asymmetric organocatalytic functionalization of α,α ...szolcsanyi/education/files/organicka...low...

lable at ScienceDirect

Tetrahedron 70 (2014) 2491e2513

Contents lists avai

Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Tetrahedron report number 1033

Asymmetric organocatalytic functionalization of a,a-disubstitutedaldehydes through enamine activation

Alaric Desmarchelier, Vincent Coeffard, Xavier Moreau *, Christine GreckInstitut Lavoisier de Versailles, UMR CNRS 8180, Universit�e de Versailles-Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis,78035 Versailles Cedex, France

a r t i c l e i n f o

Article history:Received 15 October 2013Received in revised form 20 December 2013Accepted 22 January 2014Available online 5 February 2014

Keywords:OrganocatalysisEnamineQuaternary stereocentreDisubstituted aldehydes

* Corresponding author. Tel.: þ33 139254410; fax:dress: [email protected] (X. Moreau).

0040-4020/$ e see front matter � 2014 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2014.01.056

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24922. Stereoselective CeC bond-forming reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2492

2.1. Addition to electrodeficient olefins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24922.1.1. Addition to nitroalkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24922.1.2. Addition to maleimides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24922.1.3. Addition to vinyl sulfones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24942.1.4. Addition to a,b-unsaturated ketones or esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2494

2.2. Aldolization/Mannich reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24962.3. a-Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2497

3. Stereoselective a-heterofunctionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25023.1. CeN bond-forming reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25023.2. CeO bond-forming reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25053.3. CeS bond-forming reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25063.4. CeF bond-forming reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2506

4. Stereoselective formation of three-membered rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25084.1. Epoxidation reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25084.2. Aziridination reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25084.3. Cyclopropanation reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2508

5. Stereoselective proton-transfers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25086. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2510

References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2511Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2513

þ33 139254472; e-mail ad-

All rights reserved.

Delta:1_given nameDelta:1_surnameDelta:1_given nameDelta:1_surnamemailto:[email protected]://crossmark.crossref.org/dialog/?doi=10.1016/j.tet.2014.01.056&domain=pdfwww.sciencedirect.com/science/journal/00404020http://www.elsevier.com/locate/tethttp://dx.doi.org/10.1016/j.tet.2014.01.056http://dx.doi.org/10.1016/j.tet.2014.01.056http://dx.doi.org/10.1016/j.tet.2014.01.056

A. Desmarchelier et al. / Tetrahedron 70 (2014) 2491e25132492

1. Introduction

Asymmetric aminocatalysis has been subjected to extensive de-velopment since the renewed interest of iminium and enaminechemistry in the early 2000s.1,2 In this context, a-functionalization oflinear aldehydes3 has been largely studied in the past ten years. Bycontrast, there has been very limited success in developing stereo-selective carbonecarbon and carboneheteroatom bond-formingreactions of a-branched aldehydes. Indeed, the enamine activationof a,a-disubstituted aldehydes suffers from several drawbackscompared to their counterpart unbranched aldehydes. The sterichindrance around the carbonyl moiety makes the condensation ofthe aldehyde with amino catalyst difficult to accomplish4 and leadsto a less reactive enamine.5 In addition, the absence of a proton in thea-position leads to the irreversible formation of intermediates thatinhibit the catalytic cycle.6 Another issue concerns the stereochem-ical outcome of the reaction: the enamine formation from a-branched aldehydes could lead to a Z/E mixture of enamines andthus affect the level of stereoselectivity. This is magnified when a,a-dialkyl aldehydes are used. This report will highlight the efforts toovercome these problems towards the stereoselective constructionof quaternary carbon centers7 via enamine catalysis.

2. Stereoselective CeC bond-forming reactions

2.1. Addition to electrodeficient olefins

2.1.1. Addition to nitroalkenes. The organocatalytic conjugate ad-dition of enamines derived from a,a-disubstituted aldehydes toelectrodeficient alkenes is a powerful method for the stereo-selective formation of CeC bonds. In 2004, Barbas and co-workersdescribed the first stereoselective Michael addition of various a-branched aldehydes to nitrostyrene (Scheme 1).8 Among thepyrrolidine-derived catalysts tested, (S)-1-(2-pyrrolidinylmethyl)pyrrolidine in combination with TFA afforded Michael adducts ingood yields (64e96%), moderate diastereoselectivities (10e78% de),and variable enantioselectivities (18e91% ee).

Scheme 1.

Therefore, substantial efforts were devoted to the design of newcatalytic systems in order to increase both reactivity and stereo-selectivities and decrease the catalyst loading. Primary9 and sec-ondary10 amine catalysts were used to promote the addition ofisobutyraldehyde or cyclic aldehydes to nitroalkenes but the scopewas usually limited. Reports that relayed a general methodologyusing different a-branched aldehydes leading to enantioenrichedquaternary stereocentres remained rare.

In 2006, Jacobsen and co-workers disclosed the first use ofprimary amineethiourea catalyst11 for this transformation(Scheme 2).12 A broad range of both partners was investigated todetermine the scope and limitations of the reaction. Excellent re-sults in terms of yield (34e98%) and enantioselectivity (92e99% ee)were observed in almost all cases but the level of diastereoselectivitywasmore contrasted. It is worthwhile noting that aldehydes bearingphenyl or ethereal substituents afforded high dr (>10:1) while a,a-dialkyl aldehydes led to moderate dr (7.1:1 to 2.1:1).

In 2007, Connon and Mc Cooey reported the addition of alde-hydes and ketones to nitroolefins promoted by amino cinchona-alkaloid derivatives and benzoic acid as a cocatalyst (10 mol % each)(Scheme 3).13 The scope of a-branched aldehydes was limited totwo examples allowing the formation of a quaternary stereocentre.Nevertheless, this communication brought to light for the first timethis type of catalyst,14 which is now one of the most popular pri-mary amine catalysts.15

In 2011, Nugent and co-workers detailed an unusual catalyticsystem to promote conjugate additions. A combination of an O-protected-threonine (5 mol %, enamine activation of aldehydes),sulfamide (5 mol %, hydrogen-bond donor, nitroolefin activation),and DMAP (15 mol %) was used to promote the reaction of variousa,a-dialkyl aldehydes with nitroalkenes (Scheme 4).16 g-Nitro-aldehydeswere obtained in good yields (70e89%) and high levels ofenantioselectivity (90e99% ee) while moderate diastereoselectivity(40e56% de) was observed due to the possibility of forming Z or Eenamine from a,a-dialkyl aldehydes.

The Michael adducts formed in this transformation can readilybe converted to amino acids. Yoshida and co-workers applied theirown methodology17 to the enantioselective synthesis of cyclicgabapentin analogues (Scheme 5).18 A 4:1 mixture of phenylalanineand its lithium salt (20 mol %) served as an effective catalyst for theaddition of a-branched aldehydes to b-nitroacrylates and theenantioenriched amino acids were obtained in good overall yieldsafter hydrogenolysis over Pd/C.

An intramolecular version of this transformation was alsoapplied to the synthesis of the atropurpuran A-ring.19 Despite the

screening of various primary and secondary amine catalysts, lowlevels of stereoselectivity were observed.

2.1.2. Addition to maleimides. Conjugate addition of a-branchedaldehydes to maleimides has also attracted substantial attentionsince substituted succinimides are an interesting class of hetero-cycles as synthetic biologically active compounds or as in-termediates in the synthesis of functionalized g-lactams or

Scheme 2.

Scheme 3.

Scheme 4.

A. Desmarchelier et al. / Tetrahedron 70 (2014) 2491e2513 2493

Scheme 5.


pyrrolidines. The first example of this transformation was reportedby C�ordova and co-workers in 2007.20 The HayashieJørgensencatalyst (10 mol %) was used to catalyze the reaction betweenisobutyraldehyde and N-phenylmaleimide but a moderate yield(40%) and enantioselectivity (51% ee) were obtained. The apparentlow catalytic activity of secondary amines was also pointed out ina racemic version of this reaction.21 Consequently, different pri-mary amine catalysts were developed to overcome this problemand several chiral bifunctional primary amineethiourea22 or-guanidine23 catalysts were used to promote the addition of iso-butyraldehyde to maleimides.

In 2010, two independent studies explored the formation ofcontiguous quaternaryetertiary stereogenic centers.24 Optimizedconditions involved primary amineethiourea catalysts synthesizedfrom 1,2-cyclohexyldiamine and a catalytic amount of water orbenzoic acid. Substituted succinimides were obtained in excellentyields (>79%) and enantioselectivities (>75% ee) but with moder-ate diastereoselectivities (from 1:1 to 9:1 dr depending on the al-dehydic substituents) (Scheme 6).

