ORGANIC TRANSFORMATIONS CATALYZED BY PROLINE AND
ITS DERIVATIVES
The thesis deals with the development of new methodologies for the
formation of C - C and C - N bond formation reactions and synthesis of biologically
active molecules using proline and its derivatives. The first chapter details the
importance of asymmetric catalysis and chiral ligands which are used as chiral
backbones in asymmetric catalysis and organocatalysts encountered in the
conventional homogeneous processes. The
most important organocatalyst is
proline. The applications of the proline are described in the first chapter. Chapter 2
describes the proline catalyzed asymmetric two and three component and self
Mannich reaction of propanal under ultrasonic conditions. Chapter 3 describes the
proline catalyzed asymmetric Michael addition of unmodified ketones and
aldehydes with nitro styrenes accelerated by triethylamine. Chapter 4 is divided
into two sections; section A deals with the synthesis of (+)-epi-cytoxazone and (-)cytoxazone via proline catalyzed asymmetric Mannich reaction. Section B
describes the proline catalyzed selective oxidation of sulfides to sulfoxides using L
- proline as catalyst and H2O2 as an oxidant. Chapter 5 is divided into two sections;
section A deals with the N - Boc proline promoted CuI catalyzed N - arylation of
heterocycles with aryl halides. Section B describes the CuI catalyzed S - arylation
of aryl thiols with aryl halides.
CHAPTER-I: Introduction
This chapter describes the area of asymmetric catalysis mediated by metal
complexes and metal free catalysts in homogeneous conditions. In this chapter,
chirality, enantiomeric compounds are described. The importance of asymmetric
synthesis and role of organocatalysts in asymmetric synthesis is highlighted.
Various chiral ligands are described in combination with different metals for
various asymmetric organic transformations. The importance of organocatalysts
for asymmetric synthesis and the necessity to develop environmentally cleaner
catalytic methodologies is highlighted. Reaction intermediates such as enamine,
i
iminium, acylammonium ion and carbene nucleophiles are described. Importantly
proline catalyzed asymmetric aldol, Mannich and asymmetric Michael additions
are described.
CHAPTER-II: Proline catalyzed asymmetric Mannich reactions under
ultrasonic conditions
Proline catalysis has recently been applied to the direct three component
asymmetric Mannich reactions of ketones, aldehydes and amines to give  -amino
ketones in high yield and enantioselectivities. This reaction constitutes the first
catalytic asymmetric three component Mannich reaction of a free aldehyde with
unmodified ketone and an amine. It is also the first organo catalytic
enantioselective Mannich reaction. In the most effective and enantioselective
proline - catalyzed Mannich reactions, hydroxyacetone is used as the donor, which
furnishes syn - 1, 2 - amino alcohols in high chemo -, regio -, diastero, and
enantioselectivities and in good yields. The use of aldehydes as nucleophilic
donors offers a particularly attractive route to fuctionalized β - amino acids and
their derivatives including β - lactams and amino alcohols. Moreover, not only the
strategy involves the creation of two contiguous stereo centres upon carbon carbon bond formation, but also provides ready structural and functional diversity.
Recently, the wide applications of ultrasonic conditions for various organic
transformations were reported. Under ultrasonic conditions condition the rate of
reaction, increases many folds than the conventional conditions. With this
knowledge, proline catalyzed two component and three component and self
Mannich reactions are reported with improved enantioselectvities than the
conventional conditions.
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O
NPMP
+
L- proline
(15 mol%)
NHAR
O
H
OH
DMSO, rt, 1 h
R
OH
Ultrasonic conditions
R
Yield : 90 - 98%
ee
: 81 - 99%
Scheme 1. Proline catalyzed two component asymmetric Mannich reaction under
ultrasonic conditions.
O
O
+
H
R
+
ArNH 2
OH
L- proline
(20 mol%)
NHAR
O
DMSO, rt
1h
Ultrasonic conditions
R
OH
Yield : 85 - 92 %
ee
: 45 - 99%
Scheme 2. Proline catalyzed three component asymmetric Mannich reaction
under ultrasonic conditions.
NH2
O
CH3
OMe
2 eq
NHPMP
CH3
HO
DMF, 1 h
Ultrasonic conditions
+
H
1. L - proline
(15 mol%)
CH 3
2. NaBH4, Methanol,
15 min
Yield
dr
ee
1 eq
:
:
:
80%
95:5
91%
Scheme 3. Self Mannich reaction of propanal and p - anisidine under ultrasonic
conditions.
