Accepted Manuscript

Asymmetric organocatalytic functionalization of α,α-disubstituted aldehydes throughenamine activation

Alaric Desmarchelier, Vincent Coeffard, Xavier Moreau, Christine Greck

PII: S0040-4020(14)00098-2

DOI: 10.1016/j.tet.2014.01.056

Reference: TET 25230

To appear in: Tetrahedron

Received Date: 15 October 2013

Revised Date: 20 December 2013

Accepted Date: 22 January 2014

Please cite this article as: Desmarchelier A, Coeffard V, Moreau X, Greck C, Asymmetric organocatalyticfunctionalization of α,α-disubstituted aldehydes through enamine activation, Tetrahedron (2014), doi:10.1016/j.tet.2014.01.056.

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ACCEPTED MANUSCRIPTDifferent carbon-carbon and carbon-heteroatom bond-forming reactions were explored using

the asymmetric organocatalytic enamine activation of α,α-disubstituted aldehydes. Elegant methodologies to create quaternary carbon stereocentres have been developed and their incorporation into organocascade sequences has been nicely demonstrated.

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Asymmetric organocatalytic functionalization of α,α-disubstituted aldehydes through enamine activation.

Alaric Desmarchelier, Vincent Coeffard, Xavier Moreau*, Christine Greck

Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles-Saint-Quentin-en-Yvelines, 45, Avenue des Etats-Unis, Versailles, 78035 Cedex (France)

Contents 1. Introduction 2. Stereoselective C-C bond-forming reactions 2.1. Addition to electrodeficient olefins 2.1.1. Addition to nitroalkenes 2.1.2. Addition to maleimides 2.1.3. Addition to vinyl sulfones 2.1.4. Addition to α,β-unsaturated ketones or esters 2.2. Aldolization/Mannich reaction 2.3. α-Alkylation 3. Stereoselective α-heterofunctionalization 3.1. C-N bond-forming reactions 3.2. C-O bond-forming reactions 3.3. C-S bond-forming reactions 3.4. C-F bond-forming reactions 4. Stereoselective formation of 3-membered rings 4.1. Epoxidation reactions 4.2. Aziridination reactions 4.3. Cyclopropanation reactions 5. Stereoselective proton-transfers 6. Conclusion References and notes Biographical sketch

Corresponding author. Tel : +33139254410; Fax +33139254472; email address : xavier.moreau@uvsq.fr

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1. Introduction

Asymmetric aminocatalysis has been subjected to extensive development since the renewed interest of iminium and enamine chemistry in the early 2000s.1,2 In this context, α-functionalization of linear aldehydes3 has been largely studied in the past ten years. By contrast, there has been very limited success in developing stereoselective carbon-carbon and carbon-heteroatom bond-forming reactions of α-branched aldehydes. Indeed, the enamine activation of α,α-disubstituted aldehydes suffers from several drawbacks compared to their counterpart unbranched aldehydes. The steric hindr ance around the carbonyl moiety makes the condensation of the aldehyde with amino catalyst difficult to accomplish4 and leads to a less reactive enamine.5 In addition, the absence of a proton in the α-position leads to the irreversible formation of intermediates that inhibit the catalytic cycle.6 Another issue concerns the stereochemical outcome of the reaction: the enamine formation from α-branched aldehydes could lead to a Z/E mixture of enamines and thus affect the level of stereoselectivity. This is magnified when α,α-dialkylaldehydes are used. This report will highlight the efforts to overcome these problems towards the stereoselective construction of quaternary carbon centres7 via enamine catalysis. 2. Stereoselective C-C bond-forming reactions 2.1. Addition to electrodeficient olefins 2.1.1. Addition to nitroalkenes The organocatalytic conjugate addition of enamines derived from α,α-disubstituted aldehydes to electrodeficient alkenes is a powerful method for the stereoselective formation of C-C bonds. In 2004, Barbas and co-workers described the first stereoselective Michael addition of various α-branched aldehydes to nitrostyrene (scheme 1).8 Among the pyrrolidine-derived catalysts tested, (S)-1-(2-pyrrolidinylmethyl)pyrrolidine in combination with TFA afforded Michael adducts in good yields (64-96%), moderate diastereoselectivities (10-78% de) and variable enantioselectivities (18-91% ee).

Scheme 1

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Therefore, substantial efforts were devoted to the design of new catalytic systems in order to increase both reactivity and stereoselectivities and decrease the catalyst loading. Primary9 and secondary10 amine catalysts were used to promote the addition of isobutyraldehyde or cyclic aldehydes to nitroalkenes but the scope was usually limited. Reports that relayed a general methodology using different α-branched aldehydes leading to enantioenriched quaternary stereocentres remained rare. In 2006, Jacobsen and co-workers disclosed the first use of primary amine-thiourea catalyst11 for this transformation (scheme 2).12 A broad range of both partners was investigated to determine the scope and limitations of the reaction. Excellent results in terms of yield (34-98%) and enantioselectivity (92-99% ee) were observed in almost all cases but the level of diastereoselectivity was more contrasted. It is worthwhile noting that aldehydes bearing phenyl or ethereal substituents afforded high dr (>10:1) while α,α-dialkyl aldehydes led to moderate dr (7.1:1 to 2.1:1).

Scheme 2

In 2007, Connon and Mc Cooey reported the addition of aldehydes 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 α-branched aldehydes was limited to two examples allowing the formation of a quaternary stereocentre. Nevertheless, this communication brought to light for the first time this type of catalyst14 which is now one of the most popular primary amine catalysts.15

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O

R1

(10 mol%)

+ PhNO2

NO2

R1

PhPhCO2H (10 mol%)

Neat, r.t., 55-98h

N

N

OMe

NH2

95%2:1 dr

syn 92% ee

NO2

Ph

93%>20:1 dr

syn 65% ee

NO2

PhO O

O

Scheme 3

In 2011, Nugent and co-workers detailed an unusual catalytic system 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 various α,α-dialkyl aldehydes with nitroalkenes (scheme 4).16 γ-Nitroaldehydes were obtained in good yields (70-89%) and high levels of enantioselectivity (90-99% ee) while moderate diastereoselectivity (40-56% de) was observed due to the possibility of forming Z or E enamine from α,α-dialkyl aldehydes.

