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1
CHAPTER 1
INTRODUCTION
1.1 BACKGROUND
Synthesis of optically active drugs and optically active drug
intermediates has been achieved by applying a gamut of synthetic techniques
with the use of chiral auxiliaries and reagents, chiral catalysts inclusive of
chiral ligands, diastereoselective and biochemical methods. The asymmetric
construction of molecules with quaternary carbon stereocenters, that is,
carbon centers with four different non-hydrogen substituents, represents a
very challenging and dynamic area in organic synthesis.
The ephedrines constitute one of the significant therapeutic
segments viz. antitussives, narcotic analgesics, mydriatics, bronchodilator,
decongestants, antiallergics, central nervous system stimulants, etc.
Continuous and aggressive molecular modification of the parent molecules
for better therapeutic efficacy and lower toxicity are the current thrust area of
research by industrial research and development units. 1-Phenyl-2-
pyrrolidinyl-1-propanol, 1-phenyl-2-piperidinyl-1-propanol, N-tosylnorephedrine
and levo-phenylacetylcarbinol have been identified as substrates for the
study of molecular modification through synthetic strategy involving
diasteroselective approach with the intention of adding value to the afore
mentioned library of molecules.
As applied chemistry constitutes the backbone of any industrial
research and development, the immediate application of the synthesized chiral
2
molecules from the above-mentioned group of substrates towards the
chemical separation of racemic carboxylic acids, the drug precursors for
commercialization has been undertaken.
1.2 CHIRAL –ALKYLATION OF 1-PHENYL-2-(1-
PYRROLIDINYL/1-PIPERIDINYL)-1-PROPANOL
The nucleophilic addition of organometallic reagents to carbonyl
compounds is a well known reaction, This represents a powerful tool for the
construction of stereoselective carbon-carbon bonds. Several versatile
methods for the synthesis of alcohols by addition of Grignard reagents to
carbonyl compounds have been reported (Kharasch and Reinmuth 1954,
Stowell 1979, Nigishi 1980). However, side reactions such as enolisation,
reduction, condensation or conjugate addition have resulted in poor yield of
the desired alcohols. Several alternatives (Imamoto et al 1982, Imamoto et al
1985, Imamoto and Sugiura 1985) such as organocerium (III) reagents,
RMgX-CeCl3 system, organolanthanides, etc., are reported to overcome the
yield reduction due to side reactions. New types of organomagnesium
reagents such as di-Grignard reagents, magnesiocycles and highly
functionalized organomagnesium reagents (Oestreich and Hoppe 2001, Fang
et al 2005), alkyl, alkenyl, alkynyl, aryl, allylic and benzylic Grignard
reagents have been reported (Yanagisawa 2004). Grignard reactions have
been carried out on solid supports constituting solid-phase synthesis (Franzen
2000) as well as in aqueous media (Wada et al 1999).
Chiral tertiary alcohols bearing a quaternary stereocenter are still a
challenge to synthetic organic chemists (Fuji 1993, Corey and Perez 1998).
The particular challenge is the stereoselective addition to ketones as compared
to aldehydes, which produces a tertiary alcohol of defined relative
configuration. Lower reactivity of ketones compared to aldehydes and the
difference in steric demand between two substituents on carbonyl carbon
3
leading to stereoselection being less in ketones than in aldehydes contribute to
the complexity of devising a sound synthetic method. The enantioselective
addition of organometallic reagents to ketones resulting in chiral tertiary
alcohols has been reported by Yus and Ramon (2002). Several examples of
addition of organolithium and Grignard reagents to ketone in the presence of a
chiral ligand have been reported (Thompson et al 1995, Thompson et al 1998,
Reider et al 1999, Kauffman et al 2000).
Efficient organic synthesis requires control over absolute and
relative stereochemistry. Among the many chemical transformations that form
stereogenic centers, addition to ketones is especially important. Their value
to organic synthesis arises from several characteristics: many types of
nucleophiles will react with ketones; addition reactions display high atom
economy and represent convergent fragment couplings; the product tertiary
alcohols are ubiquitous in natural products, pharmaceutical agents, and other
biologically active materials; and tertiary alcohol products are substrates for a
rich diversity of subsequent synthetic transformations (Antczak et al 2011).
The synthetic route to Idoxifene (Ace et al 2001), a selective
estrogen receptor modulator (SERM) involves diastereoselective synthesis of
a tertiary alcohol, (1RS,2SR)-1-(4-iodophenyl)-2-phenyl-1-[4-2-pyrrolidin-1-
yl-ethoxy)phenyl] butan-1-ol by Grignard addition to the ketone, 1-(4-
iodophenyl)-2-phenyl-1-butanone as the essential part of the synthetic
sequence (Scheme1.1). A little excess of the Grignard reagent was used with
respect to the ketone and the product was isolated in 79% yield essentially as
a single diastereoisomer as determined by1HNMR. Homoallylic alcohols are
versatile synthetic intermediates used for stereoselective synthesis of complex
natural products. One such anti-cancer natural product, Fostriecin isolated
from Streptomyces pulveraceus, has been synthesised.
4
Scheme 1.1
The synthesis involved chelation controlled nucleophilic addition to
alkoxyketones with a high degree of stereoselectivity (Ramachandran et al
2003). C1-C11 subunit of fostriecin has been synthesized with stereoselective
addition of methylmagnesium bromide to the alkoxyketone (Scheme 1.2).
Scheme 1.2
The reaction of allyltitanocenes with phenyl and alkyl methyl
ketones produced anti tertiary homoallylic alcohols with complete
diastereoselectivity (Yatsumonji et al 2009). They have suggested chair-like
cyclic transition states for the observed antiselectivity.
5
Synthesis of Periplanone C (Ivkovic et al 2004), diarylbutylamine
pharmacophores (Maertens et al 2004) and neodolabellane diterpenoids
(Mehta and Umarye 2003) involved addition of Grignard type reagents to beta
keto ester units (Marcantoni et al 2006). These authors have employed the
combined use of organocerium compounds and titanium tetrachloride to
produce tertiary alcohols with high diastereoselectivity. The results have
been rationalised by the formation of chelation-controlled diasteromer. The
interaction between TiCl4 and bidentate beta-ketoester moiety resulted in the
formation of a rigid cyclic intermediate in such a stable conformation as to
provide high stereofacial discrimination to the incoming nucleophile.
1.2.1 Grignard Reaction of Aminoketone
Synthesis of , -dialkylphenethylamines from the corresponding
ketones with the appropriate Grignard reagent and their physiological action
was the subject of research by Suter and Weston (1942). Their study
revealed that an alkyl group in the -position of phenethylamines and -
methylphenethylamines lowered the toxicity without appreciable lowering of
their pressor activity. This study was extended to explore alkylation of
carbon bearing the hydroxyl group in ArCH(OH)CHRNHR. These are
obtained by reaction between a suitable Grignard reagent and aminoketone
hydrochloride.
The -dialkylaminopropiophenones and -alkyl- -dialkylamino-
propiophenones were allowed to react with benzylmagnesium chloride to
yield tert-carbinol viz., 4-dialkylamino-1,2-diphenyl-2-butanol. Ketones
containing an asymmetric centre yielded predominantly one diastereoisomer
either or (Pohland and Sullivan 1953).
Correlation between the structure of Grignard reagents and
stereochemistry of the addition reaction with a variety of -aminoketones has
6
been reported. The study revealed that the stereoselectivity decreased with
increasing size of the halide ion. It also depends on the degree of solvation
or aggregation of the Grignard reagent by the solvent. The products were
racemates with the same configurations at both asymmetric carbons or with
opposite configuration at asymmetric carbons. The ratios of racemates
obtained depend on R and R’ as well as the solvent (Audoyea and Lattes
1975). The 3-substituted-3-tropanols were prepared by Grignard reaction of
the corresponding aminoketones (Fischer and Mikite 1971). The Grignard
reactions of -asymmetric -aminoketones were highly stereospecific. All the
phenylketo bases yielded only one of the two possible diastereoisomeric 1-
phenyl-1-methyl-3-aminopropan-1-ol while the corresponding methyl keto
bases yielded the other diastereoisomer (Scheme 1.3). The diastereoisomer
ratios were determined and the steric configurations have been assigned.
