Chemical resolution of enantiomers of 3,4...

155

Chapter-5

Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones

using chiral auxiliary approach

5.1 Introduction

4-Aryl-1,4-dihydropyridines (DHPs)1-3

such as nifedipine 1 as well as its chiral

analogues 2 and 3 are one of the most studied classes of calcium channel modulators. Since

their introduction into clinical medicine in 1975, these drugs are implemented for the

treatment of cardiovascular diseases such as hypertension, cardiac arrhythmias and angina.

3,4-Dihydropyrimidin-2(1H)-ones (DHPMs), show very similar pharmacological

profile to classical DHP calcium channel modulators.4-6

In contrast to nifedipine type

DHPs, DHPMs are inherently asymmetric molecules4,5

and the influence of the absolute

configuration at the stereogenic center C-4 on biological activity is well documented.7

The

proposed binding-site model for a series of DHPM calcium channel modulators based on a

detailed structure-activity profile is shown in Figure 1.

By performing pharmacological studies with uniquely designed

single-enantiomer DHPM such as 4, it has been established that

calcium channel modulation (antagonistic vs agonistic activity) is

dependent on the absolute configuration at C-4, whereby the

orientation of the C-4 aryl group (R- vs S-configuration) acts as a

“molecular switch” between antagonistic (aryl group, up) and agonistic

(aryl group, down) activity. Pharmacological studies probing the effect of absolute

configuration at the C-4 stereogenic center are well understood7 and in some cases

individual enantiomers are reported to show opposing biological activities. For example, in

the conformationally restricted DHPM 4, the (S)-enantiomer (aryl group, up) possesses

only calcium antagonistic (blocking) activity, whereas the (R)-enantiomer (aryl group,

down) is a calcium agonist.7 Likewise, in related DHPM analogues, the individual

enantiomers have been demonstrated to have opposing (antagonist vs agonist)

pharmacological activity.7

NH

Me Me

COOMe

NH

Me Me

COOMe

NH

Me CN

21 3

MeOOC EtOOCi-PrOOC COOMe

O2N Cl

ClNO2

NH

N

Me SMe

S

O

( )5

4

O

X

Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach

156

Figure 1. Proposed binding site model for DHPM (The receptor sensitive groups are on

the „left hand side‟ of the molecule).

Only (R)-enantiomers of SQ 32926 5, SQ 32547 6 and 7 carry the therapeutically

desired antihypertensive effect.4,5

The (S)-enantiomer of α1a-selective adrenoceptor

antagonist L-771, 688 8, is significantly more active than the (R)-enantiomer,8 and the (S)-

enantiomer of the mitotic kinesin Eg5 inhibitor monastrol 99,10

is more potent inhibitor of

Eg5 activity.11,12

Similar effect was also observed for Bay 41-4109 10, a non-nucleosidic

inhibitor of hepatitis B virus replication, where the (S)-enantiomer was found to be more

active than the (R)-enantiomer.13

The (S)-enantiomer of the melanin concentrating

harmone receptor (MCH1-R) antagonist SNAP-7941 11, is significantly more active than

the (R)-enantiomer.14

Similarily, in case of inhibitor of fatty acid transporter 12, the (S)-

enantiomer was found to be more active than the (R)-enantiomer.15

Thus, (R)- or (S)-

enantiomers of DHPMs depict different (sometime opposing) biological effects and

representative examples have been tabulated in table 1.

5.2 General approaches to enantiomerically pure 3,4-dihydropyrimidin-2(1H)-

ones

Whereas a number of methods have been reported for the synthesis of racemic

DHPMs,16

approaches to the enantiopure DHPMs are relatively scanty and have relied

either on catalytic enantioselective synthetic routes or through chemical or enzymatic

resolution methods and have been reviewed recently.17

In fact, access to

diastereomerically/enantiomerically pure DHPM derivatives utilizing the tools of

asymmetric synthesis has been a formidable task and is still being pursued with vigor.

In an attempt to develop a practical asymmetric version of the three-component

Biginelli condensation, the condensation of (-)-menthyl acetoacetate 13, 2-napthaldehyde

14 and urea 15 resulted in diastereomeric mixture of DHPMs 16a and 16b in 1:1 ratio

(Scheme 1). However, 16a and 16b could not be separated using recrystallization or

chromatographic techniques.17

A limited success was achieved through resolution of the

N HH

X

O

ORMe

right-hand side

(non-essential)

X = syn

aryl UP

(antagonist)

left-hand side

(essential)

cis carbonyl

hydrogen bond

Chapter 5

157

Table 1. Representative pharmacologically active enantiomers of DHPMs.

Compound Structure Activity profile of enantiomers

5 (SQ32,926)

NH

N

Me O

NO2

O

i-PrO

O

NH2

Antihypertensive agent

(R) > (S)

400 folds

6 (SQ 32,547)

HClNH

NCO2

Me

i-PrOOC

S

CF3

N

F


(R) > (S)

75 folds

7

NH

N

Me S

NO2

O

i-PrOCO2Et


(R) > (S)

1000 folds

8 (L-771,688)

NH

N

O

F

O

MeO

O

NH

F

OMe

N N3

α1a-adrenoceptor antagonist

(S) > (R)

9 (Monastrol)

NH

NH

Me S

OH

O

EtO

Mitotic kinesin Eg5 inhibitor

(S) > (R)

15 folds

10 (Bay 41-4109)

NH

N

Me

O

MeO

F

Cl

N

F

F

Antiviral

(S) > (R)

11 (SNAP-7941)

NH

N

O

F

O

MeO

O

NH

F

OMe

N NH

CH3O

3

MCH1 receptor antagonist

(S) > (R)

12

NH

NH

Me O

O

O

NO2

Inhibitors of fatty acid transporter

(S) > (R)

100 folds


158

corresponding racemic DHPM 5-carboxylic acid derivatives via fractional crystallization

of their diastereomeric -methylbenzylammonium salts.17,18

The absolute configuration of

these acids was proven by single crystal x-ray analysis.

Scheme 1

Chiral aldehydes derived from carbohydrates19

or amino acids20

have also been

used to induce chirality at C-4 of the DHPM ring. The latter approach, however, lacks

generality as the substituent at the C-4 position of the DHPM will invariably be derived

from the carbonyl component employed.

Analytical separation of the enantiomers of DHPMs has also been achieved through

enantioselective HPLC using a variety of different chiral stationary phases (CSPs). The use

of “designer-CSPs” proved extremely useful for the efficient separation of DHPMs.21,22

Especially chiral selectors (SO) consisting of 4- or 2-chloro-3,5-dinitrobenzoic acid, L-

alanine, N-(3,5-dinitrobenzoyl)-L-leucine, (S)- and (R, S)-2-hydroxypropyl-β-cyclodextrin

and different -donor aromatic units, have decreased the retention time and increased the

separation and resolution factor.23-29

A considerably simpler biocatalytic pathway was reported30

by Sidler et al. The

methyl ester 17 could be hydrolyzed selectively by the protease subtilisin (lipases and

esterases were unreactive), allowing hydrolysis of the undesired (R)-enantiomer. The

desired (S)-18 was recovered from the solution in 80-90% chemical yield (98% ee)

(Scheme 2) and was further acylated at N-3 position with 1,1‟-carbonyldiimidazole (CDI)

using LDA as a base to furnish (S)-19. The side chain 25 containing two heterocyclic rings

was synthesized through palladium catalyzed cross coupling (Scheme 3), which on further

reaction with (S)-19 furnished the required (S)-L-771,688 6 in 80% yield (Scheme 4).30

A catalytic enantioselective version of the Biginelli reaction has been reported31

by

Juaristi et al. using CeCl3 and InCl3 as Lewis acids in the presence of chiral ligands such as

an amide 26 and sulfonamide 27 (Scheme 5). Moderate enantioselectivities (up to 40% ee)

Chapter 5

159

of DHPMs were obtained by performing the reaction at low temperature under the

conditions of kinetic control.

Scheme 2

Scheme 3

Scheme 4

Scheme 5

N Br N ZnX

N

N

(i) n-BuLi, THF Low temp

(ii) ZnCl2, THF

-60oC to r.t.

N

Br

/MTBE

Pd(OAc)2, Ph3PDMF DMF, 95oC

90% N

N

Br

PtO2/

H2

20 21

22

23

24 X = Br25 X = H

(CH2)3NHX

Br(CH2)3NH2.HBr

NH

NMeOOC

O

F

F

OMe

(S)-L-771,688

O

NH

N

N

6

NH

NMeOOC

O

F

F

OMe

NN

O

(S)-19

25/IPAc

-60oC to r.t.

80%

NH

NH

Me O

Ar

EtOOC

Me O

H O

H2N

NH2

O

CeCl3 or InCl3chiral ligand

THF

8-40% ee

N NPh

Me O

Ph

Me

Me N

Ph

SO2

N

Ph

O2S

Me

Me26

27

MeEtOOC

Ar

NH

NHMeOOC

O

F

17

F

OMe

NH

NHMeOOC

O

F

(S)- 18

F

OMe

protease

NH

NMeOOC

O

F

F

OMe

NN

O

LDA, CDI

THF, -60oC to r.t.buffer

(S)-19


160

Another catalytic approach to highly enantioselective multi-component Biginelli

condensation using a recyclable ytterbium triflate with a chiral hexadentate ligand 28 has

been developed (ee up to 99%).32

Likewise, in an organocatalytic asymmetric Biginelli

reaction employing chiral phosphoric acid, derived from H8-BINOL 29, DHPMs were

obtained in high yields with excellent enantioselectivities up to 97%.17,33

A wide range of

aldehyde and β-keto esters were employed.