Scheme 4

The Michael adducts formed in this transformation can readily be converted to amino acids. Yoshida and co-workers applied their own methodology17 to the enantioselective synthesis of cyclic gabapentin analogues (scheme 5).18 A 4:1 mixture of phenylalanine and its lithium salt (20 mol%) served as an effective catalyst for the addition of α-branched aldehydes to

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β-nitroacrylates and the enantioenriched aminoacids were obtained in good overall yields after hydrogenolysis over Pd/C.

Scheme 5 An intramolecular version of this transformation was also applied to the synthesis of the atropurpuran A-ring.19 Despite the screening of various primary and secondary amine catalysts, low levels of stereoselectivity were observed. 2.1.2. Addition to maleimides Conjugate addition of α-branched aldehydes to maleimides has also attracted substantial attention since substituted succinimides are an interesting class of heterocycles as synthetic biologically active compounds or as intermediates in the synthesis of functionalized γ-lactams or pyrrolidines. The first example of this transformation was reported by Córdova and co-workers in 2007.20 The Hayashi-Jørgensen catalyst (10 mol%) was used to catalyze the reaction between isobutyraldehyde and N-phenylmaleimide but a moderate yield (40%) and enantioselectivity (51% ee) were obtained. The apparent low catalytic activity of secondary amines was also pointed out in a racemic version of this reaction.21 Consequently, different primary amine catalysts were developed to overcome this problem and several chiral bifunctional primary amine-thiourea22 or -guanidine23 catalysts were used to promote the addition of isobutyraldehyde to maleimides. In 2010, two independent studies explored the formation of contiguous quaternary-tertiary stereogenic centers.24 Optimized conditions involved primary amine-thiourea catalysts synthetized from 1,2-cyclohexyldiamine and a catalytic amount of water or benzoic acid. Substituted succinimides were obtained in excellent yields (>79%) and enantioselectivities (>75% ee) but with moderate diastereoselectivities (from 1:1 to 9:1 dr depending on the aldehydic substituents) (scheme 6).

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O

R1

+

R1

N

O

O

Arconditions

conditions ACat. (5-15 mol%)H2O (15 mol%)

CHCl3, r.t., 70-84h

N

O

O

Ar**

NH2

NH

S

NH

conditions BCat. (10-20 mol%)

PhCO2H (10-20 mol%)CH2Cl2, r.t., 1-60h

NH2

NH

S

NH

CF3

CF3

N

O

O

Ph**

N

O

O

Ph**

N

O

O

Ph**

Ph

N

O

O

Ph**

O

OOOO

tBu

B : 96%2:1 dr

99/96% ee

B : 95%1:1 dr

98/96% ee

B : 99%2:1 dr

99/97% ee

B : 90%8:1 dr

91% ee (major product)

N

O

O

Ph N

O

O

N

O

O

Ph

OOO

A : 79%2.3:1 dr

syn 98% eeanti 96% ee

A : 81%5.5:1 dr

syn 99% eeanti 96% ee

A : 91%5:1 dr

syn 99% eeanti 75% ee

Br Br

Cl

Scheme 6

More recently, Nugent and co-workers showed that the three-component catalytic system previously developed for the addition of aldehydes to nitroolefins16 was an efficient general catalyst for 1,4-addition reactions. Different catalytic systems based on an amino acid (L-threonine or L-isoleucine), a base (DMAP or KOH) and a hydrogen-bond donor (sulfamide, thiourea) promoted the addition of α-branched aldehydes to maleimides to afford substituted pyrrolidinediones in excellent yields and moderate to high levels of stereoselectivity (scheme 7).25 DFT calculations were performed in order to support a noncovalent assembly of the catalyst components and explain the origin of the stereoselectivity via two hydrogen bonds.

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O

R1

(5 mol%)

+

(5 mol%)

Toluene, r.t., 4-24h

H2NSNH2

O OHO2C

NH2

OtBu

DMAP (15 mol%)

R1N

O

O

ArN

O

O

Ar

N

O

O

Ph N

O

O

Ph

Ph

N

O

O

Ph

OO O

82%99:1 dr

syn 92% ee

89%97:3 dr

syn 94% ee

98%90:10 dr

syn >99% eeanti >99% ee

O

N

O

O

Ph

O

88%74:26 dr

syn 98% eeanti 86% ee

O

O

H

PhO

OPh

OO

HHN S

NH

OO

H

H N NMe2

R H

DFT supported intermediate

Scheme 7

In 2013, Kokotos identified β-phenylalanine/Cs2CO3 as an efficient catalyst (1 mol% catalyst loading) for this transformation which was used in a straightforward one-pot synthesis of γ-butyrolactones (scheme 8).26

Scheme 8

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ACCEPTED MANUSCRIPT2.1.3. Addition to vinyl sulfones The scope of Michael acceptors in enamine catalysis was also extended to vinyl sulfones. Alexakis et al. reported the first addition of α,α-disubstituted aldehydes to vinyl disulfones catalyzed by N-iPr-2,2’-bipyrrolidine but only modest yields and stereoselectivities were observed.27 The reaction was initially improved by using the Hayashi-Jørgensen catalyst28 but the best results were obtained through the development of new aminal-pyrrolidine catalysts (scheme 9).29

Scheme 9

The same group reported the asymmetric addition of unusual α-chloro, α-hydrazino and α-hydroxy aldehydes to vinyl sulfones leading to highly functionalized tetrasubstituted carbon stereocentres (scheme 10).30 Different experimental results prompted the authors to postulate a kinetic resolution mechanism.