The results are discussed based on a cyclic model in which Mg
atom of the Grignard reagent coordinates with both the carbonyl oxygen and
the amine nitrogen; the entering organic group then approaches the carbonyl
from the side opposite to R group (Andrisano et al 1970).
C
O
C
CH2
HPh
NR'2
R
C
O
C
CH2
HMe
NR'2
R
C
Me
C
CH2
HPh
NR'2
R
C C
CH2
H
OHPh
Me
NR'2
R
+ Me MgI
+ PhMgX
+
R = Me, CH2-Ph,Ph NR'2 = NMe2, N(CH2)5
X = Cl,Br, I
Ia-f
IIa-f
IIIa-f IVa-f
Note: Only one enantiomer of the racemic pairsis represented here
OH
Reaction B
Reaction A
Scheme 1.3
7
Several pure erythro- and threo-aminoalcohols were synthesized by
reduction of the corresponding -aminoketone with lithium aluminium
hydride as well as by the treatment of the corresponding -aminoaldehydes
with Grignard reagents. The ratio of erythro- and threo- products was
dependent on the size of NR2 group. A mechanism was proposed to explain
the results (Scheme 1.4) (Duhamel et al 1972).
H NR'2
R
H
OHR
R NR'2
H
H
OHR
R CH
NR'2
C R
O
LiAlH4RMgX R CH
NR'2
C H
O
+
erythro (E) threo (T)
LiAlH4
Ph
O
NR'2
Ph
Ph
HO
NR'2
Ph
H Ha b
Scheme 1.4
The stereochemistry of Mannich keto bases has been studied in
order to clarify the stereochemistry of reactions between -substituted -
aminoketones and Grignard reagent (Angeloni et al 1969). For example, the
absolute configuration of (+)- -methyl- -dimethylaminopropiophenone was
found to be ‘S’ by chemical correlation with (R)-(-)- -methyl- -alanine as
shown in Scheme 1.5 (Angeloni et al 1969).
8
CO
CH2N(CH3)2
CH3H
C6H5
S (+)
CH2NH2
HCH3
HOOC
R (-)
CH2N(CH3)2
HCH3
HOOC
R (-)
CH2N(CH3)2
HCH3
PhOC
R (-)
CH2N(CH3)2
CH3H
HO(C6H5)2C
S (+)
CH2N(CH3)2
HCH3
HO(C6H5)2C
R (-)
Scheme 1.5
1.2.2 Cram’s Rule of Asymmetric Induction
The Crams rule of steric control of asymmetric induction (Cram
and Elhafez 1952) is applicable in correlating and predicting the
stereochemistry of asymmetric induction in reactions of acyclic systems in
which a new asymmetric centre is created adjacent to the old one. This rule is
stated simply that “in non-catalytic reactions of the type shown above, that
diastereomer will predominate which would be formed by the approach of the
entering group from the least hindered side of the double bond when the
rotational conformation of C-C bond is such that the double bond is flanked
by the two least bulky groups attached to the adjacent asymmetric centre”.
This type of acyclic system was chosen to study stereochemical
direction of asymmetric induction because
i. the two asymmetric centres are on adjacent carbon atoms
ii. carbon-2 does not carry any groups capable of complexing with
reagents involved in the creation of asymmetry at carbon-1
9
iii. the structures of the diastereomeric alcohols can be readily
demonstrated as shown in scheme 1.6.
OH
R
Ar
R
R'
OH
H
ArReagent
R1 R1
On -carbon, R>Ar>H in order of decreasing effective bulk
OR
C6H5
H
OHR
C6H5
H
2. H3O+
1. R2MgX
R1 R1
R2
Scheme 1.6
The foregoing summary of examples, selective synthesis of chiral
tertiary alcohols using suitable organometallic reagent, application of Cram’s
rule in predicting the stereochemistry of resultant alcohols and excellent
enantioselectivity observed when chiral catalysts were employed as the
catalyst bears ample testimony to the proven methodology of synthesis of
achiral and chiral tertiary alcohols using Grignard method.
1.3 ENANTIOSELECTIVE -AMINATION OF 1-PHENYL-2-(1-
PIPERIDINYL)-1-PROPANOL AND N-TOSYLNOREPHEDRINE
-Amination reactions constitute an important class of
regiospecific substitution reactions in view of their impact on mechanistic and
synthetic organic chemistry as well as their commercial applications. The
products of -amination such as diamines and triamines and their derivatives
are known to exhibit vital applications such as chelating agents in
radiopharmaceuticals (Jones et al 1989, de Riemer et al 1981), precursors of
10
aza-macrocycles (Lehn 1978) and heterocycles and in medicinal chemistry
(Kasina 1986). They also play a vital role as chiral auxiliaries in a variety of
asymmetric transformations involving chiral phosphonamides (Hanessian
1984), Lewis acids (Corey 1989), metal enolates (Corey 1990), dienophiles
(Gruseck et al 1987) and transition metal reagents (Onuma et al 1980, Fiorini
et al 1979). N-Alkylated derivatives of (1R,2S)-(–)-ephedrine, (1R,2R)-(–)-
pseudo ephedrine and (1R,2S)-(–)-norephedrine are excellent substrates for
regiospecific -amination reactions via the intermediacy of reactive -halo
derivatives or -ester derivatives such as mesylates, tosylates, etc. These
substitution reactions could be with sodium azide, amines, imides, thiols,
thiolactic acid, N-hydroxypthalimide and diphenylphosphine to give a single
isomeric product in each case.
Highly enantioselective alkylation of protected glycine amides with
alkyl halides under phase-transfer conditions using chiral quaternary
ammonium salt as the catalyst has been reported to yield optically active
monosubstituted vicinal diamines as shown in Scheme 1.7 (Ooi et al. 2003).
NNH
PhPh
Ph
O
NNH
PhPh
Ph
O
R
PTC
RX
Hydrolysis
Reduction
H2NNH
Ph
R
Scheme 1.7
An efficient homocoupling of imines to give vicinal diamines
promoted by low-valent niobium has been reported (Arai et al 2005). The use
of zinc and NbCl5 for the in situ formation of the active niobium species gave
the coupling product in excellent yield with good DL/meso ratio (Scheme
1.8).
11
Ph
N
OMe
NbCl5,Zn
rt, 1h NH
Ph
MeOPh
NH
OMe
N N+
Low valent NbNH
NH
Scheme 1.8
1.3.1 Preparation of Unsymmetrical Vicinal Diamines
The role of N-tert. butane sulfinylimines in asymmetric synthesis of
chiral diamines has been highlighted elaborately (Lin et al 2008).
Enantiopure 1,2-diamines which are important precursors to many chiral
ligands and organocatalysts are best made by direct reductive coupling
between two imine species. Cross-coupling of two imines is rather difficult
because of the competition of the homocoupling of each imine substrate.
However, upon treatment with two equivalents each of 2SmI2 and HMPT,
the homocoupling of aldimine proceeded smoothly to provide the product
as a single diastereomer. After removal of the chiral auxiliary under
acidic condition, the free diamines were obtained in excellent enantiomeric
excess. The proposed mechanism for the reaction is also shown in
Scheme 1.9.
