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Tetrahedron: Asymmetry Report Number 138
Advances in the chemistry of proline and its derivatives: an excellent amino acid
with versatile applications in asymmetric synthesis
Sharad Kumar Panday
Department of Chemistry, Faculty of Engineering and Technology, M. J. P. Rohilkhand University, Bareilly, U.P., India
a r t i c l e i n f o
Article history:
Received 29 July 2011Accepted 27 September 2011
Available online 4 November 2011
a b s t r a c t
Non-proteinogenic prolines have been acknowledged as an important pool for the synthesis of conform-
ationally rigid bioactive peptides, angiotensin converting enzyme inhibitors and as pharmacologicalprobes. Proline and its derivatives are often used as asymmetric catalysts in organic reactions, such as
CBS reductions and proline catalyzed aldol reactions, Mannich reactions, and so on. FurthermoreL-proline
is an osmoprotectant and is therefore frequently used in many pharmacological as well as biotechnolog-
ical applications. The wide range of chemical and biological applications associated with L-proline has
prompted researchers to develop new methodologies for the synthesis of prolines and substituted pro-
lines and to further explore their chemical and biological applications. The present article is an attempt
to discuss all the major advances available till date, describing the use of proline in organic asymmetric
synthesis, the synthesis of various bioactive molecules or proline as a constituent part of bioactive
molecules.
2011 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1818
2. Structure and synthesis of proline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1818
3. Advancements in the chemistry of proline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1819
3.1. Proline as an organocatalyst. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1819
3.1.1. Proline catalyzed asymmetric aldol condensations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1820
3.1.2. Proline catalyzed asymmetric Mannich reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1822
3.1.3. Proline catalyzed asymmetric Michael additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1823
3.1.4. Proline catalyzed amination and aminoxylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824
3.1.5. Proline catalyzed oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824
3.1.6. Proline catalyzed DielsAlder reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824
3.1.7. Proline catalyzed cyclopropanation/nucleophilic substitutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824
3.1.8. Proline catalyzed oxidative and reductive cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825
3.1.9. Synthesis of heterocycles through a proline catalyzed multicomponent reaction strategy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825
3.1.10. Proline catalyzed reduction and reductive alkylations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825
3.1.11. Studies on microwave assistance in proline catalyzed organic reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825
3.2. Replacement of proline with modified proline derivatives and their outcome as organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18263.2.1. Different proline amides as organocatalysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1826
3.2.2. Substituted prolinol derivatives as organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1827
3.2.3. Replacement of the carboxylic group of proline with tetrazole moiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1827
3.2.4. 4-Substituted prolines as organocatalysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1827
3.2.5. A recoverable fluorous CBS methodology using fluorous prolinol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1828
3.2.6. Suitably derivatized proline derivative as heterogeneous catalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1828
3.2.7. Prolinal dithioacetals as organocatalysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1828
3.2.8. Ionic liquid supported proline as organocatalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1829
3.3. Proline as a metal ligand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1829
3.4. Differentially substituted prolines: asymmetric synthesis and applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1832
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3.4.1. 2-Substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1835
3.4.2. 3-Substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1835
3.4.3. 4-Substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1838
3.4.4. 5-Substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1839
3.4.5. Synthesis of multi-substituted prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1841
3.4.6. N-Acylation of proline derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1842
3.4.7. Synthesis of azanucleosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1844
3.4.8. Reduction of the carboxylic functionality of proline: asymmetric synthesis of (+)-hygrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845
3.4.9. Synthesis of enantiopureb-endo-substituted aza bicyclic proline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18454. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845
1. Introduction
Proline and substituted prolines can be found in many a natu-
ral1 and synthetic2 bioactive products. The last three decades have
witnessed a large increase in the number of publications on the
chemistry and biology of many products where substituted pro-
lines act as essential components of the target molecules.Non-proteinogenic prolines have emerged as important inter-
mediates due to their use in the synthesis of conformationally rigid
bioactive peptides,310 angiotensin converting enzyme inhibitors
and as pharmacological probes.11,12 Proline and its derivatives
are often used as asymmetric catalysts1322 in organic reactions
such as CBS reductions, proline catalyzed aldol reactions, Mannich
reaction, and so on. Furthermore, L-proline is an osmoprotectant23
and is therefore frequently used in many pharmacological as well
as biotechnological applications. As a result of this, the asymmetric
synthesis of proline derivatives coupled with exploring the possi-
bilities for their chemical and biological uses has become an area
of interest in proline chemistry, and much attention has been paid.
In addition to synthetic methodologies for the synthesis of 2, 3, 4,
and 5-substituted prolines being available,2432 the angiotensinconverting enzyme inhibitory potential of N-acyl derivatives of
substituted prolines has also been well established.33,34 Herein
the aim of the present article is to discuss all of the major advances
available to date, describing the use of proline in organic asymmet-
ric synthesis, the synthesis of various bioactive molecules, or as a
constituent part of bioactive molecules.
2. Structure and synthesis of proline
Proline1 is an a-amino acid. It is not an essential amino acid,suggesting that the human body is capable of synthesizing it. It
is a unique amino acid among 20 natural amino acids in the sense
that, the a-amino group is secondary in nature. In neutral media, it
exists as zwitterion 2 (betaine type structure)35,36 (Fig. 1).
An early synthesis of racemic proline was carried out3537 by
the Michael addition of acrylonitrile to diethyl malonate. Catalytic
hydrogenation followed by treatment with thionyl chloride affords
compound7. Compound7, upon treatment with hydrochloric acid
followed by alkaline hydrolysis and subsequent treatment withhydrochloric acid afforded racemic proline 1 (Scheme 1).
NH
COOH NH2
C O
O-
1 2
Figure 1. Structure of proline.
CN
Ni/H2H2N HN
(EtOOC)2
O
COOEt
HN
O
COOEt
Cl HCl
NH3COOH
Cl+
i) OH -
ii) HClNH2
COOH NHCOOH
CH2(COOEt)2 + CHCH2CH2CN
EtOOC
SOCl2
Cl-
-HCl
EtO-
3 45
6
78
9 1
COOEt
Cl
-
Scheme 1.
NH
O CO2HTriethyloxonium fluoroborate
NaBH4 NH
CO2H
10 1
NH
OCO2H NaBH4
NH
CO2H
11 12
Ph Ph
BH3THF
(i)
(ii)
Scheme 2.
O
O
O
L-proline, DMFMe
OHO
O
99%, 93%ee13
14
Scheme 3.
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Various synthetic strategies have been reported for the asym-
metric synthesis of prolines.38,39 One of the earliest synthetic strat-
egies was developed starting from pyroglutamic acid38a via the
reduction of the lactam carbonyl. Pyroglutamic acid 10 has been
transformed into L-proline in a one pot, two step reaction.38
Theconversion involved the treatment of pyroglutamic acid 10 with
triethyloxoniumfluoroborate and reduction of the resulting crude
imino ether with sodium borohydride (Scheme 2, i).
An alternative procedure for the reduction of pyroglutamates to
prolines has been developed by Rapoport et al.,39 where (2S)-
trans-4-phenylpyroglutamate 11was converted into 4-phenyl pro-
linate 12 by reduction with BH3THF, followed by the reduction of
resultant crude compound with sodium borohydride (Scheme2, ii).
3. Advancements in the chemistry of proline
3.1. Proline as an organocatalyst
The beginning of 1970s may well be remembered as a turningpoint in the history of organo catalyzed asymmetric reactions,
when proline was first investigated as a small molecule in the
HajosParrishEdersauerWieahert reaction.40 In this reaction,
naturally occurring L-proline was employed as an asymmetric cat-
alyst in an aldol reaction,40 where the starting material was trike-
tone 13, and only a small quantity (3%) of proline was required to
furnish the reaction product, ketol 14, in 93% enantiomeric excess
(Scheme 3).
Since the discovery of above successful proline catalyzed aldol
reaction, great strides have been made in understanding and
exploring the newer routes and strategies for various asymmetric
reactions catalyzed by L-proline or its derivatives.1322 Proline is
now regarded as an efficient and important organocatalyst in sev-
eral asymmetric transformations, such as aldol reactions, crossedaldol reactions involving different aldehydes as donors or
acceptors, Mannich reactions involving ketones, aldehydes, and
amines, Michael additions involving ketones and aldehydes,
N CO2HH
Asymmetric aldol,crossed aldol,intramolecular aldolreactions etc.
Mannich reaction
Michael addition
Diels - Alderreaction
SN2 alkylation
Amination,aminoxylation
1
Synthesis of heterocyclesReductivealkylations
Oxidations
Reductions
Figure 2. The spectrum of proline as organocatalyst in organic reactions.
NH
COOHN
Me R
Bi functional catalysis Iminium catalysis
NCO2H
Enamine catalysis
CO2-
R
Figure 3. Possible modes of proline catalysis.
O
20 vol%
+ H
O
NO2
L-proline
30 mol%DMSO
O
NO2
OH
68%(76%ee)15 16 17
Scheme 4.
