Review de L-prolina y Sus Derivados en Sintesis Asimetrica

8/13/2019 Review de L-prolina y Sus Derivados en Sintesis Asimetrica

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Tetrahedron: Asymmetry Report Number 138

Advances in the chemistry of proline and its derivatives: an excellent amino acid

with versatile applications in asymmetric synthesis

Sharad Kumar Panday

Department of Chemistry, Faculty of Engineering and Technology, M. J. P. Rohilkhand University, Bareilly, U.P., India

a r t i c l e i n f o

Article history:

Received 29 July 2011Accepted 27 September 2011

Available online 4 November 2011

a b s t r a c t

Non-proteinogenic prolines have been acknowledged as an important pool for the synthesis of conform-

ationally rigid bioactive peptides, angiotensin converting enzyme inhibitors and as pharmacologicalprobes. Proline and its derivatives are often used as asymmetric catalysts in organic reactions, such as

CBS reductions and proline catalyzed aldol reactions, Mannich reactions, and so on. FurthermoreL-proline

is an osmoprotectant and is therefore frequently used in many pharmacological as well as biotechnolog-

ical applications. The wide range of chemical and biological applications associated with L-proline has

prompted researchers to develop new methodologies for the synthesis of prolines and substituted pro-

lines and to further explore their chemical and biological applications. The present article is an attempt

to discuss all the major advances available till date, describing the use of proline in organic asymmetric

synthesis, the synthesis of various bioactive molecules or proline as a constituent part of bioactive

molecules.

2011 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1818

2. Structure and synthesis of proline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1818

3. Advancements in the chemistry of proline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1819

3.1. Proline as an organocatalyst. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1819

3.1.1. Proline catalyzed asymmetric aldol condensations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1820

3.1.2. Proline catalyzed asymmetric Mannich reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1822

3.1.3. Proline catalyzed asymmetric Michael additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1823

3.1.4. Proline catalyzed amination and aminoxylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824

3.1.5. Proline catalyzed oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824

3.1.6. Proline catalyzed DielsAlder reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824

3.1.7. Proline catalyzed cyclopropanation/nucleophilic substitutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824

3.1.8. Proline catalyzed oxidative and reductive cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825

3.1.9. Synthesis of heterocycles through a proline catalyzed multicomponent reaction strategy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825

3.1.10. Proline catalyzed reduction and reductive alkylations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825

3.1.11. Studies on microwave assistance in proline catalyzed organic reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825

3.2. Replacement of proline with modified proline derivatives and their outcome as organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18263.2.1. Different proline amides as organocatalysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1826

3.2.2. Substituted prolinol derivatives as organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1827

3.2.3. Replacement of the carboxylic group of proline with tetrazole moiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1827

3.2.4. 4-Substituted prolines as organocatalysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1827

3.2.5. A recoverable fluorous CBS methodology using fluorous prolinol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1828

3.2.6. Suitably derivatized proline derivative as heterogeneous catalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1828

3.2.7. Prolinal dithioacetals as organocatalysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1828

3.2.8. Ionic liquid supported proline as organocatalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1829

3.3. Proline as a metal ligand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1829

3.4. Differentially substituted prolines: asymmetric synthesis and applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1832

0957-4166/$ - see front matter 2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.tetasy.2011.09.013

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Tetrahedron:Asymmetry22 (2011) 18171847

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3.4.1. 2-Substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1835




3.4.5. Synthesis of multi-substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1841

3.4.6. N-Acylation of proline derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1842

3.4.7. Synthesis of azanucleosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1844

3.4.8. Reduction of the carboxylic functionality of proline: asymmetric synthesis of (+)-hygrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845

3.4.9. Synthesis of enantiopureb-endo-substituted aza bicyclic proline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18454. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845

1. Introduction

Proline and substituted prolines can be found in many a natu-

ral1 and synthetic2 bioactive products. The last three decades have

witnessed a large increase in the number of publications on the

chemistry and biology of many products where substituted pro-

lines act as essential components of the target molecules.Non-proteinogenic prolines have emerged as important inter-

mediates due to their use in the synthesis of conformationally rigid

bioactive peptides,310 angiotensin converting enzyme inhibitors

and as pharmacological probes.11,12 Proline and its derivatives

are often used as asymmetric catalysts1322 in organic reactions

such as CBS reductions, proline catalyzed aldol reactions, Mannich

reaction, and so on. Furthermore, L-proline is an osmoprotectant23

and is therefore frequently used in many pharmacological as well

as biotechnological applications. As a result of this, the asymmetric

synthesis of proline derivatives coupled with exploring the possi-

bilities for their chemical and biological uses has become an area

of interest in proline chemistry, and much attention has been paid.

In addition to synthetic methodologies for the synthesis of 2, 3, 4,

and 5-substituted prolines being available,2432 the angiotensinconverting enzyme inhibitory potential of N-acyl derivatives of

substituted prolines has also been well established.33,34 Herein

the aim of the present article is to discuss all of the major advances

available to date, describing the use of proline in organic asymmet-

ric synthesis, the synthesis of various bioactive molecules, or as a

constituent part of bioactive molecules.

2. Structure and synthesis of proline

Proline1 is an a-amino acid. It is not an essential amino acid,suggesting that the human body is capable of synthesizing it. It

is a unique amino acid among 20 natural amino acids in the sense

that, the a-amino group is secondary in nature. In neutral media, it

exists as zwitterion 2 (betaine type structure)35,36 (Fig. 1).

An early synthesis of racemic proline was carried out3537 by

the Michael addition of acrylonitrile to diethyl malonate. Catalytic

hydrogenation followed by treatment with thionyl chloride affords

compound7. Compound7, upon treatment with hydrochloric acid

followed by alkaline hydrolysis and subsequent treatment withhydrochloric acid afforded racemic proline 1 (Scheme 1).

NH

COOH NH2

C O

O-

1 2

Figure 1. Structure of proline.

CN

Ni/H2H2N HN

(EtOOC)2

O

COOEt

HN

O

COOEt

Cl HCl

NH3COOH

Cl+

i) OH -

ii) HClNH2

COOH NHCOOH

CH2(COOEt)2 + CHCH2CH2CN

EtOOC

SOCl2

Cl-

-HCl

EtO-

3 45

6

78

9 1

COOEt

Cl

-

Scheme 1.

NH

O CO2HTriethyloxonium fluoroborate

NaBH4 NH

CO2H

10 1

NH

OCO2H NaBH4

NH

CO2H

11 12

Ph Ph

BH3THF

(i)

(ii)

Scheme 2.

O

O

O

L-proline, DMFMe

OHO

O

99%, 93%ee13

14

Scheme 3.

1818 S. K. Panday/ Tetrahedron:Asymmetry22 (2011) 18171847


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Various synthetic strategies have been reported for the asym-

metric synthesis of prolines.38,39 One of the earliest synthetic strat-

egies was developed starting from pyroglutamic acid38a via the

reduction of the lactam carbonyl. Pyroglutamic acid 10 has been

transformed into L-proline in a one pot, two step reaction.38

Theconversion involved the treatment of pyroglutamic acid 10 with

triethyloxoniumfluoroborate and reduction of the resulting crude

imino ether with sodium borohydride (Scheme 2, i).

An alternative procedure for the reduction of pyroglutamates to

prolines has been developed by Rapoport et al.,39 where (2S)-

trans-4-phenylpyroglutamate 11was converted into 4-phenyl pro-

linate 12 by reduction with BH3THF, followed by the reduction of

resultant crude compound with sodium borohydride (Scheme2, ii).

3. Advancements in the chemistry of proline

3.1. Proline as an organocatalyst

The beginning of 1970s may well be remembered as a turningpoint in the history of organo catalyzed asymmetric reactions,

when proline was first investigated as a small molecule in the

HajosParrishEdersauerWieahert reaction.40 In this reaction,

naturally occurring L-proline was employed as an asymmetric cat-

alyst in an aldol reaction,40 where the starting material was trike-

tone 13, and only a small quantity (3%) of proline was required to

furnish the reaction product, ketol 14, in 93% enantiomeric excess

(Scheme 3).

Since the discovery of above successful proline catalyzed aldol

reaction, great strides have been made in understanding and

exploring the newer routes and strategies for various asymmetric

reactions catalyzed by L-proline or its derivatives.1322 Proline is

now regarded as an efficient and important organocatalyst in sev-

eral asymmetric transformations, such as aldol reactions, crossedaldol reactions involving different aldehydes as donors or

acceptors, Mannich reactions involving ketones, aldehydes, and

amines, Michael additions involving ketones and aldehydes,

N CO2HH

Asymmetric aldol,crossed aldol,intramolecular aldolreactions etc.

Mannich reaction

Michael addition

Diels - Alderreaction

SN2 alkylation

Amination,aminoxylation

1

Synthesis of heterocyclesReductivealkylations

Oxidations

Reductions

Figure 2. The spectrum of proline as organocatalyst in organic reactions.

NH

COOHN

Me R

Bi functional catalysis Iminium catalysis

NCO2H

Enamine catalysis

CO2-

R

Figure 3. Possible modes of proline catalysis.

O

20 vol%

+ H

O

NO2

L-proline

30 mol%DMSO

O

NO2

OH

68%(76%ee)15 16 17

Scheme 4.

