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

Article abstract of DOI:10.1016/j.tet.2012.05.073

Inherently racemic DHPMs have been resolved using chemical resolution methodology by appending enantiopure chiral auxiliary at N-1 or N-3 position of the DHPMs, leading to the formation of both diastereomers, which were separated chromatographically to ob

Full text of DOI:10.1016/j.tet.2012.05.073

Tetrahedron 68 (2012) 6169e6176
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Chemical resolution of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones using
chiral auxiliary approach
*
Kamaljit Singh , Kawaljit Singh, Hardeep Kaur
Organic Synthesis Laboratory, Department of Applied Chemical Sciences and Technology, Guru Nanak Dev University, Amritsar 143005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Inherently racemic DHPMs have been resolved using chemical resolution methodology by appending
enantiopure chiral auxiliary at N-1 or N-3 position of the DHPMs, leading to the formation of both di-
astereomers, which were separated chromatographically to obtain both enantiomers (ee upto 99.9%) of
DHPMs, after removal of the auxiliary. Absolute configuration of the enantiomers has been assigned.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 February 2012
Received in revised form 16 May 2012
Accepted 20 May 2012
Available online 26 May 2012
Keywords:
DHPM
Calcium channel modulator
Diastereomer
Enantiomer
Chiral auxiliary
Circular dichroism
1. Introduction
32926 1 and SQ 32547 2 depict antihypertensive effect.3aec The (S)-
enantiomer of a1a-selective adrenoceptor antagonist L-771, 688 3,
3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) are a class of het-
erocyclic compounds,1 which possess diverse range of biological
properties.2 DHPMs show very similar pharmacological profile to
classical 1,4-dihydropyridine (DHPs) based calcium channel mod-
ulators.3 In general, DHPMs and their derivatives have been found
to possess equivalent or even superior calcium channel binding
properties than the traditional DHP based drugs. This has fueled
considerable interest in creating diversity in these molecules to
search for better calcium channel modulators. In addition, these
molecules also act as mitotic kinesin inhibitors,4 a1a-adrenergic
receptor antagonists,5 hepatitis B virus replication inhibitors,6 and
depict a variety of other biological effects.1 The DHPM core also
constitutes a key component of polycyclic guanidine containing
marine alkaloids, such as batzelladine A7 and very active natural
products, such as dehydrocrambine A and Sch 575948,8 which are
potent inhibitors of HIV glycoprotein gp120-CD4 receptor in-
teraction. In contrast to DHPs, DHPMs are inherently racemic
molecules3aec and the influence of the absolute configuration at the
stereogenic center C-4 on biological activity is well documented.9
The DHPM enantiomers exhibit different or even opposite
pharmacological profiles. For example, only (R)-enantiomers of SQ
is significantly more active than the (R)-enantiomer,5 and the (S)-
enantiomer of the mitotic kinesin Eg5 inhibitor monastrol 4 is
a more potent inhibitor of Eg5 activity.4 Similar effects were also
observed for Bay 41-4109 5, a non-nucleosidic inhibitor of hepatitis
B virus replication, where the (S)-enantiomer was found to be more
active than the (R)-enantiomer6 (Fig. 1).
Whereas a number of methods have been reported for the
synthesis of racemic DHPMs,10 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.11 In fact,
access to diastereomerically/enantiomerically pure DHPM de-
rivatives utilizing the tools of asymmetric synthesis has been
a formidable task and is still being pursued with vigor. In-
corporation of chiral auxiliary, such as menthyl carboxylate,3b (R)-
a
-methyl benzyl amine derivatives,3a chiral amine,12 ribofuranosyl
amide13 or sulfonylation with (1S)-(þ) camphorsulfonyl chloride,14
at N-3 position were of limited success. Alternatively employing
protease subtilisin (lipases and esterases were unreactive), selec-
tive hydrolysis of C-5 methyl ester of only (R)-enantiomer15 led to
the recovery of the desired (S)-enantiomer in 80e90% chemical
yield and high (98%) enantioselectivity, which was further manip-
ulated into (S)-L-771,668 3. Similarly, a lipase-catalyzed kinetic
resolution strategy has been reported to yield optically pure
DHPMs.16
* Corresponding author. Tel.: þ91 183 2258853; fax: þ91 183 2258819/20; e-mail
address: kamaljit19in@yahoo.co.in (K. Singh).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.073

6170
K. Singh et al. / Tetrahedron 68 (2012) 6169e6176
F
NO2
O
F
O
O
O
CF3
i-PrOOC
CO2
N
N
i-PrO
Me
N
NH2
MeO
N
N
N
N
H
3
HCl
N
H
O
N
H
O
Me
N
H
S
OMe
F
1
3
2
(S)-L-771,688
(R)-SQ32,926
(R)-SQ 32,547
(
α
(antihypertensive agent)
1 -adrenoceptor antagonist)
(antihypertensive agent)
a
F
OH
O
Cl
O
MeO
Me
N
F
EtO
Me
NH
N
H
N
H
S
N
F
4
5
(S)-Monastrol
(S)-Bay 41-4109
(mitotic kinesin Eg5 inhibitor)
(Antiviral)
Fig. 1. Therapeutically potent enantiomers of DHPMs.
Direct asymmetric induction using chiral aldehydes17,18 or
enantioselective HPLC separation using chiral stationary phases
(CSPs)19,20 furnished a useful but expensive separation of DHPM
enantiomers.
Catalytic enantioselective synthesis of Biginelli DHPMs has re-
lied on the use of acids21e24 in the presence of different chiral li-
gands. Moderate to excellent enantioselectivities (upto 99%) have
Thus, appropriate DHPMs 6aec (R3¼H), unsubstituted at N-1
position, were treated with n-BuLi (1.1 equiv) in anhydrous THF at
low temperature (ꢀ78 ꢁC) under an atmosphere of dry nitrogen and
reaction mixture was stirred for 0.5 h. The pale yellow colored
anion was than quenched with the drop wise addition of the acid
chloride 7 (1.5 equiv) in anhydrous THF at ꢀ78 ꢁC. The reaction was
allowed to warm to room temperature and stirred until completion
of the reaction (TLC) and then treated with a saturated aqueous
solution of ammonium chloride at ꢀ78 ꢁC (Scheme 1) and the di-
astereomeric mixture comprising of 8e10a and 8e10b, which re-
solved on TLC, was carefully chromatographed leading to the
isolation of the diastereomers 8e10a and 8e10b in moderate to
good yields (Table 1). The characteristic feature of the 1H NMR
spectra of 8e10a/b included the appearance of doublet in case of 8
and 9 and multiplet in case of 10, which corresponds to C4-H. The
appearance of signal corresponding to N3-H and absence of reso-
nance corresponding to N1-H are the other features of the
spectrum.
