Review de L-Prolina y Sus Derivados en Sintesis Asimetrica

Tetrahedron: Asymmetry 22 (2011) 18171847
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
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
a b s t r a c t
Non-proteinogenic prolines have been acknowledged as an important pool for the synthesis of conformationally rigid bioactive peptides, angiotensin converting enzyme inhibitors and as pharmacological probes. 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. Furthermore L-proline is an osmoprotectant and is therefore frequently used in many pharmacological as well as biotechnological 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 prolines 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.
Article history: Received 29 July 2011 Accepted 27 September 2011 Available online 4 November 2011
Contents 1. 2. 3. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure and synthesis of proline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Advancements in the chemistry of proline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Proline as an organocatalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Proline catalyzed asymmetric aldol condensations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Proline catalyzed asymmetric Mannich reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Proline catalyzed asymmetric Michael additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Proline catalyzed amination and aminoxylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5. Proline catalyzed oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.6. Proline catalyzed DielsAlder reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.7. Proline catalyzed cyclopropanation/nucleophilic substitutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.8. Proline catalyzed oxidative and reductive cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.9. Synthesis of heterocycles through a proline catalyzed multicomponent reaction strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.10. Proline catalyzed reduction and reductive alkylations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.11. Studies on microwave assistance in proline catalyzed organic reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Replacement of proline with modified proline derivatives and their outcome as organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Different proline amides as organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Substituted prolinol derivatives as organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Replacement of the carboxylic group of proline with tetrazole moiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. 4-Substituted prolines as organocatalysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.5. A recoverable fluorous CBS methodology using fluorous prolinol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.6. Suitably derivatized proline derivative as heterogeneous catalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.7. Prolinal dithioacetals as organocatalysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.8. Ionic liquid supported proline as organocatalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Proline as a metal ligand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Differentially substituted prolines: asymmetric synthesis and applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1818 1818 1819 1819 1820 1822 1823 1824 1824 1824 1824 1825 1825 1825 1825 1826 1826 1827 1827 1827 1828 1828 1828 1829 1829 1832
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E-mail address: skpandey@mjpru.ac.in 0957-4166/$ - see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.09.013
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S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847
4.
3.4.1. 2-Substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. 3-Substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. 4-Substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.4. 5-Substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.5. Synthesis of multi-substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.6. N-Acylation of proline derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.7. Synthesis of azanucleosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.8. Reduction of the carboxylic functionality of proline: asymmetric synthesis of (+)-hygrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.9. Synthesis of enantiopure b-endo-substituted aza bicyclic proline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1835 1835 1838 1839 1841 1842 1844 1845 1845 1845 1845 1845
1. Introduction Proline and substituted prolines can be found in many a natural1 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 prolines act as essential components of the target molecules. Non-proteinogenic prolines have emerged as important intermediates 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 possibilities 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 angiotensin converting 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 asymmetric synthesis, the synthesis of various bioactive molecules, or as a constituent part of bioactive molecules.
(i)
CH 2(COOEt)2 3
+ 4
CN
EtO-
(EtOOC)2 CHCH2CH2CN 5
Ni/H 2 H2N EtOOC COOEt O 6 HN COOEt
SOCl2
HN O 7
Cl COOEt
HCl
+ NH3 Cl8
Cl COOH
i) OH ii) HCl N Cl- H2 9 COOH
-HCl N H 1 COOH
Scheme 1.
Triethyloxonium fluoroborate O N H 10 CO2H NaBH4 N H 1 Ph BH3THF N H 11 CO2H NaBH4 N H 12 CO2H CO2H
2. Structure and synthesis of proline Proline 1 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).
Ph O
(ii)
Scheme 2.
N H 1 COOH N H2 2 O O Me L-proline, DMF O C O
O-
Figure 1. Structure of proline.
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 compound 7. Compound 7, upon treatment with hydrochloric acid followed by alkaline hydrolysis and subsequent treatment with hydrochloric acid afforded racemic proline 1 (Scheme 1).
O 13
OH 99%, 93%ee 14
Scheme 3.
1819
Amination, aminoxylation Diels - Alder reaction
Oxidations
Mannich reaction Asymmetric aldol, crossed aldol, intramolecular aldol reactions etc.
Reductive alkylations SN 2 alkylation
N H 1
CO2H
Synthesis of heterocycles Reductions Michael addition
Figure 2. The spectrum of proline as organocatalyst in organic reactions.
COOH N H Me Bi functional catalysis N R
CO2N
CO2H R
Me R2 O + N H O OH
H2O -H2O
R2
N Me 19 O
H O
Iminium catalysis
Enamine catalysis
18
Figure 3. Possible modes of proline catalysis.
O O + 20 vol% H NO2 L-proline

N
OH
H O O O H Me R2 R
1
30 mol% DMSO 68%(76%ee) 17
R CHO
N R2 Me HO
H O
NO2
H
15
16
20
Scheme 4.
Transition state
Various synthetic strategies have been reported for the asymmetric synthesis of prolines.38,39 One of the earliest synthetic strategies 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 The conversion involved the treatment of pyroglutamic acid 10 with triethyloxoniumuoroborate 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 11 was converted into 4-phenyl prolinate 12 by reduction with BH3THF, followed by the reduction of resultant crude compound with sodium borohydride (Scheme 2, ii). 3. Advancements in the chemistry of proline 3.1. Proline as an organocatalyst The beginning of 1970s may well be remembered as a turning point in the history of organo catalyzed asymmetric reactions, when proline was rst investigated as a small molecule in the HajosParrishEdersauerWieahert reaction.40 In this reaction, naturally occurring L-proline was employed as an asymmetric catalyst in an aldol reaction,40 where the starting material was triketone 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 efcient and important organocatalyst in several asymmetric transformations, such as aldol reactions, crossed aldol reactions involving different aldehydes as donors or
O R2 N OH Me HO N H H O H2O -H2O R
1
R1
OH + R
2
21
Me OH O 22
H R2 O H Me N H OO
R1
metal- free Zimmeraman- Traxler model
Figure 4. Mechanism of the aldol reaction.13,1921,42
O R1 H + H
O L-proline R
2
O 10 mol%, DMF, 4oC H R

1
OH R2
23
24
25
Scheme 5.
acceptors, Mannich reactions involving ketones, aldehydes, and amines, Michael additions involving ketones and aldehydes,
1820

OH OHC CHO L-proline CH2Cl2, rt, 12h 95% 26a OHC H 99%ee 26b OH i. (R)-proline H CH3 28 29 O i. OH CH3 Prelactone B 31 ii. HCl OBut , BF3 O OTMS ii. TBSOTf CH3 30 H O
O CH 3 + H3C
Scheme 6.
additions to imines, nitro alkenes, in addition to many other reactions as well (Fig. 2). The reactivity and enantioselectivity of proline catalyzed reactions amount to a series of interactions involving proline that are comparable to enzyme catalyzed reactions,41 such as substrate recognition, transition state stabilization, and the resulting formation of the product. Due to these similarities Movassaghi and Jacobson have regarded proline as the simplest enzyme.41 Proline is the only natural amino acid with a secondary amine functionality, which raises the pKa value and induces better nucleophilicity when compared to other amino acids. There are several modes by which proline is capable of exerting its catalytic activity,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 transition state with a systematic framework of hydrogen bonding.13,17,1921,42 Due to the unique behavior of proline as an organocatalyst, the last two decades have witnessed a large increase in the number of publications exploring various reactions and reaction methodologies, whereby proline has been successfully employed as a catalyst for achieving the desired chemical or stereochemical outcome.1322 A few of the more important applications 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 primarily in aldol reactions,40 led researchers to further explore its applications toward a variety of aldol reactions and to establish it as one of the best catalysts for various other similar reactions. Even though the rst application of proline as an asymmetric catalyst was explored in the early seventies,40 the detailed investigation was carried out by List et al. in 2000,13 when the direct asymmetric aldol reactions of ketones and aldehydes using L-proline as a catalyst were described, whereby product formation occurred 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 in Figure 4. In aldol reactions, proline executes its action through enamine catalysis. Enamine 20, is formed from the pyrrolidine nitrogen and the carbonyl donor. Iminium ion 21, created by the attack of the enamine on the re-face of the aldehyde, is subsequently hydrolyzed to afford an asymmetric b-hydroxyl ketone. It is postulated that the reaction
H3C
Scheme 8.
O H 32
L-proline Acetone
OH
33
OH
(S)-Ipsenol 34
Scheme 9.
O + OH 35 H
O R
L-proline, 20 mol % DMSO H3C
OH R OH
24
36
Scheme 10.
O R H 35 + EtO2C
O CO2Et 37 L-proline, 20mol% CH 2Cl 2, rt, 3h
O H R 38
OH
CO2Et CO2Et
Scheme 11.
HO
CO2H
OH O
OH L-proline(15 mol%) NTs Direct 6-enolexo aldolization O
OH
OH
NTs O 70% dr>10:1
HO
CO2H
L-(+)-Tartaric acid
27a
27b
Scheme 7.

