14

CHAPTER 1

INTRODUCTION TO THE CHEMISTRY OF N-tert-BUTANESULFINYL

IMINES, CHIRAL AMINE DRUGS AND 3-SUBSTITUTED-1,2-

BENZISOXAZOLES

1.1 General:

The discovery that chiral amines as powerful pharmacophores

[1] in new pharmaceutical drugs and the great demand for new

molecules of biological and medicinal importance has led to an

extreme significance of the development of research activities in the

area of syntheses on chiral amine drugs and chiral amine auxiliaries

like tert-butanesulfinamide [2,3].

As the chiral nitrogen-containing compounds are widely

distributed in nature and many biologically important molecules, the

asymmetric synthesis of chiral amines has long been a popular and

challenging research area [1]. The most promising and convenient

route for the synthesis of chiral nitrogen-containing carbon frame

works is through imines, as electrophiles [1].

The definition of a “chiral amine” which in particular is a “α-

chiral amine” is a nitrogen atom with an adjacent, or α-stereogenic

carbon [1]. The two generic structural features of chiral amines are

useful to point out i.e. first, the nitrogen can be primary (I), secondary

(II), tertiary (III) or even quaternary (ammonium salt) and second, the

15

α-stereogenic carbon, by necessity, can only be secondary or tertiary

[3].

C

NH2

R1

R2 R3

C

NH2

H

R1 R2

1°-aminetert-a-carbon

1°-aminesec-a-carbon

C

NHR

H

R1 R2

2°-amine

C

NR2

H

R1 R2

3°-amine

(I) (II) (III)

Of these, chiral primary amine building blocks are often sought

after because of the flexibility they lend to the synthetic design of

pharmaceutical drugs and alkaloid natural products [4].

1.2. IMPORTANCE OF CHIRALITY AND CHIRAL AMINE

FUNCTIONALITY

Chirality is a phenomenon which plays a key role in both the life

of plants and animals and also in pharmaceutical, agricultural and

other chemical industries [5]. For example, all the vital elements

necessary for the life are nucleosides, proteins, enzymes, amino acids,

carbohydrates and a number of alkaloids, hormones and almost all

natural products are chiral compounds [5].

A large number of chiral amines and its derivatives find use as

pharmaceuticals like antidepressant [6], antidiabetic [7], antimalarial

[8], antituberculosis agents [9], antihypertensive [10], anticholinergic

agents [11], calcimimetic compounds [12], antiviral derivatives [13]

16

and analgesics [14]. Some of the important chiral drug derivatives,

which are of commercial importance, are shown in Table-1.1

Table 1.1: Some important chiral drug derivatives:

S.No. Structure & Name

Importance

1.

NHCH3 HClCl

Cl Zoloft / Sertraline

Antidepressant agent

2.

N

NH

O

OEt

COOH

Repaglinide

Antidiabetic agent

3. N

HO

F3C

CF3

HN

H

Lariam

Antimalarial agent

4.

NH

HN

HO

OH Ethambutol

Antituberculosis agent

5. H3CO

H2NO2S NH

CH3

O

O Flomax / Tamsulosin

Antihypertensive Agent

6.

ON

NH3C

CH3 CH3

H

CH3

CH3O

Rivastigmine

Alzheimer’s [Anti cholinergic agent]

17

7. H3CO

NH

Cl Tecalcet

Calcimimetic agent

8. H. HClN F

F

F

Sensipar / Mimpara /

Cinacalcet

Hyperparathyroidism /Calcimimetic agent

9.

HN N

ONHO OH

NH

O

O

PhPh

Lopinavir

Anti viral [HIV-protease inhibitor]

10.

O

H3CO

HO

H

NCH3

Codeine

Analgesic / pain relief agent

1.3. SYNTHESIS AND REACTIVITY OF N-SULFINYL IMINES

Detailed reviews [15-17] and articles [18-23] covering the

chemistry of both Imines and chiral amines based on the chiral amine

reagent, tert-butanesulfinamide (IV) have been published earlier

(Covered up to Jan, 2010). Therefore, only a brief account is given

here.

Notably, the most common imine auxiliaries are of two types.