O
MeR2
+NH
O
OH
-H2O
H2O N
O
O
Me
R2H
N
HO
O
Me
HR1CHON
OH
O
R2Me
R1
OH
H
Transition state
N
HO
O
Me
HR
2
OH
R1 H2O
-H2O
NH
O
OH
R1 Me
R2
OH O
+
N
O
O-
H
R2
Me
R1
H
O H
metal- free Zimmeraman- Traxler model
18 1 19
20
21
22
1
R2
Figure 4. Mechanism of the aldol reaction.13,1921,42
HR1
H R2
O O
+ L-proline
10 mol%, DMF, 4oC H R2
O OH
R1
23 24 25
Scheme 5.
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additions to imines, nitro alkenes, in addition to many other reac-
tions as well (Fig. 2). The reactivity and enantioselectivity of pro-
line catalyzed reactions amount to a series of interactions
involving proline that are comparable to enzyme catalyzed reac-
tions,41 such as substrate recognition, transition state stabilization,
and the resulting formation of the product. Due to these similari-
ties Movassaghi and Jacobson have regarded proline as the sim-
plest enzyme.41
Proline is the only natural amino acid with a secondary amine
functionality, which raises the pKavalue and induces better nucle-
ophilicity when compared to other amino acids. There are several
modes by which proline is capable of exerting its catalytic activ-
ity,19 that is, it could be bifunctional catalysis, iminium catalysis,
or enamine catalysis (Fig. 3).The excellent enantioselectivity of proline as a catalyst can
be accounted for due to the formation of a highly organized transi-
tion state with a systematic framework of hydrogen bond-
ing.13,17,1921,42 Due to the unique behavior of proline as an
organocatalyst, the last two decades have witnessed a large in-
crease in the number of publications exploring various reactions
and reaction methodologies, whereby proline has been successfully
employed as a catalyst for achievingthe desired chemical or stereo-
chemical outcome.1322 A fewof themore importantapplications of
proline as an organocatalyst are discussed in the current section.
3.1.1. Proline catalyzed asymmetric aldol condensations
Investigations of L-proline as an important organocatalyst pri-
marily in aldol reactions,40 led researchers to further explore itsapplications toward a variety of aldol reactions and to establish
it as one of the best catalysts for various other similar reactions.
Even though the first application of proline as an asymmetric cat-
alyst was explored in the early seventies,40 the detailed investiga-
tion was carried out by List et al. in 2000,13 when the direct
asymmetric aldol reactions of ketones and aldehydes using L-pro-
line as a catalyst were described, whereby product formation oc-
curred with high enantiomeric excess13,43 (Scheme 4).
3.1.1.1. Mechanism of proline catalyzed aldol reactions. The
earlier probable mechanism for proline catalyzed aldol reactions,
as explained by List et al.13,17,1921,42 is shown inFigure 4. In aldol
reactions, proline executes its action through enamine catalysis.
Enamine20, is formed from the pyrrolidine nitrogen and the car-bonyl donor. Iminium ion21, created by the attack of the enamine
on there-face of the aldehyde, is subsequently hydrolyzed to afford
an asymmetricb-hydroxyl ketone. It is postulated that the reaction
OHC CHO L-proline
CH2Cl2, rt, 12h95%
OH
OHC
99%ee
26a 26b
Scheme 6.
HO
HO
CO2H
CO2H
L-(+)-Tartaric acid
L-proline(15 mol%)
Direct 6-enolexoaldolization
NTsNTs
OHOHO
O
OH OHO
O
70%
dr>10:1
27a 27b
Scheme 7.
HCH3
CH3
H3C
H
OO
+ H
OOH
CH3
i. (R)-proline
ii. TBSOTf
i.
OTMS
OBut , BF3
ii. HCl
O
O
OHCH3
Prelactone B
28 29 30
31
Scheme 8.
H
OL-proline
Acetone
O OH
OH
(S)-Ipsenol
32 33
34
Scheme 9.
H3C
OH
O
+H R
O
H3C
O OH
OH
R
L-proline, 20 mol %
DMSO
35 24
36
Scheme 10.
HR
O
+
O
CO2EtEtO2C
L-proline, 20mol%CH2Cl2, rt, 3h
H
OH
R
OCO2Et
CO2Et
35 37
38
Scheme 11.
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proceeds through a transition state following a synclinical ap-proach of the aldehyde, where the alkyl or aryl substituent of alde-
hyde occupies a pseudo equatorial position. The stereochemistry is
controlled by a hydrogen transfer between the carboxylate on the
proline and the oxygen of the aldehyde, thus providing the
enantioselectivity.
However in recent years, scientific debates have been made to
study the mechanistic aspects as well as the role of water as a sol-
vent, or added in small amounts to the organic solvents; all of
these features have been well discussed.19,20
3.1.1.2. Scope of proline catalyzed aldol reactions. The investi-
gations on proline catalyzed aldol reactions, were extended further
to encompass a wide variety of ketones and aldehydes, during
which, reactions between two dissimilar aldehydes using prolineas a catalyst were attempted, similar to those in traditional crossed
aldol reactions, where dimerized products were obtained with
excellent enantioselectivity44 (Scheme 5).L-Proline catalyzed intramolecular aldol reactions have also
been accomplished45 successfully (Scheme 6) and direct catalytic
asymmetric enol-exo-aldolizations have been reported. This pro-
cess made it possible to synthesize substituted cyclohexanes in
excellent diastereo and enantioselectivity, for example, heptane-
dial26a, is converted into the corresponding cyclicanti-configured
aldol26b in 99% enantiomeric excess.The successful accomplishment of L-proline catalyzed direct
diastereoselective 6-enol-exo-aldolization enabled Kumar et al. to
develop a synthetic strategy46 for imino sugars starting from tar-
taric acid (Scheme 7). This proline catalyzed approach provided
high levels ofsyn-selectivity (dr >10:1) with stereocontrolled CC
bond formation between C4 and C5, which in turn could serve to
synthesize the imino-sugar skeleton.
An (R)-proline catalyzed aldol reaction enabled Pihko et al. to
synthesize prelactone B 31, in four steps from isopropylaldehyde
and propaldehyde.47 A direct proline catalyzed aldehyde-aldehyde
aldol reaction was employed, as the exclusive source of asymmetry
(Scheme 8).
The use ofL-proline as an asymmetric catalyst in the aldol reac-
tion allowed a concise synthesis of (S)-ipsenol 34 to be investi-gated48 starting from 3-methyl butyraldehyde (Scheme 9).
R1
O
+NH
CO2HN CO2H
R1
H
N CO2H
R1
H
R3 H
O
+
NH2
OMe N
R3 H
H2O
-H2O
N
R1
H
R3 N
O
OH
N O
O-
R1
R3
NH
PMP
R3
O
R1
NH PMP
42
24
40
43
44
R2
R2 R2
R2R2R2
41
39
Transition state
PMP
OMe
Figure 5. Probable mechanism for the proline catalyzed Mannich reaction.17,1921
R1 R2
O
CO2Et
R1
O
R2
NHPMPL-proline
20 mol%DMSO
+
H
NPMP
CO2Et
39 45 46
Scheme 13.
+ NPMP
H CO2Et
HR
O i. L-prolineTHF, rt, 16-20 h
ii. Et2AlCN NC CO2Et
OH
R
NHPMP
23 45 48
Scheme 14.
O
R + 2
CHO
X
+ NH3
XNH
R
O
X
L-proline
30 mol%
4950
51
Scheme 15.
R2
O
+H R
3
O
+
NH2
OMe
L-proline, DMSO
5-35 mol%
R3
O NHPMP
R2
R1
R1
99% ee
39 24 40
41
Scheme 12.
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Proline catalyzed asymmetric aldol reactions and their success-
ful outcome encouraged Sakthivel et al. to synthesize anti-diols
3649 by the reaction of hydroxyl acetone35with aldehydes24cat-
alyzed by L-proline (Scheme 10).
The scope of the proline catalyzed aldol reactions was further
applied to activated carbonyls, resulting in the formation of alde-
hyde aldols 3850 (Scheme 11).
3.1.2. Proline catalyzed asymmetric Mannich reactions
Parallel to the aldol reactions, proline catalyzed Mannich reac-
tions were also investigated simultaneously by List et al., 51 where-
by proline catalyzed direct asymmetric three component Mannich
reactions of ketones, aldehydes, and amines were explored. Most of
these reactions provided b-amino carbonyl compounds (Mannich
adducts) in excellent enantio, regio, and chemoselectivities
(Scheme 12).
3.1.2.1. Mechanism of the proline catalyzed Mannich reac-
tions. The mechanism of the proline catalyzed Mannich reactions
is comparable to the aldol reactions17,1921(Fig. 5), where enamine
42, is formed from proline, and an aldehyde or ketone. Imine 43,
generated in situ, is then added. The imine, upon attack by the en-
amine, creates new stereocenters in the iminium product 44,
which upon hydrolysis gives Mannich product 41, with excellent
stereoselectivity. The stereoselectivity is controlled via the transi-
tion state as shown in Figure 5.
TheE-aldimine is attacked by the enamine on itssi-face to give
the syn-product with a minimum of one new asymmetric center.
Due to the E-geometry of the aldimine, the re-face is blocked due
to the steric hindrance between the aryl ring of the p-methoxyphenyl group and the proline ring. As in the aldol reactions, the
enantioselectivity was controlled through hydrogen transfer that
prefers attacking one face of the enamine.
3.1.2.2. Scope of the proline catalyzed Mannich reactions. Once
the direct Mannich reactions were standardized, the scope of the
reaction was extended further to modified systems, where two
component modified Mannich reactions using functionalizeda-amino acids were accomplished52 (Scheme 13).
