Cascade enantioselective synthesis of γ-aryl-γ-butyrolactones with a delayed stereoselective step

Article abstract of DOI:10.1016/j.tet.2008.01.077

Enantioselective synthesis of γ-aryl-γ-butyrolactones is achieved using (S)-1-phenylethylamine as a chiral auxiliary. The synthesis involves cascade formation-destruction-formation of the chiral centre with a delayed stereoselective step. The actual stere

Full text of DOI:10.1016/j.tet.2008.01.077

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2992e2996
www.elsevier.com/locate/tet
Cascade enantioselective synthesis of g-aryl-g-butyrolactones
with a delayed stereoselective step
*
Anil V. Karnik , Suchitra S. Kamath
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E), Mumbai 400098, India
Received 6 October 2007; received in revised form 2 January 2008; accepted 17 January 2008
Available online 25 January 2008
Abstract
Enantioselective synthesis of g-aryl-g-butyrolactones is achieved using (S)-1-phenylethylamine as a chiral auxiliary. The synthesis involves
cascade formationedestructioneformation of the chiral centre with a delayed stereoselective step. The actual stereoselective step has been found
to be intramolecular nucleophilic attack on a diastereotopic carbocation formed, thereby resulting in the formation of non-racemic g-aryl-g-
butyrolactones.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Enantioselective synthesis; g-Aryl-g-butyrolactones; Chiral auxiliary; Diastereotopic carbocation
1. Introduction
reduction of 3-aroylpropanoic acids and their derivatives
achieved by chiral reagent, chiral catalyst or chiral auxiliary
followed by lactonization. Noyori et al. reported BINAPe
Ru(II) catalyzed enantioselective hydrogenation of prochiral
4-oxo carboxylic esters followed by acid catalyzed cyclization
of the resulting hydroxy esters giving optically active
g-substituted-g-butyrolactones.16 Reduction of g-keto acids
with diisopinocampheylborane to the corresponding hydroxy
acids with predictable stereochemistry in very high enantio-
meric excess followed by cyclization to the corresponding
g-lactones was achieved by Ramachandran et al.17 Moderate
to good diastereoselectivity was achieved in the reduction of
1,4-keto esters controlled by anhydrosugar auxiliaries derived
from D-glucose.18 Chelation of the zinc cation appeared to be
important for good selectivities and the reduction with sodium
borohydride alone was unselective. Diastereoselective reduc-
tion of g-keto esters was achieved using 20-[2-(2-methoxy-
ethoxy)ethoxy]-1,10-binaphthalen-2-ol as a chiral auxiliary in
the presence of Lewis acid.19 Chelation of the oxygen atoms
of the oxyethylene chain and the carbonyl groups to the Lewis
acid (MgBr2eEt2O) plays an important role in the asymmetric
induction. Enzymatic reduction of g-keto acids followed
by acid catalyzed lactonization also yields non-racemic
g-substituted-g-butyrolactones.20
g-Butyrolactone frameworks are present in a large number of
natural products and biologically active compounds, such as
aroma1,2 and flavour2e4 components used in the perfume and
food industry, sex attractant pheromones of different insects5,6
and as plant-growth regulators.7 The chiral g-substituted-g-bu-
tyrolactones are found as lichen, moss and fungus components,8
polyketide metabolites, which are known to be hydrolysis prod-
ucts of (þ)-antimycin A3 (an antibiotic reagent effective against
fungi and yeast),9,10 phospholipase A2 inhibitors,11 muricata-
cins12 with potent cytotoxicity against several human tumour
cell lines and Stemona and Croomia alkaloids.13e15 Since
most of the naturally occurring chiral g-substituted-g-butyro-
lactones are found only as one enantiomer and biological activ-
ity is strongly dependent on their configuration, efficient and
stereoselective synthetic routes to these active compounds in
enantiomerically pure form are therefore highly desirable.
