Asymmetric induction by (S)-4-isopropyl-1-phenylimidazolidin-2-thione in titanium-mediated aldol reactions and its application in enantioselective synthesis of (R)-baclofen

Article abstract of DOI:10.1055/s-0030-1260187

The usefulness of (S)-4-isopropyl-1-phenylimidazolidin-2-thione as a chiral auxiliary in stereoselective propionate and acetate aldol reactions is discussed. Further, the enantioselective synthesis of (R)-baclofen by acetate aldol reaction using the chiral auxiliary was demonstrated. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260187

PAPER
3123
Asymmetric Induction by (S)-4-Isopropyl-1-phenylimidazolidin-2-thione in
Titanium-Mediated Aldol Reactions and Its Application in Enantioselective
Synthesis of (R)-Baclofen
(S
)-4-Isopropyl-1-
o
phenylimidaz
p
olidin-2-thio
a
ne as Chir
a
l
l
A
uxiliary L. Khatik, Ravi Khurana, Varun Kumar, Vipin A. Nair*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160062, India
Fax +91(172)2214692; E-mail: vn74nr@yahoo.com; E-mail: vnair@niper.ac.in
Received 25 May 2011; revised 14 July 2011
states were hypothesized for the reactions where the bulk
Abstract: The usefulness of (S)-4-isopropyl-1-phenylimidazolidin-
of the Lewis acid was thought to have a significant bear-
2-thione as a chiral auxiliary in stereoselective propionate and ace-
ing on the outcome. Fujita and Nagao had successfully
tate aldol reactions is discussed. Further, the enantioselective syn-
employed 4-alkylthiazolidinethione as a chiral auxiliary
in aldol type reactions of a,b-unsaturated aldehydes, using
tin(II) triflate as the Lewis acid.7a A chiral synthesis of
(+)-Prelog–Djerassi lactonic acid methyl ester had been
illustrated by chiral induction using thiazolidinethione.7b
Lithium and titanium(IV) enolates of conformationally
rigid camphor-derived N-propionyloxazolidinones exhib-
ited syn-selective aldol condensation.8 The diastereofacial
selectivity is attributed to intramolecular chelation be-
tween the oxazolidinone carbonyl oxygen and the metal in
the transition state, which induces p-facial differentiation
of the enolate. Significant improvement in aldol reaction
to obtain either Evans or non-Evans syn-aldol in high dia-
steromeric purity was illustrated by changing the stoichi-
ometry of the Lewis acid and the nature of the amine base
in the reactions of titanium enolates of N-acyloxazolidi-
nethiones and thiazolidinethiones.9,10a,b It has been pro-
posed that the reactions proceed through a highly ordered
and rigid transition state due to the higher affinity of tita-
nium for sulfur. Though expensive, the use of (–)-
sparteine with TiCl4 afforded higher selectivities, while
the mechanistic details are unclear.10 The (thio)oxazolidi-
nethione auxiliaries are easily cleavable, facilitating the
transformation of the aldol adducts to various functional
groups.10d
thesis of (R)-baclofen by acetate aldol reaction using the chiral
auxiliary was demonstrated.
Key words: titanium, aldol reaction, asymmetric synthesis, chiral
auxiliaries, stereoselectivity
The stereoselectivity in kinetically controlled aldol reac-
tion is defined by enolate geometry where new stereo-
centers are created. For sterically demanding Z- and E-
lithium enolates a high level of diasteroselection have
been reported, forming the erythro and threo aldol ad-
ducts, respectively.1 The reactions are assumed to proceed
through pericyclic transition states and greater stereo-
chemical control has been achieved by increasing the
pseudo 1,3-diaxial interaction between the aldehyde sub-
stituent and the metal ligands. Using boron enolates, it
was demonstrated that minimizing the metal–oxygen and
metal–ligand bond lengths and maximizing the bulk of the
ligand results in a high degree of diastereoselection.2
Masamune had successfully employed the strategy of
chiral boron enolates to obtain enantiopure aldol adducts
for the synthesis of the biosynthetic precursor 6-deoxy-
erythronolide,3a while Evans and co-workers demonstrat-
ed the usefulness of oxazolidinone and (1S,2R)-
norephidrine as chiral auxiliaries in erythro selective aldol
condensations.3b Unfortunately the high level of asym-
metric induction observed with N-propionyloxazolidinone
was not reflected in the case of N-acetyloxazolidinone.
Titanium enolates are also known to afford stereoselectiv-
ity comparable to that of the boron enolates.4 It has been
exemplified that the stereoselectivity in titanium-mediat-
ed aldol reactions is dependent on the amine base. The ti-
tanium-mediated aldol reaction remains appealing to the
synthetic chemists on account of the advantages like low
cost, low toxicity, and ease of handling.5 Heathcock had
examined the scope of Evans asymmetric aldol reaction
for anti- and non-Evans syn-aldols in Lewis acid mediated
reactions of boron enolates, providing access to either of
the desired product diastereoselectively.6 Open transition
The aldol reactions of boron enolates of N-propionyl-2-
imidazolidinones, synthesized from L-valinol and L-phe-
nylalaninol, with aldehydes afforded high diastereoselec-
tivity.11 The utility of these auxiliaries were also explored
for stereoselective alkylation reactions, and Diels–Alder
reactions.12 The acetate aldol reaction of valine-derived
oxazolidinethione auxiliary is known to occur in high dia-
stereoselectivity with aliphatic aldehydes. Titanium(IV)
chloride, along with (–)-sparteine and N-methylpyrrolidi-
none, was used for enolization.13 A highly diastereoselec-
tive acetate aldol reaction that employed a tert-leucine-
derived thiazolidinethione auxiliary and dichlorophenyl-
borane has also been reported.14 N-Acetylthiazolidine-
thione undergoes highly diastereoselective aldol reactions
upon enolization with dichlorophenylborane and (–)-
sparteine and subsequent treatment with a variety of alde-
hydes.15 Acetate aldol additions using chlorotitanium eno-
lates of mesityl-substituted N-acetyloxazolidinethione
SYNTHESIS 2011, No. 19, pp 3123–3132
x
x.
x
x
.
2
0
1
1
Advanced online publication: 24.08.2011
DOI: 10.1055/s-0030-1260187; Art ID: Z54411SS
© Georg Thieme Verlag Stuttgart · New York

3124
G. L. Khatik et al.
PAPER
and N-acetylthiazolidin-2-thione auxiliaries also proceed
in high yields and diastereoselectivities for aliphatic,
aromatic, and a,b-unsaturated aldehydes.16 A highly
diastereoselective anti-aldol reaction with chiral acylox-
azolidinone promoted by catalytic amount of MgCl2 in the
presence of triethylamine and chlorotrimethylsilane was
reported.17 Computational investigations on the aldol re-
actions of the chiral titanium enolates derived from Evans
propionyloxazolidinone and its variants, oxazolidine-
thione and thiazolidinethione led to the identification of a
nonchelated transition state pathway for the Evans syn-
aldol and a chelated transition state pathway for the non-
Evans syn-aldol.18 With the support of the exhaustive lit-
erature available on aldol reactions,19 it was intriguing to
explore the stereoselectivity in aldol reactions attainable
with the N-propionyl- and N-acetylimidiazolidine-2-
thiones, which remains uninvestigated. These systems
would have the advantages of the previously discussed
auxiliaries incorporated into one template. A UV absor-
bance (lmax) of 310 nm will facilitate chromatographic
monitoring of the reaction. Also a highly organized and
chelated transition state can be expected due to the pres-
ence of the thione group, providing diastereofacial selec-
tivity in favor of the syn-aldol products. The imidazolidin-
2-thione may tolerate wider experimental conditions/
reagents allowing the release of the aldol adducts from the
auxiliary, with the desired functional group transforma-
tions.