Likewise, when metalated DHPMs, substituted at N-1 position
6dee (R3¼Me) were similarly reacted with chiral auxiliary 7 using
similar set of reaction conditions [n-BuLi (1.1 equiv)/ꢀ78 ꢁC, 7
(1.5 equiv)/ꢀ78 ꢁC], corresponding diastereomers 11e12a/b were
isolated through column chromatography (Table 1). The charac-
teristic features of the 1H NMR spectrum of diastereomers 11e12a/b
included the presence of singlet signals corresponding to C4-H
accompanied by the absence of N3-H resonance. Thus, it has been
observed that in the reaction of N-1 unsubstituted DHPM 6aec
(R3¼H), with chiral auxiliary 7, substitution proceeded at N-1 po-
sition while the N-1 substituted DHPM 6dee (R3¼Me) furnished,
N-3 substituted diastereomers upon reaction with 7. In addition to
the specific NMR characteristics of N-1 (8e10) and N-3 (11e12)
another characteristic feature was the presence of an ABX splitting
pattern of CH2 and CH of the chiral auxiliary. Further, it was also
observed that in case of N-1 substituted DHPMs 6dee, reaction
proceeded smoothly, without formation of any byproducts,
but in case of N-1 unsubstituted DHPMs 6aec, corresponding
N1,N3-disubstituted DHPM were formed, which led to lowering of
been reported for a wide range of aldehydes and/or b-keto esters.
Biginelli reaction has also been catalyzed by a simple chiral sec-
ondary amine and achiral bronsted acid by dual activation route,25
leading to products upto 98% ee. Recently, enantioselective (ee up to
99%) multicomponent Biginelli reactions catalyzed by chiral cata-
lysts in combination with a Bronsted acid26 or organocatalyst27
have been reported. However, in many instances, the reactions
lack practicability owing to high cost of catalysts and/or tedious
preparative routes. Further, availability of characteristic data of
both the enantiomers, which is often required for comparison
purposes has been lacking as the reactions are enantioselective. In
continuation of our interest toward the structural diversification of
DHPMs,28 herein we have developed a reaction to append a readily
available amino acid based chiral auxiliary (CA) at N-1 and N-3 of
DHPMs.
2. Result and discussion
We employed N-acylation reaction29 with an optically pure
amino acid chloride 7 as electrophile to obtain diastereomeric
DHPMs, which subsequent to the removal of the chiral auxiliary
furnished both enantiomers of DHPMs. The chiral amino acid
chloride 7 could be easily prepared in optically pure form using
a reported protocol.30 In order to position the chiral auxiliary at the
two different nitrogen centers of DHPM 6, we chose both, N-1
unsubstituted and N-1 methyl substituted DHPM. Substitution
variation at C-4 position of DHPM by way of choosing bulkier as
well as simple alkyl substituents, has also been undertaken to see
the effect on resolution outcome (Scheme 1).

K. Singh et al. / Tetrahedron 68 (2012) 6169e6176
6171
O
R1
R4
O
R2O
N
S
Me
N
O
H
R3
O
R1
(i) n-BuLi (1.1 equiv)
N
a
-78 oC/N2 atmosphere
CA =
R2O
Me
NH
O
S
O
O
(ii)
N
R3
O
N
O
R1
S
O
H
O
R4
O
7
Cl
R2O
Me
N
R
THF, -78 oC to r.t.
(iii) NH4Cl/-78 oC
6
N
R3
b
8 a/b. R1 = 3,4,5-(OMe)3C6H2, R2 = Et, R3 = CA, R4 = H
9 a/b. R1 = C6H5, R2 = Et, R3 =CA, R4 = H
a. R1 = 3,4,5-(OMe)3C6H2, R2 = Et, R3 = H
b. R1 = C6H5, R2 = Et, R3 = H
10 a/b. R1 = CH3, R2 = Et, R3 = CA, R4 = H
11 a/b. R1 = C6H5, R2 = Et, R3 = Me, R4 = CA
12 a/b. R1 = C6H5, R2 = i-Pr, R3 = Me, R4 = CA
c. R1 = CH3, R2 = Et, R3 = H
d. R1 = C6H5, R2 = Et, R3 = Me
e. R1 = C6H5, R2 = i-Pr, R3 = Me
Scheme 1. Synthesis of diastereomers of 3,4-dihydropyrimidin-2(1H)-ones.
The absolute configuration (S)- and (R)- at the C-4 of enantio-
mers 13e17a and 13e17b, respectively, was assigned in analogy
with the sign of optical rotation of the known (S)- and (R)- enan-
tiopure DHPMs.22,26 The absolute configuration at C-4 of 13, 14, 15,
16, 17aeb were also confirmed by recording CD spectra of the en-
antiomers and comparing them with enantiomers of known ab-
Table 1
Synthesis of diastereomers 8e12 from racemic DHPMs
a 20
Entry R1
R2
R3 R4 Producta Yield (%) ½ ꢂD (CH2Cl2)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
3,4,5-(OMe)3C6H2 C2H5
3,4,5-(OMe)3C6H2 C2H5
CA
CA
CA
CA
CA
CA
H
H
H
H
H
H
8a
8b
9a
9b
10a
10b
40
42
40
38
30
28
52
48
45
44
þ180ꢁ (c¼0.1)
þ60ꢁ (c¼0.1)
þ175ꢁ (c¼0.2)
ꢀ185ꢁ (c¼0.2)
þ15ꢁ (c¼0.2)
þ5ꢁ (c¼0.2)
C6H5
C6H5
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
solute configuration. Fig.
2 shows the CD spectra of both
enantiomers of DHPM 13, 14, 15, 16 and 17. Based on comparison
with reference CD spectra of DHPMs with known absolute config-
uration,19d enantiomers showing a positive cotton effect around
288 and 300 nm were assigned the (S)-configuration and those
with mirror image CD spectrum, were assigned the (R)-configura-
tion at the C-4. This data corroborated well with the optical rotation
data (Table 2).
CH3
C6H5
C6H5
C6H5
C6H5
CH3 CA 11a
CH3 CA 11b
þ205ꢁ (c¼0.2)
ꢀ245ꢁ (c¼0.2)
þ160ꢁ (c¼0.2)
ꢀ250ꢁ (c¼0.2)
CH(CH3)2 CH3 CA 12a
CH(CH3)2 CH3 CA 12b
a
(i) n-BuLi/THF/ꢀ78 ꢁC; (ii) 7/ꢀ78 ꢁC to r.t.; (iii) NH4Cl/ꢀ78 ꢁC.
The enantiomeric purity of enantiomers 13e17a and 13e17b
was determined by chiral HPLC using chiracel ODH column and is
reported in the Supplementary data. The aryl substituted com-
pounds depicted ee upto 99.9% (entry 7, Table 2), however, in case of
C-4 alkyl substituted derivative (entries 5 and 6, Table 2), it was
miserably low.
the isolated yield of 8e10 (Table 1). The specific optical rotation of
all the diastereomers were recorded using dichloromethane as
solvent and are mentioned in Table 1.
