Chemical resolution of inherently racemic dihydropyrimidinones via a site selective functionalization of Biginelli compounds with chiral electrophiles: a case study

Article abstract of DOI:10.1016/j.tet.2009.03.060

Lithiation/substitution of 4-aryl-6-methyl-3,4-dihydropyrimidin-2(1H)-one ester derivatives with n-BuLi can be directed selectively at N-3 or C-6 positions, depending upon nature and equivalents of the base used and 'hardness or softness' of the metalated

Full text of DOI:10.1016/j.tet.2009.03.060

Tetrahedron 65 (2009) 4106–4112
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemical resolution of inherently racemic dihydropyrimidinones via a site
selective functionalization of Biginelli compounds with chiral
electrophiles: a case study
*
Kamaljit Singh , Sukhdeep Singh
Organic Synthesis Laboratory, Department of Applied Chemical Sciences & Technology, Guru Nanak Dev University, Amritsar 143 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Lithiation/substitution of 4-aryl-6-methyl-3,4-dihydropyrimidin-2(1H)-one ester derivatives with n-BuLi
can be directed selectively at N-3 or C-6 positions, depending upon nature and equivalents of the base
used and ‘hardness or softness’ of the metalated site/electrophile used. Biginelli dihydropyrimidinone
Received 15 November 2008
Received in revised form 17 March 2009
Accepted 23 March 2009
substrate appended with enantiopure N-protected
after resolution and deprotection yielded both enantiomers of 3,4-dihydropyrimidinones.
Ó 2009 Elsevier Ltd. All rights reserved.
L-phenylalanine amino acid chloride, at N-3 position
Available online 27 March 2009
Keywords:
Biginelli compounds
Lithiation
Enantiopure DHPMs
Calcium channel blockers
Antihypertensive
1. Introduction
The Biginelli reaction, which involves the three-component
cyclocondensation of ureas, -ketoesters, and aldehydes exclu-
b
The Biginelli reaction, known for over 100 years,1 is much sought
after multicomponent reaction for accessing dihydropyrimidinones
(DHPMs). Dihydropyrimidinones are
sively furnishes racemic DHPMs. In recent decades, many efforts
have focused on developing protocols for the preparation of
optically pure Biginelli products. However, only a limited number
of synthetic methods provide access to enantiomerically pure
DHPMs with high optical purity. Such approaches have thus far
relied either on catalytic enantioselective synthetic routes or
through chemical or enzymatic resolution methods and have
recently been reviewed.10
a class of heterocyclic
compounds2 that possess wide ranging biological activities.3 Many
derivatives have been identified as calcium channel modulators 1,4
antihypertensive agents 2–3,5 mitotic kinesin Eg5 inhibitors 4,6 and
melanin concentrating hormone receptor 5 (MCH1-R) antagonists.7
The individual enantiomers of inherently racemic DHPMs exhibit
different pharmacological profiles. For example, only (R)-enantio-
mer of SQ 32547 2 and SQ 32926 3 possesses the desired antihy-
pertensive effect (Fig. 1).4b,5 In some related DHPM analogs, the
individual enantiomers have in fact been demonstrated to have
opposing (antagonist vs agonist) pharmacological activity.4a For
instance the a1A-selective adrenoceptor antagonist L-771,668 6, the
(S)-enantiomer is significantly more active than the (R)-enantio-
mer,6c and recent work on the mitotic kinesin Eg5 inhibitor mon-
astrol 46a,b has shown that the (S)-enantiomer is a more potent
inhibitor of Eg5 activity.8 A similar effect was also observed for Bay
41-4109 7, a non-nucleosidic inhibitor of hepatitis B virus replica-
tion, where the (S)-enantiomer was found to be more active than the
(R)-enantiomer (Fig. 1).9
Initial classical approaches in the synthesis of enantiomerically
pure DHPM derivatives were based on resolution of the DHPM
diastereomers of N-3 menthyl carboxylate5a or (R)-
a-methyl benzyl
amine derivatives.5b Resolution of diastereomeric salts of DHPM
5-carboxylate with chiral amine11 however was of limited success.
A useful preparative scale resolution of diastereomeric N-3 ribo-
furanosyl amide derivative of DHPM led to the resolution of racemic
monastrol.12 In a study aimed at enantioselective total synthesis of
polycyclic marine alkaloid (ꢀ) batzelladine, construction of an
enantiomerically enriched DHPM has been achieved through
regioselective (N-3) sulfonylation with (1S)-(þ) camphorsulfonyl
chloride.13 Biocatalytic pathways employing protease subtilisin
(lipases and esterases were unreactive!), wherein a C-5 methyl
ester could be hydrolyzed selectively via hydrolysis of the
undesired (R)-enantiomer has been reported14 that allowed the
recovery of the desired (S)-enantiomer in 80–90% chemical yield
and high (98%) enantioselectivity, which was further manipulated
* Corresponding author. Tel.: þ91 183 2258853; fax: þ91 183 2258819–20.
E-mail address: kamaljit19in@yahoo.co.in (K. Singh).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.060

K. Singh, S. Singh / Tetrahedron 65 (2009) 4106–4112
4107
NO2
O
NO2
O
CF3
O
O
O
O
N
R
i-PrO
N
NH2
EtO
H3C
N
OCH3
R
i-PrO
H3C
R N
O
F
N
H
O
H3C
N
H
O
N
H
S
1
3
2
Ca2+ Channel blocker
(R)-SQ 32926
(R)-SQ 32547
(antihypertensive agent)
(antihypertensive agent)
OH
H
N
O
H3C
F
N
F
EtO
H3C
NH
S
F
O
N
H
S
N
O
O
O
(CH2)3
4
F
MeO
N
N
H
S
N
(S)-Monastrol
(mitotic kinesin Eg5 inhibitor)
N
H
O
O
F
OMe
S
MeO
N
N
H
6
N
H
O
O
Cl
N
OMe
(S)-L-771,668
(α1A-adrenoceptor antagonist)
MeO
Me
S
N
F
5
N
H
(S)-SNAP-7941
(MCH1 receptor antagonist)
F
7
Bay 41-4109
(Antiviral)
Figure 1. Therapeutically potent enantiomers of DHPMs.
into (S)-L-771,668 6.16 Similarly, a lipase-catalyzed kinetic resolu-
tion strategy has been reported to yield optically pure DHPMs.15,16
Analytical separation of DHPM derivatives has also been ach-
ieved by enantioselective HPLC using a variety of different chiral
stationary phases (CSPs).17 The implementation of ‘designer-CSPs’18
paved way for useful and efficient separation of DHPMs.
metalation–substitution reaction of a DHPM derivative. However,
selective attachment of the chiral auxiliary at C-6 methyl position of
DHPM did not effect diastereomeric separation.