O H2O R1 39 NH2 O + R
3
1821
H N CO2H + N
H CO2H
R2
N H
CO2H
-H2O OMe R1 R2 R1 42 R2
H 24 OMe 40 R
3
N H 43 R1
R1 R2 O R NH
3
N R3 NH PMP PMP R
2
O O
-
O N R1 H R3 N R2 H PMP O
41
44
Transition state
Figure 5. Probable mechanism for the proline catalyzed Mannich reaction.17,1921
NH 2 O + R1 R2 H O R3 + L-proline, DMSO OMe 39 24 40 5-35 mol%

H
O + R 23
PMP N H CO2Et 45
i. L-proline THF, rt, 16-20 h ii. Et2AlCN NC
OH
NHPMP CO2Et R
48
Scheme 14.
O R1 R2
NHPMP R3 O R + 2 X 49 50 CHO + NH 3 L-proline 30 mol% X N H X 51 O R
99% ee 41
Scheme 12.
Scheme 15.
O NPMP + R1 39 R2 H 45 CO2Et 20 mol% DMSO R1 46 R2 L-proline CO2Et O NHPMP
Scheme 13.
proceeds through a transition state following a synclinical approach of the aldehyde, where the alkyl or aryl substituent of aldehyde 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, scientic debates have been made to study the mechanistic aspects as well as the role of water as a solvent, 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 investigations 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 proline as 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 process made it possible to synthesize substituted cyclohexanes in excellent diastereo and enantioselectivity, for example, heptanedial 26a, is converted into the corresponding cyclic anti-congured aldol 26b 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 tartaric acid (Scheme 7). This proline catalyzed approach provided high levels of syn-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 of L-proline as an asymmetric catalyst in the aldol reaction allowed a concise synthesis of (S)-ipsenol 34 to be investigated48 starting from 3-methyl butyraldehyde (Scheme 9).
1822

R ( )n DMSO, 60oC i) (HCHO)n ( )n ii) Azole iii) L-proline O 53 Basic conditions O R 52 H2O,100oC O ( )n N OH N X N N X
X=CH; Imidazole X=N;1,2,3-Triazole 54
Scheme 16.
O Ph + L-proline 15 mol% DMSO, 16h 94%
O NO2
Ph NO2 ee;23% dr>20:1
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 reactions. 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 enamine, creates new stereocenters in the iminium product 44, which upon hydrolysis gives Mannich product 41, with excellent stereoselectivity. The stereoselectivity is controlled via the transition state as shown in Figure 5. The E-aldimine is attacked by the enamine on its si-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-methoxy phenyl 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 modied systems, where two component modied Mannich reactions using functionalized aamino 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
55
56
57
Scheme 17.
O R
1
R4 + R2 R3
NO2
L-proline 10-20 mol% DMSO,rt R1
R3 NO2 R 60
2
58
59
Scheme 18.
Proline catalyzed asymmetric aldol reactions and their successful outcome encouraged Sakthivel et al. to synthesize anti-diols 3649 by the reaction of hydroxyl acetone 35 with aldehydes 24 catalyzed by L-proline (Scheme 10). The scope of the proline catalyzed aldol reactions was further applied to activated carbonyls, resulting in the formation of aldehyde aldols 3850 (Scheme 11). 3.1.2. Proline catalyzed asymmetric Mannich reactions Parallel to the aldol reactions, proline catalyzed Mannich reactions were also investigated simultaneously by List et al.,51 whereby proline catalyzed direct asymmetric three component Mannich
O (i) R2 H
BnO2C
L-proline N N CO2Bn 10 mol% NaBH4 HO R2 62
NHCO2Bn N CO2Bn
23
61
O O (ii) R1 R2 N + Ph O L-proline 10-30 mol% DMSO,2-3 h,rt

1 2
O ONHPh + R
1
OH N Ph R
2
39
63
7-11%ee >99% ee O/N selectivity> 100:1 to 8:22 64 65
Scheme 19.

i) -aminoxylation, L-proline HWE-olefination and reduction ii) TBS-Cl -amination, D-proline HWE-olefination CO2Et R1: TBS; (anti/syn>40:1) 68 CBz OR1 R CO2Et R1: TBS;(syn/anti>10:1) to 6:1; CBz= benzyloxy carbonyl 69 N NHCBz -amination, L-proline HWE-olefination OTBS R CO2Et ee>94% 67
1823
R CHO R: nPr, (CH3)2, Ph, etc 66 CBz OR1 R N
NHCBz
Scheme 20.
O R H Ph +
O O N L-proline, 5mol% CHCl3, 4oC H R R= alkyl, aryl, allyl n-Pr O N H Ph H + O Me Me S Ph O 20 mol% CHCl3, 23 C CHO 78 79 80 72% yield; 46% ee
o
N H
CO2H n-Pr COPh
23
63
70
Scheme 21.
Scheme 23.
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 asymmetric Mannich reactions, Srinivasan et al. carried out54 the synthesis of 3-substituted-2, 6-diaryl piperidin-4-ones 51, by the one pot reaction of ketones 49, various arylaldehydes 50, and ammonia using Lproline as the catalyst (Scheme 15). Recently Srinivas et al. have described55 a proline catalyzed access to Mannich adducts using unsubstituted azoles. They reported a unied and facile approach for the direct construction of a CCN bond with unsubstituted azoles under Mannich conditions. The reaction was catalyzed efciently by L-proline to give the Mannich adduct 53, 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).
CO2-
CO2Ylide N CO2-
S Ph
E Zwitterionic iminium poor iminium control
O Directed electrostatic activation
Figure 6. A probable stereoselectivity.
explanation
for
good
reactivity
but
diminished
3.1.3. Proline catalyzed asymmetric Michael additions Efcient proline catalyzed Michael additions of unmodied ketones into nitro olens have also been carried56 out successfully.
R i) NO2 + Me
O L-proline R1 71 THFor CH3OH rt R
R1 NO2 72
R NO2 73
R1
59
R = Ph, 4-MeoC6H4, 1-naphthyl, 2-CF3C6H4 R1 = Ph, 2-thienyl, 2-furyl Moderate selectivity for 72 O L-proline S NO2 74 75 CF3 * * * CF3 * * * NO2 S
CF3 ii) +
O + S
NO2 76 ratio 76:77=4:1
77
Scheme 22.
1824
EtO2C Br EtO2C 81 catalyst: N H 82 Ar' Ar' OTMS Ar'=3,5-CF3C6H3 + OHC Ar

CHO CHO + Ar 83 R 50 92 R O O OEt N H 95 20% ee EtO2C 85 I L-proline (10%) Et3N 75% 86 OHC 60% ee EtO2C CO2Et 87
R2 R1
3 + R NH2
0.2 eq catalyst H2O, rt, 96 h
EtO2C EtO2C
O O + O 93 94 O OEt + NH 4Ac
L-proline (cat), EtOH reflux
Scheme 24.
OHC i) OHC EtO2C 84 OHC ii) EtO2C EtO2C I CO2Et L-proline (10%) Et3N 75% CO2Et
Scheme 27.
R5 O + O R4
5 + R CHO
O R4
L-proline EtOH,rt,50 o C 12-24h 62-86%
R1
R2
N R3
Scheme 25.
95
96
97
24
98
Scheme 28.
Successful accomplishment of such a reaction made it possible to synthesize c-nitroketones 57, in reasonable enantiomeric excess coupled with excellent yields (Scheme 17). 3.1.3.1. Scope of proline catalyzed Michael additions. The possibility of proline catalyzed Michael additions has been applied successfully to a wide variety of asymmetric conjugate additions57,58 where the product was formed in high enantiomeric excess (Scheme 18). 3.1.4. Proline catalyzed amination and aminoxylation The proline catalyzed a-amination of aldehydes, as well as the aminoxylation 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 aminoxylation. The enantioselective synthesis of syn/anti-1,3-amino alcohols via proline catalyzed sequential a-aminoxylation/a-amination followed by HornerWadsworthEmmons olenation of the aldehydes has recently been described by Jha et al..60 Using this methodology, they explored a short and efcient synthetic path-
way to the bioactive molecule (R)-1-(methylpyrrolidin-2-yl)-5phenylpentane-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 enantiomeric excess (Scheme 21). 3.1.6. Proline catalyzed DielsAlder reaction The potential of L-proline as a DielsAlder catalyst for the reaction of nitro olens and a,b-unsaturated ketones to furnish cyclohexanone 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 cyclohexanone derivatives can be carried out with moderate to good enantioselectivity (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 dened chemical/ biological properties, due to its unique reactivity and structural properties. As a result of this, the investigation of different strategies for the construction of cyclopropane rings has received much attention. One of the synthetic strategies involves64 the enal-cyclopropanation reaction of a,b-unsaturated aldehydes 78, with dimethylphenylacyl sulfonium ylid 79, and a range of asymmetric 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 efcacy 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 electrostatic association via the 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. Furthermore, the iminium ion can equally populate both the E- and
O O CH3
L-proline(10%) Cu(OAc)2(5%) i) PhCO3t-Bu, EtCO2H 16h 88
39%, 61% ee 89
H3C
O (L)-proline
CH 3 OH
ii)
ZrCl4, NaBH4,THF rt, 3h 90
60%, 44% ee 91
Scheme 26.