(i)
S
H2N
CO2H
S
1,4-dioxane–H2O
Ph
N
NH
(S)
NCS
Ph
LiAlH4
Et2O
Et3N
N
NH
(S)
(ii) concd HCl
O
3
1
2
Scheme 1 Synthesis of (S)-4-isopropyl-1-phenylimidazolidin-2-
thione
reaction mixture was subsequently reacted with the corre-
sponding acid chlorides. After completion of the reaction
and workup, the N-acylated products were obtained in
reasonable yields.
S
S
O
Ph
Ph
NaH, THF
O
N
N
N
X
NH
(S)
(S)
X
Cl
4, X = Me
5, X = H
3
Scheme 2 N-acylation of (S)-4-isopropyl-1-phenylimidazolidin-2-
thione
N-Propionylimidazolidin-2-thione (4) was reacted with 2
equivalents of titanium(IV) chloride and 1 equivalent of
DIPEA in freshly distilled dichloromethane and under N2
atmosphere in the presence of benzaldehyde. Chromato-
graphic separation of the crude product afforded two dias-
tereomers of the syn-aldol in the ratio 99:01. A vicinal
coupling constant22 of J2¢,3¢ = 4.0 Hz observed in the NMR
spectral data of the major isomer indicated it to be the non-
Evans syn-aldol, while the other diastereomer turned out
to be the Evans syn-aldol (Scheme 3). The absolute stereo-
chemistry of the major isomer was further confirmed by
hydrolysis of 6a(i) to furnish the (2R,3R)-3-hydroxy-2-
methyl-3-phenylpropanoic acid [8a(i)] (Scheme 6) and
measurement of its specific rotation.23 The high diastereo-
selectivity observed for non-Evans syn-aldol with benzal-
dehyde was faithfully reproduced in the reactions of aryl
aldehydes bearing both electron-withdrawing and elec-
tron-donating groups (Table 1). Employing one equiva-
lent of TiCl4 with DIPEA gave inconsistent results.
Aliphatic aldehydes like propionaldehyde and isobutyral-
dehyde gave good diastereoselectivity. The reaction with
a,b-unsaturated compound, trans-cinnamaldehyde also
afforded a high diastereoselectivity.
Our current research pursuits on reactions of heterocyclic
substrates,20 prompted us to investigate the aldol reactions
of imidazolidin-2-thione nucleus. These substrates could
be prepared by a simple and straight forward synthetic
strategy from less expensive starting materials. The syn-
thesis as outlined in Scheme 1 involves the addition of
phenyl isothiocyanate (1) to a solution of L-valine in 1,4-
dioxane–water mixture (1:1) at 0 °C in the presence of tri-
ethylamine to yield (S)-5-isopropyl-3-phenyl-2-thioxo-
imidazolidin-4-one (2).21 Reduction of 2 with lithium
aluminum hydride in anhydrous diethyl ether afforded
(S)-4-isopropyl-1-phenylimidazolidin-2-thione (3) in
60% yield with 97% ee. Recrystallization in methanol af-
forded the desired product with 99% ee, as determined by
chiral HPLC.
To investigate the aldol reactions, N-propionylated 4 and
N-acetylated 5 derivatives of (S)-4-isopropyl-1-phenyl-
imidazolidin-2-thione (3) were prepared (Scheme 2). The
acidic thioureido proton was removed by treating a solu-
tion of the imidazolidin-2-thione (3) in anhydrous THF at
0 °C and under N2 atmosphere with sodium hydride. The
S
S
O
S
O
O
OH
OH
TiCl4 (2 equiv)
Ph
Ph
N
N
N
DIPEA (1 equiv)
N
N
R
R
Ph
N
+
CH2Cl2, –78 °C
RCHO
4
"non-Evans" syn aldol (major)
"Evans" syn aldol (minor)
6b
6a
Scheme 3 Aldol reactions of N-propionylimidazoldin-2-thione
Synthesis 2011, No. 19, 3123–3132 © Thieme Stuttgart · New York

PAPER
(S)-4-Isopropyl-1-phenylimidazolidin-2-thione as Chiral Auxiliary
3125
S
S
O
O
S
OH
OH
O
TiCl4 (2 equiv)
DIPEA (1 equiv)
Ph
Ph
N
N
Ph
N
N
N
R
R
N
+
CH2Cl2, –78 °C
RCHO
acetate syn aldol (major)
acetate anti aldol (minor)
5
7a
7b
Scheme 4 Aldol reactions of N-acetylimidazoldin-2-thione
aldehydes using 2 equivalents of TiCl4 and 1 equivalent of
DIPEA (Scheme 4). As expected, the reactions favored
the syn-aldol products. H NMR spectrum of the aldol
Table 1 Reactions of Aldehydes with Titanium Enolate of N-Propi-
onylimidazoldin-2-thione
1
Entry Aldehyde
Product
Yield dr
product obtained from the typical reaction of the titanium
enolate with benzaldehyde indicated the characteristic
chemical shifts for the a-protons at 3.81 ppm (dd,
J = 17.2, 9.4 Hz) and 4.05 ppm (dd, J = 17.2, 3.0 Hz). The
minor less polar anti-product showed the corresponding
chemical shift values at 3.72 ppm (dd, J = 16.5, 3.0 Hz)
and 4.17 ppm (dd, J = 16.5, 9.6 Hz), respectively.10b The
absolute stereochemistry of the product was further con-
firmed by hydrolysis of the compound 7a(i) to afford (R)-
3-hydroxy-3-phenylpropanoic acid [9a(i)] (Scheme 6)
and measurement of its specific rotation.24 Very high dia-
stereoselectivity for the syn-isomer was observed in the
cases of aryl aldehydes (Table 2). A similar pattern was
witnessed with pivaldehyde and a,b-unsaturated alde-
hydes, while the selectivity with propionaldehyde and
isobutyraldehyde were only moderate.
(%)a
(6a/6b)b
CHO
1
2
6a(i):6b(i)
6a(ii):6b(ii)
65
99:1
98:2
CHO
63
70
68
67
CHO
3
4
5
6a(iii):6b(iii)
6a(iv):6b(iv)
6a(v):6b(v)
99:1
99:1
99:1
MeO
Cl
CHO
CHO
Br
Concordant with the well validated theories we propose a
chelated transition state for the observed selectivity
(Scheme 5). The thiophilic nature of the titanium leading
to chelation is contemplated in this model, affording the
acetate syn-aldol with N-acetylimidazolidin-2-thione and
the non-Evans syn-aldol with N-propionylimidazolidin-2-
thione. The steric factors appear to play a prominent role
in the diastereoselectivity. Overall, very high selectivities
were observed with aryl aldehydes when compared to ali-
phatic aldehydes. Various other parameters like solvent
effect, chelation, dipole moment etc. could also contribute
to the stereoselectivity in aldol reactions.3b,6,25
6
7
6a(vi):6b(vi)
61
72
93:7
93:7
CHO
CHO
6a(vii):6b(vii)
CHO
8
6a(viii):6b(viii) 69
90:10
a Total yield of the isomers after chromatographic purification.
b The diastereomeric ratio was determined from 1H NMR spectra and
HPLC of the crude product.
