organocatalytic formation of quaternary stereocenters · given that organocatalysis a fast-growing...

REVIEW 1583

Organocatalytic Formation of Quaternary StereocentersOrganocatalytic Formation of Quaternary StereocentersMarco Bella,* Tecla Gasperi1

Dipartimento di Chimica and Istituto di Chimica Biomolecolare, ‘Sapienza’ Università di Roma, P.le Aldo Moro 5, 00185 Roma, ItalyFax +39(06)490631; E-mail: [email protected] 27 February 2009This paper is dedicated, on the occasion of his last lecture, to Professor Giovanni Piancatelli, who for over forty years taught organic chemistry to many generations of students at ‘Sapienza’ Università di Roma.

SYNTHESIS 2009, No. 10, pp 1583–1614xx.xx.2009Advanced online publication: 04.05.2009DOI: 10.1055/s-0029-1216796; Art ID: E23509SS© Georg Thieme Verlag Stuttgart · New York

Abstract: This work reviews the authors’ choice of recently pub-lished papers where at least one asymmetric quaternary stereocenterhas been formed via organocatalysis. The scope and limitations ofthe reactions are highlighted.

1 Introduction2 Alkylation and Arylation Reactions3 Addition to Carbon–Carbon Multiple Bonds4 Addition to N=X Double Bonds 5 Nucleophilic Aziridine-Ring Opening6 Aldol and Related Reactions7 Brønsted Acid Organocatalyzed Formation of Nitrogen-

Containing Quaternary Stereocenters8 Halogenation and Pseudohalogenation Reactions9 Epoxidation10 Diels–Alder Reaction11 N-Heterocyclic Carbene Catalysis12 Cascade Reactions 13 Conclusion and Outlook

Key words: alkaloids, amino acids, asymmetric catalysis, car-benes, Michael additions

1 Introduction

The formation of quaternary stereocenters in a complexmolecule is often one of the most challenging tasks in or-ganic synthesis.2 Owing to steric encumbrance, relativelyharsh reaction conditions are required and only limitedcombinations of nucleophile and electrophile can be suit-able. Moreover, quaternary centers are, in most cases, alsostereogenic centers, and once they are in place it is diffi-cult, if not impossible, to invert their configuration. Thelast few years have witnessed a flourish of new organocat-alyzed reactions targeting the asymmetric formation ofquaternary stereocenters with excellent control of the ste-reoselection, employing relatively mild reaction condi-tions and simple organic molecules, thereby avoiding theuse of transition metals. The purpose of this work is to re-view the most recent advances in this field to offer a ‘crit-ical catalogue’ of reactions to the synthetic organicchemist from where it will be possible to grasp new ideasand choose the best disconnection. The asymmetric for-mation of quaternary stereocenters has been the subject ofseveral excellent reviews.3 Specific aspects of this fieldwhich have already been extensively reviewed (e.g., alky-

lation reactions via asymmetric phase-transfer catalysis)will not be further discussed here. This review is not in-tended to be comprehensive nor exhaustive: a personalchoice has been made, selecting some work from differentauthors, and we apologize for any relevant omissions.

1.1 General Considerations and Limitations

Every chemical reaction has limitations in its substratescope. Reactions forming quaternary carbon stereocentersare especially challenging because of additional limita-tions. As an example, in an SN2 process, it is unlikely fora nucleophile to attack a highly substituted carbon; on theother hand, a crowded tertiary anion could not react withelectrophiles.

Reaction conditions to form a quaternary stereocenter canbe quite unusual (high temperatures and concentration;extremely long reaction times) and therefore in most ofthe cases enantioselection can be strongly affected; ac-ceptable reaction rates at low temperatures are indeedmore common and employ metal catalysis.

Furthermore, minor changes either in the electrophile orin the nucleophile partner (not mentioning the catalyst it-self) sometimes lead to a complete loss of stereocontrol.These strong limitations in the ‘partners combination’ areindeed common to all asymmetric reactions, but is a majorissue with organocatalyzed reactions.

A ‘case study’4 is illustrated in Scheme 1.

Nearly complete loss of stereoselectivity in the products isobserved when a subtle change in the nucleophile is intro-duced. Excellent enantioselection is achieved using the

Scheme 1 Quaternary ammonium salt catalyzed addition of cy-anoacetates to alkyno esters: small variations of the substrate lead tostrong effects on the enantioselection

N

Ar

Ar

O

Ar = 3,5-(3,5-(CF3)2C6H3)2C6H3

Br

1a

CO2t-Bu

CNR1OR2

O

+R1

NC CO2t-Bu

CO2R2

R1 = PhCH2CH2, R2 = t-Bu: 94% ee (E), 84% ee (Z)

R1 = Ph, R2 = t-Bu: 18% ee (E), 0% ee (Z)

1a

Cs2CO3, toluene, –40 °C

R1 = PhCH2CH2

R1 = PhR2 = t-BuR2 = Et

1584 M. Bella, T. Gasperi REVIEW

Synthesis 2009, No. 10, 1583–1614 © Thieme Stuttgart · New York

phenethyl-substituted cyanoacetate (R1 = PhCH2CH2):the enantiomeric excess of the resulting product (R1 =PhCH2CH2, R

2 = t-Bu) is 94% (E-isomer) and 84% (Z-iso-mer). This value drops dramatically when the correspond-ing phenyl cyanoacetate (R1 = Ph) is used instead: theproduct (R1 = Ph, R2 = t-Bu) is obtained with 18% ee (E-isomer) and 0% ee (Z-isomer). Modification of the acety-lenic ester also decreases the enantioselection to a moder-ate level: from tert-butyl propiolate, the ee values for theproduct (R1 = PhCH2CH2, R

2 = t-Bu) are 90% (E-isomer)and 85% (Z-isomer), whereas ethyl propiolate gives theproduct (R1 = PhCH2CH2, R

2 = Et) with ee values of 77%(E-isomer) and 71% (Z-isomer), for reactions performedat 0 °C. Therefore both of the tert-butyl ester moieties arenecessary for high enantioselectivity and the syntheticvalue of this reaction is limited because high strereocon-trol is obtained only without orthogonal protective groups.

Given that organocatalysis a fast-growing and very com-petitive field, it should be noted that the restriction of thesubstrate scope is not always clearly highlighted by theauthors, sometimes it is either relegated to the supportinginformation, hidden, or even omitted altogether. The needto pass the peer-review system sometimes leads authors tothe paradox of presenting less information in order to‘hide’ the limitations of their catalytic system.

As an example, if a specific process exploiting a given or-ganocatalyst is reported to afford high enantiomeric ex-cesses with cyclic b-keto esters, it cannot be assumed thatemploying b-diketones, or even just acyclic b-keto esters,will lead to similar results. Cyclic and acyclic nucleo-philes, in particular, have very different behaviors with re-spect to enantioselection, and it is unusual for the sameorganocatalytic system to perform well with both classes.Limitations of the catalytic system further reduce the uses

of these reactions. Surely, presentation of all the dataavailable – at the very least in the supporting information– would better allow researchers to judge if a certainmethodology can be useful in the preparation of a highlyfunctionalized intermediate. In the case of Maruoka’s pa-per discussed in Scheme 1, all data and limitations wereclearly indicated in the main text of the article.

Despite all these limitations, the asymmetric organocata-lyzed synthesis of quaternary stereocenters is a powerfultool for the preparation of several bioactive and naturalsubstances.5

1.2 Organization of this Review and Mechanistic Considerations

The reactions presented in this review have been groupedaccording to their type: conjugate addition to multiplebonds, a-aldehyde functionalization, and so on. In order toeffectively organocatalyze the reactions forming quater-nary stereocenters, two possible approaches are feasible:nucleophile or electrophile activation.

Activation of the nucleophile can occur in various ways(Scheme 2):

i. Tertiary amines: When nucleophiles have an acidic pro-ton (pKa < 10–11) which is deprotonated to an appreciableextent by the amine; the nucleophile forms an ion pairwith the protonated amine as the counterion which is at-tacked preferentially from one face by the electrophile.Generally, the combined effect of two electron-withdraw-ing groups is required for deprotonating the acidic protonof the nucleophile (e.g., b-keto esters, b-diketones, andcyanoacetates), with the exception of nitroalkanes. For-mation of the quaternary stereocenter generally occurs onthe nucleophile. Tertiary amine catalysts are mostly cin-

Marco Bella was born inRome in 1972. Four days af-ter obtaining his PhD fromthe Università di Roma ‘LaSapienza’ under the guid-ance of Professor G. Pianca-telli (Dec. 2000), he joinedthe group of Professor K. C.Nicolaou in sunny Califor-

nia for a first postdoctoralappointment, where he wasinvolved in the total synthe-sis of diazonamide A. Hethen moved to cold Den-mark (2003) for a secondpostdoc with Professor K.A. Jørgensen concerning thedevelopment of new asym-

metric organocatalytic reac-tions. Since November2005, he is ‘Ricercatore’(lecturer) back at RomaUniversity ‘La Sapienza’where he set up a small re-search group that studiesnew concepts and reactionsfor asymmetric synthesis.

Tecla Gasperi was born in1976 in Pescara. She gradu-ated with a degree in chem-istry from the Università diRoma ‘La Sapienza’ in2001. In 2005, she obtainedher PhD studying the syn-thesis and reactivity of allyl-silane esters in Professor M.A. Loreto’s research group.

Afterwards, she moved toRWTH Aachen as a post-doctoral fellow in the re-search group of Professor D.Enders, where she dealtwith proline organocataly-sis. Once back to ‘La Sapi-enza’, her research interestsaddressed the multistep syn-thesis of heterocyclic com-

pounds and asymmetriccatalysis. Since December2008, she has been ‘Ricer-catore’ (lecturer) at Univer-sità degli Studi Roma Tre,where, joining Professor A.Gambacorta’s group, she iscontinuing her studies onheterocyclic chemistry andorganocatalysis.

Biographical Sketches

REVIEW Organocatalytic Formation of Quaternary Stereocenters 1585


chona alkaloid derivatives. It is well known that when thetwo pseudoenantiomers (or quasienantiomers) of a givenstructure are used in two distinct reactions as chiral cata-lysts, the respective products are formed in comparableenantiomeric excesses but the major enantiomers show al-ways opposite absolute configuration.6a The privilegedstructures that have been employed extensively are themore basic cupreines (desmethyl quinines) and their de-rivatives (Figure 1).6b,c Some notable examples of newclasses of amine catalysts, such as chiral guanidines, arenow appearing in the literature.6d

Figure 1 Structures of the most common cinchona alkaloids

ii. Inorganic bases and quaternary ammonium salts: Nu-cleophiles with pKa values between 10–11 and 20–22 canbe deprotonated by strong inorganic bases, either as con-centrated solutions or in solid form, and the reaction withelectrophiles is catalyzed by quaternary ammonium salts.The quaternary ammonium salts used are those derivedfrom alkylation of cinchona alkaloids or prepared fromaxially chiral quaternary ammonium salts.7

iii. Enamine activation of aldehydes with secondary orprimary amines: The activation of aldehydes via proline

and derivatives has been rediscovered in the last fewyears;8 however, enamines derived from branched a,a-disubstituted aldehydes are much less reactive with re-spect to those derived from a-monosubstituted aldehydes,and therefore only very strong electrophiles can be used toform quaternary stereocenters. Enamines catalyticallygenerated from ketones are weak nucleophiles, and, to thebest of our knowledge, no example of asymmetric organo-catalyzed functionalization of an a,a-disubstituted ketoneenamine has been reported.

The most common methods for electrophile activation(Scheme 2) are:

iv. Iminium ions of a,b-unsaturated carbonyl compounds:These can be formed with secondary amines and are acti-vated versus nucleophile attack on the b-position or as di-enophile in a Diels–Alder reaction.9 The first approachhas not been exploited for the formation of quaternary ste-reocenters since the electrophile would be too hindered;there are, however, several examples of the latter ap-proach.

v. Activation by Brønsted acids: While several effectivechiral base organocatalysts are easily available from natu-ral sources such as alkaloids and amino acids, the corre-sponding chiral Brønsted acids have not experienced thesame popularity. Only recently, with the development ofsynthetic axially chiral phosphoric acids, has it been pos-sible to achieve reactions with high control over stereo-selection. A quaternary stereocenter is formed on theelectrophile that began as a ketone or imine.10

vi. Activation via heterocyclic carbenes:11 This is one ofthe most elegant and evident expressions of the Umpolungconcept. A result of the coupling between a heterocycliccarbene and a carbonyl compound, the key intermediatespecies represents an active aldehyde or ketone with an in-verted reactivity at the carbonyl carbon.

