TiCl4 promoted menthyl ester chiral auxiliary mediated synthesis of chiral syn-β-amino esters and applications of a representative syn-β-amino ester

Article abstract of DOI:10.1016/j.tetasy.2010.02.010

β-Amino esters were obtained in up to 78% yield with 72:28-96:4 diastereomeric ratios by the reaction of the chiral titanium enolate of menthyl esters, prepared using the TiCl₄/Et₃N reagent system with prochiral imines. A representative syn-β-amino ester derivative has been used for the resolution of racemic mandelic acid to obtain a sample with >99% ee in a single step. A representative syn-β-amino ester was converted to the corresponding N-deprotected amino ester using the Pd-C/HCOOH reagent system, and then to the corresponding β-amino acid using the glacial CH₃COOH/HCl reagent system, and to the corresponding β-lactam derivative with partial epimerization by the reaction using C₂H₅MgBr.

Full text of DOI:10.1016/j.tetasy.2010.02.010

Tetrahedron: Asymmetry 21 (2010) 385–392
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
TiCl4 promoted menthyl ester chiral auxiliary mediated synthesis of chiral
syn-b-amino esters and applications of a representative syn-b-amino ester
*
Mariappan Periasamy , Subramaniapillai Selva Ganesan, Surisetti Suresh
School of Chemistry, University of Hyderabad, Central University PO, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
b-Amino esters were obtained in up to 78% yield with 72:28–96:4 diastereomeric ratios by the reaction of
the chiral titanium enolate of menthyl esters, prepared using the TiCl4/Et3N reagent system with prochi-
ral imines. A representative syn-b-amino ester derivative has been used for the resolution of racemic
mandelic acid to obtain a sample with >99% ee in a single step. A representative syn-b-amino ester
was converted to the corresponding N-deprotected amino ester using the Pd–C/HCOOH reagent system,
and then to the corresponding b-amino acid using the glacial CH3COOH/HCl reagent system, and to the
corresponding b-lactam derivative with partial epimerization by the reaction using C2H5MgBr.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 October 2009
Revised 8 February 2010
Accepted 16 February 2010
Available online 16 March 2010
1. Introduction
the corresponding acid chloride and triethylamine in dichloro-
methane solvent under ambient conditions (Fig. 1).
b-Amino acids and esters are useful building blocks for the syn-
thesis of b-lactams, which are important structural elements in
many therapeutic drug molecules.1 b-Amino acid moieties are
present in several natural products and bioactive molecules.2
Amongst the several methods available for the synthesis of b-ami-
no acid derivatives,3 asymmetric Mannich-type reactions have at-
tracted considerable interest.4 The use of titanium enolates in
Mannich-type reaction gave high levels of selectivity.5 Herein, we
report the diastereoselective synthesis of syn-b-amino esters by
an asymmetric Mannich-type reaction using a TiCl4/Et3N reagent
system.
Initially, the reaction between
L
-(ꢀ)-menthyl ester and N-ben-
zylidenebenzylamine 7a was screened with TiCl4 in combination
with different tertiary amines (Table 1, entries 1–4). The TiCl4/
Et3N reagent system gave the corresponding b-amino esters in rel-
atively good yield and with high selectivity (Scheme 2, Table 1, en-
tries 4 and 7). The lowering of temperature below ꢀ45 °C did not
increase the yield of selectivity of the amino ester product formed
(Table 1, entry 6). The results are summarized in Table 1.
The major product 8a was isolated from the diastereomeric
mixture 8 by column chromatography. It readily forms a complex
with (R)-(ꢀ)-mandelic acid 10a in a CH2Cl2–acetone mixture at
25 °C (Scheme 3). Crystals suitable for X-ray single crystal struc-
ture analysis were obtained by crystallizing complex 11 from a tol-
uene–isopropanol mixture.
2. Results and discussion
The X-ray analysis of complex 11 revealed that the product has
an (R,R) absolute configuration at the newly formed stereogenic
centers. The crystal structure of the complex 11 is given in
Figure 2.8
The diastereoselective Mannich-type reaction of chiral imine 2
and ester 1 with TiCl4/Et3N reagent system gave the corresponding
b-amino ester 3 in good yield with good diastereoselectivity
(Scheme 1).6
The reaction of
L
-(ꢀ)-menthyl butyrate 5 and imines 7b–g with
However, it is difficult to remove and reuse the
a-methylben-
TiCl4/Et3N reagent system gave the corresponding b-amino esters
12–16 and 18 in moderate to good yield and with good selectivity
(Scheme 4, Table 2, entries 1–5, 7). The syn-b-amino ester 17 was
zylamine group present in the syn-b-amino ester product 3.
Accordingly, we have undertaken efforts to utilize chiral ester moi-
eties, which can be easily removed and reused. The readily avail-
obtained by the reaction of D-(+)-menthyl butyrate and imine 7a
able, naturally occurring
auxiliary to prepare the chiral menthyl esters 5 and 6. Menthol
L
-(ꢀ)-menthol 4 was chosen as a chiral
with the aforementioned reagent system (Table 2, entry 6). The
diastereomeric ratios of the b-amino esters 12–18 were estimated
from the 1H NMR signals. The results are summarized in Table 2.
The imines derived from aliphatic amines gave better yield and
selectivity compared to the aniline-derived imines (Table 2, entry
7). The stereochemistry of the major products 12–16 and 18 was
assigned as syn by making a comparison of the 1H NMR data of
and its derivatives have proven applications as chiral handles in
various asymmetric transformations.7 The
and 6 were easily accessed by the reaction of
L
-(ꢀ)-menthyl esters 5
L
-(ꢀ)-menthol with
* Corresponding author. Tel.: +91 40 23134814; fax: +91 40 23012460.
E-mail address: mpsc@uohyd.ernet.in (M. Periasamy).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.010