R1
1825
NH 2 + R1 40 R2
CHO + H C 3
NH O O L-proline/TFA OR 20 mol% N
O OR
50
99
R2 R1 100
R2
Scheme 29.
R O R H 24 O + H H O H H Ar CN 101 H 103 L-proline, 20mol% H2SO4, 30mol% R N H 102 H
Ar CN
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 strategy L-Proline has been effectively employed as an efcient organocatalyst for the synthesis of polyhydroquinolines 95,69 via multicomponent Hantzsch reaction (Scheme 27). Likewise L-proline catalyzed synthesis of highly functionalized multisubstituted 1,4-dihydropyridines 98 has recently been described 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 alkynones 95, amines 96, b-dicarbonyl compounds 97, and aldehydes 24 under mild reaction conditions. The process involved hydroamination/Knoevenagel condensation/Michael type addition/intramolecular cyclization processes and led to the formation of 1, 4-dihydopyridines. In a similar manner Misra et al. have described71 a highly atom economic one-pot synthesis of tetrahydropyridines 100 as antimalarials, 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 efcient approach for a one-pot three component reductive alkylation reaction of arylacetonitriles containing electron withdrawing groups with aldehydes and ketones and 1,4-dihydropyridine 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-inammatory 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
Ar COOH 104
Scheme 30.
OMe OMe O N Me Me + H 15 CO2Et 105 oil bath, or MW(49W), or MW(207 W) (S)-proline, DMSO o 60 C, 10 min Me O NH CO2Et 90-92% (99% ee) 106
Scheme 31.
Z-iminium isomers, a congurational equilibrium that is responsible for furnishing the diminished stereocontrol (Fig. 6). Recently, the use of water as a reaction medium for the O-TMSdiarylprolinol catalyzed cyclopropanation reaction of diethyl bromoacetate 81 with a,b-unsaturated aldehydes 82 has been investigated65 as a base free reaction system. A modied O-TMSdiaryl prolinol incorporating hydrophobic side chains has been explored as a promising catalyst for this reaction having high efciency coupled with good stereoselectivity (Scheme 24). Proline as an organocatalyst has been proven to be equally useful in nucleophilic substitution reactions, when it showed its ability to catalyze the intramolecular SN2 alkylations66 of diethyl2-(iodomethyl)-2-(2-oxoethyl) malonate 84, and diethyl-2-(3-iodopropyl)-2-(2-oxoethyl) malonate 86, thereby furnishing the corresponding cyclopropyl and cyclopentyl derivatives 85 and 87, respectively, with the desired stereochemistry (Scheme 25).
O O R R=H, aryl + O N N
O MeCN, L-proline O MW, 60oC, 30 min O R
CO2Et N NH CO2Et
54-97% (52-90% ee) 107 108 109
Scheme 32.
1826

O O 10-20 mol % cat R 24 cat.: N H 110 solvent: DMF, DMSO, CHCl3 H + 55 O R1 solvent, rt 111a where R1= substituted aromatic, heteroaromatic and alicyclic amines R OH O + R OH O
111b
Scheme 33.
O Ph N H N H 112 H Ph O N H O N H 1 O H N 113 Acid function HN N H 114 S O2 O R HN N N
Figure 7. Structures of proline derivatives used as a catalyst.76
O N CH 2 O H H
-
N O
O N O
Figure 8. An activated intermediate complex showing the possible mode of interaction and hydrogen bonding by the proline derivative in aldol reaction.
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 optimization studies with regards to solvent, temperature, time, and catalyst loading for the microwave mediated organocatalytic aamination of disubstituted aldehydes 107 with diethylazodicarboxylate 108. The optimum reaction conditions, as described by Baumann et al. proved to be MeCN as the solvent, 50 mol % of Lproline as the catalyst, a reaction temperature of 60 C 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 efcacy and enantioselectivity (Scheme 32). 3.2. Replacement of proline with modied proline derivatives and their outcome as organocatalysts 3.2.1. Different proline amides as organocatalysts A slight modication in the catalyst structure may change the pKa value of the catalyst affecting the strength of hydrogen bonding to such an extent that a high degree of enhancement of the catalytic 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 catalysts resulted in high yields, enantioselectivity, and diastereoselectivity under mild reaction conditions. Taking into consideration the above rationale, successful enantioselective aldol reactions could be accomplished75 by using Lprolinamide 110 as a catalyst in the place of L-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 efcient 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 an activated intermediate (Fig. 7).
O (ii). 55 + O H R 50 N H CO2H (20%) ZnCl 2(10%) DMSO/H2O (8:2)
OH
R d.r. up to 16:1 e.e. up to 99% 115
Scheme 34.
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 conditions for (S)-proline catalyzed asymmetric Mannich and aldol reactions, 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 eld. According to Hosseini et al. the results obtained either with microwave

F 3C Ph N H Ph OTMS HN TMSO Ph CF3 117 118 119 1 CF3 CF3 O H N N H N H CO2H
1827
Figure 9. Different proline derivatives used as a catalyst.
OMe O MeO OMe + Ph 82 HN O O MeO 1. Catalyst 117 , 20mol% DCM, 3days, rt 2. HCl in Et2O, 40 mol% -78 C to rt, 30 min. Ph MeO
o
OMe MeO
OMe
H N O O
H N Ph MeO O O
Yield; 69%, 90% ee 116 120 121
Scheme 35.
OH RCHO + Sn Br3 Catalyst 2 eq, i-Pr2 NEt 4 MS, CH2Cl2 -78oC R * 62% ee 123
24
122
Catalyst:
Ph N Bn 124 OH Ph
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 stereoselectivities. The optimized catalytic conditions (catalytic system: Lproline: 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 quinolizidines.78 To carry out their synthetic strategy, they standardized the enantioselective Michael addition of cinnamic aldehyde 82, 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 cyclization 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 derivative 124, as an asymmetric catalyst in dichloromethane in the presence of a Lewis base.79 The synthesis 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 catalyst 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 organocatalysts for asymmetric aldol reactions.81 It was envisaged that using (2S,4R)-4-camphorsulfonyloxy proline 127, in aldol reactions gave much higher enantiomeric excesses in comparison to proline.
Scheme 36.
O R R1 NPMP + CO2Et 45 Catalyst, 5 mol% CH2Cl2, rt, 8-24h R R1 125 O NHPMP CO2Et
58
Catalyst:
N H 113
N N HN N
Scheme 37.
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 activated intermediate complex. In addition, these systems allow variation of the steric environment for the standardization of their catalytic properties76 (Fig. 8). Recently, direct asymmetric aldol reactions co-catalyzed by Lproline 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
1828
R1O
O O N H HCl 126 OH R1= O O , O O SO2 127 128 , O
O + H 15
2
O R 24 R = 4-NO2Ph, 4-BrPh, 2-ClPh

2
O Catalyst 127 (10-30mol%) Et3N, DMF
OH R2 44-90% ee 129
Scheme 38.
N N 1. O H R
1
TiO
R2O 2C N + N CO 2R
2
N H [bmim][BF4], 0 C
o
CO2H (10 mol%)
NHCO2R2 HO R1 Yield; 89-96% ee;92-96% 62 N CO2R2
2. NaBH4, MeOH, 0oC, 5 min
R1 = Me, Et, n-Pr, n-Bu, i-Pr, Bn R2 = Bn, i-Pr, Et 23 61
Scheme 39.
O 0.1 eq, precatalyst R

1
OH R1 R2 131
(i) N Boc 135 O H
2 eq RSH N Boc 136
SR SR H
R 39
BH3THF,THF,rt
a: R=Ph b: R=p-Me-C6H4 c: R=2,6-Me2-C6H3 d: R= t-Bu
Rf8 Rf8 = C8F17 N H HO Rf8 130
(ii) R1
Precatalyst:
R2 +
Ar
NO2
catalyst 136b (10 mol%) CH2Cl2 R

2
O * R1
Ar * NO2
58
56
>90% ee, >90% de 137
Scheme 40.
Scheme 42.
O O + H L-ProLDH 133
OH
90%, 94% ee 15 132 134
3.2.5. A recoverable uorous CBS methodology using uorous prolinol A recoverable uorous CBS methodology for the asymmetric reduction of ketones using a uorous prolinol catalyst has been successfully developed by Dalicsek et al.83 They generated a uorous oxaborolidine in situ, which efciently 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 obtained in good yield (90%) and with high enantiomeric excess (94%) (Scheme 41). 3.2.7. Prolinal dithioacetals as organocatalysts Mandal et al. discovered prolinal dithioacetals 136 (Scheme 34) could be used as a catalyst for highly stereoselective Michael
Scheme 41.
In addition, the improved solubility of these new catalysts in organic solvents permitted their use in lower amounts when compared to proline (Scheme 38). Recently, the direct asymmetric a-amination of unmodied aldehydes 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 recycled and reused at least four times without a signicant loss of yield or enantioselectivity (Scheme 39).
1829
(i)
1. BrCH2CH2OH Me N N 138 2. NaBF4, acetone
Me
N 139
OH BF4-
Boc-Pro-OH DCC, DMAP CF3CO2H Me N N 141 O (ii) 15 + R

1
Me O-Pro-H CF3COOO Catalyst 141 H 24 O
N 140 OH R1
O-Pro-Boc BF4-
129
Scheme 43.
H N H M
O O
Metal catalysis
Figure 10. Proline as a metal ligand.
Rh
136. These prolinal dithioacetals could be synthesized in one step from N-Boc-prolinal 135 and thiols (Scheme 42).
PPh2
Ph2P H N N O NH O O O HN
NH 2
Figure 11. Rhodium metal complex of a proline derivative with phosphanyl groups.
3.2.8. Ionic liquid supported proline as organocatalyst Ionic liquid supported proline 141 has also been investigated86 as an efcient catalyst in the direct aldol reactions of acetone with aldehydes. The ionic liquid supported proline derivative was synthesized from L-proline. The yield and enantiomeric purity of the condensation products, the corresponding b-hydroxyl carbonyl compounds 129, have been found to be comparable to those obtained under homogenous conditions (Scheme 43). The major advantage 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 exible approach for catalyzing and determining the reaction pathway
additions of ketones and aldehydes to b-nitrostyrenes.85 They observed a high degree of enantioselectivity (99%ee) and diastereoselectivity (99% de) in the Michael additions of ketones and aldehydes to b-nitrostyrenes, catalyzed by prolinal dithioacetals
TsCl, Na2CO3 N H COOH H2O, rt, 48h 94% N Ts 1 TsCl, pyridine 0oC, 20h 83% OTs N Ts 144 142 COOH
NaBH4/BF3Et 2O THF, rt, 18 h 81% OH N Ts 143
KI, acetone, 74% N Ts 145
1-substituted imidazoles MeCN, 80oC N Ts
I-
146
Scheme 44.
1830
N N N Ts N I[Rh(COD)Cl]2, KI KOBu , THF 76%