2. Results and discussion
Asymmetric multicomponent reaction using sugar appended
reactants has also been shown to induce chirality at C4 of the DHPM
ring.19 A catalytic enantioselective version of the Biginelli reaction
has been reported20 by Juaristi et al. using CeCl3 and InCl3 as Lewis
acids in the presence of chiral ligands. Moderate enantioselectiv-
ities (up to 40% ee) of DHPMs were obtained by performing the
reaction at low temperature under the conditions of kinetic control.
We have already demonstrated lithiation of Biginelli com-
pounds resulting in regioselective elaboration of key diversity ori-
ented C-626 and N-327 and other positions of the DHPM core,
depending upon the equivalents of the base used and ‘hardness/
softness’ of the electrophiles implemented. Thus whereas C-6 anion
of DHPMs reacted regioselectively with ‘soft’ electrophiles, N-3 site
was substituted with relatively ‘hard’ counterparts. The lithiation–
substitution of Biginelli compounds has also been extended for the
synthesis of bicyclic DHPM analogs,26b which constitute an im-
portant synthetic sequence reminiscent of key structural feature of
certain marine alkaloids such as betzelladine A and crambescin A.28
Utilizing the promising regioselective differentiation of lithiation–
substitution of Biginelli DHPMs, toward a variety of electrophiles
we appended an appropriate, removable, enantiopure chiral aux-
iliary at the ‘soft’ (C-6) and the ‘hard’ (N-3) sites of DHPMs, leading
to the resolution of the diastereomers. The factors affecting stereo-
selection and our efforts to isolate enantiomerically pure DHPMs
have also been described.
The asymmetric Mannich reaction of
b-ketoesters to acylimines
catalyzed by the Cinchona alkaloids as a means of constructing
chiral DHPM heterocycles has been reported.7c,21 Another catalytic
approach to highly enantioselective multicomponent Biginelli
condensation using a recyclable ytterbium triflate with a chiral
hexadentate ligand has been developed (ee up to 99%).22 Versatile
organocatalytic asymmetric reactions using chiral phosphoric
acid,23 5-(pyrrolidin-2-yl) tetrazole derivatives,24 and a trans-4-
hydroxyproline derived secondary amine in combination with
achiral Bronsted acid25 have furnished DHPMs in moderate-to-
good yields and very high (up to 98%) enantioselectivity. These
methods strongly rely on the accessibility of the chiral reagents
and/or catalysts to obtain DHPMs possessing useful levels of
enantioselectivity. Thus access to diastereomerically/enantiomeri-
cally pure DHPM derivatives utilizing the tools of asymmetric
synthesis is of general current interest and a formidable task.
Herein we report a chemical resolution method allowing accessi-
bility to both enantiomers of a DHPM derivative by appending
chiral auxiliary at N-3 position through highly selective
2.1. Incorporation of chiral auxiliary at C-6 position
Chiral sulfoxides have been used in numerous enantioselective
transformations of synthetic and biological interest.29 Many re-
actions can be stereocontrolled using a sulfinyl moiety, which can
at a later stage be removed by reductive methods or
b-elimination,
etc. A barrage of information is available on the synthesis and use of

4108
K. Singh, S. Singh / Tetrahedron 65 (2009) 4106–4112
O
R1
R2O
O
NH
N
H
X
O
R1
S
R2O
NH
Me
10a
O
O
O
R1
S
O
R1
Me
N
H
X
Me
R2O
Me
NH
R2O
LiH2C
NLi
Me
Me
Me
lithium
base
9
Reductive
Desulfurization
8a
N
H
X
N
Li
X
R1
O
R1
O
8
R2O
O
NH
R2O
Me
NH
N
H
X
N
H
X
S
8b
10b
Me
Scheme 1. Strategy for resolution of racemic DHPMs by trick through C-6 position.
chiral sulfoxides.29 Also in certain instances the biological proper-
ties of some natural products are correlated to the absolute con-
figuration at sulfur atom.29a Utilizing our standard conditions26a of
regioselective alkylation of C-6 position of DHPMs, we envisaged
that incorporation of a chiral sulfoxide shall furnish diastereomers
such as 10a and 10b of 8 (Scheme 1), which subsequent to chro-
matographic separation and removal of chiral auxiliary shall pro-
vide access to enantiomers 8a and 8b. The sequence would also
offer an opportunity to probe the effect of remote stereocenter
created at C6-methyl of DHPM 8 on the resolution of diastereomers.
In order to test this hypothesis, DHPM 8 (R1¼Ph, R2¼Et, X¼O)
was treated with 4.0 equiv of freshly prepared LDA in anhydrous
THF at ꢀ10 ꢁC, under a blanket of dry nitrogen gas followed by
stirring at room temperature for 3 h.26 The resultant red colored
anionic solution was subsequently quenched with 3.0 equiv of
optically pure (1R,2S,5R)-(ꢀ)-menthyl (S)-p-toluenesulfinate 930 at
ꢀ10 ꢁC, which upon stirring for 12 h at room temperature furnished
a mixture of three products 10, 11, and 12 along with unreacted
starting DHPM 8 (Scheme 2). Product 12 was identified as adduct of
LDA with 9, thus depriving the anion of 8 to undergo complete
quenching with 9, leading to incomplete reaction. The formation of
12 (10–12% yield) was further corroborated through an alternate
synthesis involving a direct reaction of diisopropylamine with 9
(vide Experimental). In an attempt to improve the reaction and to
avoid the formation of 12, we switched over to the use of n-BuLi
(3.5 equiv) as the base. In this reaction, metalation of 8 followed by
treatment with 9 furnished only 10 and 11, in 40% and 25% yields,
respectively, and the formation of 12 was avoided.
diastereomers was attested from the appearance of duplicated
signals in their 1H and 13C NMR spectra. All attempts to separate the
diastereomers using chromatography and/or fractional crystalliza-
tion failed to yield any significant separation of the diastereomers.