One is N-alkyl imine auxiliaries derived from naturally occurring chiral

amines and amino acids. Second type is N-sulfinyl auxiliaries, which

18

were developed and pioneered by Davis [16] and Ellman groups [17]

separately. N-sulfinyl imines were mainly of two types, N-tert-

butanesulfinyl aldimines (V) and N-tert-butanesulfinyl ketimines (VI),

are a special class of imines that display unique reactivity and

stereoselectivity due to the presence of a chiral and electron

withdrawing sulfinyl group (VII). They had been introduced three

decades ago, since then; they have emerged as versatile intermediates

in asymmetric synthesis of a variety of structurally diverse nitrogen

containing compounds.

S

O

NH2S

O

NH2S

O

NH2

tert-butanesulfinamide(IV)

(R)-tert-butanesulfinamide(IVa)

(S)-tert-butanesulfinamide

(IVb)

S

O

N R S

O

N R

R1

N-tert-butanesulfinyl aldimine(V)

N-tert-butanesulfinyl ketimine(VI)

S OR

Sulfinyl group(VII)

Due to its weak electron withdrawing nature, compared to

carbonyl group, the N-sulfinyl auxiliary activates the imino carbon for

nucleophilic addition, allowing reactions to proceed at lower

temperature. Thus, the sulfinyl group shows a powerful stereodirecting

19

effect, which results in the addition of organometallic reagents and

enolates to both steric and enolizable sulfinimines with high and

predictable asymmetric induction. Moreover, unlike other imine N-

auxiliaries, the sulfinyl group is easily removed under relatively mild

conditions.

N-tert-butanesulfinimines may be synthesized from:

1. condensation reaction with aldehydes

2. condensation reaction with ketones

3. condensation reaction with orthoesters

4. Oxidation of N-sulfenyl imines and

5. Miscellaneous reactions.

1.3.1. Condensation reaction with aldehydes:

The reaction between an aldehyde and tert-butanesulfinamide

was first investigated by Ellman and co-workers in 1997 [24] who,

prepared tert-butanesulfinyl aldimine (V) by condensing 2-3 equimolar

amounts of aldehyde (VIII) and tert-butanesulfinamide (IV) in the

presence of acidic catalyst pyridinium p-toluenesulfonate (PPTS) and

excess amount of MgSO4 in methylene dichloride at RT for. (Scheme -

1.1).

20

R H

NS

O

R H

O+ S

O

H2N

R H

O+ S

O

H2N

R H

O+ S

O

H2N

R H

O+ S

O

H2N

R H

O+ S

O

H2N

R H

O+ S

O

H2N

R H

O+ S

O

H2N

R H

O+ S

O

H2N

CuSO4 (2 eq)

MDC, rt

MgSO4 (5 eq)

PPTS (0.5 eq)

MDC, rt

TH

F,

r t

Ti(O

Et)

4 (2 e

q)

THF, rtBnBr (

2 eq)

Zn (3 eq

)

Cs

2 CO

3 (1 eq)

MDC, 40 - 45°C

KH

SO

4 (2 e

q)

Tolu

en

e, 45° C

NaO

H (1 eq)

MeO

H, rt Yb(O

Tf) 3 (0

.1 eq)

THF, rt

(V)

(VIII) (IV)

(VIII) (IV)

(VIII) (IV)

(VIII) (IV)

(VIII) (IV)

(VIII) (IV)

(VIII) (IV)

(VIII) (IV)

. . . . . Scheme 1.1

Further studies revealed that the more Lewis acidic CuSO4 was

a more effective agent for this condensation reaction at reduced

equivalents (1.1) of aldehydes [25]. But, some substrates were found to

be unreactive with this reagent, in these cases, Ti(OEt)4 was found to

be effective both as Lewis acid catalyst and water scavenger.

All these aldimines were found to be reasonably hydrolytically

stable and were isolated by silica gel column chromatography. The

aldimines can be handled at room temperature in air, although minor

21

decomposition was observed over a period of weeks or months for

prolonged storage at room temperature in air and with exposure to

light. Thus the aldimines could be stored in closed containers at -5°C

to prevent the decomposition [25].

Since then many groups synthesized V from VIII and IV [26-29].