t
N N Rh I
Ts
146
147
Scheme 45.
B(OH)2 +
CHO NHC-Rh, KOBu DME/H2O Cl

t
OH O + Ph Cl 50 H CO2Me CN i-Pr2EtN,CH2Cl 2
Ph O Cat.155 or 156 N major 157a
CO2Me +
Ph O N
CO2Me
minor 157b
148
149
150
Methylisocyanate
Scheme 46.
Scheme 48.
for many of the organic reactions with a large range of chemical and biological applications; over the years, metal based methodologies 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 asymmetric rhodium phosphine complexes in asymmetric hydrogenations,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 diversied structures 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
O [RuCl2(p-cym)]2 X N H HN O Ph
OH
X 98%ee
HCOOH/Et3N 158 159
Scheme 49.
the other groups of the pincer backbone are also well investigated.9193 Depending on the choice of metal, these complexes have been applied in different catalytic reactions, such as aldol condensation reactions,9499 Michael additions,9193,100 DielsAlder reactions,94 cyclopropanations,101 allylation of aldehydes,102 allylic alkylations94 and hydrogen transfers,103 etc with moderate to high enantioselectivity.
H N H N CO2R Et3N,CH2Cl2 rt, 16h N LMe R=Me LBn R=Bn 151 152 153 Br H
CO2R
Br Br + Br
CO2R
H N [Pd2(dba)3].CHCl3 C6H6,50oC,3h Pd N R=Me R=Bn 154
CO2R
H N
CO2R
Br H CO2R
AgBF4, acetone/H2O,rt or NH4PF6/H2O,CH3OH,rt
Pd H N
O C O
R 155a: R=Me, X=BF4 155b: R=Me, X=PF6 156a: R=Bn, X=BF4 156b: R=Bn, X=PF6
Scheme 47.

H R Ti(OiPr)4 ligand 30% H2O2 96-98%ee Ph ligand 160 161 Ph R O N OH N H HO
1831
Scheme 50.
VO(acac)2 5 mol% O + N H tBuOOH H N hygrine 10 mol% 162 15 Proline 163 O
Scheme 51.
N O P* Ph 164a Ar
PPh2 N O Ph P* 164a Ar
PPh2
PPh2 N H2 ClAr P* Ph OH O
Figure 12. Amido- and amino diphosphine ligands.
OAc Ph 164b Ph
i. Pd catalyst ii. Asymmetric ligand 164a (iii).CH 2(COOMe)2 Ph
CH(COOMe) 2 Ph 165
Scheme 52.
On the other hand, proline as a metal ligand has had a great impact on biological systems as well; for example, proline as a heme ligand is employed in CooA, the only protein which is a co-activated 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 peptidemetal complexes. FMoc and Boc derivatives of proline with phosphanyl groups have also been synthesized,90 and these modied proline derivatives have been incorporated into short peptides possessing secondary 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 from L-proline has been achieved with the aim of developing 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 of 142, with NaBH4 and BF3Et2O at room temperature followed by quenching the reaction mixture with methanol furnished (2S)-2-(hydroxymethyl)-1-(4-tolylsulfonyl) pyrrolidine
143. The resulting alcohol, after a sequence of reactions as shown in Scheme 44, provided the desired imidazolonium salt 146. Salt 146 was used for the preparation of an asymmetric NHC-Rh complex 147, where [Rh(COD)Cl]2 was treated with KOBut in THF, and subsequently allowed to react with proline derivative 146, 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 148 to p-chlorobenzaldehyde 149 in dimethoxyethane (DME)H2O (3:1) in the presence of a base under various reaction conditions have been studied. It was concluded that the 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 coordination 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 reactions between benzaldehyde and methyl isocyanate in the presence of i-Pr2EtN. The reactions were carried out in CH2Cl2 with 1 mol % of catalyst. In each case, the trans-oxazolines 157a was obtained 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 from proline as asymmetric ligands in the ruthenium(II) catalyzed transfer hydrogenation reaction of prochiral ketones, where product formation occurred with approximately 98% ee (Scheme 49). The highly enantioselective epoxidation of styrenes 160 catalyzed 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. hydrogen peroxide as an oxidant, with high enantiomeric excesses ranging 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 combination of vanadium and proline as an organocatalyst enabled the direct oxidative coupling of cyclic tertiary amines 162, with nonactivated ketones without the requirement of preformed leaving groups. In this catalytic system, elemental oxygen was employed as a terminal oxidant (Scheme 51). The above strategy was successfully employed for the synthesis of hygrine 163. The synthesis of P-chirogenic diarylphosphinocarboxylic acids was carried out, from which a new class of amido- and aminodiphosphine 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 1,3diphenylpropenylacetate 164b (Scheme 52). Li et al. have developed two asymmetric metal clusters utilizing the nucleophilic addition of L-proline to di-2-pyridylketone 166 as the key step.111 In the presence of cobalt (nickel) acetate, an asymmetric ligand with the molecular formula (S)-(C5NH4)2 C(OH) (C4NH7CO2H) was rst obtained via the nucleophilic addition of
1832

H N + N O 166 {Na[M4L3(OAc)3](ClO4)1.5(H2O)1.5}(ClO4)(OH)0.5 .3H2O (M=Co, Ni) {L= (S)-(C5NH4)2 C(OH)(C 4NH7CO2H)} N
CO2H
Co(OAc)2 or Ni(OAc)2
(S)-(C5NH4)2 C(OH)(C4NH7CO2H) Ligand formed in situ
two asymmetric tetranuclear isomorphous complexes 167a and 167b
Scheme 53.
O F3C C HN I + R 168 CuI (20%) Ligand (40%) -45 to -20 oC DMF/H2O NaOH (2equiv.) O 169 O 175a, R1=H 175b , R1=Ph HO Ligand N H CO2H
L-proline
R1 CuI, (L)-proline Me OR R2 NaIO4, AcOH, 80oC R2
OH R1 OAc R1=H(or) Ar 85% yield 176
Scheme 55.
(2S,4R)-4-hydroxyproline O F3C C
O HN *
Me OR O
R 60 to 90% ee 170
Scheme 54.
OH OH2 O O O Th N O O N N O O O Th N O O [Th(Q)2(Pro)NO3H2O] complex 171 [Th(Q)2(Hyp)NO3H2O] complex 172 OH O N NH
NH
OH2 O N O
NH O O H2O
O OH2 U N O O O
NH
O OH2 U N O
H2O
as a secondary amine to di-2-pyridylketone.The above ligand was synthesized in situ, and ultimately afforded two asymmetric 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 Co4 cluster 167a, was found to possess prominent ferromagnetic properties. Xie et al. achieved112,113 an original CuI catalyzed asymmetric coupling of various 2-iodotriuoroacetanilides 168 with 2methylacetoacetates 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-arylmethylacetoacetates 170, with the generation of enantiomerically pure aaryl carbon quaternary centers. The asymmetric products were obtained in good yields in the presence of NaOH as the base and at lower temperatures when compared to the original Ullmann coupling. The much simpler reaction conditions in this synthetic strategy was one of the key factors in the breakthrough which was investigated by Xie et al., as the rst example of a catalytic asymmetric 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-Lprolines as the secondary ligands, respectively (Fig. 13). These mixed ligand complexes 171174 were prepared from metal salts (aqueous solution), primary ligand (ethanolic solution), and secondary ligands (aqueous solution). These complexes were found to exhibit prominent antibacterial activity against the pathogenic bacteria Staphylococcus aureus and Escherichia coli. Recently the CuI/proline catalyzed selective one-step mono acylation of styrenes 175a and stilbenes 175b has been described115 by Prathima et al. Vicinal di-oxygenation of styrene-type olens was achieved with the less expensive and less toxic CuI in the presence of L-proline as a ligand and NaIO4 as the oxidant. This approach provided a straightforward and efcient access to mono-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
[U(Q)(Pro)2H 2O] complex 173
[U(Q)(Hyp)2H2O] complex 174
Figure 13. Proposed structures and bonding for the thorium and uranium complexes involving 8-hydroxy quinoline as the primary ligand and L-proline and 4-hydroxy-L-prolines as the secondary ligands.
1833
O OH O N H OH O HO
H CH3 H N O N OH H H CH3 H O OH Boc
R OH O
a, R=Ph b, R= CH2CH2CH3 c, R=CO2R1 Conformationally constrained analogues of phenylalanine, norleucine and aspartate respectively149
Kainica cid: 27,31 a potent neurotransmitter
(-)-Domoic acid:116 a neurotoxin
OH HO O N H OH N H OH O
HO O N H OH
(-)-Bulgecinine: 117-119 a constituent of bioactive glycopeptide bulgecin
(S)-4-Exomethyleneproline: 162 an inhibitor of the enzyme proline dehydrogenase
4-Hydroxy-L-proline:174 a constituent of Collagen
R1 OH N O O R
2
HO O H N N H H OH OH
O OH SCH3
a: R1=H, R2= Captopril189
SH CH3 H N
Lincomycin:121,122 an antibiotic CO2Et CH2CH2Ph O O P ( )4 Ph N Me Me (+)-Hygrine:198 an alkaloid O
b: R1=H, R2= Enalaprilat192
c :R =cyclohexyl, R = Fosinopril194 H 3C H 3C O a,b,c: Potent ACE inhibitors O O
Figure 14. Applications of various proline derivatives.
Multisubstituted prolines R R N H CO2H N H CO2H
5-substituted prolines N H 1 N H CO2H Synthesis of bioactive molecules, natural products, azanucleosides etc. CO2H
2-substituted prolines
N H
CO2H
Figure 15. Differentially modied prolines as unnatural aminoacids/aminoacid derivatives.
bioactive natural products, such as ()-domoic acid116 a potent neurotoxin, 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-methyl4-ethylproline in lincomycin B,121 4-methylproline in peptide
1834
CHO N H CO2H CF3CO2H (cat) H N O O
LDA,-78oC Electrophile
1 E N H CO2H
177 E Hydrolysis H N O O
179
178
Scheme 56.
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 inhibitors.123,124 The presence of proline itself is associated with conformational changes in proteins including a strong preference for secondary structural modications, for example, a-helixes and reverse turns.3,4125128 This property has marked effects ranging from its role in collagen biosynthesis in protein folding to peptide hormone recognition events.129137 Substituted prolines have also found use in the synthesis of conformationally constrained peptides, which have been acknowledged as useful tools in the development of peptide derived pharmaceutical agents.11,12,138 Due to such a wide 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.
NO2 1.KHMDS 2.Nitroarene N H CO2H N H O O 3.DDQ H N O O
177 NO2 Hydrolysis
180
Z N H HO 181 O
Scheme 57.
OH H N H + CO2H Cl OEt Cl Cl CHCl3 reflux 65% Cl Cl 1 182 Cl 183 N
H O
LDA, THF, -78 oC, Br N Cl Cl Cl 184 O O
82%
Na CH3OH N CHO CO2Me
AcCl, MeOH, reflux 74% over two steps CO2Me N H HCl 185
Scheme 58.
CF3 O CF3 O HN O Ph Ph 186 187 N H OH 189 Iodocyclization N O HO OH CF3 O I CF3 O 188 N H OH
Scheme 59.