The proline catalyzed Mannich reaction was successfully
applied to a one-pot cyanation53 via reaction of an aldehyde or
ketone with an enamine using diethyl aluminum cyanide as the
R( )n
O
NX
N
R( )n
O
R( )n
O
NX
N
OH
Basic conditions
i) (HCHO)nii) Azoleiii) L-proline
DMSO, 60oC
H2O,100oC
X=CH; ImidazoleX=N;1,2,3-Triazole
52
53
54
Scheme 16.
O
+Ph
NO2
O
NO2
Ph
L-proline
15 mol%DMSO, 16h94%
ee;23%dr>20:1
55 56 57
Scheme 17.
R1
R2
O
+
R3
R4 NO2
R1 NO2
O
R2 R4
R3L-proline
10-20 mol%DMSO,rt
58 59 60
Scheme 18.
(i)H
R2O
N N
CO2Bn
BnO2C
HON
CO2Bn
NHCO2BnL-proline
10 mol%NaBH4
R2
O
R1 + N
O
R2
O
R1
+
R2
O
R1
NPh
OH
L-proline
10-30 mol%DMSO,2-3 h,rt
(ii)
23 61 62
39 63 64 65
R2
ONHPh
>99% ee 7-11%ee
O/N selectivity> 100:1 to 8:22
Ph
Scheme 19.
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cyanating agent and L-proline as the catalyst to give b-cyanohydrin
48, stereoselectively (Scheme 14).
Encouraged by the outcome of the L-proline catalyzed asymmet-
ric Mannich reactions, Srinivasan et al. carried out54 the synthesisof
3-substituted-2, 6-diaryl piperidin-4-ones51, by the one pot reac-
tion of ketones49, various arylaldehydes50, and ammonia using L-
proline as the catalyst (Scheme 15).
Recently Srinivas et al. have described55 a proline catalyzed ac-
cess to Mannich adducts using unsubstituted azoles. They reported
a unified and facile approach for the direct construction of a CCN
bond with unsubstituted azoles under Mannich conditions. The
reaction was catalyzed efficiently by L-proline to give the Mannich
adduct53, in DMSO, whereas in water, insertion of two successive
bonds, CCN and CCO occurred to furnish compound 54. The
latter was readily deformylated into the desired product 53, under
basic conditions (Scheme 16).
3.1.3. Proline catalyzed asymmetric Michael additions
Efficient proline catalyzed Michael additions of unmodified
ketones into nitro olefins have also been carried56 out successfully.
RCHO R CO2Et
OTBSi) -aminoxylation, L-prolineHWE-olefination and reduction
ii) TBS-Cl ee>94%
RCO2Et
OR1 N NHCBz
CBz
R: nPr, (CH3)2, Ph, etc
-amination, L-proline
HWE-olefinationR
CO2Et
OR1 N NHCBz
CBz
HWE-olefination
-amination, D-proline
R1
: TBS; (anti/syn>40:1)
R1: TBS;(syn/anti>10:1)to 6:1; CBz= benzyloxy carbonyl
66 67
68
69
Scheme 20.
HR
O+
O
NPh
L-proline, 5mol%
CHCl3, 4oC H
ONH
Ph
O
R
R= alkyl, aryl, allyl
23 63 70
Scheme 21.
R
NO2
+
R1
O
Me
R R1
NO2
O O
R1
NO2R
L-proline
THFor CH3OHrt
i)
CF3
NO2
+
S
O
CF3
S
NO2
O
* *
*
+ CF3
S
O
* * *
NO2
L-prolineii)
59 71 72 73
74 75 76 77
R = Ph, 4-MeoC6H4, 1-naphthyl, 2-CF3C6H4R1 = Ph, 2-thienyl, 2-furylModerate selectivity for72
ratio 76:77=4:1
Scheme 22.
n-Pr O
H
MeS
Ph
OMe
+ 20 mol%CHCl3, 23
oC
NH
CO2H
CHO
COPhn-Pr
72% yield; 46% ee
78 79 80
Scheme 23.
N NCO2
- CO2-
E Z
Zwitterionic iminiumpoor iminium control
N CO2-
O
Ph
SYlide
Directed electrostatic activation
Figure 6. A probable explanation for good reactivity but diminished
stereoselectivity.
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Successful accomplishment of such a reaction made it possible to
synthesizec-nitroketones 57, in reasonable enantiomeric excesscoupled with excellent yields (Scheme 17).
3.1.3.1. Scope of proline catalyzed Michael additions. The possi-
bility of proline catalyzed Michael additions has been applied suc-
cessfully to a wide variety of asymmetric conjugate additions 57,58
where the product was formed in high enantiomeric excess
(Scheme 18).
3.1.4. Proline catalyzed amination and aminoxylation
The proline catalyzeda-amination of aldehydes, as well as theaminoxylation of ketones, has been studied and accomplished with
great success; in these reactions, at least one stereogenic center is
generated with the predominance of one stereoisomer59 with high
enantiomeric excess (Scheme 19).
3.1.4.1. Scope of proline catalyzed amination and aminoxyla-
tion. The enantioselective synthesis of syn/anti-1,3-amino
alcohols via proline catalyzed sequentiala-aminoxylation/a-ami-nation followed by HornerWadsworthEmmons olefination of
the aldehydes has recently been described by Jha et al..60 Using this
methodology, they explored a short and efficient synthetic path-
way to the bioactive molecule (R)-1-(methylpyrrolidin-2-yl)-5-
phenylpentane-2-ol (Scheme 20).
3.1.5. Proline catalyzed oxidations
Proline catalyzed oxidations of aldehydes with nitroso benzenes
have been reported61 to furnish the product 70 in high enantio-
meric excess (Scheme 21).
3.1.6. Proline catalyzed DielsAlder reaction
The potential ofL-proline as a DielsAlder catalyst for the reac-tion of nitro olefins anda,b-unsaturated ketones tofurnish cyclo-hexanone derivatives has been investigated.62,63 It has been
envisaged that amine catalyzed direct DielsAlder reactions of
a,b-unsaturated ketones with dienophiles to give cyclohexanonederivatives can be carried out with moderate to good enantioselec-
tivity (Scheme 22).
3.1.7. Proline catalyzed cyclopropanation/nucleophilic
substitutions
The cyclopropane skeleton is one of the most common moieties
in the synthesis of complex molecules having defined chemical/
biological properties, due to its unique reactivity and structural
properties. As a result of this, the investigation of different strate-
gies for the construction of cyclopropane rings has receivedmuchattention. One of the synthetic strategies involves64 the
enal-cyclopropanation reaction ofa,b-unsaturated aldehydes 78,with dimethylphenylacyl sulfonium ylid 79, and a range of asym-
metric amine catalysts. In this strategy, the use of a catalytic amine
provided good reaction yield (72%) with moderate stereocontrol
(46%) (Scheme 23).
A mechanistic hypothesis for the high efficacy but moderate
stereocontrol was proposed by Kunz et al. based on the concept
of directed electrostatic activation (DEA). According to the authors,
a proline derived iminium and ylid might readily undergo electro-
static associationviathe carboxylate and thionium substituents. In
the process the ylid carbanion and the iminium b-carbon would be
transiently activated while being in close association, thereby
enhancing the carboncarbon bond formation process. Further-more, the iminium ion can equally populate both the E- and
EtO2C
EtO2C
Br +Ar
OHC 0.2 eq catalyst
H2O, rt, 96 h
EtO2C
EtO2C
CHO
Ar
catalyst:NH
Ar'
Ar'
OTMS
Ar'=3,5-CF3C6H3
81 82 83
Scheme 24.
i) OHC I
EtO2C CO2Et EtO2CCO2Et
OHC
L-proline (10%)
Et3N75%
20% ee
ii)
OHC I
EtO2C
EtO2C OHC
CO2Et
EtO2C60% ee
L-proline (10%)
Et3N75%
84 85
8687
Scheme 25.
ii)
OH3C CH3
OH(L)-proline
ZrCl4,NaBH4,THFrt, 3h
60%, 44% ee
i)
OCH3
O
L-proline(10%)Cu(OAc)2(5%)
PhCO3t-Bu, EtCO2H16h
39%, 61% ee
88 89
90 91
Scheme 26.
+
O
O
CHO
R
+ OEt
O O
+
NH
O O
R
OEt
L-proline (cat), EtOH
reflux
50 92 93 94
95
NH4Ac
Scheme 27.
R1
R2
+ R3NH2 + R4
O O
+ R5CHO
N
R4
R2
R1R5 O
R3
L-prolineEtOH,rt,50 Co
12-24h62-86%
95 96 97 24 98
Scheme 28.
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Z-iminium isomers, a configurational equilibrium that is responsi-
ble for furnishing the diminished stereocontrol (Fig. 6).
Recently, the use of water as a reaction medium for the O-TMS-
diarylprolinol catalyzed cyclopropanation reaction of diethyl
bromoacetate 81 with a,b-unsaturated aldehydes 82 has beeninvestigated65 as a base free reaction system. A modified O-TMS-
diaryl prolinol incorporating hydrophobic side chains has been ex-
plored as a promising catalyst for this reaction having high effi-
ciency coupled with good stereoselectivity (Scheme 24).