Scheme 2 Activation mechanism of nucleophiles and electrophiles in organocatalytic reactions leading to the formation of quaternary stereo-centers

(chiral tertiary amine)EWG

EWG R1

H EWG

EWG R1

N(R3)3*

H

N(R3)3*

chiral ion pair

EWG

EWG R1

EE

*

pKa < 11

via tertiary amine

(chiral quaternary ammonium salt)

R2

EWG R1

H

X– +N(R3)4, MOH*

R2

EWG R1

E

E

*

11 < pKa < 21

nucleophile

via inorganic base–chiral quaternary ammonium salt

R2

EWG R1

N(R3)4*

chiral ion pair

cation exchange: increased solubility of the salt in organic solvents

nucleophile

via enamine

R2

O

HR1

NH

G N G

HR1

R2

NH

G

– R2

O

HR1E

*

O

H

NH

G

E

R2

R1

HR2

R1 N G

Nu

via iminium ion

NH

G

HR2

R1 ONu *

via Brønsted acid

Z

R2

Z = O, NH

R1

enamine: adds to an electrophile in the β-position

iminium ion: attacked by a nucleophile on the γ-position

Nu

Z

R2R1

H

Z

R2R1

Nu

HHXNuH

– H2O

– H2O

H2O

–

H2O

– HX

N

NHO

H

R2

HH

N

N

H

HO

R2

H

HR1 R1

R1 = OMe, R2 = vinyl (quinine, Q)R1 = H, R2 = vinyl (cinchonidine, CD)R1 = OMe, R2 = Et (dihydroquinine, DHQ)R1 = H, R2 = Et (dihydrocinchonidine, DHCD)R1 = OH, R2 = vinyl (cupreine, Cp)R1 = OH, R2 = Et (dihydrocupreine, DHCp)

R1 = OMe, R2 = vinyl (quinidine, QD)R1 = H, R2 = vinyl (cinchonine, C)R1 = OMe, R2 = Et (dihydroquinidine, DHQD)R1 = H, R2 = Et (dihydrocinchonine, DHC)R1 = OH, R2 = vinyl (cupreidine, CpD)R1 = OH, R2 = Et (dihydrocupreidine, DHCpD)



vii. Mixed activation: The most recent developments inorganocatalysis involve the use of catalyst combinationsin order to overcome the lower reactivity of the substrates.An example is the deprotonation of a,a-disubstitutedenamines via cinchona alkaloids and other tertiary aminesand subsequent addition to enones.12

2 Alkylation and Arylation Reactions

Following the pioneering work performed at Merck,13

where for the first time asymmetric phase-transfer cataly-sis (PTC) was employed for preparative purposes achiev-ing a significant level of stereoselection, the use ofquaternary ammonium salts became a standard methodol-ogy widely applied in laboratories. Initially, quaternarycinchona alkaloids were employed as asymmetric PTCbut in the last few years the use of axially chiral quaterna-ry ammonium salts has gathered momentum.14 The nu-cleophiles that can be alkylated (or arylated in an SNArprocess using activated aryl fluorides)15 in good enantio-selectivity to form asymmetric quaternary stereocentersinclude indanones, esters of p-chlorobenzaldehyde gly-cine imines, and cyclic b-keto esters. A simple amine can-not be used as the catalyst because it would be alkylatedand therefore inactivated; for such reactions, an externalinorganic base is needed. This field has recently been ex-cellently and extensively covered by Maruoka7b,16 andtherefore these papers should be consulted for further de-tails.

Enamine-mediated a-alkylation of a-substituted alde-hydes remains an unresolved problem.

3 Addition to Carbon–Carbon Multiple Bonds

3.1 ‘Classic’ Conjugate Addition: Formation of a Single Stereocenter

Here we arbitrarily define ‘classic’ conjugate addition toinclude all reactions where a nucleophile is added to a car-bon–carbon double or triple bond that is conjugated withan electron-withdrawing group.

In order to facilitate a comparison among the different ap-proaches, the classes of activated dicarbonyl compoundsthat can be employed are presented in Table 1.

The reactions are grouped according to the electrophiles:acrolein (entries 1–3) and methyl vinyl ketone (entries 4–11) were the first to be employed, vinyl aryl ketones (en-try 12) and then sulfonates, phosphonates, enenitriles andalkynones followed.

The two classes of catalysts widely employed are the ter-tiary amines cinchona alkaloids 2 and the quaternary am-monium salts 3 (Figure 2).

The usage of tertiary amine catalysts was pursued in theearliest example of asymmetric organocatalytic formationof quaternary stereocenters by conjugate addition, by

Wynberg,17 wherein activated b-dicarbonyl compoundswere deprotonated by cinchona alkaloids and reacted withacrolein or methyl vinyl ketone. In this seminal work,enantioselectivities were evaluated only on the basis ofoptical rotation, and the strong solvent effect on the enan-tioselection, typical of all cinchona alkaloid catalyzed re-actions, was first reported. In recent years, the reactionswith each of the nucleophiles originally employed byWynberg have been optimized to give compounds withexcellent enantiocontrol, varying the cinchona alkaloidderivatives employed or the ester moiety. Selected resultsfrom several authors are presented in Table 1.

The second approach, using quaternary ammonium salts,was developed later. In analogy with studies on the alky-lation reaction,13,18 researchers at Merck disclosed an or-ganocatalytic conjugate addition, but in this casedeprotonation occurs via inorganic base/chiral quaternaryammonium salts. In both cases, the chiral induction isprobably due to the ion pairs formed between the proto-nated amine or the chiral quaternary ammonium salt andthe enolate, which is attacked preferentially from one faceby the activated olefin.6a,19 In agreement with this hypoth-esis, tighter ion pairs gave better enantioselection,6a there-fore solvents such as toluene or halogenated solvents,which favor strong association between ions, are chosento achieve products with the highest enantiomeric excess-es. If present, hydrogen bonding can stabilize preferential-ly one of the two diastereotopic transition states, therebyenhancing the enantioselectivity.

The preparation of the quaternary ammonium salts 3 isachieved by simply treating, at high temperature, the cor-responding cinchona alkaloid 2 with an alkyl halide. Thisis an attractive method because it offers the possibility offine-tuning the catalyst for each specific reaction. Forhigh stereoselection to be achieved, the presence of a ben-zylic group on the quaternary nitrogen of the cinchona al-kaloids was necessary. For comparison, see the lowenantiomeric excess achieved employing N-methyl qui-ninium salt 3a (entry 9). One of the best N-alkylationgroups in terms of enantioselection control in these andseveral other reactions is the 9-methylanthracenyl group,disclosed by Corey and Lygo in 1997.20a,b

More recently, Maruoka demonstrated the effectivenessof his ‘synthetic’ quaternary ammonium salts 1.20c

Chiral thioureas such as 4a (Figure 2) are also effective inpromoting the asymmetric Michael reaction (entry 12).

In 1998, Zhang and co-workers21 disclosed an interestingaddition of b-keto esters and b-diketones to conjugatedtriple bonds using chiral phosphines as catalysts. Al-though the enantioselectivity was only moderate, this isone of the rare examples where catalysts other than theprivileged cinchona alkaloids have been employed. Itwould be interesting to have a comparison between thesechiral phosphines and chiral amines; however, we are un-aware of such research having been performed to date.22



Figure 2 Structures of catalysts 1b, 2a–k, 3a–c, 4a used in Table 1; for additional catalysts, see individual schemes

N

N

H

HO

H

HHO

BocNBocHN

2a

N

Ar

Ar

Br

N

NO

H

HHO

N

N

Ph

Ph

Cl

H

2b

N

N

H

RO

H

HHO

R =

2c

N

NHO

HH

H

Me OHMeO

3aN

N

H

HO

H

H

CF3

Br

N

NHO

HH

H

CF3

Br

3b 3c

N

NH

NH

MeMe

S

CF3

CF3

4a

N

HO N

H

H

HMeO

2d 2e

N

NRO

HH

H

HOR =

2f

N

NHO

HH

H

MeO

2g

N

NNH

HH

H

NH

Ar

2hAr = 3,5-(CF3)2C6H3

S

N

O

N

HMeO

O

N

HOMe

NNN

2i

N

OH

O

N

H

H

2j

N

N

H

BnO

H

HHO

2k

1bAr = 3,5-(CF3)2C6H3

N

N

H

HO

H

HMeO

Table 1 ‘Classic’ Conjugate Addition of Activated Carbonyl Compounds to Michael Acceptors: Formation of a Single Quaternary Stereocenter

Entry Carbonyl compound Michael acceptor

Catalyst (amount)reaction conditions

ee (%) (yield, %)

Ref.

1n = 1n = 2

2aPhI, r.t.

93 (99)88 (91)

23

2E = 9-fluorenylE = t-Bu

1bK2CO3, cumene from –78 to –40 °C

84 (79)92 (90)

24

EWG+EWG EWG

EWG R

α βγ*EWG

EWG R

α H

βγ

CH2

O

OEt

O

n

O

H

O

OE

O O

H



3

Ar = Ph,4-ClC6H4,3-ClC6H4,4-MeOC6H4,2-thienyl

2b (10 mol%)CH2Cl2, –50 °C

80–95 (98–100) 25

4X, Y = H,X = OMe, Y = H,X = H, Y = Cl

2c (1–10 mol%)CH2Cl2, r.t.

94–98 (94–96) 26

5n = 1, E = t-Bu,n = 1, E = CH(CF3)2,n = 2, E = t-Bu

2c (1–10 mol%)CH2Cl2, r.t.

93–95 (96) 26

62c (1–10 mol%)CH2Cl2, r.t.

82 (90) 26

72a (10 mol%)PhI, r.t.

74 (99) 23

8 E = 9-fluorenyl1b (1 mol%)K2CO3, cumene from –78 to –40 °C

97 (99) 24

9R = H,-OCH2CH2O-,-SCH2CH2S-

3a (1.25–2.0 mol%) CCl4, –20 °C

22 (99) 27

102d2eCCl4, –21 °C

76 (98)69 (99)

27

113b3ctoluene, r.t.

80 (95)52 (93)

28

12

Ar = Ph,4-MeC6H4,4-MeOC6H4,4-FC6H4,2-FC6H4,4-ClC6H4,4-BrC6H4,3-ClC6H4,3-F3CC6H4,1-naphthyl,2-thienyl

R = Me,Ph,4-BrC6H4,4-MeOC6H4,2-thienyl

4a (10 mol%)toluene, 4 Å MS, –60 °C

91–97 (72–98) 29

Table 1 ‘Classic’ Conjugate Addition of Activated Carbonyl Compounds to Michael Acceptors: Formation of a Single Quaternary Stereo-center (continued)



ee (%) (yield, %)

Ref.

EWG+EWG EWG

EWG R

α βγ*EWG

EWG R

α H

βγ

CO2Et

CNAr

O

H

O

CO2t-Bu

X

Y

O

CH2

O

OE

O

n

O

CO2CH(CF3)2

OO

O

OEt

O O

O

OE

O O

O

CO2Et

RR

O

O

CO2Me

O

O

n-Pr

Cl

Cl

MeO

O

CO2Et

CNAr

O

R



3.2 ‘Classic’ Conjugate Addition: Formation of Multiple Stereocenters

Table 2 presents further examples for the formation of aquaternary stereocenter together with a tertiary stereo-center. The electrophiles used include nitroolefins, male-imides, cyclohex-2-en-1-one and enenitriles; there arealso some notable examples where non-adjacent stereo-centers are formed (entries 6–10).

3.3 Addition–Elimination Conjugate Addition

Addition–elimination reactions are additions to conjugatedouble or triple bonds where a bromo or chloro atom ispresent; the electronegative halogen atom has a doublerole because it first activates the double bond toward nu-cleophilic attack and then is eliminated as HX, therebyrecreating the multiple bond. Examples where halogen-substituted triple38 and double39 bonds are attacked by b-keto esters in good enantioselectivity are illustrated inScheme 3. Since a stoichiometric amount of HX is pro-duced, an excess of an inorganic base is needed, as in thealkylation reaction.

13

Ar = Ph,4-MeC6H4,4-MeOC6H4,4-FC6H4,4-ClC6H4,4-BrC6H4,3-ClC6H4,2-naphthyl,2-thienyl

2f (20 mol%)toluene, 0 °C or –25 °C

93–97 (86–98) 30

14

Y = H, OMe, ClX = CH2, O, SE = Me, Bn, i-Pr, t-Bu

R1 = Me, R2 = HR1 = OMe, R2 = Me

2gtoluene, –60 °C

94–99 (75–97) 31

15

Ar = Ph,4-FC6H4,4-ClC6H4,4-BrC6H4,4-MeC6H4,4-MeOC6H4,2-naphthyl

2htoluene, r.t.

87–90 (84–97) 32

16n = 1n = 2

R = Me, Ar

2ifor R = Me: toluene, r.t.for R = Ar: toluene, –20 °C

R = Me:70 (E), 40 (Z)(E/Z = 2:1) (99)R = Ar:88–95 (95–99)

33

Table 1 ‘Classic’ Conjugate Addition of Activated Carbonyl Compounds to Michael Acceptors: Formation of a Single Quaternary Stereo-center (continued)



ee (%) (yield, %)

Ref.

EWG+EWG EWG

EWG R

α βγ*EWG

EWG R

α H

βγ

CO2Et

CNArSO2Ph

X

O

CO2E

Y

O

CO2t-Bu

O

CO2t-BuR1

R2

PO(OEt)2

PO(OEt)2

CO2Et

CNArCN

CH2

O O

n

O OR

O



Table 2 Conjugate Addition to Various Activated Alkenes: Formation of Multiple Stereocenters

Entry Carbonyl compound Olefin Product Catalyst,conditions

ee (%), dr, (yield, %)

Ref.

1

R = OMe, X = CH2

R = OEt, X = (CH2)2

R = Me, X = OR = Me, X = CH2

R = Ph, 4-BrC6H4, 4-ClC6H4, 2-thienyl, i-Bu

2c or 2f or 2jTHF, –20 or –60 °C

98–9986:14–98:2(73–96)

34

2R1 = COMe, R2 = MeR1 = NO2, R2 = MeR1 = CN, R2 = Me, Et R = Ph, C5H11

(stereochemistry not determined)

2c or 2f or 2jTHF, –20 or –60 °C

92–9993:7–98:2(73–95)

34

3 R = H, CF3, Br, OMeR = Ph, 2-naphthyl, heteroaryl

2htoluene or CH2Cl2, 0 °C

60–89>98:2(65–88)

35

42d or 2eCH2Cl2, –15 to –60 °C

82–9584:16–98:2(72–99)

36

5R1 = Et, R2 = MeR1 = Et, R2 = BnR1 = t-Bu, R2 = Me

2dCH2Cl2, –15 to –60 °C

85–9277:23–93:7(52–75)

36

6 n = 1–32fa

toluene, r.t.

91–9611:1–25:1(87–95)

32, 37

72fa

toluene, r.t.