Ph HN F 3C CF3 O CO2Et N H CO2H
1835
(S)- -Tfm-proline 190 188
CO2H N H CF3 N H
CF3 OH
(R)- -Tfm-proline 191
(S)--Tfm-prolinol 192
of proline with commercially available 2,2,2-trichloro-1-ethoxyethanol 182 (Scheme 58). Recently Caupene et al. described a versatile strategy142 for the synthesis of enantiopure a-triuoromethyl prolines 188 and atriuoromethyl dihydroxy prolines 189 through efcient iodocyclization of asymmetric triuoromethyl allyl morpholinone 186 (Scheme 59). A straightforward asymmetric synthesis of (S)- and (R)-atriuoromethyl prolines 188 and 191, respectively, from oxazolidines 190, derived from ethyl triuoropyruate has been described by Chaume et al.143 (Scheme 60). The key steps in this synthetic strategy were the diastereoselective allylation reaction of ethyltriuoropyruvate 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-Tfmallylglycine and (S)-a-Tfm-norvaline in enantiomerically pure form. 3.4.2. 3-Substituted prolines 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 conformational 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 the b-carbon of standard amino acids; for example, 3-phenyl prolines, 3-n-propyl prolines, and proline-3-carboxylates are conformationally constrained 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,bunsaturated aldehydes 193 under basic conditions. The condensation product, hydroxyl lactam 195, was subjected to acid catalyzed silane reduction enabling subsequent transformations to occur cleanly and in good yield. The trans-isomers were resolved via their diastereomeric (S)-a-methyl benzyl amides and the absolute congurations 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 efcient conversion to prolines, via reduction of the lactam carbonyl functionality. By taking advantage of this fact, Oba et al. carried 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-
Scheme 60.
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 advances 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 synthesis of 2-a-substituted prolines through self reproduction of chirality, where the acid catalyzed condensation of proline with pivaldehyde furnished a bicyclic derivative (2R,5S)-2-t-butyl-1azabicyclo[3,3,0]octan-4-one 177, where the t-butyl group acquired a pseudo equatorial position. The lithium enolate derived reaction of this bicyclic derivative with electrophiles resulted in the formation of 2-substituted derivative 178, where the incoming group approached from the same side as occupied by the t-butyl group, that is, the a-side with the retention of conguration. Hydrolysis of compound 178 afforded 2-a-substituted proline 179 (Scheme 56). The enantioselective synthesis of (R)-a-(p-nitroaryl)proline 181 via an oxidative nucleophilic substitution of hydrogen in nitroarynes has been carried out140 in a similar manner as described by Seebach et al., exploring the self reproduction of chirality in prolines (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
H R O 193 + O N H 194 CO2Et CO2Et R EtO-Na+ HO N Ac 195 CO2Et CO2Et [H+], Silane reduction - CO2Et N Ac O R OEt
R=Ph, R=n-propyl
196
Resolution Pure stereoisomers of 196
Scheme 61.
1836

Me O Michael additiion N Boc 197a ABO O N Boc 197b ABO HCl, MeOH, then (Boc)2O, DMAP O N Boc 198 BH3THF Me 1M HCl N H 200 CO2H DOWEX 50WX8 N Boc 199 CO2Me Me CO2Me Me
Scheme 62.
OBn
OBn
H2N O N Ts
HO
H N O N Ts
HO
NH2 OH N H
* N3 CO2But H (i) Hydroboration * (ii) Cycloalkylation N FMoc 207 208 CO2H H
201
202
203
Scheme 63. Scheme 65.
Boc-3-methylpyroglutamate 198. Reduction of 198 with BH3THF, followed by the deprotection of 199, in reuxing 1 M HCl and subsequent ion exchange treatment with DOWEX 50X 8 resin furnished (2S,3S)-3-methyl praline 200 in quantitative yield (Scheme 62). Curtis et al. carried out the rst 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 trisubstituted pyrrolidine (Scheme 63). Kamenecka et al. described an enantioselective approach to 3-substituted prolines.152 The enantioselective synthesis of 3substituted prolines 206, was achieved starting from commercially available 3-hydroxy-(S)-proline 204. A palladium mediated coupling was used to introduce various groups at C-3 using the corresponding enol triate derived from N-trityl-3-oxo-(S)-2-proline methyl ester. Cleavage of the trityl residue and hydrogenation afforded nal product 206, with satisfactory diastereoselectivity (Scheme 64). The synthesis of diastereomeric substituted proline peptidomimetics as a conformationally restricted tyrosine derivative 208, has been accomplished153 utilizing the intramolecular hydroboration cycloalkylation of azido olens 207, as the key step (Scheme 65). The asymmetric synthesis of proline based conformationally constrained tryptophan mimetic 212, has been reported by Delaye et al.154 The strategy involved the in situ generation of an allyl metal species containing the indole moiety, which was allowed to undergo coupling with asymmetric imine 210. The construction of the 3-substituted proline skeleton was achieved through a hydrozirconation/iodination sequence to the resultant homoallylic amine (Scheme 66).
Boc (i) Et 2Zn ZrCp2 N Boc 209 OR (ii) HN O Boc N OBn 210 BnO Ph 211 NH OH Ph N
HO2C
N Fmoc 212
Scheme 66.
i,ii,iii N Ph 213 212 CO2Bn 3 Steps N Fmoc CO2H
N Boc
R = -H, -OMe, -NO2, Cl, -CO2Me
Scheme 67. Reagents and conditions: (i) Amino zinc-ene-enolate cyclization; (ii) transmetallation; (iii) Negishi-cross-coupling.
OH
OTf
(i) Pd-mediated coupling (ii) HCl; H2 N Cl - H2 206
N H 204
CO2H
N Tr 205
CO2Me
CO2Me
Scheme 64.

HO HO OH O OH i ii OH D-(+)-Glucose H N Cbz 214 O O O iii,iv v,vi N H H CO2H H OH
1837
L-cis-3-hydroxyproline 204
Scheme 68. Reagents and conditions: (i) Conversion to N-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.
i. NCS ii. Cbz-Cl CO2Me N H HCl 215 one pot N Cbz 216 CO2Me
R i. R-MgX Cu(I)X ii. LiOH N Cbz 217 CO2H
Scheme 69.
A short access to cis-3-substituted prolino homotryptophan derivative 212, was developed through amino zinc-ene-enolate cyclization sequences.155 The asymmetric synthesis of cis-3-substituted 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 Nprotected compounds were obtained, which could be utilized in peptide synthesis.
Recently the total synthesis of natural cis-3-hydroxy-L-proline 204, from D-glucose was described156 by Kalamkar et al. The methodology involved the conversion of D-glucose into N-benzyloxycarbonyl-c-alkenyl amine, which upon 5-endo-trig-amino mercuration afforded the pyrrolidine ring skeleton with a sugar attachment in roughly 25% yield. In an alternative procedure, the N-benzyloxycarbonyl-c-alkenyl amine upon hydroboration-oxidation, mesylation, and intramolecular SN2 cyclization furnished a pyrrolidine ring compound in high yield. Hydrolysis of a 1,2-acetonide, NaIO4 cleavage, followed by oxidation of the aldehyde into an acid and subsequent hydrogenolysis afforded cis-3-hydroxy-L-proline 204, in 29% yield from D-glucose (Scheme 68). Huy et al. have investigated157 a convenient synthesis of trans3-substituted proline derivatives through a 1,4-addition (Scheme 69). A four step synthesis of 3-alkyl-, vinyl-, and arylsubstituted proline derivatives 217, has been achieved. These 3-substituted prolines have been acknowledged as important building blocks for conformationally constrained peptide analogues. 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
R1O Ph2CuLi/Et 2O/THF N Boc 218a, R =H 218b , R1=Ts

1
Ph CF3CO2H N Boc 219 CO2R2 CO2R2
Ph
NH 4Cl-H2O
N H 220
CO2H
Scheme 70.
(i) ROH/H+ O N H 10 CO2H (ii) NaBH4 O N H 221 CH2OH
PhCHO/H+ O N O Ph 222
Br LDA, -78 C
o
LAH/THF O N O Ph 223 Ph 224 N CH2OH
H2/Pd-C
Z-Cl/K2CO3 N H CH2OH H2O-THF N Z 226
(i) Jones oxidation (ii) H2/Pd-C CH2OH N H 227 COOH
225
Scheme 71.
1838