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Scheme 10

Simultaneously, Maruoka and co-workers developed a new anthracenyl-derived primary amine catalyst which promoted the conjugate addition of α-heterosubstituted aldehydes (amino and alkoxy aldehydes) or 2-phenylpropionaldehyde to 1,1-bis(benzenesulfonyl)ethylene.31 Very good yields (90-99%) and high levels of enantioselectivity (81-95% ee) were observed using 10 mol% of catalyst and 10 mol% of 2,6-dihydroxybenzoic acid in toluene at room temperature. α-Benzenesulfonylphosphate instead of vinyl sulfones was also tested leading to the desired adduct in 99% yield with high diastereo- and enantioselectivity (14:1 dr, 85% ee) (scheme 11).

Scheme 11

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ACCEPTED MANUSCRIPTTwo other primary amine catalysts bearing a sulfonamide group were also described to catalyze the reaction.32 In 2010, Zhu and Lu disclosed 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 (76-95%) and satisfying enantioselectivities (68-86% ee) (condition A, scheme 12). The methodology was improved two years later by Miura and co-workers. The threonine backbone was replaced with valine and a stronger electron-withdrawing perfluorobutanesulfony group was utilized (instead of NTf) to enhance the acidity of the sulfonamide group. Better yields (95-99%) and selectivities (83-93% ee) were obtained in shorter reaction times (condition B, scheme 12).

O

R1

+SO2Ph

SO2Ph

O

SO2Ph

SO2Ph

R1

*

O

SO2Ph

SO2PhO

SO2Ph

SO2Ph

O

SO2Ph

SO2Ph

O

SO2Ph

SO2Ph

Conditions

TBSO

NHTfNH2

NHSO2C4F9NH2

conditions ACat. (5 mol%)

p-F-toluene, r.t., 12-24h

conditions BCat. (10 mol%)TFA (10 mol%)

m-xylene, r.t., 2-10-h

A : 93%, 83% eeB : 95%, 93% ee

A : 87%, 80% eeB : 97%, 89% ee

A : 93%, 82% eeB : 98%, 83% ee

A : 90%, 86% eeB : 97%, 92% ee

Br

OMe

Scheme 12

Heteroarylvinyl sulfones have also been used as Michael partners in such a transformation (scheme 13).33 9-Amino-(9-deoxy)-epiquinine (20 mol%) in combination with p-nitrobenzoic acid (20 mol%) afforded the best results and the corresponding sulfones were obtained in moderate to good yields (30-83%) and different levels of stereoselectivity (40-94% ee). Subsequent Julia-Kocienski transformation completed a two-step organocatalytic allylation of α-branched aldehydes.

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Scheme 13

2.1.4. Addition to α,β-unsaturated ketones or esters Organocatalytic Michael addition of α-branched aldehydes to vinyl ketones or esters has not been developed as a synthetic methodology but has been involved in several organocatalytic one-pot sequences. Melchiorre and co-workers reported one example of a triple-cascade reaction from 2-phenylpropionaldehyde, ethyl cyanoacrylate and cinnamaldehyde leading to the synthesis of a densely substituted cyclohexane (scheme 14). The secondary amine-mediated reaction afforded the product in good yield as a separable mixture of two diastereomers (C5-epimers).34

Scheme 14

Kotsuki and co-workers35 explored a catalytic version of a two-step asymmetric synthesis of cyclohexenone derivatives described in 1969 by Yamada and Otani.36 (1R,2R)-1,2-cyclohexanediamine (30 mol%) and (1R,2R)-1,2-cyclohexanedicarboxylic acid (30 mol%) composed the catalytic system that promoted the Michael addition of α-branched aldehydes to MVK or EVK (scheme 15). One example using cyclohexenone instead of vinyl ketones was reported by Bella and co-workers.37 The reaction was also detailed by Carter and co-workers

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Scheme 15

A double Michael addition of a β-ketoester bearing an electrodeficient olefin and α-substituted-α,β-unsaturated aldehydes was disclosed by Ma and co-workers (scheme 16).39 The organocascade mediated by the Hayashi-Jørgensen catalyst (2-5 mol%) afforded highly functionalized cyclopentanones in excellent yields (67-81%) and good levels of selectivity.

Scheme 16

2.2. Aldolization/Mannich reaction A few reports in the literature have described direct catalytic aldol or Mannich reactions of α,α-disubstituted aldehydes leading to β-hydroxy or amino aldehydes bearing a quaternary

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O

R1

NH (10 mol%)

+

R1

OH

96%62:38 dr

anti 91% eesyn 75% ee

N

TFA (10 mol%)

DMSO, r.t., 48h

OH

97%84:16 dr,anti 95% eesyn 74% ee

OHO

O

O

91%77:23 dranti 90% eesyn 53% ee

OHO

NO2

O

O O

NO2NO2NO2

NO2

Scheme 17

Primary amino acids such as histidine41 or isoleucine42 could also promote asymmetric aldol additions and proved to be an alternative to pyrrolidine-based catalysts whereby aldehyde substrates are limited to aromatic substituents (scheme 18). The authors also explored the influence of chiral stereocentre-containing aldehydes as an electrophilic partner (matched-mismatched effect).