Our efforts were further directed to examine the diastereo-
selectivity in acetate aldol reactions. N-Acetylimidazoli-
din-2-thione (5) was subjected to aldol reactions with
The aldol adducts were successfully cleaved from the
chiral acetate and propionate templates under various re-
action conditions to afford different chiral intermediates
HO
N
O
S
O
S
R
TiCl4 (2 equiv)
DIPEA (1 equiv)
X
S
H
N
N
N
N
N
X
TiCl3
R
O
RCHO
O
X
X = Me or H
chelated TS
X = Me; "non-Evans" syn aldol
X = H; acetate syn aldol
highly favored
Scheme 5 Proposed transition state models for the formation of aldol diastereomers
Synthesis 2011, No. 19, 3123–3132 © Thieme Stuttgart · New York

3126
G. L. Khatik et al.
PAPER
Table 2 Reactions of Aldehydes with Titanium Enolate of
N-Acetylimidazoldin-2-thione
O
OH
Ph
S
X = Me; 6a(i)
X = H; 7a(i)
N
Ph
N
Entry Aldehyde
Product
Yield dr
X
(%)a
(7a/7b)b
Ph
NH2
THF
LiOH⋅H2O
syn aldol
major
CHO
1
2
7a(i):7b(i)
7a(ii):7b(ii)
77
90:10
97:3
H2O–MeCN
NaBH4
O
OH
Ph
CHO
THF, H2O
O
OH
Ph
68
65
69
OH
HO
Ph
N
HO
Ph
H
X
X
CHO
X = Me; 8a(i) (95%)
X = H; 9a(i) 97%)
X
3
4
7a(iii):7b(iii)
7a(iv):7b(iv)
99:1
98:2
X = Me; 12a(i) (92%)
X = H; 13a(i) (95%)
X = Me; 10a(i) (93%)
X = H; 11a(i) (90%)
MeO
Cl
S
CHO
Ph
N
NH
CHO
3
5
6
7a(v):7b(v)
72
73
92:8
98:2
recovered
(89–95%)
Br
7a(vi):7b(vi)
CHO
Scheme 6 Cleavage of the aldol products 6a(i) and 7a(i)
CHO
7
8
7a(vii):7b(vii)
7a(viii):7b(viii)
75
60
99:1
98:2
3-(4-chlorophenyl)propanoate (14). It was subsequently
converted into ethyl (S)-3-bromo-3-(4-chlorophenyl)pro-
panoate (15) with PBr3, and then to ethyl (R)-3-cyano-3-
(4-chlorophenyl)propanoate (16) with TMSCN/TBAF31
under reflux conditions. Reduction using NiCl2/NaBH4
gave (R)-4-(4-chlorophenyl)pyrrolidin-2-one (17), and
hydrolysis by concentrated HCl under reflux afforded the
(R)-baclofen hydrochloride salt 18 in good yields and high
enantiopurity.
CHO
a Total yield of the isomers after chromatographic purification.
b The diastereomeric ratio was determined from 1H NMR and HPLC
of the crude product.
demonstrating the usefulness of the auxiliary. Reaction
with LiOH in acetonitrile–water medium afforded b-hy-
droxy carboxylic acids 8, 9. Reduction with NaBH4 yield-
ed the corresponding alcohols 10, 11 and reactions with
amines gave the respective amides 12, 13 (Scheme 6).
The chiral auxiliary was quantitatively recovered in all the
cases and successfully reused. Subsequently the useful-
ness of this auxiliary was explored in the enantioselective
synthesis of (R)-baclofen, a drug molecule. Baclofen, an
antispasmodic drug and a lipophilic analogue of the neu-
rotransmitter GABA (g-aminobutyric acid), is adminis-
tered as racemic mixture, but the biological activity
mainly resides with the R-enantiomer.26a
To conclude, the efficiency of (S)-4-isopropyl-1-phe-
nylimidazolidin-2-thione as a chiral auxiliary in stereose-
lective propionate and acetate aldol reactions were
examined. The reactions are expected to proceed through
a highly organized chelated transition state. Further, the
utility of the auxiliary in the enantioselective synthesis of
(R)-baclofen was demonstrated. A detailed investigation
of this auxiliary in metal-mediated reactions is currently
underway.
1
The H and 13C NMR spectra were recorded at 400 MHz and 100
MHz, respectively, on Bruker Avance DPX 400 spectrometers in
CDCl3 using TMS as the internal standard. The chemical shifts (d)
A few reports are available on the stereoselective synthe-
sis of (R)-baclofen through resolution,26 chemoenzymat-
ic,27 or by asymmetric synthesis/organocatalysis.28
Synthesis of (R)-baclofen using Evans auxiliary involved
a lengthy procedure.29,30 The high stereoselectivity ob-
served in acetate aldol reactions of aryl aldehydes using
the auxiliary prompted us to explore its efficiency in the
stereospecific synthesis of (R)-baclofen. Thus, an acetate
type aldol approach attempted with N-acetylimidazolidin-
2-thione and 4-chlorobenzaldehyde afforded the syn- and
anti-aldol adducts in a ratio of 98:02 (Scheme 7). The de-
sired syn aldol product was purified and cleaved with
K2CO3 in ethanol medium to obtain ethyl (R)-3-hydroxy-
1
for H and 13C are given in ppm relative to residual signals of the
solvent. Coupling constants are given in Hz. Standard abbreviations
are used to indicate the multiplicity. Specific rotations were taken
on Rudolph Autopol IV instrument and HRMS spectra were record-
ed on Bruker Maxis TOF. The reactions were monitored by TLC
(Merck). Evaporation of solvents was performed under reduced
pressure using a rotary evaporator. Melting points are uncorrected.
Commercial grade reagents and solvents were used without further
purification: diisopropylamine (DIPEA), Et3N, CSCl2, 1,4-dioxane,
benzaldehyde, trans-cinnamaldehyde, 4-bromobenzaldehyde, 4-
chlorobenzaldehyde, 4-methoxybenzaldehyde, propionaldehyde,
isobutyraldehyde, 4-methylbenzaldehyde, trimethylsilyl cyanide
(TMSCN), PBr3, LiOH, CH2Cl2, THF (Spectrochem), TiCl4, 3-
methylbut-2-enal, trimethylacetaldehyde, NiCl2, Bu4NF (TBAF)
Synthesis 2011, No. 19, 3123–3132 © Thieme Stuttgart · New York

PAPER
(S)-4-Isopropyl-1-phenylimidazolidin-2-thione as Chiral Auxiliary
3127
O
OH
O
S
S
TiCl4 (2 equiv)
DIPEA (1 equiv)
(R)
N
(S)
N
(S)
Ph
Ph
N
N
CH2Cl2, –78 °C
Cl
5
OHC
Cl
7a(iv) 69% (dr 98:02)
O
Br
O
OH
PBr3, Et2O
5 h
EtOH, K2CO3
r.t., 2 h
(S)
EtO
(R)
EtO
Cl
Cl
15 (79%)
recovered
auxiliary
(87%)
14 (95%)
O
O
CN
NiCl2⋅6H2O
NH
TMSCN, TBAF
NaBH4, MeOH
(R)
EtO
(R)
MeCN, reflux
12 h
r.t., 1 h
Cl
16 (65%)
NH2⋅HCl
Cl
17 (86%)
concd HCl, reflux
12 h
(R)
HO
O
Cl
18 (80%)
(R)-baclofen
Scheme 7 Stereospecific synthesis of (R)-baclofen
(Aldrich), and NH4Cl, NaHCO3, and NaBH4 (CDH). THF was dried
by distillation over sodium metal and benzophenone. CH2Cl2 was
dried by distillation over CaH2.
of EtOAc–hexane (20:80) to give the title compound 3 (2.8 g, 60%);
white solid; mp 63–65 °C; [a]D20 –35.4 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.96 (d, J = 6.8 Hz, 3 H), 1.01 (d,
J = 6.8 Hz, 3 H), 1.81–1.86 (m, 1 H), 3.72–3.76 (m, 1 H), 3.82–3.86
(m, 1 H), 4.17–4.20 (m, 1 H), 6.62 (br s, 1 H), 7.22–7.24 (m, 1 H),
7.37–7.42 (m, 2 H), 7.55–7.58 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 17.94, 18.10, 32.76, 55.65, 59.55,
124.40, 126.35, 128.78, 139.92, 181.95.
HRMS (ESI-TOF): m/z calcd for C12H16N2S ([M + Na]+): 243.0932;
found: 243.0938.