The assignment of the absolute configuration at C-4 position of
a series of DHPM derivatives, has been based on the combination of
enantioselective HPLC and circular dichroism (CD) spec-
troscopy,19e,f through correlation with DHPM derivatives of known
configuration.19b,c The correlation of specific optical rotation has
also been used for predicting the configuration at C-4. Since the
chiral auxiliary used in this reaction has (S)-configuration at the
chiral carbon, the diastereomers 8e12a and 8e12b have been
assigned, (S)- and (R)- configuration, respectively, at C-4.
Reductive deacylation of the diastereomers 8e12 was accom-
plished using lithium aluminum hydride (LiAlH4) (Scheme 2). Thus,
treatment of 8e12a/b with LiAlH4 at 0 ꢁC in anhydrous THF under
the atmosphere of dry nitrogen gas furnished corresponding
13e17a/b in good yield. The superimposable spectral data of
compounds having equal and opposite specific optical rotations
(Table 2) confirmed the formation of enantiomers of 13e17. The
plausible mechanism of reduction deacylation is outlined in
Scheme 3. The initially formed 18 might get further reduced to N-
phthalimido protected amino alcohol 19 by action of the excess
LiAlH4 used in the reaction.
3. Conclusion
Thus, diastereomers of inherently racemic DHPMs were re-
solved using chiral auxiliary, which after chromatographic sepa-
ration and removal of chiral auxiliary furnished both enantiomers
of DHPMs. DHPMs bearing both aryl and alkyl groups at C-4 posi-
tion could be resolved using this methodology. Absolute configu-
ration of the enantiomers has also been assigned.
4. Experimental
4.1. General information
All liquid reagents were dried/purified following recommended
drying agents and/or distilled over 4 A molecular sieves. 1H NMR
ꢀ
(300 MHz) and 13C NMR (75 MHz) spectra were recorded in

6172
K. Singh et al. / Tetrahedron 68 (2012) 6169e6176
O
R1
O
R1
O
H
R4
O
R2O
Me
N
R2O
Me
NH
N
LiAlH4 THF
0 oC to r.t.
CA =
O
S
N
R3
N
R3
O
O
Configuration at C-4
Configuration at C-4
13-17a:
13-17b:
(S)-
(R)-
8-12a:
8-12b:
(S)-
(R)-
13a/b. R1 = 3,4,5-(OMe)3C6H2, R2 = Et, R3 = H
14a/b. R1 = Ph, R2 = Et, R3 = H
8a/b. R1 = 3,4,5-(OMe)3C6H2, R2 = Et, R3 = CA, R4 = H
9a/b. R1 = Ph, R2 = Et, R3 =CA, R4 = H
15a/b. R1 = Me, R2 = Et, R3 = H
10a/b. R1 = Me, R2 = Et, R3 = CA, R4 = H
11a/b. R1 = Ph, R2 = Et, R3 = Me, R4 = CA
12a/b. R1 = Ph, R2 = i-Pr, R3 = Me, R4 = CA
16a/b. R1 = Ph, R2 = Et, R3 = Me
17a/b. R1 = Ph, R2 = i-Pr, R3 = Me
Scheme 2. Synthesis of enantiomers of 3,4-dihydropyrimidin-2(1H)-ones.
Institute of Integrative Medicine (CSIR), Jammu, under electron
impact at 70 eV on a Bruker Daltonics Esquire 3000 spectrometer.
Elemental analysis was performed on FLASH EA 112 (Thermo-
electron Corporation) analyzer at the Department of Chemistry,
Guru Nanak Dev University, Amritsar and the results are quoted in
%. IR recorded on FTIR Shimadzu 8400 Fourier-transform spectro-
photometer in the range 400e4000 cmꢀ1 using KBr. The optical
rotation was recorded on Atago (AP-100) digital polarimeter at
25 ꢁC. The CD spectra were recorded on Applied Photophysics
Chirascan Circular Dichrosim Spectrometer. Enantiomeric excess
was determined from chiral HPLC using chiracel ODH column
Table 2
Specific optical rotation and enantiomeric excess of enantiomer 13e17
Entry R1
R2
R3 Producta Yield (%) ½a 2D0
ꢂ
(MeOH) ee (%)b
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
3,4,5-(OMe)3C6H2 C2H5
3,4,5-(OMe)3C6H2 C2H5
H
H
H
H
H
H
13a
13b
14a
14b
15a
15b
90
90
70
70
70
65
80
75
70
65
þ30ꢁ (c¼0.2) 96.2
ꢀ30ꢁ (c¼0.1) 97.4
þ50ꢁ (c¼0.1) 86.8
ꢀ50ꢁ (c¼0.1) 83.5
ꢀ15ꢁ (c¼0.1) 45.7
þ14ꢁ (c¼0.1) 41.7
ꢀ40ꢁ (c¼0.2) 99.9
þ40ꢁ (c¼0.2) 89.7
ꢀ24ꢁ (c¼0.2) 97.0
þ25ꢁ (c¼0.2) 96.0
C6H5
C6H5
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
C6H5
C6H5
C6H5
C6H5
CH3 16a
CH3 16b
CH(CH3)2 CH3 17a
CH(CH3)2 CH3 17b
(4.6 mmꢃ250 mm, particle size 5
mM). Melting points were de-
a
LiAlH4/THF/0 ꢁC to r.t.
termined in open capillaries and are uncorrected. Pre-coated alu-
minum sheets Merck (60F254, 0.2 mm) and silica gel (60e120 mesh)
were employed for TLC and column chromatography, respectively.
b
Enantiomeric excess determined from HPLC using chiracel ODH column
(4.6 mmꢃ250 mm, particle size 5 M).
m
DMSO-d6 and CDCl3 on a multinuclear BrukereJeol FT-AL-300 in-
4.2. Synthesis of diastereomers of DHPMs 6aee
struments with chemical shifts being reported in parts per million
(
d
) relative to internal tetramethylsilane (TMS,
d
0.0, 1H NMR) or
To a suspension of DHPM 6 (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
(CDCl3,
d
77.0, 13C NMR). Mass spectra were recorded from Indian
-
H AlH3
O
O
O
O
R1
O
H
R4
O
N
R2O
Me
N
N
R3 (8-10) or R4 (11-12) =
N
DHPM
O
O
N
R3
DHPM
O
R1
O
O
OH
CHO
H3O+
LiAlH4
R2O
NR4
+
N
N
Me
N
R3
O
O
O
13-15: R3 = H
16-17: R4 = H
18
19
Scheme 3. Plausible mechanism of deacylation of 8e12.