One of the approaches for the preparation of non-racemic
g-substituted-g-butyrolactones involves enantioselective
* Corresponding author. Tel.: þ91 022 26526091; fax: þ91 022 26528547.
E-mail address: avkarnik@chem.mu.ac.in (A.V. Karnik).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.077

A.V. Karnik, S.S. Kamath / Tetrahedron 64 (2008) 2992e2996
2993
Initial investigations into the enantioselective synthesis of
g-butyrolactones had been successfully carried out by our
group.21 Sodium borohydride reduction of chiral menthyl
and bornyl esters of 3-aroylpropanoic acids followed by acid
catalyzed cyclization at low temperature resulted in the forma-
tion of optically active g-aryl g-butyrolactones. A mechanism,
close to the AAL1 type mechanism, was proposed for the
formation of optically active g-aryl g-lactones.21
O
H
N
H
1. NaBH4, 0 °C
2. 6M HCl, -5 to 0 °C
H
O
O
CH3
O
R
R
R'
R'
3a-e
2a-e
Scheme 2. Enantioselective synthesis of (S)-g-aryl-g-butyrolactones.
In any asymmetric synthesis, identification of stereoselective
step is essential as this understanding of the mechanism can only
result in better control over the stereochemical outcome. With
this objective in mind the following work was carried out. In
the present work, a chiral auxiliary route is invoked and a mech-
anism involving a delayed stereoselective step is proposed.
The next step in our investigation was the enantioselective
synthesis of g-aryl-g-butyrolactones. This was achieved
in a one-pot reaction by sodium borohydride reduction of
(S)-3-aroyl-N-(a-phenylethyl)propanamides (2aee) followed
by acid catalyzed lactonization (Scheme 2).
The enantiomeric excesses of (S)-g-aryl-g-butyrolactones
(3aee) were determined by HPLC using a chiral stationary
phase (Chiralcel OD-H, n-hexane/2-propanol 95:5) (Table 1).
There are two major possibilities for the formation of non-
racemic g-aryl-g-butyrolactones (3aee). The first possibility
is that optical induction occurs in the reduction step. Nucleo-
philic attack of the chiral hydroxyl group on the carbonyl of
amide followed by subsequent removal of the amine could re-
sult in the formation of optically active g-aryl-g-butyro-
lactones (AAC2 type mechanism) (Scheme 3).
The second possibility is that optical induction does not
occur in the reduction step. The g-hydroxyamide obtained
by reduction loses water molecule on protonation resulting
in the formation of a diastereotopic carbocation. Nucleophilic
attack of the carbonyl oxygen of the chiral amide in an enan-
tioselective manner on the carbocation could result in the for-
mation of non-racemic g-aryl-g-butyrolactones (AAL1 type
mechanism). Asymmetric induction could be expected to oc-
cur in this step under the dissymmetric influence of the chiral
auxiliary (Scheme 4).
2. Results and discussion
In this work we have employed a chiral amine as chiral
auxiliary resulting in the formation of 3-aroyl propanamides.
Effectively we decreased the electrophilic nature of the car-
bonyl group of the propanoic acid derivative compared to
the 3-aroyl propanoates employed in our earlier work. This
would minimize the chances of lactonization by nucleophilic
attack of the hydroxyl group on the carbonyl carbon of the
propanoic acid derivative.
We aimed at studying the route, which involves creation of
only one chiral centre but undergoes a series of reactions for
the formation of the same. Our approach for enantioselective
formation of g-aryl-g-butyrolactones involved the use of (S)-
1-phenylethylamine as a chiral auxiliary. The synthesis of
novel chiral ketoamides of 3-aroylpropanoic acids and (S)-1-
phenylethylamine and their utility in the preparation of opti-
cally active g-aryl-g-butyrolactones are discussed.
The chiral ketoamides of 3-aroylpropanoic acids were syn-
thesized by first converting the g-keto acids into reactivebuteno-
lidesfollowedbytheirreactions withoptically activeamine. The
reaction of butenolides (1aee) with (S)-1-phenylethylamine re-
sulted in the formation of novel chiral ketoamides, (S)-3-aroyl-
N-(a-phenylethyl)propanamides (2aee) (Scheme 1).