Proline as an organocatalyst has been proven to be equally use-
ful in nucleophilic substitution reactions, when it showed its
ability to catalyze the intramolecular SN2 alkylations66 of diethyl-
2-(iodomethyl)-2-(2-oxoethyl) malonate84, and diethyl-2-(3-iod-
opropyl)-2-(2-oxoethyl) malonate 86, thereby furnishing the
corresponding cyclopropyl and cyclopentyl derivatives 85 and 87,
respectively, with the desired stereochemistry (Scheme 25).
3.1.8. Proline catalyzed oxidative and reductive cleavage
Proline as an organocatalyst, has also been found to be useful
toward various oxidative and reductive cleavages,67,68 as well,
which have been accomplished successfully (Scheme 26).
3.1.9. Synthesis of heterocycles through a proline catalyzed
multicomponent reaction strategyL-Proline has been effectively employed as an efficient organo-
catalyst for the synthesis of polyhydroquinolines 95,69 via multi-
component Hantzsch reaction (Scheme 27).
Likewise L-proline catalyzed synthesis of highly functionalized
multisubstituted 1,4-dihydropyridines 98 has recently been de-
scribed by Jiang et al.70(Scheme 28). These 1,4-dihydropyridines
have been synthesized in moderate to good yields via a L-proline
catalyzed one pot multicomponent reaction of alkynoates or alky-
nones95, amines 96, b-dicarbonyl compounds 97, and aldehydes
24under mild reaction conditions. The process involved hydroam-
ination/Knoevenagel condensation/Michael type addition/intra-
molecular cyclization processes and led to the formation of 1,
4-dihydopyridines.
In a similar manner Misra et al. have described
71
a highly atomeconomic one-pot synthesis of tetrahydropyridines 100 as anti-
malarials, via a L-proline/TFA catalyzed multicomponent reaction
of b-keto-esters 99, aromatic aldehydes 50, and anilines 40
(Scheme 29).
3.1.10. Proline catalyzed reduction and reductive alkylations
An efficient approach for a one-pot three component reductive
alkylation reaction of arylacetonitriles containing electron with-
drawing groups with aldehydes and ketones and 1,4-dihydropyri-
dine via an L-proline catalyzed iminium catalysis has been
described72 (Scheme 30). These reaction products 103 and 104
have direct applications in agriculture and the pharmaceutical
chemistry; for example, both have been acknowledged as useful
intermediates for non-steroidal anti-inflammatory drugs (NSAIDs).
3.1.11. Studies on microwave assistance in proline catalyzed
organic reactions
With the aim of evaluating the effect of microwave assistance
over conventional heating in (S)-proline catalyzed Mannich and
NH2 CHO
R1 R2
+ + H3C OR
O OL-proline/TFA
20 mol% N
OR
NH
R1
O
R2
R1
R240 50 99
100
Scheme 29.
H
O
R
H Ar
CNH
NH
OH H
+
O
R
H CN
Ar
R
H COOH
Ar
L-proline, 20mol%
H2SO4, 30mol%
24 101
103
104102
Scheme 30.
Me Me
O
+N
H CO2Et
OMe
Me CO2Et
O NH
OMe
90-92% (99% ee)
(S)-proline, DMSO60oC, 10 min
oil bath, orMW(49W), or
MW(207 W)
15 105 106
Scheme 31.
O
R
R=H, aryl
+ O N
O
N O
O
ON
NH
R
CO2Et
CO2Et
MeCN, L-proline
MW, 60oC, 30 min
54-97%(52-90% ee)
107 108 109
Scheme 32.
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aldol type reactions (Scheme 31). Hosseini et al. attempted73 a
microwave-assisted asymmetric organocatalysis as a probe for
non-thermal microwave effects and a concept of simultaneous
cooling. After a series of reactions under different reaction condi-
tions for (S)-proline catalyzed asymmetric Mannich and aldol reac-
tions, they observed that enhancements were the result of the
increased temperature attained by microwave dielectric heating
and not due to the presence of a microwave field. According toHosseini et al. the results obtained either with microwave
irradiation or microwave irradiation with simultaneous cooling
could be reproduced by normal heating at the same temperature
and time using an oil bath.
In a similar manner, Baumann et al. have performed74 optimiza-
tion studies with regards to solvent, temperature, time, and
catalyst loading for the microwave mediated organocatalytica-amination of disubstituted aldehydes 107with diethylazodicarb-
oxylate 108. The optimum reaction conditions, as described byBaumann et al. proved to be MeCN as the solvent, 50 mol % of L-
proline as the catalyst, a reaction temperature of 60C and
30 min of reaction time. More importantly the reaction time could
be decreased from several days to 30 min by heating, as compared
to room temperature conditions with a prominent increase in effi-
cacy and enantioselectivity (Scheme 32).
3.2. Replacement of proline with modified proline derivatives
and their outcome as organocatalysts
3.2.1. Different proline amides as organocatalysts
A slight modification in the catalyst structure may change the
pKa value of the catalyst affecting the strength of hydrogen bond-
ing to such an extent that a high degree of enhancement of the cat-alytic activity coupled with stereoselectivity could be
observed.75,76 As a result, the replacement of the carboxylic group
of proline with amides/substituted amides and their use as cata-
lysts resulted in high yields, enantioselectivity, and diastereoselec-
tivity under mild reaction conditions.
Taking into consideration the above rationale, successful enan-
tioselective aldol reactions could be accomplished75 by using L-
prolinamide110as a catalyst in the place ofL-proline (Scheme 33).
Maleev et al. developed new L-proline derivatives as catalysts76
for enantioselective aldol reactions. They discovered proline
amides containing an alcohol group to be efficient catalysts in aldol
reactions, due to the fact that the pyrrolidine ring has an amide and
a hydroxyl group is capable of hydrogen bonding to the substrate
molecule to greater extent for stabilization of the enamine in anactivated intermediate (Fig. 7).
R H
OO
+
O O
R R
OH OH
+10-20 mol % cat
solvent, rt
cat.:
NH
R1
O
where R1= substituted aromatic, heteroaromaticand alicyclic amines
solvent: DMF, DMSO, CHCl3
24 55 111b
110
111a
Scheme 33.
Acid function
NH
O
N
H OH
Ph
Ph
HN
NN
N
N
H
OHN
NSH
O2
R
NH
O
O H
112
113
1
114
Figure 7. Structures of proline derivatives used as a catalyst.76
N
CH2
O
NH
N
H
O
O
-O
OH
Figure 8. An activated intermediate complex showing the possible mode of
interaction and hydrogen bonding by the proline derivative in aldol reaction.
+
O
H
O
R
NH
CO2H(20%)
ZnCl2(10%)
DMSO/H2O
(8:2)
O
R
OH
d.r. up to 16:1
e.e. up to 99%
50
55
115
(ii).
Scheme 34.
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Such prolinamide derivatives have been regarded as potential
catalysts, as they contain the asymmetric pyrrolidine ring and
the amide and hydroxyl groups capable of hydrogen bonding to
substrate molecules for the stabilization of the enamine in the acti-
vated intermediate complex. In addition, these systems allow var-
iation of the steric environment for the standardization of their
catalytic properties76 (Fig. 8).
Recently, direct asymmetric aldol reactions co-catalyzed by L-
proline and group 12 element Lewis acids in the presence of water
have been described77 by Penhoat et al., who explored an approach
based on the combinations of various water compatible Lewis
acids and L-proline co-catalysts for the direct asymmetric aldol
reaction. The investigations suggested that chloride salts from
group 12 elements (ZnCl2, CdCl2, HgCl2) led to the highest stereose-
lectivities. The optimized catalytic conditions (catalytic system: L-
proline: 20%/ZnCl2: 10%; solvent mixture: DMSO/H2O, 8:2) gave
anti-aldol products 115 with improved enantioselectivity (>99%
ee) compared to the moderately stereoselective procedure based
on proline activation only (Scheme 34).
3.2.2. Substituted prolinol derivatives as organocatalysts
An elegant one pot method was developed recently by Franzen
and Fischer for the asymmetric synthesis of substituted quinolizi-
dines.78 To carry out their synthetic strategy, they standardized the
enantioselective Michael addition of cinnamic aldehyde82, and an
activated indole substituted amide 116, using different proline
derivatives (Fig. 9) as organocatalysts exploring different solvents,
temperatures as well as the various acids required at the cycliza-
tion step of the acyliminium ion.
Out of the various proline derivatives used in the reaction,
derivative 117, showed the best activity78 (Scheme 35).
An asymmetric alkylation of aldehydes with allyltintribromide
was achieved using L-proline derivative124, as an asymmetric cat-
alyst in dichloromethane in the presence of a Lewis base.
79
Thesynthesis of various optically active homoallylic alcohols 123 in
high yields, but with moderate enantioselectivity of up to 62%
enantiomeric excess has been reported (Scheme 36).
3.2.3. Replacement of the carboxylic group of proline with
tetrazole moiety
Cobb et al. described proline derivative 113, as an improved cat-
alyst for the asymmetric aldol, Mannich, nitro-Michael, and other
reactions80 (Scheme 37).
3.2.4. 4-Substituted prolines as organocatalysts
Bellis et al. explored various 4-substituted prolines as organo-
catalysts for asymmetric aldol reactions.81 It was envisaged that
using (2S,4R)-4-camphorsulfonyloxy proline127, in aldol reactions
gave much higher enantiomeric excesses in comparison to proline.