O

MeR2

+NH

O

OH

-H2O

H2O N

O

O

Me

R2H

N

HO

O

Me

HR1CHON

OH

O

R2Me

R1

OH

H

Transition state

N

HO

O

Me

HR

2

OH

R1 H2O

-H2O

NH

O

OH

R1 Me

R2

OH O

+

N

O

O-

H

R2

Me

R1

H

O H

metal- free Zimmeraman- Traxler model

18 1 19

20

21

22

1

R2

Figure 4. Mechanism of the aldol reaction.13,1921,42

HR1

H R2

O O

+ L-proline

10 mol%, DMF, 4oC H R2

O OH

R1

23 24 25

Scheme 5.

S. K. Panday / Tetrahedron:Asymmetry22 (2011) 18171847 1819
http://-/?-http://-/?-


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additions to imines, nitro alkenes, in addition to many other reac-

tions as well (Fig. 2). The reactivity and enantioselectivity of pro-

line catalyzed reactions amount to a series of interactions

involving proline that are comparable to enzyme catalyzed reac-

tions,41 such as substrate recognition, transition state stabilization,

and the resulting formation of the product. Due to these similari-

ties Movassaghi and Jacobson have regarded proline as the sim-

plest enzyme.41

Proline is the only natural amino acid with a secondary amine

functionality, which raises the pKavalue and induces better nucle-

ophilicity when compared to other amino acids. There are several

modes by which proline is capable of exerting its catalytic activ-

ity,19 that is, it could be bifunctional catalysis, iminium catalysis,

or enamine catalysis (Fig. 3).The excellent enantioselectivity of proline as a catalyst can

be accounted for due to the formation of a highly organized transi-

tion state with a systematic framework of hydrogen bond-

ing.13,17,1921,42 Due to the unique behavior of proline as an

organocatalyst, the last two decades have witnessed a large in-

crease in the number of publications exploring various reactions

and reaction methodologies, whereby proline has been successfully

employed as a catalyst for achievingthe desired chemical or stereo-

chemical outcome.1322 A fewof themore importantapplications of

proline as an organocatalyst are discussed in the current section.

3.1.1. Proline catalyzed asymmetric aldol condensations

Investigations of L-proline as an important organocatalyst pri-

marily in aldol reactions,40 led researchers to further explore itsapplications toward a variety of aldol reactions and to establish

it as one of the best catalysts for various other similar reactions.

Even though the first application of proline as an asymmetric cat-

alyst was explored in the early seventies,40 the detailed investiga-

tion was carried out by List et al. in 2000,13 when the direct

asymmetric aldol reactions of ketones and aldehydes using L-pro-

line as a catalyst were described, whereby product formation oc-

curred with high enantiomeric excess13,43 (Scheme 4).

3.1.1.1. Mechanism of proline catalyzed aldol reactions. The

earlier probable mechanism for proline catalyzed aldol reactions,

as explained by List et al.13,17,1921,42 is shown inFigure 4. In aldol

reactions, proline executes its action through enamine catalysis.

Enamine20, is formed from the pyrrolidine nitrogen and the car-bonyl donor. Iminium ion21, created by the attack of the enamine

on there-face of the aldehyde, is subsequently hydrolyzed to afford

an asymmetricb-hydroxyl ketone. It is postulated that the reaction

OHC CHO L-proline

CH2Cl2, rt, 12h95%

OH

OHC

99%ee

26a 26b

Scheme 6.

HO

HO

CO2H

CO2H

L-(+)-Tartaric acid

L-proline(15 mol%)

Direct 6-enolexoaldolization

NTsNTs

OHOHO

O

OH OHO

O

70%

dr>10:1

27a 27b

Scheme 7.

HCH3

CH3

H3C

H

OO

+ H

OOH

CH3

i. (R)-proline

ii. TBSOTf

i.

OTMS

OBut , BF3

ii. HCl

O

O

OHCH3

Prelactone B

28 29 30

31

Scheme 8.

H

OL-proline

Acetone

O OH

OH

(S)-Ipsenol

32 33

34

Scheme 9.

H3C

OH

O

+H R

O

H3C

O OH

OH

R

L-proline, 20 mol %

DMSO

35 24

36

Scheme 10.

HR

O

+

O

CO2EtEtO2C

L-proline, 20mol%CH2Cl2, rt, 3h

H

OH

R

OCO2Et

CO2Et

35 37

38

Scheme 11.



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proceeds through a transition state following a synclinical ap-proach of the aldehyde, where the alkyl or aryl substituent of alde-

hyde occupies a pseudo equatorial position. The stereochemistry is

controlled by a hydrogen transfer between the carboxylate on the

proline and the oxygen of the aldehyde, thus providing the

enantioselectivity.

However in recent years, scientific debates have been made to

study the mechanistic aspects as well as the role of water as a sol-

vent, or added in small amounts to the organic solvents; all of

these features have been well discussed.19,20

3.1.1.2. Scope of proline catalyzed aldol reactions. The investi-

gations on proline catalyzed aldol reactions, were extended further

to encompass a wide variety of ketones and aldehydes, during

which, reactions between two dissimilar aldehydes using prolineas a catalyst were attempted, similar to those in traditional crossed

aldol reactions, where dimerized products were obtained with

excellent enantioselectivity44 (Scheme 5).L-Proline catalyzed intramolecular aldol reactions have also

been accomplished45 successfully (Scheme 6) and direct catalytic

asymmetric enol-exo-aldolizations have been reported. This pro-

cess made it possible to synthesize substituted cyclohexanes in

excellent diastereo and enantioselectivity, for example, heptane-

dial26a, is converted into the corresponding cyclicanti-configured

aldol26b in 99% enantiomeric excess.The successful accomplishment of L-proline catalyzed direct

diastereoselective 6-enol-exo-aldolization enabled Kumar et al. to

develop a synthetic strategy46 for imino sugars starting from tar-

taric acid (Scheme 7). This proline catalyzed approach provided

high levels ofsyn-selectivity (dr >10:1) with stereocontrolled CC

bond formation between C4 and C5, which in turn could serve to

synthesize the imino-sugar skeleton.

An (R)-proline catalyzed aldol reaction enabled Pihko et al. to

synthesize prelactone B 31, in four steps from isopropylaldehyde

and propaldehyde.47 A direct proline catalyzed aldehyde-aldehyde

aldol reaction was employed, as the exclusive source of asymmetry

(Scheme 8).

The use ofL-proline as an asymmetric catalyst in the aldol reac-

tion allowed a concise synthesis of (S)-ipsenol 34 to be investi-gated48 starting from 3-methyl butyraldehyde (Scheme 9).

R1

O

+NH

CO2HN CO2H

R1

H

N CO2H

R1

H

R3 H

O

+

NH2

OMe N

R3 H

H2O

-H2O

N

R1

H

R3 N

O

OH

N O

O-

R1

R3

NH

PMP

R3

O

R1

NH PMP

42

24

40

43

44

R2

R2 R2

R2R2R2

41

39

Transition state

PMP

OMe

Figure 5. Probable mechanism for the proline catalyzed Mannich reaction.17,1921

R1 R2

O

CO2Et

R1

O

R2

NHPMPL-proline

20 mol%DMSO

+

H

NPMP

CO2Et

39 45 46

Scheme 13.

+ NPMP

H CO2Et

HR

O i. L-prolineTHF, rt, 16-20 h

ii. Et2AlCN NC CO2Et

OH

R

NHPMP

23 45 48

Scheme 14.

O

R + 2

CHO

X

+ NH3

XNH

R

O

X

L-proline

30 mol%

4950

51

Scheme 15.

R2

O

+H R

3

O

+

NH2

OMe

L-proline, DMSO

5-35 mol%

R3

O NHPMP

R2

R1

R1

99% ee

39 24 40

41

Scheme 12.



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Proline catalyzed asymmetric aldol reactions and their success-

ful outcome encouraged Sakthivel et al. to synthesize anti-diols

3649 by the reaction of hydroxyl acetone35with aldehydes24cat-

alyzed by L-proline (Scheme 10).

The scope of the proline catalyzed aldol reactions was further

applied to activated carbonyls, resulting in the formation of alde-

hyde aldols 3850 (Scheme 11).

3.1.2. Proline catalyzed asymmetric Mannich reactions

Parallel to the aldol reactions, proline catalyzed Mannich reac-

tions were also investigated simultaneously by List et al., 51 where-

by proline catalyzed direct asymmetric three component Mannich

reactions of ketones, aldehydes, and amines were explored. Most of

these reactions provided b-amino carbonyl compounds (Mannich

adducts) in excellent enantio, regio, and chemoselectivities

(Scheme 12).

3.1.2.1. Mechanism of the proline catalyzed Mannich reac-

tions. The mechanism of the proline catalyzed Mannich reactions

is comparable to the aldol reactions17,1921(Fig. 5), where enamine

42, is formed from proline, and an aldehyde or ketone. Imine 43,

generated in situ, is then added. The imine, upon attack by the en-

amine, creates new stereocenters in the iminium product 44,

which upon hydrolysis gives Mannich product 41, with excellent

stereoselectivity. The stereoselectivity is controlled via the transi-

tion state as shown in Figure 5.

TheE-aldimine is attacked by the enamine on itssi-face to give

the syn-product with a minimum of one new asymmetric center.

Due to the E-geometry of the aldimine, the re-face is blocked due

to the steric hindrance between the aryl ring of the p-methoxyphenyl group and the proline ring. As in the aldol reactions, the

enantioselectivity was controlled through hydrogen transfer that

prefers attacking one face of the enamine.