Recently, Wang et al. have synthesized and evaluated a series of chiral substituted

5-(pyrrolidin-2-yl)tetrazoles as organocatalysts for the asymmetric Biginelli reaction.34

By

using catalyst 5-(pyrrolidin-2-yl)tetrazole C10 (10 mol%) 30, a series of DHPMs have

been obtained in 68-81% ee. In another Biginelli reaction catalyzed by a simple chiral

secondary amine 31 and achiral bronsted acid by dual activation route,35

DHPMs (98% ee)

have been obtained using mild reaction conditions. Recently, an enantioselective

multicomponent Biginelli reaction (ee up to 99%) catalyzed by a chiral bifunctional

primary amine-thiourea 32 and a bronsted acid as the combined catalyst with tert-

butylammonium triflouroacetate as additive has been developed.36

Novel prolinamide

catalyst 33 with reinforced chirality, enhanced hydrogen acidity and steric built proved to

be an excellent organocatalyst in asymmetric Biginelli reaction. The reaction works very

N N

N NPh Ph

OH HO

R RR R

(R = H, t-Bu)

O

O

P OH

O

Ar

Ar

28 29

NH

N

Me

Ts

HN N

NN

30

31

NH

HO

O

HN

NH2NH

S

O

OAc

AcO

AcO OAc

NH

32

33

Ph

Ph

Ph

NH

O

NH

HNS

O

O

Me

Chapter 5

161

well with all aliphatic and aromatic aldehydes, yielding chiral DHPMs in respectable yield

(44-68%) but in a remarkably high enantioselectivity (94-99% ee).37

Following a different approach, the enantioselective synthesis of SNAP-7941 11

was achieved by using organocatalytic methods.38

The first method utilized Cinchona

alkaloid-catalyzed Mannich reaction of β-keto esters 34 and acylimines 35 (route A) to

synthesize the enantio-enriched DHPM 36 and in the second method chiral phosphoric acid (route

B) was employed as catalyst in the three-component Biginelli condensation reaction (Scheme 6).

Scheme 6

Synthesis of 3-(4-phenylpiperidin-1-yl)propylamine side chain fragment 44 was

achieved through Suzuki coupling (Scheme 7). Reaction of 36 with p-nitrophenyl

chloroformate furnished N-substituted DHPM carbamate 45. SNAP-7941 11 was obtained

via selective urea formation at the N-3 position of 45 upon reaction with 3-(4-

phenylpiperidin-1-yl)propylamine 44 (Scheme 8).38

Scheme 7

N

OTf

Boc

(HO)2B

HN

Me

O

NH

MeO

N

Boc

NH

MeO

N

NH

MeO

N

K2CO3

H2, Pd/C

38 39 4041 R1 = Boc (94%)

42 R1 = H.HCl (92%)43 R2 = Boc (40%)

44 R2 = H (96%)

Pd(PPh3)4 Br(CH2)3NHBoc

(CH2)3NHR2R1


162

Scheme 8

A useful preparative approach to the enantiomerically pure antihypertensive agent

(R)-5 was disclosed by Atwal et al. (Scheme 9).4 In the first step, the 1,4-

dihydropyrimidine intermediate 46 was acylated at N-3 with 4-nitrophenyl chloroformate,

followed by hydrolysis with HCl in THF to give DHPM 47. Treatment of 47 with (R)-α-

methylbenzylamine provided a mixture of diastereomeric ureas 48 from which the (R,R)-

48 was separated by crystallization. Cleavage of (R,R)-48 with TFA provided (R)-5 in high

enantiomeric purity. Similar strategies have been used to obtain a number of

pharmacologically important DHPMs in enantiomerically pure form.4,5

Scheme 9

As an alternative to the chemical resolution methods described by Atwal et al.

(Scheme 9), a biocatalytic strategy towards the preparation of enantiopure (R)- and (S)- 5

was developed (Scheme 10). The key step in the synthesis was the enzymatic resolution of

an N-3 acetoxymethyl activated dihydropyrimidinone precursor 50 by Thermomyces

lanuginosus lipase39

with excellent enantioselectivity. DHPM 50 was obtained through

hydroxymethylation of the racemic DHPM 49 with formaldehyde followed by resolution

NH

N

Me OMe

NO2

O

i-PrO

NH

N

Me O

NO2

O

i-PrO

O

OR H2N

Ph

Me

NH

N

Me O

NO2

O

i-PrO

O

NH

Me

Ph

NH

N

Me O

NO2

O

i-PrO

O

NH2

47 R = 4-nitrophenyl

(i) ClCO2R

(ii) HCl, THF

crystallization

TFA

(R,R)-48 (R)-5

46

Chapter 5

163

using a lipase enzyme and treatment with ammonia to obtain (R)-49, which was converted

into the target DHPM (R)-5 in a single step by N-3 carbamoylation with trichloroacetyl

isocyanate.39

Scheme 10

In a chemical resolution strategy for enantiopure 9,40

the O-protected monastrol 51

was acetylated regioselectively at the N-3 position with a chiral, β-linked C-glycosyl

carboxylic acid chloride (Scheme 11). The resulting diastereomeric amides 52 were

separated by chromatography, and simultaneous removal of the TBDMS and the chiral

sugar moiety by treatment with sodium ethoxide provided the desired enantiopure (S)- 9, in

good overall yield (Scheme 11).

Scheme 11

Enantioselective biocatalytic synthesis of (S)-monastrol 9 has been reported through

hydrolysis of racemic O-butanoyl monastrol (97% ee) using lipase obtained from Candida

Antarctica B. Cleavage of the O-butanoyl moiety then gave the desired (S)-monastrol 9 with

96% ee.41

NH

NH

Me O

NO2

O

i-PrO

NH

N

Me O

NO2

O

i-PrO OAc

NH

NH

Me O

NO2

O

i-PrO

NH

N

Me O

NO2

O

i-PrO

O

NH2

50

(i) CH2O

(ii) AcCl

(R)-49 (R)-5

49

(i) lipase

(ii) aq. NH3

OCN CCl3

O

NH

NH

Me S

OTBDMS

O

EtO

O

BzO OBz

COClBzO

toluene, 100oC, 4 hNH

N

Me S

OTBDMS

O

EtO EtONa (S)-9

51 52

O

OBz

OBz

OBz

O

H


164

In a study aimed at enantioselective total synthesis of polycyclic marine alkaloid (-)

-batzelladine, construction of enantiomerically enriched DHPM derivatives 54a and 54b

has been achieved through regioselective N-3 sulfonylation of DHPM 53 with (1S)-(+)

camphorsulfonyl chloride (Scheme 12).42

Scheme 12

Thus, these few examples emphasize the requirement of an efficient method for the

preparation of optically pure DHPMs and we have explored it through the chiral auxiliary

approach as outlined in Scheme 13.

Scheme 13

5.3 Synthesis of enantiomerically pure DHPMs through N-functionalization route

In our investigation, we focused on the N-acylation methodology43

and making use

of a removable optically pure amino acid chloride as electrophile. The chiral amino acid

chloride could be easily prepared in optically pure form using a reported protocol.44

Thus,

L-phenylalanine 55 was N-protected using phthalic anhydride at 150oC to obtain N-

phthaloyl derivative 56, which upon treatment with PCl5 in dry benzene furnished the

NH

NHMeOOC

O

(i) LiHMDS, THF/0oC

53

(ii) (1S)-(+)-camphorsulfonyl chloride

NH

NMeOOC

O

54a

Me Me

NH

NMeOOC

O

Me

+

54b

CA = (1S)-(+)-camphorsulfonyl chloride

CA CA

N

NH

Me

R2O

O R1

O

(i) Base

(ii)Chiral auxiliary (CA)

R3

R3 = H, Me

N

N

Me

R2O

O R1

O

Me

R3 = Me

N

NH

Me

R2O

O R1

O

CA

R3 = H

or

CA

N

NH

Me

R2O

O R1

O

R3

R3 = H, Me

(S)- or (R)- Enantiomers

deprotection

Chapter 5

165

corresponding acid chloride 57 in high yield as well as in optical purity {[α]D25

= -197o

(benzene, c = 2.25)} (Scheme 14).

Scheme 14

In order to position the chiral auxiliary at the two different nitrogen centers, we chose

both, N-1 unsubstituted and N-1 methyl substituted DHPMs (Scheme 15). Variation at C-4

position by way of choosing bulkier as well as simple alkyl substituents, have also been

incorporated to see the effect on resolution outcome.

In order to determine favorable conditions, N-acylation of DHPM 58a was

performed using n-BuLi as base for N-deprotection followed by reaction with the chiral

auxiliary (CA) 57 as an electrophile. Thus, when a THF solution of 58a was treated with n-

BuLi (1.1 equiv.) at -78oC, under the blanket of purified anhydrous N2 gas, a pale yellow

colored solution resulted, which upon quenching with 57 at the same low temperature

yielded a mixture of two products with Rf 0.7 and 0.6 (ethyl acetate:hexane/60:40) (TLC)

(Scheme 15). Careful chromatographic separation of the mixture resulted in the isolation of

two compounds.

Scheme 15

HO

O

NH2H

O

O

O

150oC

HO

O

NH

O

O

PCl5, benzene

50-55oCCl

O

NH

O

O

S

S S

55 56 57

N

N

Me

R2O

O R1

O

N

NH

Me

R2O

O R1

O

(i) n-BuLi (1.1 equiv.)

-78oC/N2 atmosphere

(ii)(1.5 equiv.)/THF

-78oC to r.t.

(iii) NH4Cl/-78oC R

N

N

Me

R2O

O R1

O

S

58

a

b

R3

R3

R4

R3

R4

a. R1 = 3,4,5-(OMe)3C6H2, R2 = Et, R3 = H

b. R1 = C6H5, R2 = Et, R3 = Me

c. R1 = C6H5, R2 = i-Pr, R3 = Me

d. R1 = CH3, R2 = Et, R3 = H

e. R1 = C6H5, R2 = Et, R3 = H

59a/b. R1 = 3,4,5-(OMe)3C6H2, R2 = Et, R3 = CA, R4 = H

60a/b. R1 = C6H5, R2 = Et, R3 = Me, R4 = CA

61a/b. R1 = C6H5, R2 = i-Pr, R3 = Me, R4 = CA

62a/b. R1 = CH3, R2 = Et, R3 = CA, R4 = H

63a/b. R1 = C6H5, R2 = Et, R3 =CA, R4 = H

O

NH

O

O

SCA =


166

The 1H NMR (CDCl3) spectrum (Figure 2) of the upper Rf component depicted

signals at 1.27 (t, 3H, J 7.2 Hz, CH3), 2.51 (s, 3H, C6-CH3), 3.69 (s, 6H, 2×OCH3), 3.73

(dd, 1H, J 2.4 Hz, J 17.4 Hz, CH), 3.79 (s, 3H, OCH3), 3.80 (dd, 1H, J 6.0 Hz, J 13.8 Hz,

CH), 4.21 (q, 2H, J 7.2 Hz, CH2), 5.35 (d, 1H, J 3.9 Hz, CH), 6.20 (d, 1H, J 3.9 Hz, D2O

exchangeable, NH), 6.29 (dd, 1H, J 4.5 Hz, J 4.5 Hz, CH), 6.44 (s, 2H, ArH), 7.19 (m, 5H,

ArH), 7.67 (m, 2H, ArH), 7.74 (m, 2H, ArH), indicating the incorporation of the N-

phthaloyl L-phenylalanine group. The presence of N3-H ( 6.20) resonance and a doublet

corresponding to C4-H (5.35) and the absence of N1-H resonance indicated substitution

of the chiral auxiliary at N-1 position. The characteristic ABX splitting pattern (AB

protons at 3.73 and 3.80and X proton at 6.29) of CH2 and CH of the chiral auxiliary

also confirmed its incorporation. Its 13

C NMR (CDCl3) spectrum (Figure 2) depicted

signals at 14.1, 19.6, 34.1, 54.8, 55.9, 59.1, 60.7, 61.2, 103.0, 115.4, 123.3, 126.8, 128.5,

128.7, 131.4, 134.0, 135.3, 136.8, 137.5, 147.0, 151.3, 153.5, 164.6, 167.8 and 172.1.