The first possibility of asymmetric reduction of prochiral ke-
tones followed by lactonization appeared to be quite a strong
possibility. However, there were two aspects, which worked
against this proposed mechanism. The dissymmetric influence
Table 1
Percentage enantiomeric excess data of enantioselective synthesis of (S)-g-
aryl-g-butyrolactones
H
N
H
O
H
CH3
NH2
THF
0 °C
Entry
Compound
R
R0
Yield
ee (%)
O
O
+
CH3
O
1
2
3
4
5
3a
3b
3c
3d
3e
H
H
56
65
57
66
59
67
69
73
71
68
R
R
CH3
OCH3
CH3
Cl
H
R'
R'
H
1a-e
2a-e
CH3
H
Scheme 1. Synthesis of novel chiral ketoamides.
H
H
H
H
H
R'
H
R'
H
R'
H+
..
N
N
O
N
O O
2a-e
OH
OHO+
R*
R*
R*
H
R
R
R
H
+ N
O
H
H
R*
-H+
-R*NH2
H
N
O
H
R*
R'
R'
R'
O
O
O+
H
O
H
R
R
R
3a-e
Scheme 3. First possibilitydAAC2 type mechanism.

2994
A.V. Karnik, S.S. Kamath / Tetrahedron 64 (2008) 2992e2996
H+
H
H
-H2O
H
R'
R'
R'
N
N
N
OH
H
O O
2a-e
OH
O
+
O
R*
R*
R*
R
R
R
H
H
H
R'
H
R'
H
R'
+
+
N
N
N
O
O
O
+
R*
R*
R*
R
R
R
H2O
H
H
R*
H
H
H
+ N
O
-H+
-R*NH2
H
N
R'
R'
O
R*
+ OH2
R'
O
O
O
H
R
R
R
3a-e
Scheme 4. Proposed mechanism (AAL1 type mechanism) for the enantioselective formation of (S)-g-aryl-g-butyrolactones.
of the chiral auxiliary situated five atomic centres away was less
likely to influence the chiral induction significantly (67% ee,
experimental result). Secondly, the carbonyl of amide group is
not sufficiently electrophilic and hence the AAC2 type lactoniza-
tion becomes a remote possibility under acidic conditions.
To confirm the second possibility, it was decided to isolate
the intermediate hydroxyamide 4 (Scheme 5).
Lactone formation via the intermediate diastereotopic carbo-
cation is the route, which needed a closer look. The % ee found
are satisfactory to good (67e73% ee). The diastereoselectivity
in the reduction step was almost non-existent as established by
HPLC analysis of the isolated hydroxyamide indicating that
the chiral auxiliary was unable to exert any dissymmetric influ-
ence on the first reduction step. The direct nucleophilic displace-
ment of the hydroxyl group by intramolecular attack of the
amide carbonyl would have resulted in the same proportion of
enantioselectivity as that observed for the intermediate
hydroxyamide. The enhancement of enantioselectivity clearly
indicates that the reduced carbinol carbon goes to the carboca-
tion stage in order to facilitate enantioselective formation of
g-substituted-g-lactones. Thus the results indicate that a reac-
tion where only one chiral centre is created, can actually involve
a series of steps where the chiral centre can be created and de-
stroyed before actual formation of products. In view of these re-
sults all similar reactions, which involved such series of
reactions need to be verified to find out the actual step responsi-
ble for the final data as regards stereoselectivity observed.
H
N
H
O
H
N
H
HO
H
NaBH4
0 °C
CH3
CH3
O
O
R
R
R'
R'
2a,b
4a,b
Scheme 5. Preparation of g-hydroxyamide.
