper(I) catalysisare not

subject to a concerted 1,3-dipolar cycloaddition because of a step-

wise copper(I)-catalyzed process [26bd].

1,3-Dipolar cycloadditions have been employed to con-

struct 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 cyclohex-

anone to nitrostyrenes with an excellent stereoselectivity (syn/anti

up to 99:1, ee up to 96%) [27].

Click chemistry simplifies the synthesis of efficient 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 remark-

able improvement for the synthesisof metal-labeled conjugates for

diagnostic purposes (Scheme 5).

An efficient 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 tria-

zoles 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].


4/15


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

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 efficient,

simple and green routes to design dendrimer macromolecules[29e]. Polymerizationby a click reaction was summarized recently,

and research to incubate alkyne-azide click reactions into a versa-

tile 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 animpressive rate since 2000; an increasing trend in the use of metal-

free catalysts is seen because of the high cost of transition metals

[30,31]. Asymmetric 1,3-dipolar cycloadditions using organocatal-

ysis occupy a prominent position in chiral synthesis because they

provide some of the most efficient methods for creating chiral cen-

terswith excellentcontrolof stereochemistry, which has permitted

the preparation of a number of valuable chiral compounds andnat-

ural products. Vesterager summarized some of these reactions but

the references cited were only from 1994 to 2001 [7d].

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 stereospecificity. Usu-

ally coordination between the metal and the chiral ligand should

be stronger than the metal and reactants resulting in high enan-

tioselectivity. 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 enan-

tioselective[3 + 2] cycloaddition reactionbetween,-unsaturatedaldehydes andazomethineylides. Thisreaction proceedswith com-

plete regioselectivity and high diastereo- and enantioselectivity to

furnish almost stereoisomerically pure functionalized polysubsti-

tuted pyrrolidines (Table 1) [32].

Scheme 7. Chiral phosphoramide-catalyzed 1,3-dipolar cycloaddition of diaryl

nitrones with ethyl vinyl ether. Tf = trifluoromethanesulfonyl [33a].

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

N

OEtOEt

OO

N

OEt

O

H

OEt

O

R1 R1

The use of a Brnsted acid as catalyst in the 1,3-dipolar cycload-

dition 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].

Recentlyenantioselective[3 + 2] cycloaddition of allenes to acry-

lates 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 regiospe-

cific and enantioselective manner [33b].

Catalytic enantioselective 1,3-dipolar cycloaddition reac-

tions of azomethine ylides and alkenes use a monodentate

phosphoramiditesilver complex. This novel complex is a very

efficient chiral catalyst for a wide range of 1,3-dipolar cycload-

dition reactions between azomethine ylides and dipolarophiles

[34a]. Chiral phosphoramidite catalysts are shown in Table 2.

O

O

P N

Monophos 14

L*= O

O

P N

(Sa,R,R-15)

L* AgClO4 16

L2* AgClO4 17

Ph

Ph

Efficient chiral silver amide-catalyzed enantioselective [3 + 2]

cycloaddition of-amino-phosphonates with olefins was reported[34b]. A chiral silver amide catalyzes the [3 + 2] cycloaddition of

aminoester Schiff bases to olefins [34c]; this afforded the corre-

sponding pyrrolidine derivatives in high yields with high exo- and

enantioselectivities with several activated olefins. A silver complexprepared from AgHMDS (HMDS = hexamethyldisilazide) and a chi-

ral phosphine ligand worked as an efficient 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 reac-

tion, using highly enantioselective [3 + 2] cycloadditions based on

the Fesulphos-Cu-mediated 1,3-dipolar cycloaddition of azome-

thine 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].


5/15


Table 1

[3 + 2] Cycloaddition reaction of4 and crotonaldehyde [33a]a .

N CO2Et

CO2Et+

H

OCatalyst

(20 mol%)