K. Singh et al. / Tetrahedron 68 (2012) 6169e6176
6173
Fig. 2. CD spectra of 13e17.
at ꢀ78 ꢁC, whereupon pale yellow anion was formed. After the
addition, reaction mixture was stirred at ꢀ78 ꢁC for 30 min and
quenched at ꢀ78 ꢁC with enantiopure amino acid chloride 7
(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 ac-
etate (3ꢃ25 ml), treated with brine, washed with water (2ꢃ25 ml),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The diastereomers were separated by column chroma-
tography using silica gel-G (230e400 mesh) and mixtures of ethyl
acetate/hexane as eluent.
d, J 3.9 Hz, exchanged with D2O, N3-H), 5.35 (1H, d, J 3.9 Hz, C4-H),
4.21 (2H, q, J 7.2 Hz, estereCH2), 3.80 (1H, dd, J 6.0 Hz, J 13.8 Hz, CH),
3.79 (3H, s, OCH3), 3.73 (1H, dd, J 2.4 Hz, J 17.4 Hz, CH), 3.69 (6H, s,
2ꢃOCH3), 2.51 (3H, s, C6-CH3), 1.27 (3H, t, J 7.2 Hz, estereCH3); dC
(75 MHz, CDCl3) 172.1, 167.8, 164.6, 153.5, 151.3, 147.0, 137.5, 136.8,
135.3, 134.0, 131.4, 128.7, 128.5, 126.8, 123.3, 115.4, 103.0, 61.2, 60.7,
59.1, 55.9, 54.8, 34.1, 19.6, 14.1; m/z 650 (Mþþ23).
4.2.2. 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 (8b). White solid; [Found: C, 64.78; H,
5.58; N, 6.40. C34H33N3O9 requires C, 65.07; H, 5.26; N, 6.70%]; Rf:
(60% EtOAc/Hexane) 0.6; mp 150 ꢁC (methanol); ½a 2D0
ꢂ
þ60ꢁ (c 0.1,
4.2.1. 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 (8a). White solid; [Found: C, 64.99; H,
5.35; N, 6.35. C34H33N3O9 requires C, 65.07; H, 5.26; N, 6.70%]; Rf:
CH2Cl2); nmax (KBr) 3264, 2937, 1728, 1642, 1462, 1236 cmꢀ1
; dH
(300 MHz, CDCl3) 7.77 (2H, m, ArH), 7.67 (2H, m, ArH), 7.14 (5H, m,
ArH), 6.45 (2H, s, ArH), 6.07 (1H, d, J 3.6 Hz, exchanged with D2O,
N3-H), 5.90 (1H, dd, J 6.0 Hz, J 5.7 Hz, CH), 5.25 (1H, d, J 3.9 Hz, C4-
H), 4.18 (2H, q, J 7.2 Hz, estereCH2), 3.80 (3H, s, OCH3), 3.73 (6H, s,
2ꢃOCH3), 3.41 (1H, dd, J 6.0 Hz, J 5.7 Hz, CH), 3.30 (1H, dd, J 9.6 Hz, J
9.6 Hz, CH), 2.54 (3H, s, C6-CH3), 1.23 (3H, t, J 7.2 Hz, estereCH3); dC
(75 MHz, CDCl3) 171.1, 167.2, 164.8, 153.6, 151.3, 137.5, 136.4, 135.0,
(60% EtOAc/Hexane) 0.7; mp 183 ꢁC (methanol); ½a 2D0
ꢂ
þ180ꢁ (c 0.1,
CH2Cl2); nmax (KBr) 3294, 2938, 1720, 1648, 1464, 1228 cmꢀ1
; dH
(300 MHz, CDCl3) 7.74 (2H, m, ArH), 7.67 (2H, m, ArH), 7.19 (5H, m,
ArH), 6.44 (2H, s, ArH), 6.29 (1H, dd, J 4.5 Hz, J 4.5 Hz, CH), 6.20 (1H,

6174
K. Singh et al. / Tetrahedron 68 (2012) 6169e6176
134.0, 131.6, 129.1, 128.3, 126.8, 123.4, 103.4, 61.1, 60.7, 57.4, 56.0,
1289 cmꢀ1
; dH (300 MHz, CDCl3) 7.76 2H, (m, ArH), 7.64 (2H, m,
54.7, 35.2, 19.0, 14.1; m/z 650 (Mþþ23).
ArH), 7.21 (10H, m, ArH), 6.63 (1H, dd, J 4.5 Hz, J 4.5 Hz, CH), 6.54
(1H, s, C4-H), 4.22 (2H, m, estereCH2), 3.82 (1H, dd, J 11.4 Hz, J
11.4 Hz, CH), 3.31 (1H, d, J 4.2 Hz, CH), 3.27 (3H, s, N1-CH3), 2.56 (3H,
s, C6-CH3),1.27 (3H, t, J 7.2 Hz, estereCH3); dC (75 MHz, CDCl3) 170.7,
168.2, 165.0, 151.9, 148.2, 138.5, 136.7, 133.8, 131.7, 128.8, 128.6,
128.4, 128.0, 126.8, 126.4, 123.3, 109.4, 60.8, 57.0, 53.2, 34.1, 31.4,
16.2, 14.1; m/z 552 (Mþþ1).
4.2.3. 5-Ethoxycarbonyl-6-methyl-4(S)-phenyl-1-[2(S)-(1,3-dioxo-
1, 3 - d i hy d r o - i s o i n d o l - 2 - yl ) - 3 - p h e n yl p r o p i o n yl ] - 3 , 4 -
dihydropyrimidin-2(1H)-one (9a). White solid; [Found: C, 69.10; H,
4.82; N, 7.62. C31H27N3O6 requires C, 69.27; H, 5.03; N, 7.82%]; Rf:
(40% EtOAc/Hexane) 0.5; mp 105 ꢁC (methanol); ½a 2D0
ꢂ
þ175ꢁ (c 0.2,
CH2Cl2); nmax (KBr) 3280, 2960, 1711, 1648, 1375, 1220 cmꢀ1
; dH
(300 MHz, CDCl3) 7.75 (2H, m, ArH), 7.67 (2H, m, ArH), 7.20 (10H,
m, ArH), 6.28 (1H, dd, J 5.4 Hz, J 5.4 Hz, CH), 5.96 (1H, d, J 3.6 Hz,
exchanged with D2O, N3-H), 5.42 (1H, d, J 3.3 Hz, C4-H), 4.17 (2H,
m, estereCH2), 3.75 (2H, dd, J 2.1 Hz, J 7.5 Hz, CH2), 2.50 (3H, s,
C6-CH3), 1.22 (3H, t, J 7.2 Hz, estereCH3); dC (75 MHz, CDCl3)
171.2, 167.6, 153.6, 150.7, 136.9, 134.0, 131.5, 129.1, 128.6, 128.3,
126.8, 126.4, 123.3, 105.7, 60.6, 57.3, 54.8, 34.0, 17.8, 14.1; m/z 560
(Mþþ23).