12
R
NS
O
S NHHN S
OO
R R
NH2
RR
H2N
HMPA, -78°C
HCl
R= 4-ClC6H4. 4-BrC6H4, 4-AcOC6H4, 4-MeC6H4
2SmI2/THF
R
NSH
O
SmI2/L
L=HMPAR
NS
O
LI2Sm
R
NS
O
LI2Sm
S-cis-S-trans
RH
RH
NS
O
LnI2Sm
NS
O
SmI2Ln
H2O NH2
RR
H2N
Scheme 1.9
Synthesis of unsymmetrical chiral vicinal diamines via a three-step
reaction starting with the commercially available 5-oxo-pyrrolidine-2-
carboxylic acid as the chiral source has been reported (Kohn et al 2007).
Reaction between 5-oxo-pyrrolidine-(S)-2-carboxylic acid and anhydrous
chloral in the presence of catalytic amount of PTS in toluene gave the known
diastereomeric oxazolidinone derivative (Scheme 1.10).
NO
H
O
OH NO
O
O
Cl3C
NO
H
O
NR
H N
H
O
NR
H
a b c
a: 5-oxo-L-proline, anhydrous chloral, toluene
b: R-NH2, toluene R= aniline, 4-chloroaniline, p-toludine , benzylamine
c: LiAlH4, THF
Scheme 1.10
13
Limonene, the inexpensive, enantiomerically pure natural
compound from the chiral pool has been used for synthesis of chiral diamines
containing a trans-1,2-diamminocyclohexane skeleton, widely fused in chiral
reagents, scaffolds and ligands for catalysis (Cimarelli et al 2009) The
cis/trans-epoxides of 4S-(-)-limonene were converted to enantiomerically
pure diaminolimonene through the intermediacy of azidoalcohols, aziridines
and azidoamines (Scheme 1.11).
O
S S
NH2
NH2R R
2 (COOH)2
S
NH2
NH2R R
S
OH
N3R R
S
N3
OHR R
PPH3
THF, r,t48 hrs, 89%
S
NH
S R
NaN3
CeCl37H2O
CH3CN/H2O
relux 12 hrs, 74%
S
N3
NH2R R
PPH3
1,4-Dioxan,reflux24 hrs, 77%
S
NH
S S
NaN3
CeCl37H2O
CH3CN/H2O
relux 12 hrs, 71%
S
NH2
N3R R
cis/trans-(4S)-(-)-Limonene oxide
NaN3
NH4Cl
MeOH
reflux 24 hrs
LiAlH4
MTBE
0°C to r.t
95-97%
H2C2O4
EtOH
Scheme 1.11
1.3.2 Synthesis of Diamines by Diaza-Cope Rearrangement
Synthesis of chiral vicinal diamines scaffolds of natural products
and therapeutic agents has been achieved by the application of Diaza-Cope
rearrangement (DCR) (Scheme 1.12). This rearrangement taken place under
mild conditions without catalyst, is highly stereospecific and eliminates
tedious optimization of chiral resolution procedures (Kim et al 2008). The
14
known syntheses of C2-symmetrical, primary vicinal diamines are described
in Scheme 1.12.
H2N NH2OH OH
(Ar)R
O
Ar
N
O
t-Bu
Ar Ar
H2N NH2
or
R R
H2N NH2
N N
PhPh
t-BuMgCl
Ar Ar
HO OH
Ar Ar
H2N NH2Ar Ar
H2N NH2
or
R R
H2N NH2
Ar
NTMS
CN
CN
N N
Ar Ar
N
Ph
Ph Ph
reductive
coupling
OpticalResolution
(+ ) or (- )dialyl diamine
(+ ) or (- )diaryl diamine
Grignarnd
reaction
DACHProduction
Reduction ofPhenyl
Reduction ofimine
DAENProduction
Reductivecoupling
Substitution
racrac
Diaza-CopeRearrangement(DCR)
(R,R) or (S,S) HPEN'mother' Diamine
Scheme 1.12
1,2-Bis-(2-hydroxyphenyl)-1,2-diaminoethane (HPEN) is the
“mother” diamine from which a variety of “daughter” diamines are produced.
In a typical reaction, addition of two equivalents of aromatic aldehyde to
HPEN resulted in the formation of corresponding diimine which undergone
DCR to give rearranged diimine. This on hydrolysis gave the product
diamine (Scheme 1.13).
15
OH
NH2
NH2
2ArCHO
OH
OH
N
N
OH
Ar
Ar
OH
N
N
OH
Ar
Ar
OOH NH2Ar
Ar NH2
HPEN'mother diamine
Doughter Diamine
Scheme 1.13
The progress of the rearrangement reaction can be conveniently
monitored by the appearance of1H NMR signal from the resonance-assisted
hydrogen bond that is highly shifted downfield away from other signals. The
DCR reaction takes place by a chair-like, six-membered –ring transition state
with all the substituents in pseudoequatorial position. This resulted in a
highly stereospecific transfer of stereochemistry from the starting diimine to
the rearranged imine. Chiral HPLC indicated no loss of enantiopurity in the
preparation of daughter diamine from the mother diamine. This method could
be extended to the preparation of alkyl-aryl vicinal diamine and dialkyl
vicinal diamine.
1.3.3 Synthesis of Chiral 1,2-Diamines from 1,2-Aminoalcohols
The methods for preparing the vicinal diamines are rather limited,
particularly when other sensitive functionalities are present elsewhere in the
molecule. Olefins react with azide anion oxidatively to form vicinal diazides
(Fristad 1985, Moriarty 1986). The reduction of these diazides to diamines is
16
prone to alternative reactions and requires careful selection of reductants.
Another drawback of the use of azides is their possible explosiveness.
Vicinal diazides can also be prepared from vicinal dihalides or
stereospecifically from an epoxide with a hydroxyazide (Swift 1966).
Alternatively, iodoisocyanation of an olefin followed by hydrolysis results in
the formation of an aziridine, which can be opened with ammonia to give a
vicinal diamine stereospecifically.
Cycloaddition of chlorosulphonyl isocyanate to olefins followed by
Curtius rearrangement and hydrolysis of the resulting cyclic urea gave vicinal
diamines (Fraenkel 1984). Reductive amination of -aminoketones, Michael
addition of urethanes of dehydroalanine derivatives, reduction of -
aminonitriles, reduction of -aminoamides (Gutsche 1985) all these
processes led to vicinal diamines which can also prepared from dienes via a
Diels Alder adduct of sulphone bisimides (Weinreb 1984). Jones et al (Jones
1989) have used the readily available and inexpensive 1,3-diamino-2-
propanols as starting materials for the synthesis of diamines. A highly
stereo- and regioselective route to a series of chiral diamines and triamines for
use as ligands in organocopper conjugate addition reactions was developed
with ephedrine and pseudoephedrine as starting aminoalcohols by Dieter et al
(1992).
The -hydroxy tertiary amines were readily obtained by alkylation
of (1R,2S)-(–)-ephedrine and (1R,2R)-(–)-pseudoephedrine with -chloro-
N,N-dimethylacetamide. These -hydroxy tertiary amines were mesylated in-
situ with methanesulphonyl chloride in tetrahydrofuran (THF) in the presence
of triethylamine and then treated with various amines and the corresponding
diamines were isolated. The substitution had preceded regiospecifically and
stereospecifically with retention of configuration was confirmed by single
crystal X-ray analysis of the aniline derivative. The treatment of the mesylate
17
in-situ with sodium azide gave the corresponding azide, which on reduction
with lithium aluminium hydride gave the triamine in good yield (Scheme
1.14).