The hydroxyamide was found to be formed as a mixture of
two diastereoisomers. The formation of 4 as a mixture of two
diastereoisomers in almost equal proportion (Fig. 1a) supports
the second possibility, i.e., AAL1 type mechanism for the for-
mation of non-racemic g-aryl-g-butyrolactones. The % diaste-
reomeric excess of 4 does not match the % enantiomeric
excess found for 3 (Fig. 1), which indicates that the chiral cen-
tre formed initially during reduction step goes to the carbo-
cation stage in the subsequent step (acid catalyzed removal
of protonated hydroxyl group). The benzylic cations are reso-
nance stabilized and hence the formation of diastereotopic
carbocation is favoured. This is in accordance with our previ-
ously reported enantioselective synthesis of g-substituted
g-butyrolactones.21
3. Conclusion
The process does not involve dry conditions and does not use
expensive chiral metal catalysts/reagents such as BINAPe
Ru(II), diisopinocampheylborane, etc. In this methodology, the
stereoselective step does not involve diastereoselective carbonyl
group reduction. Rather the stereoselective step has been shown
to be involving the diastereotopic carbocation in the cyclization
Figure 1. HPLC chromatogram of (a) (R,S)-4-hydroxy-4-phenyl-N-(aS-phenylethyl)butanamide 4a and (b) (S)-g-phenyl-g-butyrolactone 3a.

A.V. Karnik, S.S. Kamath / Tetrahedron 64 (2008) 2992e2996
2995
process. Establishment of actual stereoselective step can facili-
tate the use of more efficient and inexpensive chiral auxiliaries.
144.1, 143.4, 134.1, 129.3, 128.6, 128.2, 127.2, 126.1 (aro-
matic carbons), 48.8 (AreCeNH), 34.0 (CH2), 30.4 (CH2),
21.9 (Me of PheCHCH3), 21.7 (AreMe). Anal. Calcd for
C19H21NO2: C, 77.29; H, 7.12; N, 4.75. Found: C, 77.35; H,
7.17; N, 4.68; m/z: 296.85 [MþH]þ.
4. Experimental
4.1. General
4.1.1.3. (S)-3-(40-Methoxybenzoyl)-N-(a-phenylethyl)propan-
amide 2c. White solid (1.21 g, 78%); mp 119e121 ꢀC; [a]D19
ꢁ91.7 (c 1, CHCl3); IR (KBr): 3262, 3065, 2976, 2929,
Optical rotations were measured on Jasco DIP-1000 digital
polarimeter. Enantiomeric excesses were determined on HPLC
Thermo Finnigan spectra system using Daicel Chiralcel OD
column with UV detector. IR spectra were recorded on
1
2843, 1671, 1640, 1598, 1563, 1509, 1494, 1449 cmꢁ1; H
NMR (300 MHz, CDCl3): d 7.93 (d, J¼8.7 Hz, 2H; ArH),
7.30e7.24 (m, 5H; ArH), 6.91 (d, J¼8.7 Hz, 2H; ArH), 6.10
(br s, 1H; NH), 5.13e5.04 (m, 1H; CH), 3.86 (s, 3H; CH3),
3.34e3.26 (m, 2H; CH2), 2.63e2.58 (m, 2H; CH2), 1.48 (d,
J¼6.6 Hz, 3H; CH3). Anal. Calcd for C19H21NO3: C, 73.31;
H, 6.75; N, 4.50. Found: C, 73.24; H, 6.84; N, 4.44.
1
Shimadzu FTIR-4200. H NMR and 13C NMR spectra were
scanned in CDCl3 on Bruker (300 MHz) and Varian Mercury
Plus (400 MHz) spectrometers with TMS as an internal stan-
dard. Elemental analyses were carried on Carlo Enra instru-
ment EA-1108 Elemental analyzer. Mass spectra were
obtained by using MS in ESI mode. All melting points are
uncorrected. Temperatures are recorded in degree Celsius.