NH Ph
Ph
OTMSTMSO
HN
CF3
F3C
CF3
CF3
117 118
NH
HN
NH
O
Ph
CO2H
119 1
Figure 9. Different proline derivatives used as a catalyst.
O
Ph
+
N
O
O
H
MeO
OMe
MeO
Ph
N
O
OMeO
OMe
MeO
H
Ph
+
OMe
OMe
HN
O
MeO
O
1. Catalyst117, 20mol%DCM, 3days, rt
2. HCl in Et2O, 40 mol%
-78oC to rt, 30 min.
Yield; 69%, 90% ee
82
116 120 121
Scheme 35.
RCHO + Sn Br3
OH
*R
62% ee
Catalyst
2 eq, i-Pr2NEt4 MS, CH2Cl2
-78oC
Catalyst:N
Ph
PhBn
24 122 123
124
OH
Scheme 36.
R
R1
O
+NPMP
CO2Et R CO2Et
R1
NHPMPO
CH2Cl2, rt,8-24h
Catalyst, 5 mol%
Catalyst: N
HN N
NN
58 45125
H
113
Scheme 37.
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In addition, the improved solubility of these new catalysts in or-
ganic solvents permitted their use in lower amounts when com-
pared to proline (Scheme 38).
Recently, the direct asymmetric a-amination of unmodifiedaldehydes with azodicarboxylates in ionic liquids in the presence
of a 4-imidazolium ion-tagged L-proline organocatalyst has been
reported82 to furnish excellent enantioselectivities (up to 98% ee)
coupled with high chemical yields. The system can be easily recy-
cled and reused at least four times without a significant loss of
yield or enantioselectivity (Scheme 39).
3.2.5. A recoverable fluorous CBS methodology using fluorous
prolinol
A recoverable fluorous CBS methodology for the asymmetric
reduction of ketones using a fluorous prolinol catalyst has been
successfully developed by Dalicsek et al.83
They generated a fluor-ous oxaborolidine in situ, which efficiently catalyzed the reduction
of ketones with high enantioselectivity and reactivity (Scheme 40).
3.2.6. Suitably derivatized proline derivative as heterogeneous
catalyst
A heterogeneous catalyst (L-ProLDHS) 133 was developed by
using the intercalation of L-proline in Mg-AlLDH. The asymmetric
aldol reaction of benzaldehyde 132 and acetone 15 was carried
out using L-ProLDH as a catalyst,84 where the aldol adduct was ob-
tained in good yield (90%) and with high enantiomeric excess (94%)
(Scheme 41).
3.2.7. Prolinal dithioacetals as organocatalysts
Mandal et al. discovered prolinal dithioacetals136(Scheme 34)
could be used as a catalyst for highly stereoselective Michael
NH
HCl
O
OH
R1O
O
OR1=O
O
SO2
O
O
H
O O
R2+
R2
O OH
44-90% ee
Catalyst 127 (10-30mol%)
Et3N, DMF
R2 = 4-NO2Ph, 4-BrPh, 2-ClPh
126 127 128
, ,
15 24129
O
Scheme 38.
H
O
R1HO N CO2R
2
NHCO2R2
23 61 62
R1+
N
N
CO2R2
R2O2C
NH
CO2H
NN TiO
(10 mol%)
[bmim][BF4], 0
o
C
1.
2. NaBH4, MeOH, 0oC, 5 min
R1 = Me, Et, n-Pr, n-Bu, i-Pr, BnR2 = Bn, i-Pr, Et
Yield; 89-96%ee;92-96%
Scheme 39.
R1 R2
O
R1 R2
OH0.1 eq, precatalyst
BH3THF,THF,rt
Precatalyst: NH HO
Rf8
Rf8
39 131
130
Rf8= C8F17
Scheme 40.
O+ H
O O OH
90%, 94% ee
L-ProLDH 133
15 132 134
Scheme 41.
N
O
HBoc
2 eq RSH
N
Boc
SR
SR
H
(i)
(ii)
a: R=Phb: R=p-Me-C6H4c: R=2,6-Me2-C6H3d: R= t-Bu
R2
O
R1+ NO2Ar
R2 NO2
O Ar
R1* *
catalyst136b(10 mol%)
CH2Cl2
>90% ee, >90% de
135 136
58 56137
Scheme 42.
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additions of ketones and aldehydes to b-nitrostyrenes.85 They
observed a high degree of enantioselectivity (99%ee) and diastere-
oselectivity (99% de) in the Michael additions of ketones and
aldehydes to b-nitrostyrenes, catalyzed by prolinal dithioacetals
136. These prolinal dithioacetals could be synthesized in one step
from N-Boc-prolinal135 and thiols (Scheme 42).
3.2.8. Ionic liquid supported proline as organocatalyst
Ionic liquid supported proline 141 has also been investigated86
as an efficient catalyst in the direct aldol reactions of acetone with
aldehydes. The ionic liquid supported proline derivative was syn-
thesized from L-proline. The yield and enantiomeric purity of the
condensation products, the corresponding b-hydroxyl carbonyl
compounds129, have been found to be comparable to those ob-
tained under homogenous conditions (Scheme 43). The majoradvantage of this catalyst is reported to be its easy recovery and
the fact that it could be reused several times.
3.3. Proline as a metal ligand
Metal complexes have long been recognized as a flexible
approach for catalyzing and determining the reaction pathway
NNMe(i)1. BrCH2CH2OH
2. NaBF4, acetone NNMe
OHBF4
-
NNMeO-Pro-BocBF4
-
Boc-Pro-OHDCC, DMAP
NNMeO-Pro-HCF3COO
-
CF3CO2H
(ii)
O
+R1 H
O
R1
O OH
Catalyst 141
138 139
140141
15 24 129
Scheme 43.
N O
O
H
H
M
Metal catalysis
Figure 10. Proline as a metal ligand.
N
HN
OO
NH
O
PPh2Ph2P
O
HN
NH2
O
Rh LL
Figure 11. Rhodium metal complex of a proline derivative with phosphanyl groups.
NH
COOH
TsCl, Na2CO3
H2O, rt, 48h94% N
COOH
Ts
N
Ts
OHNaBH4/BF3Et2O
THF, rt, 18 h81%
N
Ts
OTs
TsCl, pyridine
0oC, 20h83% N
Ts
IKI, acetone,
74%
N
Ts
N N R I-1-substituted imidazoles
MeCN, 80oC
1 142 143
144 145
146
Scheme 44.
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for many of the organic reactions with a large range of chemical
and biological applications; over the years, metal based methodol-
ogies have been well established in asymmetric synthesis.87,88 The
transition metal complexes incorporating asymmetric ligands and
forming a homogeneous catalyst is one of the key methods for the
synthesis of optically active materials. Since the discovery of asym-
metric rhodium phosphine complexes in asymmetric hydrogena-
tions,89 a large number of asymmetric coordination complexes
have been synthesized and applied in enantioselective catalysis.
Investigation of proline as a metal ligand has provided a greater
insight to researchers across the globe, as it plays a crucial role in a
variety of chemical as well biological processes. Asymmetric metal
ligands containing proline as an asymmetric ligand have enabled
the synthesis of a wide range of organic molecules with diversifiedstructures in a regio- and stereoselective manner, such as building
blocks for phosphonyl-substituted peptides with b-turns.90 Pincer
palladium complexes bearing pyrroloimidazololone auxiliaries
with stereogenic centers present in the proline rings, as well as
the other groups of the pincer backbone are also well investi-
gated.9193 Dependingon thechoice of metal, these complexeshave
been applied in different catalytic reactions, such as aldol conden-
sation reactions,9499 Michael additions,9193,100 DielsAlder reac-
tions,94 cyclopropanations,101 allylation of aldehydes,102 allylic
alkylations94 and hydrogen transfers,103 etc with moderate to high
enantioselectivity.
N
Ts
N N I-
N
Ts
N
N
RhI
[Rh(COD)Cl]2, KI
KOBut, THF76%
146 147
Scheme 45.
B(OH)2 CHO
Cl
+ NHC-Rh, KOBut
DME/H2O
OH
Cl
148 149 150
Scheme 46.
N
N
H CO2R
Br
LMe R=Me
LBn R=Bn
N
N
H CO2R
Pd
R=MeR=Bn
Br
N
N
H CO2R
Pd HC
O
O
155a: R=Me, X=BF4155b: R=Me, X=PF6156a: R=Bn, X=BF4156b: R=Bn, X=PF6
Br
Br
Br
+
HN CO2R Et3N,CH2Cl2
rt, 16h
[Pd2(dba)3].CHCl3
C6H6,50oC,3h
AgBF4, acetone/H2O,rt
orNH4PF6/H2O,CH3OH,rt
151 152 153
154
HCO2R
HCO2R
X
R
Scheme 47.
Ph H
O
+CN
CO2Me
i-Pr2EtN,CH2Cl2NO
Ph CO2Me
Cat.155or156major
+ NO
CO2MePh
minor
50 Methylisocyanate 157a 157b
Scheme 48.
X
O
[RuCl2(p-cym)]2
NH
O
HN Ph
HCOOH/Et3N
X
OH
98%ee
158 159
Scheme 49.
