Recent advances in organocatalytic asymmetric synthesis of polysubstituted pyrrolidines

Tetrahedron Letters 55 (2014) 784–794

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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Recent advances in organocatalytic asymmetric synthesis of polysubstituted pyrrolidines Man-Yi Han, Ju-Ying Jia, Wei Wang ⇑ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, People’s Republic of China

a r t i c l e

i n f o

Article history: Received 17 September 2013 Accepted 13 November 2013 Available online 4 December 2013 Keywords: Substituted pyrrolidine Organocatalysis Asymmetric synthesis

a b s t r a c t Chiral substituted pyrrolidines are important N-heterocyclic structural motifs, existing in many natural products, drug candidates, ligands and organocatalysts. We summarise herein the recent (between January 2010 and July 2013) developments on synthesising the chiral polysubstituted pyrrolidines through asymmetric organocatalysis. The organocatalytic strategies for constructing the pyrrolidine scaffolds can be divided into one-step and sequential approaches, respectively. The straightforward one-step approach is mainly the [3+2] cycloaddition based on the iminium activation, chiral Brønsted acid catalysis, bifunctional organocatalysis and SOMO activation. In the sequential approach (multi-step or one-pot reactions), the primary construction of chiral linear precursors is followed by the sequential cyclisation. Other important strategies, such as the organocatalytic bromoaminocyclisation were also described. These organocatalytic strategies have enriched the synthetic chemistry of chiral pyrrolidines, especially towards the target-, diversity- and application-oriented synthesis. New organocatalytic approaches are thus expected for the facile construction of polysubstituted pyrrolidines with well-controlled stereochemistry and for the practical synthesis of pyrrolidine-related natural alkaloids, drug candidates and functional proline derivatives. Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction As one of the five-membered heterocyclic structural motifs, chiral substituted pyrrolidines are prevalent in many biologically active natural products and pharmaceutical drug candidates1 (Fig. 1). Meanwhile, the pyrrolidine motifs also serve as important building blocks in organic synthesis and are featured in the structures of versatile ligands and organocatalysts.2 Consequently, great efforts have been devoted to exploiting efficient strategies towards the asymmetric synthesis of different kinds of substituted pyrrolidines. Among all the protocols developed, the catalytic asymmetric approaches prove the most attractive. In this context, much of the recent progress thanks to the asymmetric organocatalysis3 which has emerged as a powerful and environmentally benign route for the synthesis of optically active compounds. Organocatalysts are usually robust, inexpensive and non-toxic; the strict reaction conditions (such as inert atmosphere, low reaction temperatures and absolute solvents) are often not required. Accordingly, organocatalytic asymmetric synthesis of substituted pyrrolidines from simple starting materials has received considerable attention recently. Several reviews4 have surveyed the development of efficient methods for the construction of substituted pyrrolidines. We focus ⇑ Corresponding author. Tel.: +86 9318912282. E-mail address: [email protected] (W. Wang). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.11.048

herein on the recent (between January 2010 and July 2013) advances in synthesising the chiral polysubstituted pyrrolidines through asymmetric organocatalysis. Briefly speaking, the main strategies developed in this aspect can be categorised as one-step and sequential approaches, respectively. The straightforward one-step approach is mainly the [3+2] cycloaddition based on different activation strategies, such as the iminium activation, chiral Brønsted acid catalysis, bifunctional organocatalysis and SOMO activation. In the sequential approach, the chiral linear precursors

CO2 H

CO 2Me

H OAc

N Me

CO 2H N H (-)-kainic acid

OBz

N

H 2N cocaine

(-)-slaframine O

MeO

O MeO N

MeO

OH

MeO

O N H (-)-mesembrine

lepadiformine

N H (-)-coccinine

Figure 1. Representative natural products containing chiral polysubstituted pyrrolidines as the core structures.

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M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794

are firstly constructed, followed by the sequential cyclisation. In addition, other important strategies, such as the organocatalytic bromoaminocyclisation, have also been described. In this Digest, we intend not only to compile the diverse organocatalytic strategies for the construction of chiral pyrrolidines, but also to address the further applications towards the synthesis of related natural products and/or their core structures.

Me TBSO 4 steps

CO 2Et CO 2Et

H N

Me TBSO H

Me

Me

OHC H N

O

CO 2Et CO 2Et

4 steps N H

9

CO2 Et CO2 Et

TBSO

Me

H

8

7 (97% ee)

4 steps

N

2. Asymmetric [3+2] cycloaddition

CO2 Et CO2 Et

10

The asymmetric [3+2] cycloaddition is one of the most effective approaches for the formation of five-membered heterocyclic architectures from readily available raw materials. In 2007, the breakthrough of organocatalytic asymmetric [3+2] cycloaddition was realised by Vicario et al.5 towards the asymmetric synthesis of pyrrolidines via iminium activation. Thereafter, a series of [3+2] cycloaddition reactions have been successfully developed for the organocatalytic synthesis of chiral pyrrolidines from a diversity of substrates via different activation strategies. The main achievements have thus been summarised, according to the activation modes, in this section.

Scheme 2.

12 CO2Et O

CO 2Et

11

CO2Et

3 (20 mol%)

+ R H2N

H 2O (4 equiv), THF, 4 oC

2 (2 equiv)

N H R

H PCC

5

Early in 2007, Vicario et al. developed the first organocatalytic asymmetric [3+2] annulation reaction of azomethine ylides 1 and a,b-unsaturated aldehydes 2, generating the chiral pyrrolidines 4 with moderate to high ee values (Scheme 1). In these cases, the stabilised azomethine ylide 5 would be formed through the 1,2-prototropic shift of imine 1, while the a,b-unsaturated aldehyde 2 would be activated to 6 by diphenylprolinol 3 upon iminium activation. This procedure thus provides an easy and straightforward method for the organocatalytic construction of chiral polysubstituted pyrrolidines. As an elegant example6 of the diversity-oriented synthesis, the obtained cycloaddition product 7 could be facilely transformed into the densely-substituted N-heterocyclic compounds, such as the bicyclic 9 and 10, and the tricyclic 8 (Scheme 2). On the basis of these achievements, the same group7 proceeded to expand the substrate scope of this reaction. Thus, the [3+2] annulation of 2-alkenylidene aminomalonates and a,b-unsaturated aldehyde 2 was further developed. The cycloaddition adducts 12 bearing different 5-alkenyl substituents could undergo further chemical manipulation, affording a series of bicyclic tetrahydro1H-furo[3,4-b]pyrrol-6(6aH)-ones 14 and hexahydro-1H-furo[3,4-b]pyrroles 15 (Scheme 3). On the other hand, it had been under debate whether the [3+2] cycloaddition involving