More recently, Nugent and co-workers showed that the three-component catalytic system previously developed for the addi-tion of aldehydes to nitroolefins16 was an efficient general catalystfor 1,4-addition reactions. Different catalytic systems based on anamino acid (L-threonine or L-isoleucine), a base (DMAP or KOH),and a hydrogen-bond donor (sulfamide, thiourea) promoted theaddition of a-branched aldehydes to maleimides to affordsubstituted pyrrolidinediones in excellent yields and moderate tohigh levels of stereoselectivity (Scheme 7).25 DFT calculations wereperformed in order to support a noncovalent assembly of the cat-alyst components and explain the origin of the stereoselectivity viatwo hydrogen bonds.

In 2013, Kokotos identified b-phenylalanine/Cs2CO3 as an effi-cient catalyst (1 mol % catalyst loading) for this transformation,which was used in a straightforward one-pot synthesis of g-butyrolactones (Scheme 8).26

2.1.3. Addition to vinyl sulfones. The scope of Michael acceptors inenamine catalysis was also extended to vinyl sulfones. Alexakisand co-workers reported the first addition of a,a-disubstitutedaldehydes to vinyl disulfones catalyzed by N-iPr-2,20-bipyrrolidinebut only modest yields and stereoselectivities were observed.27

The reaction was initially improved by using the Hay-ashieJørgensen catalyst28 but the best results were obtained

through the development of new aminal-pyrrolidine catalysts(Scheme 9).29

The same group reported the asymmetric addition of unusuala-chloro, a-hydrazino, and a-hydroxy aldehydes to vinyl sulfonesleading to highly functionalized tetrasubstituted carbon stereo-centres (Scheme 10).30 Different experimental results promptedthe authors to postulate a kinetic resolution mechanism.

Simultaneously, Maruoka and co-workers developed a newanthracenyl-derived primary amine catalyst, which promoted theconjugate addition of a-heterosubstituted aldehydes (amino andalkoxy aldehydes) or 2-phenylpropionaldehyde to 1,1-bis(benzenesulfonyl)ethylene.31 Very good yields (90e99%) andhigh levels of enantioselectivity (81e95% ee) were observed using10 mol % of catalyst and 10 mol % of 2,6-dihydroxybenzoic acid intoluene at room temperature. a-Benzenesulfonylphosphate insteadof vinyl sulfones was also tested leading to the desired adduct in99% yield with high diastereo- and enantioselectivity (14:1 dr, 85%ee) (Scheme 11).

Two other primary amine catalysts bearing a sulfonamide groupwere also described to catalyze the reaction.32 In 2010, Zhu and Ludisclosed the use of different protected threonine and serine-derived N-trifluoromethanesulfonamide catalysts. O-TBS-N-Tf-protected threonine was found to be the most efficient catalyst,leading to the formation of the products in good yields (76e95%)and satisfying enantioselectivities (68e86% ee) (condition A,Scheme 12). The methodology was improved two years later byMiura and co-workers. The threonine backbone was replaced withvaline and a stronger electron-withdrawing per-fluorobutanesulfony group was utilized (instead of NTf) to enhancethe acidity of the sulfonamide group. Better yields (95e99%) andselectivities (83e93% ee) were obtained in shorter reaction times(condition B, Scheme 12).

Heteroarylvinyl sulfones have also been used as Michael part-ners in such a transformation (Scheme 13).33 9-Amino-(9-deoxy)-epi-quinine (20 mol %) in combination with p-nitrobenzoic acid(20 mol %) afforded the best results and the corresponding sulfoneswere obtained in moderate to good yields (30e83%) and differentlevels of stereoselectivity (40e94% ee). Subsequent JuliaeKocienskitransformation completed a two-step organocatalytic allylation ofa-branched aldehydes.

2.1.4. Addition to a,b-unsaturated ketones or esters. OrganocatalyticMichael addition of a-branched aldehydes to vinyl ketones or esters

Scheme 6.

Scheme 7.

Scheme

Scheme 8.

Scheme 9.


has not been developed as a synthetic methodology but has beeninvolved in several organocatalytic one-pot sequences. Melchiorreand co-workers reported one example of a triple-cascade reactionfrom 2-phenylpropionaldehyde, ethyl cyanoacrylate, and cinna-maldehyde leading to the synthesis of a densely substituted cy-clohexane (Scheme 14). The secondary amine-mediated reactionafforded the product in good yield as a separable mixture of twodiastereomers (C5-epimers).34

Kotsuki and co-workers35 explored a catalytic version of a two-step asymmetric synthesis of cyclohexenone derivatives describedin 1969 by Yamada and Otani.36 (1R,2R)-1,2-Cyclohexanediamine(30mol %) and (1R,2R)-1,2-cyclohexanedicarboxylic acid (30mol %)composed the catalytic system that promoted the Michael additionof a-branched aldehydes to MVK or EVK (Scheme 15). One exampleusing cyclohexenone instead of vinyl ketones was reported by Bellaand co-workers.37 The reaction was also detailed by Carter and co-workers using a combination of catalytic amount of proline sul-fonamide to activate the ketone and a stoichiometric amount ofbenzylamine to activate the a,a-disubstituted aldehyde.38

A double Michael addition of a b-ketoester bearing an electro-deficient olefin and a-substituted-a,b-unsaturated aldehydes wasdisclosed by Ma and co-workers (Scheme 16).39 The organocascademediated by the HayashieJørgensen catalyst (2e5 mol %) affordedhighly functionalized cyclopentanones in excellent yields (67e81%)and good levels of selectivity.

2.2. Aldolization/Mannich reaction

A few reports in the literature have described direct catalytic aldolor Mannich reactions of a,a-disubstituted aldehydes leading tob-hydroxy or amino aldehydes bearing a quaternary carbon stereo-centre. In 2004, Barbas and co-workers reported the cross-aldol re-action between various a,a-dialkyl aldehydes and nonenolizablearomatic aldehydes promoted by (S)-1-(2-pyrrolidinylmethyl)pyr-rolidine$TFA (10mol %) in DMSO (Scheme 17).40 Aldol products wereobtained in excellent yields (91e97%) albeit with moderate stereo-selectivities (24e70% de, 52e96% ee).

Primary amino acids, such as histidine41 or isoleucine42 couldalso promote asymmetric aldol additions and proved to be analternative to pyrrolidine-based catalysts whereby aldehydesubstrates are limited to aromatic substituents (Scheme 18).

10.

Scheme 11.

Scheme 12.


The authors also explored the influence of chiral stereocentre-containing aldehydes as an electrophilic partner (matched-mis-matched effect).

Examples of Mannich reactions of a-branched aldehydes arescarce and only imino esters were engaged as an electrophilicpartner. In 2004, Barbas and co-workers described the use of L-proline (30 mol %) to promote the Mannich reaction and the prod-ucts were obtained in reasonable yields and stereoselectivities.43 Inall cases a syn diastereoselectivity was observed. For example, 2-phenylpropanal was engaged in this reaction and furnished thecorresponding b-amino aldehydes in 66% yield and moderate ster-eoselectivities (85:15 dr and 86% ee for the major diastereomer,Scheme 19). Another pyrrolidine-based catalyst developed by Blan-chet and co-workers,44 3-trifluoromethanesulfonamido-pyrrolidine,showed anti-selectivity but only one example involved the con-struction of a quaternary stereocentre. The Mannich product derived

from 2-phenylpropanal was obtained in 82% yield, a 20:80 di-astereomeric ratio and 20% ee for the anti diastereomer (Scheme 19).In 2012, Nugent and co-workers applied their noncovalent bi-functional organocatalyst (O-tBu-Thr, sulfamide, DMAP, 5 mol %each) to this transformation (Scheme 19).25 The substrate scope forthis reaction remained rather limited and the results were compa-rable to those obtained by Barbas.

2.3. a-Alkylation

Although great efforts have been made in this area, organo-catalytic a-alkylation of simple aldehydes still remains a challeng-ing transformation.45 As a consequence, only a few methodologiesemploying a,a-disubstituted aldehydes were reported in the liter-ature. In 2008, Enders and co-workers developed an organo-catalytic domino Michael addition/a-alkylation reaction of various

Scheme 14.

Scheme 15.

Scheme 13.


aliphatic aldehydes and 5-iodo-1-nitropentene promoted by theHayashieJørgensen catalyst and benzoic acid.46 This sequenceproceeded via an enamineeenamine activation pathway. The firststep gave rise to the a-branched aldehyde, which cyclized in

the second step. Under these conditions, the correspondinga-quaternary cyclopentene carboxaldehydes were synthesized inmoderate yields (40e62%) and good stereoselectivities (Scheme20).

Jacobsen and co-workers reported an SN1-like substitution re-action involving various 2-arylpropionaldehydes and diary-lbromomethane.47 The anion-binding capacity of thiourea wasexploited to form benzhydryl cations within a bifunctional primaryamineethiourea catalyst that also generates the enamine nucleo-philic partner (Scheme 21).

List and co-workers reported an SN2-like substitution reactionbetween various a-branched aldehydes and benzyl bromide de-rivatives.48 The reaction was promoted by an unusual stericallydemanding proline-derived catalyst (30 mol %) in the presence ofan organic mixed acidebase ‘buffer’ system. This particular reactionmediumwas used instead of a base alone because it was supposedto accelerate the enamine formation (through acid catalysis), to actas a HBr scavenger and to suppress the alkylation reaction of baseand/or catalyst. Under these conditions, the benzylated productswere obtained in good yields (60e82%) and high levels of enan-tioselectivity (76e97% ee) for such a transformation (Scheme 22).