The other product 11 too was a complex mixture of diasteromers
as observed from its NMR data. However, one of the diastereomers
rapidly crystallized out from hot methanol and corroborated the
structure of DHPM 11, bearing two p-tolyl-sulfinyl moieties at C-6
methyl position.31 The formation of 11 could be envisaged through
the second deprotonation of C-6 methylene protons of initially
formed 10, by the unreacted excess base in the reaction, which is
invariably required to drive the reaction to completion. The second
deprotonation of 10 obviously represents a case of favorable for-
mation of sulfur (sulfoxide) stabilized a-carbanion. In order to gain
unequivocal corroboration of its structure, single crystal of 11 was
grown from its solution in 1:1 v/v mixture of methanol and
dichloromethane. The X-ray crystal structure analysis32 confirmed
the incorporation of two p-tolyl-sulfinyl substituents at the C-6
methyl of DHPM 8 (Fig. 2).
Removal of both sulfur stereocenters from 11 with Raney-Ni in
methanol furnished DHPM 8 in 75% yield, which did not exhibit any
specific optical rotation.
In order to develop an alternative route for exclusive synthesis
of 10 and to probe the effect of chiral auxiliary at remote position C-
6 on the diastereoselectivity of the process, a three-component
Biginelli reaction was performed as depicted in Scheme 3. For this,
ethyl (þ)-(R)-4-(p-tolylsulfinyl)-3-oxobutyrate 13 was synthesized
by reacting the dianion of ethylacetoacetate with 9, following
a reported protocol.33 The oxobutyrate 13 was then reacted with
benzaldehyde and urea using the standard three-component Bigi-
nelli protocol employing dysprosium triflate as Lewis acid catalyst
The reaction depicted smooth reactivity of C-6 carbanion with 9
resulting in the formation of diastereomeric mixture of 10 thus
creating a chiral center at C-6 position of DHPM. The formation of
Me
O
O
O
(i) LDA (4.1 equiv)
THF/-10 °C/N2
EtO
Me
EtO
O
NH
Me
EtO
Me
NH
NH
Me
Me
(ii) 9/THF/-10 °C
N
H
O
N
H
O
N
H
O
N
S
O
S
S
S
O
8
Me
O
Me
Me
10
11
12
Scheme 2. Reaction of lithiated DHPM 8 with (1R,2S,5R)-(ꢀ)-menthyl (S)-p-toluenesulfinate 9.

K. Singh, S. Singh / Tetrahedron 65 (2009) 4106–4112
4109
Recently, we have developed a mild and general one-pot protocol
for N-3 acylation of Biginelli DHPMs, which tolerates various sub-
stituents around the DHPM nucleus.27 Employing this strategy,
when the N-3 anion (generated using 1.1 equiv of n-BuLi)27 of 15
was reacted with the enantiopure 9 (Scheme 4), only starting ma-
terials were recovered. We envisaged, choosing a relatively ‘hard’
and bulky electrophile such as optically pure N-protected amino
acid chloride 17, might furnish diastereomeric mixtures of DHPM
derivative 18 (Scheme 4).
Thus the DHPM derivative 15 bearing the substitution pattern of
the potent calcium channel blocker SQ 32926, i.e., a 3-nitrophenyl
group at C4 and i-propyl ester at C-5 position was metalated [n-BuLi
(1.1 equiv)/THF/ꢀ78 ꢁC] and quenched with 1.5 equiv of N-phtha-
loyl
L
-phenylalanine acid chloride35 17a (R3¼benzyl) at ꢀ78 ꢁC
(Scheme 5). The reaction furnished a diastereomeric mixture
comprising of 18a and 18b, which was resolved on TLC [Rf: 0.4 and
0.25 (ethyl acetate/hexane/50:50)]. Careful chromatographic sep-
aration of the mixture resulted in the isolation of the diastereomers
18a (45%) and 18b (42%) yield, respectively.
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) spectro-
scopy,11,17b through correlation with DHPM derivatives of known
configuration.12,15 However, correlation of specific optical rotation
could also be used for predicting the configuration at C-4. Since the
chiral auxiliary used in this reaction has (S)-configuration at one
chiral carbon, the two diastereomers 18a and 18b have been
assigned, (R) and (S) configuration, respectively, at C4. Reductive
deacylation of the diastereomers 18a and 18b could be accom-
plished using lithium aluminum hydride (LiAlH4) (Scheme 5). Thus
treatment of 18a with LiAlH4 at 0 ꢁC in anhydrous THF under the
atmosphere of dry nitrogen gas furnished a single product, 5-iso-
Figure 2. X-ray structure of 11 showing the stereoview of the molecule and the la-
beling scheme used in the structure analysis.
to obtain 10 in 80% yield. Alternatively, the use of protected benz-
aldehyde, as 1,3-oxazinane derivative 14 in simple three-compo-
nent reaction using TFA as acid catalyst also furnished 10 in 75%
yield (Scheme 3).34 Unfortunately, 10 obtained using these routes
showed complete lack of stereoselection of the reaction.
O
O
EtO
propoxycarbonyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-
PhCHO/THF
EtO
O
NH
25
Dy(CF3SO3)3/r.t.
2(1H)-one 19a in 92% yield {[
a]
þ104 (methanol, c 0.5)}. In
O
D
NH2CONH2
N
H
O
analogy with the sign of optical rotation of the known (S)-enan-
tiopure DHPMs,36 the configuration (S) is assigned at C-4 position of
DHPM 19a.
S
or
S
O
O
NH
14
MeCN/TFA/r.t.
Me
Likewise, reductive deacylation of the diastereomer 18b with
LiAlH4 furnished a single product. The spectral data of this com-
pound was exactly similar to that of 19a and it was identified as the
Me
10
13
Scheme 3. An alternative route for synthesis of DHPM 10.
enantiomer: 5-isopropoxycarbonyl-6-methyl-4-(3-nitrophenyl)-
25
Thus appending chiral sulfoxide at C-6 methyl of DHPM 8 did
not allow separation of diastereomers 10 and 11. We reason that the
absence of stereoselection in this reaction could be owing to the
distance of the chiral auxiliary from the C4 stereocenter19a as ob-
served by others during the synthesis of DHPM glycoconjugates
employing three-component Biginelli condensations.
