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.

39

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.

42

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.