Scheme 18

Examples of Mannich reactions of α-branched aldehydes are scarce and only imino esters were engaged as an electrophilic partner. In 2004, Barbas and co-workers described the use of

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ACCEPTED MANUSCRIPTL-proline (30 mol%) to promote the Mannich reaction and the products were obtained in reasonable yields and stereoselectivities.43 In all cases a syn diastereoselectivity was observed. For example, 2-phenylpropanal was engaged in this reaction and furnished the corresponding β-amino aldehydes in 66% yield and moderate stereoselectivities (85:15 dr and 86% ee for the major diastereomer, scheme 19). Another pyrrolidine-based catalyst developed by Blanchet and co-workers,44 3-trifluoromethanesulfonamido-pyrrolidine, showed anti-selectivity but only one example involved the construction of a quaternary stereocentre. The Mannich product derived from 2-phenylpropanal was obtained in 82% yield, a 20:80 diastereomeric ratio and 20% ee for the anti diastereomer (scheme 19). In 2012, Nugent and co-workers applied their noncovalent bifunctional organocatalyst (O-tBu-Thr, sulfamide, DMAP, 5 mol% each) to this transformation (scheme 19).25 The substrate scope for this reaction remained rather limited and the results were comparable to those obtained by Barbas.

Scheme 19

2.3. α-Alkylation Althrough great efforts have been made in this area, organocatalytic α-alkylation of simple aldehydes still remains a challenging transformation.45 As a consequence, only a few methodologies employing α,α-disubstituted aldehydes were reported in the literature. In 2008, Enders and co-workers developed an organocatalytic domino Michael addition/α-alkylation reaction of various aliphatic aldehydes and 5-iodo-1-nitropentene promoted by the Hayashi-Jørgensen catalyst and benzoic acid.46 This sequence proceeded via an enamine-enamine activation pathway. The first step gave rise to the α-branched aldehyde which cyclised in the second step. Under these conditions, the corresponding α-quaternary cyclopentene carboxaldehydes were synthesized in moderate yields (40-62%) and good stereoselectivities (scheme 20).

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Scheme 20

Jacobsen and co-workers reported an SN1-like substitution reaction involving various 2-arylpropionaldehydes and diarylbromomethane.47 The anion-binding capacity of thiourea was exploited to form benzhydryl cations within a bifunctional primary amine-thiourea catalyst that also generates the enamine nucleophilic partner (scheme 21).

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O (20 mol%)

+CH3CO2H (10 mol%)

H2O (1 eq)Et3N (1 eq)

Toluene, r.t., 2-4 d.

70%91% ee

57%92% ee

R1

Br

R2 R2

NH2

NH

NH

S

CF3

F3C

O

R1

R2

R2

O

Ph

O

60%90% ee

O

PhF

F

O

F OMe52%

85% ee

HN

N

Ar

S

NAr

H H

Br

Ph Ph

Possible activation mode

Scheme 21

List and co-workers reported an SN2-like substitution reaction between various α-branched aldehydes and benzyl bromide derivatives.48 The reaction was promoted by an unusual sterically demanding proline-derived catalyst (30 mol%) in the presence of an organic mixed acid-base “buffer” system. This particular reaction medium was used instead of a base alone because it was supposed to accelerate the enamine formation (through acid catalysis), to act as a HBr scavenger and to suppress the alkylation reaction of base and/or catalyst. Under these conditions, the benzylated products were obtained in good yields (60-82%) and high levels of enantioselectivity (76-97% ee) for such a transformation (scheme 22).

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N

Proposed transition stateO

O

N

N

N

H

HHH

Br

O(30 mol%)

+tetramethylguanidine

p-anisic acid4Å M.S.

CHCl3, 50°C, 144h

R1

R2 Br

O

R2

R1

HNCO2H

O O

Cl

O

Br80%

91% ee71%

82% ee65%

76% ee

Scheme 22

Another methodology to create a chiral all-carbon quaternary centre was described by Cozzi and co-workers in 2012.49 A series of α-substituted aldehydes reacted with commercially available 1,3-benzodithiolylium tetrafluoroborate in the presence of a primary amine catalyst derived from quinidine and (-)-CSA as a chiral cocatalyst. The products were isolated in good yields (52-89%) and moderate enantioselectivities (32-87% ee) after reduction of the aldehyde moiety (scheme 23).

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Scheme 23

Combining transition-metal catalysis and aminocatalysis has recently gained widespread currency to promote C-C bond formation.50 Racemic versions of the direct carbocyclisation of aldehydes and alkynes were first developed using an achiral secondary amine catalyst for the nucleophilic activation and gold,51 indium52 or copper-based promoter53 to enhance the reactivity of the triple bond. An enantioselective version of this transformation has recently been disclosed by Michelet, Ratovelomanana-Vidal and co-workers. A chiral metallo-organocatalytic system composed of 10 mol% of cyclohexylamine, 6 mol% of Cu(OTf)2 and 15 mol% of the chiral bidentate ligand (R)-DTBM-MeOBIPHEP allowed the direct access to a range of enantioenriched cyclopentanes (Scheme 24).54

Scheme 24

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List and co-workers reported a direct α-allylation of α,α-disubstituted aldehydes with allylic alcohols promoted by the synergistic action of a primary amine, a chiral phosphoric acid and [Pd(PPh3)4] (scheme 25).55 The Tsuji-Trost reaction involving a chiral π-allyl-Pd-TRIP ion pair and an achiral β,β-disubstituted enamine afforded products in excellent yields (66-98%) and enantioselectivities (69-99.6% ee).

Scheme 25

More recently, Yoshida and co-workers reported an alternative procedure for the formation of pent-4-enal derivatives that avoids the use of phosphoric acids.56 A combination of two catalytic systems, an achiral palladium complex and O-TBS-L-threonine, promoted the α-allylation of α-branched aldehydes with allyl pivalate. The use of a chiral primary amine catalyst explained the origin of the stereoselectivity observed in this reaction. The products were obtained in good yields and acceptable levels of enantioselectivity (scheme 26). The comparison of both procedures revealed that the use of a combination of a chiral phosphoric acid and an achiral amine seemed to be a more efficient and general: better yields and levels of stereoselectivity were generally observed and the α-allylation of α,α-dialkyl aldehydes was only possible by using List’s protocol.