3,4-dihydropyrimidin-2(1H)-one 19b {[
0.4)}. Comparing the specific optical rotation with a known C-4 (R)
DHPM,22 configuration (R) is assigned at C-4 position of 19b.
a
]
ꢀ103 (methanol, c
D
3. Conclusions
Following the C-6 and N-3 metalation approach, enantiopure
chiral auxiliaries could be appended at C-6 and N-3 positions of
DHPMs, leading to the formation of diastereomers, which only in
the latter case, could be expeditiously resolved, chromatographi-
cally to obtain both the enantiomers of medicinally potent DHPM
nucleus. The close proximity of the chiral auxiliary appended at N-3
position was found to be effective for separation of diastereomers,
in comparison to the distant C-6 position. The applicability of this
2.2. Incorporation of chiral auxiliary at N-3 position
If distance of the chiral auxiliary from the stereogenic C-4 center
was any determinant of the stereocontrol of the reaction depicted
in Scheme 3, appending a chiral auxiliary at N-3 position might
result in separation of diastereomers, which subsequent to the
removal of chiral auxiliary may furnish enantiomers of DHPMs.
Me
O
R1
*
O
S
O
R1
*
O
R1
*
O
X
O
O
pro
O
*
N
pro
S
Cl
9
R2O
Me
N
N
R2O
Me
NLi
Me Me
Me
R2O
Me
N
*
R3
R3
*
17
N
H
X
Me
N
H
X
N
H
(Ref. 27)
16
15
18
Scheme 4. Strategy to append chiral auxiliary at closest proximal N-3 position.

4110
K. Singh, S. Singh / Tetrahedron 65 (2009) 4106–4112
NO2
NO2
O
NO2
O
O
O
O
O
O
O
(i) n-BuLi (1.1 equiv)
N
S
S
N
-78 °C/N2 atmosphere
S
i-PrO
Me
NH
i-PrO
Me
N
R
i-PrO
N
O
O
(ii) 17a (1.5 equiv)/TH F
-78 °C to r.t.
N
H
O
N
H
O
Me
N
H
15
18b
18a
LiAlH4/THF
0 °C to r.t.
NO2
NO2
O
O
i-PrO
Me
S
i-PrO
Me
NH
R
NH
O
N
H
O
N
H
19b
19a
Scheme 5. Regioselective N-3 acylation of DHPM 15 and reductive deacylation. Synthesis of enantiomers 19a and 19b.
approach for resolution of diastereomers of a number of DHPM
derivatives is currently in progress.
ꢀ10 ꢁC. Upon addition of the electrophile, the red color was
quenched, indicating the consumption of the carbanion. Reaction
was warmed to room temperature and stirring was continued for
additional 12 h, to complete the reaction (TLC), after which a satu-
rated aqueous solution of NH4Cl was introduced to terminate the
reaction. The reaction was extracted with ethyl acetate (3ꢂ25 ml)
treated in sequence with brine and water. The extracts were dried
over anhydrous Na2SO4 and the mixture concentrated under re-
duced pressure. The products 10 (0.79 g, 40%), 11 (0.67 g, 25%), and
12 (0.14 g, 12%) were isolated by chromatography using silica gel-G
(60–120 mesh) and mixtures of ethyl acetate and hexane as eluent.
For preparing samples for micro-analytical analysis, crystallization
was done using combinations of dry DCM/methanol and DCM/
hexane.
4. Experimental
4.1. General information
Melting points were determined in open capillaries and are
uncorrected. 1H/13C NMR (300/75 MHz; CDCl3þDMSO-d6) spectra
were recorded using commercial deuterated solvents on multinu-
clear spectrometer Jeol FT-AL-300 and Bruker AC 200 instrument
using tetramethylsilane as internal standard. Data are reported as
follows: chemical shifts (multiplicity [singlet (s), doublet (d), dou-
ble doublet (dd) triplet (t), quartet (q), AB quartet (ABq), broad (br),
and multiplet (m)], coupling constant [Hz], integration). The
diastereomeric ratios were determined from the comparison of
intensity ratio of the key signals in 1H NMR spectrum of the com-
pounds. Mass spectra (MS) were recorded on Bruker Daltonics
esquire 3000 spectrometer. Elemental analyses were performed on
FLASH EA 1112 (Thermo Electron Corporation) analyzer at
Department of Chemistry, Guru Nanak Dev University, Amritsar.
Optical rotation was recorded on Atago (AP-100), digital polari-
meter at 25 ꢁC.
Thin layer chromatography (TLC) was performed on Merck
(60F254, 0.2 mm) using an appropriate solvent system. The chro-
matograms were visualized under UV light. Separation of various
products was carried out by column chromatography on silica gel
(60–120 mesh). All solvents and electrophiles were dried with
appropriate reagents before use. 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 (ꢀ10 ꢁC and ꢀ78 ꢁC) was
attained in Dewar flasks using organic solvent–liquid N2 slush.
4.2.1. 5-Ethoxycarbonyl-6-(toluene-4-sulfinylmethyl)-4-phenyl-
3,4-dihydropyrimidin-2(1H)-one (1:1 diastereomeric mixture) (10)
Found: C, 63.35; H, 5.48; N, 6.91; S, 8.13. C21H22N2O4S requires C,
63.31; H, 5.52; N, 7.03; S, 8.04%; Rf (60% ethyl acetate/hexane) 0.24;
mp: 181 ꢁC (acetone). nmax (KBr) 3100, 1730, 1695 cmꢀ1
; dH
(300 MHz, CDCl3) 7.43 (10H, m, ArHþ1H, D2O exchangeable, N1–H),
5.29 (1H, m, C4–Hþ1H, D2O exchangeable, N3–H), 4.52 and 4.36
(2H, ABq, J 14.1 and 13.2 Hz, CH2SO), 4.01 (2H, q, J 7.2 Hz, –OCH2),
2.40 and 2.42 (3H, s, CH3), 1.13 and 1.10 (3H, t, J 7.2 Hz, CH3); dC
(75 MHz, CDCl3) 14.4, 21.9, 56.0, 60.8, 104.6, 124.7, 124.9, 127.0,
127.1, 128.2, 128.5, 129.0, 129.2, 130.3, 139.7, 141.7,142.1, 142.3, 143.6,
152.6, 152.9, 165.4; m/z 398 (Mþ).