NH

CO2Et

CO2Et

Ph

OHC

NH

R

COOH

6 R=H7 R=OH8 R=OTBS

9

NH

N

O

10

NH

Ar

Ar

OR

11 Ar=Ph, R=H12 Ar=Ph, R=TMS13 Ar=3,5-(CF3)2C6H3, R=H

4 5

NH Ph

Ph

Ph

Ph

Entry Catalyst Solvent T(C) Yield (%)b Endo/exoc ee (%)d

1 6 DMF 30 77 >95:5 72

2 7 DMF 30 60 >95:5 82

3 8 DMF 30 44 90:10 84

4 9 DMF 30 86 60:40 5

5 10 DMF 30 95:5 >99

7 12 DMF 30 95:5 >999 11 DMF 4 67 >95:5 98

10 11 THF 4 65 >95:5 98

11 11 THFe 4 89 >95:5 98

12 11 THFe , f 4 55 >95:5 97

13 11 THFe , g 4 79 >95:5 98

DMF, N,N-dimethylformamide; TBS, tert-butyldimethylsily; TMS, trimethylsilyl; n.d., not determined.a Reactions were carried out with 4 (0.75mmol), crotonaldehyde (0.70 mmol), and the catalyst (0.14mmol) 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 1H NMR spectroscopic analysis of the crude reaction mixture.d Determined by HPLC analysis of the corresponding alcohol on a chiral phase.e H2O (4.0 equiv) was used as an additive.f PhCO2H (0.14 mmol) was used as an additive.

g Catalyst: 10 mol%.

Arai developed a new bis(imidazolidine)pyridineCu(II) complexfor the highly endoselective [3 + 2] cycloaddition of imino esters

to nitroalkenes. The unique reaction sphere produced by pyri-

dine has the potential to furnish highly efficient asymmetric

catalysis [35b]. A general procedure for the catalytic asymmetric

1,3-dipolar cycloaddition of (Z)-sulfonyl acrylates with azome-

thine 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 thecatalyst system [35c]. Interestingly, in this process the phenyl-

sulfonyl 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 man-ifolds 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].

Ph N CO2Me

CO2tBu

chiral ligand (5 mol%)

Ag 1 salt (5 mol%)

NH

CO2MePh

tBuO2C

endo-19

18

Et3N (5 mol%)toluene, RT, 8h

Entry Ag1 salt Ligand Conv. (%) e.r.a

1 AgClO4 14 98 76:24

2 AgClO4 15 98 85:15

3 AgClO4 15b 95 74:26

4 AgOAc 15 98 80:20

5 AgOTf 15 98 84:16

6 AgF 15 90 76:24

7 AgBF4 15 95 60:40

8 AgClO4 15c 98 90:10

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

Reaction performed at 20

C.


6/15


7/15


NPh

O

O

+ O

N

O

Me

Ph

2 mol% (S)-Cy-SEGPHOS(AuOBz)2, PhF

TMSCHN276% yield, 95% ee

N

NPh

O O

PhCO2Me

Me

HOBz [AuL]OBz

O

N

O

Me

Ph[AuL]

NPh

O

O

[3+2]

NPh

OO

N

Me

OO

[AuL]

Ph

N

NPh

O O

PhCO2H

Me

TMSCHN2

Scheme 8. 1,3-Dipolar cycloadditions of mnchnone with electron-deficient 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 Ligand Cu/L (mol) Time (min) T(C) Yield (%)b eec (%)

1 1a 3 10 r.t. 97 88

2 1b 3 720 r.t. 96 57

3 1c 3 720 r.t. 77 8

4 1d 3 1440 r.t. 64 28

5 1e 3 10 r.t. 68 97

6 1e 3 10 0 97 >99

7 1e 0.5 10 0 96 >99

8 1e 0.1 60 0 85 97

a All of the reaction were carried out with 0.33 mmol of32 and 0.40mmol of33

in 2 mL of solvent. CuBF4 = Cu(CH3CN)4BF4.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-psico-

nucleosides were synthesized by using (R)-N-phenylpantolactam

as a resolution agent [38a] (Table 5).

Copper(I) catalyzes an enantioselective 1,3-dipolar cycloaddi-

tion of azomethine ylides with dimethyl maleate. The Cu(I)/TF-

biphamPhos complex served as a highly efficient catalyst for the

asymmetric 1,3-dipolar cycloaddition reaction with good reactiv-

ity and selectivity observed for various azomethine ylides [38b]

(Scheme 9).

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 sub-

stitution 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 azome-

thine 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 Fesulphos-

Cu-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-dipolarcycloaddition of azomethine ylides is catalyzed by copper(I)/TF-

biphamphos complexes and the behaves as a 1,3-dipole [38b].