Boiling point of petroleum ether used was in the range of 60e
80 ꢀC. 5-Arylfuran-2(3H)-ones or butenolides (1aee) were
prepared by lactonization of 3-aroylpropanoic acids using ace-
tic anhydride following literature procedure.22
4.1.1.4. (S)-3-(30,40-Dimethylbenzoyl)-N-(a-phenylethyl)propan-
amide 2d. White solid (1.38 g, 89%); mp 138 ꢀC; [a]D19 ꢁ75.6
(c 1, CHCl3); IR (KBr): 3323, 3060, 3031, 2974, 2922, 1679,
1646, 1607, 1572, 1537, 1493, 1447 cmꢁ1
;
1H NMR
(400 MHz, CDCl3): d 7.75e7.70 (m, 2H; ArH), 7.31e7.20
(m, 6H; ArH), 6.15 (br s, 1H; NH), 5.13e5.09 (m, 1H; CH),
3.40e3.27 (m, 2H; CH2), 2.63e2.57 (m, 2H; CH2), 2.31 (s,
6H; 2ꢂCH3), 1.48 (d, J¼6.9 Hz, 3H; CH3). Anal. Calcd for
C20H23NO2: C, 77.67; H, 7.44; N, 4.53. Found: C, 77.75; H,
7.47; N, 4.45.
4.1.1. Preparation of (S)-3-aroyl-N-(a-phenylethyl)-
propanamides 2aee
A solution of 5 mmol of butenolide (1aee) and 0.73 g
(0.77 mL, 6 mmol) of (S)-1-phenylethylamine in 25 mL of
THF was stirred at 0 ꢀC for 4 h. The reaction was quenched
with dilute hydrochloric acid and extracted with chloroform.
The organic extract was washed with sodium carbonate solu-
tion, dried over anhydrous sodium sulfate and evaporated.
The crude compound obtained was washed well with ice-
cold ether to give (2aee) as white solid.
4.1.1.5. (S)-3-(40-Chlorobenzoyl)-N-(a-phenylethyl)propana-
mide 2e. White solid (1.25 g, 79%); mp 134e136 ꢀC; [a]D19
ꢁ85.7 (c 1, CHCl3); IR (KBr): 3304, 3065, 3029, 2974, 2925,
1
1684, 1648, 1590, 1570, 1546, 1494, 1447 cmꢁ1; H NMR
(300 MHz, CDCl3): d 7.91 (d, J¼8.4 Hz, 2H; ArH), 7.43 (d,
J¼8.4 Hz, 2H; ArH), 7.38e7.30 (m, 5H; ArH), 6.00 (br d,
J¼6.3 Hz, 1H; NH), 5.15e5.06 (m, 1H; CH), 3.42e3.22 (m,
2H; CH2), 2.70e2.55 (m, 2H; CH2), 1.49 (d, J¼6.9 Hz, 3H;
CH3). Anal. Calcd for C18H18ClNO2: C, 68.46; H, 5.71; Cl,
11.25; N, 4.44. Found: C, 68.37; H, 5.75; Cl, 11.31; N, 4.51.
4.1.1.1. (S)-3-Benzoyl-N-(a-phenylethyl)propanamide 2a. White
solid (1.19 g, 85%); mp 133 ꢀC; [a]D19 ꢁ84.5 (c 1, CHCl3); IR
(KBr): 3337, 3057, 3033, 2972, 2925, 1685, 1654, 1596, 1579,
1
1526, 1494, 1445 cmꢁ1; H NMR (300 MHz, CDCl3): d 7.98
(d, J¼6.9 Hz, 2H; ArH), 7.59e7.55 (m, 1H; ArH), 7.49e7.44
(m, 2H; ArH), 7.32e7.26 (m, 5H; ArH), 6.04 (br s, 1H; NH),
5.15e5.07 (m, 1H; CH), 3.41e3.33 (m, 2H; CH2), 2.66e2.61
(m, 2H; CH2), 1.49 (d, J¼6.9 Hz, 3H; CH3); 13C NMR
(300 MHz, CDCl3): d 199.2 (AreCO), 171.1 (NHeCO), 143.3,
136.7, 133.3, 128.6, 128.1, 127.2, 126.1 (aromatic carbons),
48.9 (AreCeNH), 34.1 (CH2), 30.4 (CH2), 21.9 (Me of
PheCHCH3). Anal. Calcd for C18H19NO2: C, 76.87; H, 6.76;
N, 4.98. Found: C, 76.81; H, 6.84; N, 4.89.