OH
PhNHCH
3
R
N
OOH
RPh
Me
NMe2
O
N
O
Me
Ph Me
N
X
Ph
O
NMe2
Me
N
X
Ph NMe2
Me
N
X
Ph
O
NMe2
Me
N
X
Ph NMe2
Me
N
OOH
H CH3
Ph
Me
NMe2
N
OOH
CH3
HPh
Me
NMe2
R RR1
Reaction conditions A or B
R1
+
Na2CO3
Xylene, reflux
Mesyl chloride
RNH2 or NaN3
LiAlH4
Mesyl chlorideRNH2 or NaN3 LiAlH4
A= ClCH2CONMe2, Na2CO3,
NaI, PhH, reflux, 20h
B=ClCH2CONMe2,Et3N
PhH, reflux
X=N3, NH2, PhNH, BuNH, c-C6H11NH
R1 R1=H; =CH3=CH3; =H
Scheme 1.14
The above methodology described above was also extended to
(1R,2S)-N-ethylephedrine, (1R,2S)-N-methylephedrine, (1R,2R)-N-
ethylpseudoephedrine and N,N-bis-protected-(2R)-phenylglycinol.
The novel diamine formation was anticipated by N,N-bis alkylation
of norephedrine with 1,4 dibromobutane and subsequent double inversion of
the benzylic stereogenic centre in pyrrolidinenorephedrine (Scheme 1.15).
Thus, the treatment of (1R,2S)-norephedrine with 1,4-dibromobutane, tetra-
butylammonium iodide and sodium carbonate in refluxing THF for 48 h
followed by mesylation and reaction with methylamine gave the expected
diamine viz. (1R,2S)-1-N-methyl-1-phenyl-2-N-pyrrolidinylpropanamine in
83% overall yield as the only diastereoisomer as shown by1H NMR. The
other diastereoisomer was prepared by a similar approach in 84% yield from
(1S,2R)-norephedrine.
18
OH
MePh
N
OH
Me
NH2
PhH
N
Me
H
PhNH
N
Me
Ph
Me
-Norephedrine
+
(1R,2S)-1- N-Methyl-1-phenyl-2-(N-pyrrolidinyl)propanamine
(1R,2S) Aziridinium ion
Scheme 1.15
(1S,2S)-Norpseudoephedrine hydrochloride was synthesized by a
reported procedure and converted into the required (1S,2S)-1-N-methyl-1-
phenyl-2-N-pyrrolidinyl propanamine by following the afore-mentioned
procedure. The structure of the propanamine was confirmed by1H and
13C
NMR (Scheme 1.16).
OH
MePh
N
OH
Me
NH3
Ph
N
Me
H
H
Ph
NH
N
Me
Ph
Me
++
(1S,2S)-Norpseudonorephedrinehydrochloride
(1S,2S)-1-N-Methyl-1-phenyl-2-N-pyrrolidinylpropanamineAziridinium ion
Cl
Scheme 1.16
Synthesis of (R*,R*)-benzyl-(1’,2’-diphenyl-2-pyrrolidin-1-yl-
ethyl)amine has been achieved by Carter and co-workers (Carter et al 2003) in
a four step synthetic sequence starting from 1,2-diphenylethene (Scheme
1.17). The significance of this synthetic sequence is that the -chloro
derivative has been isolated and fully characterized by spectroscopic
investigation. This resulted low but significant enantio selectivity (15%) and
yield of 82% was observed as a result of selective stabilization of one of the
enantiomeric transition states by ion pairing with the chiral anion present.
19
Ph
Ph
O
Ph
Ph
OHPh
Ph N
NH
NHBzPh
Ph N
m-CPBA
DCM, 0ºC
Toluene
MsCl,NEt3
DCM, 0ºC
BzNH2, Et3N
THF-Toluene
(R*,R*)-Benzyl-(1',2'-diphenyl-2-pyrrolidin-1-yl-ethyl)amine
OMsPh
Ph N
Aziridiniumintermediate
R
R
R
R
R
R
Scheme 1.17
The following two examples are representative of the role of
1-N-methyl-1-phenyl-2-pyrrolidinylpropanamine as a chiral catalyst.
Reaction of epoxide (E) with lithium amide derived from racemic 1-N-
methyl-1-phenyl-2-pyrrolidinylpropanamine in cyclopentane resulted in (F) as
the sole diastereoisomer in 89% yield. Conversion of (F) into the hitherto
unknown triacetate (G) was accomplished in 88% yield by deprotection with
TBAF and subsequent acetylation (Kee et al 2000 (Scheme1.18).
TBSO
TBSO
O
OH
TBSO
TBSO OAc
AcO
AcON
NH
Me
Me
13
1,3cis(E) (F)
1. TBAF
2. Ac2O
13
(G)
BuLi, THF
Scheme 1.18
20
C2-Symmetric vicinal diamines derived from L-tartaric acid with increasingly
bulky terminal ether functionalities were prepared from the corresponding
vicinal diols (Scheurer et al., 1999) as shown in Scheme 1.19.
OR
OR
HO
HO
OR
OR
MsO
MsOOR
OR
N3
N3
OR
ORH2N
H2N
R= CH2C6H5,
R= CH3,
R= CH2-2-napthyl
Scheme 1.19
1.4 DIASTEROSELECTIVE GRIGNARD ADDITION TO
(R)-(-)- PHENYL ACETYLCARBINOL (R-PAC)
Grignard addition to carbonyl function constitutes one of the core
concepts of carbonyl chemistry. Addition to aldehydes and ketones has been
well–documented. Grignard alkylation of prochiral ketones and acyloins has
been the subject of chiral chemistry especially the stereoselective and
regioselective reactions leading to the synthesis of drugs and drug
intermediates.
1.4.1 Methods of Preparation of (R)-(-)-Pheylacetylcarbinol
(R)-(-)-Phenylacetylcarbinol is manufactured from pyruvic acid
and benzaldehyde in a medium containing carbon source with Saccharomyces
yeast (Netraval and Vojtisek 1982). Baker’s yeast was precultured in a
medium containing molasses and simultaneous addition of benzaldehyde and
acetaldehyde (50%) in a ratio 1:1.15 to give L-phenylacetylcarbinol (Groeger
et al 1966). Phenylacetylcarbinol (PAC) was obtained by transformation of
benzaldehyde and pyruvate using Saccharomyces cerevisiae (Long and ward
21
1989) or Candida utilis (Shukla and Kulkarni 2000) as biocatalysts. The
productivity was improved by mutagenesis of yeast cell with N-methyl-N -
nitro-N-nitrosoguanidine (NTG) or UV light and selection of highly
producing mutants (Seelay et al 1989). Optimum conditions of fermentation
and composition of production medium have been established. In another
mehod (Gupta et al 1979), benzaldehyde added to yeast cells in the presence
of fermentable sugars is transformed to phenylacetylcarbinol.
Studies were conducted to find the producing capacity of various
yeasts, uptake of benzaldehyde, formation of PAC and benzyl alcohol and the
factors affecting PAC formation. All Saccharomyces strains studied grew in
the presence of 0.05% benzaldehyde. One strain, S. cerevisiae CBS 1171, was
adapted to grow in 0.15% benzaldehyde. This strain formed 225, 200, 50 and
50 g benzyl alcohol/100mL culture medium in the presence of glucose,
sucrose, mannitol and lactose respectively. 10 g cells/100 mL broth and pH
5.0 were the optimum conditions for PAC formation. Maximum PAC (5.24
g/L) was obtained in 8 h if 0.6% peptone was added. Yeast extract (0.4%)
gave 5.14 g/L in 4 h and malt extract (0.2%) gave 5.04 g/L in 8 h.
Commercially (R)-(-)-Phenylacetylcarbinol is generated biologically through
the pyruvate decarboxylase (PDC)-mediated condensation of added
benzaldehyde with acetaldehyde generated metabolically from feedstock
sugars via pyruvate. Some of the added benzaldehyde is converted through
the action of alcohol dehydrogenase (s) to benzyl alcohol, an undesired by-
product. (R)-(-)-Phenylacetylcarbinol is extracted from the fermentation broth
by toluene and isolated by concentration under vacuum.