Correlation of the other data such as MS (m/z 650, M++23) and microanalytical analysis,

led us to assign the structure, 5-ethoxycarbonyl-6-methyl-4-(3,4,5-trimethoxyphenyl)-1-

[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenylpropionyl]-3,4-dihydropyrimidin-

2(1H)-one 59a (40%, Table 2) to this compound {[α]D25

= +180o (CH2Cl2, c =0.1)}.

Figure 2. 1

H NMR (300 MHz, CDCl3) spectrum and 13

C NMR (75 MHz, CDCl3)

assignments of 59a.

The lower Rf component in its 1H NMR (CDCl3) spectrum (Figure 3) showed signals

at 1.23 (t, 3H, J 7.2 Hz, CH3), 2.54 (s, 3H, C6-Me), 3.30 (dd, 1H, J 9.6 Hz, J 9.6 Hz, CH),

55.9

N

NHO

O

O

O

S

O

O

O

N OO

S

14.1

61.2

34.1

19.6

60.7

59.159.1

128.5

128.5

128.7

128.7

123.3137.5

134.0

151.3 151.3

103.0 103.0

54.8

134.0

126.8 126.8

131.4 131.4167.8 167.8

172.1

147.0

115.4

164.6

136.8

135.3

153.5

Chapter 5

167

3.41 (dd, 1H, J 6.0 Hz, J 5.7 Hz, CH), 3.73 (s, 6H, 2×OCH3), 3.80 (s, 3H, OCH3), 4.18 (q,

2H, J 7.2 Hz, CH2), 5.25 (d, 1H, J 3.9 Hz, CH), 5.90 (dd, 1H, J 6.0 Hz, J 5.7 Hz, CH), 6.07

(d, 1H, J 3.6 Hz, D2O exchangeable, NH), 6.45 (s, 2H, ArH), 7.14 (m, 5H, ArH), 7.67 (m,

2H, ArH), 7.77 (m, 2H, ArH). The spectral assignments are similar to 59a with slight shift in

the positions of the signals (Figure 3). On the basis of the 1H NMR data and other spectral

and microanalytical analysis (vide experimental) structure, 5-ethoxycarbonyl-6-methyl-4-

(3,4,5-trimethoxyphenyl)-1-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenylpropionyl]-

3,4-dihydropyrimidin-2(1H)-one 59b (42%, Table 2) has been assigned to this compound {[

α]D25

= +60o (CH2Cl2, c = 0.1)}.

Figure 3. 1



assignments of 59b.

It was also observed that temperature and equivalents of base significantly affected

the yield of the N-1 acylated DHPM 59. Thus, upon using 1.1 equiv. of n-BuLi at -20οC, 59

could be isolated in 65% overall yield. Increasing the equiv. of n-BuLi (2.1 equiv), decreased

the yield. Thus, the optimized reaction conditions were found to be n-BuLi, 1.1 equiv./-

78οC/57, 1.5 equiv./NH4Cl, -78

οC.

The assignment of the absolute configuration at the C-4 position of a series of DHPM

derivatives, has been based on combination of enantioselective HPLC and circular dichroism

(CD) spectroscopy,27,28

through correlation with DHPM derivatives of known

configuration.24,25

However, correlation of specific optical rotation has also been used for

predicting the configuration at C-4.32

Since the chiral auxiliary used in this reaction has (S)-

configuration at the chiral carbon, the two diastereomers 59a and 59b have been assigned,

56.0

N

NHO

O

O

O

R

O

O

O

N OO

S

14.1

61.1

35.2

19.0

60.7

57.457.4

128.3

128.3

129.1

129.1

123.4137.5

134.0

151.3 151.3

103.4 103.4

54.7

134.0

126.8 126.8

131.6 131.6167.8 167.2

171.1

103.4

164.8

136.4

135.0

153.6137.5


168

(S)- and (R)- configuration at C-4. This was also confirmed by correlating the optical rotation

of enantiomers obtained (vide infra) after removal of chiral auxiliary, with known

enantiomerically pure DHPMs.

Table 2. Resolution of diastereomers 59-63 from racemic DHPMs.

Reductive deacylation of the diastereomers 59a and 59b could be accomplished using

LAH (Scheme 16). Treatment of 59a with LAH (5.5 equiv.) at 0oC in THF furnished a single

product at Rf 0.2 (ethyl acetate:hexane/80:20) (TLC) in 90% yield.

Scheme 16

Entry R1 R

2 R

3 R

4 Product Yield

(%)

1. 3,4,5-(OMe)3C6H2 Et CA H 59a 40

2. 3,4,5-(OMe)3C6H2 Et CA H 59b 42

3. Ph Et Me CA 60a 52

4. Ph Et Me CA 60b 48

5. Ph i-Pr Me CA 61a 45

6. Ph i-Pr Me CA 61b 44

7. Me Et CA H 62a 30

8. Me Et CA H 62b 28

9. Ph Et CA H 63a 40

10. Ph Et CA H 63b 38

N

N

Me

R2O

O R1

O

R3

R4

64a/b. R1 = 3,4,5-(OMe)3C6H2, R2 = Et, R3 = H (90%/90%)

65a/b. R1 = Ph, R2 = Et, R3 = Me (80%/75%)

66a/b. R1 = Ph, R2 = i-Pr, R3 = Me (70%/65%)

67a/b. R1 = Me, R2 = Et, R3 = H (70%/65%)

68a/b. R1 = Ph, R2 = Et, R3 = H (70%/70%)

59a/b. R1 = 3,4,5-(OMe)3C6H2, R2 = Et, R3 = CA, R4 = H

60a/b. R1 = Ph, R2 = Et, R3 = Me, R4 = CA

61a/b. R1 = Ph, R2 = i-Pr, R3 = Me, R4 = CA

62a/b. R1 = Me, R2 = Et, R3 = CA, R4 = H

63a/b. R1 = Ph, R2 = Et, R3 =CA, R4 = H

N

NH

Me

R2O

O R1

O

R3

LAH, THF

0oC to r.t.

59-63a: (S)-59-63b: (R)-

64-68a: (S)-64-68b: (R)-

Configuration at C-4 Configuration at C-4

O

NH

O

O

SCA =

Chapter 5

169

The 1H NMR (CDCl3) spectrum (Figure 4) of the compound depicted signals at

1.20 (t, 3H, J 7.2 Hz, CH3), 2.36 (s, 3H, C6-CH3), 3.82 (s, 9H, 3×OCH3), 4.10 (m, 2H, CH2),

5.37 (d, 1H, J 2.7 Hz, CH), 5.48 (br, 1H, D2O exchangeable, NH), 6.53 (s, 2H, ArH), 7.33

(br, 1H, D2O exchangeable, NH). 13

C NMR (CDCl3) spectrum (Figure 4) showed signals at

14.1, 18.3, 55.7, 56.0, 60.0, 60.7, 101.1, 103.6, 137.7, 139.3, 146.2, 153.3, 153.5 and 165.6.

In its EIMS spectrum a peak at m/z 373 (M++23) corresponded to the molecular formula

C17H22N2O6+Na. These spectral data was well supported by correct micoanalytical analysis

(vide experimental) and structure, 5-ethoxycarbonyl-6-methyl-4-(3,4,5-trimethoxyphenyl)-

3,4-dihydropyrimidin-2(1H)-one 64a has been assigned to this compound, obtained in 90%

yield. The specific optical rotation was found to be +30o (methanol, c = 0.2). Correlating the

sign of optical rotation of the known (S)-enantiopure DHPMs,39

the configuration (S) is

assigned at C-4 position of 64a.

Figure 4. 1



assignments of 64a.

Likewise, reductive deacylation of the diastereomer 59b with LAH furnished a single

product. The spectral data of this compound was superimposable with that of 64a and it was

identified as the (R)-enantiomer, 5-ethoxycarbonyl-6-methyl-4-(3,4,5-trimethoxyphenyl)-

3,4-dihydropyrimidin-2(1H)-one 64b (90%). The specific optical rotation of 64b is –28o

(methanol, c = 0.2) which is nearly equal but with opposite sign compared to 64a (S-

enantiomer). In addition, 64b showed good correlation with the specific optical rotation sign

of known C4-(R) DHPM.32

The absolute configuration of 64a and 64b were also confirmed by recording circular

dichroism (CD) spectra of the enantiomers and comparing them with known enantiomers.

NH

NHO

O

O

O

O

O

165.6

18.3

14.1

60.7

56.0

139.3

55.7

153.5

103.6

146.3

101.1153.3

137.7

103.6

153.5 56.0

60.0


170

Figure 5 shows the CD spectra of both enantiomers of DHPM 64. Based on comparison with

reference CD spectra of DHPMs with known absolute configuration,26

64a showing a

positive cotton effect at 288 nm was assigned the (S)-configuration and 64b which exhibits

the corresponding mirror image CD spectrum, was assigned the (R)-configuration.

(S)-64a

(R)-64b

Figure 5. Experimental CD spectra of 64a and 64b.