386
M. Periasamy et al. / Tetrahedron: Asymmetry 21 (2010) 385–392
Ph
Ph
(R)
CH3
CH3
(R)
(R)
Ph
1. TiCl4, -45 ºC, CH2Cl2
0.5 h
HN
(S)
Ar
CH3
HN
(R)
Ar
N
MeOOC
+
MeOOC
(S)
MeOOC
(R)
R1
+
Ar
R1
1
2. Et3N, -45 ºC to 25 ºC,
3 h
R1
3a
2
3b
major-(S,S,R)
minor-(R,R,R)
i
R1 = C2H5, Bn, Pr
Yield = 73 to 93%
dr = 86:14 to 96:4
Ar = p-MeC6H4,p-MeOC6H4,p-ClC6H4, C6H5
Scheme 1.
these products with the data for compound 8. The 1H NMR spec-
trum of the product mixture 15 is shown in Figure 3. The coupling
constants of the –CH proton adjacent to the amine group of the
minor anti product mixture is smaller (J = 2.8 and 2.4 Hz) com-
pared to those of the major syn-product (J = 8.4 Hz) (Fig. 3).
Similar observations have been previously reported in some
menthyl-derived anti- and syn-b-amino esters.9a From the diaste-
reomeric mixture 15, the major syn-b-amino ester product 15a
was isolated in pure form. The minor anti product mixture 15b
was also separated and the 1H spectroscopic analysis revealed that
it was a 1:1 mixture of anti diastereomers.
O
O
Ph
OH
O
O
L-(-)-menthol
L-(-)-menthyl butyrate
L-(-)-menthylphenyl acetate
Yield = 82%
4
5
Yield = 89%
6
Figure 1.
The origin of the asymmetric induction in the asymmetric Man-
nich-type reaction and the formation of the major product can be
rationalized as outlined in Figure 4. It is reported in the literature
that the presence of a chelating atom or a group in the substrate
favors the preferential formation of the Z-titanium ester enolate
over an E-enolate.9b,c In other cases, the equilibrium is favored to
the E-enolate (alkyl group and O–Ti are trans to each other).6,10
Based on the stereochemistry of the major product formed and
the absence of chelating atom or group in the menthyl ester moi-
ety, the preferred geometry of the titanium menthyl ester enolate
participating in the reaction was assigned as E. The Re face attack of
the E-titanium menthyl ester enolate onto the imine in TS-1 is
more favorable because the bulky isopropyl group is positioned
far away from the C–C bond-forming side. Hence, the low-energy
transition state TS-1 would give the major product with an (R,R)-
absolute configuration. The Re and Si face attack of the Z-titanium
menthyl ester enolate onto the imine (TS-II and TS-III) is less
favorable because of the enhancement in the steric interaction be-
tween ethyl and benzyl groups. Hence, these high-energy transi-
Table 1
Reaction of menthyl ester and imine 7a with TiCl4/R3N reagent systema
Entry
R3N
TiCl4 (equiv)
Temp (°C)
Yieldb (%)
1
2
iPr2NEt
iPr2NCH2Ph
nBu3N
Et3N
Et3N
Et3N
2
2
2
2
1
2
2
ꢀ45
ꢀ45
ꢀ45
ꢀ45
ꢀ45
ꢀ65
ꢀ45
0
<10
3
44
72
36
70e
54
4c
5
6d
7f
Et3N
a
Unless otherwise mentioned, all reactions were carried out using 2.2 mmol of
menthyl ester 5 and 2 mmol of benzylidenebenzylamine 7a in 20 mL of CH2Cl2. R3N
(2.1 mmol) was added after 0.5 h from the addition of TiCl4 (4.5 mmol) at ꢀ45 °C
and the reaction mixture was stirred for a further 6 h at ꢀ45 °C.
b
Yields are for the isolated products.
c
With Ti(OiPr)4 and TiCl2(OiPr)2, the formation of product 8 was not observed.
d
The reaction was carried out for 12 h.
The diastereomeric ratios of entry 4 are similar to those of entry 6.
The reaction was carried out with menthyl ester 6.
e
f
CH2Ph
CH2Ph
Ph
O
PhH2C
O
HN
O
HN
1. TiCl4, -45 ºC, 0.5 h
2. Et3N, -45 ºC, 6 h
N
+
O
+
O
Ph
O
Ph
R
R
R
8-9a
R = Et 5, Ph 6
8-9b
7a
8 Yield = 72%, dr = 92:8
9 Yield = 54%, dr = 86:14
Scheme 2.
OH
OH
O
NHCH2Ph
OH
CH2Cl2/acetone
25 ºC, 3 h
O
NH2CH2Ph
O
O
O
Et
O
OH
Et
8a
10a
11
Scheme 3.