1.4.2 Grignard Addition Reaction to -Hydroxyketones
A high level of substrate induction by hydroxyl group by virtue of
coordinating property and its location proximal to the reacting functional
group fulfil the criteria of a privileged synthon (Horton et al 2003) and hence
22
an -hydroxy ketone is the starting material for the ideal motif for creation of
structural diversity and complexity as exemplified in Scheme 1.20 (Plietker
2005).
Boehringer Ingelheim GMBH, Germany (GB, 1962) prepared a
series of propargyl diols by Grignard reaction between synthetic racemic
phenylacetylcarbinol and propargyl magnesium bromide and incorporated the
products in the formulation for sedative therapy. The photochemical reaction
of the unusual -diketone, 2,2,5,5-tetramethyltetrahydrofuran-3,4-dione with
aldehyde gave the corresponding -hydroxy ketone. The alcoholic group was
protected as an ester and Grignard reaction with 4-methylbenzylmagnesium
bromide was investigated with special reference to the stereochemistry of the
reaction (Rubin and Bassat 1978).
XC G XC G ---B
A
C GXA
B
A B
Precoordination R eaction
C G : C oordinating group
O
HO HO R
HO
HO R
HO
HO
HO
OH
HO
O H
HO
N H R
1,2
- addit
ion
R eduction
Red
ucti
on
R eductiveA mination
Scheme 1.20
23
The isolation of cis- diol in almost quantitative yield has been
rationalized by the formation of the bulky solvated magnesium salt which is
attacked from the side of the molecule to the hydroxyl group as well as
stabilization of the transition state for cis- diol formation by coordination with
magnesium. The authors have claimed that the factors for trans-diol formation
were unclear. It is significant to note that both benzoin and its methyl ether
followed the same stereochemical course in Grignard reactions similar to this
observation (Curtin et al 1952). The results are summarized in Scheme 1.21.
O
O
BOH
O
CH2C6H4 p-CH3
O
OH
O
p-CH3C6H4 CH2MgCl O
OH
OH
CH2C6H4 p-CH3
O
O
O
CH2C6H4 p-CH3
C
cis- Isomer
THF
H3O
Acetone
O
OH
CH2C6H4p-CH3
OH
trans - Isomer
CuSO4
H
HH
Scheme 1.21
The above-mentioned benzoin reaction was further explored by a
research group in Fordham University, NY, USA (Ciaccio et al 2001) in the
diastereoselective synthesis of (+/-)-1,2-diphenyl-1,2-propanediol from the
Grignard reaction of (+/-)-benzoin with methylmagnesium iodide. The
reaction is indicated in Scheme 1.22.
24
O
PhPh
HO
1.MeMgIOH
PhPh
HO
H CH3
OH
CH3Ph
HO
H Ph2. H2O,H
Scheme 1.22
(+/-)-Diol was formed in 92% yield and very pure compound was
isolated after a few crystallizations. The -facial discrimination was
demonstrated by the application of Cram’s rule to stereochemical course of
the kinetically controlled addition to the carbonyl of an inexpensive -chiral
ketone (Scheme 1.23).
Ph
O
HC
O
PhPh
HO
MeMgI
CH C
O
Mg
O
Ph Ph
LL
Ph
O
MgL L
CH3CH3
-CH4
Ph
HO
H
OH
CH3Ph
MeMgI H3O
OH
PhPh
HO
H CH3
(+/-)
(+/-)
Scheme 1.23
The enantiospecific synthesis of phospholipase A2 inhibitor leavo
Cinatrin B from D- arabinose derivative involved a chelation controlled
addition of the Grignard reagent derived from trimethylsilylacetylene to -
hydroxyketone has been reported (Cuzzupe et al 2002) (Scheme 1.24).
25
O
HO
MeO
O
O
CH2)9CH3
THF, -78°C to 0°C
O
HO
MeO
O
CH2)9CH3
HO
R
C C Mg BrTMS
Scheme 1.24
The search for C1,20-lyase inhibitor responsible for the
management of male prostrate cancer widely prevalent in the USA led to a
practical stereo-controlled synthesis of (S)-1-(6,7-dimethoxy-2-naphthyl)-1-
(1H-imidazol-4-yl)-2-methyl-1-propanol involving enantioselective oxidation
of a keto intermediate to -hydroxyketone and diastereoselective Grignard
reaction with isopropylmagnesium bromide (Matsunaga et al 2004). The
partial profile of the synthetic scheme, relevant to this investigation, is given
in Scheme 1.25.
Cl
Cl
N SO
O
O
MeO
MeO
O
Cl
AlCl3, 77%
MeO
MeO
O
LDA, THF,-78°C
MeO
MeO
O
OH
R
MeO
MeO
O
1. NaHMDS,THF
2. TBCL
MeO
MeO
OTBS
CH3SO2NH2
t.BuOH, H2O
MeO
MeO
O
OH
R
MeO
MeO
O
OH
R i-PrMgBr
THF
HO
OH
MeO
MeO
RS
Scheme 1.25
26
The two pronged approach to chiral 1,2-diols (from aldehydes
and ketones) form the backbone of carbohydrates, polyketides
and alkaloids (Ohmori et al 2004) involving organocatalytic oxidation
and diastereoselective (Scheme 1.26) Grignard addition reaction has been
the subject of recent research investigation by Peng Jiao and co-workers from
the university of Chicago, USA. The methodology involved nitrosoaldol
formation followed by Grignard reaction (Jiao et al 2009). The details
of reaction with cyclohexanone as the starting material are given in
Scheme 1.26.
R1
R2
O
Enentioselectiveoxidation
OrganocatalystR1
R2
O
OArHN
Diasteroselective addition
R3MgX/R3LiR1
R2
OH
OHR3
NO
DMSO
O
O
O
NH
RMgCl
CeCl3,2LiCl
THF, -78°C-RT
HORHON
HNH
N
NN
Scheme 1.26
1.5 CHIRAL SEPARATION OF RACEMIC CARBOXYLIC
ACID USING 1,2-DIAMINES
1.5.1 Chiral Separation of Racemic Mixtures and its Imporatance
In all biological systems homochirality is predominant and this has
been preserved since the beginning of evolutionary time. Homochirality refers
to spatial configuration of molecules such as D- and L- amino acids, which
are either produced by biological organisms or synthetically created (Alberty
and Silbey 1992). This spatial configuration is vital to biological activity
27
because asymmetry dominates at the molecular level. From Pasteur’s first
studies involving biotransformations to Fisher’s “lock–and–key” concept, our
understanding of biomolecular interactions have grown, resulting in the
development of highly specific pharmaceuticals (Valentine 2002).
By definition, a chiral material is one which lacks reflectional
symmetry, i.e. exhibits a non-superimposable mirror image structure, and is
termed as being “handed”. The most common chiral compounds which exist
are enantiomers. These materials are typically characterized by an
asymmetric, tetrahedral carbon atom located at the center of the molecule.
These molecules can exist as stable, observable stereoisomers if their energy
barrier of conversion exceeds 80 KJ/mole. In addition, compounds which
exist as enantiomers have nearly identical physical and chemical properties in
an achiral environment, making their resolution into individual components a
challenging one. These differences in stereochemistry can influence the
pharmacological, metabolic or toxicological activity of the finished drug
formulations. In other words, isomer specific pharmaceuticals often exhibit
increased potency, higher bioavailability and reduced side effects when
compared to racemic pharmaceutical compounds. The development of new
practical methods for the preparation of enantiomerically pure substances is
thus vital and nowadays, pharmaceutical industry demands detailed
investigations of chiral molecules, in compliance with the regulatory
requirements.