The synthetic scope of this methodology was further explored by using DHPMs

substituted with different substituents around the DHPM core (C-4, C-5 and N-1) (Scheme

15, Table 2). Therefore, when metalated N-1 methyl DHPM 58b (R3 = Me) was reacted

with 57, using optimized reaction conditions, two products were isolated from the reaction

mixture at Rf 0.5 and 0.3 (ethyl acetate:hexane/40:60) (TLC) after column

chromatography. The 1H NMR (CDCl3) spectrum (Figure 6) of the upper Rf component

depicted signals at 1.27 (t, 3H, J 7.2 Hz, CH3), 2.56 (s, 3H, C6-CH3), 3.27 (s, 3H, N1-

CH3), 3.31 (d, 1H, J 4.2 Hz, CH), 3.82 (dd, 1H, J 11.4 Hz, J 11.4 Hz, CH), 4.22 (m, 2H,

CH2), 6.54 (s, 1H, CH), 6.63 (dd, 1H, J 4.5 Hz, J 4.5 Hz, CH), 7.21 (m, 10H, ArH), 7.64

(m, 2H, ArH), 7.76 (m, 2H, ArH), indicating the incorporation of the N-phthaloyl L-

phenylalanine group. The presence of singlet at corresponded to C4-Haccompanied

by the absence of N3-H resonance indicated substitution of the chiral auxiliary at the N-3

position. The 1H NMR spectrum of this compound also showed an ABX splitting pattern

(AB protons at 3.31 and 3.82and X proton at 6.63), corresponding the relevant

protons of the CA, similar to 59a.

Its 13

C NMR (CDCl3) spectrum (Figure 6) depicted signals at 14.1, 16.2, 31.4,

34.1, 53.2, 57.0, 60.8, 109.4, 123.3, 126.4, 126.8, 128.0, 128.4, 128.6, 128.8, 131.7, 133.8,

136.7, 138.5, 148.2, 151.9, 165.0, 168.2 and 170.7. The peak at m/z 552 (M++1) in its

EIMS spectrum corresponded to the molecular formula C32H29N3O6 and correct

microanalytical analysis (vide experimental) confirmed the structure, 5-ethoxycarbonyl-

-6

-4

-2

0

2

4

6

210 230 250 270 290 310 330 350

nm

∆ε

∆ε

Chapter 5

171

1,6-dimethyl-3-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenylpropionyl]-4-phenyl-

3,4-dihydropyrimidin-2(1H)-one 60a assigned to this compound (52%, Table 2) {[α]D25

=

+205o (CH2Cl2, c = 0.2)}.

Figure 6. 1



assignments of 60a.

The lower Rf product in its 1H NMR (CDCl3) spectrum (Figure 7) showed signals at

1.24 (t, 3H, J 7.2 Hz, CH3), 2.36 (s, 3H, C6-CH3), 3.03 (s, 3H, N1-CH3), 3.70 (m, 2H,

CH2), 4.19 (m, 2H, CH2), 5.98 (dd, 1H, J 6.3 Hz, J 6.6 Hz, CH), 6.67 (s, 1H, CH), 7.23 (m,

Figure 7. 1



assignments of 60b.

34.1

14.1

16.2 60.8

31.4

148.2

138.5

109.4 57.0

126.8

53.2165.0

N

NO

O

O

O

N

O

O

Me

126.8

128.6 128.6

126.4

170.7

151.9

136.7 128.4

128.4

128.8

128.8

123.0

168.2

168.2

131.7

131.7128.0

128.0

133.8

133.8

34.3

14.1

15.8 60.7

31.1

148.3

138.6

109.3 56.8

126.6

52.3164.9

N

NO

O

O

O

N

O

O

Me

126.6

128.6 128.6

126.3

171.3

151.5

137.0 128.3

128.3

129.2

129.2

123.3

167.4

167.4

131.4

131.4128.0

128.0

133.9

133.9


172

10H, ArH), 7.67 (m, 2H, ArH), 7.76 (m, 2H, ArH), similar to 60a with slight shift in the

position of the signals. On the basis of the 1H NMR data and other spectral and physical

data (vide experimental) structure, 5-ethoxycarbonyl-1,6-dimethyl-3-[2(S)-(1,3-dioxo-1,3-

dihydro-isoindol-2-yl)-3-phenylpropionyl]-4-phenyl-3,4-dihydropyrimidin-2(1H)-one 60b

has been assigned to this compound (48%, Table 2) {[ α]D25

= -245o (CH2Cl2, c = 0.2)}.

Reductive deacylation of the diastereomer 60a was accomplished using LAH

(Scheme 16). Thus, treatment of 60a with LAH (5.5 equiv.) at 0oC in THF furnished a single

product at Rf 0.5 (ethyl acetate:hexane/60:40) (TLC). The 1H NMR (CDCl3) spectrum

(Figure 8) of this compound depicted signals at 1.18 (t, 3H, J 7.2 Hz, CH3), 2.51 (s, 3H,

C6-CH3), 3.23 (s, 3H, N1-CH3), 4.10 (q, 2H, J 7.2 Hz, CH2), 5.38 (d, 1H, J 3.3 Hz, CH),

5.58 (br, 1H, D2O exchangeable, NH), 7.28 (m, 5H, ArH). The peaks in its 13

C NMR

(CDCl3) spectrum (Figure 8) appeared at 14.0, 16.4, 30.1, 53.6, 60.0, 104.1, 126.1, 127.5,

128.5, 143.3, 149.2, 154.0 and 166.0 and corroborated well with 1H NMR spectral data. The

peak at m/z 297 (M++23) in its EIMS spectrum corresponding to the molecular formula

C15H18N2O3+Na and correct microanalytical analysis (vide experimental) confirmed the

structure, 5-ethoxycarbonyl-1,6-dimethyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one 65a,

obtained in 80% yield. The specific optical rotation [α]D25

was found to be -40o (methanol, c

= 0.2).

Figure 8. 1



assignments of 65a.

Likewise, reductive deacylation of the diastereomer 60b with LAH furnished a

single product. The spectral data of this compound was exactly similar to that of 65a and it

was identified as the (R)-enantiomer, 5-ethoxycarbonyl-1,6-dimethyl-4-phenyl-3,4-

14.0

16.4

60.0

30.1

149.2

143.3

104.1 53.6

127.5

166.0

128.5 128.5

126.1

154.0

N

NHO

O

O

127.5

Chapter 5

173

dihydropyrimidin-2(1H)-one 65b. The specific optical rotation of 65b was found to be

+40o (methanol, c = 0.2), which is equal but opposite to 65a.

The absolute configuration of 65a and 65b was also correlated by circular dichroism

(CD) spectroscopy. Figure 9 shows the CD spectra of both enantiomers of DHPM 65. In

analogy with 64a and 64b, the enantiomer 65a showing positive cotton effect was assigned

the (S)-configuration and 65b was assigned the (R)-configuration.

(S)-65a

(R)-65b


It has been observed that in the reaction of N-1 unsubstituted DHPM 58a (R3 = H),

with chiral auxiliary 57, substitution proceeded at N-1 position. On the other hand, the N-1

substituted DHPM 58b (R3 = Me) furnished, N-3 substituted diastereomers upon reaction

with 57.

The distinction between the N-1 (59a-b) and N-3 (60a-b) substituted products was

based on the 1H NMR spectral analyses (vide infra). In case of the former, the presence of

N3-H resonance accompanied by C4-H doublet and the absence of N1-H resonance

indicated substitution of the chiral auxiliary at N-1 position, while in case of later, the

presence of singletcorresponding to C4-Haccompanied by the absence of N3-H indicated

substitution of the chiral auxiliary at N-3 position. Other spectral, analytical and optical

rotation data corroborated these assignments.

Similarly, reaction of metalated 5-isopropoxycarbonyl-1,6-dimethyl-4-phenyl-3,4-

dihydropyrimidin-2(1H)-one 58c with 57 using optimized reaction conditions yielded two

products at Rf 0.3 and 0.5 (ethyl acetate:hexane/40:60) (TLC) (Scheme 15). The upper Rf

component was identified as 5-isopropoxycarbonyl-1,6-dimethyl-3-[2(S)-(1,3-dioxo-1,3-

dihydro-isoindol-2-yl)-3-phenylpropionyl]-4-phenyl-3,4-dihydropyrimidin-2(1H)-one 61a

Reaction proceeded smoothly, without formation of any by products in case of N-1 substituted DHPMs, but

in case of N-1 unsubstituted DHPMs, N1,N3-disubstituted DHPM formed as minor component (not

discussed in present thesis).

-60

-40

-20

0

20

40

60

210 230 250 270 290 310 330 350

nm

∆ε

∆ε


174

(45%, Table 2). The structural assignment was based on spectral data as well as

microanalytical analysis (vide experimental). The specific optical rotation was found to be

+160o (CH2Cl2, c = 0.2). Similarly, the lower Rf component has been assigned the structure,

5-isopropoxycarbonyl-1,6-dimethyl-3-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-

propionyl]-4-phenyl-3,4-dihydropyrimidin-2(1H)-one 61b (44%, Table 2) based upon

spectral data as well as microanalytical data (vide experimental). The specific optical rotation

was found to be -250o (CH2Cl2, c = 0.2).

Reductive deacylation of the diastereomers 61a and 61b was accomplished using

LAH (Scheme 16). Treatment of 61a with LAH (5.5 equiv.) at 0oC in THF furnished a

single product, 5-isopropoxycarbonyl-1,6-dimethyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-

one 66a in 70% yield. The structural assignment was based on spectral data as well as

microanalytical analysis (vide experimental). The specific optical rotation was found to be

-20o (methanol, c = 0.2). Likewise, reductive deacylation of the diastereomer 61b with

LAH furnished a single product. The spectral data of this compound was exactly similar to

that of 66a and it was identified as the (R)-enantiomer, 5-isopropoxycarbonyl-1,6-

dimethyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one 66b (65%, Scheme 16). The specific

optical rotation of 66b is +25o (methanol, c = 0.2), which is nearly equal but opposite to

66a.

The absolute configuration of 66a and 66b were determined by circular dichroism

(CD) spectroscopy. Figure 10 shows the CD spectra of both enantiomers of DHPM 66.

Enantiomer 66a was assigned (S)-configuration and enantiomer 66b was assigned (R)-

configuration on the basis of CD spectra.