(S)-5-Isopropyl-3-phenyl-2-thioxoimidazolidin-4-one (2)
L-Valine (5.0 g, 42.7 mmol, 1.0 equiv) was added to a solution of
phenyl isothiocyanate (5.8 mL, 42.7 mmol, 1.0 equiv) in 1,4-diox-
ane–H2O (100 mL; 1:1, v/v) and cooled to 0 °C. Et3N (11.9 mL,
85.4 mmol, 2.0 equiv) was added slowly to it and the solution was
stirred for 1 h, followed by the addition of concd HCl (13.0 mL,
128.1 mmol, 3.0 equiv) at 0 °C until the pH became ~2. The reaction
mixture was stirred for another 12 h at r.t., and the precipitate
formed was filtered and dried to yield the desired compound 2 (9.5
g, 95%); white solid; mp 148–151 °C; [a]D20 –54.4 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.06 (d, J = 6.8 Hz, 3 H), 1.15 (d,
J = 6.8 Hz, 3 H), 2.38–2.40 (m, 1 H), 4.18–4.20 (m, 1 H), 7.19–7.34
(m, 2 H), 7.39–7.60 (m, 3 H), 8.04 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 16.21, 18.80, 31.18, 64.99,
128.26, 129.21, 129.32, 132.61, 172.97, 184.29.
(S)-N-Propionyl-4-isopropyl-1-phenylimidazolidin-2-thione (4)
and (S)-N-Acetyl-4-isopropyl-1-phenylimidazolidin-2-thione
(5)
To a stirred solution of 3 (1.0 g, 4.5 mmol, 1.0 equiv) in anhyd THF
(20 mL) under N2 atmosphere was added NaH (0.2 g, 4.9 mmol, 1.1
equiv) portionwise at 0 °C. After 1 h, propionyl or acetyl chloride
(1.1 equiv) was added dropwise and the mixture was stirred for 1 h.
The reaction mixture was washed with aq NaHCO3 (20 mL), dried
(Na2SO4), evaporated under vacuum to give a gum, which solidified
in n-hexane on refrigeration for 2 days.
HRMS (ESI-TOF): m/z calcd for C12H14N2OS ([M + Na]+):
257.0725; found: 257.0722.
(S)-4-Isopropyl-1-phenylimidazolidin-2-thione (3)
4
To a stirred solution of 2 (5.0 g, 21.4 mmol, 1.0 equiv) in anhyd
Et2O (100 mL) under N2 atmosphere was added LiAlH4 (8.2 g,
214.0 mmol, 10.0 equiv) portionwise at 0 °C. The reaction mixture
was stirred at reflux for 12 h, cooled, and slowly quenched with aq
NaOH (1 M, 30 mL) to form a slurry, which was filtered through a
Celite bed. The filtrate was taken in EtOAc (100 mL), washed with
brine (50 mL), dried (Na2SO4), and evaporated under vacuum to
give a crude solid. The crude product was purified by column chro-
matography on silica gel (60–120 mesh) by eluting with a mixture
Yield: 1.2 g (97%); white solid; mp 64–67 °C; [a]D20 +98.2 (c 1.00,
CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.94 (d, J = 6.8 Hz, 3 H), 0.96 (d,
J = 6.8 Hz, 3 H), 1.20 (t, J = 7.3 Hz, 3 H), 2.36–2.49 (m, 1 H), 3.33
(dq, J = 17.8, 7.2 Hz, 1 H), 3.51 (dq, J = 17.8, 7.4 Hz, 1 H), 3.64
(dd, J = 10.7, 2.4 Hz, 1 H), 4.06 (dd, J = 10.8, 9.3 Hz, 1 H), 4.73
(ddd, J = 9.3, 3.6, 2.4 Hz, 1 H), 7.32–7.40 (m, 3 H), 7.42–7.50 (m,
2 H).
Synthesis 2011, No. 19, 3123–3132 © Thieme Stuttgart · New York

3128
G. L. Khatik et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 9.05, 15.00, 18.19, 29.51, 31.86,
(2R,3R)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimida-
zolidin-1-yl]-3-(4-methoxyphenyl)-2-methylpropan-1-one
[6a(iii)]
50.27, 60.32, 126.14, 127.91, 129.36, 139.92, 175.80, 179.15.
HRMS (ESI-TOF): m/z calcd for C15H20N2OS ([M + H]+):
277.1375; found: 277.1378.
Gum; [a]D20 +21.8 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.66–0.95 (m, 6 H), 1.15 (d,
J = 6.7 Hz, 3 H), 2.21–2.24 (m, 1 H), 3.61 (dd, J = 10.8, 4.3 Hz, 1
H), 3.78 (s, 3 H), 4.01 (dd, J = 10.8, 9.1 Hz, 1 H), 4.72–4.74 (m, 1
H), 5.19 (d, J = 4.0 Hz, 1 H), 5.57 (dd, J = 6.7, 4.0 Hz, 1 H), 6.85–
6.93 (m, 2 H), 7.34–7.45 (m, 7 H).
13C NMR (100 MHz, CDCl3): d = 11.60, 14.86, 18.31, 29.59, 44.09,
50.00, 55.36, 60.37, 73.59, 113.55, 126.29, 127.74, 128.30, 129.58,
133.84, 139.72, 158.88, 178.47, 178.73.
5
20
Yield: 1.15 g (98%); white solid; mp 62–65 °C; [a]D +125.2 (c
1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.94 (d, J = 6.8 Hz, 3 H), 0.96 (d,
J = 6.8 Hz, 3 H), 2.44 (m, J = 6.9, 3.7 Hz, 1 H), 2.89 (s, 3 H), 3.65
(dd, J = 10.7, 2.4 Hz, 1 H), 4.06 (dd, J = 10.7, 9.2 Hz, 1 H), 4.73
(ddd, J = 9.2, 3.6, 2.3 Hz, 1 H), 7.33–7.41 (m, 3 H), 7.43–7.50 (m,
2 H).
13C NMR (100 MHz, CDCl3): d = 14.97, 18.20, 27.11, 29.41, 50.24,
60.19, 126.09, 128.00, 129.41, 139.84, 172.01, 179.45.
HRMS (ESI-TOF): m/z calcd for C23H28N2O3S ([M + Na]+):
435.1718; found: 435.1719.
(2R,3R)-3-(4-Chlorophenyl)-3-hydroxy-1-[(S)-5-isopropyl-3-
phenyl-2-thioxoimidazolidin-1-yl]-2-methylpropan-1-one
[6a(iv)]
HRMS (ESI-TOF): m/z calcd for C14H18N2OS ([M + H]+):
263.1218; found: 263.1222.
Gum; [a]D20 +63.2 (c 0.25, CHCl3).
Aldol Reaction of 4 with Aldehydes; (2R,3R)-3-Hydroxy-1-[(S)-
5-isopropyl-3-phenyl-2-thioxoimidazolidin-1-yl]-2-methyl-3-
phenylpropan-1-one [6a(i)]; Typical Procedure
1H NMR (400 MHz, CDCl3): d = 0.92–0.95 (m, 6 H), 1.09 (d,
J = 6.0 Hz, 3 H), 2.13–2.22 (m, 1 H), 3.64 (dd, J = 10.5, 3.8 Hz, 1
H), 4.05 (dd, J = 10.5, 9.1 Hz, 1 H), 4.73–4.75 (m, 1 H), 5.24 (d,
J = 3.9 Hz, 1 H), 5.58 (dd, J = 6.5, 3.9 Hz, 1 H), 7.29–7.31 (m, 2 H),
7.33–7.38 (m, 3 H), 7.42 (d, J = 7.7 Hz, 2 H), 7.47 (d, J = 7.7 Hz, 2
H).
13C NMR (100 MHz, CDCl3): d = 11.17, 14.91, 18.30, 29.66, 43.72,
50.12, 60.58, 73.40, 126.15, 126.24, 127.92, 128.31, 128.39,
129.61, 139.54, 140.84, 178.40, 178.70.