OH R LiHMDS, -78oC O N Z 228 CO2But RCHO O + N Z 229 H2/Pd-C, 50psi, MeOH R (i) Lawesson's reagent (ii) Nickel-boride R CO2But dr:3:1 O N Z 230 CO2But R OH
N H 232
CO2But
N H 231
CO2But
Scheme 72.
215 in two steps. The 1,4-addition products were obtained with good trans-selectivity (dr 5:1 to 25:1). 3.4.3. 4-Substituted prolines Interest in the synthesis of 4-substituted prolines was increased when 4-hydroxy-L-proline was discovered for the rst time as the constituent 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 modied captopril and enalapril analogues. Since then, rapid progress has been made in investigating and developing newer methodologies for the synthesis of 4-substituted prolines. trans-4-Phenyl-L-proline 220, and trans-4-cyclohexyl-L-proline 227, are effective intermediates for potent ACE inhibitors. The synthesis of trans-4-phenyl-L-proline 220 was 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 deprotection, furnished excellent yields of 4-phenyl substituted L-prolines and the reaction proceeded with net retention of conguration at the carbon center bearing the tosyloxy group. Taking advantage of the possibility for easy conversion of pyroglutamic acid into proline, Thottahil et al. developed39,123 an efcient strategy for the synthesis of trans-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 benzaldehyde, furnished a bicyclic derivative 222, where the phenyl group acquired a pseudo equatorial position. Alkylation of the lithium 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 oxidative reactions 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-pyroglutamate 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 by the reduction of the resultant thiolactam with nickel boride (generated in situ) furnished t-butyl-(2S)-4-a(phenylmethyl) prolinate 232, in reasonable yield (Scheme 72). Racemic 4-exomethylene proline is a natural product isolated from the seeds of loquat (Eriobotrya japonica).162 Enantiomerically pure (2S)-4-exomethyleneproline, a structurally modied proline has been found to be the inhibitor of proline dehydrogenase. It has also been found to be useful as an element of peptides and drugs such as tomaymycin analogues. The total synthesis of (S)4-exomethylene proline benzyl ester 238, has been carried out starting from pyroglutamic acid,162 where the lithium enolate derived reaction of N-protected (2S)-benzyl pyroglutamate 233 with Eischenmosers salt afforded 4-dimethylaminomethyl derivative 234. Compound 234, upon selective reduction with DIBAL-H, followed by treatment with sodium cyanoborohydride in acetic acid afforded compound 236. N-Oxidation of 236 with m-chloro
N LiHMDS, -78oC N Boc 233 CO2Bn N I ,THF

-
N DIBAL-H N Boc 234 CO2Bn HO
N Boc 235
CO2Bn
NaBH3CN CH3CO2H O(i) N H 238 CO2Bn (ii) CF3CO2H N Boc 237 N N MCPBA CH2Cl2 CO2Bn N Boc 236 CO2Bn
Scheme 73.
1839
CF3CO2H O N H CO2H O N H CH2OH PhCHO, O N O Ph 10 221 222
(i) LDA,-78oC PhSeBr (ii) Oxidation
O t-Bu-OOH O N O Ph Ph 239 240 OCOPh OCOPh CF3CO2H O DIBAL-H N R1 OR2 R2O N Boc 243a: R1=R2=H 243b: R1=H, R2=CH(Me)OEt 243c: R1=Boc, R2=CH(Me)OEt OR1 K2CO3-nBu 4NF O N O SmI 2 THF-MeOH
OR O
N O Ph 241, R=H 242, R=COPh
THF- H 2O
PhCOCl, CH2Cl2, Et3N
MeOH/H+
244, R1=CH(Me)OEt, R2=H 245, R1=H, R2=H
OCOPh OH Me3SiCN SnCl4, CH 2Cl2 NC N Boc 246 OH HCl HO2C OH N H (-)- Bulgecinine
Scheme 74.
perbenzoic acid (MCPBA) and subsequent heating at 85 C in THFtoluene gave the elimination product, which after deprotection of the nitrogen provided (2S)-4-exomethyleneproline benzyl ester 238 (Scheme 73). ()-Bulgecinine, a proline derivative, is the common constituent of the o-sulfonated glycopeptide bulgecin.117119 The natural product induces a bulge formation in the cell wall of gram-negative bacteria and is a potent b-lactam synergist. Consequently, the synthesis of its non-proteinogenic amino acid has received much attention. There are various synthetic strategies reported for the total synthesis of ()-bulgecinine. One of the synthetic approaches is described118 in Scheme 74, which was started from (2S)-pyroglutamic acid 10. (2S)-Pyroglutamic acid was converted to (5S)-pyroglutaminol 221. Acid catalyzed condensation of 221, with benzaldehyde afforded bicyclic derivative 222. Compound 222, upon a lithium enolate derived reaction with phenylselenium bromide, followed by oxidative elimination, furnished the unsaturated compound 239. Compound 239, upon epoxidation followed by ring opening, furnished derivative 241. The hydroxyl group of derivative 241, was protected as its O-benzoyl derivative 242. Compound 242, upon acid hydrolysis with triuoroacetic acid afforded derivative 243a. After suitable protection of the NH and OH of 243a, with (Boc)2O and ethyl vinyl ether, respectively, the resulting compound 243c was subjected to selective reduction of lactam carbonyl with DIBAL-H, followed by cyanation and hydrolysis sequences to afford ()-bulgecinine in satisfactory yield (Scheme 74). Caputo et al. described a novel method for the synthesis of sulfur and selenium containing bis-a-amino acids from 4-hydroxyl proline.163 The (S)-alkylation reaction of trans-4-hydroxy-L-proline at C-4 by the cysteine residue occurred via an SN2 process involving the existing hydroxyl group. The stereochemical outcome was controlled by transforming the hydroxyl group either into its tosyl
ester, thus maintaining the trans-conguration, or else by replacement with an iodine complex, leading to cis-4-iodo-L-proline. The subsequent attack by the cysteinyl nucleophile afforded trans(4S)-cysteinyl-L-proline 250 from iodide and cis-(4S)-cysteinylL-proline 251 from tosylate (Scheme 75). In the same way, two diastereomeric trans- and cis-4-selenocysteinyl-L-prolines 254 and 257, respectively, were synthesized through the attack of the selenocysteinyl nucleophile (Scheme 75). A series of novel cis-4-substituted proline analogues have been synthesized from N- and O-protected glutamic acid 203.164 Highly stereoselective alkylations at the c-position of glutamic ester 258, were achieved to give compound 259. Compound 259 upon reductive mesylation followed by cyclization afforded the title compound 260, in good yields and with high diastereoselectivity (Scheme 76). Lenda et al. described the synthesis of new tetrazole and triazole substituted pyroglutamic acid and proline derivatives from dimethyl-2,4-dibromoglutaryle 261 in good yields using mild reaction conditions.165 The key step for the synthesis of the triazole substituted molecule 264 was the 1,3-dipolar cycloaddition of an acetylenic compound with an azido derivative (Scheme 77). 3.4.4. 5-Substituted prolines Concentration of 5-hydroxyproline in injured tissues is a parameter associated with their wound healing capacity.166,167 These are also building blocks for the preparation of various optically active proline derivatives,149,168 and are considered to be versatile precursors for the synthesis of conformationally constrained peptidomimetics.169173 Keeping these aspects in mind, different protocols have been explored to obtain 5-hydroxylated prolines. Recently, cyclobutane serine amino acid derivatives have been used for the synthesis of 5-hydroxyproline.174 Cyclobutane serine amino acid 268, upon reaction with one equivalent of sodium hydride in THF at room temperature, furnished a mixture of
1840
HO
HO (i) (Boc)2O, NaOH CO2H N H trans- 4-hydroxy (S)-proline H2O-AcCN (ii) BnBr, DMF, K2CO3 N Boc 247 S CO2Bn TPP-I2,ImH CH 2Cl2, 1h
N Boc 248
CO2Bn
TsCl, pyridine, 12h
I HCl, L-Cys-OEt O N Boc 248 TsO HCl, L-Cys-OEt O N Boc 249 Se I i O N Boc 252 OMe H2N HO2C OBn DMF, Cs2CO3, 50oC 3h OBn DMF, Cs2CO3, rt 3h
H2N EtO2C
TsO N Boc 250 H2N EtO2C N Boc 251 S 249 CO2Bn CO2Bn N Boc CO2Bn
O N Boc 253 Fmoc-HN HO2C N Boc 254 O N Boc 256 Se Fmoc-HN HO2C O N Boc 257 OMe OMe ii Se O OMe OMe ii
TsO O N Boc 255 OMe i
H2N HO2C
Se
(i). L-(Sec)2, EtOH, NaBH4, (ii). THF, Fmoc-Cl, DIEPA, 0oC to rt, 1h
Scheme 75.
O MeO 258
O OBut NHBoc alkylation MeO
O OBu
t
Br MeO O 261
Br OMe O NaN3, acetone Acetylene derivative MeO2C N Br
N N
CO2Me CO2Me CO2Me
R 259
NHBoc
(i) Reductive mesylation (ii) Cyclization
262 NaN3, acetone Pd/C, MeOH
R
t
CO2H CO2Bu N N N CO2H i. BH3THF ii. 6M HCl Propylene oxide, CH2Cl2 CO2H N N
CO2Me CO2Me N
N Boc 260
Scheme 76.
N H 264
N H 263
CO2H
cis-5-hydroxyproline 269, and trans-5-hydroxyproline 270, in a ratio of 68/32 (Scheme 78). A possible mechanism for the aforementioned reaction, as proposed by Fernandez et al.,174 is described in Figure 16. First a retro-aldol process occurred after deprotonation of the hydroxyl
Scheme 77.
proton by a base. The aldehyde formation coupled with cyclobutane ring opening led to a tertiary carbanion. A series of acidbase equilibria resulted in an amide formation. A nal amide