4.1.2. Enantioselective synthesis of (S)-g-aryl-g-butyro-
lactones 3aee
To a stirred solution of 2 mmol of chiral ketoamide (2aee)
in 20 mL of methanol at 0 ꢀC, 38 mg (1 mmol) of sodium bo-
rohydride was added in portions and the mixture was stirred
for 2 h at the same temperature. Once complete conversion
of 2 was observed on TLC, the reaction mixture was treated
with 100 mL of cold 6 M HCl. The mixture was stirred for fur-
ther 12 h at ꢁ5 to 0 ꢀC. The reaction mixture was extracted
with chloroform, dried over anhydrous sodium sulfate and
evaporated. The crude compound was crystallized using petro-
leum ether to give (3aee) as white crystals (majority of
g-aryl-g-butyrolactones are solids).
4.1.1.2.
(S)-3-(40-Methylbenzoyl)-N-(a-phenylethyl)propan-
amide 2b. White solid (1.27 g, 86%); mp 133 ꢀC; [a]D19
ꢁ86.2 (c 1, CHCl3); IR (KBr): 3309, 3063, 3028, 2973,
1
2925, 1682, 1651, 1607, 1540, 1493, 1446 cmꢁ1; H NMR
(300 MHz, CDCl3): d 7.88 (d, J¼7.8 Hz, 2H; ArH), 7.31e
7.24 (m, 7H; ArH), 6.03 (br s, 1H; NH), 5.15e5.06 (m, 1H;
CH), 3.38e3.31 (m, 2H; CH2), 2.64e2.60 (m, 2H; CH2),
2.41 (s, 3H; CH3), 1.49 (d, J¼6.6 Hz, 3H; CH3); 13C NMR
(300 MHz, CDCl3): d 198.8 (AreCO), 171.3 (NHeCO),
4.1.2.1. (S)-g-Phenyl-g-butyrolactone 3a. Colourless oil (0.18 g,
56%); [a]1D9 ꢁ22.6 (c 0.5, CH2Cl2) (lit.23 [a]D þ31.0 (c 0.675,
CH2Cl2) for 92% ee in the R-isomer); IR (KBr): 3064,
;
3034, 2985, 2950, 1770, 1606, 1496, 1455 cmꢁ1 1H NMR

2996
A.V. Karnik, S.S. Kamath / Tetrahedron 64 (2008) 2992e2996
(400 MHz, CDCl3): d 7.40e7.31 (m, 5H; ArH), 5.49 (t, 1H;
CH), 2.69e2.60 (m, 3H; CH2, CH), 2.24e2.12 (m, 1H; CH).
Anal. Calcd for C10H10O2: C, 74.07; H, 6.17. Found: C, 74.15;
H, 6.11.
Anal. Calcd for C18H21NO2: C, 76.33; H, 7.42; N, 4.95.
Found: C, 76.27; H, 7.49; N, 4.86; m/z: 283 [M]þ. For R-iso-
mer, mp 79e80 ꢀC; [a]D19 þ73.1 (c 1, CHCl3).
4.1.3.2.
4-Hydroxy-4-(40-methylphenyl)-N-(aS-phenylethyl)-
4.1.2.2. (S)-g-(4-Methylphenyl)-g-butyrolactone 3b. White
crystals (0.23 g, 65%); mp 71e72 ꢀC; IR (KBr): 2926, 1765,
butanamide 4b. White solid (0.58 g, 98%); mp 100e102 ꢀC;
[a]1D9 ꢁ66.3 (c 1, CHCl3); IR (KBr): 3558, 3306, 3063,
1
1615, 1520, 1455 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
3029, 2973, 2923, 2868, 1646, 1542, 1493, 1444 cmꢁ1; H
d 7.23 (d, J¼8.3 Hz, 2H; ArH), 7.20 (d, J¼8.3 Hz, 2H;
ArH), 5.48 (t, 1H; CH), 2.69e2.59 (m, 3H; CH2, CH), 2.36
(s, 3H; CH3), 2.23e2.15 (m, 1H; CH). Anal. Calcd for
C11H12O2: C, 75.00; H, 6.82. Found: C, 75.07; H, 6.85.