When these enantiomers are present in equimolar amounts within a
mixture, the resultant mixture is termed racemic. These preparations are
optically inactive because the net rotation of plane polarized light is negated
by equal concentrations of each enantiomer. The first successful attempt to
resolve enantiomers from their racemic mixture was performed by Louis
28
Pasteur, in which he manually resolved a racemic mixture of sodium
ammonium tartrate into its individual enantiomers (Sheldon 1993).
Diastereoisomers are non mirror image stereoisomers that possess
more than one asymmetric center. Unlike enantiomers, diastereomers may be
individually isolated because differences exist in their physical and chemical
properties such as solubility and melting point. Enantiomers may be
transformed into diastereomers by either covalently or non-covalently
coupling the enantiomers of a racemic mixture to another chiral molecule
possessing at least one asymmetric center. This methodology defines a
separation route by which two previously inseparable materials may be
isolated by conventional techniques.
The importance of determining the pharmacological activity of
each component in a drug has now gained full acceptance as shown by the
substantial number of single isomer pharmaceuticals entering the commercial
market. The motivation for this single isomer trend has been provided in part
by the Food and Drug Administration (FDA) and in part by the production of
a host of pharmaceuticals previously protected by patent laws. The
pharmaceutical producers have been addressing the following issues:
pharmacological properties of the individual enantiomers and of
the racemic mixture
assays which determine enantiomeric purity
the need to produce as a single isomer
economic incentives to develop separation methods for existing
racemic mixtures
Those particular chiral drugs whose patents are expiring are
attracting a multitude of global producers. This would provide pricing
29
competition and increase the generic brand availability from producers with
large scale capacities. (Stinson 1997).
There exists a multitude of methods and techniques specifically
designed for enantiomeric separations, though not all methods are equally
applicable for every racemic mixture. Drug development within the
pharmaceutical industry focuses heavily on asymmetric synthesis, enzymatic
resolution, crystallization techniques, chromatographic and membrane
processes and combinatorial chemistry. The common denominator in all these
processes is that these are organic media based methods (Valentine 2002).
The present investigation is the development of an organic media- free
separation process, while drawing heavily from the practices and principles of
traditional separation methods (Newman 1981).
Salient methods of resolution from the prior-art literature such as
kinetic resolution, enantioenrichment by crystallization, chiral column
resolution, capillary electrophoresis, diastereomers separation and combo-
resolution techniques. The separation by using diastereomeric salt formation
and combo-resolution techniques are described below to highlight the vital
aspect of this concept and practice in the field of pharmaceutical technology
and the relative contribution of the present investigation towards resolution
technique in the process of chiral bulk drug manufacture.
1.5.2 Diastereomeric Separation
Optical resolution of racemic 2,6-bis(hydroxymethyl) derivative
was achieved (Wang et al 2010) via the diastereomeric (R)-1,1’-bis-2-
naphtholethers (Scheme 1.27). Absolute configuration of the enantiomers was
determined by circular dichroism (CD) exciton model analysis. The
electronic circular dichroism (ECD) spectra and the specific rotation of the
30
enantiomers were found to agree with the results of Density Functional
Theory (DFT) calculations. The benzylic dialcohols were identified by 2D
NMR spectroscopy and X-ray crystallographic analysis. They are used as the
starting point for the synthesis of several novel dithiametacyclophanes. The
usefulness of such thiacyclophanes as fluorescent chemosensors for different
metal ions is also demonstrated.
Me
Me
Me
HOH2C
CH2OH
Me
13 (rac)
c
b a0
PBr3/CH2Cl220°C, 2h
95%
Me
Me
Me Me
16 (rac)Br
Br
1) (R)-BINOL, Cs2CO3
acetone, 25°C2) Chromatography
87%
45% 42%
Me
Me
Me Me
17 aX*
X*
Me
Me
Me Me
17 b
X*
X*
0
BBr3/CH2Cl220°C, 1h
85%
Me
Me
Me Me
17 b
R
R
(pS,pS)
(+)-16 R = Br
NaOAc/HOAc
(+)-18 R = OAc
NaOMe/HOMe
(+)-13 R = OH
96%
86%
OH
OX*
(-)-16 R = Br
NaOAc/HOAc
(-)-18 R = OAc
NaOMe/HOMe
(-)-13 R = OH
95%
89%
0BBr3/CH2Cl2
20°C, 1h
89%
Me
Me
Me Me
17 aR
R
(pR,pR)
Scheme 1.27
The selective crystallization of ibuprofen lysinate from one mole of
(R,S)-ibuprofen and 0.5mol of (S)-lysine has been reported. An
unprecedented temperature selective diastereo-recognition (TSD) led to the
preparation of either enantiomer of ibuprofen (as well as the preferred lysinate
salt) utilizing the inexpensive, naturally occurring and readily available (S)-
lysine as the chiral resolving agent and appropriate choice of resolution
conditions.
31
In addition, we also report a convenient, waste-free, thermal
racemization of (S)-(+)-ibuprofen that does not require any external reagent,
catalyst, and/or solvent, thus rendering alternate racemization technologies
less attractive. This racemization method, when utilized in conjunction with
the selective crystallization technology, provided an efficient and
environmentally benign technology to prepare (S)-(+)-ibuprofen lysinate in an
overall yield which is nearly quantitative (Bhattacharya and Murphy 2003)
(Scheme 1.28).
CO2H
L-Lysine (<0.5 mol)
RS-lbuprofen
lbu:lys (2.5:1)24°C,EtOH:H2O (97:3)
lbu:lys (2.5:1) 0°C,EtOH:H2O (95:5), seed
S-lbuprofen lysinate [93(S):7(R)]
R-lbuprofenlysinate [80(R):20(S)]
(Kinetic)
(Thermodynamic)
Crystallization inaq.EtOH
S-lbuprofenlysinate
(99% d.e]
Scheme 1.28
It has been shown that (+)-tramadol is metabolised to primary
metabolite (+)-O-desmethyltramadol, which has significant opiate side
effects (of the order of 100 times more than those of tramadol isomers
themselves). It is possible that further investigations in this field will lead to
better understanding of the pharmacology of tramadol enantiomers, which
could, in turn, allow for improved pharmaceutical composition. Hence the
separation of racemic tramadol was undertaken with chiral mandelic acid
(Evans et al 2002) (Scheme 1.29).
32
Scheme 1.29
The first resolution of racemic 2-amino-5-methoxytetralin is
achieved via diastereomeric salt formation with (S)-(-)-mandelic acid to give
(S)-2-amino-5-methoxytetralin hydrochloride of 99.7% ee in 29% overall
yield from the racemate, a chiral intermediate to assemble N-0923, a potent
dopamine D agonist effective against Parkinson’s disease. Preparation of
racemic 2-amino-5-methoxytetralin involved the Birch reduction of 1,6-
dimethoxynaphthalene and reductive amination of 5-methoxy-2-tetralone with
aqueous ammonia over Raney nickel under hydrogen atmosphere. The
another isomer (R) arising from the resolution, its xylene solution is heated at
130 °C over Raney cobalt under hydrogen atmosphere to regenerate racemic
2-amino-5-methoxytetralin hydrochloride in 95% yield, which enhanced the
overall throughput of the resolution process (Hirayama et al 2005).