R

N

CO2 Et +

R2

6 steps

H

H O

4

O

O

CO2 Et N CO 2Et H yield: 57-93%, ee: 85 to >99% endo:ex o: 91:9 to >95:5 R1

3 Ph + N

5

6

Ph O-

Ph Ph

OR2

+N

H R

H 2O

R2

OEt 2

R2

OHC

H 2O (4 eq.), THF, 4 o C

Ph

N

+

14 H

R CO2Et

O N H Bz

CO2Et

azomethine ylides is a concerted or stepwise reaction. On the basis of the DFT calculations, they proposed that the reaction pathway should follow the initial Michael addition and subsequent intramolecular Mannich reaction. In most cases, a-imino esters are used as the precursors for preparing the azomethine ylides. However, the drawback is that the 2,5-diastereoselectivity of the pyrrolidine cycloadduct is difficult to control. In a modification to their original protocol, Vicario and co-workers8 introduced the a-imino cyanoacetates 16 bearing two different electron-withdrawing groups to generate azomethine ylides (Scheme 4). The 2,5-diastereoselectivity of chiral pyrrolidines could be well controlled through the formation of an intramolecular hydrogen bond between the NH and ethoxycarbonyl groups. As a result, the cycloaddition reaction could afford

Ph N

CO2Et

Scheme 3.

H 2O

EtO

CH2 Cl2 , rt 43-53% yield

CO2Et N H Bz

15

3

R1

Et3SiH, BF3 .OEt 2

13

2

1

O

CO2Et

N H Bz

R

O

CO2Et

O HO

Ph Ph N H OH 3 (20 mol%)

O

CO2 Et

12

CH2 Cl2 , 40 oC 78-99% yield

R

H

CO2Et

yield: 50-90% endo/exo: 90:10-96:4 ee: 90 to >99%

2.1. [3+2] cycloaddition via iminium activation

1

R

OHC

EtO 2C R NH EtO 2C - +

Scheme 1.

R1 1

N H

CO2 Et CO2 Et

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M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794 17 H

R1

N

O +

OEt

R2

CN

3 (20 mol%) o H H 2O (4 eq), THF, 4 C

CN R1

2 R1

N

R2

OHC

O

CO2 Et

N H

yield: 58-80% 2,5-cis/2,5-tr ans: > 95:5 endo/exo: 94:6 to >95:5 ee: 90 to >99%

CO 2Et CN

16

Scheme 4.

the desired adducts 17 (four continuous stereogenic centres, including a quaternary one at C-2) with moderate yields and excellent ee. Hydrogen bonding interaction could be applied to direct the reaction outcome and to control the selectivity of dynamic procedures in multicomponent organic synthesis. In 2011, Córdova and co-workers9 reported a dynamic transformation involving the three-component reaction of protected a-cyanoglycine ester 18, aldehydes 19 and enals 2. Initially, the Michael reaction between a-cyanoglycine ester and enal plagued such three-component reaction. As shown in Scheme 5, adding of co-catalyst 20 could create an intramolecular hydrogen-bonding network. The hydrogenbonding interaction not only activates the imine, but also locks its conformation to I, and thus enhances the chemoselectivity and diastereoselectivity of the multicomponent reaction. A following [3+2] cycloaddition between intermediate I and a,b-unsaturated aldehydes 2 proceeded through a similar mechanism to that depicted in Scheme 1, affording a-quaternary proline derivatives in high dr and ee, together with moderate to good yields (Scheme 5). 2.2. 1,3-Dipolar cycloaddition via Brønsted acid activation Despite the remarkable progress that has been made through the iminium activation strategy, the dipolarophile substrates are limited to unsaturated aldehydes only. Thus, development of the [3+2] cycloaddition (especially the asymmetric 1,3-dipolar cycloaddition) catalysed by chiral Brønsted acids has shown great importance for synthesising polysubstituted pyrrolidines with a broad substrate scope. Gong and co-workers4a found that chiral phosphoric acids could activate azomethines in a variety of 1,3dipolar cycloaddition reactions and, thereby, developed a series of organocatalytic methods for constructing the chiral pyrrolidine derivatives. Isoindolines are privileged structural motifs found in a variety of pharmaceuticals. In 2010, Gong and co-workers10 successfully developed the 1,3-dipolar addition of quinone derivatives 24 to

Ph Ph N H OTES 21 (5 mol%)

O R

CO 2t Bu H 2N

CN 18

H 2

+

20 (75 mol%), THF, 4

R 1CHO 19

azomethine ylide so as to construct the synthetically useful isoindoline derivatives. The chiral phosphoric acid 25 was applied as the optimal catalyst to activate azomethine. After a subsequent isomerisation mediated by Ac2O/Et3N, the desired products 26 were obtained with moderate to excellent yields and enantioselectivities (Scheme 6). Notably, this transformation could produce isoindolines with a diversity of substituents at both 3- and 5-positions. Gong and co-workers11 found that 4-(2-formylphenoxy) butenoates 27 could not only act as the precursors of the azomethine ylide but also as the dipolarophiles. As a result, catalysed by the BINOL-derived phosphoric acid 29, 27 and amino esters 28 could be transformed into hexahydromeno[4,3-b]pyrrolidines 30 with high to excellent yields and ee, together with high dr (Scheme 7). This elegant work represents the first example of applying organocatalytic intramolecular 1,3-dipolar cycloaddition reaction for the synthesis of hexahydromeno[4,3-b]pyrrolidine and its structural analogues. The spiro[pyrrolidin-3,30 -oxindole] unit exists in a large variety of alkaloids with high bioactivity and structural uniqueness. On the basis of the previous achievements, Gong and co-workers12 further expanded the substrate scope to the electron-deficient methyl 2-(2-nitrophenyl)acrylates 31 so as to construct the spiro[pyrrolidin-3,30 oxindole] 33. In this case, the 1,3-dipolar cycloaddition reaction was performed in toluene and catalysed by BINOL-based phosphoric acid 32 (Scheme 8). After nine-step transformation, the obtained spiro[pyrrolidin-3,30 -oxindole] 34 could further be converted into the diastereoisomers of spirotryprostatin A, 35 and 36. The subsequent biological investigation demonstrated that the two diastereo-isomers had the similar effects (although a little lower than the corresponding natural products) in inhibiting MDA MB-468 cells. Gong and co-workers13 further extended the substrate range of electron-deficient dipolarophiles for 1,3-dipolar cycloaddition. In comparison with maleates 40, the more challenging substrates, fumarates 38, could also yield the tetra-substituted pyrrolidines (Scheme 9). In addition, the more interesting dipolarophile substrates 42, such as vinyl ketones and acrylate esters, could provide the tri-substituted pyrrolidines as well. The yields and ee in these transformations were moderate to excellent, and the product ratio of endo to exo was moderate. On the basis of the DFT calculations, they proposed that the BINOL-derived phosphoric acid catalysts

R2 H2 N

OAc

O

R1 CHO 19

R

1) 25 (10 mol%), toluene, 0 oC

+

2) Ac 2O, Et3 N, DMAP, CH 2Cl2

R

CO2 R3 23

Ar

O 24

R

OHC

NC

H

CO 2t Bu H 2N

CN

+ R1 CHO

OMe

OMe

N CO2 tBu H yield: 56-88% dr: 10:1 to >19:1 ee: 93-98%

25

Ar O

NC

CHO

OMe

R1

O H

N O H

O

N

OtBu CN

R1

O H N

Ot Bu CN

Scheme 5.