Nakata and co-workers, in 2004 reported a procedure using equimolar

amounts of aldehydes, sulfinamide and base. This procedure was on

the use of Cs2CO3 as an activating and dehydrating agent with gentle

heating. Another protocol was developed by Qin and co-workers, which

was mediated by KHSO4 in toluene at 45°C. These conditions were

found to be effective for a broad range of substrates, including electron

rich and electron poor aromatic aldehydes, α, β-unsaturated

aldehydes, and both sterically hindered and unhindered aliphatic

aldehydes. Thus various Lewis acids like Yb(OTf)3, Sc(OTf)3 etc.. were

used in the condensation reaction.

Another method for the synthesis of sulfinyl aldimines utilizes

NaOH or tBuOK as a base. But these conditions did not show

beneficial characteristics for the synthesis of imines derived from

enolizable aliphatic aldehydes, high yields were observed in case of α,

β-unsaturated aldehydes [30].

Recently, Fan et al [31] prepared aldimines under Barbier-type

conditions using benzyl bromide and zinc dust, which were reacted to

form BnZnBr in situ and then the aldehydes and sulfinamide are

22

added. The proposed mechanism for this reaction is that the BnZnBr

acts as a base to deprotonate the sulfinamide, and then the

coordinated zinc acts as a Lewis acid to activate the carbonyl to attack

via a 4-membered transition state.

1.3.2. Condensation reaction with ketones:

The condensation reaction of ketones (IX) with IV is more

challenging than that of aldimines as in most cases, the conditions

reported for the preparation of aldimines were failed to provide the

desired products with ketones as the reactant [17]. The preparation of

N-tert-butanesulfinyl ketimines was also first reported by Ellman

group in the same year [32]. After several attempts, they arrived to use

1.1 equiv of ketone, 1.0 equiv of sulfinamide and 2 equiv of Ti(OEt)4 in

THF at higher temperatures to get higher yields of the desired imine

VI. (Scheme - 1.2).

S

O

NH2O

R1

R+

(VI)(IX) (IV)

S

O

N R

R1Ti(OEt)4

THF,

. . . . . Scheme 1.2

The condensation of several aliphatic and aromatic ketones with

IV were depicted in Table-1.2.

23

Table 1.2: Condensation of ketones with IV:

S.No. R1 R2 temp (°C) time (h) yield (%)

1. isopropyl Me 60 7 84

2. isobutyl Me 60 10 88

3. butyl Me 60 10 77

4. isopropyl butyl 75 24 77

5. tert-butyl Me 75 24 82

6. Phenyl Me 75 15 89

7. Phenyl butyl 75 5 77

8. 2-naphthyl Me 75 15 73

---------------------------------------------------------------------------------------

Most of the tert-butanesulfinyl ketimines (VI) were stable to

handle in the air and found to be less hydrolytically stable than the

corresponding aldimines. The aliphatic ketimine derivatives were

found to be more prone to hydrolysis than the α-aryl derivatives and

could be stored in closed containers at -5°C for months without any

decomposition [17].

A variety of cyclic ketimines (X – XIV) were prepared via Ti(OEt)4

mediated condensation of ketones with tert-butanesulfinamide [25].

24

NS

O

NO

N SO

PMB

N SO

NS

O

Y

NS

O

(X) (XI) (XII) (XIII) (XIV)

Y = NBocY = OY = S

1.3.3. Condensation reaction with orthoesters:

The condensation reaction of orthoesters (XV) with IV was

described to proceed in 83-92% yields of the N-tert-butanesulfinyl

imidate esters (XVI), under neat and mild acidic conditions [33] or in

the presence of triphenylphosphine [34]. (Scheme - 1.3).

S

O

NH2

R1

+

(XVI)(XV) (IV)

S

O

N O

p-TsOH

THF,O OO

R R

R R1

R

. . . . . Scheme 1.3

1.3.4. Oxidation of N-sulfenyl imines:

Aldehydes or ketones when reacted with S-

methylthiohydroxylamine (XVII) yields the N-sulfenimine (XVIII) which

on oxidation with a chiral oxidant, such as (+)- or (-)-N-

(phenylsulfonyl)-3,3-dichlorocamphoryloxaziridine (XIX) and achiral

oxidant, like m-CPBA yielded the desired enantiopure N-sulfinimines

V or VI in 80-95% yield [35, 36]. (Scheme - 1.4).