Park developed a novel regioselective synthesis of tetra-

substituted pyrroles via the classic 1,3-dipolar cycloaddition

of ,-unsaturated benzofuran-3(2H)-one and azlactones fol-lowed 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 com-

position [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 deriva-

tives were carried out in the presence of chiral binaphthyldiimine

(BINIM)Ni(II) complexes as catalysts. By using the (R)-BINIM-

4(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-dimethyl-

2-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)


8/15


Ar C N O +Me

O

Y

(R)-BINIM-Ni(II)O

N

Me

Ar

O

Y

ONAr

MeO

Y

+

1a

Ar=Mesityl

N

NY=

O

Ph

N

N

N

N

X

X

(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 thesereactions

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 stereose-

lectivity [10d].

Sc(OTf)3 catalyzed intramolecular [3 + 2] cycloadditionof cyclo-

propane 1,1-diesters with carbonyls and imines is a good method

for the construction of chiral bridged [n.2.1] skeletons. The reac-

tions 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 com-

plex 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 seemsthat naked 1,3-

dipoles are not involved in these [3 + 2] cycloadditions, but high

enantioselectivity and good yields were still successfully obtained.

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)

O

O

P N

Ph

Ph

O

O

PNO

O

PN

La Lb Lc

Trost also reported a palladium-catalyzed asymmetric [3 + 2]

cycloaddition of trimethylenemethane with imines; a new phos-

phoramidite ligand effects the palladium-catalyzed asymmetric

CO2R

CO2

R

+ -

- +

X=Y

(X=N, Y=C)

CO2R

CO2R

+ -

- +

X=Y

12

2 1

Lewis Acid X YCO2RCO2R12

Fused [n.3.0]

(X=C, Y=N, O)

Lewis Acid Y XCO2RCO2R1

2

Bridged [n.2.1]

Type I

Type II

Scheme 11. Two types of intramolecular [3 + 2] cycloadditions of cyclo-propane

1,1-diesters [38f].


9/15


Table 6

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

NCO2Me

O

R

CN

TMS

OAc36

1.5 eq.

2.5% Pd2dba3 CHCl310% Ligand, toluene

NCO2Me

O

R

CN

NCO2Me

O

CN

+

R

trans-37 cis-3835

Substrate 35 Ligand Yield (%) 37/38 37 ee (%) 38 ee (%)

(R = H) Lbb 97 1:6.2 37a 96 38a >99

35a Lcc 97 4.3:1 92 95

(R = 6-Cl) Lbb 90 1:2.7 37b 99 38b 92

35b Lcc 99 19:1 93 77

(R = 6-MeO) Lbc 94 1:2.7 37c 95 38c 99

35c Lcd 94 4:1 85 84

(R = 6,7-MeO) Lbb 96 1.3:1 37d >99 38d 99

35d Lcc 97 14:1 96 80

N

O O

MeO2C 35e

Lbb 99 1:2.3 37e 99 38e 99

Lcc 99 15:1 86 76

O

O

35f

Lbb 99 1:5.7 37f >99 38f >99

Lcc 91 4.6:1 94 92

a All reactions were performed at 0.2M in toluene and stirred for 12h; 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 inthe asymmetric synthesis of biologically important natural prod-

ucts [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 efficient and diastereoselective approachto fusedfive-

membered ring systems [42a] (Table 8).

(Chiral ligand)

Scheme 12. Asymmetric palladium-catalyzed [3 + 2] cycloadditions of TMM and

alkenes [41].


10/15


Table 7

Imine optimization study of [3+ 2] cycloaddition [40].

TMS OAc +N

Ar2

Ar1

NAr2

Ar1

mol%5 Pd(dba)210 mol% Ld

toluene, T C

Entry Substrate Product T( C) Yield (%)a ee (%)

1b N

N

45 80 82

2 N

Cl

OCH3

N

H3CO

Cl

45 80 84

3 N

H3CO

Cl

N

OCH3

Cl

45 87 83

4 N

F

F

N

F

F

4 83 83

Table 8

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

TsNconditions

TsN

H

H

44 45

TsN

46

Entry CO (atm) Catalyst (mol%) T(C) Solvent t[h] Yield (%)b

1 0.2c 5% [Rh(CO)2Cl]2 80 Dioxane 23 59

2 1.0 5% [Rh(CO)2Cl]2 80 Dioxane 17 28d

3 0 5% [Rh(CO)2Cl]2 80 Dioxane 17 77

4 0 10% RhCl(PPh3)3 80 Dioxane 23 13d

5 0 10% RhCl(PPh3)3 + 10% AgOTf 80 Dioxane 23 21e6 0 5% [Rh(CO)2Cl]2 110 Toluene 5.5 83

7 0 5% [Rh(CO)2Cl]2 + 10% AgOTf 50 Toluene 10 62

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


11/15


Table 9

Effect of oxophilic Lewis acids on the efficiency and diastereoselectivity of 1,2-

isoxazolidine formation [43].a .