Another methodology to create a chiral all-carbon quaternarycenter was described by Cozzi and co-workers in 2012.49 A series ofa-substituted aldehydes reacted with commercially available 1,3-benzodithiolylium tetrafluoroborate in the presence of a primary

Scheme 16.

Scheme 17.

Scheme 19.Scheme 18.


Scheme 20.

Scheme 21.


amine catalyst derived from quinidine and (�)-CSA as a chiral co-catalyst. The products were isolated in good yields (52e89%) andmoderate enantioselectivities (32e87% ee) after reduction of thealdehyde moiety (Scheme 23).

Combining transition-metal catalysis and aminocatalysis hasrecently gained widespread currency to promote CeC bond for-mation.50 Racemic versions of the direct carbocyclization of alde-hydes and alkynes were first developed using an achiral secondaryamine catalyst for the nucleophilic activation and gold,51 indium52

or copper-based promoter53 to enhance the reactivity of the triplebond. An enantioselective version of this transformation has re-cently been disclosed by Michelet, Ratovelomanana-Vidal and co-

workers. A chiral metallo-organocatalytic system composed of10 mol % of cyclohexylamine, 6 mol % of Cu(OTf)2, and 15 mol % ofthe chiral bidentate ligand (R)-DTBM-MeOBIPHEP allowed thedirect access to a range of enantioenriched cyclopentanes(Scheme 24).54

List and co-workers reported a direct a-allylation of a,a-di-substituted aldehydes with allylic alcohols promoted by the syn-ergistic action of a primary amine, a chiral phosphoric acid and[Pd(PPh3)4] (Scheme 25).55 The TsujieTrost reaction involvinga chiral p-allyl-Pd-TRIP ion pair and an achiral b,b-disubstitutedenamine afforded products in excellent yields (66e98%) andenantioselectivities (69e99.6% ee).

Scheme 22.

Scheme 23.


More recently, Yoshida and co-workers reported an alternativeprocedure for the formation of pent-4-enal derivatives that avoidsthe use of phosphoric acids.56 A combination of two catalytic sys-tems, an achiral palladium complex and O-TBS-L-threonine, pro-moted the a-allylation of a-branched aldehydes with allyl pivalate.The use of a chiral primary amine catalyst explained the origin ofthe stereoselectivity observed in this reaction. The products wereobtained in good yields and acceptable levels of enantioselectivity(Scheme 26).

The comparison of both procedures revealed that the use ofa combination of a chiral phosphoric acid and an achiral amineseemed to be a more efficient and general: better yields and levels

of stereoselectivity were generally observed and the a-allylation ofa,a-dialkyl aldehydes was only possible by using List’s protocol.

Carreira and co-workers developed an elegant a-allylation ofaldehydes based on a stereodivergent dual catalysis.57 The catalyticsystem combined a chiral primary amine, which controlled thestereoselectivity of the a-center and a chiral iridium complex,which controlled the stereoselectivity of the b-position of theresulting product. The authors anticipated the minimization of thematchedemismatched effects by exploiting the relative planarity ofboth reactive species (enamine and allyliridium) and discloseda straightforward synthesis of all possible stereoisomers in excel-lent yields and very high levels of stereoselectivity (Scheme 27).

Scheme 24.

Scheme 25.


3. Stereoselective a-heterofunctionalization

3.1. CeN bond-forming reactions

Among the a-heterofunctionalization reactions of a-branchedaldehydes, the electrophilic amination of carbonyl compounds isthe most reported in the literature. The first report was publishedby Br€ase and co-workers in 2003.58 Proline (50 mol %) was shownto promote the transformation with different azodicarboxylates(DEAD or DBAD) as the electrophilic nitrogen source. The hydrazinoaldehydes were obtained in moderate to good yields (26e99%) andvariable enantioselectivities, 4e39% ee for challenging a,a-dialkylsubstituted products and 35e86% ee for those derived from 2-arylpropionaldehydes. The same group noticed that the use ofmicrowave irradiation dramatically decreased the reaction time

and increased slightly the yields and the enantioselectivities(Scheme 28).59

Further to thiswork, great efforts havebeenmade to improvebothreactivity and selectivity of this transformation. A comparison of thedifferent catalytic systems reported in the literature to promote theelectrophilic amination of 2-phenylpropionaldehyde is detailed inTable 1. Two other bifunctional pyrrolidine-based catalysts weredesigned in 2010. The first one merged the pyrrolidine frameworkwith a camphor scaffold.60 A lower catalyst loading (5 mol %) wasrequired for the a-amination of disubstituted aldehydes but the re-sults were disappointing (entry 2). The second one merged a proli-namide and a thiourea linked together by a chiral diamine (10mol %)and o-hydroxybenzoic acid (20 mol %).61 Excellent results in termsof reactivity and selectivity were obtained when different2-arylpropionaldehydes were engaged in the reaction (entry 3).

Scheme 26.

Scheme 27.


Different primary amine catalysts were also found to promotestereoselective CeN bond formation. Two groups have accounted forthe use of modified cinchona alkaloids, one with chiral cam-phorsulfonic acid as cocatalyst62 and the other with trifluoroaceticacid.63 In both cases, the use of 9-amino(9-deoxy)epi-quinine wascrucial to reach excellent levels of enantioselectivity (entries 4 and 5).

Chiral primary amino acids were also tested for this trans-formation and 3-(1-naphtyl) alanine hydrochloride64 (entry 6) orb-tert-butyl aspartate65 (entry 7) were identified as promoters forthe a-amination. Both of them are efficient catalysts but the alaninederivative did not give satisfactory yield when di-tert-butyl

azodicarboxylate was used and no reaction occurred when theaspartate derivative was engaged with dibenzyl azodicarboxylateas the amination reagent.

Finally, Wang, Xu and co-workers recently reported that a sim-ple chiral primary amine, such as 1-(1-naphtyl)ethylamine, TFA,and 4-chloro-2-nitrobenzoic acid (10 mol % each) catalyzed theformation of hydrazino aldehydes (entry 8).66

It is worth noting that the stereoselective CeN bond formationwas investigated with different reagents than azodicarboxylatesincluding nitrosobenzene67 or sulfonyl azides68 but results in termsof reactivity or selectivity were disappointing (Scheme 29).

Scheme 28.

Table 1Electrophilic amination of 2-phenylpropionaldehyde

Entry Catalytic system Conditions R Yield ee

1 CH3CN, rt, 0.5 h, MW Bn 99% 84%

2 CH2Cl2, rt, 168 h Bn 46% 75%

3 CH2Cl2, 0 �C, 32 h iPr 87% 97%

4 CHCl3, rt, 24 h iPr da 95%Bn da 84%tBu 99% 97%

5 CHCl3, rt, 3 h iPr 95% 90%Bn 72% 82%tBu 96% 95%

6 THF, 0 �C, 32 h iPr 82% 95%tBu 33% 92%

7 THF, 0 �C, 24 h iPr 93% 93%Bn n.r. n.d.tBu 98% 94%

8 Et2O, �20 �C, 48e70 h iPr 92% 91%Bn 68% 88%tBu 75% 93%

a Yields are not reported in the publication.


Scheme 29.


This methodology was successfully applied to different syn-theses of natural products, such as hydantoin BIRT-377,69 aminoacids AIDA, and APICA59b,70 or antibiotic fumimycin71 (Scheme 30).

Scheme 30.

Electrophilic a-amination reactions were also included inorganocascade sequences. In 2009, Melchiorre and co-workersrevealed that the construction of contiguous quaternary and ter-tiary stereocentres could be achieved via an iminium/enamine ac-tivation of a,b-disubstituted enals.72 The Michael addition/amination sequence promoted by a primary amine catalyst(20 mol %) and TFA (30 mol %) allowed the formation of highlyfunctionalized hydrazino aldehydes in moderate to good yields(31e80%), appropriate levels of diastereoselectivity (3:1 to 20:1 dr)and excellent enantiomeric excesses (83e99% ee) (Scheme 31).

Another example dealt with the a,a-bifunctionalization of pro-pionaldehyde in a sequential multicatalytic process based on sec-ondary amine-catalyzed Michael addition and a primary amine-promoted a-amination.73 The corresponding hydrazino aldehydeswere obtained in good yields (73e90%) and excellent levels of se-lectivity (>95:5 dr, 96e98% ee) but the scope was limited to pro-pionaldehyde (Scheme 32).

A primary amine-catalyzed direct conversion of a,a-di-substituted aldehydes into 3-pyrrolines bearing a quaternary ster-eocenter was reported in 2012 (Scheme 33).74 The combination ina single flask of a-amination, aza-Michael addition of hydrazine,and aldol condensationedehydration afforded the heterocycles ingood yields (42e83%) and moderate to excellent levels of enan-tioselectivity (30e98% ee). The choice of di-tert-butyl azodi-carboxylate proved to be crucial since a selective carbamatedeprotection in acidic conditions was required during the sequenceto trigger the aza-Michael addition.