25

But this methodology was found to have limited synthetic value

due to the complex nature of both the chiral oxidants and N-

sulfenimines.

RS RL

NS

R

ClCl

O N O2SPh

RS RL

NS

O

RCl

Cl

O N O2SPh

RS RL

NS

O

R

(XVIII)

RS RL

O+ R

SH2N

(VIII) or (IX) (XVII)

m-CPBAR=OR1

S

RS RL

NS

O

R

RS RL

NS

O

R

+

83-99%72:28-99:1 dr

(RS)-(V) or (VI) (SS)-(V) or (VI)

80-95%>97ee

59-80%>97ee

(XIX) (XIX)

. . . . . Scheme 1.4

1.3.5. Miscellaneous reactions:

In addition to N-tert-butanesulfinyl aldimines and ketimines,

several aliphatic and aromatic imines bearing α-heteroatom

functionality, including α-alkoxy aldimines (XX) [37] and ketimines

(XXI) [38], α-halo aldimines (XXII) [39] and ketimines (XXIII) [40] and

α-amino aldimines (XXIV) [41] and ketimines (XXV) [42] have been

synthesized.

26

S

O

N

H

OR S

O

N

R

OR1 S

O

N

H

X

(XX) (XXI) (XXII)

S

O

N

H

R

S

O

NNHBoc

S

O

N

R1

X

NBn2

F

R R

(XXIV) (XXV)(XXIII)

Ellman et al reported the first preparation of N-tert-

butanesulfinyl imino esters (XXVII) by condensing methyl glyoxalate

(XXVI) with IV in the presence of CuSO4 at RT, in 65% yield [25].

(Scheme - 1.5).

S

O

NH2

O

+

(XXVII)(XXVI) (IV)

S

O

N

HCuSO4

MDC, rtOH CH3

OCH3

O

O

. . . . . Scheme 1.5

Similarly, tert-butyl ester (XXVIII) [43]and benzyl ester (XXIX)

[44] have also been synthesized under these conditions, which are

more stable enough to be purified by column chromatography and can

be stored in closed containers for long period when compared to N-

sulfonyl and N-Boc imino esters.

27

(XXVIII)

S

O

N

H

O

O

CCH3

CH3

CH3

(XXIX)

S

O

N

H

O

O

1.3.6. Reactivity of N-tert-butanesulfinyl imines:

Due to its weak electron withdrawing nature, N-tert-

butanesulfinyl imines favor the nucleophilic addition reaction at very

low temperatures. In particular, N-tert-butanesulfinyl aldimines are

prone to conjugate and 1,2-additions and N-tert-butanesulfinyl

ketimines favors reduction of imine bond with borohydride reagents

and transition metal catalyzed reductions.

a) 1,2-Additions to N-tert-butanesulfinyl aldimines :

Conjugate addition of Copper reagents to α,β-unsaturated N-tert-

butanesulfinyl imines (XXX) was first developed by Ellman and

McMahon [45]. The highest yields (68-76%) with diastereoselectivities

(≥ 92:8) were obtained by the addition of a butyl cuprate with n-BuLi,

CuCN and BF3.OEt2 in THF. The facial selectivity of conjugate addition

of copper reagent was rationalized by the transition state XXXI, where

coordination of the cuprate to the sulfinyl oxygen and delivery of the

nucleophile occurs on the face opposite to the tert-butyl group.

(Scheme - 1.6).

28

S

O

N

R

R1

R2[Cu]

n-BuLi, CuCN

BF3.OEt2, THF

-78°C

R

NS

O

R1

Li

CuLmXn

R2 O

R

N

R1

R2

(XXX) (XXXI) (XXXII)

S

. . . . . Scheme 1.6

1,2-Addition of organometallic reagents, like Grignard reagents

and organolithium reagents to N-tert-butanesulfinyl aldimines V in the

presence of a Lewis acid (e.g. AlMe3 or Ti(OET)4) was first developed in

1997 by Ellman and co-workers [24]. The addition afforded chiral

sulfinamides XXXV and XXXVI, via a six-membered ring transition

states XXXIII and XXXIV respectively, with the metal cation

coordinated to the oxygen atom of the sulfinyl group and the Lewis

acid coordinated to the nitrogen lone pair, in high yields with excellent

stereoselectivity. (Scheme - 1.7).