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Scheme 26

Carreira and co-workers developed an elegant α-allylation of aldehydes based on a stereodivergent dual catalysis.57 The catalytic system combined a chiral primary amine which controlled the stereoselectivity of the α-center and a chiral iridium complex which controlled the stereoselectivity of the β-position of the resulting product. The authors anticipated the minimization of the matched-mismatched effects by exploiting the relative planarity of both reactive species (enamine and allyliridium) and disclosed a straightforward synthesis of all possible stereoisomers in excellent yields and very high levels of stereoselectivity (scheme 27).

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O

R1

R2R3

OH

+

[{Ir(cod)Cl}2] (2 mol%)ligand (8 mol%)Amine (10 mol%)

Cl3CCO2H (50 mol%)DCE, r.t., 24h

O

R1 R2

R3

O

OP NN

H N

NH2

N

N

NH2

H

O

OP N

A1 A2 (R)-L (S)-L

O

Ph

PhO

Ph

Ph O

Ph

PhO

Ph

Ph

A1 + (R)-L

77 %>20:1 dr>99% ee

A1 + (S)-L

78 %15:1 dr>99% ee

A2 + (S)-L

71 %>20:1 dr>99% ee

A2 + (R)-L

80 %20:1 dr>99% ee

RL

RS

NH

RLn*Ir

R*

Local control-center

Local control-center

Scheme 27

3. Stereoselective α-heterofunctionalization 3.1. C-N bond-forming reactions Among the α-heterofunctionalization reactions of α-branched aldehydes, the electrophilic amination of carbonyl compounds is the most reported in the literature. The first report was published by Bräse and co-workers in 2003.58 Proline (50 mol%) was shown to promote the transformation with different azodicarboxylates (DEAD or DBAD) as the electrophilic nitrogen source. The hydrazino aldehydes were obtained in moderate to good yields (26-99%) and variable enantioselectivities, 4-39% ee for challenging α,α-dialkyl substituted products and 35-86% ee for those derived from 2-arylpropionaldehydes. The same group noticed that the use of microwave irradiation dramatically decreased the reaction time and increased slightly the yields and the enantioselectivities (scheme 28).59

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Scheme 28

Further to this work, great efforts have been made to improve both reactivity and selectivity of this transformation. A comparison of the different catalytic systems reported in the literature to promote the electrophilic amination of 2-phenylpropionaldehyde is detailed in table 1. Two other bifunctional pyrrolidine-based catalysts were designed in 2010. The first one merged the pyrrolidine framework with a camphor scaffold.60 A lower catalyst loading (5 mol%) was required for the α-amination of disubstituted aldehydes but the results were disappointing (entry 2). The second one merged a prolinamide and a thiourea linked together by a chiral diamine (10 mol%) and o-hydroxybenzoic acid (20 mol%).61 Excellent results in terms of reactivity and selectivity were obtained when different 2-arylpropionaldehydes were engaged in the reaction (entry 3). Different primary amine catalysts were also found to promote stereoselective C-N bond formation. Two groups have accounted for the use of modified cinchona alkaloids, one with chiral camphorsulfonic acid as cocatalyst62 and the other with trifluoroacetic acid.63 In both cases, the use of 9-amino(9-deoxy)epi-quinine was crucial to reach excellent levels of enantioselectivity (entries 4 and 5). Chiral primary amino acids were also tested for this transformation and 3-(1-naphtyl) alanine hydrochloride64 (entry 6) or β-tert-butyl aspartate65 (entry 7) were identified as promoters for the α-amination. Both of them are efficient catalysts but the alanine derivative did not give satisfactory yield when di-tert-butyl azodicarboxylate was used and no reaction occurred when the aspartate derivative was engaged with dibenzylazodicarboxylate as the amination reagent. Finally, Wang, Xu and co-workers recently reported that a simple chiral primary amine such as 1-(1-naphtyl)ethylamine, TFA and 4-chloro-2-nitrobenzoic acid (10 mol% each) catalyzed the formation of hydrazino aldehydes (entry 8).66

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Entry Catalytic system

Conditions R Yield Ee

1

CH3CN, r.t., 0.5h, MW Bn 99% 84%

2

CH2Cl2, r.t.,168h

Bn

46%

75%

3

CH2Cl2, 0°C, 32h

iPr

87%

97%

4

CHCl3, r.t., 24h

iPr Bn tBu

-a -a 99%

95% 84% 97%

5

CHCl3, r.t., 3h

iPr Bn tBu

95% 72% 96%

90% 82% 95%

6

THF, 0°C, 32h

iPr tBu

82% 33%

95% 92%

7

THF, 0°C, 24h

iPr Bn tBu

93% n.r. 98%

93% n.d. 94%

8

Et2O, -20°C, 48-70h

iPr Bn tBu

92% 68% 75%

91% 88% 93%

a- Yields are not reported in the publication.

It is worth noting that the stereoselective C-N bond formation was investigated with different reagents than azodicarboxylates including nitrosobenzene67 or sulfonyl azides68 but results in terms of reactivity or selectivity were disappointing (scheme 29).

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Scheme 29

This methodology was successfully applied to different syntheses of natural products such as hydantoin BIRT-377,69 amino acids AIDA and APICA70 or antibiotic fumimycin71 (scheme 30).