3.2. CeO bond-forming reactions

Compared with electrophilic a-amination of a-branched alde-hydes, the stereoselective CeO bond formation leading to a quater-nary stereocentre received little attention. In 2006, Kim and Park

reported the lack of regioselectivity for the nitroso-aldol reaction.While the use of 2-arylpropionaldehydes afforded a-hydroxyamina-tion products as major regioisomer, the reaction of a,a-dialkyl alde-hydes catalyzed by L-proline led to amixture of N- and O-nitrosoaldolproducts.62Tocircumvent thisproblem,List andco-workersdescribedan asymmetric a-benzoyloxylation of different 2-substituted-pro-pionaldehydes promoted by a combination of a primary amine cata-lyst derived from quinine and a chiral phosphoric acid.75 Thecorresponding oxygenated aldehydes were obtained in moderate togoodyields (41e83%)andpromisingenantioselectivities (Scheme34).

Scheme 31.

Scheme 32.


3.3. CeS bond-forming reactions

Jørgensen and co-workers have described the only example ofa-sulfenylation of 2-phenylpropionaldehyde promoted by a diphe-nylprolinol silyl ether (10 mol %) as a catalyst (Scheme 35).76

3.4. CeF bond-forming reactions

In 2005, Jørgensen77 and Barbas78 independently reported thestereoselective a-fluorination of 2-phenylpropionaldehyde using

N-fluorobenzenesulfonamide (NFSI) as the electrophilic fluori-nating reagent and a secondary amine catalyst (Scheme 36). Thecorresponding quaternary stereocentre was formed in excellentyield but low enantioselectivity and the scope was limited to oneor two examples. Nevertheless, this methodology has beenemployed in the synthesis of b-fluoroamines.79 In 2006,Jørgensen and co-workers described the synthesis of unusualatropisomer organocatalysts based on aminated quinoline ornaphtyl scaffolds and their applications in the CeF bond forma-tion.80 Despite good enantioselectivities for a-fluorination of

Scheme 33.

Scheme 34.

Scheme 35.


2-arylpropionaldehydes, the products were isolated in moderateyields.

More recently, Shibatomi and Yamamoto disclosed the synthesisof a,a-chlorofluoro carbonyl compounds.81 The construction offluorinated quaternary carbon stereocentres was completed withgood yields and selectivities by using NFSI as the fluorinesource and a diarylprolinol silyl ether (10 mol %) as the catalyst(Scheme 37).

Scheme 36.

Scheme 37.


4. Stereoselective formation of three-membered rings

a-Functionalization of a,a-disubstituted aldehydes was includedin different stereoselective organocascade sequences involvingiminiumeenamine activation and allowed the formation of three-membered carbo- or heterocycles. As depicted in Scheme 38, thisstrategy has been illustrated with epoxidation, aziridination orcyclopropanation reactions.

Scheme 38.

4.1. Epoxidation reactions

Since 2010, four independent reports established the amino-catalyzed synthesis of enantioenriched epoxides bearing a chiralquaternary stereocentre (Scheme 39).

List and co-workers utilized the combination of a primary aminederived from quinine (10 mol %) and a chiral phosphoric acid, (R)-TRIP (20 mol %) as the catalyst and aqueous hydrogen peroxide asthe oxidant. A series of a-branched and a,b-disubstituted enalswere transformed into epoxides in good yields (43e84%) and highdegrees of stereoselectivity (52e90% de, 70e98% ee).82

Luo and co-workers also described an association of a chiralamino catalyst and an achiral Br€onsted acid to synthesize epoxides.After a careful screening to find the optimized conditions, a pri-maryetertiary diamine catalyst derived from trans-1,2-diphenylethane-1,2-diamine and 5-sulfosalicylic acid (10 mol %each) was identified as the optimal catalyst combination to trans-form a-branched acroleins to corresponding epoxides in excellentyields (79e95%) and good selectivities (32e88% ee).83

A pyrrolidine-based catalyst was employed by Hayashi and co-workers to promote efficiently the formation of 1,1-dialkyl-substituted terminal epoxides with good results in terms of yield(61e80%) and selectivity (74e94% ee).84 It is worth noting that thisreaction proceeded without additives. Acid co-catalysts did notproduce any positive effects on the rate, yield or selectivity of thetransformation.

In 2012, Gilmour and co-workers disclosed the epoxidationof cyclic a,b-disubstituted enals catalyzed by 2-(fluo-rodiphenylmethyl)pyrrolidine (10 mol %) and highlighted the

influence of the fluorine gauche effect on the iminium-in-termediate’s conformation. Despite the fact that the scope waslimited to cyclic enals, this methodology pushed back some limi-tations shown by other reports and notably the epoxidation oftetrasubstituted cyclohexene derivatives.85

4.2. Aziridination reactions

Two independent groups explored the aziridination of a-substituted a,b-unsaturated aldehydes in the presence of a prolinolsilyl ether catalyst (20 mol %), NaOAc as a base and an N-protected-O-(p-toluenesulfonyl)hydroxylamine (Scheme 40).86 The publica-tions detailed the formation of terminal aziridines and C�ordova andco-workers successfully expanded the scope of the reaction to a,b-disubstituted enals. The corresponding nitrogen-containing het-erocycles were elaborated in yields of up to 90% and diaster-eoselectivities of up to 25:1.

4.3. Cyclopropanation reactions

Marcia de Figueiredo, Campagne and co-workers have de-veloped an efficient secondary amine-mediated enantioselectivecyclopropanation of a-substituted acroleins with diethyl bromo-malonate (Scheme 41).87 The choice of the base was crucial to reachgood yields (35e81%) and high levels of enantioselection (79e97%ee). Reaction time decreased dramatically when N-methyl-imidazole was used compared to 2,6-lutidine but decomposition orside products were detected in some cases.

5. Stereoselective proton-transfers

An iminiumeenamine-mediated process involving a Friedele-Crafts alkylation of indole with a-substituted acroleins and a sub-sequent enantioselective protonationwas described by Luo and co-workers.88 The sequence afforded a-chiral carbonyl compoundswith moderate to good yields (40e95%) and good levels of ster-eoselectivity (68e94% ee) by using a primaryetertiary diaminecatalyst and trifluoromethanesulfonic acid (10mol % each) (Scheme42). According to DFT calculations, the stereoinduction wasexplained by the stereospecific H2O-bridged protonation of thedominant E-enamine and an OeH/p interaction.

The FriedeleCrafts/enantioselective protonation sequence wasutilized a few years ago for the synthesis of a potent serotoninreuptake inhibitor.89 MacMillan’s imidazolidinone catalyst wasused for the transformation and the product was obtained in goodyield and excellent selectivities (Scheme 43).

Scheme 40.

Scheme 39.


Scheme 42.

Scheme 43.

Scheme 41.


6. Conclusion

Different carbonecarbon and carboneheteroatom bond-formingreactions were explored using the asymmetric organocatalytic

enamine activation of a,a-disubstituted aldehydes. In spite of ad-vances in this field, thanks to the introduction of primary aminecatalysts, some methodologies still suffer from a narrow substratescope and low levels of stereoselectivity. Nevertheless, elegant


methodologies to create quaternary carbon stereocentres have beendeveloped and their incorporation into organocascade sequenceshas been efficiently demonstrated.

References and notes

1. Asymmetric Organocatalysis 1: Lewis Base and Acid Catalysts; List, B., Ed.;Thieme: Stuttgart, Germany, 2012.

2. Comprehensive Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley: Wein-heim, Germany, 2013.

3. (a) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178e2189; (b)Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K.A. Chem. Commun. 2011, 632e649.

4. S�anchez, D.; Bastida, D.; Bur�es, J.; Isart, C.; Pineda, O.; Vilarrasa, J. Org. Lett. 2012,14, 536e539.

5. Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem.dEur. J. 2003, 9, 2209e2218.6. Bur�es, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2012, 134,

6741e6750.7. For a general review see: Bella, M.; Gasperi, T. Synthesis 2009, 1583e1614.8. Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6,

2527e2530.9. (a) Zhang, X.-J.; Liu, S.-P.; Lao, J.-H.; Du, G.-J.; Yan, M.; Chan, A. S. C. Tetrahedron:

Asymmetry 2009, 20, 1451e1458; (b) Zhang, X.-J.; Liu, S.-P.; Li, X.-M.; Yan, M.;Chan, A. S. C. Chem. Commun. 2009, 833e835; (c) Chen, J.-R.; Zou, Y.-Q.; Fu, L.;Ren, F.; Tan, F.; Xiao, W.-J. Tetrahedron 2010, 66, 5367e5372.