To a stirred solution of 4 (0.2 g, 0.72 mmol, 1.0 equiv) in CH2Cl2 (5
mL) at –78 °C and under N2 atmosphere was added TiCl4 (1.44 mL,
1.44 mmol, 2.0 equiv, 1.0 M in CH2Cl2), followed by DIPEA (0.12
mL, 0.72 mmol, 1.0 equiv) after 10 min. Stirring was continued for
1 h and then benzaldehyde (0.08 mL, 0.72 mmol, 1.0 equiv) was in-
troduced into the reaction. The reaction mixture was quenched after
30 min with sat. aq NH4Cl (5 mL). The CH2Cl2 layer was washed
with brine (10 mL), dried (Na2SO4), and concentrated under vacu-
um to obtain a crude mixture. Separation of the mixture by column
chromatography using a combination of EtOAc–hexane (25:75) as
the eluent on silica gel (230–400 mesh) afforded the diastereomers
of the aldol adduct; yield: 0.18 g (65%); gum; [a]D20 +153.0 (c 1.00,
CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.87 (d, J = 6.8 Hz, 3 H), 0.90 (d,
J = 6.8 Hz, 3 H), 1.13 (d, J = 6.8 Hz, 3 H), 2.22–2.29 (m, 1 H), 3.60
(dd, J = 10.8, 2.3 Hz, 1 H), 4.00 (dd, J = 10.8, 9.3 Hz, 1 H), 4.72–
4.74 (m, 1 H), 5.26 (d, J = 4.0 Hz, 1 H), 5.60 (dd, J = 6.8, 4.0 Hz, 1
H), 7.19–7.28 (m, 1 H), 7.28–7.37 (m, 4 H), 7.39–7.51 (m, 5 H).
HRMS (ESI-TOF): m/z calcd for C22H25ClN2O2S ([M + Na]+):
439.1223; found: 439.1226.
(2R,3R)-3-(4-Bromophenyl)-3-hydroxy-1-[(S)-5-isopropyl-3-
phenyl-2-thioxoimidazolidin-1-yl]-2-methylpropan-1-one
[6a(v)]
Gum; [a]D20 +148.4 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.88 (d, J = 6.9 Hz, 3 H), 0.91 (d,
J = 3.5 Hz, 3 H), 1.08 (d, J = 6.9 Hz, 3 H), 2.27–2.29 (m, 1 H),
3.60–3.63 (m, 1 H), 4.02–4.05 (m, 1 H), 4.71–4.74 (m, 1 H), 5.21
(d, J = 3.8 Hz, 1 H), 5.58 (dd, J = 6.7, 3.8 Hz, 1 H), 7.32–7.39 (m,
5 H), 7.42–7.49 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 11.87, 14.95, 18.19, 29.66, 42.48,
50.19, 60.57, 73.82, 126.61, 128.24, 128.49, 128.95, 129.49,
131.27, 136.93, 139.66, 177.62, 178.91.
13C NMR (100 MHz, CDCl3): d = 11.34, 14.83, 18.20, 29.50, 43.97,
49.97, 60.34, 74.03, 126.47, 127.27, 128.17, 128.42, 129.45,
129.50, 139.66, 141.62, 178.47, 178.64.
HRMS (ESI-TOF): m/z calcd for C22H26N2O2S ([M + Na]+):
405.1613; found: 405.1620.
HRMS (ESI-TOF): m/z calcd for C22H25BrN2O2S ([M + Na]+):
483.0718; found: 483.0723.
(2R,3R)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimida-
zolidin-1-yl]-2-methyl-3-p-tolylpropan-1-one [6a(ii)]
Gum; [a]D20 +110.4 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.84 (d, J = 6.6 Hz, 3 H), 0.90 (d,
J = 3.5 Hz, 3 H), 1.12 (d, J = 8.3 Hz, 3 H), 2.16–2.31 (m, 1 H), 2.40
(s, 3 H), 3.60 (dd, J = 10.7, 3.2 Hz, 1 H), 3.99 (dd, J = 10.7, 9.2 Hz,
1 H), 4.71–4.75 (m, 1 H), 5.21 (d, J = 4.1 Hz, 1 H), 5.59 (dd, 6.8,
4.1 Hz, 1 H), 7.12 (d, J = 7.9 Hz, 2 H), 7.32–7.37 (m, 5 H), 7.34–
7.37 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 11.37, 14.79, 18.20, 21.14, 29.50,
44.02, 49.96, 60.30, 74.01, 126.38, 128.14, 128.79, 129.17, 129.44,
130.18, 138.63, 139.71, 178.50, 178.67.
HRMS (ESI-TOF): m/z calcd for C23H28N2O2S ([M + Na]+):
419.1769; found: 419.1776.
(2R,3S)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimida-
zolidin-1-yl]-2-methylpentan-1-one [6a(vi)]
Gum; [a]D20 +257.4 (c 0.25, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.82–1.01 (m, 9 H), 1.16 (d,
J = 6.6 Hz, 3 H), 1.51–1.62 (m, 2 H), 2.39–2.43 (m, 1 H), 3.65 (dd,
J = 10.7, 2.4 Hz, 1 H), 3.95–3.99 (m, 1 H), 4.04 (dd, J = 10.7, 9.2
Hz, 1 H), 4.76 (ddd, J = 9.1, 3.7, 2.4 Hz, 1 H), 5.26 (dq, J = 6.9, 4.0
Hz, 1 H), 7.34–7.38 (m, 2 H), 7.45–7.49 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 10.51, 10.54, 15.00, 18.21, 26.50,
29.63, 41.33, 50.11, 60.47, 73.67, 126.18, 128.17, 129.46, 139.67,
178.86, 179.22.
HRMS (ESI-TOF): m/z calcd for C18H26N2O2S ([M + H]+):
335.1793; found: 335.1797.
(2R,3S)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimida-
zolidin-1-yl]-2,4-dimethylpentan-1-one [6a(vii)]
Gum; [a]D20 +105.4 (c 1.00, CHCl3).
Synthesis 2011, No. 19, 3123–3132 © Thieme Stuttgart · New York

PAPER
(S)-4-Isopropyl-1-phenylimidazolidin-2-thione as Chiral Auxiliary
3129
1H NMR (400 MHz, CDCl3): d = 0.93–0.98 (m, 9 H), 1.06 (d,
J = 6.5 Hz, 3 H), 1.18 (d, J = 6.5 Hz, 3 H), 1.70–1.78 (m, 1 H),
2.37–2.44 (m, 1 H), 3.63–3.65 (m, 2 H), 4.06 (dd, J = 10.9, 9.2 Hz,
1 H), 4.75 (ddd, J = 9.2, 3.7, 2.4 Hz, 1 H), 5.42 (dq, J = 6.9, 3.8 Hz,
1 H), 7.32–7.37 (m, 3 H), 7.34–7.37 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 10.33, 14.95, 18.24, 18.94, 19.53,
29.57, 30.98, 39.53, 50.02, 60.40, 76.98, 126.17, 128.12, 129.43,
139.69, 178.71, 180.13.
5.27 (m, 1 H), 6.81 (d, J = 7.3 Hz, 2 H), 7.21–7.34 (m, 5 H), 7.34–
7.43 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.14, 18.19, 29.61, 46.61, 50.48,
55.38, 60.53, 70.24, 113.87, 126.18, 127.29, 128.27, 129.56,
135.03, 139.63, 159.06, 174.00, 178.69.
HRMS (ESI-TOF): m/z calcd for C22H26N2O3S ([M + Na]+):
421.1562; found: 421.1554.
HRMS (ESI-TOF): m/z calcd for C19H28N2O2S ([M + H]+):
349.1950; found: 349.1954.
(R)-3-(4-Chlorophenyl)-3-hydroxy-1-[(S)-5-isopropyl-3-phe-
nyl-2-thioxoimidazolidin-1-yl]propan-1-one [7a(iv)]
Gum; [a]D20 +90.4 (c 0.50, CHCl3).