XR Lewis acid [2+2] cycloaddition XR CO2R NHR1 X=O,S 266 OH H2, Pd-C CO2Me NHAc 267 EtOAc CO2Me NHAc 268 HO N Ac 270 CO2Me NaH,THF rt HO N Ac 269 + Base induced elimination CO2Me R TsHN CO2Me I2 R N Ts 274 275a CO2Me R N Ts 275b I
1841
CO2R NHR1 265 OBn
CO2Me
N H 276
CO2Me
Scheme 78.
nucleophilic attack onto the aldehyde carbonyl group furnished the cis/trans mixture of 5-hydroxy-L-proline 269 and 270, respectively, after protonation. The electron withdrawing character of the carboxylate group might be the driving force for the reaction, as it possibly leads to the stabilization of the carbanion formed in the retro-aldol process. Skrinjar et al. described the synthesis of 5-substituted prolines from N-acylated pyroglutamates 271.175,176 The reduction of lactam carbonyl of 271, afforded hydroxyl derivative 272a, which was converted to methoxy derivative 272b. The addition of RCu, BF3 to 5methoxy proline ester (272b) was found to be highly trans-selective (>96%) thereby furnishing the trans-5-substituted proline ester 273a. The above strategy led to the synthesis of the ant trail feromone trans-2-butyl-5-heptylpyrrolidine 273b (Scheme 79). Knight et al. explored177 a novel strategy for the synthesis of 5substituted proline derivatives 275a and 275b by 5-endo cyclization of the C-allylic glycine sulfonamides 274, leading to the formation of 2,5-cis- or 2,5-trans-pyrrolidine-2-carboxylates, respectively (Scheme 80), depending upon the presence or absence of base. The base induced elimination of both hydrogen iodide and p-toluene
Scheme 80.
sulfonic acid from the corresponding iodopyrrolidine 275a or 275b led to 5-substituted pyrrole-2-carboxylates 276. An effective synthetic approach to 5-substituted proline derivatives 279, using silver catalyzed cyclization as the key step was described by Essseveldt et al..178 The methodology involved a silver catalyzed-5-endo-dig cyclization of enantiomerically pure arylsubstituted acetylene-containing amino acids 277, thereby furnishing the target molecule (Scheme 81). Recently Lygo et al. described179 an enantioselective synthesis of cis-5 substituted proline esters 282, using a phase transfer catalyst. The strategy involved an asymmetric PTC Michael addition, followed by an acid catalyzed imine exchange and a catalytic hydrogenation (Scheme 82). 3.4.5. Synthesis of multi-substituted prolines 3.4.5.1. Synthesis and reactivity of 2, 4, 5-substituted prolines. Cycloaddition reactions of various types are well known to be one of the most efcient transformations in organic synthesis.
O OH B CO2Me NHAc
-
O CO2Me NHAc
O CO2Me NAc H H
O NAc H CO2Me BH
NAc CO2Me
HO
N Ac
CO2Me
Figure 16. A possible mechanism for the transformation of cyclobutane serine amino acid to 5-hydroxy proline.
H+ (reduction) N CO2R 271 CO2R2

1
R3O
R4Cu N CO2R CO2R2

1
BF 3
R4
N CO2R1 273a
CO2R2
272a; R3=H 272b ; R3=OMe
Bu
N CO2R1 273b
Hept
Scheme 79.
1842
Ar
(i) H2N 277 CO2H R

1
N 278
CO2R R
1
N H 279
CO2R
Scheme 81. Reagents and conditions: (i) Silver catalyzed-5-endo-dig cyclization.
Ph2C
N 280 + O R 281
CO2t-Bu (i) Asymmetric PTC Michael addition (ii) Acid catalyzed imine exchange (iii) Catalytic hydrogenation R N H 282 R=Ph,Me,n-Bu 50-77% yield 89-96% ee CO2t-Bu O R Ar N H 290 CO2Me
O Pd(OH)2, AcOH O EtOAc O R Ar H2N CO2Me
Scheme 82.
Ar
N R 283 + O
CO2Me MeO2C R Ph2P OMe PPh2 Ar N H 286 CO2Me
Ph R O AgOTf N H 291 CO2Me
Scheme 86.
284
N Bn 285
Scheme 83.
Ar
N R 283 +
CO2Me PPh2 AgOAc, i-Pr2NEt, THF Ar N H 288 OBut But O2C R CO2Me
287
Chen et al. described181 asymmetric 1,3-dipolar additions using diphenylphosphine chiral ligands to induce stereoselectivity. Schiffs bases of different amino acids 283 upon 1,3-dipolar addition reaction with t-butyl acrylate 287 in the presence of silver acetate and (S)-QUINAP, furnished efciently asymmetric 2,4,5substituted proline derivatives 288 (Scheme 84). A simple and efcient one-pot synthetic strategy has been developed for the synthesis of (2S,4S,5R)-substituted prolines 290, through lithium bromide or silver acetate catalyzed 1,3-dipolar addition reactions of Schiffs bases of amino acid esters 283 with homochiral menthyl acrylate 289.182186 This reaction proceeded with high diastereoselectivity (Scheme 85). The (2S,4S,5R)-substituted prolinates 290 have been used effectively as precursors in the one-pot synthesis of the (4S)-a-substituted pyroglutamates 291, through hydrogenolysis, ring opening, and cyclization sequences187 (Scheme 86). 3.4.5.2. Synthesis of 3,3,4,4-tetra substituted prolines. The uorination free synthesis of 4,4-diuoro-3,3-dimethyl proline derivative 298 has been described.188 A Claisen rearrangement/ iodolactamization sequence starting from commercially available triuoroacetaldehyde methyl hemiacetal 292, followed by resolution, provided enantiomerically pure 4,4-diuoro-3,3-dimethyl proline 298, and thus avoided the use of hazardous uorination reagents to be utilized (Scheme 87).
Scheme 84.
O O O 289 + Ar N R 283 CO2Me LiBr, TMEDA THF Ar N H 290 O R CO2Me
Scheme 85.
These reactions furnish functionally and stereochemically complex carbo- and heterocyclic structures present as the key intermediates in many biologically important molecules. Transition metal catalyzed 1,3-dipolar addition reactions of imines with various dipolarophiles clearly indicated that copper(I) and silver(I) compounds are highly superior promoters in these reactions180(Scheme 83).
3.4.6. N-Acylation of proline derivatives With the introduction of captopril to the market in 1980s, as a potent angiotensin converting enzyme inhibitor,189192 N-acylated prolines as such, or suitably modied N-acylated proline derivatives have been designed and synthesized for the evaluation of their angiotensin converting enzyme inhibitory potential.193,194 Recently, the synthesis and angiotensin converting enzyme inhibitory activity of N-[30 -(acetylthio)alkanoyl] and N-[30 -mercaptoalkanoyl]-(4S)-a-(phenylmethyl) prolines 300 and 302, respectively, have been described.195 The synthetic strategy utilized the lithium enolate derived N-acylation of (4S)-a-(phenylmethyl) prolinate 232, with 3-(acetylthio)-(2S)-methyl propionyl chloride,
1843
OMe n-BuLi O CF3 O
OMe F F
Claisen rearrangement MeO
F 294
292 Bn Iodolactamization N O F 295 F F
293 I Boc N CO2H Boc
CO2H N
O BnHN
F 296
F 297
F 298
Scheme 87.
Ph LiHMDS, -78oC, THF N H 232 CO2Bu