917:1(93)

32, 37

82fa

toluene, r.t.

9817:1(94)

32, 37

92fa

toluene, r.t.

949:1(71)

32, 37

EWG+ cinchona alkaloidsR2

R3 EWG EWG

R3R2

R4 HEWG R1R4

αβ

γ* **

EWG

EWG R1

α Hβ

γ

X

O

R

ONO2

R

X

O

OR1

R2NO2

R2

R1

OEt

O

NO2R

R1 NO2

R3

R2

**

O

EtO

O

O CF3

CF3

O

R

NO2R

O2NO

O CF3

CF3

O

Ar

R

CH2

O O

n

n = 1, 2

O

CO2Me

O

CO2Et

O

CO2Me

O O

BnNO O

BnNO O

R1

R3

O

OR2

*

*

R2

OR1

OO BnNO O

BnNO O

R1O

O

OR2

*

*

(CH2)n

O

CN CN

Cl

(CH2)n

O

CN

CN

Cl

O

CNCN

ClO

CN

Cl

CN

O

CO2t-Bu CN

ClO

CO2t-Bu

CN

Cl

O

O

O

CF3

CF3

CN

Cl

O

O

O

CF3

CF3

CNCl



3.4 1,6-Conjugate Addition

Michael-type addition occurs also on g,d-conjugate dou-ble bonds and an asymmetric version of this transforma-tion was published recently (Scheme 4).40

3.5 Conjugate Addition–Aromatization

When quinones are employed as electrophiles in theMichael addition, the reaction occurs with subsequent ar-omatization. Jørgensen and co-workers proved this con-cept using aldehydes41a and b-keto esters41b asnucleophiles. Selected examples with products bearingquaternary stereocenters are depicted in Scheme 5. Sim-ple adducts were isolated with the aryl moiety oxidized toquinone, probably due to air, while use of a dichloro-quinone as the electrophile led to the formation of cyclicacetals.

3.6 Miscellaneous Conjugate Additions

Following their studies on the organocatalytic deconjuga-tive Michael addition, where an electrophile reacts on theallylic position of an activated olefin,42 Jørgensen and co-workers disclosed an addition of acrolein to activatedalkylidenes (Scheme 6).43 The enantioselectivities andyields, however, were moderate and acrolein reacted atthe a-position with respect to the activating group, there-fore this method access the same structures reported byDeng.25

Hiemstra and co-workers44 reported in 2007 the construc-tion of adjacent quaternary and tertiary stereocenters via atransition-metal-free allylic alkylation of Morita–Baylis–Hillman carbonates (Scheme 7). The reaction proceedswith moderate to good enantioselectivity but the usage oftwo very similar ester moieties, such as methyl and ethyl,raises issues about protecting groups with regard to possi-ble functionalization of the adducts.

3.7 Conjugate Addition via Enamine Catalysis

While conjugate additions in general can be promoted byiminum–enamine,45 and the stoichiometric formation ofquaternary stereocenters via preformed enamines hasbeen widely described by D’Angelo and co-workers,46

there is a rare example, reported by the Barbas group,47 inwhich a,a-branched aldehydes were added to nitroalk-enes, with moderate diastereoselection and enantioselec-tion (Scheme 8).

4 Addition to N–X Double Bonds

4.1 Addition to Nitrogen–Nitrogen Double Bonds

Diazodicarboxylates are strong electrophiles that readilyreact with carbon nucleophiles even in the absence of cat-alyst.48 They allow the introduction of a nitrogen atom viaelectrophilic amination and have been employed since2002 in organocatalysis for the a-amination of aldehydesand ketones.49

Diazodicarboxylates are so reactive as electrophiles thatthey react even with the sterically hindered enamines de-rived from branched a,a-disubstituted aldehydes; this re-action was exploited by the Barbas research group in theirtotal synthesis of the LFA-1 antagonist BIRT-37750 em-ploying tetrazole catalyst 6 (Scheme 9).51 In this specificcase, tetrazole 6 performs significantly better than L-pro-line (7a) in terms of enantioselectivity. A few months lat-er, the same research group reported the preparation ofmetabotropic glutamate receptor ligands52 using here L-proline (7a) as the catalyst (Scheme 10). These are alsosome of the few examples where cyclic aldehydes are suc-cessfully a-functionalized.

10R = Ph, E = OEtR = Me, E = SMeR = allyl, E = SMe

2c or 2ftoluene, r.t.

79–932:1–10:171–99

37

11E = t-BuEt

1atoluene, –40 °C

9185:1591

3

12

R = Me, Et, C6H13

2c or 2kCH2Cl2, r.t.

92–9918:1–25:197–100

25

a Opposite diastereoselection was observed when catalyst 2h was used.

Table 2 Conjugate Addition to Various Activated Alkenes: Formation of Multiple Stereocenters (continued)

Entry Carbonyl compound Olefin Product Catalyst,conditions

ee (%), dr, (yield, %)

Ref.

EWG+ cinchona alkaloidsR2

R3 EWG EWG

R3R2

R4 HEWG R1R4

αβ

γ* **

EWG

EWG R1

α Hβ

γ

COE

CNR CN

ClE

CN

O

CN

R

Cl

COE

CNPh

O

R

EO

OCN O

* *

O

CO2t-Bu

O

H

RO

CO2t-Bu

CHO

R*

*



High-temperature and microwave–mediated amination ofvarious phenyl acetaldehydes was examined by Bräse andco-workers. Significantly, the amination of branched al-dehydes is one of the few organocatalytic reactions wheregood to moderate levels of enantioselection can beachieved at high temperatures (60–70 °C).53

Following the work on the metal-catalyzed asymmetricamination of activated dicarbonyl compounds,54 Jørgensenand co-workers showed that cyanoacetates and b-dicarbo-nyl compounds can be aminated in excellent yields andgood enantiomeric excess using b-isocupreidine 2j as cat-

alyst (Scheme 11).55 It appears that the high enantioselec-tivity is achieved thanks to a stabilizing hydrogen bondbetween the substrates and the free hydroxy group on the

Scheme 3 Conjugate addition–elimination reactions

O

CO2t-Bu

NuX

EWG+Nu

EWG

N

N

H

O

H

H

ClO

catalystK2CO3 or K2HPO4, o-xylene, –20 °C

96% ee99% yield

98% ee82% yield

96% ee84% yield

3d

Michael acceptor

CO2Allyl

CO2t-Bu

CO2Allyl

O

CO2t-Bu

CO2Allyl

O

CO2t-Bu

CO2Allyl

84% ee94% yield

* **

Michael acceptor = Br CO2Allyl

O

O

CO2t-Bu

95% ee88% yield

96% ee96% yield

80% ee74% yield

CO2Me

Michael acceptor =

Br CO2Me Br

O

Cl Ts

O

CO2t-Bu

O

O

CO2t-Bu

Ts

Michael acceptor =

Cl

O

Ph

CO2t-Bu

CN

F CO2t-Bu

CN

CO2t-Bu

CN

84% eeZ/E = >95:580% yield

PhO PhO PhO

N

N

H

O

H

H

Br

N

O

H

catalyst =

N

H

HBr

94% eeZ/E = 98:299% yield

92% eeZ/E = 99:195% yield

CO2t-Bu

CNn-Bu

PhO

76% eeZ/E = >95:175% yield

3e

catalyst =

Scheme 4 1,6-Conjugate addition: significant examples

O

CO2t-Bu

Nu EWG+ EWG

3dCs2CO3 or K2HPO4

o-xylene, –20 °C Nu

O

O

CO2t-Bu

OMeO

O

CO2t-Bu

SO2Ph

O

CO2t-Bu

OMeO

O

CO2t-Bu

OMeO

O

CO2t-Bu

OMeO

96% ee99% yield

97% ee96% yield

95% ee94% yield

94% ee78% yield

91% ee84% yield

79% ee95% yield

Scheme 5 Conjugate addition–aromatization reactions

O

CO2t-Bu

Nu +

O

CO2t-Bu

O

O

OH

OH

O

O

R R

Nu2dCH2Cl2, –20 °C

94% ee76% yield

O

O

96% ee59% yield

O

CO2t-Bu

HOCl

Cl

OHO

CO2t-Bu

HO

Cl

Cl

OH

94% ee88% yield

90% ee66% yield

Scheme 6 Deconjugative Michael addition

CO2R1

H

NC

R2

CO2R1

H

NC

R2

CHO

40–56% ee39–50% yield

2l (10 mol%)O

H+

CH2Cl2, –20 °C

N

N

H

HO

H

H

2l

Ph3Si

R1 = Me, i-Pr, BnR2 = Me, Et, n-Hex, allyl i-Pr, t-Bu, Bn



catalyst’s quinoline moiety. Within a few months, similarresults were reported by Pihko,56a who focused on the am-ination of b-keto esters, employing instead unmodifiedcinchonine (2n) and Deng,56b who examined the amina-tion of cyanoacetates mediated by cupreine catalyst 2m(Figure 3). Notably, the latter methodology allows accessto both enantiomers of the aminated cyanoacetate prod-ucts, while 2j affords only one enantiomer of the productin high enantiomeric excess.

The reaction of aryl cyanocetates with di(tert-butyl) di-azodicarboxylate is reported in Scheme 11. It should benoted here that the reaction proceeds in high enantioselec-tivity only with aryl cyanoacetates: with alkyl cyanoace-tates, it is much slower – requiring room temperatureinstead of –78 °C to proceed at an acceptable rate – andenantiomeric excesses drop from 90–99% to 20–30%.The nitrogen–nitrogen double bond can be cleaved by sa-

marium(II) iodide to afford N-protected quaternary aminoacids.

More recently, this reaction has been catalyzed by the bi-aryl guanidine derivative 8 (Figure 3). A comparison be-tween the different amination of cyclic and acyclic b-ketoesters is presented in Table 3; again, full experimental de-tails are reported since only a specific combination of theester and the diazodicarboxylate will afford the high enan-tioselectivity under the reaction conditions.57

4.2 Addition to Nitrogen–Oxygen Double Bonds

Nitrosobenzene is an electrophile that can be attacked oneither the oxygen or the nitrogen atom. The enamine-mediated reaction actually affords only the correspondingO-functionalized aldehydes; in contrast, only N-function-

Scheme 7 Allylic conjugate addition

2j (20 mol%)

CO2MeR2

OBoc

R1 = Me, Ph

R1

NC CO2Et+

R2 = Ph, 2-MeC6H4, 3-ClC6H4, 3-BrC6H4, 1-naphthyl

CO2MeR2

toluene, –20 to 20 °C

R1 CO2EtCN

**

79–85% eedr = 1.4:1 to 4:166–95% yield

Scheme 8 Addition of a,a-disubstituted aldehydes to nitroolefinsusing catalyst 5

O

HR NO2

Ph

+i-PrOH, 4 °C

O

H

R

NO2

Ph

R = Ph, Bn, alkyl 18–86% ee (syn), 67–79% ee (anti)dr (syn/anti) = 1.2:1 to 8:1

75–96% yield

5·TFA

NH

N

TFA.5·TFA

Scheme 9 Addition of a,a-disubstituted aldehydes to diazodicar-boxylates: synthesis of LFA-1 antagonist BIRT 377

O

H N N

CO2Bn

BnO2C

+6 or 7a

MeCN, r.t.

O

HN

NH

CO2Bn

CO2Bn

Br Br

NH

O

OH

44% ee90% yield

NH

80% ee99% ee (recryst.)

95% yield

N N

N

HN

Br

N

N

O

Cl

ClO

BIRT-377

7a 6

Scheme 10 Preparation of metabotropic glutamate receptor ligands

N N

CO2Bn

BnO2C

+MeCN, r.t.

(S)-AIDA(S)-APICA

OH

R

R = H, Br, CO2Me

R

N NHCO2Bn

CO2BnOH

>99% ee75–98% yield

NH

L-Pro (7a) (30 mol%)

orD-Pro (7b) (20 mol%)

O

OHNH

O

OH

L-proline (7a) D-proline (7b)

Scheme 11 a-Amination of cyanoacetates

O

R1OR2

CN

N N

CO2t-Bu

t-BuO2C+

2j

toluene, –78 °C

O

EON

N

RNC

CO2t-Bu

CO2t-Bu

R1 = Et, t-BuR2 = aryl, naphthyl, heteroaryl

87–99% ee72–96% yield

*

Figure 3 Catalysts employed in the amine-catalyzed a-amination ofactivated b-dicarbonyl compounds

N

Ar

Ar

Ar =

t-Bu

t-Bu

N

N

H

H

H

N

OH

O

N

H

H

2j

N

N

H

HO

H

H

2m

N

NHO

HH

H

HO

axially chiral guanidine8

2n



alization is observed in the reaction with aryl cyanoace-tates (Scheme 12). The reaction proceeds with moderateenantioselectivity and complete regioselectivity, and itshould be noted that the corresponding adducts, despitetheir bearing a quaternary stereocenter, are not configura-tionally stable, probably because the addition reaction canbe reversible. Determination of enantiomeric excess waspossible only after reduction with zinc and acetic acid inorder to cleave the nitrogen–oxygen bond.58

Scheme 12 Addition of a-aryl cyanoacetates to nitrosobenzene

4.3 Addition to Carbon–Nitrogen Double Bonds

L-Proline has been broadly used to catalyze Mannich re-actions of enolizable carbonyl donors; for example, theaddition of an iminium ion to afford a- and b-amino struc-tural motifs.59 However, despite the tremendous amountof work concerning Mannich reactions, the organocatalyt-ic enantioselective version that employs ketoimines,which are much less reactive toward nucleophilic attack,had been unprecedented until Jørgensen’s studies.60 Theauthors highlighted how cyclic ketoimines have enoughelectrophilic character to react with enamines; this is theonly example where a tertiary stereocenter is formed onthe aldehyde and a quaternary stereocenter is generated onthe electrophile in good stereoselection. It should be notedthat acyclic ketoimines give no reaction under these con-ditions, providing evidence for the enhanced reactivity ofthe cyclic substrates (Scheme 13).