NH2

MeOOC

OH

30 CO2 R2

Ar Ar = 2-naphthyl

toluene, 25

oC,

Ar1 28

72 h

COOMe

O

29 (10 mol%)

+

O

I

CO2 R 2

O

O P

27

R1 N O

yield: 76-98% ee: 83-97%

R1

O 20 CN

26

O Ar = P O OH

O O N

NH R2 3 CO R 2 OAc

Scheme 6.

CN oC

R

O

Ar

22

R1

N H

Ar 1

yield: 42-93% dr: 94:6-99:1, ee: 53-94%

Scheme 7.

R1

R

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M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794 EtO2 C CO 2Et 33

RCHO 19

R1

CO2 Et H2 N

32 (10mol%)

CO2 Me

+ 31

CO2Et 11

NO2 O O O PO HO

EtO 2C CO2 Et

O

NH

O O P O OH

32

N

H

9 steps

CO2Me MeO

R CO2 Me R2 NO2 yield: 25-97% dr: 20:1 to >99:1 ee: 74 to >99%

toluene, 30 o C R2

N

O

O

H

H O

N

+

O MeO

MeO

34 (>99% ee)

N

H

O N H 9,18-bis-epispirotryprostatin A 35

NO2

NH

R1

N H

18-epispirotryprostatin A 36

Scheme 8.

R 4O2 C 38

CO 2R

4

32 (10 mol%)

CO 2R 4

R 4O2 C

1

4

R N H 39

R3

R O2C

CO2 R2

CO 2R

4

46 32 (15 mol%)

yield: 77-99%, ee: 50-97% R1 H 2N

CO 2R 2 37 +

O

CO2 Me MeO 2C

CO2Me MeO 2C

40 32 (20 mol%)

R3 CHO 19

N H 41

R3

R1 CO2 R 2

R1

O N R2 44 +

yield: 58-98%, ee: 74-98% O R5 R6 42 32 (10 mol%)

R5 R6

R O2 C

HN

R6

48 32 (25 mol%)

CO2R 3 45

R1

3 R 3O 2C CO2 R

MeO2 C

Ph

50

Scheme 9.

could activate the dipole and dipolarophile simultaneously via the hydrogen-bonding interaction. In the cases of maleate substrates, the hydrogen bonds were formed between the two hydroxyl groups of bisphosphoric acid 32 and the two ester groups of maleates. On the contrary, in the cases of acrylate or fumarate substrates, only one hydroxyl group of 32 was used to form the hydrogen bond with the ester group of acrylate or fumarate; while another one of 32 to adjust the acidity of the two phosphoric acids. As mentioned above, the azomethine ylides for 1,3-dipolar cycloaddition are often generated from the corresponding aldehydes. Presumably due to the low reactivity, ketones have rarely been used as the precursors of azomethine ylides. Gong and co-workers14 reported the first example of organocatalytic 1,3-dipolar cycloaddition involving the low reactive reactants of unsymmetrical isatins 44. Catalysed by biphosphoric acid 32, this asymmetric reaction was applicable to various isatins, affording the chiral spiro[pyrrolidin-3,20 -oxindole] scaffolds with one or two quaternary stereogenic centres in high to excellent yields, dr and ee values (Scheme 10). Inspired by the biosynthesis of a-amino acids from a-keto acids, Gong and co-workers15 realised an intriguing synthesis of pyrrolidines and spirooxindole derivatives from a-keto esters 52 (Scheme 11). The three-component 1,3-dipolar cycloaddition could

CO2 R5 O

N 49 R2 yield: 41-92% dr: 30:1 to >99:1, ee: 87-97%

R1 CO2 R2

N H 43 yield: 43-96%, ee: 84-98% R3

3 R 3O 2C CO2 R 6 R 5

CO2 R3 H2 N

O

3 R 3O 2C CO2 R CO2 R 4 HN CO2 R4 1 R O N 47 R2 yield: 48-95% dr >99:1, ee: 80-98%

32 (25 mol%)

HN R1

Ph CO2 Me O

N 51 R2 yield: 41-57% dr > 99:1, ee: 93-97%

Scheme 10.

be efficiently catalysed by chiral phosphoric acid 32. The tetrasubstituted pyrrolidines 57 were accordingly synthesised from the reaction of aldimine intermediates 55 (in situ generated from ketimines 54 via 1,3-proton shift) and electron-deficient olefins 56 (Scheme 11). Via a similar protocol and with the use of organocatalyst 29, the spirooxindole derivatives 61 could also be obtained in high to excellent yields and ee values. In terms of the easy accessibility of the starting materials, the a-keto esters are superior to the corresponding amino esters. 2.3. [3+2] cycloaddition via bifunctional activation Along with the expansion of new substrates in the [3+2] cycloaddition, it is desirable to exploit new catalytic systems for practical transformations as well. In this context, the bifunctional catalysis, in which the simultaneous activation of two reacting substrates occurs via multiple and relatively weak interactions (e.g., hydrogen bonding), has broadened the scope of research in asymmetric organocatalysis. Particularly, the bifunctional thio-

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M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794 R3 O

R1

CO2

R2

PG = CONHPh or Boc

CH 2 Cl2 , 50 oC

N R3

52

R 2O2 C

32 (10-20 mol%)

-H 2 O

+

R1

53

CO 2R 2

N

R4

CO2 R6

+

R 6 O2C R4

O MeO

R1

CO2 R 2

N H

50 o C R

56

R5

66 +

3

N PG

H N

H N

N CONHPh 69a

CF3

or R3 O2 C Ph

N Boc 69b

R7 CO2 Et 58

Ph CO 2Me EtO2 C

O N Ac

+ R3

H2 N

29 (10 mol%)