3.1.2.2. Scope of the proline catalyzed Mannich reactions. Once

the direct Mannich reactions were standardized, the scope of the

reaction was extended further to modified systems, where two

component modified Mannich reactions using functionalizeda-amino acids were accomplished52 (Scheme 13).

The proline catalyzed Mannich reaction was successfully

applied to a one-pot cyanation53 via reaction of an aldehyde or

ketone with an enamine using diethyl aluminum cyanide as the

R( )n

O

NX

N

R( )n

O

R( )n

O

NX

N

OH

Basic conditions

i) (HCHO)nii) Azoleiii) L-proline

DMSO, 60oC

H2O,100oC

X=CH; ImidazoleX=N;1,2,3-Triazole

52

53

54

Scheme 16.

O

+Ph

NO2

O

NO2

Ph

L-proline

15 mol%DMSO, 16h94%

ee;23%dr>20:1

55 56 57

Scheme 17.

R1

R2

O

+

R3

R4 NO2

R1 NO2

O

R2 R4

R3L-proline

10-20 mol%DMSO,rt

58 59 60

Scheme 18.

(i)H

R2O

N N

CO2Bn

BnO2C

HON

CO2Bn

NHCO2BnL-proline

10 mol%NaBH4

R2

O

R1 + N

O

R2

O

R1

+

R2

O

R1

NPh

OH

L-proline

10-30 mol%DMSO,2-3 h,rt

(ii)

23 61 62

39 63 64 65

R2

ONHPh

>99% ee 7-11%ee

O/N selectivity> 100:1 to 8:22

Ph

Scheme 19.



7/31

cyanating agent and L-proline as the catalyst to give b-cyanohydrin

48, stereoselectively (Scheme 14).

Encouraged by the outcome of the L-proline catalyzed asymmet-

ric Mannich reactions, Srinivasan et al. carried out54 the synthesisof

3-substituted-2, 6-diaryl piperidin-4-ones51, by the one pot reac-

tion of ketones49, various arylaldehydes50, and ammonia using L-

proline as the catalyst (Scheme 15).

Recently Srinivas et al. have described55 a proline catalyzed ac-

cess to Mannich adducts using unsubstituted azoles. They reported

a unified and facile approach for the direct construction of a CCN

bond with unsubstituted azoles under Mannich conditions. The

reaction was catalyzed efficiently by L-proline to give the Mannich

adduct53, in DMSO, whereas in water, insertion of two successive

bonds, CCN and CCO occurred to furnish compound 54. The

latter was readily deformylated into the desired product 53, under

basic conditions (Scheme 16).

3.1.3. Proline catalyzed asymmetric Michael additions

Efficient proline catalyzed Michael additions of unmodified

ketones into nitro olefins have also been carried56 out successfully.

RCHO R CO2Et

OTBSi) -aminoxylation, L-prolineHWE-olefination and reduction

ii) TBS-Cl ee>94%

RCO2Et

OR1 N NHCBz

CBz

R: nPr, (CH3)2, Ph, etc

-amination, L-proline

HWE-olefinationR

CO2Et

OR1 N NHCBz

CBz

HWE-olefination

-amination, D-proline

R1

: TBS; (anti/syn>40:1)

R1: TBS;(syn/anti>10:1)to 6:1; CBz= benzyloxy carbonyl

66 67

68

69

Scheme 20.

HR

O+

O

NPh

L-proline, 5mol%

CHCl3, 4oC H

ONH

Ph

O

R

R= alkyl, aryl, allyl

23 63 70

Scheme 21.

R

NO2

+

R1

O

Me

R R1

NO2

O O

R1

NO2R

L-proline

THFor CH3OHrt

i)

CF3

NO2

+

S

O

CF3

S

NO2

O

* *

*

+ CF3

S

O

* * *

NO2

L-prolineii)

59 71 72 73

74 75 76 77

R = Ph, 4-MeoC6H4, 1-naphthyl, 2-CF3C6H4R1 = Ph, 2-thienyl, 2-furylModerate selectivity for72

ratio 76:77=4:1

Scheme 22.

n-Pr O

H

MeS

Ph

OMe

+ 20 mol%CHCl3, 23

oC

NH

CO2H

CHO

COPhn-Pr

72% yield; 46% ee

78 79 80

Scheme 23.

N NCO2

- CO2-

E Z

Zwitterionic iminiumpoor iminium control

N CO2-

O

Ph

SYlide

Directed electrostatic activation

Figure 6. A probable explanation for good reactivity but diminished

stereoselectivity.



8/31

Successful accomplishment of such a reaction made it possible to

synthesizec-nitroketones 57, in reasonable enantiomeric excesscoupled with excellent yields (Scheme 17).

3.1.3.1. Scope of proline catalyzed Michael additions. The possi-

bility of proline catalyzed Michael additions has been applied suc-

cessfully to a wide variety of asymmetric conjugate additions 57,58

where the product was formed in high enantiomeric excess

(Scheme 18).

3.1.4. Proline catalyzed amination and aminoxylation

The proline catalyzeda-amination of aldehydes, as well as theaminoxylation of ketones, has been studied and accomplished with

great success; in these reactions, at least one stereogenic center is

generated with the predominance of one stereoisomer59 with high

enantiomeric excess (Scheme 19).

3.1.4.1. Scope of proline catalyzed amination and aminoxyla-

tion. The enantioselective synthesis of syn/anti-1,3-amino

alcohols via proline catalyzed sequentiala-aminoxylation/a-ami-nation followed by HornerWadsworthEmmons olefination of

the aldehydes has recently been described by Jha et al..60 Using this

methodology, they explored a short and efficient synthetic path-

way to the bioactive molecule (R)-1-(methylpyrrolidin-2-yl)-5-

phenylpentane-2-ol (Scheme 20).

3.1.5. Proline catalyzed oxidations

Proline catalyzed oxidations of aldehydes with nitroso benzenes

have been reported61 to furnish the product 70 in high enantio-

meric excess (Scheme 21).

3.1.6. Proline catalyzed DielsAlder reaction

The potential ofL-proline as a DielsAlder catalyst for the reac-tion of nitro olefins anda,b-unsaturated ketones tofurnish cyclo-hexanone derivatives has been investigated.62,63 It has been

envisaged that amine catalyzed direct DielsAlder reactions of

a,b-unsaturated ketones with dienophiles to give cyclohexanonederivatives can be carried out with moderate to good enantioselec-

tivity (Scheme 22).

3.1.7. Proline catalyzed cyclopropanation/nucleophilic

substitutions

The cyclopropane skeleton is one of the most common moieties

in the synthesis of complex molecules having defined chemical/

biological properties, due to its unique reactivity and structural

properties. As a result of this, the investigation of different strate-

gies for the construction of cyclopropane rings has receivedmuchattention. One of the synthetic strategies involves64 the

enal-cyclopropanation reaction ofa,b-unsaturated aldehydes 78,with dimethylphenylacyl sulfonium ylid 79, and a range of asym-

metric amine catalysts. In this strategy, the use of a catalytic amine

provided good reaction yield (72%) with moderate stereocontrol

(46%) (Scheme 23).

A mechanistic hypothesis for the high efficacy but moderate

stereocontrol was proposed by Kunz et al. based on the concept

of directed electrostatic activation (DEA). According to the authors,

a proline derived iminium and ylid might readily undergo electro-

static associationviathe carboxylate and thionium substituents. In

the process the ylid carbanion and the iminium b-carbon would be

transiently activated while being in close association, thereby

enhancing the carboncarbon bond formation process. Further-more, the iminium ion can equally populate both the E- and

EtO2C

EtO2C

Br +Ar

OHC 0.2 eq catalyst

H2O, rt, 96 h

EtO2C

EtO2C

CHO

Ar

catalyst:NH

Ar'

Ar'

OTMS

Ar'=3,5-CF3C6H3

81 82 83

Scheme 24.

i) OHC I

EtO2C CO2Et EtO2CCO2Et

OHC

L-proline (10%)

Et3N75%

20% ee

ii)

OHC I

EtO2C

EtO2C OHC

CO2Et

EtO2C60% ee

L-proline (10%)

Et3N75%

84 85

8687

Scheme 25.

ii)

OH3C CH3

OH(L)-proline

ZrCl4,NaBH4,THFrt, 3h

60%, 44% ee

i)

OCH3

O

L-proline(10%)Cu(OAc)2(5%)

PhCO3t-Bu, EtCO2H16h

39%, 61% ee

88 89

90 91

Scheme 26.

+

O

O

CHO

R

+ OEt

O O

+

NH

O O

R

OEt

L-proline (cat), EtOH

reflux

50 92 93 94

95

NH4Ac

Scheme 27.

R1

R2

+ R3NH2 + R4

O O

+ R5CHO

N

R4

R2

R1R5 O

R3

L-prolineEtOH,rt,50 Co

12-24h62-86%

95 96 97 24 98

Scheme 28.



9/31

Z-iminium isomers, a configurational equilibrium that is responsi-

ble for furnishing the diminished stereocontrol (Fig. 6).

Recently, the use of water as a reaction medium for the O-TMS-

diarylprolinol catalyzed cyclopropanation reaction of diethyl

bromoacetate 81 with a,b-unsaturated aldehydes 82 has beeninvestigated65 as a base free reaction system. A modified O-TMS-

diaryl prolinol incorporating hydrophobic side chains has been ex-

plored as a promising catalyst for this reaction having high effi-

ciency coupled with good stereoselectivity (Scheme 24).