(2R,3S,E)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimi-
dazolidin-1-yl]-2-methyl-5-phenylpent-4-en-1-one [6a(viii)]
Gum; [a]D20 +40.6 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.94–0.98 (m, 6 H), 1.26 (d,
J = 6.9 Hz, 3 H), 2.40–2.42 (m, 1 H), 3.64 (dd, J = 10.8, 2.4 Hz, 1
H), 4.05 (dd, J = 10.8, 9.2 Hz, 1 H), 4.78–4.82 (m, 2 H), 5.48–5.50
(m, 1 H), 6.32 (dd, J = 6.0, 15.8 Hz, 1 H), 6.70 (d, J = 15.8 Hz, 1 H),
7.21–7.25 (m, 1 H), 7.30–7.33 (m, 2 H), 7.37–7.39 (m, 5 H), 7.39–
7.43 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 11.87, 14.95, 18.19, 29.66, 42.48,
50.19, 60.57, 73.82, 126.21, 126.61, 127.50, 128.24, 128.49,
128.95, 129.49, 131.27, 136.93, 139.66, 177.62, 178.91.
HRMS (ESI-TOF): m/z calcd for C24H28N2O2S ([M + Na]+):
431.1769; found: 431.1779.
1H NMR (400 MHz, CDCl3): d = 0.84–0.88 (m, 6 H), 2.35 (m, 1 H),
3.56 (dd, J = 10.0, 2.5 Hz, 1 H), 3.65 (dd, J = 16.5, 9.2 Hz, 1 H),
3.92 (dd, J = 10.0, 9.2 Hz, 1 H), 4.00 (dd, J = 16.5, 2.5 Hz, 1 H),
4.54–4.78 (m, 1 H), 5.18 (m, 1 H), 7.05–7.31 (m, 7 H), 7.37 (d,
J = 6.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.13, 18.29, 29.71, 46.50, 50.50,
60.55, 69.95, 126.15, 127.44, 128.54, 128.66, 129.59, 133.21,
139.54, 141.40, 173.70, 178.79.
HRMS (ESI-TOF): m/z calcd for C21H23ClN2O2S ([M + Na]+):
425.1066; found: 425.1069.
(R)-3-(4-Bromophenyl)-3-hydroxy-1-[(S)-5-isopropyl-3-phe-
nyl-2-thioxoimidazolidin-1-yl]propan-1-one [7a(v)]
Gum; [a]D20 +124.9 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.95–0.98 (m, 6 H), 2.37–2.48 (m,
1 H), 3.65 (dd, J = 11.0, 2.3 Hz, 1 H), 3.72 (dd, J = 17.2, 9.2 Hz, 1
H), 4.01 (dd, J = 11.0, 9.0 Hz, 1 H), 4.05 (dd, J = 17.2, 2.5 Hz, 1 H),
4.72 (ddd, J = 9.1, 3.6, 2.4 Hz, 1 H), 5.24 (dd, J = 9.3, 2.8 Hz, 1 H),
7.29–7.39 (m, 5 H), 7.42–7.50 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 15.06, 18.18, 29.63, 46.30, 50.44,
60.47, 69.92, 121.30, 126.04, 127.68, 128.22, 129.48, 131.50,
139.47, 141.87, 173.58, 178.73.
(R)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimidazoli-
din-1-yl]-3-phenylpropan-1-one [7a(i)]
Gum; [a]D20 +152.9 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.96 (dd, J = 6.8 Hz, 3 H), 0.97
(dd, J = 6.8 Hz, 3 H), 2.42–2.44 (m, 1 H), 3.63 (dd, J = 10.8, 2.3 Hz,
1 H), 3.81 (dd, J = 17.2, 9.4 Hz, 1 H), 3.95–4.00 (m, 1 H), 4.05 (dd,
J = 17.2, 3.0 Hz, 1 H), 4.72 (ddd, J = 9.1, 3.7, 2.3 Hz, 1 H), 5.25–
5.31 (m, 1 H), 7.24–7.30 (m, 1 H), 7.31–7.38 (m, 5 H), 7.41–7.48
(m, 4 H).
13C NMR (100 MHz, CDCl3): d = 15.08, 18.18, 29.66, 46.45, 50.45,
60.47, 70.55, 125.92, 126.07, 127.51, 128.13, 128.43, 129.43,
139.58, 142.83, 173.84, 178.82.
HRMS (ESI-TOF): m/z calcd for C21H23BrN2O2S ([M + Na]+):
469.0561; found: 469.0562.
(R)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimidazoli-
din-1-yl]-4,4-dimethylpentan-1-one [7a(vi)]
Gum; [a]D20 +169.2 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.93–1.00 (m, 15 H), 2.41–2.43
(m, 1 H), 3.44 (dd, J = 17.1, 10.8 Hz, 1 H), 3.65 (dd, J = 10.8, 2.3
Hz, 1 H), 3.79 (dd, J = 16.9, 1.9 Hz, 1 H), 3.84 (dd, J = 10.8, 1.8 Hz,
1 H), 4.05 (dd, J = 10.8, 9.3 Hz, 1 H), 4.75 (ddd, J = 9.2, 3.6, 2.3 Hz,
1 H), 7.33–7.38 (m, 3 H), 7.41–7.49 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.09, 18.18, 25.88, 29.67, 34.63,
40.47, 50.43, 60.44, 75.78, 126.14, 128.08, 129.41, 139.67, 175.24,
179.11.
HRMS (ESI-TOF): m/z calcd for C19H28N2O2S ([M + Na]+):
371.1769; found: 371.1777.
HRMS (ESI-TOF): m/z calcd for C21H24N2O2S ([M + Na]+):
391.1456; found: 391.1462.
(R)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimidazoli-
din-1-yl]-3-p-tolylpropan-1-one [7a(ii)]
Gum; [a]D20 +146.7 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.96 (d, J = 6.7 Hz, 3 H), 0.86 (d,
J = 6.7 Hz, 3 H), 2.42–2.45 (m, 1 H), 3.65 (dd, J = 10.8, 2.3 Hz, 1
H), 3.78 (s, 3 H), 3.84 (dd, J = 17.0, 9.0 Hz, 1 H), 3.97–4.07 (m, 2
H), 4.74 (ddd, J = 9.0, 3.8, 2.3 Hz, 1 H), 5.26 (dd, J = 9.3, 2.8 Hz, 1
H), 6.86–6.93 (m, 2 H), 7.34–7.40 (m, 5 H), 7.42–7.50 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.07, 18.20, 29.64, 46.55, 50.41,
55.29, 60.45, 70.16, 113.80, 126.05, 127.22, 128.13, 129.44,
135.07, 139.59, 158.97, 173.84, 178.80.
(R,E)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimidazo-
lidin-1-yl]-5-phenylpent-4-en-1-one [7a(vii)]
Gum; [a]D20 +99.1 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.94–1.02 (m, 6 H), 2.41–2.52 (m,
1 H), 3.62–3.73 (m, 2 H), 3.99 (dd, J = 17.2, 3.1 Hz, 1 H), 4.02–4.10
(m, 1 H), 4.77 (ddd, J = 9.1, 3.6, 2.4 Hz, 1 H), 4.85–4.94 (m, 1 H),
6.35 (dd, J = 15.9, 6.0 Hz, 1 H), 6.73 (d, J = 15.9 Hz, 1 H), 7.20–
7.28 (m, 1 H), 7.32–7.41 (m, 4 H), 7.42–7.52 (m, 5 H).
HRMS (ESI-TOF): m/z calcd for C21H26N2O2S ([M + Na]+):
405.1613; found: 405.1790.