(S)-66a

(R)-66b


DHPM having methyl substituent at the C-4 position was also metalated and reacted

with 57, using optimized reaction conditions. Therefore, reaction of metalated 5-

-60

-40

-20

0

20

40

60

210 230 250 270 290 310 330 350

nm

∆ε

∆ε

Chapter 5

175

ethoxycarbonyl-4,6-dimethyl-3,4-dihydropyrimidin-2-(1H)-one 58d (n-BuLi, 1.1 equiv./

THF/-78οC) with 57, furnished two products at Rf 0.3 and 0.4 (ethyl acetate:hexane/40:60)

(TLC) (Scheme 15). Careful chromatographic separation of the mixture resulted in the

isolation of two components. The 1H NMR (CDCl3) spectrum (Figure 11) of the upper Rf

component depicted signals at 1.24 (d, 3H, J 6.6 Hz, CH3), 1.31 (t, 3H, J 7.2 Hz, CH3),

2.43 (s, 3H, C6-CH3), 3.76 (m, 2H, CH2), 4.26 (m, 2H, CH2), 4.35 (m, 1H, CH), 5.72 (d, 1H,

J 4.2 Hz, D2O exchangeable, NH), 6.22 (dd, 1H, J 4.2 Hz, J 4.5 Hz, CH), 7.16 (m, 5H, ArH),

7.66 (m, 2H, ArH), 7.76 (m, 2H, ArH), indicating the incorporation of the N-phthaloyl L-

phenylalanine group. The appearance of the doublet of C4-CH3 at accompanied by

multiplet of C4-H (and doublet of N3-H at were characteristic of the

substitution of the chiral auxiliary at N-1 position. Another characteristic feature of the 1H

NMR spectrum was presence of an ABX splitting pattern (AB protons at and X

proton at 6.22). Correlation of 13

C NMR, MS (m/z 498, M++23) and microanalytical data

structure, 5-ethoxycarbonyl-4,6-dimethyl-1-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-

phenylpropionyl]-3,4-dihydropyrimidin-2(1H)-one 62a (30%, Table 2) was assigned to this

compound {[α]D25

= +15o (CH2Cl2, c =0.2)}.

Figure 11. 1



assignments of 62a.

The lower Rf component in its 1H NMR (CDCl3) spectrum (Figure 12) showed

signals at 1.25 (d, 3H, J 6.3 Hz, CH3), 1.31 (t, 3H, J 7.2 Hz, CH3), 2.46 (s, 3H, CH3),

3.49 (d, 2H, J 7.8 Hz, CH2), 4.24 (m, 2H, CH2), 4.31 (m, 1H, CH), 5.91 (d, 1H, J 4.8 Hz,

47.0

14.1

19.3 60.9

22.4

171.4

137.0

117.6 34.0

58.7

164.7

152.3

128.4

146.8123.3

128.8

167.9131.6

133.9

126.7

N

NHO

O

O

O

N OO

128.4

128.8

167.9

131.6

126.7

133.9


176

D2O exchangeable, NH), 5.97 (t, 1H, J 7.8 Hz, CH), 7.19 (m, 5H, ArH), 7.67 (m, 2H,

ArH), 7.76 (m, 2H, ArH). The spectral assignments were identical with 62a with slight

shifts in the position of signals. On the basis of the 1H NMR data and other spectral and

physical data (vide experimental) structure, 5-ethoxycarbonyl-4,6-dimethyl-1-[2(S)-(1,3-

dioxo-1,3-dihydro-isoindol-2-yl)-3-phenylpropionyl]-3,4-dihydropyrimidin-2(1H)-one 62b

(28%, Table 2) was assigned to this compound {[α]D25

= +5o (CH2Cl2, c =0.2)}.

Figure 12. 1



assignments of 62b.

Reductive deacylation of the diastereomer 62a was also accomplished using LAH

(Scheme 16). Treatment of 62a with LAH (5.5 equiv.) at 0oC in THF furnished a single

product at Rf 0.3 (ethyl acetate:hexane/60:40) (TLC) in 70% yield. The 1H NMR (CDCl3)

spectrum (Figure 13) of the compound showed signals at 1.26 (d, 3H, J 5.1 Hz, CH3), 1.28

(t, 3H, J 7.2 Hz, CH3), 2.28 (s, 3H, CH3), 4.18 (m, 2H, CH2), 4.41 (m, 1H, CH), 5.65 (br, 1H,

D2O exchangeable, NH), 7.98 (br, 1H, D2O exchangeable, NH). The 13

C NMR (CDCl3 and

DMSO-d6) spectrum (Figure 13) depicted signals at 13.6, 17.5, 22.8, 46.4, 58.8, 101.1,

146.5, 153.5 and 165.3 and corroborated well with 1H NMR spectral data. The peak at m/z

221 (M++23) in its EIMS spectrum corresponding to the molecular formula C9H14N2O3+Na

and correct microanalytical data (vide experimental), confirmed the structure, 5-

ethoxycarbonyl-4,6-dimethyl-3,4-dihydropyrimidin-2(1H)-one 67a assigned to this

compound. The specific optical rotation was found to be -15o (methanol, c = 0.1).

Likewise, reductive deacylation of the diastereomer 62b with LAH furnished a single

product. The spectral data of this compound was exactly similar to that of 67a and it was

46.9

14.2

19.2 60.9

22.2

170.1

136.5

118.6 35.0

57.2

164.8

152.6

128.4

147.4123.3

129.1

167.4131.6

133.9

126.8

N

NHO

O

O

O

N OO

128.4

129.1

167.4

131.6

126.8

133.9

Chapter 5

177

Figure 13. 1


C NMR (75 MHz, CDCl3 and

DMSO-d6) assignments of 67a.

identified as the (R)-enantiomer, 5-ethoxycarbonyl-4,6-dimethyl-3,4-dihydropyrimidin-

2(1H)-one 67a. The specific optical rotation of 67b was found to be +10o (methanol, c = 0.1)

which is nearly equal but opposite to 67a.

Likewise, reaction of 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-

2(1H)-one 58e with 57 furnished two products at Rf 0.3 and 0.5 (ethyl acetate:hexane/40:60)

(TLC) (Scheme 15). The upper Rf component was found to be 5-ethoxycarbonyl-6-methyl-

4-phenyl-1-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenylpropionyl]-3,4-

dihydropyrimidin-2(1H)-one 63a (40%, Table 1). The structural assignment was based on

spectral data as well as microanalytical analysis (vide experimental). The specific optical

rotation was found to be +175o (CH2Cl2, c = 0.2). Similarly, the lower Rf component has

been assigned the structure, 5-ethoxycarbonyl-6-methyl-4-phenyl-1-[2(S)-(1,3-dioxo-1,3-

dihydro-isoindol-2-yl)-3-phenylpropionyl]-3,4-dihydropyrimidin-2(1H)-one 63b (38%,

Table 1) based upon spectral data as well as microanalytical data (vide experimental). The

specific optical rotation was found to be -185o (CH2Cl2, c = 0.2).

Reductive deacylation of these diastereomers has been achieved by using LAH

(Scheme 16). Treatment of 63a with LAH (5.5 equiv.) at 0oC in THF furnished a single

product, 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one 68a in 70%

yield. The structural assignment was based on spectral data as well as microanalytical

analysis (vide experimental). The specific optical rotation was found to be +50o (methanol, c

= 0.1). Likewise, reductive deacylation of the diastereomer 63b with LAH furnished a single

product. The spectral data of this compound was exactly similar to that of 68a and it was

17.5

13.6

58.8

22.8

146.5

101.1153.5

165.3 46.4

NH

NHO

O

O


178

identified as the (R)-enantiomer 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-

2(1H)-one 68b (70%, Scheme 16). The specific optical rotation of 68b is -50o (methanol, c =

0.1) which is nearly equal but opposite to 68a.

The absolute configuration of 68a and 68b were determined by circular dichroism

(CD) spectroscopy. Figure 14 shows the CD spectra of both enantiomers of DHPM 68.

Enantiomer 68a was assigned (S)-configuration and enantiomer 68b was assigned (R)-

configuration on the basis of CD spectra.

(S)-68a

(R)-68b


5.4 Conclusions

Thus, in this investigation, inherently racemic DHPMs have been resolved using

chemical resolution methodology. Enantiopure chiral auxiliary was incorporated at N-1

or N-3 position of the DHPMs, leading to the formation of both diastereomers, which

were separated chromatographically to obtain both enantiomers of DHPMs, after

removal of the chiral auxiliary. DHPMs bearing both aryl and alkyl group at C-4 position

could be resolved using this methodology. Absolute configuration of the enantiomers has

been assigned using circular dichrosim (CD) spectral correlations.

5.5 Experimental

5.5.1 General information

General experimental details are same as reported in Chapter 3 at page 115. The

optical rotation was recorded on Atago (AP-100) digital polarimeter at 25οC. The CD

spectra were recorded on Applied Photophysics Chirascan Circular Dichrosim

Spectrometer.

-40

-30

-20

-10

0

10

20

30

40

210 230 250 270 290 310 330 350

nm

∆ε

∆ε

Chapter 5

179

5.5.2 Materials and methods

The solvents: MeOH (Na metal followed by Mg treatment), dichloromethane

(DCM) (CaCl2), hexane and tetrahydrofuran (THF) (Na-benzophenone ketyl) were

adequately dried and drawn under N2 atmosphere using hypodermic glass syringes. The

commercially available reagents (LR grade) were used as such without further purification.

Liquids, low boiling reagents were at times distilled over 4Å molecular sieves. n-BuLi

(2.0-2.3 N in hexane) was prepared using the method reported in literature.45

Its strength

was determined by titration against diphenylacetic acid following reported method.46

Reactions were run under a blanket of dry nitrogen gas in a sealed (rubber septum,

Aldrich) round-bottomed flasks. Organometallic reagents were added using cannula. The

low temperature (-10oC and -78

oC) was attained in Dewar flasks using organic solvent-

liquid N2 slush.

5.5.3 Synthesis of enantiomerically pure DHPMs

5.5.3.1 Synthesis of diastereomers of DHPMs

To a suspension of DHPM 58 (5.0 mmol) in 50 ml dry THF under a blanket of dry

N2, 2.1 N n-BuLi (5.5 mmol) was added drop wise at -78oC, whereupon pale yellow anion

was formed. After the addition, reaction mixture was stirred at -78oC for 30 min. and

quenched at -78oC with enantiopure amino acid chloride 57 (7.5 mmol), dissolved in 10 ml

dry THF. The reaction was stirred at same low temperature till it was completed (TLC). A

cold saturated aqueous solution of NH4Cl (30 ml) was introduced at the same low

temperature. The reaction contents were extracted with ethyl acetate (3×25 ml), treated with

brine, washed with water (2×25 ml), dried over anhydrous Na2SO4 and concentrated under

reduced pressure. The diastereomers were separated by column chromatography using silica

gel-G (230-400 mesh) and mixtures of ethyl acetate / hexane as eluent.