CHO
O
+
H
+
CH 3
Excess
NH 2
OMe
HN
HO
OMe
1 eq
1. L - Proline
(20 mol%)
DMSO,rt, 1 h
Ultrasonic conditions
2. NaBH4 ,Methanol
0.5 h
Yield :
1.1 eq
ee
30%
:
30%
Scheme 4. Three component proline catalyzed asymmetric Mannich reaction with
propanal under ultrasonic conditions.
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CHAPTER-III:
L- Proline Catalyzed
Asymmetric Michael addition of
unmodified ketones and aldehydes to nitro olefins
An efficient L-proline/Et3N catalyzed Michael addition of unmodified ketones
and aldehydes with nitro olefins to afford -nitroketones in excellent yields and
moderate enantioselectivities is reported. Rate enhancement of Michael addition
of aldehydes and unmodified ketones to nitro olefins over those previously
reported conditions is presented. It was noticed recently by Ji et. al that certain
additives accelerate the conjugate addition, for example they observed an
increase of five fold rate enhancement in conjugate addition of 1, 3 -dicarbonyl
compounds to nitro olefins with N-methylmorpholine as an additive. The rate
enhancement for Michael addition was also observed with acetone as a donor
resulting 96% yield and 20% ee in 1.5 h. Particularly the conjugative addition of
aldehydes to nitrostyrenes produced γ - formyl nitro compounds in one step.
These useful synthons can be further converted into a wide rage of interesting
building blocks such as 1, 4- aminoalcohols or amino acids in a straightforward
manner. Moreover, the above strategy is successfully applied for the synthesis of
substituted pyrrolidines. The substituted chiral and achiral pyrrolidines are
common structural motifs found in many natural and unnatural products that
possess important biological activities and a great deal of effort has been devoted
towards the development of asymmetric methods for their synthesis.
O
+
Ar
NO 2
L-proline
(20 mol%)
NEt3 (1eq),
O
Ar
NO 2
CHCl3, r.t,
2- 5 h.
Yield : 90 - 98%
ee : 10 - 54%
Scheme 5. Michael addition of cyclohexanone to nitrostyrenes.
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O
L-proline
(20 mol%)
NO 2
+
H
NEt3 (1 eq)
Ph
R
O
Ph
NO 2
H
R
THF, rt, 1 - 10 h
Yield : 90 - 98%
ee
: 15 - 19%
Scheme 6. Michael addition of aldehydes to nitro styrenes.
CHAPTER-IVA: Synthesis of biologically active (+) - epi - cytoxazone and (-)
– cytoxazone via L - proline catalyzed asymmetric Mannich reaction
Cytoxazone 1, a novel 4, 5 - disubstituted-2 - oxazolidinone compound
isolated from streptomyces species in 1998 by Osada et.al, has shown cytokine
modulating activity. It interferes with cytokine IL4, IL 10 and IgG production by
selective inhibition of the signaling pathway of Th2 cells, but not Th1 Cells.
Inhibition of Th2 dependent cytokine production has been used as potential potent
chemotherapeutic agents in the field of immuno therapy. Cytoxazone 1 is different
from known immunomodulators such as Rapamycin and FK 506 in respect of
structure and biological activity. As such, cytoxazone 1 should be a useful tool for
understanding signaling pathways in Th2 cells.
Therefore, the synthesis of
cytoxazone 1 and its analogues has been a new subject of synthetic studies for
the development of new cytokine modulators.
OMe
OMe
H H
H H
HO
HO
O
NH
O
(-)- Cytoxazone
O
NH
O
(+) 5 - epi- cytoxazone
I
2
Figure 1
Enantiomerically pure substituted 2 - oxazolidines are important target
molecules in organic synthesis. Some of them act as antibiotics against highly
resistant gram-positive bacteria. Oxazolidinones are a novel class of synthetic
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antmicrobial agents active against gram-positive pathogenic bacteria including
methicillin-resistant
Staphylococcus
aureas
(MRSA),
penicillin
resistant
Streptococcus pneumonia (PRSP) and vancomycin-resistant Enterococcus
faecium (VREF). Oxazolidinones are antibacterial agents that act primarily against
a wide spectrum of gram-positive and anaerobic bacteria by inhibiting protein
synthesis.