Almost contemporaneously, Barbas and co-workers61 ac-complished the synthesis of quaternary b-formyl a-aminoacid derivatives with excellent yields (66–99%) and enan-tioselectivities (syn/anti = 60:40 to 96:4; syn ee values inthe range of 86 to >99%; anti in the range of 5 to 64%)throughout direct asymmetric Mannich reactions of N-

PMP-protected a-imino ethyl glyoxylate with variousa,a-disubstituted aldehydes (Scheme 14).

Besides the examples that have already been reviewed62

since the earliest experiments, we present here some of thevery recent developments achieved in this field.

The simplest example involving L-proline (7a) as organo-catalyst was presented by Vovk and co-workers(Scheme 15).63 Aryl trifluoromethyl ketimines react withacetone, giving facile access to chiral b-aryl-b-trifluoro-methyl-b-amino ketones that can be synthesized in high

Table 3 Scope of Amine-Mediated Amination Reaction

R1 R2 E1 E2 Catalyst Conditions ee (%) (yield, %) Ref.

-(CH2)4- Et t-Bu 2j toluene, r.t. 83 (86) 54

-(CH2)4- Et Bn 2n CH2Cl2, –25 °C 84 (92) 56

-(CH2)4- Et t-Bu 8 THF, –60 °C 98 (99) 57

Et Me Ph t-Bu 2j toluene, r.t. 90 (99) 54

Me Et Et Bn 2n CH2Cl2, –25 °C 47 (72) 56

Me Me Et t-Bu 8 THF, –60 °C 85 (99) 57

R2

R1

O

OE1

O

N N

OE2

E2O

O

O

O

t-BuOAr

CN

N OPh

+

1. 2d, CH2Cl2, –78 °C

2. Zn, AcOH

O

t-BuONHPh

ArNC

22–59% ee71–85% yield

Scheme 13 Enamine-mediated addition of aldehydes to cyclicketoimines

NO

R3

R1

R2

O

CO2Et

NHO

R3

R1

R2

O

R4

O

H

CO2Et

CHO

R4Et2O or CH2Cl2, 0 °C, 20 h

NH

N

+

R1, R2 = H, OMe, -(CH2)4-R3 = H, Me, OMe, FR4 = H, Me, i-Pr, Allyl

83–98% eedr = 4:1 to 20:172–99% yield

5

Scheme 14 a,a-Disubstituted aldehydes as donors in the synthesisof quaternary b-formyl-substituted a-amino acid derivatives

H

O

R2

R1

N

H CO2Et

PMP

H

O

CO2Et

R1 R2

HNPMP


DMSO, r.t.+

R1 = MeR2 = Ph, thienyl, 4-MeC6H4, 4-(i-Pr)C6H4CH2

syn/anti 60:40 to 96:486–99% ee (syn)5–64% ee (anti)

66–99% yield

Scheme 15 Preparation of b-amino ketones

Ar

NH

CF3

O ONH2

ArF3C

L-Pro (7a)+

Ar = Ph, 3-MeC6H4, 4-MeC6H4, 4-MeOC6H4, 4-FC6H4

74–92% ee75–86% yield

DMSO, –20 °C



yields (75–86%) and good enantioselectivity (74–92%ee).

A more complex catalyst was introduced by Takemotoand co-workers64 who, following the previous efforts ofDeng65a and Dixon,65b developed a highly enantio- anddiastereoselective Mannich reaction of a broad range ofcyclic 1,3-dicarbonyl compounds catalyzed by thiourea4a (Scheme 16).

Scheme 16 Mannich reaction catalyzed by a chiral thiourea

3-Substituted oxindoles are reactive nucleophiles; theyhave been added to the especially electrophilic N-Bocimines shown in Scheme 17.66

Scheme 17 Thiourea-catalyzed addition of oxindoles to imines

More recently, Chen and co-workers67 applied a similarorganocatalytic strategy to the concurrent construction ofadjacent quaternary and tertiary stereocenters via nitro-Mannich reaction of simple a-substituted nitroacetatesand N-Boc imines (Scheme 18).

Although bifunctional thiourea–tertiary amines have beenused successfully in various 1,2- and 1,4-addition reac-tions, only similar catalysts bearing a secondary amino

group and a chiral 1,2-diphenylethylenediamine (DPEN)scaffold were actually effective and efficient. An exten-sive screening of solvents, temperature and other condi-tions led to excellent levels of diastereoselection(dr = 3.8:1 to 17.2:1) and enantioselection (91–96% ee)for aryl imines bearing a number of electron-withdrawingor -donating substituents.

N-Substituted iminoethanoates are also reactive electro-philes that are readily attacked by cyanoacetates or b-di-carbonyl compounds (Scheme 19).68

Scheme 19 Addition of activated b-cyanoacetates to an imino-ethanoate

The extensive investigations by Ricci and co-workers69

led that Italian research group to develop a new catalyticsystem, based on a cinchona alkaloid derived phase-trans-fer catalyst (PTC), which avoids the isolation of unstableN-protected imines (Scheme 20).

Among the reported examples, representative are the re-sults for the catalytic asymmetric Mannich reaction be-tween b-keto esters and a-amido sulfones which weretransformed in the corresponding products with notewor-thy diastereoselectivities (58:42 to 98:2 dr) and enantio-selectivities (69–99% ee). The proposed reaction pathwayis illustrated in Scheme 21.

Finally, pyridinium 1,1¢-binaphthyl-2,2¢-disulfonates,such as the combination of 9 with an arylpyridine 10, havevery recently been introduced by Ishihara and co-workers

Ph

N+

Boc O

MeO2C

n

4a (10 mol%)

CH2Cl2, –60 °C

O

nMeO2C

NH

Ph

Boc

O

MeO2C

NH

Ph

BocO

MeO2C

NH

Ph

BocO

MeO2C

NH

Ph

Boc

88% eedr = 92:889% yield

56% eedr = 91:981% yield

92% eedr = 80:2081% yield

90% eedr = 54:4681% yield

83% eedr = 99:189% yield

O

MeO2C

NH

Ph

BocO

MeO2C

NH

Ph

Boc

R1

NO

R2

R3

Boc

NHBoc

N

R2

O

Boc

R1

CF3NH

NH

S

Ph

Ph

NMe2

xylene, 4 Å MS, 5–10 °C

N

R3

Boc

85–95% ee75–95% yield

R1 = H, 5-F, 5-MeR2 = Bn, 4-FC6H4CH2, 2-ClC6H4CH2, 4-MeOC6H4CH2, 2-thienylmethyl, n-Pr, i-Pr, PhR3 = Ph, 4-FC6H4, 2-ClC6H4, 3-ClC6H4, 4-MeC6H4, 2-thienyl, n-Pr, i-Pr

4b,

4b

Scheme 18 Stereoselective nitro-Mannich reaction

4c (10 mol%)

xyene, 4 Å MS, –20 or –10 °CR1

NO2

CO2Me R2N

Boc

+MeO2C R2

O2N NHBocR1 H

NH

Ph

Ph

NH

S

NH

Ar

R1 = Me, Bn, Ph, i-PrR2 = Ph, 4-FC6H4, 2-ClC6H4, 3-ClC6H4, 4-MeC6H4, 2-thienyl, 3-MeC6H4, 2-furyl

91–96% eedr = 3.8:1 to 17.2:1

38–86% yield

4c

CO2Bn

CNAr

Ar = Ph, 2-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-MeC6H4, 4-MeOC6H4, 2-naphthyl

N

CO2Et

Boc

+Ar

CO2Et

NC CO2Bn

HNBoc

N

O

N

N N

O

N

N

Ph

Ph

HHMeO OMe

2o

2o

CH2Cl2, –20 °C

91–97% eedr = 80:20 to 88:12

95–99% yield



as highly effective chiral Brønsted acid–base combinedsalt catalysts.70 The usage of these tailor-made catalystsoffers an alternative access to Mannich adducts, such asthose shown in Scheme 22, that have a quaternary carboncenter. The products were obtained in excellent yield(98%) with remarkable syn/anti diastereoselectivity(83:17) and enantioselectivity (91% ee and 96% ee, re-spectively).

4.3.1 Strecker Reaction

The Strecker reaction, known since 1850, is the oldest re-ported synthesis of a-amino acids and their derivatives.71

Although a peak of perfection has recently been reachedin the catalyzed cyanation of aldimines,72 only limited re-ports were related to the more hindered ketoimines to af-ford the pharmaceutically important disubstituted a-amino nitriles. Pioneering work was done by Jacobsenwho first reported a highly enantioselective hydrocyana-tion of ketimines by means of a Schiff base bearing achiral urea as organocatalyst (Scheme 23).73 A complete

overview of this work was recently presented by Gröger;74

therefore, we refer the reader to the corresponding papers.

Since these first remarkable successes, effort has beenmade to develop highly efficient catalysts for the Streckerreaction of ketimines. Among others, Feng’s75 is one ofthe most prolific research groups that through the yearshave developed a few types of bifunctional catalysts. Dur-ing the first studies on ketimines, they disclosed that pro-linamide-derived aryl-linked N,N¢-dioxides such ascatalyst 12a proved to be conformationally rigid enoughto perform the Strecker reaction in high yields with mod-erate to excellent enantioselectivities (Scheme 24).

Scheme 24 Asymmetric Strecker reaction of ketoimines catalyzedby a chiral bifunctional N,N¢-dioxide; DAHQ = 2,5-di(1-adaman-tyl)hydroquinone

Scheme 20 Catalytic asymmetric reaction of b-keto esters with a-amido sulfones

R

HN+

PGO

MeO2C

n

3f (1.0–10 mol%)

toluene, inorganic base

O

nMeO2C

NH

R

PG

69–99% eedr = 58:42 to 98:2

55–98% yield

MeO

N

N

MeOHO

H Cl

3f

R = Ph, 2-BrC6H4, 4-ClC6H4, 4-MeOC6H4, 1-naphthyl, PhCH2CH2, Me, i-Pr, c-Hex

SO2 Ar

Scheme 21 Proposed reaction pathway

MeO

O O

OMe

MeO

O O

OMe

Q Ph

NH

SO2 Ph

MeO

O O

OMe MeO

O O

OMe

QQPhSO2

Ph

NPG

PG

Ph

NPG

O

OMe

O OMe

Q

K2CO3 Q+X– KHCO3 + KX K2CO3 PhSO2–K+ + KHCO3

toluene

aqueous phase

Ph

NHPG

O

OMe

O OMe

MeO

O O

OMe

Scheme 22 Enantioselective Mannich-type reaction catalyzed bypyridinium 1,1¢-binaphthyl-2,2¢-disulfonate

Ph

N

H

OO

Ph

HNAc

Cbz

OPh

HNAc

Cbz

+9 (1 mol%), 10 (2 mol%),

MgSO4, CH2Cl2, 0 °C+

91% ee (syn) 96% ee (anti)

dr = 83:17

SO3H

SO3H

BINSA (9)

N

Ar

Ar

2,6-diarylpyridine 10

OCbz

98% yield

Scheme 23 Strecker-type reaction using ketimines

NR1

R2

PhHN

O

NH

t-Bu O

NH

N

HO

t-Bu O

11 (2 mol%)

HCN, toluene, –75 °CR2

HNR1

CN

R1 = Ph, AllylR2 = Ar, t-Bu

42–97% ee45–99% yield

11O

t-Bu

NH

N N

HN

O O

O O

NTs

R

12a (5 mol%), DAHQ (20 mol%)

TMSCN, toluene, –20 °C

NHTs

R CN

R = Ph, aryl, 2-thienyl, c-Hex, t-Bu

61–91% ee82–99% yield

12a



Subsequently, the stereocontrol was enhanced by employ-ing more complex chiral linkers based on the structure ofBINOL. These increased the enantioselectivity up to 99%ee and widened the substrate scope (Figure 4).

Figure 4 N,N¢-Dioxide catalysts derived from BINOL and prolin-amide

A voice apart was that of Kunz and co-workers76 who re-garded the enantiomerically pure glucosamine 13 as an at-tractive and efficient alternative backbone structure forthe design of a new generation of organocatalyst(Figure 5).

Figure 5 Glucosamine catalyst 13

In this catalyst, the carbohydrate residue has been coupledwith a second amino function and a urea-derived sidechain in order to maintain the optimal structural featuresnecessary for the enantioselective Strecker reaction(Scheme 25).

Scheme 25 Strecker reaction of ketimines catalyzed with glucos-aminylurea derivative 13

5 Nucleophilic Aziridine-Ring Opening

Given the strong annular tension, three-membered cyclesshow analoguous reactivity with respect to double bonds;aziridines and epoxides are readily attacked by carbon nu-

cleophiles. An asymmetric quaternary stereocenter can beformed when b-keto esters are employed as nucleophiles.Dixon77a and, shortly thereafter, Jørgensen77b both provedthis concept (Scheme 26).