ONNs

PhH

Lewis acid

5 A MS

toluene, 2 3 oC

NONs

PhPh

+

51 5250

Ph

Entry Catalyst Loading (mol%) t(h) Yield (%)b d.r.c (syn/anti)

1 Sc(OTf)3 20 6 23 1.2:1

2 BF3 Oet2 20 6 58 >10:1

3 SnCl4 20 6 80 6:1

4 TiCl4 20 1 93 >10:1

5 TiCl4 10 4 95 >10:1

a Ns = 4-nitrobenzenesulfonyl.b Isolated yield.c Diastereomer ratio determined by 1H 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]:

N

Ph CO2Me

N2

Rh2(R-DOSP)4

CH2Cl2, -45oC

N

H

HPh

MeO2C

N

H

H

Ph

CO2Me+

72% yield 80% ee 17% yield > 99% eeratio: 4/1

An effective Rh2(S-DOSP)4-catalyzed asymmetric cyclopentan-

nulation 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 N-sulfonyl 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] cycload-

dition conditions, the synthesis of three diastereomers wasachieved [44b].

Recently Zheng and She completed a platinum-catalyzed tan-

dem reaction involving enynyl ester isomerization and subsequent

intramolecular [3 + 2] cyclization [45]. This strategy provides a new

approach to five-, six-, or seven-membered cyclic compounds [45].

A synthetic access to -substituted amino acid derivatives via1,3-dipolar cycloadditions was reported recently, and the [3 + 2]

cycloaddition reactions were investigated under thermal solvent-

free 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 substi-

tuted pyrrolidines, and it was possible to obtain high enantio-

and diastereomeric excesses by matching substrate classes with

the appropriate ligand [47]. The asymmetric organocatalytic [3 + 2]

cycloaddition between allenoates and doubly activated olefins

usingnovel 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];

Kwonalso reportedphosphine-catalyzed [3 + 2] cycloadditionreac-

tion and other cycloadditions [50a].

5. Summary and outlook

A 1,3-dipolar cycloaddition reaction is defined as a reaction

involving a dipolarophile and 1,3-dipolar compounds containing

one or more heteroatoms whichcan be described as havingat least

one mesomeric state structure that represents a charged dipole.

Since Huisgen led to the general concept of 1,3-dipolar cycload-

dition, this reaction has developed into a very useful method

for five-membered heterocyclic ring synthesis and this area has

experienced strong growth. Asymmetric 1,3-dipolar cycloaddition

chemistryprovides very efficient methods for the synthesis of five-

membered heterocyclic ring systems and is extremely useful in

the synthesis of many biologically important natural products and

medical molecules.

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

ionand an organocatalytic ligandas well as thereactants canset up

a verycomplex transition state withstereospecificity;coordinationbetween 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 understandingof these

mechanistic details could lead to efficient asymmetric cycloaddi-

tion 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, enan-

tiomeric 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 dipo-

larophilies [50b,50c]. Based on the importance frontier interac-

tions, he classified 1,3-dipolar cycloadditions to three classes, (1)

dipoledipolarophile,(2) dipolarophiledipole, or (3) both.Firstclass 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

typesof dipolar cycloadditions havethe 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 asym-

metric [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 pres-

ence of organocatalysts or metalligand complex.

Johnson proposed a mechanism on substituent and geomet-

ric effects in enantioselective [3+ 2] cycloadditions, cyclopropane


12/15


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

MeO

CO2Me

CO2Me

O Ph

H

O

CO2Me

MeO2C

R Ph+

MgI2(0.10 eguiv)

ligand(0.12 equiv),CCl4, rt, 48h dr>50:1 [a]

R= 4-MeOPh

N

X

O

N N

O

tBu tBu

L1: X = HL2: X = MeOL3: X = F3CL4: X = PhL5: X = MesL6: X = N3

N

N

NL7: X =

L8: X = ClL9: X = Br

Ph

Scheme 14. Preparation of enantioenriched tetrahydrofuran derivatives through an asymmetric [3 + 2] cycloaddition. [a] Determined by 1H NMR spectroscopy of the unpu-

rified product. [b] Determined by 1H NMR spectroscopy using a mesitylene internal standard. [c] Determined by chiral SFC analysis. [e] Average isolated yield of two trials.