H

O

NN

CO2BnBnO2C

(15 mol%)

CH3CN

Br H

O

N

Br

Cbz

HNCbz

NN

O

O

Cl

Cl

BrBIRT-377

O

X

NN

CO2BnBnO2C

(20 mol%)

CH3CN

X

NOCbz

NH

CbzX

HO2C NH2

NN

CO2tButBuO2C

O

MeO

O

OMe

NBoc

NHBoc

O

HO

HO

O

NH

O

NH HN N

NN

+

NH

CO2H

+

AIDA X= CO2HAPICA X= P(O)(OH)2

+

CO2H

Fumimycin

O

MeO

O

OMe (200 mol%)

1,4-dioxane

NH

CO2H

71%60% ee

>99% ee

95%80% ee

Scheme 30

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Electrophilic α-amination reactions were also included in organocascade sequences. In 2009, Melchiorre and co-workers revealed that the construction of contiguous quaternary and tertiary stereocentres could be achieved via an iminium/enamine activation of α,β-disustituted enals.72 The Michael addition/amination sequence promoted by a primary amine catalyst (20 mol%) and TFA (30 mol%) allowed the formation of highly functionalized hydrazino aldehydes in moderate to good yields (31-80%), appropriate levels of diastereoselectivity (3:1 to 20:1 dr) and excellent enantiomeric excesses (83-99% ee) (scheme 31).

(20 mol%)

N

OMe

NH2

N

31%3:1 dr83% ee

80%11:1 dr98% ee

47%3:1 dr91% ee

OR1

R2 NuHN

N

Boc

BocO

R1 NBocR2

Nu

BocHN

ONBoc

BocHN

TFA (30 mol%)

CHCl3, 48-96h++

NH

ONBoc

BocHN

NH

ONBoc

BocHN

NH

40%20:1 dr99% ee

54%6.5:1 dr>99% ee

47%4:1 dr92% ee

ONBoc

StBu

BocHN

OPh NBoc

SBn

BocHN

ONBoc

Ph

StBu

BocHN

Scheme 31

Another example dealt with the α,α-bifunctionalization of propionaldehyde in a sequential multicatalytic process based on secondary amine-catalyzed Michael addition and a primary amine-promoted α-amination.73 The corresponding hydrazino aldehydes were obtained in good yields (73-90%) and excellent levels of selectivity (>95:5 dr, 96-98% ee) but the scope was limited to propionaldehyde (scheme 32).

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Scheme 32

A primary amine-catalyzed direct conversion of α,α-disubstituted aldehydes into 3-pyrrolines bearing a quaternary stereocenter was reported in 2012 (scheme 33).74 The combination in a single flask of α-amination, aza-Michael addition of hydrazine and aldol condensation-dehydratation afforded the heterocycles in good yields (42-83%) and moderate to excellent levels of enantioselectivity (30-98% ee). The choice of di-tert-butyl azodicarboxylate proved to be crucial since a selective carbamate deprotection in acidic conditions was required during the sequence to trigger the aza-Michael addition.

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+

thenR2

R1

ON R1

R2

NHBocTFA (70 mol %)

r.t., 16h

R3R3

N

BocHN

N

BocHN

N

BocHN

83%94% ee

78%98% ee

OO O

75%50% ee

N

N

Boc

Boc

(10 mol%)

N

OMe

NH2

N

TFA (30 mol%)CHCl3, r.t., 2h

N

BocHN2:1 d.r.

major product: 46%, 94% eeminor product: 26%, 94% ee

O

OO

Scheme 33

3.2. C-O bond-forming reactions Compared with electrophilic α-amination of α-branched aldehydes, the stereoselective C-O bond formation leading to a quaternary 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 α-hydroxyamination products as major regioisomer, the reaction of α,α-dialkylaldehydes catalyzed by L-proline led to a mixture of N- and O-nitrosoaldol products.62 To circumvent this problem, List and co-workers described an asymmetric α-benzoyloxylation of different 2-substituted-propionaldehydes promoted by a combination of a primary amine catalyst derived from quinine and a chiral phosphoric acid.75 The corresponding oxygenated aldehydes were obtained in moderate to good yields (41-83%) and promising enantioselectivities (scheme 34).

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O

R1

+

(10 mol%)

N

OMe

NH2

N

Ar

Ar

O

OPO

OH

Ar= 2,4,6-(iPr)3-C6H2

(10 mol%)

BHT (10 mol%)THF, r.t., 18h

PhO

O O

OPh

R1

BzO

OPh

BzOOBzO

OTBSOBzO

OBzO

MeO

tBu

78%40% ee

76%68% ee

57%83% ee

76%68% ee

O

Scheme 34

3.3. C-S bond-forming reactions Jørgensen and co-workers have described the only example of α-sulfenylation of 2-phenylpropionaldehyde promoted by a diphenylprolinol silyl ether (10 mol%) as a catalyst (scheme 35).76

Scheme 35

3.4. C-F bond-forming reactions In 2005, Jørgensen77 and Barbas78 independently reported the stereoselective α-fluorination of 2-phenylpropionaldehyde using N-fluorobenzenesulfonamide (NFSI) as the electrophilic fluorinating reagent and a secondary amine catalyst (scheme 36). The corresponding quaternary stereocentre was formed in excellent yield but low enantioselectivity and the scope was limited to one or two examples. Nevertheless, this methodology has been employed in the synthesis of β-fluoroamines.79 In 2006, Jørgensen and co-workers described the synthesis of unsual atropisomer organocatalysts based on aminated quinoline or naphtyl scaffolds and their applications in the C-F bond formation.80 Despite good enantioselectivities for α-fluorination of 2-arylpropionaldehydes, the products were isolated in moderate yields.

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Ph+

O

F

Ph

Conditions

NH HN N

NN

99%45% ee

NH

78%48% ee

(5 mol %)toluene, 60°C, 18h

(30 mol %)THF, r.t., 2h

PhO2SN

SO2Ph

F

Ar

Ar

Ar : 3,5-(CF3)2C6H3

H2N NOH

Boc NHBoc

36%90% ee

(10 mol %)hex/iPrOH, 2°C, 16h

Scheme 36

More recently, Shibatomi and Yamamoto disclosed the synthesis of α,α-chlorofluoro carbonyl compounds.81 The construction of fluorinated quaternary carbon stereocentres was completed with good yields and selectivities by using NFSI as the fluorine source and a diarylprolinol silyl ether (10 mol%) as the catalyst (scheme 37).