Proline as an organocatalyst has been proven to be equally use-

ful in nucleophilic substitution reactions, when it showed its

ability to catalyze the intramolecular SN2 alkylations66 of diethyl-

2-(iodomethyl)-2-(2-oxoethyl) malonate84, and diethyl-2-(3-iod-

opropyl)-2-(2-oxoethyl) malonate 86, thereby furnishing the

corresponding cyclopropyl and cyclopentyl derivatives 85 and 87,

respectively, with the desired stereochemistry (Scheme 25).

3.1.8. Proline catalyzed oxidative and reductive cleavage

Proline as an organocatalyst, has also been found to be useful

toward various oxidative and reductive cleavages,67,68 as well,

which have been accomplished successfully (Scheme 26).

3.1.9. Synthesis of heterocycles through a proline catalyzed

multicomponent reaction strategyL-Proline has been effectively employed as an efficient organo-

catalyst for the synthesis of polyhydroquinolines 95,69 via multi-

component Hantzsch reaction (Scheme 27).

Likewise L-proline catalyzed synthesis of highly functionalized

multisubstituted 1,4-dihydropyridines 98 has recently been de-

scribed by Jiang et al.70(Scheme 28). These 1,4-dihydropyridines

have been synthesized in moderate to good yields via a L-proline

catalyzed one pot multicomponent reaction of alkynoates or alky-

nones95, amines 96, b-dicarbonyl compounds 97, and aldehydes

24under mild reaction conditions. The process involved hydroam-

ination/Knoevenagel condensation/Michael type addition/intra-

molecular cyclization processes and led to the formation of 1,

4-dihydopyridines.

In a similar manner Misra et al. have described

71

a highly atomeconomic one-pot synthesis of tetrahydropyridines 100 as anti-

malarials, via a L-proline/TFA catalyzed multicomponent reaction

of b-keto-esters 99, aromatic aldehydes 50, and anilines 40

(Scheme 29).

3.1.10. Proline catalyzed reduction and reductive alkylations

An efficient approach for a one-pot three component reductive

alkylation reaction of arylacetonitriles containing electron with-

drawing groups with aldehydes and ketones and 1,4-dihydropyri-

dine via an L-proline catalyzed iminium catalysis has been

described72 (Scheme 30). These reaction products 103 and 104

have direct applications in agriculture and the pharmaceutical

chemistry; for example, both have been acknowledged as useful

intermediates for non-steroidal anti-inflammatory drugs (NSAIDs).

3.1.11. Studies on microwave assistance in proline catalyzed

organic reactions

With the aim of evaluating the effect of microwave assistance

over conventional heating in (S)-proline catalyzed Mannich and

NH2 CHO

R1 R2

+ + H3C OR

O OL-proline/TFA

20 mol% N

OR

NH

R1

O

R2

R1

R240 50 99

100

Scheme 29.

H

O

R

H Ar

CNH

NH

OH H

+

O

R

H CN

Ar

R

H COOH

Ar

L-proline, 20mol%

H2SO4, 30mol%

24 101

103

104102

Scheme 30.

Me Me

O

+N

H CO2Et

OMe

Me CO2Et

O NH

OMe

90-92% (99% ee)

(S)-proline, DMSO60oC, 10 min

oil bath, orMW(49W), or

MW(207 W)

15 105 106

Scheme 31.

O

R

R=H, aryl

+ O N

O

N O

O

ON

NH

R

CO2Et

CO2Et

MeCN, L-proline

MW, 60oC, 30 min

54-97%(52-90% ee)

107 108 109

Scheme 32.



10/31

aldol type reactions (Scheme 31). Hosseini et al. attempted73 a

microwave-assisted asymmetric organocatalysis as a probe for

non-thermal microwave effects and a concept of simultaneous

cooling. After a series of reactions under different reaction condi-

tions for (S)-proline catalyzed asymmetric Mannich and aldol reac-

tions, they observed that enhancements were the result of the

increased temperature attained by microwave dielectric heating

and not due to the presence of a microwave field. According toHosseini et al. the results obtained either with microwave

irradiation or microwave irradiation with simultaneous cooling

could be reproduced by normal heating at the same temperature

and time using an oil bath.

In a similar manner, Baumann et al. have performed74 optimiza-

tion studies with regards to solvent, temperature, time, and

catalyst loading for the microwave mediated organocatalytica-amination of disubstituted aldehydes 107with diethylazodicarb-

oxylate 108. The optimum reaction conditions, as described byBaumann et al. proved to be MeCN as the solvent, 50 mol % of L-

proline as the catalyst, a reaction temperature of 60C and

30 min of reaction time. More importantly the reaction time could

be decreased from several days to 30 min by heating, as compared

to room temperature conditions with a prominent increase in effi-

cacy and enantioselectivity (Scheme 32).

3.2. Replacement of proline with modified proline derivatives

and their outcome as organocatalysts

3.2.1. Different proline amides as organocatalysts

A slight modification in the catalyst structure may change the

pKa value of the catalyst affecting the strength of hydrogen bond-

ing to such an extent that a high degree of enhancement of the cat-alytic activity coupled with stereoselectivity could be

observed.75,76 As a result, the replacement of the carboxylic group

of proline with amides/substituted amides and their use as cata-

lysts resulted in high yields, enantioselectivity, and diastereoselec-

tivity under mild reaction conditions.

Taking into consideration the above rationale, successful enan-

tioselective aldol reactions could be accomplished75 by using L-

prolinamide110as a catalyst in the place ofL-proline (Scheme 33).

Maleev et al. developed new L-proline derivatives as catalysts76

for enantioselective aldol reactions. They discovered proline

amides containing an alcohol group to be efficient catalysts in aldol

reactions, due to the fact that the pyrrolidine ring has an amide and

a hydroxyl group is capable of hydrogen bonding to the substrate

molecule to greater extent for stabilization of the enamine in anactivated intermediate (Fig. 7).

R H

OO

+

O O

R R

OH OH

+10-20 mol % cat

solvent, rt

cat.:

NH

R1

O

where R1= substituted aromatic, heteroaromaticand alicyclic amines

solvent: DMF, DMSO, CHCl3

24 55 111b

110

111a

Scheme 33.

Acid function

NH

O

N

H OH

Ph

Ph

HN

NN

N

N

H

OHN

NSH

O2

R

NH

O

O H

112

113

1

114

Figure 7. Structures of proline derivatives used as a catalyst.76

N

CH2

O

NH

N

H

O

O

-O

OH

Figure 8. An activated intermediate complex showing the possible mode of

interaction and hydrogen bonding by the proline derivative in aldol reaction.

+

O

H

O

R

NH

CO2H(20%)

ZnCl2(10%)

DMSO/H2O

(8:2)

O

R

OH

d.r. up to 16:1

e.e. up to 99%

50

55

115

(ii).

Scheme 34.



11/31

Such prolinamide derivatives have been regarded as potential

catalysts, as they contain the asymmetric pyrrolidine ring and

the amide and hydroxyl groups capable of hydrogen bonding to

substrate molecules for the stabilization of the enamine in the acti-

vated intermediate complex. In addition, these systems allow var-

iation of the steric environment for the standardization of their

catalytic properties76 (Fig. 8).

Recently, direct asymmetric aldol reactions co-catalyzed by L-

proline and group 12 element Lewis acids in the presence of water

have been described77 by Penhoat et al., who explored an approach

based on the combinations of various water compatible Lewis

acids and L-proline co-catalysts for the direct asymmetric aldol

reaction. The investigations suggested that chloride salts from

group 12 elements (ZnCl2, CdCl2, HgCl2) led to the highest stereose-

lectivities. The optimized catalytic conditions (catalytic system: L-

proline: 20%/ZnCl2: 10%; solvent mixture: DMSO/H2O, 8:2) gave

anti-aldol products 115 with improved enantioselectivity (>99%

ee) compared to the moderately stereoselective procedure based

on proline activation only (Scheme 34).

3.2.2. Substituted prolinol derivatives as organocatalysts

An elegant one pot method was developed recently by Franzen

and Fischer for the asymmetric synthesis of substituted quinolizi-

dines.78 To carry out their synthetic strategy, they standardized the

enantioselective Michael addition of cinnamic aldehyde82, and an

activated indole substituted amide 116, using different proline

derivatives (Fig. 9) as organocatalysts exploring different solvents,

temperatures as well as the various acids required at the cycliza-

tion step of the acyliminium ion.

Out of the various proline derivatives used in the reaction,

derivative 117, showed the best activity78 (Scheme 35).

An asymmetric alkylation of aldehydes with allyltintribromide

was achieved using L-proline derivative124, as an asymmetric cat-

alyst in dichloromethane in the presence of a Lewis base.

79

Thesynthesis of various optically active homoallylic alcohols 123 in

high yields, but with moderate enantioselectivity of up to 62%

enantiomeric excess has been reported (Scheme 36).

3.2.3. Replacement of the carboxylic group of proline with

tetrazole moiety

Cobb et al. described proline derivative 113, as an improved cat-

alyst for the asymmetric aldol, Mannich, nitro-Michael, and other

reactions80 (Scheme 37).

3.2.4. 4-Substituted prolines as organocatalysts

Bellis et al. explored various 4-substituted prolines as organo-

catalysts for asymmetric aldol reactions.81 It was envisaged that

using (2S,4R)-4-camphorsulfonyloxy proline127, in aldol reactions

gave much higher enantiomeric excesses in comparison to proline.