R3 NH CO 2Et CO 2Et O

60

N 61 Ac yield: 86-98%, ee: 90-94%

59

Ph CO2 Me

N

Cl

CH 2Cl2 , rt to 50 o C

yield: 44-65% ee: 97 to >99% O dr: 1.9:1 to 5.1:1

R1

57

O EtO2 C

N

R 2 O2C

Ph 67

yield: 60-90%, ee: 90-99%

R7

yield: 41-64% O ee: 90-97% dr: 2.7:1 to 8.0:1

CF3 R 1

S N 68 (10 mol%) CHCl3, -20 oC

CO 2R 3

CN

R1 CO2 R2

N H

55

32 (10-20 mol%) CH 2Cl2,

R5

H

R1

54

55

3 Ph CO2 R N R 2 O2C

R3

NH2

O N CONHPh 70 (92% ee)

1) HSiCl3, 75% yield

NH

EtO 2C Cl

2) KOH, THF, 70% yield

O N H 71 (85% ee)

Scheme 13.

Scheme 11.

urea–tertiary amine organocatalysts have been applied to catalyse a diversity of nucleophile–electrophile addition reactions. Herein, the recent progress towards the synthesis of chiral pyrrolidines through the [3+2] cycloaddition via bifunctional organocatalysis has been surveyed. In 2011, Bai et al.16 reported the organocatalytic asymmetric 1,3-dipolar cycloaddition of azomethine 62 and N-arylmaleimides 63 (Scheme 12). The reaction was well promoted by the bifunctional thiourea catalyst 64, in which the tertiary amine acts as base to activate a-imino esters and the thiourea group activates N-arylmaleimides via double hydrogen bonds. The tetra-substituted pyrrolidines 65 with important and easily transformable succinimide motifs were thus obtained in moderate to excellent yields and ee. A wide scope of substituted azomethine ylides and N-arylmaleimides is well applicable, but the aliphatic N-maleimides gave the corresponding products with low ee only. Further extension to the isocyanoacetate substrates was achieved by the same group17 with the use of quinine-based thiourea–tertiary amine 68 as the bifunctional organocatalyst (Scheme 13). A variety of highly functionalised spirooxindole scaffolds 69 with two quaternary stereocentres could be obtained in moderate yields and dr, together with excellent ee. Notably, the formed cycloaddition products with an imine moiety 70 could be further transformed to 3,30 -pyrrolidinyl spirooxindole 71 by the S

R1

O

N

N CO 2Me 62 + R2 N

N H

65

N H O

R2 N

3. Sequential approach

63 Chiral scaffold S N O

OMe

H

H O

N Ph H

N N R2

R1 O

Scheme 12.

In 2007, MacMillan19 introduced the SOMO catalysis mode, in which one-electron oxidation of a transient enamine intermediate would provide the three-p-electron SOMO-activated species. Via the SOMO activation, MacMillan and co-workers20 realised the organocatalytic asymmetric reaction of b-amino aldehydes 76 and simple olefins 77 for the synthesis of substituted pyrrolidines (Scheme 15). With a broad range of olefins as the substrates, the reaction proceeded well in the presence of organocatalyst 78 via the SOMO-activation/cycloaddition mechanism as shown in Scheme 15. The corresponding 2,4-disubstituted pyrrolidines 79 could be obtained in moderate to high yields and excellent ee.

R1

O

N

2.4. [3+2] cycloaddition via SOMO activation

O

64 (25 mol%) CH 2Cl2, -20 oC, 72 h

sequence of transfer hydrogenation and removal of the N-phenylamide group (Scheme 13). Interestingly, changing of the protecting groups on the substrates would achieve the synthesis of 3,3-pyrrolidinyl spirooxindole diastereomers with the same organocatalyst. Recently, another work related to the assembly of the challenging spirooxindole scaffolds was disclosed by Wang and co-workers.18 In this reaction, the azomethine ylides were extended to the cyclic imino esters 72 derived from the homoserine lactone. Catalysed by rosin-derived bifunctional organocatalyst 74, the organocatalytic asymmetric 1,3-dipolar cycloaddition worked well in a mixed toluene/Et2O solvent, affording a series of spiro[c-butyrolactone-pyrrolidin-3,30 -oxindole] tricyclic motifs 75 (with two spiro quaternary stereocentres) in excellent ee (Scheme 14). The obtained spirotricyclic motifs could be useful for the synthesis of natural products and biologically relevant compounds.

CO 2Me N H yield: 51-89% ee: 30-96%

As a straightforward approach for constructing chiral pyrrolidines, the [3+2] cycloaddition has well been advanced towards the expansion of substrate scope, the application of different activation strategies and the synthesis of natural products. Meanwhile, the alternative sequential approach has also been developed, in which the chiral stereocentres are first constructed (mainly by organocatalytic Michael addition) in the linear precursors, and followed by cyclisation so as to construct the pyrrolidine ring in a stereocontrolled manner. The sequential approach mainly includes the multi-step and one-pot reactions, which will be described, respectively, in this section.

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M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794

S

N

R 2O 2C

O

N H

N H

R O O H

R=

O

+ R4

N

74 (10 mol%)

O

R1 72

R1 O

R4

toluene: Et 2 O = 1: 1, rt

N R3

NH

R 2O 2C

N 75 R 3 yield: 83-97% dr: 14:1 to >20:1 ee: 90 to >99%

73

Scheme 14.

Me

Ph

O N

2

tBu

H O 76

NHNs + A 77 B

C

Bn N H . 78(20mol%)2 TFA Fe(phen)3(PF6)3 THF, Na2HPO4 Me

O

tBu

O2 N R1

O

+

80

81

Ar Ar N OTMS H Ar = naphthyl 83

NHR2

OHC

Me

O N

tBu

N

O N

A R

tBu

N

-1 e-

R A

NHPG

OHC

NHR2 NO 2

R1 84 yield: 80-99% dr: 1:1.4-26:1 ee: 68-99%

1

Zn/HOAc, H2 O

N

R

H

N H

H NH PG

85

A

NHPG

Scheme 15.