10. (a) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369e1371; (b)Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem.dEur. J. 2006, 12,4321e4332; (c) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Barbas, C. F., III. J.Am. Chem. Soc. 2006, 128, 4966e4967; (d) Zhang, Q.; Ni, B.; Headley, A. D.Tetrahedron 2008, 64, 5091e5097; (e) Belot, S.; Massaro, A.; Tenti, A.; Mordini,A.; Alexakis, A. Org. Lett. 2008, 10, 4557e4560; (f) Zhu, S.; Yu, S.; Ma, D. Angew.Chem., Int. Ed. 2008, 47, 545e548; (g) Bai, J.-F.; Xu, X.-Y.; Huang, Q.-C.; Peng, L.;Wang, L.-X. Tetrahedron Lett. 2010, 51, 2803e2805; (h) Chen, J.-R.; Cao, Y.-J.;Zou, Y.-Q.; Tan, F.; Fu, L.; Zhu, X.-Y.; Xiao, W.-J. Org. Biomol. Chem. 2010, 8,1275e1279; (i) Ting, Y.-F.; Chang, C.; Reddy, R. J.; Magar, D. R.; Chen, K. Chem.dEur. J. 2010, 16, 7030e7038; (j) Xiao, J.; Xu, F.-X.; Lu, Y.-P.; Loh, T.-P. Org. Lett.2010, 12, 1220e1223.

11. For a general review see: (a) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Org.Biomol. Chem. 2013, 11, 7051e7071; (b) Tsakos, M.; Kokotos, C. G. Tetrahedron2013, 69, 10199e10222.

12. Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,6366e6370.

13. Mc Cooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599e602.14. At the same time, Chen, Deng and co-workers and Melchiorre and co-workers

reported the use of cinchona alkaloid derivatives for iminium activation, see:(a) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu,J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389e392; (b) Bartoli, G.; Bosco, M.;Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403e1405.

15. (a) Jiang, L.; Chen, Y.-C. Catal. Sci. Technol. 2011, 1, 354e365; (b) Melchiorre, P.Angew. Chem., Int. Ed. 2012, 51, 9748e9770.

16. Nugent, T. C.; Shoaib, M.; Shoaib, A. Org. Biomol. Chem. 2011, 9, 52e56.17. (a) Sato, A.; Yoshida, M.; Hara, S. Chem. Commun. 2008, 6242e6244; (b) Yoshida,

M.; Sato, A.; Hara, S. Org. Biomol. Chem. 2010, 8, 3031e3036.18. Yoshida, M.; Masaki, E.; Ikehara, H.; Hara, S. Org. Biomol. Chem. 2012, 10,

5289e5297.19. Chen, H.; Zhang, D.; Xue, F.; Qin, Y. Tetrahedron 2013, 69, 3141e3148.20. Zhao, G.-L.; Xu, Y.; Sund�en, H.; Eriksson, L.; Sayah, M.; C�ordova, A. Chem.

Commun. 2007, 734e735.21. N€oth, J.; Frankowski, K. J.; Neuenswander, B.; Aub�e, J.; Reiser, O. J. Comb. Chem.

2008, 10, 456e459.22. (a) Bai, J.-F.; Peng, L.; Wang, L.-L.; Wang, L.-X.; Xu, X.-Y. Tetrahedron 2010, 66,

8928e8932; (b) Miura, T.; Nishida, S.; Masuda, A.; Tada, N.; Itoh, A. TetrahedronLett. 2011, 52, 4158e4160; (c) Miura, T.; Masuda, A.; Ina, M.; Nakashima, K.;Nishida, S.; Tada, N.; Itoh, A. Tetrahedron: Asymmetry 2011, 22, 1605e1609; (d)Ma, Z.-W.; Liu, Y.-X.; Li, P.-L.; Ren, H.; Zhu, Y.; Tao, J.-C. Tetrahedron: Asymmetry2011, 22, 1740e1748; (e) Durmaz, M.; Sirit, A. Tetrahedron: Asymmetry 2013, 24,1443e1448.

23. (a) Avila, A.; Chinchilla, R.; N�ajera, C. Tetrahedron: Asymmetry 2012, 23,1625e1627; (b) Avila, A.; Chinchilla, R.; G�omez-Bengoa, E.; N�ajera, C. Eur. J. Org.Chem. 2013, 5085e5092.

24. (a) Xue, F.; Liu, L.; Zhang, S.; Duan, W.; Wang, W. Chem.dEur. J. 2010, 16,7979e7982; (b) Yu, F.; Jin, Z.; Huang, H.; Ye, T.; Liang, X.; Ye, J. Org. Biomol.Chem. 2010, 8, 4767e4774.

25. Nugent, T. C.; Sadiq, A.; Bibi, A.; Heine, T.; Zeonjuk, L. L.; Vankova, N.; Bassil, B. S.Chem.dEur. J. 2012, 18, 4088e4098.

26. Kokotos, C. G. Org. Lett. 2013, 15, 2406e2409.27. Moss�e, S.; Alexakis, A. Org. Lett. 2005, 7, 4361e4364.28. Sulzer-Moss�e, S.; Alexakis, A.; Mareda, J.; Bollot, G.; Bernardinelli, G.; Filinchuk,

Y. Chem.dEur. J. 2009, 15, 3204e3220.29. Quintard, A.; Belot, S.; Marchal, E.; Alexakis, A. Eur. J. Org. Chem. 2010, 927e936.30. Quintard, A.; Alexakis, A. Chem. Commun. 2010, 4085e4087.31. Moteki, S. A.; Xu, S.; Arimitsu, S.; Maruoka, K. J. Am. Chem. Soc. 2010, 132,

17074e17076.

32. (a) Zhu, Q.; Lu, Y. Chem. Commun. 2010, 2235e2237; (b) Miura, T.; Yuasa, H.;Murahashi, M.; Ina, M.; Nakashima, K.; Tada, N.; Itoh, A. Synlett 2012,2385e2388.

33. Rodrigo, E.; Morales, S.; Duce, S.; García Ruano, J. L.; Cid, M. B. Chem. Commun.2011, 11267e11269.

34. Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli, M.; Sambri, L.; Bartoli, G.; Mel-chiorre, P. Chem.dEur. J. 2008, 14, 4788e4791.

35. Inokoishi, Y.; Sasakura, N.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Org. Lett. 2010,12, 1616e1619.

36. Yamada, S.; Otani, G. Tetrahedron Lett. 1969, 10, 4237e4240.37. Bella, M.; Scarpino Schietroma, D. M.; Cusella, P. P.; Gasperi, T.; Visca, V. Chem.

Commun. 2009, 597e599.38. (a) Pierce, M. D.; Johnston, R. C.; Mahapatra, S.; Yang, H.; Carter, R. G.; Cheong,

P. H.-Y. J. Am. Chem. Soc. 2012, 134, 13624e13631; (b) Yang, H.; Banerjee, S.;Carter, R. G. Org. Biomol. Chem. 2012, 10, 4851e4863.

39. Ma, A.; Ma, D. Org. Lett. 2010, 12, 3634e3637.40. Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2004, 43,

2420e2423.41. (a) Markert, M.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc. 2009, 131,

16642e16643; (b) Lam, Y.-H.; Houk, K. N.; Scheffler, U.; Mahrwald, R. J. Am.Chem. Soc. 2012, 134, 6286e6295; (c) Scheffler, U.; Mahrwald, R. J. Org. Chem.2012, 77, 2310e2330.

42. Rohr, K.; Mahrwald, R. Org. Lett. 2012, 14, 2180e2183.43. Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507e2510.44. Pouliquen, M.; Blanchet, J.; Lasne, M.-C.; Rouden, J. Org. Lett. 2008, 10,

1029e1032.45. Vesely, J.; Rios, R. ChemCatChem 2012, 4, 942e953.46. Enders, D.; Wang, C.; Bats, J. W. Angew. Chem., Int. Ed. 2008, 47, 7539e7542.47. Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132, 9286e9288.48. List, B.; �Cori�c, I.; Grygorenko, O. O.; Kaib, P. S. J.; Komarov, I.; Lee, A.; Leutzsch, M.;

Pan, S. C.; Tymtsunik, A. V.; van Gemmeren, M. Angew. Chem., Int. Ed. 2013, 52.49. Gualandi, A.; Petruzziello, D.; Emer, E.; Cozzi, P. G. Chem. Commun. 2012,

3614e3616.50. Du, Z.; Shao, Z. Chem. Soc. Rev. 2013, 42, 1337e1378.51. Binder, J. T.; Crone, B.; Haug, T. T.; Menz, H.; Kirsh, S. F. Org. Lett. 2008, 10,

1025e1028.52. Montaignac, B.; Vitale, M. R.; Michelet, V.; Ratovelomanana-Vidal, V. Org. Lett.