NH Ph

Ph

OTMSTMSO

HN

CF3

F3C

CF3

CF3

117 118

NH

HN

NH

O

Ph

CO2H

119 1

Figure 9. Different proline derivatives used as a catalyst.

O

Ph

+

N

O

O

H

MeO

OMe

MeO

Ph

N

O

OMeO

OMe

MeO

H

Ph

+

OMe

OMe

HN

O

MeO

O

1. Catalyst117, 20mol%DCM, 3days, rt

2. HCl in Et2O, 40 mol%

-78oC to rt, 30 min.

Yield; 69%, 90% ee

82

116 120 121

Scheme 35.

RCHO + Sn Br3

OH

*R

62% ee

Catalyst

2 eq, i-Pr2NEt4 MS, CH2Cl2

-78oC

Catalyst:N

Ph

PhBn

24 122 123

124

OH

Scheme 36.

R

R1

O

+NPMP

CO2Et R CO2Et

R1

NHPMPO

CH2Cl2, rt,8-24h

Catalyst, 5 mol%

Catalyst: N

HN N

NN

58 45125

H

113

Scheme 37.



12/31

In addition, the improved solubility of these new catalysts in or-

ganic solvents permitted their use in lower amounts when com-

pared to proline (Scheme 38).

Recently, the direct asymmetric a-amination of unmodifiedaldehydes with azodicarboxylates in ionic liquids in the presence

of a 4-imidazolium ion-tagged L-proline organocatalyst has been

reported82 to furnish excellent enantioselectivities (up to 98% ee)

coupled with high chemical yields. The system can be easily recy-

cled and reused at least four times without a significant loss of

yield or enantioselectivity (Scheme 39).

3.2.5. A recoverable fluorous CBS methodology using fluorous

prolinol

A recoverable fluorous CBS methodology for the asymmetric

reduction of ketones using a fluorous prolinol catalyst has been

successfully developed by Dalicsek et al.83

They generated a fluor-ous oxaborolidine in situ, which efficiently catalyzed the reduction

of ketones with high enantioselectivity and reactivity (Scheme 40).

3.2.6. Suitably derivatized proline derivative as heterogeneous

catalyst

A heterogeneous catalyst (L-ProLDHS) 133 was developed by

using the intercalation of L-proline in Mg-AlLDH. The asymmetric

aldol reaction of benzaldehyde 132 and acetone 15 was carried

out using L-ProLDH as a catalyst,84 where the aldol adduct was ob-

tained in good yield (90%) and with high enantiomeric excess (94%)

(Scheme 41).

3.2.7. Prolinal dithioacetals as organocatalysts

Mandal et al. discovered prolinal dithioacetals136(Scheme 34)

could be used as a catalyst for highly stereoselective Michael

NH

HCl

O

OH

R1O

O

OR1=O

O

SO2

O

O

H

O O

R2+

R2

O OH

44-90% ee

Catalyst 127 (10-30mol%)

Et3N, DMF

R2 = 4-NO2Ph, 4-BrPh, 2-ClPh

126 127 128

, ,

15 24129

O

Scheme 38.

H

O

R1HO N CO2R

2

NHCO2R2

23 61 62

R1+

N

N

CO2R2

R2O2C

NH

CO2H

NN TiO

(10 mol%)

[bmim][BF4], 0

o

C

1.

2. NaBH4, MeOH, 0oC, 5 min

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

Yield; 89-96%ee;92-96%

Scheme 39.

R1 R2

O

R1 R2

OH0.1 eq, precatalyst

BH3THF,THF,rt

Precatalyst: NH HO

Rf8

Rf8

39 131

130

Rf8= C8F17

Scheme 40.

O+ H

O O OH

90%, 94% ee

L-ProLDH 133

15 132 134

Scheme 41.

N

O

HBoc

2 eq RSH

N

Boc

SR

SR

H

(i)

(ii)

a: R=Phb: R=p-Me-C6H4c: R=2,6-Me2-C6H3d: R= t-Bu

R2

O

R1+ NO2Ar

R2 NO2

O Ar

R1* *

catalyst136b(10 mol%)

CH2Cl2

>90% ee, >90% de

135 136

58 56137

Scheme 42.



13/31

additions of ketones and aldehydes to b-nitrostyrenes.85 They

observed a high degree of enantioselectivity (99%ee) and diastere-

oselectivity (99% de) in the Michael additions of ketones and

aldehydes to b-nitrostyrenes, catalyzed by prolinal dithioacetals

136. These prolinal dithioacetals could be synthesized in one step

from N-Boc-prolinal135 and thiols (Scheme 42).

3.2.8. Ionic liquid supported proline as organocatalyst

Ionic liquid supported proline 141 has also been investigated86

as an efficient catalyst in the direct aldol reactions of acetone with

aldehydes. The ionic liquid supported proline derivative was syn-

thesized from L-proline. The yield and enantiomeric purity of the

condensation products, the corresponding b-hydroxyl carbonyl

compounds129, have been found to be comparable to those ob-

tained under homogenous conditions (Scheme 43). The majoradvantage of this catalyst is reported to be its easy recovery and

the fact that it could be reused several times.

3.3. Proline as a metal ligand

Metal complexes have long been recognized as a flexible

approach for catalyzing and determining the reaction pathway

NNMe(i)1. BrCH2CH2OH

2. NaBF4, acetone NNMe

OHBF4

-

NNMeO-Pro-BocBF4

-

Boc-Pro-OHDCC, DMAP

NNMeO-Pro-HCF3COO

-

CF3CO2H

(ii)

O

+R1 H

O

R1

O OH

Catalyst 141

138 139

140141

15 24 129

Scheme 43.

N O

O

H

H

M

Metal catalysis

Figure 10. Proline as a metal ligand.

N

HN

OO

NH

O

PPh2Ph2P

O

HN

NH2

O

Rh LL

Figure 11. Rhodium metal complex of a proline derivative with phosphanyl groups.

NH

COOH

TsCl, Na2CO3

H2O, rt, 48h94% N

COOH

Ts

N

Ts

OHNaBH4/BF3Et2O

THF, rt, 18 h81%

N

Ts

OTs

TsCl, pyridine

0oC, 20h83% N

Ts

IKI, acetone,

74%

N

Ts

N N R I-1-substituted imidazoles

MeCN, 80oC

1 142 143

144 145

146

Scheme 44.



14/31

for many of the organic reactions with a large range of chemical

and biological applications; over the years, metal based methodol-

ogies have been well established in asymmetric synthesis.87,88 The

transition metal complexes incorporating asymmetric ligands and

forming a homogeneous catalyst is one of the key methods for the

synthesis of optically active materials. Since the discovery of asym-

metric rhodium phosphine complexes in asymmetric hydrogena-

tions,89 a large number of asymmetric coordination complexes

have been synthesized and applied in enantioselective catalysis.

Investigation of proline as a metal ligand has provided a greater

insight to researchers across the globe, as it plays a crucial role in a

variety of chemical as well biological processes. Asymmetric metal

ligands containing proline as an asymmetric ligand have enabled

the synthesis of a wide range of organic molecules with diversifiedstructures in a regio- and stereoselective manner, such as building

blocks for phosphonyl-substituted peptides with b-turns.90 Pincer

palladium complexes bearing pyrroloimidazololone auxiliaries

with stereogenic centers present in the proline rings, as well as

the other groups of the pincer backbone are also well investi-

gated.9193 Dependingon thechoice of metal, these complexeshave

been applied in different catalytic reactions, such as aldol conden-

sation reactions,9499 Michael additions,9193,100 DielsAlder reac-

tions,94 cyclopropanations,101 allylation of aldehydes,102 allylic

alkylations94 and hydrogen transfers,103 etc with moderate to high

enantioselectivity.

N

Ts

N N I-

N

Ts

N

N

RhI

[Rh(COD)Cl]2, KI

KOBut, THF76%

146 147

Scheme 45.

B(OH)2 CHO

Cl

+ NHC-Rh, KOBut

DME/H2O

OH

Cl

148 149 150

Scheme 46.

N

N

H CO2R

Br

LMe R=Me

LBn R=Bn

N

N

H CO2R

Pd

R=MeR=Bn

Br

N

N

H CO2R

Pd HC

O

O

155a: R=Me, X=BF4155b: R=Me, X=PF6156a: R=Bn, X=BF4156b: R=Bn, X=PF6

Br

Br

Br

+

HN CO2R Et3N,CH2Cl2

rt, 16h

[Pd2(dba)3].CHCl3

C6H6,50oC,3h

AgBF4, acetone/H2O,rt

orNH4PF6/H2O,CH3OH,rt

151 152 153

154

HCO2R

HCO2R

X

R

Scheme 47.

Ph H

O

+CN

CO2Me

i-Pr2EtN,CH2Cl2NO

Ph CO2Me

Cat.155or156major

+ NO

CO2MePh

minor

50 Methylisocyanate 157a 157b

Scheme 48.

X

O

[RuCl2(p-cym)]2

NH

O

HN Ph

HCOOH/Et3N

X

OH

98%ee

158 159

Scheme 49.