(R)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimidazoli-
din-1-yl]-3-(4-methoxyphenyl)propan-1-one [7a(iii)]
Gum; [a]D20 +78.6 (c 0.50, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.89–0.91 (m, 6 H), 2.28–2.42 (m,
1 H), 3.58 (dd, J = 10.5, 2.3 Hz, 1 H), 3.72 (s, 3 H), 3.78 (dd,
J = 17.1, 9.0 Hz, 1 H), 3.89 (dd, J = 10.5, 9.1 Hz, 1 H), 4.00 (dd,
J = 17.1, 3.7 Hz, 1 H), 4.67 (ddd, J = 9.0, 3.7, 2.3 Hz, 1 H), 5.11–
13C NMR (100 MHz, CDCl3): d = 15.06, 18.21, 29.62, 44.91, 50.40,
60.43, 69.12, 126.09, 126.58, 127.62, 128.19, 128.56, 129.48,
130.22, 130.46, 136.73, 139.55, 173.66, 178.83.
Synthesis 2011, No. 19, 3123–3132 © Thieme Stuttgart · New York

3130
G. L. Khatik et al.
PAPER
HRMS (ESI-TOF): m/z calcd for C23H26N2O2S ([M + Na]+):
417.1613; found: 417.1620.
13C NMR (100 MHz, CDCl3): d = 10.62, 41.38, 65.97, 75.95,
126.14, 127.09, 128.08, 142.72.
HRMS (ESI-TOF): m/z calcd for C10H14O2 ([M + Na]+): 189.0891;
found: 189.1387.
(R)-3-Hydroxy-1-[(S)-5-isopropyl-3-phenyl-2-thioxoimidazoli-
din-1-yl]-5-methylhex-4-en-1-one [7a(viii)]
Gum; [a]D20 +82.1 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.95–1.00 (m, 6 H), 1.69–1.76 (m,
6 H), 2.44 (m, 1 H), 3.49 (dd, J = 17.4, 8.9 Hz, 1 H), 3.66 (dd,
J = 10.8, 2.3 Hz, 1 H), 3.77 (dd, J = 17.3, 3.0 Hz, 1 H), 4.06 (dd,
J = 10.8, 9.3 Hz, 1 H), 4.75 (ddd, J = 9.2, 3.6, 2.3 Hz, 1 H), 4.83–
5.00 (m, 1 H), 5.30 (dd, J = 8.7, 1.4 Hz, 1 H), 7.30–7.43 (m, 3 H),
7.43–7.51 (m, 2 H).
(R)-1-Phenylpropane-1,3-diol [11a(i)]
Mp 60–64 °C; [a]D20 +50.7 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.83–1.93 (m, 2 H), 3.65–3.88 (m,
2 H), 4.92 (dd, J = 8.8, 3.8 Hz, 1 H), 5.32 (br s, 2 H), 7.19–7.24 (m,
1 H) 7.29–7.39 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 40.35, 61.01, 73.79, 125.67,
127.49, 128.46, 144.23.
HRMS (ESI-TOF): m/z calcd for C9H12O3 ([M + Na]+): 175.0735;
found: 175.0733.
13C NMR (100 MHz, CDCl3): d = 15.06, 18.20, 18.37, 25.82, 29.64,
45.29, 50.40, 60.41, 65.41, 125.83, 126.11, 128.14, 129.46, 135.62,
139.61, 174.05, 178.86.
HRMS (ESI-TOF): m/z calcd for C23H26N2O2S ([M + Na]+):
369.1613; found: 369.1617.
Hydroxy Amides; (2R,3R)-N-Benzyl-3-hydroxy-2-methyl-3-
phenylpropanamide [12a(i)]; Typical Procedure
To a solution of 6a(i) (0.2 g, 0.52 mmol, 1.0 equiv) in THF (10 mL)
was added benzylamine (0.06 mL, 0.52 mmol, 1.0 equiv), and the
mixture was stirred for 5 h at r.t. The mixture was extracted with
EtOAc (2 × 10 mL), the combined organic layers were dried
(Na2SO4), and concentrated. The crude product was purified by col-
umn chromatography on silica gel (eluent: EtOAc–hexane, 1:1) to
afford the chiral auxiliary (0.11 g, 95%) and the corresponding hy-
droxy amide 12a(i) (0.13 g, 92%); [a]D20 +60.0 (c 0.25, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.06 (d, J = 7.1 Hz, 3 H), 2.51–
2.56 (m, 2 H), 4.25–4.36 (m, 2 H), 4.95–4.96 (d, J = 4.0 Hz, 1 H),
6.61 (br s, 1 H), 7.05–7.06 (m, 2 H), 7.13–7.26 (m, 5 H), 7.27–7.32
(m, 3 H).
Hydroxyphenylpropanoic Acids; (2R,3R)-3-Hydroxy-2-methyl-
3-phenylpropanoic Acid [8a(i)]; Typical Procedure
To a solution of 6a(i) (0.2 g, 0.52 mmol, 1.0 equiv) in MeCN–H2O
mixture (10 mL, 1:1, v/v) was added LiOH·H2O (0.1 g, 2.6 mmol,
5.0 equiv) and the mixture was stirred for 2 h. The mixture was ex-
tracted with CH2Cl2 (2 × 10 mL), the combined organic layers were
dried (Na2SO4), and concentrated under vacuum to recover the
chiral auxiliary 3 (0.1 g, 89%). The aqueous layer was acidified, ex-
tracted with EtOAc (2 × 10 mL), the combined organic layers were
dried (Na2SO4), and concentrated to afford the corresponding hy-
droxy acid 8a(i) (0.09 g, 95%); mp 90–95 °C; [a]D20 +28.0 (c 1.00,
CHCl3).
13C NMR (100 MHz, CDCl3): d = 11.60, 43.23, 47.27, 74.04,
126.10, 127.37, 127.57, 128.21, 128.39, 128.65, 138.01, 141.80,
175.98.
1H NMR (400 MHz, CDCl3): d = 1.10–1.18 (m, 3 H), 2.80–2.86 (m,
1 H), 5.17–5.18 (d, J = 3.9 Hz, 1 H), 7.26–7.32 (m, 1 H), 7.34–7.37
(m, 4 H).
13C NMR (100 MHz, CDCl3): d = 10.26, 46.23, 73.48, 125.97,
127.64, 128.60, 141.07, 180.68.
HRMS (ESI-TOF): m/z calcd for C10H12O3 ([M + Na]+): 203.0684;
found: 203.0681.
MS (APCI): m/z = 269.97 (M + 1)+.
(R)-N-Benzyl-3-hydroxy-3-phenylpropanamide [13a(i)]
Mp 102–106 °C; [a]D20 +40.6 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.58–2.63 (m, 2 H), 4.13 (br s, 1
H), 4.38–4.49 (m, 2 H), 5.13 (dd, J = 8.0, 4.3 Hz, 1 H), 6.23 (br s, 1
H), 7.19–7.24 (m, 2 H), 7.26–7.33 (m, 4 H), 7.34–7.38 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 43.48, 44.68, 70.91, 125.60,
127.57, 127.71, 127.85, 128.55, 128.73, 137.81, 142.97, 171.62.
(R)-3-Hydroxy-3-phenylpropanoic Acid [9a(i)]
Mp 116–118 °C; [a]D20 +54.8 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3); d = 2.71–2.86 (m, 2 H), 5.15 (dd,
J = 9.3, 3.8 Hz, 1 H), 7.31 (dd, J = 5.5, 3.0 Hz, 1 H), 7.33–7.40 (m,
4 H).
HRMS (ESI-TOF): m/z calcd for C16H17NO2 ([M + Na]+):
13C NMR (100 MHz, CDCl3): d = 43.04, 70.24, 125.69, 128.00,
128.66, 142.18, 176.55.
278.1157; found: 278.1154.