Scheme 26 Nucleophilic aziridine-ring opening

6 Aldol and Related Reactions

Addition of nucleophiles to carbonyl groups requires thestrong activation of an electron-withdrawing grouppresent in the a-position; addition to ketones occurs onlyin an intramolecular sense and is most likely the result ofa spontaneous ring closure rather than an organocatalyzedreaction (Scheme 27).78

Scheme 27 Addition of b-dicarbonyl compounds to enones and in-termolecular aldol reaction for the formation of chiral tertiary alco-hols

It is common, while running some exploratory chemistry,to test a new reaction by employing as organocatalyst pyr-rolidine 14 instead of L-proline (7a). However, the twostructures are in no way equivalent in terms of reactivity.The reaction can lead to a different product, and a relevant

NH

N N

HN

O O

O O

= linker

OH HO OH HOOH HO

27% ee43% yield

18–97% ee43–96% yield

59% ee40% yield

12b 12c 12d

12

OAcOAcO

OAc

N

HN

HN

O

O

NHOH

t-Bu

OPiv

t-Bu

13

Ph

NR

Ph

HNR

CNPh

NR

CN

O

F3CTFAA13 (2 mol%)

TMSCN (2 equiv), MeOH

toluene, –50 °C

R = 4-BrC6H4CH250% ee

63% yield

O

Ot-Bu

O

N

SO O

F3CO

Ot-Bu

NH

O

N

NOH

HH

Cl

3g

50% K2HPO4 toluene–CH3Cl (9:1)

r.t.

+

3g

O

R R

R = H 97% ee, 80% yieldR = 5-Cl 97% ee, 85% yieldR = 6-MeO 95% ee, 85% yield

O

Ot-Bu

NH

O

82% ee, 78% yield

(2-F3CC6H4)O2S

(2-F3CC6H4)O2S

O

RAr

O

Ph Ph

O

+CHCl3, r.t.

O

R

ArPh

HO

COPhR = H, MeAr = Ph, 2-naphthyl, 2-furyl, 4-ClC6H4, 4-O2NC6H4, 4-MeOC6H4

64–91% eedr = >95%

50–87% yield

O

Ar

O

PhS

Ph

O

+CH2Cl2, r.t.

O

ArPh

HO

SO2Ph

O

Ar = Ph, 1-naphthyl, 2-naphthyl, 2-furyl, 2-thienyl, 4-ClC6H4, 4-O2NC6H4, 4-HOC6H4

14

14

48–93% eedr = >95%

86–99% yield

N

NH

Bn CO2H

Me

14



example of this fact is illustrated in a paper by Liu and co-workers.79

In the reaction of an a,b-unsaturated trifluoromethyl ke-tone in acetone, whilst pyrrolidine afforded prevalentlythe Michael-initiated ring closure cyclohexanone product,similarly as reported in Scheme 28, the use of L-proline(7a) as the catalyst led instead, and in quantitative yield,to the aldol addition product.

Scheme 28 Enamine-mediated addition of acetone to trifluoro-methyl enones

The synthesis of the latter, acyclic, type of tertiary alcoholwas then optimized, with a phenylsulfonamide being usedas the catalyst (Scheme 29).

Scheme 29 Addition of ketones to trifluoromethyl enones mediatedby a sulfonamide catalyst

The asymmetric Friedel–Crafts addition reaction of in-doles to trifluoropyruvate has been developed, and useschiral copper(I) complexes as catalysts.80,81 This reactioncan also be catalyzed by bases, such as the cinchona alka-loids cinchonine and cupreine. In 2005, Prakash and co-workers reported a Friedel–Crafts-type cinchona alkaloidcatalyzed addition of indoles and pyrroles to ethyl trifluo-ropyruvate (Scheme 30).82

According to the authors, the activation of the carbonylgroup occurs via a weak hydrogen bonding through the 9-OH group of cinchonine 2n. The authors also report thatonly indoles with a free NH group are reactive, which sug-gests activation of the indole moiety via deprotonation, inagreement with the related amination of 2-naphthols in theFriedel–Crafts reaction with diazodicarboxylates(Scheme 31).23

The reaction solvent is diethyl ether, which is uncommonin cinchona alkaloid organocatalysis, especially becausecinchonine is completely insoluble in ether; however, theheterogeneous catalytic system turns into a homogeneoussolution upon addition of the trifluoropyruvate. This isevidence in favor of the hydrogen-bond-activation hypo-thesis.

Deng and co-workers extended the scope of the nucleo-philic addition of indoles to activated carbonyls employ-ing the cupreine-type catalysts. Examples include other a-keto esters and aldehydes (Scheme 32).83

Scheme 32 Other examples of indole addition to activated carbonylcompounds

The ethyl trifluoropyruvate carbonyl group activation oc-curs also with organic sulfonamides: Rueping et al. devel-oped an interesting example of carbonyl-ene reactionemploying a strong acidic chiral Brønsted acid as the cat-alyst (Scheme 33).84

The addition of nucleophiles to the more electrophile C3carbonyl of isatins is an attractive reaction since the re-sulting tertiary alcohols are bioactive substances as wellas natural products. Convolutamydine A, in particular, hasbeen prepared recently, by several groups, in a single stepthrough the secondary-amine-catalyzed addition of ace-tone to the known 4,6-dibromoisatin.85 The progress of

CF3

O

+

O

72% yield

66% ee99% yield

O

PhCF3

OH

CF3HO O

15

7a

r.t.

NH

15

NH

CO2H

7a

r.t.

81–95% ee76–99% yield

NH

O

HN

SPh

O O

R1 CF3

O

+

O CF3HO O

R1

R2

R2

TFA, Et2O, r.t.

R1 = Ph, 5-FC6H4, 4-ClC6H4, 4-BrC6H4,

4-MeOC6H4, 4-MeC6H4, 1-naphthyl, 1-furyl, PhC≡C, PhCH=CH, Ph(CH2)3

R2 = H, Me, Et

16

16

Scheme 30 Asymmetric Friedel–Crafts reaction for the synthesis ofchiral tertiary alcohols

NH

R O

CO2EtF3C+

NH

F3CCO2Et

OH

R2n

Et2O, –8 °C

R = H 90% ee, 99% yieldR = Me 92% ee, 99% yieldR = OMe 83% ee, 96% yieldR = Cl 86% ee, 98% yield

Scheme 31 Possible double activation of both electrophile ethyltrifluoropyruvate, via hydrogen bonding, and indole nucleophile, viadeprotonation

N

O

CF3

NH

F3CCO2Et

OH

R1

O

N

H

H

H

N

OH

H

H

EtO2C

R1

NH

+

NH

R2

CO2EtOH

O

CO2EtR2

R2 = Pr, t-Bu, 4-ClC6H4, 4-CNC6H4, 4-MeOC6H4, C≡Ct-Bu

R1 = H, 6-MeO, 7-Me, 6-Br, 6-Cl

R1R1

83–97% ee52–96% yield

2b

Et2O, 23 °C



the reaction can be followed visually by the gradual disap-pearance of the deep red color of the solution, which isdue to the extended carbonyl conjugation of the isatin

moiety. This reaction could be a benchmark reaction fortesting new catalysts. L-Proline (7a) as the catalyst afford-ed only moderate enantiomeric excess (40%) while betterresults were obtained with proline-based dipeptides suchas 18 (Table 4).

It should be noted that the resulting tertiary alcohols areprone to racemization in the presence of trace acid or onsilica gel, and this observation could explain the reportedlow enantiomeric excess of the natural substance. Aminoalcohols such as valinol and isoleucinol can better controlthe product’s stereochemistry, achieving enantiomeric ex-cesses up to 95%.86 The activation of the isatin carbonylgroup can occur via hydrogen bonding or, more likely,through the formation of a five-membered-ring hemiami-nal. This would also account for the low enantiomeric ex-cess observed when the reaction is stopped at lowconversion.

A 2-thienyl sulfonyl amide 20 has also been employed asthe organocatalyst in the synthesis of convolutamydine

Scheme 33 Chiral Brønsted acid catalyzed ene reaction of ethyltrifluoropyruvate

O

OP

O

NH

OMe

OMe

O

CO2EtF3C+

SO2CF3

Ar = Ph, 4-MeOC6H4, 4-MeC6H4, 3-MeC6H4, 4-EtC6H4, 4-(i-Pr)C6H4, 4-(t-Bu)C6H4, 4-FC6H4, 4-ClC6H4, 4-IC6H4, 4-BrC6H4, 2-naphthyl, biphenyl, 3,4-Me2C6H3, 4-BrC6H4-C6H4, tetralinyl, indanyl

Ar17

o-xylene, 10 °CAr CO2Et

F3C OH

17

92–97% ee71–96% yield

Table 4 One-Step Synthesis of Convolutamydine A via Secondary-Amine-Mediated Addition of Acetone to 4,6-Dibromoisatin: Comparison of Catalysts

Organocatalyst Preparation of convolutamydine A Other substrates tested

Conditions ee (%) (yield, %) Config.

Cozzi, Garden, Tomasini2005–2006

acetone–15 °C

68 (99)97 (50) (after recryst.)

R

R1 = H, BrR2 = H, Me, EtR3, R4 = Br73–77% ee90–99% yield

acetone–15 °C

52 (99) S

R1 = HR2 = HR3, R4 = Br33% ee99% yield

Malkov, Bella, Kocovsky2007

acetone–CH2Cl2

r.t.95 (98) R

R1 = H, BrR2 = HR3, R4 = Br, Cl, H94–95% ee96–99% yield

Nakamura, Toru2008

acetone–H2O0 °C

95 (99) R

R1 = H, BrR2 = HR3, R4 = Br, Cl, H92–97% ee59–99% yield

NR2

R1O

ONR2

R1

O

HOOR3

R4

R3

R4

convolutamydine AR1, R2 = HR3, R4 = Br

HN

CO2Bn

NH

O Ph18

NH

O

OH

7b

H2N OH19

NH

O

HN

S

O O

S

20



A.87 It is worth noting that the absolute configuration ofthe amino acid or amino alcohol derived catalyst em-ployed does not correlate with the stereochemistry of thenatural substance. D-Proline (7b) and D-proline-deriveddipeptide 18 gave products with opposite absolute config-uration (S and R, respectively), while L-sulfonyl prolin-amide 20, which is inverted with respect to the peptidederivative 18, also gave the product with R-configuration;D-amino alcohols afford the product with the natural sub-stance’s correct R-configuration. These examples showonce more how complex and unpredictable an organocat-alytic mechanism may be.

a-Ketophosphonates are also very reactive electrophilesand they are readily attacked by nitroalkanes to yield ter-tiary alcohols.88

Similar products, oxygenated in the 3-position, have beenobtained enantioselectively, using an asymmetric phase-transfer catalyst (Scheme 34).89

Scheme 34 Oxygenation of oxindoles

6.1 Direct Aldol Reaction

The direct aldol reaction can be claimed as one of the mostpowerful and efficient methods for carbon–carbon bondformation. Within the aldol reaction manifold, the devel-opment of asymmetric syntheses of products bearing aquaternary carbon has proven to be one of the most ap-pealing goals. Resembling Nature’s approach, in the lastfew decades, chiral amines and amino acids have beenidentified as outstanding catalysts for aldol and analogousreactions which proceed through enamine intermediates.

In this context, many results using organocatalysts such asL-proline and small amines have been published;45a,90

there have, however, been just a few reports of direct cat-alytic aldol reactions that generate a tetra-substituted car-bon atom. One of the pioneering examples was disclosedby Jørgensen and co-workers,91 who developed the firstcatalytic asymmetric aldolization of propanal with acti-vated carbonyl compounds in the presence of L-proline(Scheme 35). The reaction proceeded with high enantio-meric excess (81% ee), presumably through the proposed

transition state, affording the corresponding aldol productin very good yield (98%).

A similar approach led more recently to a concise andenantioselective synthesis of (S)-2-cyclohexyl-2-phenyl-glycolic acid.92 Inspired by the pivotal works byWiechert93 and Hajos,8 and by Barbas,90a–c the crucialasymmetric tetrasubstituted carbon center was construct-ed, by Maruoka’s group, with excellent stereoselectivity(>99% ee) through the proline-catalyzed direct asymmet-ric aldol reaction between cyclohexanone and ethyl phe-nylglyoxylate derivatives. The mild conditions(Scheme 36) afforded the intermediates in good diastere-omeric ratio (>20:1) and excellent enantioselectivity(96% to >99%).92 The major diastereomer was easilytransformed into the desired (S)-2-cyclohexyl-2-phenyl-glycolic acid.

Scheme 36 Proline-catalyzed asymmetric aldol reaction betweencyclohexanone and keto esters towards the synthesis of (S)-2-cyclo-hexyl-2-phenylglycolic acid

The catalytic asymmetric intramolecular cross-couplingbetween ketones and aldehydes have been highlighted re-cently by Enders et al.94 who studied the proline-catalyzedintramolecular cis-5-enol-exo aldolization, and achievedthe synthesis of a number of 2,3-dihydrobenzofuranols(Scheme 37). The relative topicity and the observed R-configuration at the newly formed quaternary center are inagreement with an intramolecular version of a Houk–List-type transition-state model.

More recently, Zhao and co-workers95 applied their expe-rience in the cross-aldol reaction of ketones to that of b,g-unsaturated keto esters (Scheme 38). The reactions wereperformed in water, with proline derivative 21 as catalyst,

N

R

O

NO

R OH

PMB PMB

50% KOH (aq) toluene, –20 °C

in air

67–93% ee91–99% yield

R = Allyl, Bn, HC≡CCH2, n-Pr, n-Hex, Me2C=CHCH2, 4-MeOC6H4CH2, EtO2(CH2)2CH2

N

NHO

HH

H

Br

3h *

NH

O

OH

85% ee

formal synthesis of CPC-1

NN

MeMe

MeO

H

3h

R = Allyl

Scheme 35 Direct catalytic asymmetric aldol reaction of aldehydes

H

O

+ F3C

O

CO2EtCH2Cl2, r.t.

H

O OH

CF3

CO2Et

81% eedr = 3:2

98% yieldN

O

O

OF3C

CO2Et

H


O

R2

O

R1O2C

L-Pro (7a)(30 mol%)

DMSO, r.t.+

O

R2

CO2R1HO

CO2HHO

R2 = H

R1 = Me, R2 = HR1 = Et, R2 = H, CF3, Cl, Me

96 to >99% eedr > 20:1

45–99% yield



leading to the final products in good yields (67–99%) andexcellent stereoselectivities (99% ee; 19:1 to 24:1 dr).