3.1. Multi-step reaction 3.1.1. Nitroolefins as the Michael acceptor The Michael addition reaction has emerged as one of the most important routes for constructing the carbon–carbon bond in asymmetric organocatalytic synthesis. Due to the versatile transformations of nitro groups in organic synthesis,21 nitroolefins are often applied as excellent Michael acceptors for synthesising a variety of substituted pyrrolidines via the sequential approach. Substituted 3-aminopyrrolidines are frequently found in the bioactive compounds and pharmaceutical molecules. Thus, targeting at the further transformation of c-nitroaldehyde products, the Michael addition of b-substituted nitroolefins to aldehydes has firstly been attempted. In 2010, Ma and co-workers22 applied the protected 2-nitro-ethenamines as the Michael acceptors to construct the bioactive 3-aminopyrrolidines. With diarylprolinol silyl ether 82 or 83 as the organocatalyst, the asymmetric Michael addition of aldehydes 80 and the protected 2-nitro-ethenamine 81 worked well in i-PrOH, affording a series of 1,2-diamino precursors 84 in high to excellent yields, dr and ee (Scheme 16). The diastereoselectivity of 84 could be controlled by the protected 2-nitroethenamine substrates: the major syn-products were obtained from phthaloyl-protected substrates, while the anti-products from acyl-protected substrates. After the reductive amination of 1,2-diamino precursors 84, substituted 3-aminopyrrolidine products 85 or 86 could be easily obtained (Scheme 16). Indolylnitroalkenes23 have recently been applied as the Michael acceptors towards the synthesis of pyrrolidines. The indolylnitroalkenes 87 could react with aliphatic aldehydes 80, affording the tryptamine precursors 88 in high to excellent yields, together with excellent dr and ee (Scheme 17). Furthermore, the typical Michael adduct 89 could be easily transformed into

OHC

95-99% yield

OH

R2N

R NHR2 Pd/C, H2 NO 2 MeOH

O

A

N PG

- catalyst Me

Ph 82 N OTMS H 82 or 83 (5-20 mol%)

-

-2 e

R N H catalyst

NHPG catalyst, -1e-

H

A B yield:55-85% dr:3:2-6:1 C ee:87-95% N Ns 79

O N

A

H

R = phthaloyl or acyl

OHC

1

NHAc

R1

N H

84

86

Scheme 16.

3-indole substituted pyrrolidine 90 by the reductive amination/ cyclisation cascade without any loss of the ee value (Scheme 17). Besides the expansion of the substrate (nitroolefin) scope, exploration of suitable catalytic systems is beneficial to the efficiency of the Michael reaction. Very recently, the combination of proline and lithium as the effective catalyst was introduced by Wang’s group24 for enamine activation. Utilising the proline lithium salt as the catalyst, a diversity of aldehydes 91 and nitroalkenes 92 could react to afford the desired precursors 93 in moderate to high yields, together with high dr and ee (Scheme 18). The adducts 93 bearing the formyl and nitro groups could be subject to further transformations. For instance, existing in a variety of natural products as the basic scaffolds, the 3,4-disubstituted L-proline 96 could be facilely obtained from 94 (Scheme 18). Targeting at the synthesis of N-alkylated trans-benzopyrano[3,4]pyrrolidine structural motifs, Enders and co-workers25 developed a concise and efficient organocatalytic route (Scheme 19). The best organocatalyst in this domino oxa-Michael/Michael reaction between nitrovinylphenols 97 and acrolein

R1

O 2N

NO2 + N Ts 87

R2

O

88

R2

H

R1

82 (10 mol%) CH 2Cl2, -30 to 0 o C

OHC N Ts yield: 90-98% dr: 97:3 to >99:1, ee: >99%

80

NO2

N Ts 1) Pd/C, H2 , MeOH

OHC N Ts

2) TsCl, Et3N, CH 2Cl2 58% yield (2 steps)

89 (>99% ee)

Scheme 17.

N Ts 90 (>99% ee)

790

M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794 93 R2

ProLi (10 mol%)

NO 2

+ R3 H R1 91

H 2 O (0.2 eq), MTBE

Ph

Ph NO 2

2

R R1 yield: 69-93% dr: 13:1-96:1 ee: 88-99%

H

Et

Ph

5 steps

H N SO CF 2 3 N H 105 (5-10mol%)

NO 2

H

92

O

TBDPSO

R3

O

O

R2

H R

O

1

+

4-NO 2PhCO 2H (5-10 mol%) DMF, 0 o C

O2N 104

80

CN N PG PG = p-Ns 95

94

R1

NO 2 CHO yield:56-86% dr: 79:21-99:1 ee: 70-98%

Et

2 steps

Et

106 R2

iPr

N . CO2 H H HCl

Bn

iPr

1) Zn, HOAc/H2 O Bn N Ts 108 (96% ee)

2) Et 3 N, TsCl

NO2 CHO

96

70% yield 107 (95% ee)

Scheme 18.

Scheme 20.

98 was found to be the diarylprolinol silyl ether 99. The domino products 100 were obtained with excellent dr and ee, together with the moderate yields. Subsequently, via a two-step reductive amination/N-alkylation sequence, the adduct 101 could be efficiently transformed into N-alkylated trans-benzopyrano[3,4]pyrrolidine 103 (Scheme 19). The above-mentioned examples verify that b-mono-substituted nitroolefins are excellent Michael acceptors; they participated in the conjugate addition with aldehydes, through which the chiral di-substituted pyrrolidines could be eventually obtained. In contrast to b-mono-substituted nitroolefins, the a-substituted substrates have rarely been applied in asymmetric Michael reactions. Peng and co-workers26 employed a-substituted nitroolefins 104 as the Michael acceptors to react with aldehydes, giving a variety of c-nitro carbonyl precursors 106 in moderate yields, together with high dr and ee (Scheme 20). Via a Zn/HOAc-mediated intramolecular reductive amination procedure, 2,4-di-substituted pyrrolidines 108 could thus be obtained from the c-nitro carbonyl precursor 107 (Scheme 20). In comparison to b-mono-substituted nitroolefins, the a,b-disubstituted nitroolefins are, in general, less reactive because of the steric hindrance and the electronic effect. To overcome this limitation, Wennemers and co-workers27 applied the peptide catalyst 110 or 111 to catalyse the conjugate addition of aldehydes 80 and a,b-di-substituted nitroolefins 109. The reaction gave rise to the c-nitroaldehydes 112 in good to excellent yields, dr and ee (Scheme 21). Upon the chemical conversion shown in Scheme 21, the c-nitroaldehyde 113 was further transformed into c-butyrolactam 115. Subsequently, Ma and co-workers28 found that introducing of an additional electron-withdrawing group (such as ester) could improve the reactivity of a,b-substituted nitroolefins 116. As a result, the adducts 117 were obtained with up to moderate yield and dr, together with excellent ee (Scheme 22). Furthermore, in the presence of Pd(OH)2, polysubstituted pyrrolidine 119 could be facilely produced from the Michael adduct 118 (Scheme 22).