[f] With CH2Cl2 as the solvent. [g] With C7H8 as the solvent.

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

CO2Me

CO2Me

R R

H

MeO O

OMe

O

H

R

MeO O

OMe

O

LA*

LA*

CO2Me

CO2Me

R

(S)

(R)

R1CH=N-PG

k(S)

k(R)

R

1

CH=N-PG

N

CO2MeCO2Me

R R1

PG

N

CO2MeCO2Me

R R1

PG

KintKint'

LA*

LA*

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] cycloaddi-

tion reaction of isocyanoesters to nitroolefins leading to highly

optically active dihydropyrroles catalyzed by cinchona alkaloid

derivatives to yield 2,3-dihydropyrroles with high diastereo-

and 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 eluci-

dated. 1,3-Dipolar cycloadditions will be extremely useful in the


13/15


14/15


Acknowledgments

We thank the National 973 Program Foundation (No.

2010CB732202) and the Natural Science Foundation of China

(21172227) for financial support.

References

[1] (a) E.J. Corey, Angew. Chem. Int. Ed. 48 (2009) 2100;

(b)M.B.Smith, Organic Synthesis, seconded.,The McGraw-Hill Inc., NewYork,2002, p. 999.

[2] M.B. Smith, J. March, Marchs Advanced Organic Chemistry, fifth ed., Wiley-Interscience, New York, 2001, p. 1059.

[3] (a) L. Xu, C.E. Doubleday, K.N. Houk, J. Am. Chem. Soc. 132 (2010) 3029;(b) D.H. Ess, K.N. Houk, J. Am. Chem. Soc. 130 (2008) 10187;(c) L. Xu, C.E. Doubleday, K.N. Houk, Angew. Chem. Int. Ed. 48 (2009) 2746.

[4] (a) R.A. Firestone, J. Org. Chem. 33 (1968) 2285;(b) R.A. Firestone, J. Org. Chem. 37 (1972) 2181;(c) B. Braida, C. Walter, B. Engels, P.C. Hiberty, J. Am. Chem. Soc. 132 (2010)7631.

[5] (a) K.N. Houk, J. Sims, R.E. Duke, R.W. Strozier, J.K. George, J. Am. Chem. Soc. 95(1973) 7287;(b) I. Fleming, Molecular Orbitals and Organic Chemical Reactions, ReferenceEdition, John Wiley & Sons, West Sussex, 2010, p. 322;(c) B. Engels, M. Christl, Angew. Chem. Int. Ed. 48 (2009) 7968.

[6] H.C. Shen, Tetrahedron 64 (2008) 7847.[7] (a) R. Huisgen, in: A. Padwa (Ed.), 1,3-Dipolar Cycloaddition Chemistry, Wiley,

New York, 1984, p. 1;(b) A. Padwa, in: B.M. Trost (Ed.), Comprehensive Organic Synthesis, vol. 4,Pergamon, Oxford, 1991, p. 1069;(c) J. Mulzer, Org. Synth. Highlights (1991) 77;(d)A. Padwa,W.H.Pearson, SyntheticApplicationsof 1,3-DipolarCycloadditionChemistryTowardHeterocycles andNaturalProducts, Wiley, NewJersey,2003,p. 817;(e) R. Huisgen, Angew. Chem. 75 (1963) 604.

[8] (a) A. Krasinski, Z. Radic, R. Manetsch, J. Raushel, P. Taylor, K.B. Sharpless, H.C.Kolb, J. Am. Chem. Soc. 127 (2005) 6686;(b) T.S. Seo, X. Bai, H. Ruparel, Z. Li, N.J. Turro, J. Ju, Proc. Natl. Acad. Sci. U. S. A.101 (2004) 5488.

[9] (a) H.C. Kolb, M.G. Finn, K.B. Sharpless, Angew. Chem. Int. Ed. 40 (2001) 2004;(b) V.V.Rostovtsev, L.G.Green, V.V.Fokin, K.B.Sharpless, Angew. Chem. Int.Ed.41 (2002) 2596;(c) J.E. Hein, V.V. Fokin, Chem. Soc. Rev. 39 (2010) 1302.