29

S

O

N R

H

(V)

(XXXIII) (XXXV)R1 MgBr

AlMe 3

or Ti(O

ET) 4

R 2Li

S

OMg

R1

N R S

O

NH

R1

H

R

NO

R H R2Li

(XXXVI)

S

O

NH

R

H

R2

(XXXIV)

. . . . . Scheme 1.7

It is interesting to know that Grignard reagents have shown

better selectivity when compared to organolithium reagents.

1,2-Addition of cyanide nucleophile across N-sulfinyl imines is

an important method for the synthesis of Strecker α-amino nitriles

(XXXVIII), and the corresponding α-amino acids (XXXIX) [46]. Cordi

and Mabic [47] presented the first asymmetric Strecker reaction of N-

tert-butanesulfinyl aldimine (XXXVII) with ethylaluminium

cyanoisopropoxide [EtAl(OiPr)CN] or TMSCN in the presence of a Lewis

acid and CH2Cl2. The highest diastereoselectivity (98:2) with higher

yield (90%) was obtained with Y(OTf)3. Hydrolysis of the α-amino nitrile

intermediate with acids such as HCl underwent deprotection of the N-

sulfinyl group and hydrolysis of the nitrile, giving rise to XXXIX in

moderate to good yields. (Scheme - 1.8).

30

H

NS

O

TMSCN

Y(OTf)3 (20 mol%)

CH2Cl2, 10°C

CN

HNS

O

CN

HNS

O

+

98% 2%(XXXVIII)(XXXVII)

HCl, MeOH

CO2H

NH2

CO2H

NH2

+

98% 2%(XXXIX)

. . . . . Scheme 1.8

Similarly, 1,2-addition of ester enolates (XL) to N-tert-

butanesulfinyl imines has been reported by Ellman et al in 1999 [48],

for the synthesis of β-amino esters (XLII) in highest yields and

diastereoselectivities at low temperature in THF. (Scheme - 1.9).

RL RS

NS

O + R3

OR4

OClTi(OiPr)3 (2 eq)

LDA (2.1 eq)

THF, -78°C RL

NH

R3

RS O

OR4

SO

O

TiNRS

RL

R3

OR4

SBut O

(V) or (VI) (XL)

(XLI)

(XLII)

. . . . . Scheme 1.9

b) Reductions of N-tert-butanesulfinyl ketimines :

The reduction of N-tert-butanesulfinyl ketimines with metal

borohydride reagents (XLIII) was first investigated by Ellman and co-

workers [49] who, prepared α-branched amines (XLV) in the best yield

31

(83%) and diastereoselectivity (91:9 dr) by adding NaBH4 at low

temperature in THF. (Scheme - 1.10).

R R2

NS

O +Ti(OEt)4 (2 eq)

THF, -48°CR2R

NHS

O

(XLIII)

(XLIV)

(XLV)(VI)

NaBH4

O

SN

HM

RR2

. . . . . Scheme 1.10

The delivery of the hydride was occurring from the si-face of the

imine which was evident by the proposed coordination (XLIV) of the

sulfinyl oxygen to the metal atom. Conversely, an open transition state

(XLVII) was proposed for the L-Selectride (XLVI) reduction. The

addition of the hydride occurring from the least hindered face (re-face)

in THF at -78°C. (Scheme - 1.11).

R R2

NS

O +THF, -78°C

R2R

HN

(XLVI)

(XLVII)

(XLV)(VI)

L-Selectride

N

OR

R2

H-M

SO

. . . . . Scheme 1.11

32

1.4 Recent work towards the synthesis of N-tert-butanesulfinyl

imine derivatives:

Das et al made the concise formal syntheses of the dendrobate

alkaloid (+)-241D and its C-4 epimer by means of a highly

diastereoselective Barbier-type indium mediated allylation strategy

involving an (S)-(N-tert-butanesulfinyl) imine [50]. (Scheme – 1.12).