4.2.2. 5-Ethoxycarbonyl-6-[bis-(toluene-4-sulfinyl)methyl]-4-
phenyl-3,4-dihydropyrimidin-2(1H)-one (11)
Found: C, 62.88; H, 5.01; N, 5.41; S, 12.05. C28H28N2O5S2 requires
C, 62.68; H, 5.22; N, 5.22; S, 11.94%; Rf (60% ethyl acetate/hexane)
0.6; mp: 183 ꢁC (DCM/methanol). nmax (KBr) 3018, 1703,1681 cmꢀ1
;
dH (300 MHz, CDCl3) 8.51 (1H, br, D2O exchangeable, N1–H), 7.08
(13H, m, ArH), 6.40 (1H, s, CH), 5.03 (1H, br, D2O exchangeable,
N3–H), 4.95 (1H, d, J 2.4 Hz, C4–H), 3.60 (2H q, J 7.2 Hz, –OCH2), 2.42
(3H, s, CH3), 2.37 (3H, s, CH3), 0.90 (3H, t, J 7.2 Hz, CH3); dC (75 MHz,
CDCl3) 13.6, 21.5, 55.4, 60.3, 82.5, 124.6, 125.3, 126.1, 127.9, 128.5,
129.6, 130.1, 141.9, 143.2, 150.2; m/z 536 (Mþ).
4.2. Typical procedure for C6-substitution of DHPMs
with chiral sulfoxide
To a suspension of DHPM 8 (1.3 g, 5 mmol, Scheme 2) in dry THF
(50 ml) under a blanket of dry N2, 2.1 N n-BuLi (8.33 ml, 17.5 mmol)
was added drop-wise at ꢀ10 ꢁC. After the addition, reaction mix-
ture was warmed to room temperature and stirred for additional
3 h until red colored carbanion was generated. To this carbanion,
4.4 g (15 mmol) of (1R,2S,5R)-(ꢀ)-menthyl (S)-p-toluenesulfinate 9,
dissolved in 10 ml dry THF was added drop-wise using cannula at
4.2.3. (þ)-(R)-Methyl benezenesulfinic acid diisopropylamide (12)
Found: C, 65.45; H, 8.71; N, 6.01; S, 13.28. C13H21NOS requires C,
65.27; H, 8.78; N, 5.85; S, 13.38%; Rf (60% ethyl acetate/hexane)
25
0.89; mp: 110 ꢁC (ethyl acetate/hexane). [
a
]
þ92 (c 0.5, CHCl3).
D

K. Singh, S. Singh / Tetrahedron 65 (2009) 4106–4112
4111
nmax (KBr) 3200, 1060 cmꢀ1
3.55 (2H, m, 2ꢂCH), 2.40 (3H, s, CH3), 1.40 (6H, d, J 6.6 Hz, 2ꢂCH3),
1.11 (6H, d, J 6.6 Hz, 2ꢂCH3); dC (75 MHz, CDCl3) 21.1, 23.6, 23.7,
46.3, 126.4, 129.2, 140.2, 141.3; m/z 239 (Mþ).
;
dH (300 MHz, CDCl3) 7.40 (4H, m, ArH),
4.6. Typical procedure for N3-substitution of DHPMs with
enantiopure amino acid chloride
To a suspension of DHPM 15 (1.6 g, 5 mmol, Scheme 5) in 50 ml
dry THF under a blanket of dry N2, 2.1 N n-BuLi (2.62 ml, 5.5 mmol)
was added drop-wise at ꢀ78 ꢁC whereupon pale yellow anion was
formed. After the addition, reaction mixture was stirred at ꢀ78 ꢁC for
30 min and treated at ꢀ78 ꢁC with enantiopure amino acid chloride
17a35 (2.34 g, 7.5 mmol), dissolved in 10 ml dry THF. The reaction
was warmed slowly to room temperature till it was completed (TLC).
A cold saturated aqueous solution of NH4Cl (30 ml) was introduced.
The reaction contents were extracted with ethyl acetate (3ꢂ25 ml),
treated with brine, washed with water (2ꢂ25 ml), dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
diastereomers 18a (1.34 g, 45%) and 18b (1.19 g, 40%) were isolated
by column chromatography using silica gel-G (60–120 mesh) and
mixtures of ethyl acetate/hexane as eluent.
4.3. Alternative preparation of 12
2.1 N n-BuLi (4.7 ml, 10 mmol) was treated with diisopropyl-
amine (1.39 ml, 10 mmol) in 30 ml dry THF at 0 ꢁC and stirred for
30 min to generate LDA. 9 (4.41 g, 15 mmol) dissolved in 10 ml
THF was added to the reaction at ꢀ20 ꢁC, and contents were
warmed to room temperature and stirred for additional 30 min.
The reaction was quenched with saturated aqueous solution of
NH4Cl, brine and extracted with ethyl acetate (3ꢂ25 ml),
followed by evaporation and chromatographic purification
furnished 12 (3.2 g, 89%). The characteristic data of 12 is
provided in Section 4.2.3.
4.6.1. (2S,4S)-5-Isopropoxycarbonyl-6-methyl-3-[2-(1,3-dioxo-1,3-
dihydroisoindol-2-yl)-3-phenylpropionyl]-4-(3-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-one (18a)
4.4. Synthesis of 5-ethoxycarbonyl-6-(toluene-4-sulfinyl-
methyl)-4-phenyl-3,4-dihydropyrimidin-2(1H)-one
(1:1 diastereomeric mixture) 10
Found: C, 64.35; H, 4.71; N, 9.69. C32H28N4O8 requires C, 64.42;
H, 4.69; N, 9.39%; Rf (50% ethyl acetate/hexane) 0.4; mp: 119 ꢁC
25
(DCM/hexane). [
a
]
þ186 (c 0.5, CHCl3). nmax (KBr) 3300, 2920,
D
4.4.1. Method A
1770,1720,1640,1535,1380 cmꢀ1
; dH (300 MHz, CDCl3) 7.70 (1H, br,
A mixture of ethyl(þ)-(R)-4-(p-tolylsulfinyl)-3-oxobutyrate 13
(0.268 g, 1 mmol), benzaldehyde (0.106 g, 1 mmol), and catalytic
amount of Dy(CF3SO3)3 (0.005 g) was stirred in 30 ml THF at room
temperature for 2 h, followed by addition of urea (0.09 g, 1.5 mmol)
and stirring was continued for 10 h at room temperature. The
solvent was evaporated and crude reaction was chromatographed
to obtain 10 (0.32 g, 80%).