Scheme 37

4. Stereoselective formation of 3-membered rings. α-Functionalization of α,α-disubstituted aldehydes was included in different stereoselective organocascade sequences involving iminium-enamine activation and allowed the formation of 3-membered carbo- or heretocycles. As depicted in scheme 38, this strategy has been illustrated with epoxidation, aziridination or cyclopropanation reactions.

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Scheme 38

4.1. Epoxidation reactions Since 2010, four independent reports established the aminocatalyzed synthesis of enantioenriched epoxides bearing a chiral quaternary stereocentre (scheme 39). List and co-workers utilized the combination of a primary amine derived from quinine (10 mol%) and a chiral phosphoric acid, (R)-TRIP (20 mol%) as the catalyst and aqueous hydrogen peroxide as the oxidant. A series of α-branched and α,β-disubstituted enals were transformed into epoxides in good yields (43-84 %) and high degrees of stereoselectivity (52-90% de, 70-98% ee).82 Luo and co-workers also described an association of a chiral aminocatalyst and an achiral Brönsted acid to synthesize epoxides. After a careful screening to find the optimized conditions, a primary-tertiary 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 transform α-branched acroleins to corresponding epoxides in excellent yields (79-95%) and good selectivities (32-88% 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 (61-80%) and selectivity (74-94% ee).84 It is worth noting that this reaction proceeded without additives. Acid co-catalysts did not produce any positive effects on the rate, yield or selectivity of the transformation. In 2012, Gilmour and co-workers disclosed the epoxidation of cyclic α,β-disubstituted enals catalyzed by 2-(fluorodiphenylmethyl)pyrrolidine (10 mol%) and highlighted the influence of the fluorine gauche effect on the iminium-intermediate’s conformation. Despite the fact that the scope was limited to cyclic enals, this methodology pushed back some limitations shown by other reports and notably the epoxidation of tetrasubstituted cyclohexene derivatives.85

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2- NaBH4, MeOHO

R1

R2 ROOH+ HO

R1

R2

O

* *

(10 mol%)

N

OMe

NH2

N

Ar

Ar

O

OPO

OH

Ar= Ph or 2,4,6-(iPr)3-C6H2

(20 mol%)

H2O2THF, 50°C, 24h

43-84% yield52-90% de70-98% ee

NH OSiMePh2

PhPh (20 mol%)

H2O2Hexane, r.t., 3-24h

61-80% yield(Isolated as aldehydes)

74-94% ee

(10 mol%)

cumene hydroperoxydesilica gel

aq. NaCl (2M), 0°C, 24-48h

79-95% yield32-88% ee

NH2

NPh

Ph

n-Pr

n-PrHO3S CO2H

OH

NH F

PhPh (10-30 mol%)

H2O2CHCl3, 12-84h

43-98% yield6:1 to >20:1 dr83-97% ee

Scheme 39

4.2. Aziridination reactions Two independant groups explored the aziridination of α-substituted α,β-unsaturated aldehydes in the presence of a prolinol silyl ether catalyst (20 mol%), NaOAc as a base and an N-protected-O-(p-toluenesulfonyl)hydroxylamine (scheme 40).86 The publications detailed the formation of terminal aziridines and Córdova and co-workers successfully expanded the scope of the reaction to α,β-disubstituted enals. The corresponding nitrogen-containing heterocycles were elaborated in yields of up to 90 % and diastereoselectivities of up to 25:1.

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Scheme 40

4.3. Cyclopropanation reactions Marcia de Figueiredo, Campagne and co-workers have developed an efficient secondary amine-mediated enantioselective cyclopropanation of α-substituted acroleins with diethyl bromalonate (scheme 41).87 The choice of the base was crucial to reach good yields (35-81%) and high levels of enantioselection (79-97 % ee). Reaction time decreased dramatically when N-methylimidazole was used compared to 2,6-lutidine but decomposition or side products were detected in some cases.

Scheme 41

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+N

R1

R3

N

R3

R1

(10 mol%)Ph

Ph

NH2

N

TfOH (12 mol%)

PhCl/Brine (2/1), r.t., 5-14h

R4

OR2

R4

H CHO

R2

NH

Bn

H CHO

N

Bn

Bn

H CHO

NH

MeO Bn

H CHO

NH

H CHO

82%, 80% ee82%, 68% ee 85%, 84% ee

Cl

60%, 91% ee

NH

R

NH

Ph

Ph NOH

H

H

Scheme 42

The Friedel-Crafts/enantioselective protonation sequence was utilized a few years ago for the synthesis of a potent serotonin reuptake inhibitor.89 MacMillan’s imidazolidinone catalyst was used for the transformation and the product was obtained in good yield and excellent selectivities (scheme 43).