4.2.8. 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 (11b). White solid; [Found: C, 69.76;
H, 5.34; N, 7.30. C32H29N3O6 requires C, 69.69; H, 5.26; N, 7.62%]; Rf:
(40% EtOAc/Hexane) 0.3; mp 158 ꢁC (methanol); ½a 2D0
ꢂ
ꢀ245ꢁ (c 0.2,
CH2Cl2); nmax (KBr) 3023, 1719, 1647, 1494, 1290 cmꢀ1
; dH (300 MHz,
CDCl3) 7.76 (2H, m, ArH), 7.67 (2H, m, ArH), 7.23 (10H, m, ArH), 6.67
(1H, s, C4-H), 5.98 (1H, dd, J 6.3 Hz, J 6.6 Hz, CH), 4.19 (2H, m,
estereCH2), 3.70 (2H, m, CH2), 3.03 (3H, s, N1-CH3), 2.36 (3H, s, C6-
CH3), 1.24 (3H, t, J 7.2 Hz, estereCH3); dC (75 MHz, CDCl3) 171.3,
167.4, 164.9, 151.5, 148.3, 138.6, 137.0, 133.9, 131.4, 129.2, 128.6,
128.3, 128.0, 126.6, 126.3, 123.3, 109.3, 60.7, 56.8, 52.3, 34.3, 31.1,
15.8, 14.1; m/z 574 (Mþþ23).
4.2.4. 5-Ethoxycarbonyl-6-methyl-4(R)-phenyl-1-[2(S)-(1,3-dioxo-
1, 3 - d i hy d r o - i s o i n d o l - 2 - yl ) - 3 - p h e n yl p r o p i o n yl ] - 3 , 4 -
dihydropyrimidin-2(1H)-one (9b). White solid; [Found: C, 68.92; H,
4.70; N, 7.52. C31H27N3O6 requires C, 69.27; H, 5.03; N, 7.82%]; Rf:
(40% EtOAc/Hexane) 0.3; mp 115 ꢁC (methanol); ½a 2D0
ꢂ
ꢀ185ꢁ (c 0.2,
CH2Cl2); nmax (KBr) 3293, 2981, 1719, 1650, 1382, 1229 cmꢀ1 dH
(300 MHz, CDCl3) 7.76 (2H, m, ArH), 7.66 (2H, m, ArH), 7.27 (10H, m,
ArH), 6.07 (1H, dd, J 4.5 Hz, J 4.5 Hz, CH), 5.92 (1H, d, J 3.4 Hz, ex-
changed with D2O, N3-H), 5.40 (1H, d, J 3.2 Hz, C4-H), 4.15 (2H, q, J
7.2 Hz, estereCH2), 3.57 (2H, m, CH2), 2.55 (3H, s, C6-CH3), 1.22 (3H,
t, J 7.2 Hz, estereCH3); dC (75 MHz, CDCl3) 172.3, 166.9, 152.9, 150.4,
135.9,133.5,131.9,129.6,128.8, 128.2, 127.0,126.5,122.9,105.5, 60.4,
57.3, 54.6, 34.1, 17.7, 14.1; m/z 560 (Mþþ23).
4.2.9. 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 (12a). White solid; [Found: C, 69.95;
H, 5.59; N, 7.11C33H31N3O6 requires C, 70.08; H, 5.48; N, 7.43%]; Rf:
(40% EtOAc/Hexane) 0.5; mp 100 ꢁC (methanol/petroleum ether);
½
a 2D0
ꢂ
þ160ꢁ (c 0.2, CH2Cl2); nmax (KBr) 3473, 2979, 1720, 1639, 1382,
1239 cmꢀ1
; dH (300 MHz, CDCl3) 7.76 (2H, m, ArH), 7.64 (2H, m,
ArH), 7.18 (10H, m, ArH), 6.64 (1H, dd, J 4.2 Hz, J 4.2 Hz, CH), 6.49
(1H, s, C4-H), 5.07 (1H, m, CH), 3.83 (1H, t, J 13.2 Hz, CH), 3.32 (1H, d,
J 4.2 Hz, CH), 3.27 (3H, s, N1-CH3), 2.55 (3H, s, C6-CH3), 1.32 (3H, d, J
6.3 Hz, CH3), 1.16 (3H, d, J 6.3 Hz, CH3); dC (75 MHz, CDCl3) 170.7,
168.2,164.5,151.9,147.8,138.7,136.7, 133.8,131.7, 128.8, 128.5, 128.4,
127.9, 126.7, 126.5, 123.3, 109.9, 68.5, 57.1, 53.4, 34.0, 31.4, 21.9, 21.7,
16.2; m/z 588 (Mþþ23).
4.2.5. 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 (10a). White solid; [Found: C, 65.50; H, 5.10; N, 8.54.
C26H25N3O6 requires C, 65.68; H, 5.26; N, 8.84%]; Rf: (40% EtOAc/
Hexane) 0.4; mp 180 ꢁC (methanol); ½a 2D0
ꢂ
þ15ꢁ (c 0.2, CH2Cl2); nmax
(KBr) 3373, 1703, 1442, 1385, 1240 cmꢀ1 dH (300 MHz, CDCl3) 7.76
(2H, m, ArH), 7.66 (2H, m, ArH), 7.16 (5H, m, ArH), 6.22 (1H, dd, J
4.2 Hz, J 4.5 Hz, CH), 5.72 (1H, d, J 4.2 Hz, exchanged with D2O, N3-
H), 4.35 (1H, m, C4-H), 4.26 (2H, m, estereCH2), 3.76 (2H, m, CH2),
2.43 (3H, s, C6-CH3), 1.31 (3H, t, J 7.2 Hz, estereCH3), 1.24 (3H, d, J
6.6 Hz, C4-CH3); dC (75 MHz, CDCl3) 171.4, 167.9, 164.7, 152.3, 146.8,
137.0, 133.9, 131.6, 128.8, 128.4, 126.7, 123.3, 117.6, 60.9, 58.7, 47.0,
34.0, 22.4, 19.3, 14.1; m/z 498 (Mþþ23).
4.2.10. 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 (12b). White solid; [Found: C, 69.88;
H, 5.31; N, 7.30. C33H31N3O6 requires C, 70.08; H, 5.48; N, 7.43%]; Rf:
(40% EtOAc/Hexane) 0.3; mp 125 ꢁC (methanol/petroleum ether);
½
a 2D0
ꢂ
ꢀ250ꢁ (c 0.2, CH2Cl2); nmax (KBr) 3474, 3025, 1719, 1642, 1384,
1288 cmꢀ1
; dH (300 MHz, CDCl3) 7.76 (2H, m, ArH), 7.67 (2H, m,
ArH), 7.22 (10H, m, ArH), 6.64 (1H, s, C4-H), 6.00 (1H, dd, J 5.4 Hz, J
5.7 Hz, CH), 5.05 (1H, m, CH), 3.70 (2H, dd, J 6.0 Hz, J 9.3 Hz, CH2),
3.05 (s, 3H, N1-CH3), 2.36 (3H, s, C6-CH3), 1.28 (3H, d, J 6.3 Hz, CH3),
1.15 (3H, d, J 6.3 Hz, CH3); dC (75 MHz, CDCl3) 171.4, 167.4, 164.5,
151.6, 147.9, 138.8, 137.1, 133.9, 131.4, 129.1, 128.6, 128.3, 127.9, 126.6,
126.3, 123.3, 109.7, 68.3, 56.9, 52.4, 34.2, 31.1, 21.9, 21.6, 15.8; m/z
588 (Mþþ23).
4.2.6. 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 (10b). White solid; [Found: C, 65.40; H, 5.12; N, 8.60.