50.0g (+/-)-TRAMADOL
+
28.9g (D)-(-)-MAN
PPT MLSEtOAc 400 ml
35.2g (-)-TRAMADOL (D)-(-)-MAN
DE – 93.2%, Y – 44.6%
43.7g (+)-TRAMADOL (D)-(-)-MANDE – 79.4%, Y – 55.4%
EtOAc i) NaOH
ii) L-(+)-MAN
32.7g (-)-TRAMADOL (D)-(-)-MAN
DE – 97.6%, Y – 93.0%
35.6g (+)-TRAMADOL (L)-(+)-MANDE – 99.0%, Y – 81.4%
i) NaOH
ii) HCl(g),MEK
i) NaOH
ii) HCl(g),MEK
20.9g (-)-TRAMADOL HCl
EE – >99.0%, Y – 88.5%
23.0g (+)-TRAMADOL HClEE – >99.0%, Y – 95.0%
33
A liquid-phase process for recycling of resolving agents used in the
diastereomeric resolution of chiral bases has been reported by Ferreira et al
(2006). The process is applicable to the resolution of any base by an organic
acid resolving agent which takes place in a polar solvent. The resolving agent
is first of all separated from the diastereomeric complex by addition of
aqueous HCl. The initial stage of process development is selection of a water
immiscible extracting organic solvent to recover the resolving agent from the
resulting acidic aqueous solution. Either distillation or organic solvent
nanofiltration is subsequently used to exchange the resolving agent from the
extracting organic solvent back into the polar resolution solvent. The choice
between these two technologies for solvent exchange depends on the relative
boiling points of the two solvents. The resolution of 3-hydroxymethyl-4-(4-
fluorophenyl)piperidine, a racemic amine by di-p-toluoyl-L-tartaric acid
(DTTA), was selected as an example of a typical resolution used in an organic
process. Using the conventional process, this resolution requires 1.75 mol
equiv of DTTA for each mole of racemic base fed to resolution, and thus the
bulk of the DTTA ends up in the mother liquor. Using the recycling process,
DTTA from both mother liquor and crystals was recovered and recycled over
seven consecutive resolutions, while the final product enantiomeric excess
and resolution yield were maintained at 100% and 40%, respectively. In this
way the DTTA requirement was decreased from 1.75 to 0.26 DTTA mol
equiv, reducing the amount of fresh resolving agent needed for each
resolution by 85% (Figure 1.1)
The salts of (S)- and (R)-1,4-benzodioxane-2-carboxylic acid with
eight (S)-1-arylethylamines were prepared. The determination of their melting
points and their solubilities in alcohol solvents revealed large differences
between the diastereomeric benzodioxanecarboxylates of (S)-1-(p-
nitrophenyl)ethylamine and of (S)-1-(p-methyl phenyl)ethylamine Therefore,
these latter amines were selected to resolve (±)-1,4-benzodioxane-2-
34
carboxylic acid by diastereoselective crystallization finding that both of them
displayed a very high resolution ability for such a substrate, which contrasted
with the null efficiency of unsubstituted 1-phenylethylamine.
(ia) Resolution
reaction
(PRS)
Fresh
DTTA
(ib) Resolution
separation
(solid/liquid
separation)
PRS
(ii) Extraction
DTTA (org)
EOS
(apolar)
RCl (aq)
(iii) Solvent
exchange
OSN
or
Distillation
PRS
EOS/
PRS
Unwanted
R-enant iomerHCl (aq.)Racemic
(R,S)
(in PRS)
Crystalline solid
(S.DTTA)
Recycled DTTA in PRS
Mother
liquor
(R.DTTA
DTTA in
PRS)
(ii) Extraction
S (org)
K2DTTA (aq.)
EOS
(apolar)
K2CO3 (aq.)
Final Product:
Wanted
S-enantiomer
(ii) Extraction
DTTA (org)
RCl (aq)
EOS
(apolar)
KCl (aq.)
Additional step for
DTTA recovery from
crystalline solidHCl (aq.)
Figure 1.1 Schematic representation of chiral separation of 3-hydroxymethyl-
4-(4-fluorophenyl)piperidine
These results are consistent with DSC evidences, which indicated
that the two successfully resolved diastereomeric systems are binary mixtures
exhibiting a eutectic with a high content of the more soluble diastereomeric
salt. The new procedures can advantageously replace the two resolutions we
had previously reported, that of the same acid with dehydroabietylamine and
35
that of glycerol acetonide, a precursor of 1,4-benzodioxane-2-carboxylic acid
with 1-phenylethylamine (Bolci et al 2005) (Scheme 1.30).
O
O COOHNH2
X1
2 X = p-Me
3 = p-OMe
4 = p-Cl
5 = p-Br
6 = p-NO2
7 = 2,3 -CH=CH-CH=CH-
8 = 3,4 -CH=CH-CH=CH-
Scheme 1.30
Three different resolving agents were tested for the separation of
enantiomers of (S)-1-phenylethylamine, (S)-a-naphthylethylamine, and
methyl (R)-1-phenylglycinate. Diereoisomeric salt formations were
accomplished in ethanol and the resolving agents were applied in equivalent
as well as half an equivalent amount related to the racemate. It can be seen
that enantiomer separation could be achieved with an equivalent amount of
resolving agent in ethanol solution. In a polar solvent the yield was high (both
diastereoisomeric salts crystallized). But a racemic mixture of
phenylethylamine was found in the solid phase. Good results were achieved in
ethanol when seeding crystals were used to initiate the precipitation of the
salt. Enantiomerically pure dicarboxylic acid could be obtained by repeated
resolution of non racemic 2 by either of the above resolving agents. In this
way pure enantiomer could be obtained in 31 % yield. Enantiomeric excess
(ee) of the resolved and liberated dicarboxylic acid samples were determined
by HPLC and speci c rotation of the pure samples was also measured (Faigl
et al 2010) (Scheme 1.31).
36
NO
COOH
COOH
H2N R
Ar
H
a)
(S)-(+)-2*3 + (R)-(-)-2*3
(S)-(+)-2*4 + (R)-(-)-2*4
(S)-(+)-2*5 + (R)-(-)-2*5
( + )-2
3: Ar = Ph, R = Me4: Ar = -Naphth, R = Me
5: Ar = Ph, R = COOMe
Scheme 1.31
Racemic trans 3-(9- uorenylmethyloxycarbonylamino)-1-oxyl-
2,2,5,5-tetramethyl pyrrolidine-4-carboxylic acid (Fmoc-POAC-OH),
prepared by conventional methods, was resolved upon esteri cation with
(aR)-2,2’-dihydroxy-1,1’-binaphthyl. Separation of the obtained
diastereomeric monoesters Fmoc-(±)-trans-POAC-O-(aR)- binaphthol by
crystallization/chromatography, and removal of the chiral auxiliary by
saponi cation of the aryl ester function furnished both enantiomers viz. (+)-
(3R,4R)-Fmoc-POAC-OH and (-)-(3S,4S)-Fmoc-POAC-OH. The absolute
con guration of the asymmetric C-3, C-4 carbons of POAC were assigned
from the induced circular dichroism of a flexible biphenyl probe present in the
terminally protected dipeptide derivatives (Wright et al 2008).
Classical resolution on industrial scale is very often hampered by
the formation of solid solution of diastereomeric salts. Repeated
recrystallisation resulted loss of yield of the required isomer. In order to
overcome this problem, multiple resolving agents have been used. This
process is called Dutch resolution. An alternative Dutch technique has been
applied to the resolution of 4-hydroxyphenylglycine and 4-
fluorophenylglycine by using (+)-camphorsulphonic acid as the resolving
agent (Kaptein et al 2000).
37
1.5.3 Combo-Resolution Technique
Racemic difluoromethylornithine hydrochloride (DFMO HCl) is
cyclized to form the lactam, which is acylated with pivaloyl chloride to form
rac-N-pivaloyl-DFMO lactam (Scheme 1.33).