2010, 12, 2582e2585.53. Montaignac, B.; €Ostlund, V.; Vitale, M. R.; Ratovelomanana-Vidal, V.; Michelet,

V. Org. Biomol. Chem. 2012, 10, 2300e2306.54. Montaignac, B.; Praveen, C.; Vitale, M. R.; Michelet, V.; Ratovelomanana-Vidal,

V. Chem. Commun. 2012, 6559e6561.55. Jiang, G.; List, B. Angew. Chem., Int. Ed. 2011, 50, 9471e9474.56. Yoshida, M.; Terumine, T.; Masaki, E.; Hara, S. J. Org. Chem. 2013, 78,

10853e10859.57. Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340,

1065e1068.58. (a) Vogt, H.; Vanderheiden, S.; Br€ase, S. Chem. Commun. 2003, 2448e2449; (b)

Baumann, T.; Vogt, H.; Br€ase, S. Eur. J. Org. Chem. 2007, 266e282.59. (a) Baumann, T.; B€achle, M.; Hartmann, C.; Br€ase, S. Eur. J. Org. Chem. 2008,

2207e2212; (b) Hartmann, C. E.; Baumann, T.; B€achle, M.; Br€ase, S. Tetrahedron:Asymmetry 2010, 21, 1341e1349.

60. Liu, P.-M.; Magar, D. R.; Chen, K. Eur. J. Org. Chem. 2010, 5705e5713.61. Fu, J.-F.; Xu, X.-Y.; Li, Y.-C.; Huang, Q.-C.; Wang, L.-X. Org. Biomol. Chem. 2010, 8,

4524e4526.62. Liu, C.; Zhu, Q.; Huang, K.-W.; Lu, Y. Org. Lett. 2011, 13, 2638e2641.63. Desmarchelier, A.; Yalgin, H.; Coeffard, V.; Moreau, X.; Greck, C. Tetrahedron

Lett. 2011, 52, 4430e4432.64. Fu, J.-Y.; Yang, Q.-C.; Wang, Q.-L.; Ming, J.-N.; Wang, F.-Y.; Xu, X.-Y.; Wang, L.-X. J.

Org. Chem. 2011, 76, 4661e4664.65. Theodorou, A.; Papadopoulos, G. N.; Kokotos, C. G. Tetrahedron 2013, 69,

5438e5443.66. Fu, J.-Y.; Wang, Q.-L.; Peng, L.; Gui, Y.-Y.; Wang, F.; Tian, F.; Xu, X.-Y.; Wang, L.-X.

Eur. J. Org. Chem. 2013, 2864e2868.67. (a) Guo, H.-M.; Cheng, L.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Chem.

Commun. 2006, 429e431; (b) Kim, S.-G.; Park, T.-H. Tetrahedron Lett. 2006, 47,9067e9071; (c) Qin, L.; Li, L.; Yi, L.; Da, C.-S.; Zhou, Y.-F. Chirality 2011, 23,527e533.

68. (a) Baumann, T.; B€achle, M.; Br€ase, S. Org. Lett. 2006, 8, 3797e3800; (b) Vogt,H.; Baumann, T.; Nieger, M.; Br€ase, S. Eur. J. Org. Chem. 2006, 5315e5338.

69. Chowdari, N. S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867e870.70. Suri, J. T.; Steiner, D. D.; Barbas, C. F., III. Org. Lett. 2005, 7, 3885e3888.71. Hartmann, C. E.; Gross, P. J.; Nieger, M.; Br€ase, S. Org. Biomol. Chem. 2009, 7,

5059e5062.72. Galzerano, P.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem.

, Int. Ed. 2009, 48, 7892e7894.73. Desmarchelier, A.; Marrot, J.; Moreau, X.; Greck, C. Org. Biomol. Chem. 2011, 9,

994e997.74. Desmarchelier, A.; Coeffard, V.; Moreau, X.; Greck, G. Chem.dEur. J. 2012, 18,

13222e13225.75. Demoulin, N.; Lifchits, O.; List, B. Tetrahedron 2012, 68, 7568e7574.76. Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed.

2005, 44, 794e797; For a racemic version leading to dithiocarbamoyl de-rivatives, see: Enders, D.; Rembiak, A.; Liebich, J. X. Synthesis 2011, 281e286.

77. Marigo, M.; Fielenbach, D.; Braunton, A.; Kjœrsgaard, A.; Jørgensen, K. A. Angew.Chem., Int. Ed. 2005, 44, 3703e3706.