H N

H N

COOH

N

COOH

N O

O

O

110

NH

CONH2

O

CONH2

NH

111 112 R2

O

O R

+

H R

NO 2

2

110 or 111 (5 mol%) CH 3 Cl3 /iPrOH

R3

1

80

1

N H

113

Ph

TsCl, NEt 3

MeOH

Me

Et

Ph

Et NO2 H 2 , Pd(OH)2 /C

Et

R

yield: 59-98% ee: 92-99%

Ph

H

3

R

109

O

NO 2

H

Me

CH 2 Cl2

N

Me

Ts

114

115

Scheme 21.

The utilisation of nitrodienes as the Michael acceptors has been a challenging task in organocatalysis. In 2010, Ma and co-workers29 reported an organocatalytic Michael addition of ketone 120 to a,b-c,d-unsaturated nitrodiene 121. The reaction was efficiently catalysed by the saccharide-derived bifunctional thiourea 122. In all experiments, the c-nitro carbonyl compounds 123 were formed in moderate to excellent yields and high to excellent ee. Only 1,4addition instead of 1,6-addition occurred in all the cases. Moreover, the typical Michael adduct 124 could be easily transformed into the 2,4-di-substituted pyrrolidines 126 and 128 in several steps (Scheme 23). 3.1.2. Stabilised carbanions as the Michael donor Besides nitroolefins as the Michael acceptors, other N-containing substrates, such as the stabilised carbanions, are ideal Michael donors for synthesising the substituted pyrrolidines via the multistep strategy. Despite that some progress has been made in this

Ph

CHO

+

R

O 2N

Ph OTMS 99 (10 mol%) N H

NO 2

CHO

98

O 101 (97% ee)

102 Br

N

H N

CH3 O

Scheme 19.

O

CH3 O

OHC

CO 2Et

O2 N

116

CO 2Et NO2

PhCO2 H (10 mol%) CH 2 Cl2 , rt

117 CO2Et OHC

NO2

R1 R yield: 37-83% dr: 48:9:17:26 to 97:3 ee: 95 to >99% CO 2Et

1) Pd(OH)2 , H 2, MeOH 2) TsCl, TEA, CH2 Cl2

103 61% yield dr > 95:5, 97% ee

82 (10 mol%)

+

80

H N

1) Pd(OH)2 , H 2, rt 2) K2CO3 , DMF

R1

O

O yield: 62-91% dr: 94:6-97:3 ee: 93-98%

O2 N CHO

R

H

R

chloroform or toluene, rt

OH 97

100

75% yield 118

Scheme 22.

N Ts 119

Me

791

M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794 PivO O PivO PivO

Ar 120

Ph

S

O

OPiv

N H

+ NO 2

PhCO 2H (5 mol%), CH 2Cl2 , rt

121

O

O

Ar * yield: 56-90% ee: 84-98%

O OtBu

N

O

135

Ph CO2 H O3

2 steps N R1 125 (98% ee)

O

Ph

Ph

N R1 126

Ph

124

CO2 H Ph

Ph

N R1 127 (92% ee)

N R1 128

Scheme 23.

aspect, the types of the stabilised carbanions being used are still limited so far. Considering the importance of trans-3-substituted proline scaffolds, our group30 recently developed an organocatalytic asymmetric Michael addition reaction of nitro esters 129 to a,b-unsaturated aldehydes 2. With the use of diarylprolinol silyl ether 130 as the organocatalyst, the reaction afforded the desired products 131 in high to excellent yields and excellent ee. To demonstrate the utility of this methodology, we further developed a facile five-step protocol for the enantioselective synthesis of trans-3-substituted proline derivatives 132 with high dr and excellent ee. Furthermore, by using the organocatalytic Michael addition as the key step, we accomplished the concise synthesis of L-pyrrolysine31 133 in six steps (Scheme 24). Feathered with the mild reaction conditions, inexpensive reagents and simple procedures, the phase-transfer catalysis is a powerful strategy being used in organic synthesis. In 2011, Tan and co-workers32 synthesised the pentanidium chloride 136 from commercially available starting materials. As an excellent chiral phase-transfer catalyst, 136 was successfully applied to catalyse the enantioselective Michael addition of tert-butyl glycinate benzophenone Schiff base 134 to chalcones 135. Obtained with high ee, the adduct 138 could be further converted into the substituted pyrrolidines 140 via the cyclisation and reduction sequence (Scheme 25). In 2012, Maruoka and co-workers33 achieved the organocatalytic asymmetric Michael addition of N-(diphenylmethylene)glycine ester 134 to cyclopent-1-enecarbaldehyde 141 by using the chiral

O2 N

CO2 R1

R3

H 2

129

PhCO 2H (10 mol%) toluene or Et2 O, 0 oC

s te p 3

R H N

N

CO 2Li

O

NH2

133 (L-pyrrolysine)

Scheme 24.

=M

e

R 1O 2C

R2

CHO

NO 2 yield: 44-96% dr: 1:1-1:1.7, ee: 43-99% 4 steps R2 = H

Ph2 C=N

140 (92% ee)

CO2 tBu 1) silica gel

OHC

2) Pd/C, H2

134 R

R CO 2tBu

N H

CO 2 t Bu

R = Ph 54% yield (3 steps), dr > 20:1, 91% ee

CHO 2

1) (S)-146 (2 mol%) 2) silica gel 3) Pd/C, H 2

N H

143 93% ee 75% yield (2 steps)

yield: 71% dr: 93:7, ee: 93%

144

R = n-Pr 55% yield (3 steps), dr > 20:1, 83% ee

Ar

Ar

Br

Br

R3

N

N

CO 2H N Cbz 132 dr > 20:1, up to 97% ee

CO2 tBu

CHO

CO 2t Bu

R3

N H

For quick and efficient construction of complex molecules from readily available agents, the cascade reactions have been intensively explored over the past decades. The capability of promoting distinct reactions via different activation modes has rendered organocatalysts well applicable in the cascade reactions as well.35

N=CPh2

131

Ph

139

142

Ar OTMS

6s

CO2 tBu MeOH

3.2. Cascade or one-pot reaction

(s,s)-145 (2 mol%) Cs2 CO3, Et2 O, 0 oC

Ar = 3,5-(CF3 )2 C6 H3 130 (10 mol%)

O

N

3.1.3. Organoselenium as the Michael acceptor Although a variety of substrates have been explored in asymmetric Michael reactions, applications of the selenium reagents for constructing the pyrrolidine derivatives have received little attention. In 2012, Marini and co-workers34 demonstrated that the addition reaction of indanone carboxylates 147 to vinyl selenone 148 could eventually result in the formation of 150 with complete diastereoselectivities and high ee after cyclisation and reduction (Scheme 27). The obtained products possess the general indeno[1,2-b]pyrrolidine skeletons in many pharmaceuticals.