Many common gram-positive pathogens (e.g., Staphylococcus aureus,
Enterococcus sp, and Streptococcus pneumoniae) have become increasingly
resistant to antimicrobial agents, and new drugs with activity against gram-positive
bacteria are urgently needed. The oxazolidinones, a new chemical class of
synthetic antimicrobial agent, have a unique mechanism of inhibiting bacterial
protein synthesis. Linezolid is the first member of this class recently licensed in the
USA and Europe and available in both oral formulations. Linezolid is efficacious in
treating skin and soft tissue infections, pneumonia and bacterium; and is
particularly effective against infections caused by MRSA, PRSP and VREF. New
agents with greater potency and new spectra of activity could arise from further
modification of the oxazolidinone nucleus. Presence of chiral oxazolidinone ring in
cytoxazone is responsible for antibacterial activity. Therefore, cytoxazone 1 and its
analogues are synthesized to study their antibacterial activity and other activities.
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NH 2
O
CHO
O
L-proline (15 mol %)
+
+
OMe
NO 2
OH
DMSO
Ultrasonic conditions
1h
NO 2
Yield : 98 %
ee
: 99 %
dr
: 95:5
O
O
O
NHPMP
NHPMP
Cl 3C
OH
C
PMP N
CCl 3
DCM, 0oC
1 h to rt
NO 2
Pd/C, H2
Methanol
3 h, rt
O
O
O2N
O
PMP N
O
O
1. NaNO2, AcOH,
0o C, 16 h
O
PMP N
O
2. K2CO3, CH3I,
DMF, 7 h
H2N
LIHMDAS
THF, -78o C
2h
O
MeO
O
O
PMP N
NH
1. Ozonolysis
DCM, 30 min
O
O
OH
OSiMe3
2. LiCl+ NaBH4
MeO
3. CAN, H2O
MeO
2
(+)-epi-cytoxazone
60% yield, 99 % ee
Scheme 7. Synthesis of (+) – epi - cytaxazone from Mannich product
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O
NPMP
+
L- proline
(15 mol%)
NHPMP
O
O
H
OH
+
DMSO, rt, 1 h
OMe
NHPMP
OH
OH
ultrasonic conditions
OMe
OMe
Yield : 65%
O
O
NHPMP
Cl 3C
OH
OMe
C
25%
O
PMP N
CCl 3
DCM, 0o C
1 h to rt
LiHMDS
O
THF, -78o C
2h
O
MeO
O
O
PMP N
1. Ozonolysis
DCM, 30 min
O
NH
O
OH
OSiMe3
2. LiCl + NaBH4
MeO
3. CAN, H2O
MeO
(-)-Cyatoxazone
1
Scheme 8. Synthesis of (-) - cytaxazone from Mannich product.
CHAPTER–IVB:
Proline
catalyzed selective
oxidation of sulfides to
sulfoxides
The synthesis of chiral sulfoxides with high enantiomeric purity has been a
subject of constant interest over the past two decades. A real break through
occurred in the synthesis of chiral sulfoxides at the beginning of the 1990s, when
various new methodologies appeared. The new methods allow access to a large
number of sulfoxides with different steric and stereoelectronic characteristics,
generally in both enantiomeric forms. Selective oxidation of sulfides to sulfoxides
using L - proline as catalyst and H2O2 as an oxidant is described. Various amino
acids were screened and proline is proved to be the best in terms of
chemoselectvity. The present catalytic system was easy to handle and the catalyst
is water soluble, it can be easily removed by simple water workup.
viii
R S R1
L-proline (10mol%)
30% H2O2 (2.5 mmol)
O
R S R1
CH3CN, rt, 1.5 h
R=R1 = alkyl.aryl, allyl
Yield upto 98%
Scheme 8. Proline catalyzed selective oxidation of sulfides to sulfoxides.
CHAPTER – 5a: N - Boc proline promoted coupling reactions of aryl halides
with N - heterocycles
N - Arylimidazoles and other N - Arylheterocycles are common motifs in
pharmaceutical intermediates that have biomedical use. A significant number of N
- arylimidazole derivatives have been reported to have biomedical applications,
serving as cyclic AMP phosphodiesterase inhibitors, AMPA receptor antagonists,
cardiotonic agents, thromboxane synthase inhibitors, and topical antiglaucoma
agents. Copper mediated cross - coupling reactions and Ullmann condensations
are widely used for the formation of aryl - carbon and aryl- heteroatom bonds in
organic synthesis. The C - N bond formation via transition metal catalysis is
currently a subject of great interest and intensive research is being carried out to
ensure useful organic transformations. Copper is the most ancient metal used for
the coupling of aryl halides to form biaryls. A new coupling protocol for the
synthesis N - aryl imidazoles, using N - protected proline as promoter is reported.