C26H25N3O6 requires C, 65.68; H, 5.26; N, 8.84%]; Rf: (40% EtOAc/
Hexane) 0.3; mp 173 ꢁC (methanol); ½a 2D0
ꢂ
þ5ꢁ (c 0.2, CH2Cl2); nmax
(KBr) 3216, 1723, 1647, 1495, 1341, 1241 cmꢀ1 dH (300 MHz, CDCl3)
7.76 (2H, m, ArH), 7.67 (2H, m, ArH), 7.19 (5H, m, ArH), 5.97 (1H, t, J
7.8 Hz, CH), 5.91 (1H, d, J 4.8 Hz, exchanged with D2O, N3-H), 4.31
(1H, m, C4-H), 4.24 (2H, m, estereCH2), 3.49 (2H, d, J 7.8 Hz, CH2),
2.46 (3H, s, C6-CH3), 1.31 (3H, t, J 7.2 Hz, estereCH3), 1.25 (3H, d, J
6.3 Hz, C4-CH3); dC (75 MHz, CDCl3) 170.1, 167.4, 164.8, 152.6, 147.4,
145.9, 136.5, 133.9, 131.6, 129.1, 128.4, 126.8, 123.3, 118.6, 60.9, 57.2,
46.9, 35.0, 22.2, 19.2, 14.2; m/z 498 (Mþþ23).
4.3. Reductive N1/N3-deacylation. Formation of enantiomers
To a solution of DHPM 8e12 (0.83 mmol) in dry THF (50 ml),
LiAlH4 (9.15 mmol) was added slowly at 0 ꢁC. 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
(3ꢃ25 ml), organic extracts were dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The enantiomers were sep-
arated by column chromatography using silica gel-G (60e120
mesh) and mixtures of ethyl acetate/hexane as eluent.
4.2.7. 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 (11a). White solid; [Found: C, 69.57;
H, 4.90; N, 7.47. C32H29N3O6 requires C, 69.69; H, 5.26; N, 7.62%]; Rf:
(40% EtOAc/Hexane) 0.5; mp 98 ꢁC (methanol/petroleum ether);
½
a 2D0
ꢂ
þ205ꢁ (c 0.2, CH2Cl2); nmax (KBr) 3220, 2982, 1625, 1469,

K. Singh et al. / Tetrahedron 68 (2012) 6169e6176
6175
4.3.1. 5-Ethoxycarbonyl-6-methyl-4(S)-(3,4,5-trimethoxyphenyl)-
3,4-dihydropyrimidin-2(1H)-one (13a). Colorless solid; [Found: C,
58.10; H, 5.92; N, 7.74. C17H22N2O6 requires C, 58.28; H, 6.28; N,
8.00%]; Rf: (80% EtOAc/Hexane) 0.2; mp 185e186 ꢁC (dichloro-
(1H, br, exchanged with D2O, N3-H), 4.41 (1H, m, C4-H), 4.18 (2H, m,
estereCH2), 2.28 (3H, s, C6-CH3), 1.28 (3H, t, J 7.2 Hz, estereCH3),
1.26 (3H, d, J 5.1 Hz, C4-CH3); dC (75 MHz, CDCl3 and DMSO-d6)
165.3, 153.5, 146.5, 101.1, 58.8, 46.4, 22.8, 17.5, 13.6; m/z 221
(Mþþ23); enantiomeric excess: 45.7% determined by HPLC (Chir-
methane/hexane); ½a D20
ꢂ
þ30ꢁ (c 0.2, MeOH); nmax (KBr) 3232, 3100,
2934, 1708, 1664, 1589, 1463, 1285 cmꢀ1
;
dH (300 MHz, CDCl3) 7.33
acel OD-H column, hexane/2-propanol 90:10),
l¼254 nm, flow rate
(1H, br, exchanged with D2O, N1-H), 6.53 (2H, s, ArH), 5.48 (1H, br,
exchanged with D2O, N3-H), 5.37 (1H, d, J 2.7 Hz, C4-H), 4.10 (2H, m,
estereCH2), 3.82 (9H, s, 3ꢃOCH3), 2.36 (3H, s, C6-CH3), 1.20 (3H, t, J
7.2 Hz, estereCH3); dC (75 MHz, CDCl3) 165.6, 153.5, 153.3, 146.2,
139.3, 137.7, 103.6, 101.1, 60.7, 60.0, 56.0, 55.7, 18.3, 14.1; m/z 373
(Mþþ23); enantiomeric excess: 96.2% determined by HPLC (Chir-
1.0 mL minꢀ1, tR (major)¼9.7 min, tR (minor)¼10.9 min.
4.3.6. 5-Ethoxycarbonyl-4(R),6-dimethyl-3,4-dihydropyrimidin-
2(1H)-one (15b). Colorless solid; [Found: C, 54.25; H, 6.87; N, 13.85.
C9H14N2O3 requires C, 54.54; H, 7.07; N, 14.14%]; Rf: (60% EtOAc/Hex-
ane) 0.3; mp 180e182 ꢁC (methanol); ½a 2D0
ꢂ
þ14ꢁ (c 0.1, MeOH); nmax
acel OD-H column, hexane/2-propanol 90:10),
l
¼254 nm, flow rate
(KBr) 3339, 2975, 1723, 1628, 1484, 1385, 1235 cmꢀ1
; dH (300 MHz,
1.0 mL minꢀ1, tR (major)¼29.3 min, tR (minor)¼36.2 min.
CDCl3) 8.09 (1H, br, exchanged with D2O, N1-H), 5.70 (1H, br, ex-
changed with D2O, N3-H), 4.43 (1H, m, C4-H), 4.18 (2H, m, estereCH2),
2.28 (3H, s, C6-CH3),1.30 (6H, m, estereCH3 and C4-CH3); dC (75 MHz,
CDCl3 and DMSO-d6) 165.1, 153.5, 146.4, 100.9, 58.7, 13.5, 46.2, 22.7,
17.3; m/z 221 (Mþþ23); enantiomeric excess: 41.7% determined by
4.3.2. 5-Ethoxycarbonyl-6-methyl-4(R)-(3,4,5-trimethoxyphenyl)-
3,4-dihydropyrimidin-2(1H)-one (13b). Colorless solid; [Found: C,
57.92; H, 5.99; N, 7.74. C17H22N2O6 requires C, 58.28; H, 6.28; N,
8.00%]; Rf: (80% EtOAc/Hexane) 0.2; mp 183e184 ꢁC (dichloro-
HPLC (Chiracel OD-H column, hexane/2-propanol 90:10),
l¼254 nm,
methane/hexane); ½a D20
ꢂ
ꢀ30ꢁ (c 0.2, MeOH); nmax (KBr) 3262, 3110,
flow rate 1.0 mL minꢀ1, tR (minor)¼10.1 min, tR (major)¼11.2 min.