Ethyl (3R)-3-Hydroxy-3-(4-chlorophenyl)propanoate (14)
To a solution of 7a(iv) (0.9 g, 2.2 mmol) in EtOH (20 mL) was add-
ed K2CO3 (1.5 g, 11.0 mmol) and the mixture was stirred at r.t. for
2 h. After completion of the reaction, the solvent was evaporated,
washed with H2O (10 mL), and the reaction mixture was extracted
into EtOAc (2 × 20 mL). The combined organic phases were dried
(Na2SO4) and concentrated under vacuum to afford the crude prod-
uct. Column chromatography on silica gel (60–120 mesh) using
EtOAc–hexane (10:90) as the eluent afforded the pure product;
HRMS (ESI-TOF): m/z calcd for C9H10O3 ([M + Na]+): 189.0528;
found: 189.0526.
1,3-Diols; (1R,2S)-2-Methyl-1-phenylpropane-1,3-diol [10a(i)];
Typical Procedure
To a solution of 6a(i) (0.2 g, 0.52 mmol, 1.0 equiv) in THF–H2O
mixture (10 mL, 1:1, v/v) was added NaBH4 (0.1 g, 2.6 mmol, 5
equiv), and the mixture was stirred for 1 h at r.t. The reaction mix-
ture was extracted with EtOAc (2 × 10 mL), the combined organic
phases were dried (Na2SO4), and concentrated. The crude product
was purified by column chromatography using EtOAc–hexane (1:1)
as the eluent to afford the chiral auxiliary (0.1 g, 89%) and the cor-
25
yield: 0.48 g (95%); oil; [a]D20 +44.1 (c 1.5, CHCl3) {Lit.29e [a]D
+38.7 (c 1.5, CHCl3)}, and the chiral auxiliary.
1H NMR (400 MHz, CDCl3): d = 1.26 (t, J = 7.2 Hz, 3 H), 2.65–2.75
(m, 2 H), 3.38 (br s, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 5.07–5.10 (m,
1 H), 7.27–7.32 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 14.13, 43.16, 61.00, 69.63,
127.07, 128.68, 133.48, 140.97, 172.26.
20
responding 1,3-diol 10a(i) (0.08 g, 93%); mp 73–76 °C; [a]D
+41.15 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.75–0.77 (d, J = 7.0 Hz, 3 H),
1.98–2.06 (m, 1 H), 3.59–3.63 (m, 2 H), 4.07 (br s, 2 H), 4.89–4.90
(d, J = 3.4 Hz, 1 H), 6.97–7.04 (m, 1 H), 7.15–7.46 (m, 4 H).
HRMS (ESI-TOF): m/z calcd for C11H13ClO3 ([M + Na]+):
251.0451; found: 251.0451.
Synthesis 2011, No. 19, 3123–3132 © Thieme Stuttgart · New York

PAPER
(S)-4-Isopropyl-1-phenylimidazolidin-2-thione as Chiral Auxiliary
3131
Ethyl (3S)-3-Bromo-3-(4-chlorophenyl)propanoate (15)
Acknowledgment
To the solution of 14 (0.4 g, 1.75 mmol) in Et2O (50 mL) cooled to
–20 °C was added pyridine (0.17 mL, 2.1 mmol) followed by PBr3
(0.2 mL, 2.1 mmol) dropwise and the mixture was stirred for 2 h.
The mixture was then slowly brought to r.t. and stirred for 12 h. It
was washed with H2O (20 mL), dried (Na2SO4), and concentrated to
Funding for this research work from the Department of Science and
Technology (DST) and a research fellowship to G.L.K. from the
University Grants Commission (UGC), Government of India are
gratefully acknowledged.
20
afford the desired compound 15; yield: 0.41 g (79%); oil; [a]D
+101.3 (c 2.00, CHCl3) {Lit.29e [a]D25 +96.3 (c 2.00, CHCl3)}.
References
1H NMR (400 MHz, CDCl3): d = 1.24 (t, J = 7.0 Hz, 3 H), 3.16–3.34
(m, 2 H), 4.16 (q, J = 7.0 Hz, 2 H), 5.36 (dd, J = 6.6, 8.6 Hz, 1 H),
7.31–7.39 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 14.10, 44.79, 46.70, 61.16,
128.59, 129.16, 134.50, 139.34, 169.38.
HRMS (ESI-TOF): m/z calcd for C11H12BrClO2 ([M + Na]+):
312.9607; found: 312.9598.
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Ethyl (3R)-3-Cyano-3-(4-chlorophenyl)propanoate (16)
To the solution of 15 (0.4 g, 1.37 mmol) in MeCN (15 mL) were
added TMSCN (1.2 mL, 10.2 mmol) and TBAF (2.9 mL, 10.2
mmol), and the mixture was stirred at reflux for 24 h. The solvent
was evaporated and the crude mixture was extracted with EtOAc
(2 × 20 mL). The combined organic layers were dried (Na2SO4) and
concentrated to afford the desired compound 16; yield: 0.21 g
20
(65%); yellow solid; mp 64–66 °C; [a]D +14.8 (c 1.5, CHCl3)
{Lit.29e [a]D25 +12.9 (c 1.5, CHCl3)}.
1H NMR (400 MHz, CDCl3): d = 1.24 (t, J = 7.0 Hz, 3 H), 2.78 (dd,
J = 8.0, 16.0 Hz, 1 H), 2.97 (dd, J = 8.0, 16.0 Hz, 1 H), 4.01–4.30
(m, 3 H), 7.30–7.46 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 13.66, 32.57, 39.80, 61.58,
119.54, 128.79, 129.46, 132.94, 134.64, 168.90.
HRMS (ESI-TOF): m/z calcd for C12H12ClNO2 ([M + Na]+):
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260.0454; found: 260.0446.
(R)-4-(4-Chlorophenyl)pyrrolidin-2-one (17)
NiCl2·6H2O (0.29 g, 1.26 mmol) followed by NaBH4 (0.11 g, 3.15
mmol) were added to a solution of 16 (0.15 g, 0.63 mmol) in MeOH
(20 mL). During addition, evolution of H2 was observed and the re-
action mixture turned black. The mixture was stirred at r.t. for 1 h,
filtered through a Celite bed, concentrated, and extracted with
EtOAc (2 × 20 mL). The solvent was evaporated to afford the de-
sired compound 17; yield: 0.11 g (86%); mp 114–116 °C; white sol-
id; [a]D20 –45.7 (c 1.0, EtOH) {Lit.30 [a] –39.0 (c 1.0, EtOH).
1H NMR (400 MHz, CDCl3): d = 2.46 (dd, J = 8.4, 16.7 Hz, 1 H),
2.77 (dd, J = 8.4, 16.7 Hz, 1 H), 3.34–3.45 (m, 1 H), 3.61–3.85 (m,
2 H), 7.20–7.33 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 38.43, 40.12, 51.21, 128.09,
129.33, 133.14, 140.44, 177.56.
MS (Maldi-TOF/TOF): m/z = 194.03 (M – 1)+.
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J. Am. Chem. Soc. 2002, 124, 392.
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A solution of compound 17 (0.1 g, 0.51 mmol) in concd HCl (5.0
mL, 10 N) was heated at 100 °C for 12 h. The reaction mixture was
concentrated under reduced pressure to afford the desired com-
pound 18; yield: 0.1 g (80%); white solid; [a]D20 –2.2 (c 0.2, H2O)
{Lit.29a [a]D20 –2.0 (c 0.2, H2O); Lit.30 [a]D20 –1.7 (c 0.2, H2O)}.
1H NMR (400 MHz, DMSO-d6): d = 2.55–2.60 (m, 1 H), 2.82–2.89
(m, 1 H), 2.98–3.19 (m, 3 H), 7.34–7.53 (m, 4 H), 8.06 (br s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 38.34, 39.31, 43.75, 127.66,
128.29, 129.13, 140.78, 172.89.
MS (Maldi-TOF/TOF): m/z = 214.06 (M + 1)+.
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Synthesis 2011, No. 19, 3123–3132 © Thieme Stuttgart · New York

3132
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Synthesis 2011, No. 19, 3123–3132 © Thieme Stuttgart · New York