HO
O
H2N
CHF2
NH2MeO
O
H2N
CHF2
NH2
MeO
O
H2N
CHF2
NH2HN
O
CHF2
NH2
HN
O
CHF2
HN
O
CHF2
NH2
O
Cl
O
MeOH, SOCl2
5 °C, toluene
CH3CN, pridine
DMAP, reflux
Reflux
Scheme 1.33
This lactam provided enhanced separation compared to direct
resolution of racemic DFMO HCl. A hybrid chiral resolution process is
proposed to separate the enantiomers of the lactam. This process involved a
multicolumn continuous enantioselective chromatographic process
(VARICOL) coupled with enantioselective crystallization of (D)-N-pivaloyl-
DFMO lactam. The interest of this hybrid process is based on the favorable
eutectic point providing a higher productivity of VARICOL process and
lower puri cation costs than the chromatographic process alone. A final
38
chemical modification (hydrolysis) is used to form a single enantiomer of
both (D)-DFMO (6) and (L)-DFMO in high chemical purity and enantiomeric
excess. A global optimization approach is applied to design an economical
industrial process, which is based on a parametric study of VARICOL process
and enantioselective crystallization to obtain maximum recovery and purity
while significantly lowering the cost of manufacturing the single enantiomers.
The optimized global process, a milestone in the application of combo
technique in the separation of chiral isomers (Perrin et al 2007).
1.6 SCOPE AND OBJECTIVES OF THE PRESENT WORK
1.6.1 Chiral – Alkylation of 1-Phenyl-2-(1-pyrrolidinyl/1-
piperidinyl)-1-propanol
Increase in the number of carbon atoms in an organic molecule is
best achieved through Grignard reactions. A Grignard reaction at the
carbonyl carbon of keto function of an organic molecule led to a tertiary
alcohol with the introduction of an alkyl/aryl group. Varieties of examples
are available in the literature on the alkylation/arylation at the carbonyl carbon
of a ketone. If a chiral center is present, adjacent to the carbonyl group, it is
possible that the Grignard reaction at the carbonyl carbon can induce chirality
at the reaction center. Suter and Weston (1942) alkylated racemic ephedrone
hydrochloride through Grignard reaction of the keto-function. These authors
noticed through physiological study of the racemic -alkylephedrines that,
the presence of alkyl group at the - position of ephedrines will lower the
toxicity without significant loss of therapeutic activity. But it is well known
that chiral active pharmaceutical ingredients will have much enhanced
therapeutic values. There is no detailed investigation involving a thorough
stereochemical approach and the mechanism involved in asymmetric
induction through Grignard reaction.
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It is proposed to modify the active pharmaceutical ingredient (API),
1-phenyl-2-amino-1-propanol, by constructing pyrrolidinyl/piperidinyl
moiety at carbon-2 and to study in detail the stereochemical consequence of
alkylations/arylations through Grignard reactions of the corresponding
ketones. The alkylated products thus obtained, having a new chiral center at
the alkylated/arylated carbon, can be important drug intermediates or active
pharmaceutical ingredients.
Objectives of the present investigations are
1. To synthesize chiral -alkylated/arylated derivatives of
structurally modified norephedrines.
2. To generate a new chiral center during alkylation/arylation
through Grignard reactions.
3. To synthesize chiral -aminoketones from chiral 1,2-
aminoalcohols through oxidation.
4. To ascertain the absolute configuration of the new chiral
center in the Grignard reaction with the help of Cram’s rule.
5. To obtain chemical correlation for the confirmation of
absolute configuration at the Grignard reaction centre.
1.6.2 Enantioselective -Amination of 1-Phenyl-2-(1-piperidinyl)-1-
propanol and N-Tosylnorephedrine
Chiral salicyl-1,2-diamines show great promise as anticancer
molecules. These compounds have been shown to induce inhibition of the
growth of cancer cells. These vicinal diamines display pharmaceutical
potency in the treatment of human breast cancer. Enantiomerically enriched
1,2-diamines are powerful drug intermediates in the asymmetric synthesis
40
(Fukuta 2006) of Tamiflu which is a very important antiinfluenza drug
containing a chiral 1,2-diamino functionality.
Chiral 1-phenyl-1-methylamino-2-(1-pyrrolidinyl)-propane is
synthesized (Colman B 1999) from the corresponding 1-phenyl-2-amino-1-
propanol through the intermediacy of mesyloxy derivative. The methods
available in the literature for the manufacture of vicinal diamines are limited,
particularly, when other sensitive functionalities are present elsewhere in the
molecule. Considering the enormous utility of the chiral 1,2-diamines, the
stereo- and regiospecific syntheses of several 1,2-diamines are undertaken in
this work from (1S,2R)-norephedrine through the corresponding chloro
derivatives.
Objectives of the present investigations are
1. To synthesize chiral -aminated derivatives of structurally
modified norephedrines.
2. To obtain -chloroderivatives of chiral aminoalcohols using
thionyl chloride.
3. To synthesize -aminoalkyl/aminoaryl derivatives from chloro
compounds through nucleophilic substitution reaction.
4. To study the mechanism of reactions leading to aminated
derivatives through possible formation of aziridinium chloride
intermediate.
5. To ascertain the absolute configuration at the alkyl/aryl
aminated center.
6. To derive supportive evidence for the absolute configuration
at each reaction center through chemical correlation.
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7. To synthesize -aminated derivatives for N-tosyl compounds
of norephedrine. In the N-tosylated derivatives the formation
of aziridinium intermediate is prevented through
delocalisation of electrons from amino nitrogen lo the oxygen
of the tosyl group.
1.6.3 Diasteroselective Gringnard Addition to (R)-(-)-
Phenylacetylcarbinol
1,2-Chiral diols are important chiral building blocks for the
synthesis of natural products such as macrodiolides, insect pheromones, -
lactone esterase inhibitors, -lactones and many other biologically active
substances. In the synthesis of anti-HIV pharmaceutical substance, Tenofovir
and related pharmaceuticals, the application of enantiomerically pure (R)-
propane-1,2-diol is of critical importance. A further application of terminal
optically active 1,2-diols is the resolution of atropisomeric compounds
(Kadyrov et al 2009).
The foregoing summary of asymmetric entry into chiral 1,2-diols
based on the readily accessible alpha hydroxyketones and organometallic
reagents would form the basis for extending the methodology to L-PAC to
give rise to a series of potential chiral drug intermediates in the present
investigation.
Objectives of the present investigations are
1. To synthesize alkylated/arylated derivatives of (R)-(-)-
phenylacetylcarbinol by Grignard reactions.
2. To establish the absolute configuration at newly generated
chiral center by the application of Cram’s rule.
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3. To ascertain the absolute configuration at the reaction centre
through chemical correlation.
1.6.4 Chiral Separation of Racemic Carboxylic Acids using 1,2-
Diamines
From the foregoing summary of salient resolution procedures, it is
evident that diastereomer formation and preferential crystallization remains to
date a major thrust area of innovative chiral separation in pharmaceutical
industry and the present investigation of chiral separation of racemic
carboxylic acids using 1,2-diamines is a significant step in this direction.
Also it is important in any chiral separation procedure that at least one of the
enantiomer after the separation should be enantiomerically rich and also the
other isomer should be obtainable as pure as possible. The chiral synthesis
often involves expensive chemicals, tedious reaction condition and also time
consuming. Hence the preparation of diastereomeric salts of racemic
carboxylic acids with chiral 1,2-diamines followed by simple hydrolysis of
the salts to obtain optically active carboxylic acids assumes importance as
this procedure is simple and fast.
Objectives of the present investigation are
1. To identify a novel method for chiral separation of racemic
carboxylic acids which are the intermediates for the
preparation of active pharmaceutical ingredients.
2. To prepare distereomeric salts of racemic carboxylic acid by
using chiral 1,2-diamine.
3. To identify the proper experimental condition and the choice
of solvent for the precipitation of required diasteromeric salt
from the mixture.
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4. To isolate the pure diasteromeric salt without affecting the
yield based on the solubility factor.
5. To obtain the pure optically active enantiomer of the
carboxylic acid on hydrolysis of the diasteromeric salt
separated.