NMR (300 MHz, CDCl3): d 7.34e7.26 (m, 5H; ArH), 7.22
(d, J¼7.8 Hz, 2H; ArH), 7.13 (d, J¼7.8 Hz, 2H; ArH), 5.94
(br s, 1H; NH), 5.15e5.07 (m, 1H; CH), 4.73e4.69 (m, 1H;
CH), 3.52 (br s, 1H; OH), 2.33e2.29 (m, 5H; CH3, CH2),
2.06e2.02 (m, 2H; CH2), 1.47 (d, J¼7.2 Hz, 3H; CH3); 13C
NMR (300 MHz, CDCl3): d 172.6 (NHeCO), 143.1, 141.5,
136.9, 129.0, 128.6, 127.3, 126.1, 125.7 (aromatic carbons),
48.9 (AreCeNH), 34.4 (CH2), 33.0 (CH2), 21.7 (Me of
PheCHCH3), 21.1 (AreMe). Anal. Calcd for C19H23NO2:
C, 76.77; H, 7.74; N, 4.71. Found: C, 76.71; H, 7.79; N,
4.75; m/z: 298.37 [MþH]þ. For R-isomer, mp 100e102 ꢀC;
[a]1D9 þ70.1 (c 1, CHCl3).
4.1.2.3. (S)-g-(4-Methoxyphenyl)-g-butyrolactone 3c. White
crystals (0.22 g, 57%); mp 48e50 ꢀC; IR (KBr): 2969, 2843,
1
1762, 1611, 1517, 1457 cmꢁ1; H NMR (300 MHz, CDCl3):
d 7.24 (d, J¼8.7 Hz, 2H; ArH), 6.89 (d, J¼8.7 Hz, 2H;
ArH), 5.44 (t, 1H; CH), 3.80 (s, 3H; CH3), 2.67e2.57 (m,
3H; CH2, CH), 2.22e2.16 (m, 1H; CH). Anal. Calcd for
C11H12O3: C, 68.75; H, 6.25. Found: C, 68.68; H, 6.16.
4.1.2.4. (S)-g-(3,4-Dimethylphenyl)-g-butyrolactone 3d. White
crystals (0.25 g, 66%); mp 76e77 ꢀC; IR (KBr): 2963, 2920,
Supplementary data
2855, 1769, 1615, 1505, 1456, 1444 cmꢁ1
;
1H NMR
Chiral HPLC analysis of (S)-g-aryl-g-butyrolactones and
g-hydroxyamides are available in supplementary data. Supple-
mentary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.01.077.
(400 MHz, CDCl3): d 7.14 (d, J¼7.6 Hz, 1H; ArH), 7.10 (s,
1H; ArH), 7.05 (d, J¼7.6 Hz, 1H; ArH), 5.45 (t, 1H; CH),
2.67e2.58 (m, 3H; CH2, CH), 2.27 (s, 3H; CH3), 2.26 (s,
3H; CH3), 2.24e2.14 (m, 1H; CH). Anal. Calcd for
C12H14O2: C, 75.79; H, 7.37. Found: C, 75.83; H, 7.29.
References and notes
4.1.2.5. (S)-g-(4-Chlorophenyl)-g-butyrolactone 3e. Colour-
less oil (0.23 g, 59%); IR (KBr): 3068, 2987, 2951, 1789,
1. Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron: Asymmetry 2003, 14, 1.