In a similar fashion, an efficient synthesis of (2S,3R)-3-hydroxy-3-methylproline (OHMePro) and analogues wasachieved using OHMePro itself as the best organocatalystfor the intramolecular asymmetric aldol reaction of thestarting ketoaldehyde (Scheme 39).96 The formation oftwo contiguous asymmetric carbon quaternary stereogen-ic centers was accomplished in high yields (49–90%) andexcellent stereoselectivity (syn/anti from 89:11 to >99:1;73–89% ee), probably owing to the 3-hydroxy-assistedrigid bicyclic conformation of the cyclic chairlike transi-tion state.

Scheme 39 Organocatalytic synthesis of (2S,3R)-3-hydroxy-3-methylproline (OHMePro) and analogues

Although L-proline (7a) is a strikingly powerful catalystfor the aldolization of many aldehyde donors, the asym-metric synthesis of compounds with quaternary stereo-genic centers is not efficiently addressed with thiscatalysis.90f,97 The use of a,a-dialkyl aldehyde donorsshould provide a straightforward access to a quaternarycarbon. Applying this strategy, Barbas and co-workers98

evaluated the efficiency of several chiral amines in thepresence of various acid additives, such as Lewis, Brønstedand organic acids; they found the (S)-(+)-1-(2-pyrrodinyl-methyl)pyrrolidine/trifluoroacetic acid (5·TFA) system tobe the best-performing catalyst (Scheme 40).

Scheme 40 Direct aldol reaction catalyzed by 5·TFA for the synthe-sis of aldol products with quaternary carbon centers

In addition to their leading experiments carried out withisobutyraldehyde as donors and benzaldehyde derivativesas acceptors, the Barbas research group explored thescope of this class of aldol reactions with a series of a-alkyl a-methylaldehydes. In all cases, excellent levels ofstereoselectivity were achieved [dr (anti/syn) = 62:38 to85:15; 53–96% ee], as a consequence of the proposedtransition state shown in Figure 6.

Figure 6 Proposed transition state

Following on Barbas’ concept on the use of protic acid–diamine catalysts, a system of higher complexity, such asan a-keto ester, was investigated by Dondoni and co-workers in an interesting study (Scheme 41).99 The bi-functional catalyst approach by means of the 5·TFA com-bination provided a highly enantioselectivehomoaldolization of ethyl pyruvate. Consequently, theuse of polymer-supported reagents allowed for the lacton-ization of the aldol product and isolation of the isotetronicacid derivative.

In keeping within the synthesis of interesting biologicallyactive compounds, the potential of the new proline back-bone organocatalysts described by Sampak and Zhao isnoteworthy.100 The synthesis of optically active tertiary a-hydroxy phosphonates was accomplished upon the highlyenantioselective (69–85% ee) organocatalytic cross-aldolreaction of a-ketophosphonates and ketones using pro-linamide 22 as the catalyst (Scheme 42).

Scheme 37 cis-Selective intramolecular aldol reaction

O

O

O

DMF, r.t. O

OHO

79% ee 99% de

96% yield

O

O

N

O

HO

L-Pro (7a)(30 mol%)

S

R

Scheme 38 Cross-aldol reaction

Ar

O

Ar

O

HO CO2R

cyclohexanone, H2O, r.t.

NH

O

OH

TBDPSO

21 (15 mol%)

21

Ar = Ph, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 3-ClC6H4, 2-BrC6H4, 2-furylR = Me, Et, Allyl, i-Pr, t-Bu, Bn

99% eedr = 19:1 to >24:1

67–99% yield

CO2R

R2

O

N

R1 O

H

N

R2OH

O

OH

R1

R1 = Ts, R2 = MeR1 = Cbz, R2 = MeR1 = SO2Bn, R2 = MeR1 = Ts, R2 = EtR1 = Ts, R2 = (CH2)2i-Pr N

H

OH

O

OH

1. OHMePro (5 mol%)H2O2 (5 equiv), THF, 0 °C

2. NaBH4, EtOH

OHMePro

syn/anti = 89:11 to >99:173–88% ee

49–90% yieldS

R

H

O

R

H

O

NO2

OH

NO2

O

H

R

+ (0.1 equiv)

DMSO, r.t.

91–96% yield

R = Et

91% ee (anti), 75% ee (syn)

R =


O

O




5·TFA

R =

R =

R =

R = Pr


R = nonyl


N

R1

R2

HN

O

Ar H

H+

CF3CO2–



Taking a leaf out of Nature’s book, Gong and co-workers101 designed organocatalysts such as 23 to cata-lyze the asymmetric aldol reaction of acetone with aryland alkyl a-keto acids (Scheme 43).

Scheme 43 Direct aldol reaction of acetone and a-keto acids

This new approach afforded the corresponding b-hydroxycarboxylic acids, bearing a quaternary stereogenic center,with excellent enantioselectivities of up 98% ee. The highstereocontrol of the organocatalyst is due to the transitionstate being stabilized by the double hydrogen bonds

formed between the 2-aminopyridine moiety of the cata-lyst 23 and both the keto and carboxy functional groups.

7 Brønsted Acid Organocatalyzed Formation of Nitrogen-Containing Quaternary Stereo-centers

The formation of quaternary stereocenters by counterion-directed Brønsted acid catalysis was only recently demon-strated. Zhou and co-workers showed the asymmetricconstruction of nitrogen- containing quaternary stereo-centers employing several chiral acids; among those test-ed, the best performances in terms of yields andenantioselection were given by (S)-TRIP (Scheme 44).102

Scheme 44 (S)-TRIP-catalyzed Friedel–Crafts reaction

8 Halogenation and Pseudohalogenation Reac-tions

8.1 Fluorination

The importance of fluorinated compounds is demonstrat-ed by the fact that more than 150 drugs or agrochemicalscontain at least one fluorine atom; however, prior to 2000,no reliable method was reported for the preparation offluorine-containing quaternary stereocenters.103 In 2000,Cahard developed an asymmetric fluorination of silylenolates bearing a quaternary stereocenter, by employinga cinchona alkaloid derived N-fluoro quaternary ammoni-um salt, in up to 93% yield and 61% ee.104 Jørgensen’sgroup reported the a-fluorination of aldehydes usingdiphenylprolinol derivatives; however, when this reactionwas applied to branched substrates, no significant amountof the desired product was obtained.105

Through the years, a number of different groups have triedto develop new strategies for organocatalytic fluorina-tion,106,107 but just recently, catalyst 24, where chiralitystems from restricted rotation along the Caryl–N bond axis,gave some results in the formation of fluorine-bearingquaternary stereocenters (Scheme 45).23 It should be not-

Scheme 41 Homoaldol reaction of ethyl pyruvate under catalysis bythe 5·TFA couple catalyst

O

CO2Et

NH

NTFA

DMSO, r.t.

1.

2.SO3H

NN

H H H

++

CF3CO2–

SO3–

O

CO2Et

EtO2C OHO

OH

OEtO2C O

O

OEtO2C

+

1. TBSCl, imidazole 2. chromatography

O

OTBDMS

OEtO2C

68% ee

5·TFA (30 mol%)

Scheme 42 Enantioselective synthesis of a-hydroxy phosphonates

Ph

O

P

O

OR1OR1

O

R2

+22 (15 mol%) P

O

OR1OR1

OHPhO

R2

R2 = Me, R1 = Me 69% ee, 87% yield R1 = Et 69% ee, 83% yield R1 = i-Pr 74% ee, 82% yield R2 = OMe, R1 = i-Pr 85% ee, 93% yield

*

NH

CONH2

22

O+

R

O

CO2H

23 (20 mol%)

toluene, 0 °C

O

R

OHCO2H

N

O

N N

H

O

H

O

OR

R = Ph, 2-furyl, 2-thienyl, Bn, Me, Et, i-Pr

92–98% ee 75–99% yield

NH

O

NH N

23

(S)-TRIP(10 mol%)

toluene, 4 Å MS0–25 °C

NH

NHAcAr+

NH

ArNHAc

O

OP

O

OH

i-Pr i-Pr

i-Pr

i-Pr

i-Pri-Pr

(S)-TRIP

Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, . 4-CF3C6H4, 3,4-Me2C6H3, 3-MeC6H4, 4-MeOC6H4, 2-naphthyl

90–97% ee95–99% yield



ed that the only kind of aldehydes that reacted with goodenantioselectivity (78–90% ee) and moderate yields (55–60%) were the a-substituted phenylacetaldehydes shown(R1 = Ar), probably thanks to the stabilization of the phe-nyl-conjugated enamine; when both R1 and R2 were ali-phatic groups, yields (27–30%) and enantiomeric excessvalues (7–30%) dropped dramatically. In general, the con-struction of quaternary stereocenters via enamine activa-tion, the reaction of an aldehyde of this type where bothR1 and R2 are other than aromatic represents a currentlyunsolved problem. Thus, the finding of a general catalyticsystem effective for this transformation would represent amajor and significant breakthrough in the field.

Scheme 45 Asymmetric fluorination of a,a-disubstituted alde-hydes; NFSI = N-fluorobenzenesulfonimide

More recently, Shibatomi and Yamamoto108 have proventhat quaternary stereocenters can indeed be formed withhigh enantioselection from the especially reactive a-alkyla-chlorinated aldehydes shown in Scheme 46.

Scheme 46 Asymmetric fluorination of a-chloro-substituted alde-hydes

8.2 Chlorination and Bromination

b-Keto esters can be chlorinated and brominated in highenantiomeric excesses employing the benzoyl quinine 2pas the tertiary amine catalyst and a 5,7,7-trihaloquinolin-8(7H)-one as the halogenating reagent (Scheme 47).109

8.3 Sulfenylation

The sulfenylation reaction of several b-keto esters hasbeen achieved with 1-benzylsulfanyl[1,2,4]triazole as theelectrophile (Scheme 48).110

Scheme 48 Asymmetric sulfenylation of several b-dicarbonyl com-pounds

9 Epoxidation

Epoxidations were one of the first asymmetric processesto be developed and were rooted in the Sharpless reaction.Unfortunately, this highly valuable process is limited toallylic alcohols as substrates and the development of new-er, organocatalytic, and broad-scope alkene epoxidationprocesses remains a challenging endeavor of great inter-est.

One of the most productive methods involved the actionof KHSO5, the active constituent of the triple salt Oxone®

(2KHSO5·KHSO4·K2SO4). Among the three major classesof organocatalyst that have been found for oxone-mediat-

R1 = Ph, R2 = Me 90% ee, 36% yieldR1 = 4-O2NC6H4, R2 = Me 78% ee, 56% yieldR1 = 4-BrC6H4, R2 = Me 90% ee, 60% yieldR1,R2 = -(C6H4)(CH2)3- 78% ee, 55% yieldR1 = n-Bu, R2 = Et 7% ee, 27% yield R1 = 4-(i-Pr)C6H4CH2 R2 = Me 30% ee, 29% yield R1 = c-Hex, R2 = Me 31% ee, 10% yield

R1

R2

H

O

(racemic)

hexanes–i-PrOH, r.t.R1

F

H

O

R2

*R1

FOH

R2

*

NaBH424, NFSI

NBocBocHN

NH2

OH

24

R = Ph, Bn, Hex, t-Bu

R

ClH

O

MTBE, 25 or 0 °CR

Cl

H

O

F*

R

ClOH

F*

NaBH4

88–99% ee62–86% yield

25a, NFSI

NHTMSO

25a

(racemic)

F3C

CF3

CF3

CF3

Scheme 47 Asymmetric halogenation of b-keto esters

+

2p, NaHCO3

toluene, –78 or –40 °C

96% ee83% yield

93% ee80% yield

N

OX

X

XR2

O O

R3R1

R2

O O

R3R1

X

X = Cl OCO2Et

Cl

O

Cl

CO2EtO O

OEt

O

Cl

CO2Me

O

Cl

O

O O

OEtF3C

Ph

O O

OEt

OCO2Et

Br

X = Br

Cl Cl Cl

Ph

O O

OEt

Br

76% ee75% yield

80% ee99% yield

89% ee55% yield

59% ee74% yield

83% ee82% yield

84% ee67% yield

95% ee95% yield

N

NO

HH

H

MeO

2p

O

+R1 R3

O O

R2 N

NN

BnS

toluene, –30 °CR1 R3

O O

R2 SY

*

O

CO2Et

SBn

O

CO2t-Bu

SBn

O

CO2Bn

SBn

MeO2C SBn

O TsN

O

CO2t-Bu

SBn

63% ee91% yield

88% ee89% yield

60% ee84% yield

53% ee94% yield

85% ee87% yield

2o



ed epoxidations, some include examples that are capableof catalyzing the formation of quaternary stereogenic cen-ters.

9.1 Ketone-Mediated Epoxidation

Since 1996, ketone 26a has been the most generally usefulchiral catalyst for asymmetric epoxidation; it provides ex-cellent enantioselectivities for trisubstituted and trans-1,2-disubstituted alkenes (Scheme 49) when used with amixture of acetonitrile and dimethoxymethane (DMM) asthe solvent system.111

Scheme 49 Shi epoxidation with ketone 26a

The Shi approach reveals its strong point in total synthe-sis. A noteworthy example is the construction of the tet-rahydrofuran rings of glabrescol via the highlystereoselective formation of the intermediate tetraepoxidefrom the starting polyene (Scheme 50).

Scheme 50 Reagents and conditions: (a) 26a (1.5 equiv), Oxone®

(1.38 equiv), K2CO3, MeCN–DMM–aq Na2(EDTA) (1:2:2),Na2B4O7; (b) CSA.