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On the other hand, proline as a metal ligand has had a great im-
pact on biological systems as well; for example, proline as a heme
ligand is employed in CooA, the only protein which is a co-acti-
vated transcription factor found in the bacterium Rhodospirillum
rubrum.104 As described by Pinkert et al.,104 the proline stabilizes
the heme pocket during the redox mediated ligand switch and
forms a weak metal ligand bond that is preferentially cleaved to
bind Co.
Proline also bears potential ligand sites (Fig. 10) which in turn
have provided an interesting perspective for peptidemetalcomplexes.
FMoc and Boc derivatives of proline with phosphanyl groups
have also been synthesized,90 and these modified proline deriva-
tives have been incorporated into short peptides possessing sec-
ondary structure (b-turns). The rhodium complex of the resultant
peptide was also synthesized (Fig. 11).
The synthesis of novel N-heterocyclic carbene-Rh complexes
derived fromL-proline has been achieved with the aim of develop-
ing a catalyst for the addition of arylboronic acids to aldehydes.105
The desired imidazolonium compounds were synthesized from
L-proline, which upon treatment with p-toluenesulfonylchloride
and Na2CO3 in water afforded the N-tosyl derivative 142. The
reduction of142, with NaBH4 and BF3Et2O at room temperature
followed by quenching the reaction mixture with methanol fur-nished (2S)-2-(hydroxymethyl)-1-(4-tolylsulfonyl) pyrrolidine
143. The resulting alcohol, after a sequence of reactions as shown
inScheme 44, provided the desired imidazolonium salt 146.
Salt146was used for the preparation of an asymmetric NHC-Rh
complex147, where [Rh(COD)Cl]2was treated with KOBut in THF,
and subsequently allowed to react with proline derivative146, and
KI, thereby furnishing NHCRh complex 147 in 76% yield
(Scheme 45).
The applications of the above complex in the catalytic addition
of phenylboronic acid 148to p-chlorobenzaldehyde149 in dime-
thoxyethane (DME)H2O (3:1) in the presence of a base under var-
ious reaction conditions have been studied. It was concluded thatthe NHCrhodium complex is capable of furnishing alcohol 150,
in 95% overall yield under the optimal standardized conditions
(Scheme 46).
Gosiewska et al. reported106 the synthesis and study of the coor-
dination behavior of the asymmetric NCN-pincer ligands LMe and
LBn in the solid state and in the solution (Scheme 47).
Cationic complexes 155 and 156 were tested in the aldol reac-
tions between benzaldehyde and methyl isocyanate in the pres-
ence of i-Pr2EtN. The reactions were carried out in CH2Cl2 with
1 mol % of catalyst. In each case, the trans-oxazolines157awas ob-
tained as the major product. This reaction involved the formation
of a C-C bond with the creation of two stereogenic centers
(Scheme 48).
Rhyoo et al. explored107
the use of amino amides derived fromproline as asymmetric ligands in the ruthenium(II) catalyzed trans-
fer hydrogenation reaction of prochiral ketones, where product for-
mation occurred with approximately 98% ee (Scheme 49).
The highly enantioselective epoxidation of styrenes 160 cata-
lyzed by proline derived C1-symmetric titanium (salan) complexes
has also been described.108 These novel complexes have been used
to catalyze the epoxidation of styrene derivatives with aq. hydro-
gen peroxide as an oxidant, with high enantiomeric excesses rang-
ing from 96% to 98% being achieved (Scheme 50).
Sud et al. explored the oxidative coupling of amines and ketones
with combined vanadium and proline organocatalysis.109 The com-
bination of vanadium and proline as an organocatalyst enabled the
direct oxidative coupling of cyclic tertiary amines 162, with non-
activated ketones without the requirement of preformed leavinggroups. In this catalytic system, elemental oxygen was employed
as a terminal oxidant (Scheme 51). The above strategy was suc-
cessfully employed for the synthesis of hygrine 163.
The synthesis ofP-chirogenic diarylphosphinocarboxylic acids
was carried out, from which a new class of amido- and amino-
diphosphine ligands (PNP) were derived110 bearing an L-proline
backbone (Fig. 12).
The catalytic activity of this novel ligand was evaluated in the
palladium-catalyzed allylic alkylation reaction of 1,3-
diphenylpropenylacetate 164b(Scheme 52).
Li et al. have developed two asymmetric metal clusters utilizing
the nucleophilic addition ofL-proline to di-2-pyridylketone166as
the key step.111 In the presence of cobalt (nickel) acetate, an asym-
metric ligand with the molecular formula (S)-(C5NH4)2 C(OH)
(C4NH7CO2H) was first obtained via the nucleophilic addition of
R
Ti(OiPr)4 ligand
30% H2O2
R O
96-98%ee Ph
OH
N NH
HO
Ph
H
ligand
160 161
Scheme 50.
N H+ H
OtBuOOH
VO(acac)2
Proline
5 mol%
10 mol%
N
O
hygrine
162 16315
Scheme 51.
NPPh2
P
O
Ph Ar *
NPPh2
PPh Ar
*
NH2 C l
-
PPh2
PhP
OH
Ar O
*
O
164a 164a
Figure 12. Amido- and amino diphosphine ligands.
Ph Ph
OAc i. Pd catalystii. Asymmetric ligand164a
(iii).CH2(COOMe)2Ph Ph
CH(COOMe)2
164b 165
Scheme 52.
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L-proline as a secondary amine to di-2-pyridylketone.The above li-
gand was synthesized in situ, and ultimately afforded two asym-
metric tetranuclear isomorphous complexes 167a and 167b with
the formula {Na[M4L3(OAc)3](ClO4)1.5(H2O)1.5}(ClO4)(OH)0.53H2O
(M = Co, Ni) (Scheme 53). The Co4cluster167a, was found to pos-
sess prominent ferromagnetic properties.
Xie et al. achieved112,113 an original CuI catalyzed asymmetric
coupling of various 2-iodotrifluoroacetanilides 168 with 2-
methylacetoacetates 169 assisted by (2S,4R)-4-hydroxy proline as
the ligand as well as the asymmetric source. This methodology
afforded the corresponding coupling products, 2,2-arylmethylace-
toacetates 170, with the generation of enantiomerically pure a-
aryl carbon quaternary centers. The asymmetric products were ob-tained in good yields in the presence of NaOH as the base and at
lower temperatures when compared to the original Ullmann cou-
pling. The much simpler reaction conditions in this synthetic strat-
egy was one of the key factors in the breakthrough which was
investigated by Xie et al., as the first example of a catalytic asym-
metric Ullmann type CC coupling reaction (Scheme 54).
Mixed ligand complexes of dioxouranium(VI) and thorium(IV)
in ratios of 1:1:1 and 1:2:1 were synthesized114 using 8-hydroxy
quinoline as the primary ligand and L-proline and 4-hydroxy-L-
prolines as the secondary ligands, respectively (Fig. 13). These
mixed ligand complexes 171174were prepared from metal salts
(aqueous solution), primary ligand (ethanolic solution), and sec-
ondary ligands (aqueous solution). These complexes were found
to exhibit prominent antibacterial activity against the pathogenicbacteria Staphylococcus aureusand Escherichia coli.
Recently the CuI/proline catalyzed selective one-step mono acyl-
ation of styrenes175aand stilbenes175bhas been described115 by
Prathima et al. Vicinal di-oxygenation of styrene-type olefins was
achieved with the less expensive and less toxic CuI in the presence
ofL-proline as a ligand and NaIO4as theoxidant. This approach pro-
vided a straightforward and efficient access tomono-acylated diols
176, from both styrene and stilbene derivatives with good to
excellent yields and diastereoselectivity (Scheme 55).
3.4. Differentially substituted prolines: asymmetric synthesis
and applications
Synthetic strategies toward substituted prolines have been
explored for many reasons, as these constitute as a part of various
N N
O
HN
+CO2H Co(OAc)2
or Ni(OAc)2(S)-(C5NH4)2C(OH)(C4NH7CO2H)
Ligand formedin situ
two asymmetric tetranuclear isomorphous complexes167aand167b
{Na[M4L3(OAc)3](ClO4)1.5(H2O)1.5}(ClO4)(OH)0.5.3H2O
(M=Co, Ni) {L= (S)-(C5NH4)2 C(OH)(C4NH7CO2H)}
166
Scheme 53.
IHN
R
CF3C
O
+ OR
Me
O O
HN
R
CF3C
OORO Me
*
60 to 90% ee
CuI (20%)Ligand (40%)-45 to -20oCDMF/H2ONaOH (2equiv.)
Ligand
NH
HO
CO2H
(2S,4R)-4-hydroxyproline
168 169
170
O
Scheme 54.
NH
OO
Th
N
O
N
O
OH2
O
NO
O
[Th(Q)2(Pro)NO3H2O] complex
NH
OO
Th
N
O
N
O
OH2
O
NO
O
[Th(Q)2(Hyp)NO3H2O] complex
OH
NH
OO
[U(Q)(Pro)2H2O] complex
U
O
O
O
N
OH2
H2O
NH
OO
[U(Q)(Hyp)2H2O] complex
U
O
O
O
N
OH2
H2O
OH
171 172
173174
Figure 13. Proposed structures and bonding for the thorium and uranium
complexes involving 8-hydroxy quinoline as the primary ligand and L-proline and4-hydroxy-L-prolines as the secondary ligands.
R1
R2
CuI, (L)-proline
NaIO4, AcOH, 80oC
R2
R1
OH
OAc
R1=H(or) Ar85% yield
175a, R1=H175b, R1=Ph
176
Scheme 55.