http://refhub.elsevier.com/S0040-4020(14)00098-2/sref1http://refhub.elsevier.com/S0040-4020(14)00098-2/sref1http://refhub.elsevier.com/S0040-4020(14)00098-2/sref2http://refhub.elsevier.com/S0040-4020(14)00098-2/sref2http://refhub.elsevier.com/S0040-4020(14)00098-2/bib3ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib3ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib3bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib3bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib3bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib3bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref3http://refhub.elsevier.com/S0040-4020(14)00098-2/sref3http://refhub.elsevier.com/S0040-4020(14)00098-2/sref3http://refhub.elsevier.com/S0040-4020(14)00098-2/sref3http://refhub.elsevier.com/S0040-4020(14)00098-2/sref3http://refhub.elsevier.com/S0040-4020(14)00098-2/sref4http://refhub.elsevier.com/S0040-4020(14)00098-2/sref4http://refhub.elsevier.com/S0040-4020(14)00098-2/sref4http://refhub.elsevier.com/S0040-4020(14)00098-2/sref5http://refhub.elsevier.com/S0040-4020(14)00098-2/sref5http://refhub.elsevier.com/S0040-4020(14)00098-2/sref5http://refhub.elsevier.com/S0040-4020(14)00098-2/sref5http://refhub.elsevier.com/S0040-4020(14)00098-2/sref6http://refhub.elsevier.com/S0040-4020(14)00098-2/sref6http://refhub.elsevier.com/S0040-4020(14)00098-2/sref7http://refhub.elsevier.com/S0040-4020(14)00098-2/sref7http://refhub.elsevier.com/S0040-4020(14)00098-2/sref7http://refhub.elsevier.com/S0040-4020(14)00098-2/bib9ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib9ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib9ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib9bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib9bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib9bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib9chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib9chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib9chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10dhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10dhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10dhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ehttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ehttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ehttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10fhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10fhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10fhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ghttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ghttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ghttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10hhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10hhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10hhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10hhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ihttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ihttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10ihttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10jhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10jhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib10jhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib11ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib11ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib11ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib11bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib11bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib11bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref8http://refhub.elsevier.com/S0040-4020(14)00098-2/sref8http://refhub.elsevier.com/S0040-4020(14)00098-2/sref8http://refhub.elsevier.com/S0040-4020(14)00098-2/sref9http://refhub.elsevier.com/S0040-4020(14)00098-2/sref9http://refhub.elsevier.com/S0040-4020(14)00098-2/bib14ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib14ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib14ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib14bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib14bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib14bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib15ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib15ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib15bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib15bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib15bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref10http://refhub.elsevier.com/S0040-4020(14)00098-2/sref10http://refhub.elsevier.com/S0040-4020(14)00098-2/bib17ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib17ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib17bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib17bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib17bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref11http://refhub.elsevier.com/S0040-4020(14)00098-2/sref11http://refhub.elsevier.com/S0040-4020(14)00098-2/sref11http://refhub.elsevier.com/S0040-4020(14)00098-2/sref12http://refhub.elsevier.com/S0040-4020(14)00098-2/sref12http://refhub.elsevier.com/S0040-4020(14)00098-2/sref13http://refhub.elsevier.com/S0040-4020(14)00098-2/sref13http://refhub.elsevier.com/S0040-4020(14)00098-2/sref13http://refhub.elsevier.com/S0040-4020(14)00098-2/sref13http://refhub.elsevier.com/S0040-4020(14)00098-2/sref13http://refhub.elsevier.com/S0040-4020(14)00098-2/sref14http://refhub.elsevier.com/S0040-4020(14)00098-2/sref14http://refhub.elsevier.com/S0040-4020(14)00098-2/sref14http://refhub.elsevier.com/S0040-4020(14)00098-2/sref14http://refhub.elsevier.com/S0040-4020(14)00098-2/sref14http://refhub.elsevier.com/S0040-4020(14)00098-2/bib22ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22dhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22dhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22dhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22dhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22ehttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22ehttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib22ehttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib23ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib23ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib23ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib23ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib23bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib23bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib23bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib23bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib23bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib24ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib24ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib24ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib24ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib24bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib24bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib24bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref15http://refhub.elsevier.com/S0040-4020(14)00098-2/sref15http://refhub.elsevier.com/S0040-4020(14)00098-2/sref15http://refhub.elsevier.com/S0040-4020(14)00098-2/sref15http://refhub.elsevier.com/S0040-4020(14)00098-2/sref16http://refhub.elsevier.com/S0040-4020(14)00098-2/sref16http://refhub.elsevier.com/S0040-4020(14)00098-2/sref17http://refhub.elsevier.com/S0040-4020(14)00098-2/sref17http://refhub.elsevier.com/S0040-4020(14)00098-2/sref17http://refhub.elsevier.com/S0040-4020(14)00098-2/sref18http://refhub.elsevier.com/S0040-4020(14)00098-2/sref18http://refhub.elsevier.com/S0040-4020(14)00098-2/sref18http://refhub.elsevier.com/S0040-4020(14)00098-2/sref18http://refhub.elsevier.com/S0040-4020(14)00098-2/sref18http://refhub.elsevier.com/S0040-4020(14)00098-2/sref19http://refhub.elsevier.com/S0040-4020(14)00098-2/sref19http://refhub.elsevier.com/S0040-4020(14)00098-2/sref20http://refhub.elsevier.com/S0040-4020(14)00098-2/sref20http://refhub.elsevier.com/S0040-4020(14)00098-2/sref21http://refhub.elsevier.com/S0040-4020(14)00098-2/sref21http://refhub.elsevier.com/S0040-4020(14)00098-2/sref21http://refhub.elsevier.com/S0040-4020(14)00098-2/bib32ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib32ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib32bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib32bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib32bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib32bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref22http://refhub.elsevier.com/S0040-4020(14)00098-2/sref22http://refhub.elsevier.com/S0040-4020(14)00098-2/sref22http://refhub.elsevier.com/S0040-4020(14)00098-2/sref22http://refhub.elsevier.com/S0040-4020(14)00098-2/sref23http://refhub.elsevier.com/S0040-4020(14)00098-2/sref23http://refhub.elsevier.com/S0040-4020(14)00098-2/sref23http://refhub.elsevier.com/S0040-4020(14)00098-2/sref23http://refhub.elsevier.com/S0040-4020(14)00098-2/sref24http://refhub.elsevier.com/S0040-4020(14)00098-2/sref24http://refhub.elsevier.com/S0040-4020(14)00098-2/sref24http://refhub.elsevier.com/S0040-4020(14)00098-2/sref25http://refhub.elsevier.com/S0040-4020(14)00098-2/sref25http://refhub.elsevier.com/S0040-4020(14)00098-2/sref26http://refhub.elsevier.com/S0040-4020(14)00098-2/sref26http://refhub.elsevier.com/S0040-4020(14)00098-2/sref26http://refhub.elsevier.com/S0040-4020(14)00098-2/bib38ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib38ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib38ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib38bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib38bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib38bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref27http://refhub.elsevier.com/S0040-4020(14)00098-2/sref27http://refhub.elsevier.com/S0040-4020(14)00098-2/sref28http://refhub.elsevier.com/S0040-4020(14)00098-2/sref28http://refhub.elsevier.com/S0040-4020(14)00098-2/sref28http://refhub.elsevier.com/S0040-4020(14)00098-2/bib41ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib41ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib41ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib41bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib41bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib41bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib41chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib41chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib41chttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref29http://refhub.elsevier.com/S0040-4020(14)00098-2/sref29http://refhub.elsevier.com/S0040-4020(14)00098-2/sref30http://refhub.elsevier.com/S0040-4020(14)00098-2/sref30http://refhub.elsevier.com/S0040-4020(14)00098-2/sref31http://refhub.elsevier.com/S0040-4020(14)00098-2/sref31http://refhub.elsevier.com/S0040-4020(14)00098-2/sref31http://refhub.elsevier.com/S0040-4020(14)00098-2/sref32http://refhub.elsevier.com/S0040-4020(14)00098-2/sref32http://refhub.elsevier.com/S0040-4020(14)00098-2/sref33http://refhub.elsevier.com/S0040-4020(14)00098-2/sref33http://refhub.elsevier.com/S0040-4020(14)00098-2/sref34http://refhub.elsevier.com/S0040-4020(14)00098-2/sref34http://refhub.elsevier.com/S0040-4020(14)00098-2/sref35http://refhub.elsevier.com/S0040-4020(14)00098-2/sref35http://refhub.elsevier.com/S0040-4020(14)00098-2/sref35http://refhub.elsevier.com/S0040-4020(14)00098-2/sref35http://refhub.elsevier.com/S0040-4020(14)00098-2/sref36http://refhub.elsevier.com/S0040-4020(14)00098-2/sref36http://refhub.elsevier.com/S0040-4020(14)00098-2/sref36http://refhub.elsevier.com/S0040-4020(14)00098-2/sref37http://refhub.elsevier.com/S0040-4020(14)00098-2/sref37http://refhub.elsevier.com/S0040-4020(14)00098-2/sref38http://refhub.elsevier.com/S0040-4020(14)00098-2/sref38http://refhub.elsevier.com/S0040-4020(14)00098-2/sref38http://refhub.elsevier.com/S0040-4020(14)00098-2/sref39http://refhub.elsevier.com/S0040-4020(14)00098-2/sref39http://refhub.elsevier.com/S0040-4020(14)00098-2/sref39http://refhub.elsevier.com/S0040-4020(14)00098-2/sref40http://refhub.elsevier.com/S0040-4020(14)00098-2/sref40http://refhub.elsevier.com/S0040-4020(14)00098-2/sref40http://refhub.elsevier.com/S0040-4020(14)00098-2/sref40http://refhub.elsevier.com/S0040-4020(14)00098-2/sref41http://refhub.elsevier.com/S0040-4020(14)00098-2/sref41http://refhub.elsevier.com/S0040-4020(14)00098-2/sref41http://refhub.elsevier.com/S0040-4020(14)00098-2/sref42http://refhub.elsevier.com/S0040-4020(14)00098-2/sref42http://refhub.elsevier.com/S0040-4020(14)00098-2/sref43http://refhub.elsevier.com/S0040-4020(14)00098-2/sref43http://refhub.elsevier.com/S0040-4020(14)00098-2/sref43http://refhub.elsevier.com/S0040-4020(14)00098-2/sref44http://refhub.elsevier.com/S0040-4020(14)00098-2/sref44http://refhub.elsevier.com/S0040-4020(14)00098-2/sref44http://refhub.elsevier.com/S0040-4020(14)00098-2/bib58ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib58ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib58ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib58bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib58bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib58bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib58bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib59bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref45http://refhub.elsevier.com/S0040-4020(14)00098-2/sref45http://refhub.elsevier.com/S0040-4020(14)00098-2/sref46http://refhub.elsevier.com/S0040-4020(14)00098-2/sref46http://refhub.elsevier.com/S0040-4020(14)00098-2/sref46http://refhub.elsevier.com/S0040-4020(14)00098-2/sref47http://refhub.elsevier.com/S0040-4020(14)00098-2/sref47http://refhub.elsevier.com/S0040-4020(14)00098-2/sref48http://refhub.elsevier.com/S0040-4020(14)00098-2/sref48http://refhub.elsevier.com/S0040-4020(14)00098-2/sref48http://refhub.elsevier.com/S0040-4020(14)00098-2/sref49http://refhub.elsevier.com/S0040-4020(14)00098-2/sref49http://refhub.elsevier.com/S0040-4020(14)00098-2/sref49http://refhub.elsevier.com/S0040-4020(14)00098-2/sref50http://refhub.elsevier.com/S0040-4020(14)00098-2/sref50http://refhub.elsevier.com/S0040-4020(14)00098-2/sref50http://refhub.elsevier.com/S0040-4020(14)00098-2/sref51http://refhub.elsevier.com/S0040-4020(14)00098-2/sref51http://refhub.elsevier.com/S0040-4020(14)00098-2/sref51http://refhub.elsevier.com/S0040-4020(14)00098-2/bib67ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib67ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib67ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib67bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib67bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib67bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib67chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib67chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib67chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib68ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib68ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib68ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib68ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib68bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib68bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib68bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib68bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref52http://refhub.elsevier.com/S0040-4020(14)00098-2/sref52http://refhub.elsevier.com/S0040-4020(14)00098-2/sref53http://refhub.elsevier.com/S0040-4020(14)00098-2/sref53http://refhub.elsevier.com/S0040-4020(14)00098-2/sref54http://refhub.elsevier.com/S0040-4020(14)00098-2/sref54http://refhub.elsevier.com/S0040-4020(14)00098-2/sref54http://refhub.elsevier.com/S0040-4020(14)00098-2/sref54http://refhub.elsevier.com/S0040-4020(14)00098-2/sref55http://refhub.elsevier.com/S0040-4020(14)00098-2/sref55http://refhub.elsevier.com/S0040-4020(14)00098-2/sref55http://refhub.elsevier.com/S0040-4020(14)00098-2/sref56http://refhub.elsevier.com/S0040-4020(14)00098-2/sref56http://refhub.elsevier.com/S0040-4020(14)00098-2/sref56http://refhub.elsevier.com/S0040-4020(14)00098-2/sref57http://refhub.elsevier.com/S0040-4020(14)00098-2/sref57http://refhub.elsevier.com/S0040-4020(14)00098-2/sref57http://refhub.elsevier.com/S0040-4020(14)00098-2/sref57http://refhub.elsevier.com/S0040-4020(14)00098-2/sref58http://refhub.elsevier.com/S0040-4020(14)00098-2/sref58http://refhub.elsevier.com/S0040-4020(14)00098-2/sref59http://refhub.elsevier.com/S0040-4020(14)00098-2/sref59http://refhub.elsevier.com/S0040-4020(14)00098-2/sref59http://refhub.elsevier.com/S0040-4020(14)00098-2/sref60http://refhub.elsevier.com/S0040-4020(14)00098-2/sref60http://refhub.elsevier.com/S0040-4020(14)00098-2/sref60http://refhub.elsevier.com/S0040-4020(14)00098-2/sref61http://refhub.elsevier.com/S0040-4020(14)00098-2/sref61http://refhub.elsevier.com/S0040-4020(14)00098-2/sref61http://refhub.elsevier.com/S0040-4020(14)00098-2/sref61