OH

1.PCC, CH2Cl2, r.t, 2 h, 90%

2.(S)-tert-butanesulfinamide

CuSO4 (anhyd), CH2Cl2 r.t, 24 h, 88%

H

NS

O

CH2=CHCH2Br, In

THF, 66°C, 4 h, 86% NS

O

1) 4M HCl-dioxane, MeOH, r.t, 30 min

2) CBzCl, sat. aqNaHCO3

1 h, 67%

HNCBz

NH

C9H19

OH

(XLVIII) (XLIX)

(L)

(LI) (LII)

. . . . . Scheme 1.12

Rodriguez and co-workers reported the asymmetric synthesis of

1-(9-anthracenyl)ethylamine and its trifluoromethyl analogue via

nucleophilic addition to an N-(tert-butylsulfinyl)imine [51]. (Scheme -

1.13).

33

CH3

O SO

H2N

Ti(OEt)4, THF

66°C, 48h, 15%

CH3

NS

t-Bu

O

(LIII) (LIV)

H

OS

O

H2N

Ti(OEt)4, THF

r.t, 17h, 89%

H

NS

t-Bu

O

(LV)(LIII)

CH 3MgI

THF, -45°C

4 h, 92%

CH3 Li

THF, -78°C

4 h, 79%

(LVI)

Ar CH3

HNS

t-Bu

O

(LVI)

Ar CH3

HNS

t-Bu

O

Ar CH3

HNS

t-Bu

O

Ar CH3

HNS

t-Bu

O

+

+

70% 30%

9% 91%

. . . . . Scheme 1.13

Pibworth et al [52] reported the convergent asymmetric synthesis

of two complex TRPV1 antagonists, a potential target for the treatment

of chronic pain. Ellman auxiliary was successfully used for the

asymmetric synthesis of the chiral α-methyl benzylamine fragments.

(Scheme -1.14).

34

O

Cl

NH

SO

O SO

H2N

1) Ti(OEt)4, THF

66°C, 16h+

2) NaBH4, THF

-20°C, 12h, 42% Cl

NH

S

N

O

O

S

O

Cl

NH

S

NH

O

O

S

O

1.25 M HCl/MeOH

r.t, 86%Cl

NH

S

NH2.HCl

O

O

N CF3

O

HO

50% 1-Propylphosphonic acid cyclic anhydride in EtOAc, DIPEA, THF, 50°C, 2 h, 77%

Cl

NH

S

NH

O

O

O

NCF3

(LVII) (R)-IV(LVIII)

(LIX) (LX)

(LXI)

(LXII)

. . . . . Scheme 1.14

1.5. CHIRAL AMINE DRUGS 1.5.1. INTRODUCTION:

A large number of drugs and drug candidates have an

asymmetric carbon centre attached to amine functionality [1].

Therefore, the asymmetric synthesis of optically pure chiral amine

drugs is of great value and their synthesis remains a challenge. Hence,

there is high demand for the development and production of new drug

candidates.

(S)-Cetrizine hydrochloride (LXV), Manzacidin C (LXX), (S)-

Salsolidine & (R)-Salsolidine (LXXIII), (S)-O-Methylbharatamine

35

(LXXVIII), DPP-4 inhibitor for type 2 diabetes (LXXXII), Sibutramine

(LXXXIII) and Sertraline (LXXXIV) etc., are some of the most

commonly used chiral amine drugs synthesized through N-tert-

butanesulfinyl imine intermediates [17].

a) Asymmetric synthesis of (S)-Cetrizine Dihydrochloride:

Recemic Cetrizine hydrochloride, a histidine H1-receptor

antagonist used for the treatment of allergies, is marketed in the U.S.

as Zyrtec® [53]. The asymmetric synthesis of (S)-cetrizine 2HCl was

first reported by Senanayake [54], by the addition of an aryl Grignard

reagent to 2-methyl-propane-2-sulfinic acid 4-chloro-benzylideneamide

(LXIII) in toluene at -20° to 0°C. (Scheme – 1.15).