[10] (a) K.V. Gothelf, K.A. Jrgensen, Chem. Rev. 98 (1998) 863;(b) C. Njera, J.M. Sansano, Angew. Chem. Int. Ed. 44 (2005) 6272;(c) H. Pellissier, Tetrahedron 63 (2007) 3235;

(d) G. Pandey, P. Banerjee, S.R. Gadre, Chem. Rev. 106 (2006) 4484;(e) M. Meldal, C.W. Torne, Chem. Rev. 108 (2008) 2952;(f) H.W. Frhauf, Coord. Chem. Rev. 230 (2002) 79;(g) N.T. Patil, Y. Yamamoto, Chem. Rev. 108 (2008) 3395;(h) C. Njera, J.M. Sansano, Chem. Rev. 107 (2007) 4584;(i)P. Appukkuttan, V.P.Mehtaa, E.V.E.V.Eycken, Chem.Soc.Rev. 39 (2010)1467.

[11] (a) G.D. Buckley, J. Chem. Soc. 1850 (1954);(b) R. Huisgen, L. Mbius, G. Szeimies, Chem. Ber. 98 (1965) 1138;(c) W. Kirmse, L. Horner, Annalen 614 (1958) 1.

[12] D.I. Rozkiewicz,D. Janczewski,W. Verboom, B.J.Ravoo, D.N.Reinhoudt, Angew.Chem. Int. Ed. 45 (2006) 5292.

[13] E.J. Yoo, M.Ahlquist, S.H. Kim, I.Bae,V.V.Fokin, K.B. Sharpless,S. Chang,Angew.Chem. Int. Ed. 46 (2007) 1730.

[14] C. Nolte, P. Mayer, B.F. Straub, Angew. Chem. Int. Ed. 46 (2007) 2101.[15] J.F. Lutz, Angew. Chem. Int. Ed. 46 (2007) 1018.[16] Y. Angell, K. Burgess, Angew. Chem. Int. Ed. 46 (2007) 3649.[17] M.V. Gil, O.A. Lpez, Synthesis 11 (2007) 1589.[18] P. Bertrand, J.P. Gesson, J. Org. Chem. 72 (2007) 3596.[19] S.Chassaing,M. Kumarraja, A.Sani,S. Sido,P. Pale,J. Sommer, Org. Lett.9 (2007)

883.[20] L. Bosch, J. Vilarrasa, Angew. Chem. Int. Ed. 46 (2007) 3926.[21] Y. Angell, K. Burgess, Angew. Chem. Int. Ed. 46 (2007) 3649.[22] C. Spiteri, J.E. Moses, Angew. Chem. Int. Ed. 49 (2010) 31.[23] A. Aureggi, G. Sedelmeier, Angew. Chem. Int. Ed. 46 (2007) 8440.[24] P.Y. Jin, P. Jin, Y.A. Ruan, Y. Ju, Y.F. Zhao, Synlett 19 (2007) 3003.[25] (a) S.A. Rogers, C. Melander, Angew. Chem. Int. Ed. 47 (2008) 5229;

(b)M. Jurcek, P.H.J.Kouwer, J. Rehk,J. Sly, A.E. Rowan,J. Org. Chem. 74 (2009)21;(c) W. Yan, Q. Wang, Y. Chen, J.L. Petersen, X. Shi, Org. Lett. 12 (2010) 3308;(d) J.M. Holub, K. Kirshenbaum, Chem. Soc. Rev. 39 (2010) 1325.

[26] (a) K. Kamata, Y. Nakagawa, K. Yamaguchi, N. Mizuno, J. Am. Chem. Soc. 130(2008) 15304;(b) C.W. Torne, C. Christensen, M. Meldal, J. Org. Chem. 67 (2002) 3057;(c) F. Himo, T. Lovell, R. Hilgraf, V.V. Rostovtsev, L. Noodleman, K.B. Sharpless,V.V. Fokin, J. Am. Chem. Soc. 127 (2005) 210;(d) R. Huisgen, H. Giera, K. Polborn, Tetrahedron 61 (2005) 6143;(e) J.E. Hein, J.C. Tripp, L.B. Krasnova, K.B. Sharpless, V.V. Fokin, Angew. Chem.

Int. Ed. 48 (2009) 8018.

[27] S. Luo, H. Xu, X. Mi, J. Ji, X. Zheng, J.P. Cheng, J. Org. Chem. 71 (2006) 9244.[28] T. Mindt, H. Struthers, L. Brans, T. Anguelov, C. Schweinsberg, V. Maes, D.