D2O exchangeable, N1–H), 7.67 (13H, m, ArH), 6.55 (1H, dd, J
11.4 Hz, J 4.2 Hz, CH), 6.47 (1H, s, C4–H), 5.05 (1H, m, CH), 3.85 (1H,
dd, J 13.5 Hz, J 12.0 Hz, CH), 3.38 (1H, dd, J 13.5 Hz, J 3.9 Hz, CH), 2.48
(3H, s, C6–Me), 1.17 (3H, d, J 6.0 Hz, CH3), 1.33 (3H, d, J 6.0 Hz, CH3);
dC (75 MHz, CDCl3) 18.0, 21.7, 21.9, 34.0, 55.6, 57.2, 68.8,105.3, 122.4,
123.2, 123.3, 128.5, 128.6, 129.6, 131.5, 133.2, 134.0, 136.3, 141.8,
150.9, 163.6, 168.0, 170.7, 179.3; m/z 596 (Mþ).
4.4.2. Method B
4.6.2. (2S,4R)-5-Isopropoxycarbonyl-6-methyl-3-[2-(1,3-dioxo-1,3-
dihydroisoindol-2-yl)-3-phenylpropionyl]-4-(3-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-one (18b)
A mixture of ethyl(þ)-(R)-4-(p-tolylsulfinyl)-3-oxobutyrate 13
(0.268 g, 1 mmol), 1,3-oxazinane 1434 (0.163 g, 1 mmol), urea
(0.09 g, 1.5 mmol), and catalytic amount of TFA (0.5 ml) was stirred
in acetonitrile 50 ml at 35 ꢁC for 12 h. The reaction contents were
washed with aqueous NaHCO3 solution and organic phase was
extracted with ethyl acetate (3ꢂ25 ml) and washed with water
(1ꢂ25 ml). The organic extracts were dried with sodium sulfate and
solvent was evaporated to yield crude product, which upon
chromatographic purification furnished 10 (0.29 g, 75%). The
characteristic data of 10 is provided in Section 4.2.1.
Found: C, 64.30; H, 4.52; N, 9.24. C32H28N4O8 requires C, 64.42;
H, 4.69; N, 9.39%; Rf (50% ethyl acetate/hexane) 0.25; mp: 98 ꢁC
25
(DCM/hexane). [
a
]
ꢀ276 (c 0.5, CHCl3). nmax (KBr) 3300, 2928,
D
1765, 1720, 1640, 1535, 1390 cmꢀ1
; dH (300 MHz, CDCl3) 7.67 (13H,
m, ArH), 7.43 (1H, br, D2O exchangeable, NH), 6.56 (1H, s, C4–H),
6.06 (1H, m, CH), 5.04 (1H, m, CH), 3.57 (2H, m, CH2), 2.30 (3H, s,
C6–CH3), 1.30 (3H, d, J 6.0 Hz, CH3), 1.15 (3H, d, J 6.0 Hz, CH3); dC
(75 MHz, CDCl3) 17.7, 21.7, 21.9, 34.1, 54.9, 57.0, 68.6, 104.9, 122.0,
123.2, 123.4, 126.8, 128.3, 129.0, 129.7, 131.3, 133.2, 134.2, 136.5,
142.0, 145.3, 148.3, 150.6, 163.7, 167.5, 171.5; m/z 596 (Mþ).
4.5. Reductive desulfurization
To a solution of compound 11 (1.6 g, 3 mmol) in methanol
(50 ml) was added excess of Raney-Ni (5 g) at room temperature.
The reaction was shifted to 60 ꢁC and stirred for 1 h under nitrogen
atmosphere. After completion (TLC) reaction was filtered through
a bed of Celite and the solvent was removed under reduced pres-
sure. The crude product was purified by column chromatography to
furnish 8 (0.59 g, 75%) as white crystalline solid.
4.7. Reductive deacylation
To a solution of DHPM 18a (0.5 g, 0.83 mmol) in dry THF (50 ml),
LiAlH4 (0.76 g, 20 mmol) was added slowly at 0 ꢁC. The reaction
contents were warmed to room temperature and stirred till com-
pletion (TLC). The cold saturated aqueous solution of sodium po-
tassium tartrate was introduced to terminate the reaction followed
by treatment with brine. The extraction was done with ethyl ace-
tate (3ꢂ25 ml), organic extracts were dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Column chromato-
graphic separation of the residue using silica gel-G (60–120 mesh)
and mixtures of ethyl acetate/hexane as eluent furnished enantio-
mer 19a (0.24 g, 92%). Following the similar procedure, reductive
deacylation of 18b (0.5 g, 0.83 mmol) furnished 19b (0.237 g, 90%).
4.5.1. 5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-one (8)
Found: C, 64.64; H, 6.25; N, 10.92. C14H16N2O3 requires C, 64.61;
H, 6.15; N, 10.76%; Rf (50% ethyl acetate/hexane) 0.6; mp: 210 ꢁC
(methanol). nmax (KBr) 3300, 1730, 1700 cmꢀ1
; dH (300 MHz,
CDCl3þDMSO-d6) 8.44 (1H, br, D2O exchangeable, N1–H), 7.29 (5H,
m, ArH), 6.41 (1H, br, D2O exchangeable, N3–H), 5.34 (1H, d, J
3.0 Hz, C4–H), 4.04 (2H, q, J 7.1 Hz, –OCH2), 2.33 (3H, s, C6–CH3),
1.15 (3H, t, J 7.1 Hz, CH3); dC (75 MHz, CDCl3þDMSO-d6) 13.8, 18.1,
55.0, 59.4, 100.3, 126.3, 127.2, 128.1, 144.0, 146.9, 152.6, 165.5; m/z
260 (Mþ).