5-Ethoxycarbonyl-6-methyl-4(S)-(3,4,5-trimethoxyphenyl)-1-[2(S)-(1,3-dioxo-1,3-

dihydro-isoindol-2-yl)-3-phenylpropionyl]-3,4-dihydropyrimidin-2(1H)-one (59a)

White solid. Rf: 0.7 (ethyl acetate:hexane/60:40). Yield: 40%. m.p.

183oC (methanol). IR (KBr): max 1228, 1464, 1648, 1720, 2938,

3294 cm-1

. 1H NMR (300 MHz, CDCl3, 25

oC) : 1.27 (t, 3H, J 7.2

Hz, ester-CH3), 2.51 (s, 3H, C6-CH3), 3.69 (s, 6H, 2×OCH3), 3.73

(dd, 1H, J 2.4 Hz, J 17.4 Hz, CH), 3.79 (s, 3H, OCH3), 3.80 (dd, 1H,

J 6.0 Hz, J 13.8 Hz, CH), 4.21 (q, 2H, J 7.2 Hz, ester-CH2), 5.35 (d,

1H, J 3.9 Hz, C4-H), 6.20 (d, 1H, J 3.9 Hz, D2O exchangeable, N3-

N

NH

Me

EtO

O

O

OMe

S

OMe

MeO

O

N OO

S


180

H), 6.29 (dd, 1H, J 4.5 Hz, J 4.5 Hz, CH), 6.44 (s, 2H, ArH), 7.19 (m, 5H, ArH), 7.67 (m,

2H, ArH), 7.74 (m, 2H, ArH). 13

C NMR (75 MHz, CDCl3, 25oC): 14.1, 19.6, 34.1, 54.8,

55.9, 59.1, 60.7, 61.2, 103.0, 115.4, 123.3, 126.8, 128.5, 128.7, 131.4, 134.0, 135.3, 136.8,

137.5, 147.0, 151.3, 153.5, 164.6, 167.8 and 172.1. Anal. Calcd. for C34H33N3O9: C, 65.07;

H, 5.26; N, 6.70; Found: C, 64.99; H, 5.35; N, 6.35. MS: m/z 650 (M++23). [α]D

20 +180

o

(CH2Cl2, c = 0.1).

5-Ethoxycarbonyl-6-methyl-4(R)-(3,4,5-trimethoxyphenyl)-1-[2(S)-(1,3-dioxo-1,3-

dihydro-isoindol-2-yl)-3-phenylpropionyl]-3,4-dihydropyrimidin-2(1H)-one (59b)


150oC (methanol). IR (KBr): max 1236, 1462, 1642, 1728, 2937,

3264 cm-1

. 1H NMR (300 MHz, CDCl3, 25

oC) : 1.23 (t, 3H, J 7.2

Hz, ester-CH3), 2.54 (s, 3H, C6-CH3), 3.30 (dd, 1H, J 9.6 Hz, J 9.6

Hz, CH), 3.41 (dd, 1H, J 6.0 Hz, J 5.7 Hz, CH), 3.73 (s, 6H,

2×OCH3), 3.80 (s, 3H, OCH3), 4.18 (q, 2H, J 7.2 Hz, ester-CH2),

5.25 (d, 1H, J 3.9 Hz, C4-H), 5.90 (dd, 1H, J 6.0 Hz, J 5.7 Hz, CH),

6.07 (d, 1H, J 3.6 Hz, D2O exchangeable, N3-H), 6.45 (s, 2H, ArH),

7.14 (m, 5H, ArH), 7.67 (m, 2H, ArH), 7.77 (m, 2H, ArH). 13

C NMR

(75 MHz, CDCl3, 25oC): 14.1, 19.0, 35.2, 54.7, 56.0, 57.4, 60.7, 61.1, 103.4, 123.4, 126.8,

128.3, 129.1, 131.6, 134.0, 135.0, 136.4, 137.5, 151.3, 153.6, 164.8, 167.2 and 171.1. Anal.

Calcd. for C34H33N3O9: C, 65.07; H, 5.26; N, 6.70; Found: C, 64.78; H, 5.58; N, 6.40. MS:

m/z 650 (M++23). [α]D

20 +60

o (CH2Cl2, c = 0.1).

5-Ethoxycarbonyl-1,6-dimethyl-3-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-

phenylpropionyl]-4(S)-phenyl-3,4-dihydropyrimidin-2(1H)-one (60a)

White solid. Rf: 0.5 (ethyl acetate:hexane/40:60). Yield: 52%.

m.p. 98oC (methanol/petroleum ether). IR (KBr): max 1289,

1469, 1625, 2982, 3220 cm-1

. 1H NMR (300 MHz, CDCl3,

25oC): 1.27 (t, 3H, J 7.2 Hz, ester-CH3), 2.56 (s, 3H, C6-

CH3), 3.27 (s, 3H, N1-CH3), 3.31 (d, 1H, J 4.2 Hz, CH), 3.82

(dd, 1H, J 11.4 Hz, J 11.4 Hz, CH), 4.22 (m, 2H, ester-CH2), 6.54 (s, 1H, C4-H), 6.63 (dd,

1H, J 4.5 Hz, J 4.5 Hz, CH), 7.21 (m, 10H, ArH), 7.64 (m, 2H, ArH), 7.76 (m, 2H, ArH). 13C

NMR (75 MHz, CDCl3, 25oC): 14.1, 16.2, 31.4, 34.1, 53.2, 57.0, 60.8, 109.4, 123.3, 126.4,

126.8, 128.0, 128.4, 128.6, 128.8, 131.7, 133.8, 136.7, 138.5, 148.2, 151.9, 165.0, 168.2 and

N

NH

Me

EtO

O

O

OMe

R

OMe

MeO

O

N OO

S

N

N

Me

EtO

O

O

O

N

O

O

SS

Me

Chapter 5

181

170.7. Anal. Calcd. for C32H29N3O6: C, 69.69; H, 5.26; N, 7.62; Found: C, 69.57; H, 4.90; N,

7.47. MS: m/z 552 (M++1). [α]D

20 +205

o (CH2Cl2, c = 0.2).

5-Ethoxycarbonyl-1,6-dimethyl-3-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-

phenylpropionyl]-4(R)-phenyl-3,4-dihydropyrimidin-2(1H)-one (60b)

White solid. Rf: 0.3 (ethyl acetate:hexane/40:60). Yield: 48%.

m.p. 158oC (methanol). IR (KBr): max 1290, 1494, 1647,

1719, 3023 cm-1

. 1H NMR (300 MHz, CDCl3, 25

oC): 1.24

(t, 3H, J 7.2 Hz, ester-CH3), 2.36 (s, 3H, C6-CH3), 3.03 (s,

3H, N1-CH3), 3.70 (m, 2H, CH2), 4.19 (m, 2H, ester-CH2),

5.98 (dd, 1H, J 6.3 Hz, J 6.6 Hz, CH), 6.67 (s, 1H, C4-H), 7.23 (m, 10H, ArH), 7.67 (m, 2H,

ArH), 7.76 (m, 2H, ArH). 13C NMR (75 MHz, CDCl3, 25

oC): 14.1, 15.8, 31.1, 34.3, 52.3,

56.8, 60.7, 109.3, 123.3, 126.3, 126.6, 128.0, 128.3, 128.6, 129.2, 131.4, 133.9, 137.0, 138.6,

148.3, 151.5, 164.9, 167.4 and 171.3. Anal. Calcd. for C32H29N3O6: C, 69.69; H, 5.26; N,

7.62; Found: C, 69.76; H, 5.34; N, 7.30. MS: m/z 574 (M++23). [α]D

20 -245

o (CH2Cl2, c =

0.2).

5-Isopropoxycarbonyl-1,6-dimethyl-3-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-

phenylpropionyl]-4(S)-phenyl-3,4-dihydropyrimidin-2(1H)-one (61a)

White solid. Rf: 0.5 (ethyl acetate:hexane/40:60). Yield:

45%. m.p. 100oC (methanol/petroleum ether). IR (KBr):

max 1239, 1382, 1639, 1720, 2979, 3473 cm-1

. 1H NMR

(300 MHz, CDCl3, 25oC): 1.16 (d, 3H, J 6.3 Hz, CH3),

1.32 (d, 3H, J 6.3 Hz, CH3), 2.55 (s, 3H, C6-CH3), 3.27 (s,

3H, N1-CH3), 3.32 (d, 1H, J 4.2 Hz, CH), 3.83 (t, 1H, J 13.2 Hz, CH), 5.07 (m, 1H, CH),

6.49 (s, 1H, C4-H), 6.64 (dd, 1H, J 4.2 Hz, J 4.2 Hz, CH), 7.18 (m, 10H, ArH), 7.64 (m, 2H,

ArH), 7.76 (m, 2H, ArH). 13C NMR (75 MHz, CDCl3, 25

oC): 16.2, 21.7, 21.9, 31.4, 34.0,

53.4, 57.1, 68.5, 109.9, 123.3, 126.5, 126.7, 127.9, 128.4, 128.5, 128.8, 131.7, 133.8, 136.7,

138.7, 147.8, 151.9, 164.5, 168.2 and 170.7. Anal. Calcd. for C33H31N3O6: C, 70.08; H, 5.48;

N, 7.43; Found: C, 69.95; H, 5.59; N, 7.11. MS: m/z 588 (M++23). [α]D

20 +160

o (CH2Cl2, c =

0.2).