t
Ph
CO2Me N N CO2But S C CH3 299 O CH3 305 CO2H PhI(OAc)2,I2 CH2Cl2,hv
CO2Me N
O S
O Cl CH3 O
306
Ph Ph N O CH3 301 CO2-DCHA+ S C O CH3 i.DCHA/Et2O
CF3CO2H, anisole
O N
OMe
F O TMSOTf or BF3Et 2O, F OTMS N N OTMS MeOH, 1h Lewis acid, bis(TMS)fluorouracil 307 CO2Me N OAc
N O
NH
ii.EtOAc/1M HCl O
CO2H S CH3 C O CH3
308
300 2N H2SO 4 Ph
CO2Me N O CH 3 302 CO2H SH 309 N OMe
Scheme 90. Scheme 88.
O (CH3CO)2O O R Ar O O R Ar N H 290 CO2Me O Z -L-Glu-anhydride O R Ar HO2C * NHZ Ph Z= O 304 O N O CO2Me Pyridine O CH3 303 N CO2Me
Scheme 89.
1844
DIBAL-H N Me CO2Me CH2Cl2 N Me 311 CHO
Ph3PCH 2OCH3Br, THF 10% HCl, THF N Me H 312 O
310
MeMgBr, THF N Me Me 313 OH
Dess-Martin reaction N Me Me 163 O
Scheme 91.
followed by acid hydrolysis with TFA to deprotect the t-butyl ester functionality. The free acid 300 was puried as its DCHA salt. The hydrolysis of DCHA salt 301 with 2 N H2SO4 furnished the mercapto compound 302, with simultaneous cleavage of the thioacetyl group (Scheme 88). The synthesis of (2S,4S,5R)-1-acyl-5-arylproline-2, 4-dicarboxylic esters 303 and 304, have been described,196 respectively. The prolinate 290, upon reaction with acetic anhydride and pyridine afforded (2S,4S,5R)-1-acetyl-5-(p-chlorophenyl)proline-2,4-dicarboxylic ester 303 in moderate yield. By taking advantage of the
successful N-acetylation, the same strategy was applied for the synthesis of dipeptide (2S,4S,5R)-1-(N-benzyloxy carbonyl-L-glutamoyl)-5-(p-chlorophenyl)proline-2,4-dicarboxylic ester 304, via the reaction of compound 290, with N-benzyloxy carbonyl-L-glutamic anhydride in the presence of pyridine (Scheme 89). 3.4.7. Synthesis of azanucleosides Recently Alicia Boto et al. have reported197 the one-pot synthesis of azanucleosides from proline derivatives. Proline derived carbamates were subjected to one pot scission/oxidation/addition
O
O O O O 314 N Cycloaddition with Danishefsky's diene
Ph
N O O
MeO2C (1S,2R,4R)-315
O Ph N Et3N, MeOH CHO MeO2C endo/exo (70:30) 317 Chromatographic separation rt, 4 days Ph
O N CHO MeO2C (1S,2R,4R)-316
O Ph N NaBH4 MeOH,0oC MeO2C CHO Ph
O N Ph NBS, PPh3 THF, 40oC MeO2C CH 2OH
O N
MeO2C
CH 2Br
(1S,2S,4R)-318
(1S,2S,4R)-319
(1S,2S,4R)-320
NaBH4, HMPA,70oC
O Ph N
MeO2C
CH3
(1S,2S,4R)-321
Scheme 92.
1845
sequences. N-(Methoxy carbonyl) proline 305 was treated with (diacetyliodo)benzene (DIB) and iodine at room temperature in the presence of sunlight, whereby radical decarboxylation took place followed by oxidation to the acyliminium intermediate 306, which existed in equilibrium with N,O-acetal 307. On addition of the Lewis acids, the acyliminium ion was regenerated, which was allowed to react with bis (trimethylsilyl) uorouracil, thereby affording product 308. Alternatively compound 307, was converted into the more stable a-methoxypyrrolidine 309, by treatment with methanol. Compound 309, was puried by chromatography, which upon reaction with bis-(TMS) uorouracil in the presence of a Lewis acid (BF3Et2O) and acetonitrile as the solvent afforded the desired compound 308 in 99% overall yield (Scheme 90). 3.4.8. Reduction of the carboxylic functionality of proline: asymmetric synthesis of (+)-hygrine (+)-Hygrine, a natural product, is an alkaloid present in coca leaves as well as other plants, and is associated with several biological and pharmacological applications. 198 ArevaloGarcia developed198 a short synthesis of (+)-hygrine in a series of six steps starting from readily available N-methyl proline derivative 310. The key steps involved reduction of the carboxyl group of proline derivative 310, to aldehyde 311, followed by Wittig, Grignard and DessMartin reaction sequences, thereby furnishing (+)-hygrine 163 in reasonable yield (Scheme 91). 3.4.9. Synthesis of enantiopure b-endo-substituted aza bicyclic proline A new approach for the synthesis of enantiopure b-endo -substituted aza bicyclic proline analogues has been described through base induced epimerization of a formyl derivative with the aim of utilizing b-endo-substituted azabicyclic prolines as a source to be incorporated in model peptides and to construct conformational restrictions to observe the inuence of the absolute congurations of the stereogenic centers.199 The cycloaddition of Danishefskys diene and chiral C-4 unsaturated oxazolone 314, derived from glyceraldehydes, allowed the stereo selective synthesis of methyl (1S,2R,4R)-N-benzoyl-2-[(S)2,2-dimethyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]heptanes-1carboxylate 315, which was converted to aldehyde derivative 316. The treatment of derivative (1S,2R,4R)-316, with Et3N using methanol as a solvent at room temperature for 4 days gave a crude mixture of 317, of endo/exo isomers in a ratio of 70:30, which were separated by chromatography to obtain the pure major stereoisomer (1S,2S,4R)-318. The aldehyde derivative 318, was reduced to alcohol (1S,2S,4R)-319, which upon treatment with N-bromosuccininmide, provided bromo derivative (1S,2S,4R)-320. The bromo derivative 320 upon hydride displacement with sodium borohydride in HMPA at reux afforded the target molecule 321, in excellent yield (Scheme 92). 4. Conclusion The present review gives explicit information about the versatility and importance of proline with a particular emphasis on its applications as an organocatalyst and/or metal ligand, coupled with its use in the asymmetric synthesis of a large number of bioactive molecules, natural products as well as asymmetric intermediates. On the one hand, this exceptional amino acid has proven to be a unique asymmetric catalyst, with potential to catalyze a wide variety of organic reactions, such as the aldol reaction, Mannich reaction and so on, while on the other hand, the possibility of differential derivatization/functionalization of the native proline moiety has enabled researchers to explore designed bioactive molecules e.g. angiotensin converting enzyme inhibitors such as
captopril, enalapril and so on, conformationally constrained peptides as well as peptidomimetics. Various derivatives of proline, for example, 4-exomethylene proline, ()-bulgecinine, kainic acid, ()-domoic acid etc, are themselves important bioactive natural products as such. Therefore, it may be concluded that proline has undoubtedly emerged as a unique a-amino acid, capable of catalyzing a vast spectrum of organic reactions regioand stereoselectively, either as such or in suitably derivatized form or else as a metal ligand. On the other hand, it has also provided researchers a useful asymmetric tool to exploit the possibility of differential functionalizations within the molecule and to utilize these for the asymmetric synthesis of a wide variety of bioactive compounds. However there is still a need to extend and study the scope of proline catalyzed reactions as a metal ligand on various other organic reactions, in particular asymmetric functional group transformations and ring forming reactions, with the aim to establish the versatility of proline chemistry as an important and unique asymmetric tool. Further research should also be aimed toward the synthesis of complex molecules and natural products, taking advantage of the possibility of differential functionalization of proline and to apply it for further advancements. The present review is an attempt to describe the useful and important applications on the use of this exceptional amino acid by researchers all over the world in the recent past, and may give future directions in light of progress already achieved with the objective of further advancements, and shall certainly be of help to make further progress and to develop new strategies for asymmetric synthesis based on these literature reports. Acknowledgments The author is thankful to the University Grants Commission, New Delhi, India for nancial assistance and to the Central Drug Research Institute, Lucknow, India for extending library facilities. References
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Review de L-Prolina y Sus Derivados en Sintesis Asimetrica

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Tetrahedron: Asymmetry 22 (2011) 18171847

Contents lists available at SciVerse ScienceDirect

Tetrahedron: Asymmetry Report Number 138

Tel./fax: +91 581 2529138.

S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847

Ni/H 2 H2N EtOOC COOEt O 6 HN COOEt

i) OH ii) HCl N Cl- H2 9 COOH

Triethyloxonium fluoroborate O N H 10 CO2H NaBH4 N H 1 Ph BH3THF N H 11 CO2H NaBH4 N H 12 CO2H CO2H

Figure 1. Structure of proline.

S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847

Amination, aminoxylation Diels - Alder reaction

Reductive alkylations SN 2 alkylation

Synthesis of heterocycles Reductions Michael addition

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

COOH N H Me Bi functional catalysis N R

Figure 3. Possible modes of proline catalysis.

O O + 20 vol% H NO2 L-proline

30 mol% DMSO 68%(76%ee) 17

metal- free Zimmeraman- Traxler model

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

O 10 mol%, DMF, 4oC H R

S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847

L-proline, 20 mol % DMSO H3C

O CO2Et 37 L-proline, 20mol% CH 2Cl 2, rt, 3h

OH L-proline(15 mol%) NTs Direct 6-enolexo aldolization O

NTs O 70% dr>10:1

S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847

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

NH 2 O + R1 R2 H O R3 + L-proline, DMSO OMe 39 24 40 5-35 mol%

i. L-proline THF, rt, 16-20 h ii. Et2AlCN NC

NHPMP R3 O R + 2 X 49 50 CHO + NH 3 L-proline 30 mol% X N H X 51 O R

S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847

X=CH; Imidazole X=N;1,2,3-Triazole 54

O Ph + L-proline 15 mol% DMSO, 16h 94%

Ph NO2 ee;23% dr>20:1

L-proline 10-20 mol% DMSO,rt R1

L-proline N N CO2Bn 10 mol% NaBH4 HO R2 62

O O (ii) R1 R2 N + Ph O L-proline 10-30 mol% DMSO,2-3 h,rt

7-11%ee >99% ee O/N selectivity> 100:1 to 8:22 64 65

S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847

R CHO R: nPr, (CH3)2, Ph, etc 66 CBz OR1 R N

CO2H n-Pr COPh

E Zwitterionic iminium poor iminium control

O Directed electrostatic activation

Figure 6. A probable stereoselectivity.

O L-proline R1 71 THFor CH3OH rt R

NO2 76 ratio 76:77=4:1

S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847

0.2 eq catalyst H2O, rt, 96 h

L-proline (cat), EtOH reflux

L-proline EtOH,rt,50 o C 12-24h 62-86%

L-proline(10%) Cu(OAc)2(5%) i) PhCO3t-Bu, EtCO2H 16h 88

ZrCl4, NaBH4,THF rt, 3h 90

S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847

R O R H 24 O + H H O H H Ar CN 101 H 103 L-proline, 20mol% H2SO4, 30mol% R N H 102 H

O MeCN, L-proline O MW, 60oC, 30 min O R

54-97% (52-90% ee) 107 108 109

S. K. Panday / Tetrahedron: Asymmetry 22 (2011) 18171847

O Ph N H N H 112 H Ph O N H O N H 1 O H N 113 Acid function HN N H 114 S O2 O R HN N N

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

O (ii). 55 + O H R 50 N H CO2H (20%) ZnCl 2(10%) DMSO/H2O (8:2)

R d.r. up to 16:1 e.e. up to 99% 115