Ar

R2

Ar NaBH 4

phase-transfer catalyst 145. The reaction provided the desired Michael adducts 142 in good yields, together with excellent dr and ee. As a core scaffold of telaprevir, the bicyclic amino acid 143 could be easily synthesised from the Michael adduct 142 via the hydrolysis/ imine formation and the subsequent reduction (Scheme 26). To further expand the practical use of this synthetic method, the chiral 3-substituted prolines 144 were successfully synthesised through the similar strategy. These two examples of phase-transfer catalysis32,33 could work on the gram-scale, and thus exhibited the practical and efficient entries towards the pyrrolidine synthesis.

141

N H

H R2 yield: 71-98% ee: 85-94%

Scheme 25.

O3

2 steps

H

Ar

O

Ph

Ph

O2 N

CPh 2 N CO2 tBu 15% citric acid H H THF Ph Ph Ar Ar = 4-ClC6 H 4 138 (92% ee)

CPh 2 N CO2 tBu

Cl-

R2 CsCO3, mesitylene, -20 o C R 1

R1

134

N

136 (2 mol%)

+

Ph2 C N

137

Ph N

O 2N Ph

N

Ph

123

NH2

122 (15 mol%)

Ph

Ph N

N H

Ar

Ar

145

146

Ar: 3,5-[3,5-(CF3) 2-C6H3]2-C6H3

Scheme 26.

O

792

M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794 149 O

O R1 CO 2t Bu +

151 or 152 (5 mol%)

SeO 2Ph

toluene, rt

R2 3 147 R

CO2 tBu

R2 R3

148 OH

4 steps

OH

N

H

O

H N

N

R1

O N

SeO2Ph

R1

N

CO2 tBu

R2 151

R3

152

150 ee: 20-98% yield: 40-70%

Scheme 27.

The typical examples of applying organocatalytic cascade reactions towards the pyrrolidine synthesis are thus presented herein. 3.2.1. Amine-catalysed cascade reaction The secondary amine organocatalysts are able to combine the enamine and iminium activation modes and, therefore, are widely applied in the amino-catalysed cascade reactions.36,37 In 2010, Cho and co-workers38 reported the cascade conjugate addition-aldol reactions catalysed by diarylprolinol silyl ether 130 for the synthesis of chiral pyrrolidines (Scheme 28). In the presence of 130 together with PhCO2H as the additive, the catalytic reaction between 2-trihaloacetylpyrroles 153 and a,b-unsaturated aldehydes 2 could provide the chiral pyrrolidines 154 bearing three consecutive stereogenic centres in high to excellent yields, dr and ee. Remarkably, the pyrrole containing the electrophilic carbonyl functionality plays a dual role in the cascade reaction: it acts as both the nucleophile during the initial conjugate addition and the electrophile in the following aldol reaction. As shown in Scheme 28, the proposed catalytic cycle includes the formation of iminium-ion I and of the subsequent enamine intermediate II. 5-Hydroxyproline derivatives are widely distributed in nature products, pharmaceuticals and organocatalysts. The typical iminium–enamine cascade for the synthesis of 5-hydroxyproline derivatives was presented by Córdova and co-workers39 in 2012. The reaction between a-cyanoglycine esters 155 and a,b-unsaturated aldehydes 2 was catalysed by diaryl-prolinol silyl ether

154 R2

R3

O O +

R1

N H 153

R3

1) 130 (20 mol%) PhCO2H (40 mol%)

H

2

R

N OH R1 R yield: 46-88% dr: >20:1, ee: 90-98%

2) NaBH 4 , EtOH

R4

OH R4

catalyst 82, producing the important 5-hydroxyproline derivatives 156 with moderate to high yields, dr and ee (Scheme 29). The Michael/hemiaminal cascade reaction tolerated a variety of aryl substituted aldehydes 2. Moreover, the 5-hydroxyproline derivatives 156 bearing a quaternary stereocentre are versatile intermediates for the synthesis of other proline derivatives. In 2012, an enamine-iminium cascade protocol was developed by Kumar and co-workers40 for producing the 2,3-di-substituted pyrrolidines 159. Catalysed by L-proline, the direct Mannich-cyclisation cascade (as a formal [3+2] annulation) proceeded well, providing the desired products 159 in moderate to high yields, together with excellent dr and ee. The reaction started with an enamine activation of succinaldehyde 158, followed by the Mannich reaction with N-PMP aldimines 157. The products 159 were accordingly formed through the subsequent hemiaminal cyclisation and intramolecular reductive amination. Many N-PMP aldimines were applicable to this reaction, however, the electronrich arylimines and alkyl imines failed to deliver the desired products due to the poor reactivity (Scheme 30). Amine/amide organocatalysts can also contribute to the cascade reactions for the assembly of chiral pyrrolidines. In 2013, Huang and co-workers41 disclosed an efficient cascade approach for the synthesis of 2,3,5-tri-substituted pyrrolidines. Catalysed by amine/amide cinchona alkaloid derivative 162, the reaction began with an organocatalytic asymmetric reversible aza-Henry reaction between the substrate 161 and aldimines 160. It was then followed by a subsequent DKR (dynamic kinetic resolution) aza-Michael cyclisation, leading to the formation of tri-substituted pyrrolidines 163 with high ee and moderate yields. Both aromatic and aliphatic aldimines with different substituents were tolerated. Particularly,

R 2

156 O R1

O

CN N H

CO2 Et

+ H

2-FC 6H 4CO2 H (10 mol%) R MeOH, -20 oC

Ar Ar

N

Ar OTMS

N

R4

O

153

I

N

R3

R

Ar OTMS

155

2

II

R

H2 O

R

Ar N H OTMS 130

R3 154

H 2O

Scheme 28.

N

HO N

R2

O

R1

yield: 55-90% dr: 67:33 to >95:5 ee: 95.5:4.5 to 98:2

159

Ar

Ar

CN CO 2Et

N

1

2 R4

HO

Scheme 29.

R 2

R

82 (20 mol%)

Ar OTMS

PMP

CHO

N

+ R

R

157

CHO

OH 1) L-proline (20 mol%) R N PMP yield: 56-78% dr: >25:1, ee: 90 to >99%

2) AcOH, NaBH4 , MeOH

158

R1

Scheme 30.