N

N

Me

EtO

O

O

O

N

O

O

SR

Me

N

N

Me

i-PrO

O

O

O

N

O

O

SS

Me


182

5-Isopropoxycarbonyl-1,6-dimethyl-3-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-

phenylpropionyl]-4(R)-phenyl-3,4-dihydropyrimidin-2(1H)-one (61b)

White solid. Rf: 0.3 (ethyl acetate:hexane/40:60). Yield:

44%. m.p. 125oC (methanol/petroleum ether). IR (KBr): max

1288, 1384, 1642, 1719, 3025, 3474 cm-1

. 1H NMR (300

MHz, CDCl3, 25oC): 1.15 (d, 3H, J 6.3 Hz, CH3), 1.28 (d,

3H, J 6.3 Hz, CH3), 2.36 (s, 3H, C6-CH3), 3.05 (s, 3H, N1-

CH3), 3.70 (dd, 2H, J 6.0 Hz, J 9.3 Hz, CH2), 5.05 (m, 1H, CH), 6.00 (dd, 1H, J 5.4 Hz, J 5.7

Hz, CH), 6.64 (s, 1H, C4-H), 7.22 (m, 10H, ArH), 7.67 (m, 2H, ArH), 7.76 (m, 2H, ArH).

13C NMR (75 MHz, CDCl3, 25

oC): 15.8, 21.6, 21.9, 31.1, 34.2, 52.4, 56.9, 68.3, 109.7,

123.3, 126.3, 126.6, 127.9, 128.3, 128.6, 129.1, 131.4, 133.9, 137.1, 138.8, 147.9, 151.6,

164.5, 167.4 and 171.4. Anal. Calcd. for C33H31N3O6: C, 70.08; H, 5.48; N, 7.43; Found: C,

69.88; H, 5.31; N, 7.30. MS: m/z 588 (M++23). [α]D

20 -250

o (CH2Cl2, c = 0.2).

5-Ethoxycarbonyl-4(S),6-dimethyl-1-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-

phenylpropionyl]-3,4-dihydropyrimidin-2(1H)-one (62a)


180oC (methanol). IR (KBr): max 1240, 1385, 1442, 1703, 3373 cm

-1.

1H NMR (300 MHz, CDCl3, 25

oC): 1.24 (d, 3H, J 6.6 Hz, C4-CH3),

1.31 (t, 3H, J 7.2 Hz, ester-CH3), 2.43 (s, 3H, C6-CH3), 3.76 (m, 2H,

CH2), 4.26 (m, 2H, ester-CH2), 4.35 (m, 1H, C4-H), 5.72 (d, 1H, J 4.2

Hz, D2O exchangeable, N3-H), 6.22 (dd, 1H, J 4.2 Hz, J 4.5 Hz, CH),

7.16 (m, 5H, ArH), 7.66 (m, 2H, ArH), 7.76 (m, 2H, ArH). 13C NMR

(75 MHz, CDCl3, 25oC): 14.1, 19.3, 22.4, 34.0, 47.0, 58.7, 60.9, 117.6, 123.3, 126.7,

128.4, 128.8, 131.6, 133.9, 137.0, 146.8, 152.3, 164.7, 167.9 and 171.4. Anal. Calcd. for

C26H25N3O6: C, 65.68; H, 5.26; N, 8.84; Found: C, 65.50; H, 5.10; N, 8.54. MS: m/z 498

(M++23). [α]D

20 +15

o (CH2Cl2, c = 0.2).

5-Ethoxycarbonyl-4(R),6-dimethyl-1-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-

phenylpropionyl]-3,4-dihydropyrimidin-2(1H)-one (62b)


173oC (methanol). IR (KBr): max 1241, 1341, 1495, 1647, 1723, 3216

cm-1

. 1H NMR (300 MHz, CDCl3, 25

oC): 1.25 (d, 3H, J 6.3 Hz, C4-

CH3), 1.31 (t, 3H, J 7.2 Hz, ester-CH3), 2.46 (s, 3H, C6-CH3), 3.49 (d,

2H, J 7.8 Hz, CH2), 4.24 (m, 2H, ester-CH2), 4.31 (m, 1H, C4-H), 5.91

N

N

Me

i-PrO

O

O

O

N

O

O

SR

Me

N

NH

Me

EtO

O Me

O

S

O

N OO

S

N

NH

Me

EtO

O Me

O

R

O

N OO

S

Chapter 5

183

(d, 1H, J 4.8 Hz, D2O exchangeable, N3-H), 5.97 (t, 1H, J 7.8 Hz, CH), 7.19 (m, 5H, ArH),

7.67 (m, 2H, ArH), 7.76 (m, 2H, ArH). 13C NMR (75 MHz, CDCl3, 25

oC): 14.2, 19.2, 22.2,

35.0, 46.9, 57.2, 60.9, 118.6, 123.3, 126.8, 128.4, 129.1, 131.6, 133.9, 136.5, 145.9, 147.4,

152.6, 164.8, 167.4 and 170.1. Anal. Calcd. for C26H25N3O6: C, 65.68; H, 5.26; N, 8.84;

Found: C, 65.40; H, 5.12; N, 8.60. MS: m/z 498 (M++23). [α]D

20 +5

o (CH2Cl2, c = 0.2).

5-Ethoxycarbonyl-6-methyl-4(S)-phenyl-1-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-

phenylpropionyl]-3,4-dihydropyrimidin-2(1H)-one (63a)



cm-1

. 1H NMR (300 MHz, CDCl3, 25

oC): 1.22 (t, 3H, J 7.2 Hz, ester-

CH3), 2.50 (s, 3H, C6-CH3), 3.75 (dd, 2H, J 2.1 Hz, J 7.5 Hz, CH2),

4.17 (m, 2H, ester-CH2), 5.42 (d, 1H, J 3.3 Hz, C4-H), 5.96 (d, 1H, J

3.6 Hz, D2O exchangeable, N3-H), 6.28 (dd, 1H, J 5.4 Hz, J 5.4 Hz,

CH), 7.20 (m, 10H, ArH), 7.67 (m, 2H, ArH), 7.75 (m, 2H, ArH). 13C

NMR (75 MHz, CDCl3, 25oC): 14.1, 17.8, 34.0, 54.8, 57.3, 60.6,

105.7, 123.3, 126.4, 126.8, 128.3, 128.6, 129.1, 131.5, 134.0, 136.9, 150.7, 153.6, 167.6 and

171.2. Anal. Calcd. for C31H27N3O6: C, 69.27; H, 5.03; N, 7.82; Found: C, 69.10; H, 4.82; N,

7.62. MS: m/z 560 (M++23). [α]D

20 +175

o (CH2Cl2, c = 0.2).

5-Ethoxycarbonyl-6-methyl-4(R)-phenyl-1-[2(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-

3-phenylpropionyl]-3,4-dihydropyrimidin-2(1H)-one (63b)



cm-1

. 1H NMR (300 MHz, CDCl3, 25

oC): 1.22 (t, 3H, J 7.2 Hz, ester-

CH3), 2.55 (s, 3H, C6-CH3), 3.57 (m, 2H, CH2), 4.15 (q, 2H, J 7.2 Hz,

ester-CH2), 5.40 (d, 1H, J 3.2 Hz, C4-H), 5.92 (d, 1H, J 3.4 Hz, D2O

exchangeable, N3-H), 6.07 (dd, 1H, J 4.5 Hz, J 4.5 Hz, CH), 7.27 (m,

10H, ArH), 7.66 (m, 2H, ArH), 7.76 (m, 2H, ArH). 13C NMR (75

MHz, CDCl3, 25oC): 14.1, 17.7, 34.1, 54.6, 57.3, 60.4, 105.5, 122.9,

126.5, 127.0, 128.2, 128.8, 129.6, 131.9, 133.5, 135.9, 150.4, 152.9, 166.9 and 172.3. Anal.

Calcd. for C31H27N3O6: C, 69.27; H, 5.03; N, 7.82; Found: C, 68.92; H, 4.70; N, 7.52. MS:

m/z 560 (M++23). [α]D

20 -185

o (CH2Cl2, c = 0.2).

N

NH

Me

EtO

O

O

S

O

N OO

S

N

NH

Me

EtO

O

O

R

O

N OO

S


184

5.5.3.2 Reductive N1/N3-deacylation. Formation of enantiomers

To a solution of DHPM 59-63 (0.83 mmol) in dry THF (50 ml), LAH (9.15 mmol)

was added slowly at 0oC. The reaction contents were warmed to room temperature and

stirred till completion (TLC). The cold saturated aqueous solution of sodium potassium

tartrate was introduced to terminate the reaction followed by treatment with brine. The

extraction was done with ethyl acetate (3×25 ml), organic extracts were dried over

anhydrous Na2SO4 and concentrated under reduced pressure. The enantiomers were

separated by column chromatography using silica gel-G (60-120 mesh) and mixtures of ethyl

acetate / hexane as eluent.

5-Ethoxycarbonyl-6-methyl-4(S)-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrimidin-

2(1H)-one (64a)

Colorless solid. Rf: 0.2 (ethyl acetate:hexane/80:20). Yield: 90%. m.p.

185-186οC (dichloromethane/hexane). IR (KBr): max 1285, 1463,

1589, 1664, 1708, 2934, 3100, 3232 cm-1

. 1

H (300 MHz, CDCl3,

25oC): 1.20 (t, 3H, J 7.2 Hz, ester-CH3), 2.36 (s, 3H, C6-CH3), 3.82

(s, 9H, 3×OCH3), 4.10 (m, 2H, ester-CH2), 5.37 (d, 1H, J 2.7 Hz, C4-

H), 5.48 (br, 1H, D2O exchangeable, N3-H), 6.53 (s, 2H, ArH), 7.33 (br, 1H, D2O

exchangeable, N1-H). 13

C NMR (75 MHz, CDCl3, 25oC): 14.1, 18.3, 55.7, 56.0, 60.0,

60.7, 101.1, 103.6, 137.7, 139.3, 146.2, 153.3, 153.5 and 165.6. Anal. Calcd. for

C17H22N2O6: C, 58.28; H, 6.28; N, 8.00; Found: C, 58.10; H, 5.92; N, 7.74. MS: m/z 373

(M++23). [α]D

20 +30

o (MeOH, c = 0.2).