2. May, W. A.; Peterson, R. J.; Chang, S. S. J. Food Sci. 1978, 43, 1248.
3. Mosandl, A.; Gunther, C. J. Agric. Food Chem. 1989, 37, 413.
4. Guichard, E. ACS Symp. Ser. 1995, 596, 258.
1599, 1495, 1457 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d 7.35 (d, J¼7.8 Hz, 2H; ArH), 7.25 (d, J¼7.8 Hz, 2H;
ArH), 5.47 (t, 1H; CH), 2.66e2.63 (m, 3H; CH2, CH),
2.23e2.12 (m, 1H; CH). Anal. Calcd for C10H9ClO2: C,
61.07; H, 4.58; Cl, 18.07. Found: C, 61.01; H, 4.49; Cl, 18.15.
5. Leal, W. S.; Kuwahara, S.; Ono, M.; Kubota, S. Bioorg. Med. Chem. 1996,
4, 315.
6. Mori, K. Acc. Chem. Res. 2000, 33, 102.
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K.; Sholichin, M.; Kawasaki, T. J. Nat. Prod. 1987, 50, 245.
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10. Kinoshita, M.; Aburaki, S.; Umezawa, S. J. Antibiot., Ser. A 1972, 25, 373.
11. Itazaki, H.; Nagashima, K.; Kawamura, Y.; Matsumoto, K.; Nakai, H.;
Terui, Y. J. Antibiot. 1992, 45, 38.
4.1.3. Preparation of g-hydroxyamides 4a,b
Sodium borohydride (38 mg, 1 mmol) was added in por-
tions to 2 (2 mmol) in 20 mL of methanol at 0 ꢀC, and the
mixture stirred for 2 h. The reaction mixture was poured into
cold water and extracted with chloroform. The organic extract
was dried over anhydrous sodium sulfate, which on evapora-
tion afforded the pure g-hydroxyamides 4.
12. Cave, A.; Chaboche, C.; Figadere, B.; Harmange, J. C.; Laurens, A.;
Peyrat, J. F.; Pichon, M.; Szlosek, M.; Cotte-Laffite, J.; Quero, A. M.
Eur. J. Med. Chem. 1997, 32, 617.
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Agric. Biol. Chem. 1978, 42, 457.
4.1.3.1. 4-Hydroxy-4-phenyl-N-(aS-phenylethyl)butanamide 4a.
White solid (0.56 g, 99%); mp 80e81 ꢀC; [a]D19 ꢁ74.1 (c 1,
CHCl3); IR (KBr): 3553, 3295, 3063, 3030, 2970, 2922,
14. Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571.
15. Ye, Y.; Qin, G.; Xu, R. Phytochemistry 1994, 37, 1201.
16. Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31, 5509.
17. Ramachandran, P. V.; Brown, H. C.; Pitre, S. Org. Lett. 2001, 3, 17.
18. Nair, V.; Prabhakaran, J. J. Chem. Soc., Perkin Trans. 1 1996, 593.
19. Tamai, Y.; Koike, S.; Ogura, A.; Miyano, S. J. Chem. Soc., Chem.
Commun. 1991, 799.
2864, 1645, 1546, 1494, 1445 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 7.33e7.26 (m, 10H; ArH), 5.93 (br s, 1H; NH),
5.16e5.07 (m, 1H; CH), 4.76e4.72 (m, 1H; CH), 3.70 (br s,
1H; OH), 2.34e2.29 (m, 2H; CH2), 2.07e2.00 (m, 2H;
CH2), 1.47 (d, J¼7.2 Hz, 3H; CH3); 13C NMR (300 MHz,
CDCl3): d 172.6 (NHeCO), 144.5, 143.1, 128.7, 128.4,
127.4, 127.3, 126.2, 125.7 (aromatic carbons), 48.9 (AreCe
NH), 34.3 (CH2), 33.0 (CH2), 21.7 (Me of PheCHCH3).
20. Utaka, M.; Watabu, H.; Takeda, A. J. Org. Chem. 1987, 52, 4363.
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