9.2 Iminium Salt Catalyzed Epoxidation

Oxaziridinium salts were found to be the reactive interme-diate in a catalytic epoxidation system that used iminiumsalts, such as those in Figure 7, as promoters.112

Since Aggarwal’s pioneering work in 1996,113 much ef-fort has been devoted to the development of an effectivecatalytic system, but the first high levels of enantiocontrolwere only reported in 2004, by Page and co-workers(Scheme 51).114

9.3 Amine-Catalyzed Epoxidation

Likewise, Aggarwal achieved valuable results (up to 66%ee) using chiral amines such as 28 with Oxone® as activa-tor (Scheme 52).115

Scheme 52 Amine-catalyzed epoxidation developed by Aggarwal

A potentially general electrophilic activation mechanismis also the system, developed by Miller and co-workers,116

which involved well-defined peptide-based catalyst suchas 29 (Scheme 53).

We refer the reader to the intriguing Berkessel review117

for a more exhaustive coverage of these reactions.

The demonstrated high reactivity of electrophilic oxidantsdescribed above was dramatically reduced when electron-poor alkenes, such as enoates and enones, were used;these, therefore, required a more reactive catalyst. In this

Oxone® (1.38 equiv)MeCN–DMM–aq Na2(EDTA) (1:2:2)Na2B4O7, K2CO3 (5.8 equiv), 0 °C

Ph

R1

R2

Ph

R1

R2O

R1 = Me, R2 = Ph 95% eeR1 = Me, R2 = SiMe 94% ee

OPh

98% ee

OBzO

n

n = 1, 80% een = 2, 93% een = 3, 91% een = 4, 95% ee

26a (30 mol%)

O

OO

OO

O

26a

a

OH

OH

HO

HO

OH

OH

HO

HO

O O

OO

HO OH

O O

O O

H H

H H

OH HO

b

44%66%

glabrescol

Figure 7 Chiral iminium salt catalysts

N

Ph

Me

X N MeBF4

N

O

O

Ph

BPh4

NBPh4

O

O

MeO2S

27a 27b

27c 27d

Scheme 51 Iminium salt catalyzed asymmetric epoxidation

R1

R2 27c (5 mol%)Oxone® (2 equiv)

Na2CO3

MeCN–H2O, 0 °CR3

R1

R2

R3

O

Ph

n

n = 1–355–91% ee

52–54% yield

O

PhO

95% ee66% yield

Ph

Ph

O

49% ee58% yield

O

25% ee 63% yield

t-Bu

28·HCl (0.1 equiv) Oxone® (2 equiv)

NaHCO3 (10 equiv)

pyridine (0.5 equiv)MeCN–H2O (95:5), 0 °C

PhO

25% ee93% yield

Ph

NH

Ph

Ph

NPh

PhH H

O OS

O O OH28



regard, Shi and co-workers increased the catalyst reactiv-ity by replacing the acetonide unit in 26a with more elec-tron-withdrawing ester groups, as in 26b (Scheme 54).118

Unfortunately, the enantioselectivity was strongly sub-strate-dependent and variations, such as trans/cis isomersor the presence of a bulky group, could significantly influ-ence the outcomes in terms of both yield and stereoselec-tion. Therefore, electron-poor alkenes generally preferand require nucleophilic epoxidation conditions. An im-pressive example was reported by Jørgensen and co-workers:119 prolinol derivative 25a was used to accom-plish the epoxidation – via iminium ion formation – of thea,b-unsaturated aldehyde shown in Scheme 55.

Scheme 55 Selective epoxidation of an enal

The reaction, using hydrogen peroxide as the oxidant,reached not only excellent levels of enantioselectivity (upto 96% ee) and diastereoselectivity (up to 97:3 dr), butcould also be performed regioselectively in the presenceof another non-conjugated double bond in the same mole-cule.120

10 Diels–Alder Reaction

Prompted by MacMillan’s seminal studies on iminium ca-talysis,121 many efforts have focused on the reversible for-mation of iminium ions from a,b-unsaturated aldehydesand amines that could emulate the equilibrium dynamicsand p-orbital electronics of Lewis acid activation. Therequisite catalyst features were shown to be: ‘(1) the chiralamine should undergo efficient and reversible ion forma-tion; (2) high levels of iminium geometry control; (3) se-lective p-facial discrimination of the iminium ion; (4) theease of catalyst preparation and implementation’. Onthese bases, and driven by the amazing experimental re-sults, two generations of catalysts have been developed inorder to broaden the substrate and reaction scopes(Figure 8).

Figure 8 First- and second-generation imidazolidinone catalysts

The Diels–Alder reaction was one of the first valuabletransformations involved in the development ofMacMillan’s concept of iminium catalysis.

Since the earliest publications, which highlighted how thepresence of a catalytic amount of imidazolidinone (5–20mol%) afforded the cycloadduct in good yields (75%) andhigh regio- and enantioselectivities (96% ee; exo/endo =35:1; Scheme 56),121 the amine-catalyzed Diels–Alder re-action of a,b-unsaturated aldehydes has been investigatedin some detail. Its great potential was demonstrated in thestraightforward preparation of (+)-hapalindole Q, a tricy-clic alkaloid natural product containing four contiguousstereocenters (Scheme 57).122

Scheme 56 Organocatalyzed Diels–Alder reaction

Unfortunately, MacMillan’s approach suffered from tworestrictions in the nature of the dienophile: neither a-sub-stituted a,b-unsaturated aldehydes nor simple unsaturatedketones could be used.

The former limitation was recently overcome by Nakanoand Ishihara,123 who developed the amine 31. With thisnovel organocatalyst, exo-selective cycloaddition hasbeen accomplished between a-acyloxyacroleins and anumber of dienes in high yields (81–99%) and with good

Scheme 53 Electrophilic epoxidation using the peptide-based cata-lyst 29

PhHN

O

O PhHN

O

O

O

29 (10 mol%)DIC (2 equiv)

aq H2O2 (2.5 equiv)

DMAP (0.1 equiv)CH2Cl2, H2O, –10 °C

HO2C NHBoc

ON

O

NH

O

HN

Ph

29

92% ee97% yield

Scheme 54 Epoxidation of enoates catalyzed by ketone 26b

O

AcOAcO

OO

O

26b (30 mol%)

Oxone® (5 equiv), Na2(EDTA)NaHCO3, Bu4NHSO4 (cat.)

MeCN, 0 °C

PhCO2Et Ph

CO2EtO

96% ee93% yield

26b

CHO CHOO25a (10 mol%)

aq H2O2, CH2Cl2, r.t.

85% ee73% yield

N

NH

O Me

Ph

N

NH

O Me

Ph

30b second-generation30a first-generation

O

Ph

Ph

O

O Ph

PhCHO

30a (20 mol%)

23 °C+

96% ee exo/endo = 35:1

75% yield



selectivities (79–92% ee; exo/endo = 6.7:1 to 99:1,Scheme 58).

Pursuing their studies on acid–base combination chemis-try, Ishihara et al.124 demonstrated how H-L-Phe-L-Leu-N(CH2CH2)2-reduced triamine 31 and pentafluoroben-zenesulfonic acid activate the a-(N,N-diacylamino)ac-rolein as an aldiminium cation intermediate (Scheme 59).The overall process provides the corresponding cyclic, N-protected a-quaternary a-amino acid precursor in highyield (97%) and stereoselectivity (96% ee).

Scheme 59 Organocatalytic enantioselective Diels–Alder reactionof 2,3-dimethylbuta-1,3-diene

The second drawback, that ketones could not be used, wassolved elegantly by slight adjustments to the catalyst sub-stituents, namely the introduction of both a benzyl groupat C2 and a heteroaromatic moiety at the C5 position

(Scheme 60). Thus, the 2-(5-methylfuryl)-derived imida-zolidinone 30c assures high levels of enantiocontrol (48–98% ee) and remarkable exo-selectivity (exo/endo = 5:1 to>200:1).125

Scheme 60 Enantioselective catalytic Diels–Alder reaction of a,b-unsaturated ketones

In depth analysis of the substrate activation through lonepair coordination, characteristic of Lewis acid catalysis,has recently driven several laboratories to develop a high-ly valuable hydrogen-bonding-promoted asymmetricDiels–Alder reaction.

Mimicking the Lewis acid catalysis and pursuing the in-triguing results observed with hetero-Diels–Alder reac-tions,126 the Rawal group reported the first highlyenantioselective (89–91% ee) Diels–Alder reaction cata-lyzed by the a,a,a¢,a¢-tetraaryl-1,3-dioxolane-4,5-dimeth-anol 32 (Scheme 61).127

Scheme 61 TADDOL-like catalyst used in the Diels–Alder reactionof a 1-amino-3-siloxydiene

Among other researchers, Göbel’s group128 has donesome impressive work through the years; recently, theydeveloped the first asymmetric catalysis induced bymetal-free bisoxazolines such as 33 (Scheme 62).129

Scheme 57 Proposed transition-state model for the synthesis of (+)-hapalindole Q

NTs

CHO

30a·HCl

N

N

O

TsN

endo transition state

CHOTsN

NH

SCN

(+)-hapalindole Q96% ee (endo)

65% dr26% yield

MeOH (0.05 M) KH2PO4–NaOH

+

Scheme 58 Organocatalytic enantioselective Diels–Alder reactionof 2,3-dimethylbuta-1,3-diene

NH

NH2Bn

N

t-Bu

RCO2

O

H +

O2CR

CHO

31

31 (2.5–20 mol%) HO3SC6F5 (6.9–55 mol%)

EtNO2, r.t.

R = Me, Ph, Ar exo/endo = 6.7:1 to 99:172–92% ee

81–99% yield

N

O

O

CH2OH + N

CHO O

O31 (2.5–10 mol%)2.75 HO3SC6F5

EtNO2, r.t.

96% ee97% yield

R2

R3

R4

O

R

R4

R2

R1 R1

R5

R3 O

R

R5

+

N

NH

O Me

Ph O

30c·HClO4 (20 mol%)

H2O or EtOH, 0 °C

exo/endo = 5:1 to 200:148–98% ee

78–92% yield

30c

TBSO

NMe Me

R

O

H+ 32 (20 mol%)

toluene, –80 °C

TBSO

NR

CHO

Me Me

1) LiAlH4, Et2O –78 °C to r.t.

2) HF, MeCN 0 °C to r.t.

R

OOH

O

O

OH

OH

Ar Ar

Ar Ar

Ar = 1-naphthyl32

77–85% yield

R = Me 91% eeR = i-Pr 92% eeR = Bn 89% ee

81–83% yield



11 N-Heterocyclic Carbene Catalysis

In 1943 it was made known that thiazolium salts, surpris-ingly, catalyzed the benzoin condensation.130 Only a fewyears later, however, Ronald Breslow proposed a mecha-nistic model that implicated, as the catalytically activespecies, an in situ formed nucleophilic heterocyclic car-bene (NHC) as shown in Scheme 63.131

Scheme 63 Breslow’s proposed catalytic cycle for the benzoin con-densation

Subsequently, the nucleophilic acylating reagent (a hy-droxy-enamine, also called the ‘Breslow intermediate’)which arised from the coupling between the thiazolin-2-ylidene and an aromatic aldehyde, reacts with a second al-dehyde molecule to form the product and simultaneouslyregenerate the carbene catalyst.131

Because of the fascination and challenge of forming a newstereogenic center, much effort has been spent in develop-ing this class of catalyst. Through the years, the researchgroups of Enders132 and Leeper133 have both made out-standing contributions, achieving a-hydroxy ketones ingood yields (up to 83%) and excellent selectivities (up to95% ee) using the triazolium salts 34a–c shown inFigure 9.

Figure 9 Triazolium salts developed by Enders (1996, 2002) andLeeper (1997)

As an obvious extension of the benzoin reaction, NHC ca-talysis was applied to the cross-coupling of aldehydes andketones. Despite the initial successes reported byStetter134a and Suzuki,134b who achieved high selectivitiesbecause of pre-existing stereocenters in the specific sub-strates, only recently have Enders et al. published the firstenantioselective intramolecular cross-benzoin reactionthat employs new chiral tetracyclic and pyroglutamic acidbased pre-catalysts 34d–h (Scheme 64).135

Scheme 64 Asymmetric intramolecular crossed-benzoin reaction

The a-hydroxy ketone derivatives, each with a new qua-ternary stereogenic center, were obtained in high yield (upto 93%) and excellent enantiomeric excesses (61–99%ee).

Unfortunately, to date, no example of the correspondingintermolecular crossed-benzoin reaction has been report-ed, an aspect which makes this a fascinating and challeng-ing endeavor.

Among the same class of reactions can be cited the 1,4-ad-dition of aldehydes to a,b-unsaturated carbonyl com-pounds, known as the Stetter reaction. After the ground-breaking studies by Enders’ group in 1996,136 Rovis et al.later revived interest in this important transformation byachieving significant progress with the new tetracyclic tri-azolinium salt 34i (Scheme 65).137

Scheme 62 Base-catalyzed Diels–Alder reaction of antrone deriva-tives with N-substituted maleimides

R1

R2

R1

R2

O

HH

N

O

O

R3+R2

R1

N

O

O

R3R2

R1HO

33 (25 mol%)

CH2Cl2, r.t.