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Scheme 43

6. Conclusion Different carbon-carbon and carbon-heteroatom bond-forming reactions were explored using the asymmetric organocatalytic enamine activation of α,α-disubstituted aldehydes. In spite of advances in this field, thanks to the introduction of primary amine catalysts, some methodologies still suffer from a narrow substrate scope and low levels of stereoselectivity. Nevertheless, elegant methodologies to create quaternary carbon stereocentres have been developed and their incorporation into organocascade sequences has been efficiently demonstrated. References and notes 1. Asymmetric Organocatalysis 1: Lewis Base and Acid Catalysts; List, B., Ed.; Thieme, 2012. 2. Comprehensive Enantioselective Organocatalysis, Dalko, P. I., Ed.; Wiley, 2013. 3. (a) Bertelsen, S.; Jørgensen, K. A., Chem. Soc. Rev. 2009, 38, 2178-2189; (b) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632-649. 4. Sánchez, D.; Bastida, D.; Burés, J.; Isart, C.; Pineda O.; Vilarrasa, J. Org. Lett. 2012, 14, 536-539. 5. Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem. Eur. J. 2003, 9, 2209-2218. 6. Burés, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2012, 134, 6741-6750. 7. For a general review see Bella, M.; Gasperi, T. Synthesis 2009, 1583-1614. 8. Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527-2530. 9. (a) Zhang, X.-J.; Liu, S.-P.; Lao, J.-H.; Du, G.-J.; Yan, M.; Chan, A. S. C. Tetrahedron: Asymmetry 2009, 20, 1451-1458; (b) Zhang, X.-J.; Liu, S.-P.; Li, X.-M.; Yan, M.; Chan, A. S. C. Chem. Commun. 2009, 833-835; (c) Chen, J.-R.; Zou, Y.-Q.; Fu, L.; Ren, F.; Tan, F.; Xiao, W.-J. Tetrahedron 2010, 66, 5367-5372. 10. (a) Wang, W.; Wang, J.; Li, H. Angew. Chem. Int. Ed. 2005, 44, 1369-1371; (b) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem. Eur. J. 2006, 12, 4321-4332; (c) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 4966-4967; (d) Zhang, Q.; Ni, B.; Headley, A. D. Tetrahedron 2008, 64, 5091-5097; (e) Belot, S.; Massaro, A.; Tenti, A.; Mordini, A.; Alexakis, A. Org. Lett. 2008, 10, 4557-4560; (f) Zhu, S.; Yu, S.; Ma, D. Angew. Chem. Int. Ed. 2008, 47, 545-548; (g) Bai, J.-F.; Xu, X.-Y.; Huang, Q.-C.; Peng, L.; Wang, L.-X. Tetrahedron Lett. 2010, 51, 2803-2805; (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, 1275-1279; (i) Ting, Y.-F.; Chang, C.; Reddy, R. J.; Magar, D. R.; Chen, K. Chem. Eur. J. 2010, 16, 7030-7038; (j) Xiao, J.; Xu, F.-X.; Lu, Y.-P.; Loh, T.-P. Org. Lett. 2010, 12, 1220-1223. 11. For a general review see (a) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol. Chem. 2013, 11, 7051-7071; (b) Tsakos, M.; Kokotos, C. G. Tetrahedron 2013, 69, 10199-10222. 12. Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 6366-6370. 13. Mc Cooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599-602. 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, 389-392; (b) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403-1405. 15. (a) Jiang, L.; Chen, Y.-C. Catal. Sci. Technol. 2011, 1, 354-365; (b) Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 9748-9770. 16. Nugent, T. C.; Shoaib, M.; Shoaib, A. Org. Biomol. Chem. 2011, 9, 52-56. 17 (a) Sato, A.; Yoshida, M.; Hara, S. Chem. Commun. 2008, 6242-6244; (b) Yoshida, M.; Sato, A.; Hara, S. Org. Biomol. Chem. 2010, 8, 3031-3036. 18. Yoshida, M.; Masaki, E.; Ikehara, H.; Hara, S. Org. Biomol. Chem. 2012, 10, 5289-5297. 19. Chen, H.; Zhang, D.; Xue, F.; Qin, Y. Tetrahedron 2013, 69, 3141-3148. 20. Zhao, G.-L.; Xu, Y.; Sundén, H.; Eriksson, L.; Sayah, M.; Córdova, A. Chem. Commun. 2007, 734-735. 21. Nöth, J.; Frankowski, K. J.; Neuenswander, B.; Aubé, J.; Reiser, O. J. Comb. Chem. 2008, 10, 456-459. 22. (a) Bai, J.-F.; Peng, L.; Wang, L.-L.; Wang, L.-X.; Xu, X.-Y. Tetrahedron 2010, 66, 8928-8932; (b) Miura, T.; Nishida, S.; Masuda, A.; Tada, N.; Itoh, A. Tetrahedron Lett. 2011, 52, 4158-4160; (c) Miura, T.; Masuda, A.; Ina, M.; Nakashima, K.; Nishida, S.; Tada, N.; Itoh, A. Tetrahedron: Asymmetry 2011, 22, 1605-1609; (d) Ma, Z.-W.; Liu, Y.-X.; Li, P.-L.; Ren, H.; Zhu, Y.; Tao, J.-C. Tetrahedron: Asymmetry 2011, 22, 1740-1748; (e) Durmaz, M.; Sirit, A. Tetrahedron: Asymmetry 2013, 24, 1443-1448. 23. (a) Avila, A.; Chinchilla, R.; Nájera, C. Tetrahedron: Asymmetry 2012, 23, 1625-1627; (b) Avila, A.; Chinchilla, R.; Gómez-Bengoa, E.; Nájera, C. Eur. J. Org. Chem. 2013, 5085-5092.

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ACCEPTED MANUSCRIPT 72. (a) Deiana, L.; Zhao, G.-L.; Lin, S.; Dziedzic, P.; Zhang, Q.; Leijonmarck, H.; Córdova, A. Adv. Synth. Catal. 2010, 352, 3201-3207; (b) Deiana, L.; Dziedzic, P.; Zhao, G.-L.; Vesely, J.; Ibrahem, I.; Rios, R.; Sun, J.; Córdova, A. Chem. Eur. J. 2011, 17, 7904-7917; (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, 4046-4052. 87. Terrasson, V.; Van der Lee, A.; Marcia de Figueiredo, R.; Campagne, J.-M. Chem. Eur. J. 2010, 16, 7875-7880. 88. Fu, N.; Zhang, L.; Li, J.; Luo, S.; Cheng, J.-P. Angew. Chem. Int. Ed. 2011, 50, 11451-11455. 89. Dalton King, H.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura, R.; Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437-3440.