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bioactive natural products, suchas ()-domoic acid116 a potent neu-
rotoxin, kainic acid27,31 a CNS stimulant, ()-bulgecinine, a
constituent of the glycopeptide bulgecin117119
and so on. Several
alkylated prolines are naturally occurring amino acids120 and are
also constituents of various antibiotics, for example, N-methyl-
4-ethylproline in lincomycin B,121
4-methylproline in peptide
N
Boc O
OH
R
a, R=Phb, R= CH2CH2CH3c, R=CO2R
1
HN
O
OH
HHCH3
CH3H
HO
O
H
O OH
NH
O
OH
O
OH
Kainica cid:27,31 a potentneurotransmitter
Conformationally constrainedanalogues of phenylalanine,norleucine and aspartaterespectively149
(-)-Domoic acid:116 a neurotoxin
(-)-Bulgecinine: 117-119 aconstituent of bioactiveglycopeptide bulgecin
NH
OH
OH
O
HO
NH
O
OH
(S)-4-Exomethyleneproline:162
an inhibitor of the enzyme prolinedehydrogenase
N
R1
O
OH
O R2
SH
CH3
b: R1=H, R2=
HN CO2Et
CH2CH2Ph
c:R1=cyclohexyl, R2=P Ph
O O
)4(
OO
H3C
H3CO
a,b,c: Potent ACE inhibitors
Enalaprilat192
Fosinopril194
NH
O
OH
HO
4-Hydroxy-L-proline:174
a constituent of Collagen
N
O
NH
HO
H
O
HOH
OH
OH
SCH3
Lincomycin:121,122 an antibiotic
N
Me O
Me
(+)-Hygrine:198 an alkaloid
a:R1=H, R2=Captopril189
Figure 14. Applications of various proline derivatives.
NH
CO2H
NH
CO2H
R
2-substituted prolines
NH
CO2H
3-substituted prolines
R
NH
CO2H
R
4-substituted prolines
NH
CO2H
5-substituted prolines
R
Multisubstituted prolines
Synthesis of bioactivemolecules, natural products,azanucleosides etc.
1
Figure 15. Differentially modified prolines as unnatural aminoacids/aminoacid derivatives.
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antibiotics, 1 and N-methyl-4-propylproline in lincomycin A.122
Substituted prolines have also gained interest due to their use in
the development of novel angiotensin converting enzyme inhibi-
tors.123,124 The presence of proline itself is associated with confor-
mational changes in proteins including a strong preference for
secondary structural modifications, for example, a-helixes and re-verse turns.3,4125128 This property has marked effects ranging from
its role in collagen biosynthesis in protein folding to peptide hor-mone recognition events.129137 Substituted prolines have also
founduse in thesynthesis of conformationallyconstrainedpeptides,
which have been acknowledged as useful tools in the development
of peptidederivedpharmaceutical agents.11,12,138 Duetosuchawide
range of chemical as well as biological applications ( Fig. 14), the
asymmetric synthesis of prolines, substituted at different positions,
has become an area of interest by researchers all over the world.
NH
CO2H CF3CO2H (cat)
CHO
N
OH
LDA,-78oC
Electrophile
N
OH
O
O
E
NH
CO2HE Hydrolysis
1 177
178179
Scheme 56.
NH
CO2H N
OH
O
1.KHMDS
2.NitroareneN
OH
O
NO2
3.DDQ
NH
HO
O
NO2
Hydrolysis
1 177 180
181
Z
Z
Scheme 57.
NH
CO2H
H+
Cl
ClCl
OH
OEt
CHCl3
reflux
65%
N
H
OCl
ClCl
OLDA, THF, -78oC,
Br
82%N
OCl
ClCl
O
Na
CH3OH N CO2Me
CHO
AcCl, MeOH, reflux
74% over two steps NH
CO2MeHCl
1 182 183 184
185
Scheme 58.
HN
O
O
Ph N
O
CF3
Ph
I
O
NH
OH
CF3
O
NH
OH
CF3
O
HO OH
186187
188
189
Iodocyclization
CF3
Scheme 59.
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As a result, various strategies have been investigated for the
asymmetric synthesis of 2-, 3-, 4-, or 5-substituted prolines and
the N-acylation of prolines with suitable acylating agents (Fig. 15).
The aim of the present article is to discuss all of the major ad-
vances made to date with regard to the synthesis, reactivity, and
applications of prolines substituted at different positions.
3.4.1. 2-Substituted prolines
Seebach et al. developed a novel methodology139 for the synthe-
sis of 2-a-substituted prolines through self reproduction of chiral-ity, where the acid catalyzed condensation of proline with
pivaldehyde furnished a bicyclic derivative (2R,5S)-2-t-butyl-1-
azabicyclo[3,3,0]octan-4-one 177, where the t-butyl group ac-
quired a pseudo equatorial position. The lithium enolate derived
reaction of this bicyclic derivative with electrophiles resulted in
the formation of 2-substituted derivative178, where the incoming
group approached from the same side as occupied by the t-butylgroup, that is, the a-side with the retention of configuration.Hydrolysis of compound 178 afforded 2-a-substituted proline179(Scheme 56).
The enantioselective synthesis of (R)-a-(p-nitroaryl)proline 181via an oxidative nucleophilic substitution of hydrogen in nitroary-
nes has been carried out140 in a similar manner as described by
Seebach et al., exploring the self reproduction of chirality in pro-
lines (Scheme 57).
Taking advantage of Seebachs procedure of self reproduction of
chirality in prolinates, a synthetic strategy was developed141 for
the synthesis of a-branched prolines 185 using (3R,7aS)-3-(trichloromethyl)tetrahydropyrrolo[1,2- C]oxazol-1-(3H)-one 183,
as a precursor. Compound 183 was obtained by the condensation
of proline with commercially available 2,2,2-trichloro-1-ethoxy-
ethanol 182 (Scheme 58).
Recently Caupene et al. described a versatile strategy142 for the
synthesis of enantiopure a-trifluoromethyl prolines 188 and a-trifluoromethyl dihydroxy prolines189 through efficient iodocycli-
zation of asymmetric trifluoromethyl allyl morpholinone 186
(Scheme 59).
A straightforward asymmetric synthesis of (S)- and (R)-a-trifluoromethyl prolines188and 191, respectively, from oxazoli-dines190, derived from ethyl trifluoropyruate has been described
by Chaume et al.143 (Scheme 60). The key steps in this synthetic
strategy were the diastereoselective allylation reaction of ethyltri-
fluoropyruvate and an (R)-phenylglycinol-based oxazolidine. The
lactone obtained by the cyclization of the resultant hydroxyl ester
was used as an intermediate for the synthesis of (S)-a-Tfm-allylglycineand (S)-a-Tfm-norvaline in enantiomericallypure form.
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 con-
formational space of a peptide.147149 Having this basic feature in
mind, the introduction of 3-substituted proline derivatives in the
peptides have been well examined with the assumption that the
3-substituent would correspond to the substituent on theb-carbon
of standard amino acids; for example, 3-phenyl prolines, 3-n-pro-
pyl prolines, and proline-3-carboxylates are conformationally con-
strained analogues of phenylalanine, norleucine, and aspartate,
respectively149 (Fig. 13). Taking this into consideration, Chung
et al. designed and developed a synthetic strategy coupled with a
resolution procedure for 3-substituted prolines.149 They described
the synthesis and resolution of 3-phenyl and 3-n-propyl prolines
196. The cis- and trans-3-substituted prolines were synthesized
by the condensation of acetamidomalonate 194 and a,b-unsaturated aldehydes193 under basic conditions. The condensa-
tion product, hydroxyl lactam195, was subjected to acid catalyzedsilane reduction enabling subsequent transformations to occur
cleanly and in good yield. Thetrans-isomers were resolvedviatheir
diastereomeric (S)-a-methyl benzyl amides and the absolute con-figurations of the enantiomerically pure products were assigned
(Scheme 61).
The asymmetric route for 3-substituted prolines has also been
explored from pyroglutamates due to their easy accessibility and
efficient conversion to prolines, via reduction of the lactam car-
bonyl functionality. By taking advantage of this fact, Oba et al. car-
ried out150 the synthesis of 3-methyl proline 200, using a Michael
addition onto unsaturated orthopyroglutamate derivative 197a.
The (2S,3S)-methyl-pyroglutamic acid 2,7,8-trioxabicyclo [3.2.1]
octane (ABO) ester 197b, was converted to (2S,3S)-methyl-N-
OHN
F3C CO2Et
Ph
NH
CO2H
CF3
NH
CF3
CO2H
NH
CF3
OH
(S)--Tfm-proline
(R)--Tfm-proline (S)--Tfm-prolinol
190 188
191 192
Scheme 60.
O R
H
+
NH
CO2Et
O CO2Et
N
R
CO2EtHO
Ac
CO2Et N
R
Ac O
OEtEtO-Na+
- CO2Et
R=Ph, R=n-propyl
[H+],Silane reduction
193
194
195
196
ResolutionPure stereoisomers
of196
Scheme 61.
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Boc-3-methylpyroglutamate 198. Reduction of198 with BH3THF,
followed by the deprotection of199, in refluxing 1 M HCl and sub-
sequent ion exchange treatment with DOWEX 50X 8 resin fur-
nished (2S,3S)-3-methyl praline 200 in quantitative yield
(Scheme 62).