Tourwe, R. Schibli, J. Am. Chem. Soc. 128 (2006) 15096.[29] (a) V. Declerck, L. Toupet, J. Martinez, F. Lamaty, J. Org. Chem. 74 (2009) 2004;

(b) J.C. Jewett, E.M. Sletten, C.R. Bertozzi, J. Am. Chem. Soc. 132 (2010) 3688;(c) J.C. Jewetta, C.R. Bertozzi, Chem. Soc. Rev. 39 (2010) 1272;(d) M.G. Finn, V.V. Fokin, Chem. Soc. Rev. 39 (2010) 1231;(e) G. Franc, A.K. Kakkar, Chem. Soc. Rev. 39 (2010) 1536;(f) A. Qin, J.W.Y. Lam, B.Z. Tang, Chem. Soc. Rev. 39 (2010) 2522.

[30] B. List, Chem. Rev. 107 (2007) 5413.[31] H. Pellissier, Tetrahedron 63 (2007) 9267.

[32] J.L. Vicario, S. Reboredo, D. Bada, L. Carrillo, Angew. Chem. Int. Ed. 46 (2007)5168.

[33] (a) P. Jiao, D. Nakashima, H. Yamamoto, Angew. Chem. Int. Ed. 47 (2008)2411;(b) X.Y. Han, Y.Q. Wang, F.R. Zhong, Y.X. Lu, J. Am. Chem. Soc. 133 (2011)1726.

[34] (a) C. Njera, M.G. Retamosa, J.M. Sansano, Angew. Chem. Int. Ed. 47 (2008)6055;(b) Y. Yamashita, X.X. Guo, R. Takashita, S. Kobayashi, J. Am. Chem. Soc. 132(2010) 3262;(c) Y. Yamashita, T. Imaizumi, S. Kobayashi, Angew. Chem. Int. Ed. 50 (2011)4893.

[35] (a) A. Lpez-Prez, J. Adrio, J.C. Carretero, J. Am. Chem. Soc. 130 (2008) 10084;(b) T. Arai, A. Mishiro, N. Yokoyama, K. Suzuki, H. Sato, J. Am. Chem. Soc. 132(2010) 5338;(c) A. Lpez-Prez, J. Adrio, J.C. Carretero, Angew. Chem. Int. Ed. 48 (2009)340.

[36] M.P. Sibi, D. Rane, L.M. Stanley, T. Soeta, Org. Lett. 10 (2008) 2971.[37] (a) A.D. Melhado, M. Luparia, F.D. Toste, J. Am. Chem. Soc. 129 (2007) 12638;

(b) F. Liu, Y.H. Yu, J.L. Zhang, Angew. Chem. Int. Ed. 48 (2009) 5505.[38] (a) P. Camps, T. Gmez, D. Munoz-Torrero, J. Rull, L. Snchez, F. Boschi, M.

Comes-Franchini, A. Ricci, T. Calvet, M. Font-Bardia, E.D. Clercq, L. Naesens,J. Org. Chem. 73 (2008) 6657;(b) C.J. Wang, G. Liang, Z.Y. Xue, F. Gao, J. Am. Chem. Soc. 130 (2008) 17250;(c) Y. Kim, J. Kim, S.B. Park, Org. Lett. 11 (2009) 17;(d)R. Jagasia, J.M. Holub,M. Bollinger, K. Kirshenbaum,M.G. Finn, J. Org. Chem.74 (2009) 2964;(e) H. Suga, Y. Adachi, K. Fujimoto, Y. Furihata, T. Tsuchida, A. Kakehi, T.J. Baba,Org. Chem. 74 (2009) 1099;(f)S.Y.Xing, W.Y. Pan, C. Liu, J. Ren, Z.W. Wang, Angew.Chem. Int. Ed.49 (2010)3215.

[39] B.M. Trost, N. Cramer, S.M. Silverman, J. Am. Chem. Soc. 129 (2007) 12396.[40] B.M. Trost, S.M. Silverman, J.P. Stambuli, J. Am. Chem. Soc. 129 (2007) 12398.[41] P.L. Marquand, W. Tam, Angew. Chem. Int. Ed. 47 (2008) 2926.[42] (a) L. Jiao, S. Ye, Z.X. Yu, J. Am. Chem. Soc. 130 (2008) 7178;

(b) Y. Lian, H.M.L. Davies, J. Am. Chem. Soc. 132 (2010) 440.[43] K.M. Partridge, M.E. Anzovino, T.P. Yoon, J. Am. Chem. Soc. 130 (2008) 2920.