M. Periasamy et al. / Tetrahedron: Asymmetry 21 (2010) 385–392
387
C25
C24
C26
C23
C27
C13
C12
N1
C22
C15
C14
C28
O2
C16
C21
C17
C11
O1
C3
C6
C1
C18
C19
C2
C4
C5
C33
C32
C9
C20
C34
C35
O3
C7
C8
C10
C31
C29
O4
C36
C30
O5
Figure 2. ORTEP representation of the crystal structure of complex 11 (thermal ellipsoids are drawn at 20% probability).
R
R
R
O
HN
O
HN
1. TiCl4, -45 ºC, 0.5 h
2. Et3N, -45 ºC, 6 h
O
N
+
+
O
Ar
O
Ar
O
Ar
Et
Et
Et
5
7a-g
12a-18a
D-(+)-menthyl butyrate used for preparing syn-β-amino ester 17
Ar = Ph, p-MeC6H4, p-OMeC6H4, m-MeC6H4, p-ClC6H4
12b-18b
R = CH2Ph, nBu, Ph
Scheme 4.
Table 2
Mannich-type reaction of menthyl ester 5 and imines with TiCl4/Et3Na
rotation equal in magnitude but opposite in direction to that of
the compound 8. We have observed that the major product 17a
does not form a precipitate with (R)-(ꢀ)-mandelic acid 10a even
after stirring for three days in CH2Cl2–acetone mixture at 25 °C.
Under similar conditions, the major product 17a readily forms a
precipitate with (S)-(+)-mandelic acid 10b. This difference in solu-
bility of the diastereomeric complexes prompted us to examine the
resolution of racemic mandelic acid 10 using the syn-b-amino ester
8a. The syn-b-amino ester 8a resolved the racemic mandelic acid
10 to >99% ee in a single step (Scheme 5). The complex 11 of the
syn-b-amino ester 8a and (R)-(ꢀ)-mandelic acid 10a precipitated
out leaving the (S)-(+)-mandelic acid in the filtrate fraction.
At room temperature, the syn-b-amino ester 8a is partially sol-
uble in acetone and completely soluble in CH2Cl2. Presumably, this
may be the reason for the efficient resolution of racemic mandelic
acid 10 by the syn-b-amino ester 8a in the acetone–CH2Cl2 solvent
system.
The syn-b-amino ester 8a is easily recovered from the reaction
mixture and can be reused without any loss in chirality. The crys-
talline nature and its high resistance to air and moisture would
make the syn-b-amino ester 8a an efficient reagent for the resolu-
tion of racemic carboxylic acids and hence it is a good addition to
the pool of chiral resolving agents available for the resolution of
racemic carboxylic acids.11
Entry
R (amine)
Ar (aldehyde)
Product
Yieldb (%)
syn:antic
1
2
3
4
–CH2Ph 7b
–CH2Ph 7c
–CH2Ph 7d
–nBu 7e
–CH2Ph 7f
–CH2Ph 7a
–Ph 7g
p-MeC6H4
p-OMeC6H4
m-MeC6H4
–Ph
p-ClC6H4
–Ph
12
13
14
15d
16
17f
18
69
64
71
78
54
76
45
82:18
83:17
96:4
80:20
79:21
93:7
5
6e
7g
–Ph
72:28
a
Unless otherwise mentioned, all reactions were carried out using 5.5 mmol of
menthyl ester 5 and 5 mmol of imine in 40 mL of CH2Cl2. Et3N (5 mmol) was added
after 0.5 h via the addition of TiCl4 (12 mmol) at ꢀ45 °C and the reaction mixture
was stirred for 6 h at ꢀ45 °C.
b
The structure of the products were confirmed by spectral data (IR, 1H NMR, 13
C
NMR, and mass spectrometry). Yields are for the isolated syn:anti mixture of
products. The major products 12a–18a are isolated in pure form from the mixture
by crystallization from hexane. The yield, physical constant, and spectroscopic data
for products 12a–18a are given in Section 5.
c
The diastereomeric ratios (syn:anti) were estimated from 1H NMR (400 MHz)
data.
d
The anti product mixture was isolated from the syn:anti product mixture. The
1H and 13C NMR analyses revealed that the anti product is a 1:1 mixture of two anti
diastereomers.
e
The reaction was carried out with
The absolute configuration of the major isomer of the product 17 was assigned
D
-(+)-menthyl butyrate.
f
as (S,S) from the crystal structure of its complex with (S)-(+)-mandelic acid.
g
After the addition of Et3N, the reaction mixture was warmed to 0 °C for 2 h and
then stirred at the same temperature for a further 12 h.
3. Synthesis of N-,O-deprotected derivatives and b-lactam
product of syn-b-amino ester 8a
tion states TS-II and TS-III would give the minor anti products with
(S,R)- and (R,S)-absolute configuration.
We have observed that N-debenzylation of the syn-b-amino es-
ter 8a can be readily carried out by reaction of the dispersion of Pd/
C in formic acid and methanol (1:4 v/v) at 50 °C (Scheme 6). The
The syn-b-amino ester 17 obtained by the reaction of
D-(+)-
menthyl butyrate with benzylidenebenzylamine 7a has a specific