39–70% ee67–99% yield

N

O

N

O

t-Bu

H H

t-Bu33

R1 = H, Cl R2 = H, ClR3 = Ph, Bn, Ar, i-Pr, t-Bu, c-Hex

S

NR2

R3

H

R1

– H

S

NR2

R3

R1

S

NR2

R3

R1

S

NR2

R3

R1

S

NR2

R3

R1

OH

Ar

H

O

Ar

Ar

HO

OH

ArO

Ph

H

O

Ar

O

Ar

Ar

OH*

X

NN

N

Ph

O

O

Ph

ClO4 NN

N

Ph

Cl

OPh

NN

N

Ph

BF4

Ot-Bu

(1996) (1997) (2002)

34a 34b 34c

X

O

OR1

X

OR1

OH

pre-catalyst 34d–h

(10–20 mol%)

solvent, base

NN

N

Ph

BF4

NN

N

R2O

Ph

BF4

NN

NO

t-Bu

Ph

BF4

X = O, CH2

R1 = Me, Et, n-Bu, i-Bu, n-Pr, c-Hex, BnR2 = H, 2,4-Br2, 2-NO2, 2,4-(t-Bu)2, 2,3-methylenedioxo

R2 R2

R2 = TBS, TIPS

61–99% ee24–93% yield

NN

N

Ph

BF4

pre-catalyst =

34d 34e 34f,g 34h



Scheme 65 Enantioselective synthesis of quaternary stereocentersvia catalytic asymmetric Stetter reaction

This process gave straightforward access to 1,4-dicarbon-yl compounds bearing a quaternary stereocenter in highyields (up to 96%) and selectivity (up to 99% ee) under re-markably mild conditions (Scheme 66); slight changes inthe catalyst structure were required in order to widen thesubstrate scope.

Scheme 66 Highly enantio- and diastereoselective catalytic intra-molecular Stetter reaction

The NHC-catalyzed umpolung reaction just disclosed canbe extended by the use of further functionalized aldehydesas the donor substrates. Among others, Bode and co-workers138a and Glorius and Burstein138b have indepen-dently illustrated the concept of ‘conjugated umpolung’,generating a homoenolate by the reaction of an NHC withan enal. These intermediate species rapidly undergo annu-lation with simple aldehydes and ketones, resulting in aremarkable one-step process for the stereoselective syn-thesis (25% ee) of g-butyrolactones (Scheme 67).

Although the first results did not demonstrate excellentenantioselectivity, interesting headway has been made byYou and co-workers,139 who envisioned that keto esterscould be suitable electrophilic partners in ‘conjugated um-polung’ reactions. Working on this subject, they recentlyreported a smooth synthesis of 4,5,5-trisubstituted g-buty-

rolactones bearing two stereocenters, including one qua-ternary carbon center, and have tuned the dia-stereoselectivity up to 83:17 (cis/trans) and the enantio-selectivity up to 78% ee for one substrate (Scheme 68).

Scheme 68 Annulation of enals and keto esters

12 Cascade Reactions

Asymmetric organocatalysis recently reached its greatestexpression, borne of a combined substrate activation bymeans of both enamine formation (HOMO-raising) andiminium ion formation (LUMO-lowering),140 and appliedto the catalysis of cascade reactions.

As the historical development of this challenging topichas already been extensively and exhaustively covered ina few reviews,141 we report here just the very recent devel-opments in the cascade reaction field which have led tothe formation of quaternary centers.

The most employed reaction combination involves an ini-tial iminium-ion-activated reaction followed by an en-amine-activated transformation. Examples of this are thefirst organocatalytic Robinson annulation140a and, morerecently, the domino thia-Michael–aldol reactions142

shown in Scheme 69, which gave benzothiopyran deriva-tives in high yields with up to >15:1 dr and 96–99% ee.

34i (20 mol%)

Et3N or KHMDStoluene, 25 °C

N

O

N

NBF4

F

F

FF

F34i

X

R

O

EWG X

O

R

EWG

84–99% ee55–96% yield

X = CH2, O, SR = Me, Et, n-Bu, CO2MeEWG = CO2Me, CO2Et, COMe, COPh

34j (20 mol%)

toluene, 23 °CX

O

83–99% eedr = 10:1 to 50:1

55–95% yield

X = CH2, OR1 = Me, EtR2 = OEt, OMeR1–R2 = -(CH2)n-

COR2

R1

X

O COR2

R1

H

N

N NArBn

X

H O

ROHR1

34j

N

N NBn

CF3

Scheme 67 Enantioselective synthesis of g-butyrolactones

Ph F3C

O

+34k–m (5 mol%)

KOt-Bu (10 mol%)THF, r.t.

O

O

PhF3CPh

N

O

N

N

4-TolCl

major84% yield

O

H

Ph

N

O

N

N

t-BuPh

BF4

N

O

Ni-Pr

OTf

O

25% eedr = 3:1

no reactionno reaction

34k 34l 34m

R1CHO

R2

O

O

OR3+

34n (5 mol%)

DBU (15 mol%)THF, r.t.

O

O

CO2R3R2

R1

N

O

N

N BF4

34n

cis/trans = 55:45 to 83:1714–55% ee (cis)

14–78% ee (trans)45–98% yield

R1 = Ph, 4-MeC6H4, 4-O2NC6H4, 2-furyl, n-PrR2 = Ph, 4-MeOC6H4, 4-FC6H4, 4-ClC6H4, 2-MeC6H4, CF3, 2-thienyl, c-Hex, MeR3 = Bn, Et, Me



Scheme 69 Domino thia-Michael–aldol reaction

The analogous L-proline derivative 25b proved to be themost effective catalyst in the one-pot domino Michael–a-alkylation reaction depicted in Scheme 70. The final cy-clopropane derivatives were isolated in high diastereo-and enantioselectivity (>25%:1 dr, 94% ee).143

Scheme 70 One-pot organocatalytic domino Michael–a-alkylationreactions: direct catalytic enantioselective cyclopropanation

A different mechanistic pathway, but involving the samecatalyst, has been postulated for the outstanding dominoMichael-addition–a-alkylation that was reported byEnders et al. (Scheme 71).144

Scheme 71 Organocatalytic domino reaction of aldehydes and (E)-5-iodo-1-nitropent-1-ene

According to their hypothesis, the initial enamine activa-tion of the aldehyde led to the Michael addition and thiswas followed by a second enamine activation of the inter-mediate, thereby affording the ring-closure product byway of an intramolecular nucleophilic substitution(Scheme 72). Despite the moderate yield (up to 62%) theoverall process was highly stereoselective [up to 1:99 dr(trans/cis), trans up to 94% ee, cis up to 97% ee). The ob-tained g-nitroaldehydes could betransformed in a straight-forward manner into interesting cyclic g-amino acids.

As well, cinchona alkaloid derived primary amines havebeen successfully involved in organocatalytic cascade re-actions. Highly valuable work has been done by Zhongand co-workers who, almost contemporaneously, devel-oped a tandem Michael/Henry reaction145 and a dominodouble-Michael reaction (Scheme 73).146

Both reaction were efficiently catalyzed by 9-amino-9-deoxyepiquinine 2q to give highly functionalized cyclo-hexanes and cyclopentanes with up to four stereogeniccenters in excellent enantioselectivities (up to >99% ee)and diastereoselectivities (up to > 99:1 dr).

A special mention needs to be made of the construction ofcomplex molecules through triple cascade and multicom-ponent reactions; the most elegant expression of these wasin the Michael–Michael–aldol reaction sequence present-ed by Enders et al.147

Among the most recent advances, a noteworthy study hasbeen reported by Melchiorre and co-workers.148 Complexmolecules bearing quaternary stereocenters were obtainedin good yield and excellent diastereo- and enantioselectiv-ity (up to 20:1 dr; up to >99% ee) through an organocata-

O

SH

O

R S R

HO O

R = Ph, 4-NCC6H4, 4-ClC6H4, 4-BrC6H4, 4-O2NC6H4, 2-naphthyl, CO2Et, n-Bu, n-Pr

25a (20 mmol%)

2-nitrobenzoic acid (20 mmol%)

toluene, –25 °C

+

96–99% eedr = 10:1 to 15:1

63–98% yield

PhCHO

O

O

OEt

Br

PhCHO Ph CHO

O

CO2Et

OEtO2C+ +

25b (20 mmol%)Et3N (1 equiv)

CHCl3, r.t.

94% eedr > 25:1 84% yieldN

H

Ph

TMSOPh

25b

O

H NO2+

R

25b (20 mmol%)PhCO2H

DMSO, r.t. R

O

H

NO2

R = Me, Et, i-Pr, n-Pr, n-Bu dr (trans/cis) = 13:87 to 1:99

59–94% ee (trans)93–97% ee (cis)

41–62% yield

I

Scheme 72 Proposed catalytic cycle for the Enders domino reaction

O

H

NO2

R2R2

O

H

NO2

I

NH

R1

N R1

R2

NR1

R2

I

O2N

H

NR1

R2

I

O2N

H

NR1

R2

O2N

H

I

H2O

H2O

Michaeladditionintramolecular

alkylation

Scheme 73 Tandem Michael/Henry reaction and domino double-Michael reaction

OR1

O

O

NO2HO R2

O O

OR1

R3O

R2

N

NH2N

MeO

2q

n

OR1

O

OO

OEt

NO2R3

2q (15–20 mol%)

n = 2, Et2O, r.t.n = 1, toluene, 4 °C

NO2

O O

OR1

R2

O

EtO

n = 1, 2

R1 = Me, Et, BnR2 = Me, Ph, ArR3 = Ph, Ar

90–97% ee dr = 95:5 to 99:1

81–92% yield

88–96% eedr = 78:22 to 99:1

85–95% yield

n

NO2R2

2q (15–20 mol%)

Et2O, r.t.

+

+



lytic triple cascade reaction that comprised an enamine–iminium–enamine sequence (Scheme 74).

Likewise, Jørgensen and co-workers demonstrated thata,b-unsaturated aldehydes and tricarbonyl compounds re-act in a one-pot reaction to form four carbon–carbonbonds (Scheme 75). This organocatalytic, asymmetrictwo-component reaction provides six new stereocenters,and thus one out of 64 possible stereoisomers, with excel-lent diastereo- and enantioselectivity (up to 99:1 dr; up to96% ee).149

Scheme 75 Formation of one out of 64 possible stereoisomers usingorganocatalysis

The last example of a cascade reaction is the formal [4+2]cycloaddition between 2-phenylpropanal and cyclohex-2-en-1-one (Scheme 76). Enamines derived from branchedaldehydes are reactive only when strongly activated elec-trophiles such as diazodicarboxylates are employed (seesection 4.1); in the reaction with enones, no products areobserved if proline alone or other such derivatives are em-ployed as catalysts. It is only with the use of SAOc (Syn-ergic Asymmetric Organocatalysis), the combination ofmore organocatalysts employed simultaneously, that atransformation is observed and the bicyclo[2.2.2]octan-2-one skeleton is accessed in good yield and moderate enan-tioselectivities. The deprotonation of the proline-derivedenamine 36a gives the enhanced nucleophilic enamine36b.12

13 Conclusion and Outlook

For each of the organocatalyzed reactions forming a qua-ternary stereocenter initially reported in the groundbreak-ing paper by Wynberg in 1974, there are now severaloptimized catalytic systems performing with excellentenantioselectivity. Today, there are several new transfor-mations; nonetheless, effective and, especially, generalapproaches to the production of quaternary stereocentersare limited, hence new methodologies addressing thisissue will be welcomed by the scientific community.

Among the unresolved problems are electrophile additionto double bonds, alkylation of aldehydes, addition to ster-ically hindered (i.e., b,b-disubstituted) double bonds. Inthe initial phase, the efforts of researchers were essentiallydevoted to be the first to prove a given concept, disclosingas soon as possible a new kind of reaction no matterwhether it had been developed to a useful level or not.Now, however, new organocatalytic process are morecritically analyzed, to evaluate more closely whether theapplications are really feasible – not simply to be able toput out a flag in order to claim an unexplored territory.The thorough scrutiny necessary in applying these meth-ods to total synthesis will select and validate the more ef-ficient processes in the next few years, and the most usefulmethodologies will emerge.

Scheme 74 Asymmetric, organocatalytic triple cascade reaction;E = enamine, I = iminium

R1 CHO

CHO

R3

R2

CO2Et

CN

E

E

I

CHO

R3

R1 CO2Et

R2CN

CHO

R3

R1 CO2Et

R2CN

CHO

R1

R2

*

* CN

CO2Et

HO

91–99% eedr = 2:1 to 20:132–52% yield

R1 = Me, Et, AllylR2 = ArR3 = Me, Ph, 4-O2NC6H4

212

25b (10 mol%)

toluene, r.t.

R

OMeO

O O O

OMe

MeO

O O O

OMe

+R

EtO2COH

CO2Et

CO2Et

CO2Et

HO1) 25b (10 mol%) PhCO2H (10 mol%) toluene, r.t.

2) piperidine (20 mol%)MeOH, 40 °C

89–96% eedr = 88:12 to 99:1

38–93% yieldR = Et, i-Pr, n-C7H15, EtO2C, (Z)-hex-3-en-1-yl, Ph, 4-MeOC6H4, 2-furyl, 2-BrC6H4

Scheme 76 Synergic catalyst combinations for the synthesis of bi-cyclo[2.2.2]octan-2-ones

Ph

H

O O

+

catalyst combination

HO

Ph OH

Ph

O

O

NH

CO2H

35a 35b

N

HO N

H

H

HMeO

7a no reaction2d no reaction7a + Et3N 20% ee (35a), 30% ee (35b) 76% yield7a + 2d 33% ee (35a), 44% ee (35b) 75% yield7a + 2r 64% ee (35a), 64% ee (35b) 85% yield

L-Pro (7a) 2d

Ar

H

N

Ar

H

N CO2–

HNR3NR3

O

O

H

E

deprotonated enamine: enhanced reactivity

2r

toluene, r.t.

N

N

H

HO

H

HMeO

36a 36b



Acknowledgment

M.B. kindly acknowledges financial support from ‘Progetto di Ate-neo’, ‘Sapienza’ Università di Roma for the year 2007–2008 andRSC research bursary for 2008. The authors are also grateful toProf. K. A. Jørgensen, University of Aarhus, for invaluable sug-gestions during the preparation of this review.

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organocatalytic formation of quaternary stereocenters · given that organocatalysis a fast-growing...

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