4.7.1. (4S)-5-Isopropoxycarbonyl-6-methyl-4-(3-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-one (19a)
Found: C, 56.30; H, 5.52; N, 13.23. C15H17N3O5 requires C, 56.42;
H, 5.32; N, 13.16%; Rf (65% ethyl acetate/hexane) 0.5; mp: 187 ꢁC

4112
K. Singh, S. Singh / Tetrahedron 65 (2009) 4106–4112
7. (a) Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M. R.; DeLeon, J.;
25
(methanol). [
a
]
þ104 (c 0.5, methanol). nmax (KBr) 3250, 3100,
D
Heurich, R.; Lichtblau, H.; Shaposhnik, Z.; Daniewska, I.; Blackburn, T. P.;
Branchek, T. A.; Gerald, C.; Vaysse, P. J.; Forray, C. Nat. Med. 2002, 8, 825–830;
(b) Basso, A. M.; Bratcher, N. A.; Gallagher, K. B.; Cowart, M. D.; Zhao, C.; Sun, M.;
Esbenshade, T. A.; Brune, M. E.; Fox, G. B.; Schmidt, M.; Collins, C. A.; Souers, A.
J.; Iyengar, R.; Vasudevan, A.; Kym, P. R.; Hancock, A. A.; Rueter, L. E. Eur. J.
Pharmacol. 2006, 540, 115–120; (c) Goss, J. M.; Schaus, S. E. J. Org. Chem. 2008,
73, 7651–7656.
8. (a) Maliga, Z.; Kapoor, T. M.; Mitchison, T. J. Chem. Biol. 2002, 9, 989–996;
(b) DeBonis, S.; Simorre, J. P.; Crevel, I.; Lebeau, L.; Skoufias, D. A.; Blangy, A.;
Ebel, C.; Gans, P.; Cross, R.; Hackney, D. D.; Wade, R. H.; Kozielski, F. Biochemistry
2003, 42, 338–349.
2950, 1690, 1630, 1535, 1350 cmꢀ1
; dH (300 MHz, CDCl3) 8.10 (1H,
br, D2O exchangeable, N1–H), 7.84 (4H, m, ArH), 6.10 (1H, br, D2O
exchangeable, N3–H), 5.51 (1H, s, C4–H), 4.96 (1H, m, CH), 2.37 (3H,
s, C6–CH3), 1.23 (3H, d, J 6.3 Hz, CH3), 1.06 (3H, d, J 6.3 Hz, CH3); dC
(75 MHz, CDCl3) 18.7, 21.6, 21.9, 23.9, 55.1, 67.8, 100.7, 121.8, 122.9,
129.8, 132.7, 145.8, 147.0, 148.2, 153.1, 182.6; m/z 319 (Mþ).
4.7.2. (4R)-5-Isopropoxycarbonyl-6-methyl-4-(3-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-one (19b)
Found: C, 56.32; H, 5.47; N, 13.31. C15H17N3O5 requires C, 56.42;
H, 5.32; N, 13.16%; Rf (65% ethyl acetate/hexane) 0.5; mp: 187 ꢁC
9. Deres, K.; Schroeder, C. H.; Paessens, A.; Goldmann, S.; Hacker, H. J.; Weber, O.;
Kramer, T.; Niewoehner, U.; Pleiss, U.; Stoltefuss, J.; Graef, E.; Koletzki, D.;
Masantschek, R. N. A.; Reimann, A.; Jaeger, R.; Grob, R.; Beckermann, B.;
Schlemmer, K.-H.; Haebich, D.; Ruebsamen-Waigmann, H. Science 2003, 299,
893–896.
10. Gong, L.-Z.; Chen, X.-H.; Xu, X.-Y. Chem.dEur. J. 2007, 13, 8920–8926.
11. Kappe, C. O.; Uray, G.; Roschger, P.; Lindner, W.; Kratky, C.; Keller, W. Tetrahe-
dron 1992, 48, 5473–5480.
25
(methanol). [
a
]
ꢀ103 (c 0.4, methanol). nmax (KBr) 3245, 3100,
D
2950, 1690, 1630, 1530, 1350 cmꢀ1
; dH (300 MHz, CDCl3) 8.08 (1H,
br, D2O exchangeable, N1–H), 7.84 (4H, m, ArH), 6.10 (1H, br, D2O
exchangeable, N3–H), 5.51 (1H, d, J 2.7 Hz, C4–H), 4.96 (1H, m, CH),
2.37 (3H, s, C6–CH3), 1.23 (3H, d, J 6.3 Hz, CH3), 1.06 (3H, d, J 6.3 Hz,
CH3); dC (75 MHz, CDCl3) 18.7, 21.6, 22.0, 23.9, 55.1, 67.9,100.7,121.8,
122.9, 129.8, 132.7, 145.8, 147.0, 148.2, 153.1, 182.6; m/z 319 (Mþ).
12. Dondoni, A.; Massi, A.; Sabbatini, A. Tetrahedron Lett. 2002, 43, 5913–5916.
13. Evans, P. A.; Qin, J.; Robinson, J. E.; Bazin, B. Angew. Chem., Int. Ed. 2007, 46,
7417–7419.
14. 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.;
Reider, P. J. Can. J. Chem. 2002, 80, 646–652.
15. Schnell, B.; Krenn, W.; Faber, K.; Kappe, C. O. J. Chem. Soc., Perkin Trans. 1 2000,
4382–4389.
Acknowledgements
16. Schnell, B.; Strauss, U. T.; Verdino, P.; Faber, K.; Kappe, C. O. Tetrahedron:
Asymmetry 2000, 11, 1449–1453.
The authors thank Dr. K.A. Suri, Deputy Director, Indian Institute
of Integrated Medicine (formerly Regional Research Laboratory),
Jammu for his help for getting mass spectral data. Financial support
of CSIR (01(1960)/04/EMR-II) and UGC (31-53/2005/SR), New Delhi
is gratefully acknowledged.
17. (a) Kleidernigg, O. P.; Kappe, C. O. Tetrahedron: Asymmetry 1997, 8, 2057–2067;
(b) Krenn, W.; Verdino, P.; Uray, G.; Faber, K.; Kappe, C. O. Chirality 1999, 11,
659–662; (c) Kontrec, D.; Vinkovic, V.; Sunjic, V.; Schuiki, B.; Fabian, W. M. F.;
Kappe, C. O. Chirality 2003, 15, 550–557; (d) Wang, F.; O’Brian, T.; Dowling, T.;
Bicker, G.; Wyvratt, J. J. Chromatogr., A 2002, 958, 69–77; (e) Wang, F.; Wenslow,
R. M.; Dowling, T. M.; Mueller, K. T.; Santos, I.; Wyvratt, J. Anal. Chem. 2003, 75,
5877–5885; (f) Yarim, M.; Sarac, S. Chromatographia 2002, 56, 307–312;
(g) Forjan, D. M.; Gazic, I.; Vinkovic, V. Chirality 2007, 19, 446–452.