2954, 1719, 1668, 1579, 1468, 1282 cmꢀ1
; dH (300 MHz, CDCl3) 7.64
(1H, br, exchanged with D2O, N1-H), 6.53 (2H, s, ArH), 5.58 (1H, br,
exchanged with D2O, N3-H), 5.36 (1H, d, J 2.4 Hz, C4-H), 4.11 (2H, q,
J 7.2 Hz, estereCH2), 3.82 (9H, s, 3ꢃOCH3), 2.35 (3H, s, C6-CH3), 1.20
(3H, t, J 7.2 Hz, estereCH3); dC (75 MHz, CDCl3) 165.6, 153.4, 153.3,
146.1, 139.3, 137.7, 103.6, 101.2, 60.7, 60.0, 56.1, 55.7, 18.5, 14.2; m/z
373 (Mþþ23); enantiomeric excess: 97.4% determined by HPLC
4.3.7. 5-Ethoxycarbonyl-1,6-dimethyl-4(S)-phenyl-3,4-
dihydropyrimidin-2(1H)-one (16a). Colorless solid; [Found: C,
65.39; H, 6.20; N, 9.98. C15H18N2O3 requires C, 65.69; H, 6.57; N,
10.22%]; Rf: (60% EtOAc/Hexane) 0.5; mp 140e142 ꢁC (dichloro-
methane/hexane); ½a D20
ꢂ
ꢀ40ꢁ (c 0.2, MeOH); nmax (KBr) 3230, 1685,
1624,1439,1346,1299 cmꢀ1
; dH (300 MHz, CDCl3) 7.28 (5H, m, ArH),
(Chiracel OD-H column, hexane/2-propanol 90:10),
l¼254 nm, flow
5.58 (1H, br, exchanged with D2O, N3-H), 5.38 (1H, d, J 3.3 Hz, C4-H),
4.10 (2H, q, J 7.2 Hz, estereCH2), 3.23 (3H, s, N1-CH3), 2.51 (3H, s, C6-
CH3),1.18 (3H, t, J 7.2 Hz, estereCH3); dC (75 MHz, CDCl3) 166.0,154.0,
149.2, 143.3, 128.5, 127.5, 126.1, 104.1, 60.0, 53.6, 30.1, 16.4, 14.0; m/z
297 (Mþþ23); enantiomeric excess: 99.9% determined by HPLC
rate 1.0 mL minꢀ1, tR (minor)¼30.0 min, tR (major)¼33.1 min.
4 . 3 . 3 . 5 - E t h o x y c a r b o n yl - 6 - m e t hyl - 4 ( S ) - p h e n yl - 3 , 4 -
dihydropyrimidin-2(1H)-one (14a). Colorless solid; [Found: C,
64.40; H, 6.05; N, 10.35. C14H16N2O3 requires C, 64.61; H, 6.15; N,
10.77%]; Rf: (60% EtOAc/Hexane) 0.4; mp 205e207 ꢁC (methanol);
(Chiracel OD-H column, hexane/2-propanol 90:10),
l
¼209 nm, flow
rate 1.0 mL minꢀ1, tR (minor)¼14.5 min, tR (major)¼16.7 min.
½
a 2D0
ꢂ
þ50ꢁ (c 0.1, MeOH); nmax (KBr) 3243, 3115, 1724, 1701, 1647,
1221, 1091 cmꢀ1
;
dH (300 MHz, CDCl3 and DMSO-d6) 8.65 (1H, br,
4.3.8. 5-Ethoxycarbonyl-1,6-dimethyl-4(R)-phenyl-3,4-
dihydropyrimidin-2(1H)-one (16b). Colorless solid; [Found: C,
65.35; H, 6.35; N, 9.95. C15H18N2O3 requires C, 65.69; H, 6.57; N,
10.22%]; Rf: (60% EtOAc/Hexane) 0.5; mp 133e135 ꢁC (dichloro-
exchanged with D2O, N1-H), 7.27 (5H, m, ArH), 6.47 (1H, br, ex-
changed with D2O, N3-H), 5.36 (1H, d, J 2.7 Hz, C4-H), 4.05 (2H, q, J
7.2 Hz, estereCH2), 2.33 (3H, s, C6-CH3), 1.15 (3H, t, J 7.2 Hz,
estereCH3); dC (75 MHz, CDCl3 and DMSO-d6) 164.4, 151.7, 146.6,
143.6, 127.0, 126.0, 125.3, 98.7, 58.1, 53.4, 16.8, 12.8; m/z 261
(Mþþ1); enantiomeric excess: 86.8% determined by HPLC (Chiracel
methane/hexane); ½a D20
ꢂ
þ40ꢁ (c 0.2, MeOH); nmax (KBr) 3220, 1683,
1621, 1435, 1341, 1298 cmꢀ1
; dH (300 MHz, CDCl3) 7.28 (5H, m, ArH),
5.57 (1H, br, exchanged with D2O, N3-H), 5.38 (1H, d, J 3.3 Hz, C4-H),
4.10 (2H, q, J 7.2 Hz, estereCH2), 3.23 (3H, s, N1-CH3), 2.51 (3H, s, C6-
CH3),1.18 (3H, t, J 7.2 Hz, estereCH3); dC (75 MHz, CDCl3) 166.0,154.0,
149.2, 143.3, 128.5, 127.6, 126.1, 104.1, 60.0, 53.6, 30.1, 16.4, 14.0; m/z
297 (Mþþ23); enantiomeric excess: 89.8% determined by HPLC
OD-H column, hexane/2-propanol 90:10),
l
¼207 nm, flow rate
1.0 mL minꢀ1, tR (minor)¼10.3 min, tR (major)¼11.9 min.
4 . 3 . 4 . 5 - E t h o x y c a r b o n yl - 6 - m e t h yl - 4 ( R ) - p h e nyl - 3 , 4 -
dihydropyrimidin-2(1H)-one (14b). Colorless solid; [Found: C,
64.44; H, 6.09; N, 10.44. C14H16N2O3 requires C, 64.61; H, 6.15; N,
10.77%]; Rf: (60% EtOAc/Hexane) 0.4; mp 212e214 ꢁC (methanol);
(Chiracel OD-H column, hexane/2-propanol 90:10),
l
¼208 nm, flow
rate 1.0 mL minꢀ1, tR (major)¼14.1 min, tR (minor)¼17.4 min.