Curtis et al. carried out the first asymmetric synthesis of
(2S,3S,4R)-3-amino-2-hydroxymethyl-4-hydroxy pyrrolidine
203,151 where homo allylic carbamate 202, was synthesized from
a 4-substituted proline, which was converted into the desired tri-
substituted pyrrolidine (Scheme 63).
Kamenecka et al. described an enantioselective approach to3-substituted prolines.152 The enantioselective synthesis of 3-
substituted prolines206, was achieved starting from commercially
available 3-hydroxy-(S)-proline 204. A palladium mediated cou-
pling was used to introduce various groups at C-3 using the corre-
sponding enol triflate derived from N-trityl-3-oxo-(S)-2-proline
methyl ester. Cleavage of the trityl residue and hydrogenation
afforded final product 206, with satisfactory diastereoselectivity
(Scheme 64).
The synthesis of diastereomeric substituted proline peptidomi-
metics as a conformationally restricted tyrosine derivative 208, has
been accomplished153 utilizing the intramolecular hydroboration
cycloalkylation of azido olefins 207, as the key step (Scheme 65).
The asymmetric synthesis of proline based conformationally
constrained tryptophan mimetic212, has been reported by Delayeet al.154 The strategy involved the in situ generation of an allyl me-
tal species containing the indole moiety, which was allowed to un-
dergo coupling with asymmetric imine 210. The construction of
the 3-substituted proline skeleton was achieved through a hydro-
zirconation/iodination sequence to the resultant homoallylic
amine (Scheme 66).
NBoc
ABO
Me
ON CO2Me
Me
O
Boc
BH3THF
N CO2Me
Me
Boc
NH
CO2H
Me
HCl, MeOH, then
(Boc)2O, DMAP
1M HCl
DOWEX 50WX8
197b 198
199200
NBoc
ABOO
Michaeladditiion
197a
Scheme 62.
N
Ts
O
OH2N
N
Ts
O
HN
O
NH
OH
NH2HO
201 202 203
HO
Scheme 63.
N CO2Me
Tr
OTf (i) Pd-mediatedcoupling
(ii) HCl; H2NH2
CO2Me
R
Cl-
206
NH
CO2H
OH
204 205
Scheme 64.
N3
CO2But
N H
FMoc
OBn
CO2H
OBn
(i) Hydroboration
(ii) Cycloalkylation
* *
207 208
H
Scheme 65.
N
Boc
ZrCp2
OR
N
Boc
NH
Ph OH
BnO
N
Boc
N
Fmoc
HO2C
(i) Et2Zn
(ii)
O
HN
Ph
OBn209 210
211
212
Scheme 66.
N CO2Bn N
Fmoc
CO2H
Ph
N
R
Boc
R = -H, -OMe, -NO2,Cl, -CO2Me
i,ii,iii
213 212
3 Steps
Scheme 67. Reagents and conditions: (i) Amino zinc-ene-enolate cyclization; (ii)
transmetallation; (iii) Negishi-cross-coupling.
1836 S. K. Panday/ Tetrahedron:Asymmetry22 (2011) 18171847
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A short access to cis-3-substituted prolino homotryptophan
derivative 212, was developed through amino zinc-ene-enolate
cyclization sequences.155 The asymmetric synthesis ofcis-3-substi-
tuted prolines has been achieved via amino zinc enolate cyclization
followed by transmetallation of the cyclic intermediate for further
functionalization. The synthesis of a prolinohomotryptophane
derivative was achieved through Negishi cross-coupling of the zinc
intermediate with indole rings. The Pd-catalyst from Fus
[(t-Bu3)Ph]-BF4 was used to eliminate the possibility of undesired
b-hydride elimination (Scheme 67). Enantiomerically pure and N-
protected compounds were obtained, which could be utilized in
peptide synthesis.
Recently the total synthesis of natural cis-3-hydroxy-L-proline
204, fromD-glucose was described156 by Kalamkar et al. The meth-
odology involved the conversion ofD-glucose intoN-benzyloxycar-
bonyl-c-alkenyl amine, which upon 5-endo-trig-aminomercuration afforded the pyrrolidine ring skeleton with a sugar
attachment in roughly 25% yield. In an alternative procedure, theN-benzyloxycarbonyl-c-alkenyl amine upon hydroboration-oxida-tion, mesylation, and intramolecular SN2 cyclization furnished a
pyrrolidine ring compound in high yield. Hydrolysis of a 1,2-aceto-
nide, NaIO4cleavage, followed by oxidation of the aldehyde into anacid and subsequent hydrogenolysis afforded cis-3-hydroxy-L-pro-
line204, in 29% yield from D -glucose (Scheme 68).
Huy et al. have investigated157 a convenient synthesis oftrans-
3-substituted proline derivatives through a 1,4-addition
(Scheme 69). A four step synthesis of 3-alkyl-, vinyl-, and aryl-
substituted proline derivatives 217, has been achieved. These
3-substituted prolines have been acknowledged as important
building blocks for conformationally constrained peptide ana-
logues. This methodology involved the Cu-catalyzed 1,4-addition
of a Grignard reagent onto N-protected 2,3-dehydroproline esters
216, easily obtainable from L-proline methyl ester hydrochloride
O OH
OH
HO
HO
D-(+)-Glucose
O
N
Cbz
H
HO
O N
H
CO2H
OHH
H
L-cis-3-hydroxyproline
OH
214 204
i
ii
iii,iv
v,vi
Scheme 68. Reagents and conditions: (i) Conversion toN-benzyloxycarbonyl-c-alkenyl amine; (ii) hydroborationoxidation, mesylation and intramolecular SN2 cyclization;(iii) hydrolysis of 1,2-acetonide; (iv) NaIO4 cleavage; (v) oxidation of the aldehyde into the acid; (vi) hydrogenolysis.
NH
CO2Me
HCl
i. NCSii. Cbz-Cl
one pot NCbz
CO2Me
i. R-MgXCu(I)X
ii. LiOH NCbz
CO2H
R
215 216 217
Scheme 69.
N
Boc
CO2R2
R1O
N
Boc
CO2R2
Ph
NH
CO2H
Ph
Ph2CuLi/Et2O/THF
NH4Cl-H2O
CF3CO2H
218a, R1=H
218b, R1=Ts 219 220
Scheme 70.
NH
CO2HO
(i) ROH/H+
(ii) NaBH4NH
CH2OHO
NO
OPh
NO
OPh
N CH2OH
NH
CH2OHNZ
CH2OH
(i) Jones oxidation
(ii) H2/Pd-C
PhCHO/H+
LDA,Br
-78oC
LAH/THF
Ph
H2/Pd-C
Z-Cl/K2CO3
H2O-THF
NH
COOH
10 221 222
223 224
225 226 227
Scheme 71.
S. K. Panday / Tetrahedron:Asymmetry22 (2011) 18171847 1837
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215 in two steps. The 1,4-addition products were obtained with
goodtrans-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 first time as theconstituent of collagen. The synthesis of 4-substituted prolines has
received further attention, since they have been acknowledged as
very good intermediates for the synthesis of potent angiotensin
converting enzyme inhibitors158,159 with the objective to design
and synthesize modified captopril and enalapril analogues. Since
then, rapid progress has been made in investigating and develop-
ing newer methodologies for the synthesis of 4-substituted
prolines.
trans-4-Phenyl-L-proline 220, and trans-4-cyclohexyl-L-proline227, are effective intermediates for potent ACE inhibitors. The syn-
thesis oftrans-4-phenyl-L-proline220was achieved124 as shown in
Scheme 70, where commercially available 4-hydroxy-L-proline was
used as the precursor. 4-Hydroxy-L-proline, after protection of the
carboxylic and NH-groups, converted to its O-tosyl derivative
218b. The reaction of lithium diphenylcuprate with N-protected
trans-4- and cis-4-tosyloxy-L-proline esters followed by deprotec-
tion, furnished excellent yields of 4-phenyl substituted L-prolines
and the reaction proceeded with net retention of configuration at
the carbon center bearing the tosyloxy group.
Taking advantage of the possibility for easy conversion of pyro-
glutamic acid into proline, Thottahil et al. developed 39,123 an effi-
cient strategy for the synthesis oftrans-4-cyclohexyl-L-proline as
an intermediate for fosinopril,160 starting from pyroglutamic acid
10, where pyroglutamic acid was converted to pyroglutaminol
221. The acid catalyzed condensation of pyroglutaminol with benz-
aldehyde, furnished a bicyclic derivative 222, where the phenyl
group acquired a pseudo equatorial position. Alkylation of the lith-
ium enolate of bicyclic derivative 222, with cyclohexenyl bromide
proceeded with high facial selectivity to give 4-a-product 223,
which after a series of reductive, hydrogenolytic, and oxidativereactions afforded trans-(2S)-4-cyclohexyl proline 227
(Scheme 71).
An easy route for the synthesis of 4-substituted prolinates
through a lithium enolate derived aldol reaction followed by
reduction, starting from t-butyl-(2S)-N-benzyloxy carbonyl-pyro-
glutamate 228 has been described.161 Hydrogenolysis of
t-butyl-(2S)-N-benzyloxy carbonyl-4-a-(hydroxyphenylmethyl)-pyroglutamate 229, and subsequent conversion to a thiolactam,
followed b