18. (a) Lewandowski, K.; Murer, P.; Svec, F.; Frechet, J. M. J. Chem. Commun. 1998,
2237–2238; (b) Lewandowski, K.; Murer, P.; Svec, F.; Frechet, J. M. J. J. Comb.
Chem. 1999, 1, 105–112.
References and notes
1. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–416.
19. (a) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006, 39, 451–463; (b) Dondoni, A.;
Massi, A.; Sabbatini, A.; Bertolasi, V. J. Org. Chem. 2002, 67, 6979–6994.
20. Muniz, O. M.; Juaristi, E. Arkivoc 2003, xi, 16–26.
21. (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127,
11256–11257; (b) Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72,
9998–10008.
22. Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386–16387.
23. Chen, X. H.; Xu, X. Y.; Liu, H.; Cun, L. F.; Gong, L. Z. J. Am. Chem. Soc. 2006, 128,
14802–14803.
24. Wu, Y.-Y.; Chai, Z.; Liu, X.-Y.; Zhao, G.; Wang, S.-W. Eur. J. Org. Chem. 2009,
904–911.
25. Xin, J.; Chang, L.; Hou, Z.; Shang, D.; Liu, X.; Feng, X. Chem.dEur. J. 2008, 14,
3177–3181.
26. (a) Singh, K.; Singh, S.; Mahajan, A. J. Org. Chem. 2005, 70, 6114–6117; (b) Singh,
K.; Singh, S. Tetrahedron 2008, 64, 11718–11723.
27. Singh, K.; Singh, S. Tetrahedron Lett. 2006, 47, 8143–8146.
28. Hey, L.; Moore, C. G.; Murphy, P. J. Chem. Soc. Rev. 2000, 29, 57–67.
29. (a) Carreno, M. C. Chem. Rev. 1995, 95, 1717–1760; (b) Pellissier, H. Tetrahedron
2006, 62, 5559–5601.
2. (a) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879–888; (b) Kappe, C. O. Eur. J. Med.
Chem. 2000, 35, 1043–1058.
3. (a) Bristol-Myers Squibb Co. Expert Opin. Ther. Patents 1999, 9, 321–325;
(b) Nagarathnam, D.; Miao, S. W.; Lagu, B.; Chiu, G.; Fang, J.; Murali Dhar, T. G.;
Zhang, J.; Tyagarajan, S.; Marzabadi, M. R.; Zhang, F.; Wong, W. C.; Sun, W.;
Tian, D.; Wetzel, J. M.; Forray, C.; Chang, R. S. L.; Broten, T. P.; Ransom, R. W.;
Schorn, T. W.; Chen, T. B.; O’Malley, S.; Kling, P.; Schneck, K.; Bendesky, R.;
Harrell, C. M.; Vyas, K. P.; Gluchowski, C. J. Med. Chem. 1999, 42, 4764–4777;
(c) Fewell, S. W.; Smith, C. M.; Lyon, M. A.; Dumitrescu, T. P.; Wipf, P.; Day, B.
W.; Brodsky, J. L. J. Biol. Chem. 2004, 279, 51131–51140; (d) Finch, H.; Edwards,
C.; Ray, N. C.; Fitzgerald, M. F. PCT Int. Appl. WO 2006136857 A1, 2006;
(e) Wright, C. M.; Chovatiya, R. J.; Jameson, N. E.; Turner, D. M.; Zhu, G.;
Werner, S.; Huryn, D. M.; Pipas, J. M.; Day, B. W.; Wipf, P.; Brodsky, J. L. Bioorg.
Med. Chem. 2008, 16, 3291–3301.
4. (a) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; DiMarco, J. D.;
Gougoutas, J.; Hedberg, A.; Malley, M.; McCarthy, J. P.; Zhang, R.; Moreland, S. J.
Med. Chem. 1995, 38, 119–129; (b) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.;
Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley,
M. F. J. Med. Chem. 1992, 35, 3254–3263; (c) Grover, G. J.; Dzwonczyk, S.;
McMullen, D. M.; Normandin, D. E.; Parham, C. S.; Sleph, P. G.; Moreland, S. J.
Cardiovasc. Pharmacol. 1995, 26, 289–294; (d) Singh, K.; Arora, D.; Singh, K.;
Singh, S. Mini-Rev. Med. Chem. 2009, 9, 95–106.
5. (a) Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.;
Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K. M.; Malley, M. F. J. Med.
Chem. 1990, 33, 2629–2635; (b) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd,
D. M.; Moreland, S.; Hedberg, A.; O’Reilly, B. C. J. Med. Chem. 1991, 34, 806–811.
6. (a) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.;
Mitchison, T. J. Science 1999, 286, 971–974; (b) Haggarty, S. J.; Mayer, T. U.;
Miyamoto, D. T.; Fathi, R.; King, R. W.; Mitchison, T. J.; Schreiber, S. L. Chem. Biol.
2000, 7, 275–286; (c) 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.
S.; Olah, T. V.; Ellis, J. D.; Barrish, A.; Kassahun, K.; Leppert, P.; Nagarathnam, D.;
Forray, C. J. Med. Chem. 2000, 43, 2703–2718.
30. Solladie, G.; Hatt, J.; Girardin, A. Synthesis 1987, 173.
31. When 1H NMR spectrum was recorded in the presence of a chiral shift reagent
europium tris[3-heptafluoropropylhydroxymethylene)-(þ)camphorate] (Eu(hfc)3),
a distinct separation of the ester signal upon increasing the equivalent of (Eu(hfc)3)
indicated the presence of the diastereomeric mixture.
32. Crystallographic data for 11 have been deposited with the Cambridge Crys-
tallographic Data Centre (CCDC). The coordinates can be obtained on request
from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. The CCDC
number is 269204.
33. Schneider, F.; Simon, R. Synthesis 1986, 582–584.
34. Singh, K.; Singh, J.; Deb, P. K.; Singh, H. Tetrahedron 1999, 55, 12873–12880.
35. Sheehan, J. C.; Shapman, D. W.; Roth, R. W. J. Am. Chem. Soc. 1952, 74,
3822–3825.
36. Cavazzini, A.; Massi, A.; Bergamachi, G.; Braga, S.; Dondi, F.; Dondoni, A.
Biotechnol. Prog. 2004, 20, 603–612.