5-Ethoxycarbonyl-6-methyl-4(R)-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrimidin-

2(1H)-one (64b)

Colorless solid. Rf: 0.2 (ethyl acetate:hexane/80:20). Yield: 90%.

m.p. 183-184οC (dichloromethane/hexane). IR (KBr): max 1282,

1468, 1579, 1668, 1719, 2954, 3110, 3262 cm-1

. 1

H (300 MHz,

CDCl3, 25oC): 1.20 (t, 3H, J 7.2 Hz, ester-CH3), 2.35 (s, 3H, C6-

CH3), 3.82 (s, 9H, 3×OCH3), 4.11 (q, 2H, J 7.2 Hz, ester-CH2), 5.36

(d, 1H, J 2.4 Hz, C4-H), 5.58 (br, 1H, D2O exchangeable, N3-H), 6.53 (s, 2H, ArH), 7.64

(br, 1H, D2O exchangeable, N1-H). 13

C NMR (75 MHz, CDCl3, 25oC): 14.2, 18.5, 55.7,

56.1, 60.0, 60.7, 101.2, 103.6, 137.7, 139.3, 146.1, 153.3, 153.4 and 165.6. Anal. Calcd.

for C17H22N2O6: C, 58.28; H, 6.28; N, 8.00; Found: C, 57.92; H, 5.99; N, 7.74. MS: m/z

373 (M++23). [α]D

20 -30

o (MeOH, c = 0.2).

NH

NH

Me

EtO

O

O

OMe

S

OMe

MeO

NH

NH

Me

EtO

O

O

OMe

R

OMe

MeO

Chapter 5

185

5-Ethoxycarbonyl-1,6-dimethyl-4(S)-phenyl-3,4-dihydropyrimidin-2(1H)-one (65a)


140-142oC (dichloromethane/hexane). IR (KBr): max 1299, 1346, 1439,

1624, 1685, 3230 cm-1

. 1

H (300 MHz, CDCl3, 25oC): 1.18 (t, 3H, J 7.2

Hz, ester-CH3), 2.51 (s, 3H, C6-CH3), 3.23 (s, 3H, N1-CH3), 4.10 (q,

2H, J 7.2 Hz, ester-CH2), 5.38 (d, 1H, J 3.3 Hz, C4-H), 5.58 (br, 1H,

D2O exchangeable, N3-H), 7.28 (m, 5H, ArH). 13

C NMR (75 MHz, CDCl3, 25oC): 14.0,

16.4, 30.1, 53.6, 60.0, 104.1, 126.1, 127.5, 128.5, 143.3, 149.2, 154.0 and 166.0. Anal.

Calcd. for C15H18N2O3: C, 65.69; H, 6.57; N, 10.22; Found: C, 65.39; H, 6.20; N, 9.98.

MS: m/z 297 (M++23). [α]D

20 -40

o (MeOH, c = 0.2).

5-Ethoxycarbonyl-1,6-dimethyl-4(R)-phenyl-3,4-dihydropyrimidin-2(1H)-one (65b)


133-135oC (dichloromethane/hexane). IR (KBr): max 1298, 1341, 1435,

1621, 1683, 3220 cm-1

. 1

H (300 MHz, CDCl3, 25oC): 1.18 (t, 3H, J 7.2

Hz, ester-CH3), 2.51 (s, 3H, C6-CH3), 3.23 (s, 3H, N1-CH3), 4.10 (q,

2H, J 7.2 Hz, ester-CH2), 5.38 (d, 1H, J 3.3 Hz, C4-H), 5.57 (br, 1H,

D2O exchangeable, N3-H), 7.28 (m, 5H, ArH). 13

C NMR (75 MHz, CDCl3, 25oC): 14.0,

16.4, 30.1, 53.6, 60.0, 104.1, 126.1, 127.6, 128.5, 143.3, 149.2, 154.0 and 166.0. Anal.

Calcd. for C15H18N2O3: C, 65.69; H, 6.57; N, 10.22; Found: C, 65.35; H, 6.35; N, 9.95.

MS: m/z 297 (M++23). [α]D

20 +40

o (MeOH, c = 0.2).

5-Isopropoxycarbonyl-1,6-dimethyl-4(S)-phenyl-3,4-dihydropyrimidin-2(1H)-one (66a)


120oC (dichloromethane/hexane). IR (KBr): max 1289, 1347, 1469,

1625, 1686, 2982, 3090, 3220 cm-1

. 1

H (300 MHz, CDCl3, 25oC):

1.04 (d, 3H, J 6.3 Hz, ester-CH3), 1.22 (d, 3H, J 6.0 Hz, ester-CH3),

2.50 (s, 3H, C6-CH3), 3.22 (s, 3H, N1-CH3), 4.97 (m, 1H, ester-CH),

5.37 (d, 1H, J 3.0 Hz, C4-H), 5.76 (br, 1H, D2O exchangeable, N3-H), 7.27 (m, 5H, ArH).

13C NMR (75 MHz, CDCl3, 25

oC): 16.3, 21.5, 21.9, 30.1, 53.7, 67.4, 104.4, 126.2, 127.5,



20 -20

o (MeOH, c =

0.2).

N

NH

Me

EtO

O

O

S

Me

N

NH

Me

EtO

O

O

R

Me

N

NH

Me

i-PrO

O

O

S

Me


186

5-Isopropoxycarbonyl-1,6-dimethyl-4(R)-phenyl-3,4-dihydropyrimidin-2(1H)-one (66b)


123-125oC (dichloromethane/hexane). IR (KBr): max 1279, 1337,

1455, 1620, 1676, 2972, 3099, 3210 cm-1

. 1

H (300 MHz, CDCl3,

25oC): 1.04 (d, 3H, J 6.0 Hz, ester-CH3), 1.22 (d, 3H, J 6.3 Hz, ester-

CH3), 2.51 (s, 3H, C6-CH3), 3.23 (s, 3H, N1-CH3), 4.97 (m, 1H, ester-

CH), 5.37 (d, 1H, J 3.0 Hz, C4-H), 5.54 (br, 1H, D2O exchangeable, N3-H), 7.25 (m, 5H,

ArH). 13

C NMR (75 MHz, CDCl3, 25oC): 16.4, 21.5, 21.9, 30.1, 53.9, 67.5, 104.5, 126.2,

127.6, 128.5, 143.4, 148.9, 153.9 and 165.5. Anal. Calcd. for C16H20N2O3: C, 66.67; H,

6.94; N, 9.72; Found: C, 66.45; H, 6.57; N, 9.53. MS: m/z 311 (M++23). [α]D

20 +25

o

(MeOH, c = 0.2).

5-Ethoxycarbonyl-4(S),6-dimethyl-3,4-dihydropyrimidin-2(1H)-one (67a)


176-178oC (methanol). IR (KBr): max 1237, 1380, 1474, 1626, 1713,

2971, 3332 cm-1

. 1

H (300 MHz, CDCl3, 25oC): 1.26 (d, 3H, J 5.1 Hz,

C4-CH3), 1.28 (t, 3H, J 7.2 Hz, ester-CH3), 2.28 (s, 3H, C6-CH3), 4.18

(m, 2H, ester-CH2), 4.41 (m, 1H, C4-H), 5.65 (br, 1H, D2O exchangeable, N3-H), 7.98 (br,

1H, D2O exchangeable, N1-H). 13

C NMR (75 MHz, CDCl3 and DMSO-d6, 25oC): 13.6,

17.5, 22.8, 46.4, 58.8, 101.1, 146.5, 153.5 and 165.3. Anal. Calcd. for C9H14N2O3: C,

54.54; H, 7.07; N, 14.14; Found: C, 54.29; H, 6.83; N, 13.80. MS: m/z 221 (M++23). [α]D

20

-15o (MeOH, c = 0.1).

5-Ethoxycarbonyl-4(R),6-dimethyl-3,4-dihydropyrimidin-2(1H)-one (67b)



2975, 3339 cm-1

. 1

H (300 MHz, CDCl3, 25oC): 1.30 (m, 6H, ester-CH3

and C4-CH3), 2.28 (s, 3H, C6-CH3), 4.18 (m, 2H, ester-CH2), 4.43 (m,

1H, C4-H), 5.70 (br, 1H, D2O exchangeable, N3-H), 8.09 (br, 1H, D2O exchangeable, N1-

H). 13

C NMR (75 MHz, CDCl3 and DMSO-d6, 25oC): 13.5, 17.3, 22.7, 46.2, 58.7, 100.9,

146.4, 153.5 and 165.1. Anal. Calcd. for C9H14N2O3: C, 54.54; H, 7.07; N, 14.14; Found:

C, 54.25; H, 6.87; N, 13.85. MS: m/z 221 (M++23). [α]D

20 +10

o (MeOH, c = 0.1).

N

NH

Me

i-PrO

O

O

R

Me

NH

NH

Me

EtO

O Me

O

S

NH

NH

Me

EtO

O Me

O

R

Chapter 5

187

5-Ethoxycarbonyl-6-methyl-4(S)-phenyl-3,4-dihydropyrimidin-2(1H)-one (68a)



3115, 3243 cm-1

. 1H (300 MHz, CDCl3 and DMSO-d6, 25

oC): 1.15 (t,

3H, J 7.2 Hz, ester-CH3), 2.33 (s, 3H, C6-CH3), 4.05 (q, 2H, J 7.2 Hz,

ester-CH2), 5.36 (d, 1H, J 2.7 Hz, C4-H), 6.47 (br, 1H, D2O

exchangeable, N3-H), 7.27 (m, 5H, ArH), 8.65 (br, 1H, D2O exchangeable, N1-H). 13

C

NMR (75 MHz, CDCl3 and DMSO-d6, 25oC): 12.8, 16.8, 53.4, 58.1, 98.7, 125.3, 126.0,



20 +50

o (MeOH, c =

0.1).

5-Ethoxycarbonyl-6-methyl-4(R)-phenyl-3,4-dihydropyrimidin-2(1H)-one (68b)



3245 cm-1

. 1H (300 MHz, CDCl3 and DMSO-d6, 25

oC): 1.16 (t, 3H, J

7.2 Hz, ester-CH3), 2.32 (s, 3H, C6-CH3), 4.04 (q, 2H, J 7.2 Hz, ester-

CH2), 5.31 (d, 1H, J 2.7 Hz, C4-H), 7.02 (br, 1H, D2O exchangeable,

N3-H), 7.26 (m, 5H, ArH), 8.82 (br, 1H, D2O exchangeable, N1-H). 13

C NMR (75 MHz,

CDCl3 and DMSO-d6, 25oC): 13.0, 17.0, 53.6, 58.3, 98.9, 125.4, 126.1, 127.1, 143.6,

146.7, 151.9 and 164.6. Anal. Calcd. for C14H16N2O3: C, 64.61; H, 6.15; N, 10.77; Found:

C, 64.44; H, 6.09; N, 10.44. MS: m/z 261 (M++1). [α]D

20 -50

o (MeOH, c = 0.1).

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