78. Steiner, D. D.; Mase, N.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2005, 44,3706e3710.

79. Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2009, 11, 943e946.80. Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.; Jørgensen, K. A. Chem.

dEur. J. 2006, 12, 6039e6052.81. Shibatomi, K.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 5796e5798.82. (a) Lifchits, O.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2010, 132,

10227e10229; (b) Lifchits, O.; Mahlau, M.; Reisinger, C. M.; Lee, A.; Far�es, C.;Polyak, I.; Gopakumar, G.; Thiel, W.; List, B. J. Am. Chem. Soc. 2013, 135,6677e6693.

83. Li, J.; Fu, N.; Zhang, L.; Zhou, P.; Luo, S.; Cheng, J.-P. Eur. J. Org. Chem. 2010,6840e6849.

84. Bondzic, B. P.; Urushima, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12,5434e5437.

85. Tanzer, E.-M.; Zimmer, L. E.; Schweizer, W. B.; Gilmour, R. Chem.dEur. J. 2012,18, 11334e11342.

86. (a) Deiana, L.; Zhao, G.-L.; Lin, S.; Dziedzic, P.; Zhang, Q.; Leijonmarck, H.;C�ordova, A. Adv. Synth. Catal. 2010, 352, 3201e3207; (b) Deiana, L.; Dziedzic, P.;Zhao, G.-L.; Vesely, J.; Ibrahem, I.; Rios, R.; Sun, J.; C�ordova, A. Chem.dEur. J.2011, 17, 7904e7917; (c) Desmarchelier, A.; Pereira de Sant’Ana, D.; Terrasson,V.; Campagne, J.-M.; Moreau, X.; Greck, C.; Marcia de Figueiredo, R. Eur. J. Org.Chem. 2011, 4046e4052.

87. Terrasson, V.; Van der Lee, A.; Marcia de Figueiredo, R.; Campagne, J.-M. Chem.dEur. J. 2010, 16, 7875e7880.

88. Fu, N.; Zhang, L.; Li, J.; Luo, S.; Cheng, J.-P. Angew. Chem., Int. Ed. 2011, 50,11451e11455.

89. Dalton King, H.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura, R.; Wu, D.; Gao, Q.;Macor, J. E. Org. Lett. 2005, 7, 3437e3440.

http://refhub.elsevier.com/S0040-4020(14)00098-2/sref62http://refhub.elsevier.com/S0040-4020(14)00098-2/sref62http://refhub.elsevier.com/S0040-4020(14)00098-2/sref62http://refhub.elsevier.com/S0040-4020(14)00098-2/sref63http://refhub.elsevier.com/S0040-4020(14)00098-2/sref63http://refhub.elsevier.com/S0040-4020(14)00098-2/sref64http://refhub.elsevier.com/S0040-4020(14)00098-2/sref64http://refhub.elsevier.com/S0040-4020(14)00098-2/sref64http://refhub.elsevier.com/S0040-4020(14)00098-2/sref65http://refhub.elsevier.com/S0040-4020(14)00098-2/sref65http://refhub.elsevier.com/S0040-4020(14)00098-2/bib82ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib82ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib82ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib82bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib82bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib82bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib82bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib82bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref66http://refhub.elsevier.com/S0040-4020(14)00098-2/sref66http://refhub.elsevier.com/S0040-4020(14)00098-2/sref66http://refhub.elsevier.com/S0040-4020(14)00098-2/sref67http://refhub.elsevier.com/S0040-4020(14)00098-2/sref67http://refhub.elsevier.com/S0040-4020(14)00098-2/sref67http://refhub.elsevier.com/S0040-4020(14)00098-2/sref68http://refhub.elsevier.com/S0040-4020(14)00098-2/sref68http://refhub.elsevier.com/S0040-4020(14)00098-2/sref68http://refhub.elsevier.com/S0040-4020(14)00098-2/sref68http://refhub.elsevier.com/S0040-4020(14)00098-2/bib72ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72ahttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72bhttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72chttp://refhub.elsevier.com/S0040-4020(14)00098-2/bib72chttp://refhub.elsevier.com/S0040-4020(14)00098-2/sref69http://refhub.elsevier.com/S0040-4020(14)00098-2/sref69http://refhub.elsevier.com/S0040-4020(14)00098-2/sref69http://refhub.elsevier.com/S0040-4020(14)00098-2/sref70http://refhub.elsevier.com/S0040-4020(14)00098-2/sref70http://refhub.elsevier.com/S0040-4020(14)00098-2/sref70http://refhub.elsevier.com/S0040-4020(14)00098-2/sref71http://refhub.elsevier.com/S0040-4020(14)00098-2/sref71http://refhub.elsevier.com/S0040-4020(14)00098-2/sref71

rahedron 70 (2014) 2491e2513 2513
A. Desmarchelier et al. / Tet
Biographical sketch

Alaric Desmarchelier studied chemistry at the University of Versailles, France, wherehe worked on organofluorine chemistry with Dr. Emmanuel Magnier, obtaining hismasters degree in 2009. He subsequently joined the Organocatalysis and AsymmetricSynthesis group in Versailles for his Ph.D., under the guidance of Prof. Christine Greckand Dr. Xavier Moreau. His research was focused on the design and application of or-ganocatalytic cascade reactions and electrophilic amination reactions, amines and ni-trogen heterocycles synthesis from a-branched aldehydes. He obtained his doctoraldegree in 2012, then joined the group of Prof. Syuzanna Harutyunyan in Groningen,the Netherlands, as a postdoctoral fellow, where he is currently working on catalyticenantioselective 1,2-additions of organometallic nucleophiles.

Vincent Coeffard was born in Nantes, France. He studied at University of Nantes andhe completed his Ph.D. studies in 2007 in the group of Professor Jean-Paul Quintard inwhich he worked in organometallic chemistry and organic electrosynthesis. He thenmoved to University College Dublin to work as a postdoctoral research fellow in asym-metric catalysis under the guidance of Prof. Pat Guiry and in 2009, he spent one yearfor a second postdoctoral experience in the group of Prof. Antonio Echavarren in Spainto investigate gold chemistry. In 2010, he joined the group of Prof. Christine Greck asa CNRS researcher to work on the design of organocatalysts and implementation ofcatalytic technologies to access enantioenriched organic architectures.

Christine Greck received her Ph.D. from the University of Strasbourg under the super-vision of Professor Guy Solladie in 1984 and subsequently was an Assistant at the me-dicinal faculty at the University of Paris V. In 1986, she joined the group of ProfessorSteve Ley at Imperial College in London as a postdoctoral fellow. In 1988, she movedas Maître de Conferences to the Ecole Nationale Sup�erieure de Chimie de Paris andworked with Professor Jean Pierre Genet. Since 1998, she has been Professor at theUniversity of Versailles Saint-Quentin-en-Yvelines. Her research interests involve or-ganic synthesis, organocatalysis and the application of electrophilic amination to thepreparation of cyclic and acyclic compounds.

Xavier Moreau obtained his Ph.D. under the supervision of Prof. J.M. Campagne at theICSNeGif sur Yvette working on total synthesis. In 2007, he was appointed as AssociateProfessor at the University of Versailles. His main research interests include the devel-opment of organocatalyzed cascade reactions.

Asymmetric organocatalytic functionalization of α,α-disubstituted aldehydes through enamine activation1 Introduction2 Stereoselective C–C bond-forming reactions2.1 Addition to electrodeficient olefins2.1.1 Addition to nitroalkenes2.1.2 Addition to maleimides2.1.3 Addition to vinyl sulfones2.1.4 Addition to α,β-unsaturated ketones or esters

2.2 Aldolization/Mannich reaction2.3 α-Alkylation

3 Stereoselective α-heterofunctionalization3.1 C–N bond-forming reactions3.2 C–O bond-forming reactions3.3 C–S bond-forming reactions3.4 C–F bond-forming reactions

4 Stereoselective formation of three-membered rings4.1 Epoxidation reactions4.2 Aziridination reactions4.3 Cyclopropanation reactions

5 Stereoselective proton-transfers6 ConclusionReferences and notes

asymmetric organocatalytic functionalization of α,α ...szolcsanyi/education/files/organicka...low...

Documents