15/31

On the other hand, proline as a metal ligand has had a great im-

pact on biological systems as well; for example, proline as a heme

ligand is employed in CooA, the only protein which is a co-acti-

vated transcription factor found in the bacterium Rhodospirillum

rubrum.104 As described by Pinkert et al.,104 the proline stabilizes

the heme pocket during the redox mediated ligand switch and

forms a weak metal ligand bond that is preferentially cleaved to

bind Co.

Proline also bears potential ligand sites (Fig. 10) which in turn

have provided an interesting perspective for peptidemetalcomplexes.

FMoc and Boc derivatives of proline with phosphanyl groups

have also been synthesized,90 and these modified proline deriva-

tives have been incorporated into short peptides possessing sec-

ondary structure (b-turns). The rhodium complex of the resultant

peptide was also synthesized (Fig. 11).

The synthesis of novel N-heterocyclic carbene-Rh complexes

derived fromL-proline has been achieved with the aim of develop-

ing a catalyst for the addition of arylboronic acids to aldehydes.105

The desired imidazolonium compounds were synthesized from

L-proline, which upon treatment with p-toluenesulfonylchloride

and Na2CO3 in water afforded the N-tosyl derivative 142. The

reduction of142, with NaBH4 and BF3Et2O at room temperature

followed by quenching the reaction mixture with methanol fur-nished (2S)-2-(hydroxymethyl)-1-(4-tolylsulfonyl) pyrrolidine

143. The resulting alcohol, after a sequence of reactions as shown

inScheme 44, provided the desired imidazolonium salt 146.

Salt146was used for the preparation of an asymmetric NHC-Rh

complex147, where [Rh(COD)Cl]2was treated with KOBut in THF,

and subsequently allowed to react with proline derivative146, and

KI, thereby furnishing NHCRh complex 147 in 76% yield

(Scheme 45).

The applications of the above complex in the catalytic addition

of phenylboronic acid 148to p-chlorobenzaldehyde149 in dime-

thoxyethane (DME)H2O (3:1) in the presence of a base under var-

ious reaction conditions have been studied. It was concluded thatthe NHCrhodium complex is capable of furnishing alcohol 150,

in 95% overall yield under the optimal standardized conditions

(Scheme 46).

Gosiewska et al. reported106 the synthesis and study of the coor-

dination behavior of the asymmetric NCN-pincer ligands LMe and

LBn in the solid state and in the solution (Scheme 47).

Cationic complexes 155 and 156 were tested in the aldol reac-

tions between benzaldehyde and methyl isocyanate in the pres-

ence of i-Pr2EtN. The reactions were carried out in CH2Cl2 with

1 mol % of catalyst. In each case, the trans-oxazolines157awas ob-

tained as the major product. This reaction involved the formation

of a C-C bond with the creation of two stereogenic centers

(Scheme 48).

Rhyoo et al. explored107

the use of amino amides derived fromproline as asymmetric ligands in the ruthenium(II) catalyzed trans-

fer hydrogenation reaction of prochiral ketones, where product for-

mation occurred with approximately 98% ee (Scheme 49).

The highly enantioselective epoxidation of styrenes 160 cata-

lyzed by proline derived C1-symmetric titanium (salan) complexes

has also been described.108 These novel complexes have been used

to catalyze the epoxidation of styrene derivatives with aq. hydro-

gen peroxide as an oxidant, with high enantiomeric excesses rang-

ing from 96% to 98% being achieved (Scheme 50).

Sud et al. explored the oxidative coupling of amines and ketones

with combined vanadium and proline organocatalysis.109 The com-

bination of vanadium and proline as an organocatalyst enabled the

direct oxidative coupling of cyclic tertiary amines 162, with non-

activated ketones without the requirement of preformed leavinggroups. In this catalytic system, elemental oxygen was employed

as a terminal oxidant (Scheme 51). The above strategy was suc-

cessfully employed for the synthesis of hygrine 163.

The synthesis ofP-chirogenic diarylphosphinocarboxylic acids

was carried out, from which a new class of amido- and amino-

diphosphine ligands (PNP) were derived110 bearing an L-proline

backbone (Fig. 12).

The catalytic activity of this novel ligand was evaluated in the

palladium-catalyzed allylic alkylation reaction of 1,3-

diphenylpropenylacetate 164b(Scheme 52).

Li et al. have developed two asymmetric metal clusters utilizing

the nucleophilic addition ofL-proline to di-2-pyridylketone166as

the key step.111 In the presence of cobalt (nickel) acetate, an asym-

metric ligand with the molecular formula (S)-(C5NH4)2 C(OH)

(C4NH7CO2H) was first obtained via the nucleophilic addition of

R

Ti(OiPr)4 ligand

30% H2O2

R O

96-98%ee Ph

OH

N NH

HO

Ph

H

ligand

160 161

Scheme 50.

N H+ H

OtBuOOH

VO(acac)2

Proline

5 mol%

10 mol%

N

O

hygrine

162 16315

Scheme 51.

NPPh2

P

O

Ph Ar *

NPPh2

PPh Ar

*

NH2 C l

-

PPh2

PhP

OH

Ar O

*

O

164a 164a

Figure 12. Amido- and amino diphosphine ligands.

Ph Ph

OAc i. Pd catalystii. Asymmetric ligand164a

(iii).CH2(COOMe)2Ph Ph

CH(COOMe)2

164b 165

Scheme 52.



16/31

L-proline as a secondary amine to di-2-pyridylketone.The above li-

gand was synthesized in situ, and ultimately afforded two asym-

metric tetranuclear isomorphous complexes 167a and 167b with

the formula {Na[M4L3(OAc)3](ClO4)1.5(H2O)1.5}(ClO4)(OH)0.53H2O

(M = Co, Ni) (Scheme 53). The Co4cluster167a, was found to pos-

sess prominent ferromagnetic properties.

Xie et al. achieved112,113 an original CuI catalyzed asymmetric

coupling of various 2-iodotrifluoroacetanilides 168 with 2-

methylacetoacetates 169 assisted by (2S,4R)-4-hydroxy proline as

the ligand as well as the asymmetric source. This methodology

afforded the corresponding coupling products, 2,2-arylmethylace-

toacetates 170, with the generation of enantiomerically pure a-

aryl carbon quaternary centers. The asymmetric products were ob-tained in good yields in the presence of NaOH as the base and at

lower temperatures when compared to the original Ullmann cou-

pling. The much simpler reaction conditions in this synthetic strat-

egy was one of the key factors in the breakthrough which was

investigated by Xie et al., as the first example of a catalytic asym-

metric Ullmann type CC coupling reaction (Scheme 54).

Mixed ligand complexes of dioxouranium(VI) and thorium(IV)

in ratios of 1:1:1 and 1:2:1 were synthesized114 using 8-hydroxy

quinoline as the primary ligand and L-proline and 4-hydroxy-L-

prolines as the secondary ligands, respectively (Fig. 13). These

mixed ligand complexes 171174were prepared from metal salts

(aqueous solution), primary ligand (ethanolic solution), and sec-

ondary ligands (aqueous solution). These complexes were found

to exhibit prominent antibacterial activity against the pathogenicbacteria Staphylococcus aureusand Escherichia coli.

Recently the CuI/proline catalyzed selective one-step mono acyl-

ation of styrenes175aand stilbenes175bhas been described115 by

Prathima et al. Vicinal di-oxygenation of styrene-type olefins was

achieved with the less expensive and less toxic CuI in the presence

ofL-proline as a ligand and NaIO4as theoxidant. This approach pro-

vided a straightforward and efficient access tomono-acylated diols

176, from both styrene and stilbene derivatives with good to

excellent yields and diastereoselectivity (Scheme 55).

3.4. Differentially substituted prolines: asymmetric synthesis

and applications

Synthetic strategies toward substituted prolines have been

explored for many reasons, as these constitute as a part of various

N N

O

HN

+CO2H Co(OAc)2

or Ni(OAc)2(S)-(C5NH4)2C(OH)(C4NH7CO2H)

Ligand formedin situ

two asymmetric tetranuclear isomorphous complexes167aand167b

{Na[M4L3(OAc)3](ClO4)1.5(H2O)1.5}(ClO4)(OH)0.5.3H2O

(M=Co, Ni) {L= (S)-(C5NH4)2 C(OH)(C4NH7CO2H)}

166

Scheme 53.

IHN

R

CF3C

O

+ OR

Me

O O

HN

R

CF3C

OORO Me

*

60 to 90% ee

CuI (20%)Ligand (40%)-45 to -20oCDMF/H2ONaOH (2equiv.)

Ligand

NH

HO

CO2H

(2S,4R)-4-hydroxyproline

168 169

170

O

Scheme 54.

NH

OO

Th

N

O

N

O

OH2

O

NO

O

[Th(Q)2(Pro)NO3H2O] complex

NH

OO

Th

N

O

N

O

OH2

O

NO

O

[Th(Q)2(Hyp)NO3H2O] complex

OH

NH

OO

[U(Q)(Pro)2H2O] complex

U

O

O

O

N

OH2

H2O

NH

OO

[U(Q)(Hyp)2H2O] complex

U

O

O

O

N

OH2

H2O

OH

171 172

173174

Figure 13. Proposed structures and bonding for the thorium and uranium

complexes involving 8-hydroxy quinoline as the primary ligand and L-proline and4-hydroxy-L-prolines as the secondary ligands.

R1

R2

CuI, (L)-proline

NaIO4, AcOH, 80oC

R2

R1

OH

OAc

R1=H(or) Ar85% yield

175a, R1=H175b, R1=Ph

176

Scheme 55.