793

M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794

N

H

H N

H

MeO

O

N R

162 (10 mol%)

+ O N 2

OEt

160

MeO

163 O2 N

N

O

TS

toluene, rt, 24 h

161

BocHN

MeO

O2 N

CO2 Et N Ts yield: 72-95%, ee: 90-97% R

Bn N

MeO

5 steps

3 steps

N MeO

MeO

O

O 165 (99% ee)

N Ts 164 (90% ee)

N Ts

CO2 Et

CO 2Et

MeO 166 (90% ee)

Scheme 31.

CF3

F3C

MeO 2C N

CO2 Me

PG

MeO2 C

N

Ar = 2,6-(EtO)2-C6H3

CO2Me

PG Ar CO2Me MeO2 C yield: 76-99%, ee: 75-94%

CO 2Me

167

168

NHNs

R 181

183 Br

N

N

CH 2Cl2, rt

MeO2 C

N

O

170

N H

169 (10 mol%)

+ Ar

N H

Ar NH

S

S

182 (10 mol%) n-hexane/CHCl3 (1:1) NBP, -78 to -50 o C

R N Ns yield: 56-98% ee: 47-91%

Scheme 32. Scheme 34. NHSO 2CF3 PMP

N

CO 2Et 171 + CHO 172

Ar

177

N H 173 o 173 1) (10 mol%), DMF, -40 C 2) then 175, CH 2 Cl2 , rt 3) then CF3 CO2 H, CH2 Cl2

CO 2Me

Ar N PMP

CO 2Et

yield: 20-54%, ee: 87-99%, dr > 20:1 173

CF3 CO2 H CHO

Ar

Ph 3P

CO 2Me

CO2 Me 175

HN CO 2Et PMP 174

Ar

CO2 Me

CO2Me 2 steps N

N

2 steps

HN CO2 Et PMP 176

N

4. Other strategies

CO2 Et

NC N PMP 179

CO 2Et

N PMP

CO2 Et

178 (99% ee)

3.2.3. One-pot reaction Considering the importance of chiral N-heteroarylmethylenesubstituted pyrrolidine derivatives, Jean et al.43 developed a one-pot sequence of organocatalytic asymmetric Mannich/Wittig-Horner olefination/hydroamination for the synthesis of trisubstituted pyrrolidines. Catalysed by 3-aminopyrrolidine-based 173, the asymmetric one-pot reaction proceeded well between 2-pyridyl substituted aldehyde 172 and imine 171, affording the desired products 177 in moderate yields and excellent ee. The typical product 178 could be easily transformed into the useful pyrrolidine derivatives 179 and 180 in two steps (Scheme 33).

HN CO 2Et 180

Scheme 33.

the useful intermediate 164 could readily be converted into the bicyclopyrrolidine derivatives 165 and 166 (Scheme 31). 3.2.2. Thiourea-catalysed cascade reaction In 2010, Enders and co-workers42 reported a thiourea-catalysed domino Mannich/aza-Michael addition of N-protected aryl aldimines 167 and c-malonate-substituted a,b-unsaturated esters 168. This cascade reaction was carried out in DCM and catalysed by the bifunctional thiourea catalyst 169, yielding the desired 2,3,5-tri-substituted pyrrolidines 170 in moderate to excellent yields and ee (Scheme 32).

As a complementary approach, the organocatalytic bromoaminocyclisation strategy could also efficiently provide the substituted pyrrolidines. Although halocyclisation process is an effective method for the construction of heterocyclic skeletons, the application of catalytic halocyclisation towards the synthesis of substituted pyrrolidines was not exploited until 2012. By that time, Yeung and co-workers44 developed an organocatalytic bromoaminocyclisation of trans-1,2-di-substituted olefinic amide 181. In the presence of amino-thiocarbamate 182 as the catalyst, the desired 2-substituted 3-bromopyrrolidine 183 was produced in high to excellent yields, dr and ee (Scheme 34). Moreover, the building block 183 could be converted into other biologically relevant substituted pyrrolidines. 5. Conclusions Because pyrrolidines are important structural motifs found in many natural products, drug candidates, ligands and organocatalysts, the research interest in the asymmetric synthesis of polysubstituted pyrrolidines has been continuously increasing. Tremendous efforts have been devoted recently to the synthesis

794

M.-Y. Han et al. / Tetrahedron Letters 55 (2014) 784–794

of chiral polysubstituted pyrrolidines through asymmetric organocatalysis. The versatile methodologies, such as [3+2] cycloaddition, sequential approach and bromoaminocyclisation, have been successfully employed for constructing the chiral pyrrolidine scaffolds. Though many activation modes in organocatalysis have been incorporated into the synthesis of chiral pyrrolidines, there are still many limitations for the substrates and the construction strategies. One of the key problems is that, although several stereogenic centres can be simultaneously constructed via the [3+2] cycloaddition in one step, the desired stereochemistry is hard to control for each chiral centre. In order to resolve this problem, many research groups have been developing the sequential approach to preciously control the stereochemistry for each chiral centre so as to synthesise the polysubstituted pyrrolidines with different steric configurations. In these cases, however, a long-step synthesis is often required which may limit their practical applications in the future. Considering the advantages of organocatalysis, further research in this field will probably focus on exploiting mild, facile and efficient strategies towards the construction of the polysubstituted pyrrolidines with well-controlled steric configuration. Moreover, the development of new strategies should be more oriented to the synthesis of natural alkaloids, drug candidates and functional proline derivatives. Acknowledgments We are grateful for the financial support by the National Natural Science Foundation of China (No. 21172103), the 111 Project, and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: IRT1138). References and notes 1. For selected reviews, see: (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247; (b) Hanessian, S. ChemMedChem 2006, 1, 1300; (c) Pyne, S. G.; Tang, M.-Y. Curr. Org. Chem. 2005, 9, 1393; (d) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773; (e) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825; (f) Pearson, W. H. In Studies in Natural Product Chemistry; Atta-Ur-Rahman, Ed.; Elsevier: New York, 1998; p 323. Vol. 1. 2. For selected reviews, see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (b) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416; (c) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005. 3. For selected reviews, see: (a) MacMillan, D. W. C. Nature 2008, 455, 304; (b) Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Nature 2008, 455, 323; (c) List, B. Chem. Rev. 2007, 107, 5413; (d) List, B.; Yang, J. W. Science 2006, 313, 1584; (e) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (f) Houk, K. N.; List, B. Acc. Chem. Res. 2004, 37, 487. 4. For selected reviews, see: (a) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156; (b) Pandey, S. K Tetrahedron: Asymmetry 2011, 2, 1817; (c) Companyó, X.; Alba, A.-N.; Rios, R. Targets Heterocycl. Syst. 2009, 13, 147; (d) Vicario, J.; Badia,

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