½
a 2D0
ꢂ
ꢀ50ꢁ (c 0.1, MeOH); nmax (KBr) 3245, 3125, 1734, 1711, 1642,
4.3.9. 5-Isopropoxycarbonyl-1,6-dimethyl-4(S)-phenyl-3,4-
dihydropyrimidin-2(1H)-one (17a). Colorless solid; [Found: C,
66.35; H, 6.75; N, 9.45. C16H20N2O3 requires C, 66.67; H, 6.94; N,
9.72%]; Rf: (80% EtOAc/Hexane) 0.7; mp 120 ꢁC (dichloromethane/
1211 cmꢀ1
; dH (300 MHz, CDCl3 and DMSO-d6) 8.82 (1H, br, ex-
changed with D2O, N1-H), 7.26 (5H, m, ArH), 7.02 (1H, br, ex-
changed with D2O, N3-H), 5.31 (1H, d, J 2.7 Hz, C4-H), 4.04 (2H, q, J
7.2 Hz, estereCH2), 2.32 (3H, s, C6-CH3), 1.16 (3H, t, J 7.2 Hz,
estereCH3); dC (75 MHz, CDCl3 and DMSO-d6) 164.6, 151.9, 146.7,
143.6,127.1,126.1,125.4, 98.9, 58.3, 53.6, 17.0, 13.0; m/z 261 (Mþþ1);
enantiomeric excess: 83.5% determined by HPLC (Chiracel OD-H
hexane); ½a 2D0
ꢂ
ꢀ24ꢁ (c 0.2, MeOH); nmax (KBr) 3220, 3090, 2982,
1686, 1625,1469, 1347,1289 cmꢀ1
; dH (300 MHz, CDCl3) 7.27 (5H, m,
ArH), 5.76 (1H, br, exchanged with D2O, N3-H), 5.37 (1H, d, J 3.0 Hz,
C4-H), 4.97 (1H, m, estereCH), 3.22 (3H, s, N1-CH3), 2.50 (3H, s, C6-
CH3), 1.22 (3H, d, J 6.0 Hz, estereCH3), 1.04 (3H, d, J 6.3 Hz,
estereCH3); dC (75 MHz, CDCl3) 165.5, 154.0, 148.9, 143.4, 128.4,
127.5, 126.2, 104.4, 67.4, 53.7, 30.1, 21.9, 21.5,16.3; m/z 311 (Mþþ23);
enantiomeric excess: 97.0% determined by HPLC (Chiracel OD-H
column, hexane/2-propanol 90:10),
l
¼207 nm, flow rate
1.0 mL minꢀ1, tR (major)¼10.5 min, tR (minor)¼12.3 min.
4.3.5. 5-Ethoxycarbonyl-4(S),6-dimethyl-3,4-dihydropyrimidin-
2(1H)-one (15a). Colorless solid; [Found: C, 54.29; H, 6.83; N, 13.80.
C9H14N2O3 requires C, 54.54; H, 7.07; N, 14.14%]; Rf: (60% EtOAc/
column, hexane/2-propanol 90:10),
l
¼254 nm, flow rate
1.0 mL minꢀ1, tR (minor)¼11.0 min, tR (major)¼13.8 min.
Hexane) 0.3; mp 176e178 ꢁC (methanol); ½a 2D0
ꢂ
ꢀ15ꢁ (c 0.1, MeOH);
nmax (KBr) 3332, 2971, 1713, 1626, 1474, 1380, 1237 cmꢀ1
;
dH
4.3.10. 5-Isopropoxycarbonyl-1,6-dimethyl-4(R)-phenyl-3,4-
(300 MHz, CDCl3) 7.98 (1H, br, exchanged with D2O, N1-H), 5.65
dihydropyrimidin-2(1H)-one (17b). Colorless solid; [Found: C,

6176
K. Singh et al. / Tetrahedron 68 (2012) 6169e6176
A.; Ebel, C.; Gans, P.; Cross, R.; Hackney, D. D.; Wade, R. H.; Kozielski, F. Bio-
chemistry 2003, 42, 338.
66.45; H, 6.57; N, 9.53. C16H20N2O3 requires C, 66.67; H, 6.94; N,
9.72%]; Rf: (80% EtOAc/Hexane) 0.7; mp 123e125 ꢁC (dichloro-
5. Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle, K. E.; Gilbert, K.
F.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.; Ransom, R. W.; Kling, P.; Reiss,
D.; Broten, T. P.; Schorn, T. W.; Chang, R. S. L.; O’Malley, S.; Olah, T. V.; Ellis, J. D.;
Barrish, A.; Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. J. Med. Chem.
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Kramer, T.; Niewoehner, U.; Pleiss, U.; Stoltefuss, J.; Graef, E.; Koletzki, D.;
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Mai, S.; Truneh, A.; Faulkner, D. J. J. Org. Chem. 1995, 60, 1182.
8. Yang, S.-W.; Chan, T.-M.; Pomponi, S. A.; Chen, G.; Wright, A. E.; Patel, M.; Gullo,
V.; Pramanik, B.; Chu, M. J. Antibiot. 2003, 56, 970.
9. Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; Di-Marco, J. D.; Gou-
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Chem. 1995, 38, 119.
methane/hexane); ½a D20
ꢂ
þ25ꢁ (c 0.2, MeOH); nmax (KBr) 3210, 3099,
2972, 1676, 1620, 1455, 1337, 1279 cmꢀ1
; dH (300 MHz, CDCl3) 7.25
(5H, m, ArH), 5.54 (1H, br, exchanged with D2O, N3-H), 5.37 (1H, d, J
3.0 Hz, C4-H), 4.97 (1H, m, estereCH), 3.23 (3H, s, N1-CH3), 2.51
(3H, s, C6-CH3), 1.22 (3H, d, J 6.3 Hz, estereCH3), 1.04 (3H, d, J 6.0 Hz,
estereCH3); dC (75 MHz, CDCl3) 165.5, 153.9, 148.9, 143.4, 128.5,
127.6,126.2,104.5, 67.5, 53.9, 30.1, 21.9, 21.5,16.4; m/z 311 (Mþþ23);
enantiomeric excess: 96.0% determined by HPLC (Chiracel OD-H
column, hexane/2-propanol 90:10),
l
¼254 nm, flow rate
1.0 mL minꢀ1, tR (major)¼10.7 min, tR (minor)¼14.0 min.
Acknowledgements
10. Kolosov, M. A.; Orlov, V. D.; Beloborodov, D. A.; Dotsenko, V. V. Mol. Diversity
2009, 13, 5.
We gratefully acknowledge financial assistance from CSIR, New
Delhi (project 01(2364)/10/EMR-II) and UGC, New Delhi for Special
Assistance Programme (SAP). K.S. thanks Prof. Swapandeep Singh
Chimni, Department of Chemistry for making his HPLC available for
recording of enantiomeric access of the compounds.
11. Gong, L.-Z.; Chen, X.-H.; Xu, X.-Y. Chem.dEur. J. 2007, 13, 8920.
12. Kappe, C. O.; Uray, G.; Roschger, P.; Lindner, W.; Kratky, C.; Keller, W. Tetrahe-
dron 1992, 48, 5473.
13. Dondoni, A.; Massi, A.; Sabbatini, A. Tetrahedron Lett. 2002, 43, 5913.
14. Evans, P. A.; Qin, J.; Robinson, J. E.; Bazin, B. Angew. Chem., Int. Ed. 2007, 46, 7417.
15. Sidler, D. R.; Barta, N.; Li, W.; Hu, E.; Matty, L.; Ikemoto, N.; Campbell, J. S.;
Chartrain, M.; Gbewonyo, K.; Boyd, R.; Corley, E. G.; Ball, R. G.; Larsen, R. D.;
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Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.073.
References and notes
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