chemical resolution of enantiomers of 3,4...
TRANSCRIPT
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
Antihypertensive agent
(R) > (S)
75 folds
7
NH
N
Me S
NO2
O
i-PrOCO2Et
Antihypertensive agent
(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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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 =
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
H NMR (300 MHz, CDCl3) spectrum and 13
C NMR (75 MHz, CDCl3)
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
H NMR (300 MHz, CDCl3) spectrum and 13
C NMR (75 MHz, CDCl3)
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
H NMR (300 MHz, CDCl3) spectrum and 13
C NMR (75 MHz, CDCl3)
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
H NMR (300 MHz, CDCl3) spectrum and 13
C NMR (75 MHz, CDCl3)
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
H NMR (300 MHz, CDCl3) spectrum and 13
C NMR (75 MHz, CDCl3)
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
Figure 9. Experimental CD spectra of 65a and 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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
Figure 10. Experimental CD spectra of 66a and 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
H NMR (300 MHz, CDCl3) spectrum and 13
C NMR (75 MHz, CDCl3)
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
H NMR (300 MHz, CDCl3) spectrum and 13
C NMR (75 MHz, CDCl3)
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
H NMR (300 MHz, CDCl3) spectrum and 13
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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
Figure 14. Experimental CD spectra of 68a and 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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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)
White solid. Rf: 0.6 (ethyl acetate:hexane/60:40). Yield: 42%. m.p.
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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)
White solid. Rf: 0.4 (ethyl acetate:hexane/40:60). Yield: 30%. m.p.
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)
White solid. Rf: 0.3 (ethyl acetate:hexane/40:60). Yield: 28%. m.p.
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)
White solid. Rf: 0.5 (ethyl acetate:hexane/40:60). Yield: 40%. m.p.
105oC (methanol). IR (KBr): max 1220, 1375, 1648, 1711, 2960, 3280
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)
White solid. Rf: 0.3 (ethyl acetate:hexane/40:60). Yield: 38%. m.p.
115oC (methanol). IR (KBr): max 1229, 1382, 1650, 1719, 2981, 3293
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
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)
Colorless solid. Rf: 0.5 (ethyl acetate:hexane/60:40). Yield: 80%. m.p.
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)
Colorless solid. Rf: 0.5 (ethyl acetate:hexane/60:40). Yield: 85%. m.p.
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)
Colorless solid. Rf: 0.7 (ethyl acetate:hexane/80:20). Yield: 70%. m.p.
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,
128.4, 143.4, 148.9, 154.0 and 165.5. Anal. Calcd. for C16H20N2O3: C, 66.67; H, 6.94; N,
9.72; Found: C, 66.35; H, 6.75; N, 9.45. MS: m/z 311 (M++23). [α]D
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
Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using chiral auxiliary approach
186
5-Isopropoxycarbonyl-1,6-dimethyl-4(R)-phenyl-3,4-dihydropyrimidin-2(1H)-one (66b)
Colorless solid. Rf: 0.7 (ethyl acetate:hexane/80:20). Yield: 65%. m.p.
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)
Colorless solid. Rf: 0.3 (ethyl acetate:hexane/60:40). Yield: 70%. m.p.
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)
Colorless solid. Rf: 0.3 (ethyl acetate:hexane/60:40). Yield: 65%. m.p.
180-182oC (methanol). IR (KBr): max 1235, 1385, 1484, 1628, 1723,
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)
Colorless solid. Rf: 0.4 (ethyl acetate:hexane/60:40). Yield: 70%. m.p.
205-207oC (methanol). IR (KBr): max 1091, 1221, 1647, 1701, 1724,
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,
127.0, 143.6, 146.6, 151.7 and 164.4. Anal. Calcd. for C14H16N2O3: C, 64.61; H, 6.15; N,
10.77; Found: C, 64.40; H, 6.05; N, 10.35. MS: m/z 261 (M++1). [α]D
20 +50
o (MeOH, c =
0.1).
5-Ethoxycarbonyl-6-methyl-4(R)-phenyl-3,4-dihydropyrimidin-2(1H)-one (68b)
Colorless solid. Rf: 0.4 (ethyl acetate:hexane/60:40). Yield: 70%. m.p.
212-214oC (methanol). IR (KBr): max 1211, 1642, 1711, 1734, 3125,
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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