Cl

H

NS

O

MgBr

(in Et2O)

toluene-20 to0°C Cl

HNS

O

Cl

N

N

OOH

O

.2HCl

(LXIII) (LXIV) (LXV)

. . . . . Scheme 1.15

b) Asymmetric synthesis of Manzacidin C:

Lanter and co-workers introduced the 1,3-diamine framework in

their elegant asymmetric synthesis of manzacidin C [55]. Coupling of

2-methyl-propane-2-sulfinic acid (2-benzyloxy-1-methyl-

ethylidene)amide (LXVI) and 2-methyl-propane-2-sulfonic acid (3-

phenyl-allylidene)amide (LXVII) in the presence of LHMDS in THF at -

36

78°C provided 2-methylpropane-2-sulfonic acid [4-benzyloxy-3-(2-

methyl-propane-2-sulfinyl imino)-1-styryl-butyl]amide (LXVIII) in 85%

yield. Grignard reagent was added to LXVIII to get the tertiary

carbinamine (LXIX) as a single diastereomer, followed by the removal

of sulfinyl group yielded the desired natural product LXX in ten linear

steps and 28% overall yield. (Scheme – 1.16).

N

BnO

SO + H

N LHMDS(1.1 equiv)

THF, -78°C

N

BnO

SO

HN

NH

Br

O

O

HN N

CO2H

(LXVI) (LXVII) (LXVIII)

(LXX)

SO

OS

O

O

2. HCldioxane

1. MeMgBrTHF, 0°C H2N

BnO

HN

(LXIX)

SO

O

. . . . . Scheme 1.16

c) Asymmetric synthesis of (S)-Salsolidine:

Asymmetric synthesis of the isoquinoline alkaloid LXXIII, was

reported by Kasciolowicz [56] by the stereoselective addition of

MeMgBr to aldimine (LXXI) in THF to provide LXXII in 89% yield with

97:3 dr, and further crystallization increased to 99:1 dr. Subsequent

37

transformations yielded the desired product with 98% ee in 24%

overall yield. (Scheme – 1.17).

MeO

H

NS

O MeMgBr

(in Et2O)

MeO

NS

O

MeOOMe OMe

CH2Cl2, -48°C to rt

or THF, -27°C

NH

OMe

(LXXI) (LXXII) (LXXIII)

. . . . . Scheme 1.17

d) Asymmetric synthesis of (S)-(-)-O-Methylbharatamine:

LXXVIII is an isoquinoline alkaloid, synthesized by Grajewska

[57]. The addition of laterally lithiated o-toluamide (LXXIV) to N-tert-

butanesulfinyl aryl imine (LXXV) in the presence of tBuLi in THF at -

72°C yielded (LXXVI) in 93% yield. Subsequent cleavage of sulfinyl

group followed by cyclisation provided (LXXVII) with 85% ee, which on

further transformations yielded the desired product. (Scheme – 1.18).

38

O

N + H

NS

O

OCH3

OCH3

tBuLi

THF, -72°CH3CO

OCH3

HNS

O

N

O

1. HCl/MeOHbasic workup

2. BuLi (1.0 eq)THF, -78°C

HN

O

OCH3

H3CO

N

OCH3

H3CO

(LXXIV) (LXXV) (LXXVI)

(LXXVII) (LXXVIII)

. . . . . Scheme 1.18

e) Scalable asymmetric synthesis of DPP-4 Inhibitor:

Dipeptidyl peptidase 4 (DPP-4) inhibitors are used for the

treatment of type 2 diabetes. Shieh and co-workers [58] at Novartis

Pharma developed an optimized, scalable process of chiral amine

(LXXXII) a novel and potent inhibitor of DPP-4 in clinical trials for the

treatment of type 2 diabetes. The process involves the addition of a

benzylic Grignard reagent (LXXIX) to N-tert-butanesulfinyl aldimine

(LXXX) to get chiral amine intermediate (LXXXI) in methylene

dichloride and cyclopentyl methyl ether (CPME) as a stabilizer at -70°C

with diastereoselectivity of 85:15. Pure diastereomer was isolated by

recrystallization of the crude product from methanol. Further

transformations yielded the desired DPP-4 inhibitor. (Scheme – 1.19).

39

BrMg

F

F

F+ N

H

N SO

BzC CPME (1.0 eq)

CH2Cl2, -70°C

N HN SO

BzC

F

F

F

N NH2

F

F

F

O

SN

O

O

O

(LXXIX) (LXXX)(LXXXI)

(LXXXII)

. . . . . Scheme 1.19