17/31

bioactive natural products, suchas ()-domoic acid116 a potent neu-

rotoxin, kainic acid27,31 a CNS stimulant, ()-bulgecinine, a

constituent of the glycopeptide bulgecin117119

and so on. Several

alkylated prolines are naturally occurring amino acids120 and are

also constituents of various antibiotics, for example, N-methyl-

4-ethylproline in lincomycin B,121

4-methylproline in peptide

N

Boc O

OH

R

a, R=Phb, R= CH2CH2CH3c, R=CO2R

1

HN

O

OH

HHCH3

CH3H

HO

O

H

O OH

NH

O

OH

O

OH

Kainica cid:27,31 a potentneurotransmitter

Conformationally constrainedanalogues of phenylalanine,norleucine and aspartaterespectively149

(-)-Domoic acid:116 a neurotoxin

(-)-Bulgecinine: 117-119 aconstituent of bioactiveglycopeptide bulgecin

NH

OH

OH

O

HO

NH

O

OH

(S)-4-Exomethyleneproline:162

an inhibitor of the enzyme prolinedehydrogenase

N

R1

O

OH

O R2

SH

CH3

b: R1=H, R2=

HN CO2Et

CH2CH2Ph

c:R1=cyclohexyl, R2=P Ph

O O

)4(

OO

H3C

H3CO

a,b,c: Potent ACE inhibitors

Enalaprilat192

Fosinopril194

NH

O

OH

HO

4-Hydroxy-L-proline:174

a constituent of Collagen

N

O

NH

HO

H

O

HOH

OH

OH

SCH3

Lincomycin:121,122 an antibiotic

N

Me O

Me

(+)-Hygrine:198 an alkaloid

a:R1=H, R2=Captopril189

Figure 14. Applications of various proline derivatives.

NH

CO2H

NH

CO2H

R

2-substituted prolines

NH

CO2H


R

NH

CO2H

R


NH

CO2H


R

Multisubstituted prolines

Synthesis of bioactivemolecules, natural products,azanucleosides etc.

1

Figure 15. Differentially modified prolines as unnatural aminoacids/aminoacid derivatives.



18/31

antibiotics, 1 and N-methyl-4-propylproline in lincomycin A.122

Substituted prolines have also gained interest due to their use in

the development of novel angiotensin converting enzyme inhibi-

tors.123,124 The presence of proline itself is associated with confor-

mational changes in proteins including a strong preference for

secondary structural modifications, for example, a-helixes and re-verse turns.3,4125128 This property has marked effects ranging from

its role in collagen biosynthesis in protein folding to peptide hor-mone recognition events.129137 Substituted prolines have also

founduse in thesynthesis of conformationallyconstrainedpeptides,

which have been acknowledged as useful tools in the development

of peptidederivedpharmaceutical agents.11,12,138 Duetosuchawide

range of chemical as well as biological applications ( Fig. 14), the

asymmetric synthesis of prolines, substituted at different positions,

has become an area of interest by researchers all over the world.

NH

CO2H CF3CO2H (cat)

CHO

N

OH

LDA,-78oC

Electrophile

N

OH

O

O

E

NH

CO2HE Hydrolysis

1 177

178179

Scheme 56.

NH

CO2H N

OH

O

1.KHMDS

2.NitroareneN

OH

O

NO2

3.DDQ

NH

HO

O

NO2

Hydrolysis

1 177 180

181

Z

Z

Scheme 57.

NH

CO2H

H+

Cl

ClCl

OH

OEt

CHCl3

reflux

65%

N

H

OCl

ClCl

OLDA, THF, -78oC,

Br

82%N

OCl

ClCl

O

Na

CH3OH N CO2Me

CHO

AcCl, MeOH, reflux

74% over two steps NH

CO2MeHCl

1 182 183 184

185

Scheme 58.

HN

O

O

Ph N

O

CF3

Ph

I

O

NH

OH

CF3

O

NH

OH

CF3

O

HO OH

186187

188

189

Iodocyclization

CF3

Scheme 59.



19/31

As a result, various strategies have been investigated for the

asymmetric synthesis of 2-, 3-, 4-, or 5-substituted prolines and

the N-acylation of prolines with suitable acylating agents (Fig. 15).

The aim of the present article is to discuss all of the major ad-

vances made to date with regard to the synthesis, reactivity, and

applications of prolines substituted at different positions.

3.4.1. 2-Substituted prolines

Seebach et al. developed a novel methodology139 for the synthe-

sis of 2-a-substituted prolines through self reproduction of chiral-ity, where the acid catalyzed condensation of proline with

pivaldehyde furnished a bicyclic derivative (2R,5S)-2-t-butyl-1-

azabicyclo[3,3,0]octan-4-one 177, where the t-butyl group ac-

quired a pseudo equatorial position. The lithium enolate derived

reaction of this bicyclic derivative with electrophiles resulted in

the formation of 2-substituted derivative178, where the incoming

group approached from the same side as occupied by the t-butylgroup, that is, the a-side with the retention of configuration.Hydrolysis of compound 178 afforded 2-a-substituted proline179(Scheme 56).

The enantioselective synthesis of (R)-a-(p-nitroaryl)proline 181via an oxidative nucleophilic substitution of hydrogen in nitroary-

nes has been carried out140 in a similar manner as described by

Seebach et al., exploring the self reproduction of chirality in pro-

lines (Scheme 57).

Taking advantage of Seebachs procedure of self reproduction of

chirality in prolinates, a synthetic strategy was developed141 for

the synthesis of a-branched prolines 185 using (3R,7aS)-3-(trichloromethyl)tetrahydropyrrolo[1,2- C]oxazol-1-(3H)-one 183,

as a precursor. Compound 183 was obtained by the condensation

of proline with commercially available 2,2,2-trichloro-1-ethoxy-

ethanol 182 (Scheme 58).

Recently Caupene et al. described a versatile strategy142 for the

synthesis of enantiopure a-trifluoromethyl prolines 188 and a-trifluoromethyl dihydroxy prolines189 through efficient iodocycli-

zation of asymmetric trifluoromethyl allyl morpholinone 186

(Scheme 59).

A straightforward asymmetric synthesis of (S)- and (R)-a-trifluoromethyl prolines188and 191, respectively, from oxazoli-dines190, derived from ethyl trifluoropyruate has been described

by Chaume et al.143 (Scheme 60). The key steps in this synthetic

strategy were the diastereoselective allylation reaction of ethyltri-

fluoropyruvate and an (R)-phenylglycinol-based oxazolidine. The

lactone obtained by the cyclization of the resultant hydroxyl ester

was used as an intermediate for the synthesis of (S)-a-Tfm-allylglycineand (S)-a-Tfm-norvaline in enantiomericallypure form.


Prolines have been acknowledged as a versatile source for

inducing conformational constraints into peptides.144146 Due to

the rotational restrictions associated with the pyrrolidine ring,

the presence of a proline residue greatly reduces the available con-

formational space of a peptide.147149 Having this basic feature in

mind, the introduction of 3-substituted proline derivatives in the

peptides have been well examined with the assumption that the

3-substituent would correspond to the substituent on theb-carbon

of standard amino acids; for example, 3-phenyl prolines, 3-n-pro-

pyl prolines, and proline-3-carboxylates are conformationally con-

strained analogues of phenylalanine, norleucine, and aspartate,

respectively149 (Fig. 13). Taking this into consideration, Chung

et al. designed and developed a synthetic strategy coupled with a

resolution procedure for 3-substituted prolines.149 They described

the synthesis and resolution of 3-phenyl and 3-n-propyl prolines

196. The cis- and trans-3-substituted prolines were synthesized

by the condensation of acetamidomalonate 194 and a,b-unsaturated aldehydes193 under basic conditions. The condensa-

tion product, hydroxyl lactam195, was subjected to acid catalyzedsilane reduction enabling subsequent transformations to occur

cleanly and in good yield. Thetrans-isomers were resolvedviatheir

diastereomeric (S)-a-methyl benzyl amides and the absolute con-figurations of the enantiomerically pure products were assigned

(Scheme 61).

The asymmetric route for 3-substituted prolines has also been

explored from pyroglutamates due to their easy accessibility and

efficient conversion to prolines, via reduction of the lactam car-

bonyl functionality. By taking advantage of this fact, Oba et al. car-

ried out150 the synthesis of 3-methyl proline 200, using a Michael

addition onto unsaturated orthopyroglutamate derivative 197a.

The (2S,3S)-methyl-pyroglutamic acid 2,7,8-trioxabicyclo [3.2.1]

octane (ABO) ester 197b, was converted to (2S,3S)-methyl-N-

OHN

F3C CO2Et

Ph

NH

CO2H

CF3

NH

CF3

CO2H

NH

CF3

OH

(S)--Tfm-proline

(R)--Tfm-proline (S)--Tfm-prolinol

190 188

191 192

Scheme 60.

O R

H

+

NH

CO2Et

O CO2Et

N

R

CO2EtHO

Ac

CO2Et N

R

Ac O

OEtEtO-Na+

- CO2Et

R=Ph, R=n-propyl

[H+],Silane reduction

193

194

195

196

ResolutionPure stereoisomers

of196

Scheme 61.



20/31

Boc-3-methylpyroglutamate 198. Reduction of198 with BH3THF,

followed by the deprotection of199, in refluxing 1 M HCl and sub-

sequent ion exchange treatment with DOWEX 50X 8 resin fur-

nished (2S,3S)-3-methyl praline 200 in quantitative yield

(Scheme 62).