[44] (a) A.T. Parsons, J.S. Johnson, J. Am. Chem. Soc. 131 (2009) 3122;(b) C.W. Huh, W.R. Roush, Org. Lett. 10 (2008) 3371.[45] H. Zheng, J. Zheng, B. Yu, Q. Chen, X. Wang, Y. He, Z. Yang, X. She, J. Am. Chem.

Soc. 132 (2010) 1788.[46] T.B. Nguyen, A. Beauseigneur, A. Martel, R. Dhal, M. Laurent, G. Dujardin, J. Org.

Chem. 75 (2010) 611.[47] B.M. Trost, S.M. Silverman, J. Am. Chem. Soc. 132 (2010) 8238.[48] H.Xiao,Z. Chai,C.M. Zheng,Y.Q.Yang,W. Liu,J.K.Zhang,G. Zhao,Angew. Chem.

Int. Ed. 49 (2010) 4467.[49] F. Zhong, X. Han, Y. Wang, Y. Lu, Angew. Chem. Int. Ed. 50 (2011) 7837.[50] (a) R. Na, C. Jing, Q. Xu, H. Jiang, X. Wu, J. Shi, J. Zhong, M. Wang, D. Benitez,

E. Tkatchouk, W.A. Goddard, H. Guo, O. Kwon, J. Am. Chem. Soc. 133 (2011)13337;(b) R. Sustmann, Tetrahedron Lett. 12 (1971) 2717;(c) R. Sustmann, H. Trill, Angew. Chem. Chem. Int. Ed. Engl. 11 (1972) 838;(d) A.T. Parsons, A.G. Smith, A.J. Neel, J.S. Johnson, J. Am. Chem. Soc. 130 (2010)9688;(e)C. Guo, M.X. Xue, M.K. Zhu, L.Z. Gong, Angew.Chem. Int. Ed.47 (2008)3414.

[51] G. Pandey, N.R. Gupta, T.M. Pimpalpalle, Org. Lett. 11 (2009) 2548.

[52] N. Shimada, T. Hanari, Y. Kurosaki, K. Takeda, M. Anada, H. Nambu, M. Shiro, S.Hashimoto, J. Org. Chem. 75 (2010) 6039.

[53] L.M. Repka, J. Ni, S.E. Reisman, J. Am. Chem. Soc. 132 (2010) 14418.[54] Y.Q. Zhou, N.X. Wang, S.B. Zhou, Z. Huang, L. Cao, J. Org. Chem. 76 (2011) 669.

Yalan Xing received her B.S degree from Beijing Uni-versity of Chemical Technology, China in July 2006. InFebruary 2006 shefollowedProf.Nai-XingWang in Tech-nicalInstitute of Physics andChemistry, ChineseAcademyof Sciences for her bachelor degree thesis. She obtainedher Ph.D. from West Virginia University under the super-vision of Professor George ODoherty in 2011. Now sheis pursuing the postdoctoral study under the guidanceof Prof. Yoshito Kishi in the Department of Chemistryat Harvard University Her research interests includetotal synthesis of biologically active natural products anddevelopment ofnew methodologiesfor complexmoleculesynthesis.


15/15


Nai-Xing Wang obtained his MSc from Xian ModernChemistry Research Institute in 1990 and Ph.D. from Bei-

jing Institute of Technology in 1993. He was appointedas postdoctoral fellow at Institute of chemistry, Chi-nese Academy of Sciences in 1993, he completed thepostdoctoral research in 1995 and was promoted toassociate professor there. He moved to Department ofOrganic Chemistry at Chalmers University of Technologyin Sweden and pursued postdoctoral studies in January

1996, and in October of the same year he was invited from Sweden to ClemsonUniversity and University of Nebraska-Lincoln in USA to continue the postdoctoralresearch until 1998. In June 1998, hewas selected fora RobertA. WelchFoundationPostdoctoralFellowship in Department of Chemistryat RiceUniversity in USAfrom

June 1998 to May 2000. In May 2000 he returned to Beijing and was appointed Pro-fessor at Technical Instituteof Physics and Chemistry, Chinese Academy of Sciences,and has been awarded by the Hundred Talent Program of the Chinese Academy ofSciences.

1-s2.0-S0010854512000033-main cicloaditii

Documents

Transcript of 1-s2.0-S0010854512000033-main cicloaditii