The new catalytic system is more efficient than simple proline, which can activate
bromo and iodo aromatic compounds.
The present catalytic system worked well for substituted aryl chlorides. Aryl
chlorides bearing electron - withdrawing groups underwent a smooth coupling with
imidazole. This is the first report on N -arylation of imidazoles with electron
withdrawing aryl chlorides catalyzed by CuI/ amino acid system
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CuI (10 mol%)
N - Boc proline (15 mol%)
Cs2CO3 (2 eq)
x
DMSO
110o C
+ N - heterocycle
R
18 - 36 h
x = I, Br
N - heterocycle
R
Yield up to 95%
Scheme 9. N - Boc proline promoted CuI catalyzed N - arylation of aryl halides
with N – heterocycles.
Cl
N
+
R
CuI (10 mol%)
N - Boc proline (15 mol%)
Cs2CO3 (2 eq)
R
N
H
DMSO
120o C
N
N
36 h
Yield up to 90%
x = I, Br
Scheme 10. N - Boc proline promoted CuI catalyzed N - arylation of electron
withdrawing aryl chlorides with N – imidazole
CHAPTER–V B: Copper catalyzed S - arylation of aryl halides with diphenyl
disulphide and diphenyl diselenides
The transition metal catalyzed thiolation of aryl halide is an important
transformation and which are of great significance to the pharmaceutical industry.
The use of copper catalysts for C - S bond formation is an attractive field from an
industrial perspective. The methods for C - S bonds usually require harsh reaction
conditions. Traditional copper systems have lacked the efficiency and wide
applicability in the synthesis of unsymmetrical aryl sulfides. These aryl sulfides
have interesting characteristics in organic synthesis and are often used as
effective reagents or convenient intermediates in organic synthesis. Usually metal
catalyzed preparation of aryl sulfides involve the cross coupling of thiol with aryl
halides, using a copper or palladium catalysts under basic conditions. In addition
to that diaryl selenides have also attracted considerable interest as potential
anticancer and antioxidant agents. They are also key intermediates in the
x
synthesis of a plethora of biologically and pharmaceutically important selenium
compounds such as selenium salts, selenoxides, selenimines and selenide
dihalides. In the past five years there has been resurgence in interest in
developing mild synthetic methods based on the copper catalysts as an alternative
to palladium (0) catalysts for the formation of aryl-carbon and aryl-heteroatom
bonds.
Copper catalyzed coupling reactions of aryl halides with diphenyl disulfides
and
diphenyl
diselenides
is
described.
Readily
available
reagents
disulfide/diselenide are used in place of thiols or selenols.
I
+ PhS-S-Ph
R
CuI (10 mol %)
NaOH (2eq)
DMSO, 95o C
13 h
S
R
Scheme 10. CuI catalyzed S - arylation of aryl halides using of diphenyl di
sulfides.
Significant Achievements:
 Proline catalyzed two component, three component and self Mannich reactions
are reported. Yields and enantioselectvities are improved than the conventional
conditions.
 Michael addition of unmodified ketones and aldehydes with nitro olefins to
afford -nitroketones is described. These useful synthons can be further
converted into a wide rage of interesting building blocks such as 1, 4-amino
alcohols or amino acids in a straightforward manner.
 Enantiomerically pure substituted 2 - oxazolidinones are important target
molecules in organic synthesis. Some of them act as antibiotics against highly
resistant gram-positive bacteria. Therefore the synthesis of cytoxazone and its
analogues has been described.
 Selective oxidation of sulfides to sulfoxides using L-Proline as catalyst and
H2O2 as an oxidant is described.
xi
 N - arylimidazoles and other N – arylheterocycles are common motifs in
pharmaceutical intermediates that have biomedical use. The synthesis N - aryl
imidazoles, using N-protected proline as promoter is described. The new
catalytic system is more efficient, which can activate bromo and substituted
chloro derivatives.
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