Curtis et al. carried out the first asymmetric synthesis of

(2S,3S,4R)-3-amino-2-hydroxymethyl-4-hydroxy pyrrolidine

203,151 where homo allylic carbamate 202, was synthesized from

a 4-substituted proline, which was converted into the desired tri-

substituted pyrrolidine (Scheme 63).

Kamenecka et al. described an enantioselective approach to3-substituted prolines.152 The enantioselective synthesis of 3-

substituted prolines206, was achieved starting from commercially

available 3-hydroxy-(S)-proline 204. A palladium mediated cou-

pling was used to introduce various groups at C-3 using the corre-

sponding enol triflate derived from N-trityl-3-oxo-(S)-2-proline

methyl ester. Cleavage of the trityl residue and hydrogenation

afforded final product 206, with satisfactory diastereoselectivity

(Scheme 64).

The synthesis of diastereomeric substituted proline peptidomi-

metics as a conformationally restricted tyrosine derivative 208, has

been accomplished153 utilizing the intramolecular hydroboration

cycloalkylation of azido olefins 207, as the key step (Scheme 65).

The asymmetric synthesis of proline based conformationally

constrained tryptophan mimetic212, has been reported by Delayeet al.154 The strategy involved the in situ generation of an allyl me-

tal species containing the indole moiety, which was allowed to un-

dergo coupling with asymmetric imine 210. The construction of

the 3-substituted proline skeleton was achieved through a hydro-

zirconation/iodination sequence to the resultant homoallylic

amine (Scheme 66).

NBoc

ABO

Me

ON CO2Me

Me

O

Boc

BH3THF

N CO2Me

Me

Boc

NH

CO2H

Me

HCl, MeOH, then

(Boc)2O, DMAP

1M HCl

DOWEX 50WX8

197b 198

199200

NBoc

ABOO

Michaeladditiion

197a

Scheme 62.

N

Ts

O

OH2N

N

Ts

O

HN

O

NH

OH

NH2HO

201 202 203

HO

Scheme 63.

N CO2Me

Tr

OTf (i) Pd-mediatedcoupling

(ii) HCl; H2NH2

CO2Me

R

Cl-

206

NH

CO2H

OH

204 205

Scheme 64.

N3

CO2But

N H

FMoc

OBn

CO2H

OBn

(i) Hydroboration

(ii) Cycloalkylation

* *

207 208

H

Scheme 65.

N

Boc

ZrCp2

OR

N

Boc

NH

Ph OH

BnO

N

Boc

N

Fmoc

HO2C

(i) Et2Zn

(ii)

O

HN

Ph

OBn209 210

211

212

Scheme 66.

N CO2Bn N

Fmoc

CO2H

Ph

N

R

Boc

R = -H, -OMe, -NO2,Cl, -CO2Me

i,ii,iii

213 212

3 Steps

Scheme 67. Reagents and conditions: (i) Amino zinc-ene-enolate cyclization; (ii)

transmetallation; (iii) Negishi-cross-coupling.



21/31

A short access to cis-3-substituted prolino homotryptophan

derivative 212, was developed through amino zinc-ene-enolate

cyclization sequences.155 The asymmetric synthesis ofcis-3-substi-

tuted prolines has been achieved via amino zinc enolate cyclization

followed by transmetallation of the cyclic intermediate for further

functionalization. The synthesis of a prolinohomotryptophane

derivative was achieved through Negishi cross-coupling of the zinc

intermediate with indole rings. The Pd-catalyst from Fus

[(t-Bu3)Ph]-BF4 was used to eliminate the possibility of undesired

b-hydride elimination (Scheme 67). Enantiomerically pure and N-

protected compounds were obtained, which could be utilized in

peptide synthesis.

Recently the total synthesis of natural cis-3-hydroxy-L-proline

204, fromD-glucose was described156 by Kalamkar et al. The meth-

odology involved the conversion ofD-glucose intoN-benzyloxycar-

bonyl-c-alkenyl amine, which upon 5-endo-trig-aminomercuration afforded the pyrrolidine ring skeleton with a sugar

attachment in roughly 25% yield. In an alternative procedure, theN-benzyloxycarbonyl-c-alkenyl amine upon hydroboration-oxida-tion, mesylation, and intramolecular SN2 cyclization furnished a

pyrrolidine ring compound in high yield. Hydrolysis of a 1,2-aceto-

nide, NaIO4cleavage, followed by oxidation of the aldehyde into anacid and subsequent hydrogenolysis afforded cis-3-hydroxy-L-pro-

line204, in 29% yield from D -glucose (Scheme 68).

Huy et al. have investigated157 a convenient synthesis oftrans-

3-substituted proline derivatives through a 1,4-addition

(Scheme 69). A four step synthesis of 3-alkyl-, vinyl-, and aryl-

substituted proline derivatives 217, has been achieved. These

3-substituted prolines have been acknowledged as important

building blocks for conformationally constrained peptide ana-

logues. This methodology involved the Cu-catalyzed 1,4-addition

of a Grignard reagent onto N-protected 2,3-dehydroproline esters

216, easily obtainable from L-proline methyl ester hydrochloride

O OH

OH

HO

HO

D-(+)-Glucose

O

N

Cbz

H

HO

O N

H

CO2H

OHH

H

L-cis-3-hydroxyproline

OH

214 204

i

ii

iii,iv

v,vi

Scheme 68. Reagents and conditions: (i) Conversion toN-benzyloxycarbonyl-c-alkenyl amine; (ii) hydroborationoxidation, mesylation and intramolecular SN2 cyclization;(iii) hydrolysis of 1,2-acetonide; (iv) NaIO4 cleavage; (v) oxidation of the aldehyde into the acid; (vi) hydrogenolysis.

NH

CO2Me

HCl

i. NCSii. Cbz-Cl

one pot NCbz

CO2Me

i. R-MgXCu(I)X

ii. LiOH NCbz

CO2H

R

215 216 217

Scheme 69.

N

Boc

CO2R2

R1O

N

Boc

CO2R2

Ph

NH

CO2H

Ph

Ph2CuLi/Et2O/THF

NH4Cl-H2O

CF3CO2H

218a, R1=H

218b, R1=Ts 219 220

Scheme 70.

NH

CO2HO

(i) ROH/H+

(ii) NaBH4NH

CH2OHO

NO

OPh

NO

OPh

N CH2OH

NH

CH2OHNZ

CH2OH

(i) Jones oxidation

(ii) H2/Pd-C

PhCHO/H+

LDA,Br

-78oC

LAH/THF

Ph

H2/Pd-C

Z-Cl/K2CO3

H2O-THF

NH

COOH

10 221 222

223 224

225 226 227

Scheme 71.



22/31

215 in two steps. The 1,4-addition products were obtained with

goodtrans-selectivity (dr 5:1 to 25:1).


Interest in the synthesis of 4-substituted prolines was increased

when 4-hydroxy-L-proline was discovered for the first time as theconstituent of collagen. The synthesis of 4-substituted prolines has

received further attention, since they have been acknowledged as

very good intermediates for the synthesis of potent angiotensin

converting enzyme inhibitors158,159 with the objective to design

and synthesize modified captopril and enalapril analogues. Since

then, rapid progress has been made in investigating and develop-

ing newer methodologies for the synthesis of 4-substituted

prolines.

trans-4-Phenyl-L-proline 220, and trans-4-cyclohexyl-L-proline227, are effective intermediates for potent ACE inhibitors. The syn-

thesis oftrans-4-phenyl-L-proline220was achieved124 as shown in

Scheme 70, where commercially available 4-hydroxy-L-proline was

used as the precursor. 4-Hydroxy-L-proline, after protection of the

carboxylic and NH-groups, converted to its O-tosyl derivative

218b. The reaction of lithium diphenylcuprate with N-protected

trans-4- and cis-4-tosyloxy-L-proline esters followed by deprotec-

tion, furnished excellent yields of 4-phenyl substituted L-prolines

and the reaction proceeded with net retention of configuration at

the carbon center bearing the tosyloxy group.

Taking advantage of the possibility for easy conversion of pyro-

glutamic acid into proline, Thottahil et al. developed 39,123 an effi-

cient strategy for the synthesis oftrans-4-cyclohexyl-L-proline as

an intermediate for fosinopril,160 starting from pyroglutamic acid

10, where pyroglutamic acid was converted to pyroglutaminol

221. The acid catalyzed condensation of pyroglutaminol with benz-

aldehyde, furnished a bicyclic derivative 222, where the phenyl

group acquired a pseudo equatorial position. Alkylation of the lith-

ium enolate of bicyclic derivative 222, with cyclohexenyl bromide

proceeded with high facial selectivity to give 4-a-product 223,

which after a series of reductive, hydrogenolytic, and oxidativereactions afforded trans-(2S)-4-cyclohexyl proline 227

(Scheme 71).

An easy route for the synthesis of 4-substituted prolinates

through a lithium enolate derived aldol reaction followed by

reduction, starting from t-butyl-(2S)-N-benzyloxy carbonyl-pyro-

glutamate 228 has been described.161 Hydrogenolysis of

t-butyl-(2S)-N-benzyloxy carbonyl-4-a-(hydroxyphenylmethyl)-pyroglutamate 229, and subsequent conversion to a thiolactam,

followed b

Review de L-prolina y Sus Derivados en Sintesis Asimetrica

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