388
M. Periasamy et al. / Tetrahedron: Asymmetry 21 (2010) 385–392
nBu
O
major (syn
J = 8.4 Hz
)
HN
H
O
H
nBu
15a
O
HN
H
O
H
15b
minor (anti
)
J = 2.4 Hz
J = 2.8 Hz
1.00
0.12
3.68
0.13
3.78
3.77
3.76
3.75
3.74
3.73
3.72
3.71
3.70
3.69
3.67
3.66
3.65
3.64
3.63
Figure 3. 1H NMR spectrum of the product mixture 15.
TS-I (E-enolate and E-imine-Re face attack)
Ph
Ph
H
H
Et
O
(R,R) (major)
NH
Et
H
Ph
R1OOC
H
O
N
Ph
Ti
Ln
R1= Menthyl
TS-II (Z-enolate and E-imine-Re face attack)
(R)
Ph
Ph
H
H
H
O
(S,R) (minor)
NH
R1OOC
H
Et
Ph
(S)
Et
O
N
Ph
Ti
Ln
TS-III (Z-enolate and E-imine-Si face attack)
H
H
(R)
R1OOC
H
Ph
Et
Ph
(minor)
(R,S)
O
H
Et
N
(S)
O
HN
Ph
TiLn
Ph
Figure 4. Stereochemical models.
debenzylated product 19 was obtained in 86% yield. We have
found that the syn-b-amino acid 20 can be prepared by refluxing
the syn-b-amino ester 8a with a mixture of glacial acetic acid and
conc. HCl albeit in a moderate 44% yield (Scheme 6). We have
also examined the conversion of the representative syn-b-amino
ester 8a to the corresponding b-lactam using the C2H5MgBr re-
agent. In this reaction, the b-lactam product 21 was obtained
in 56% yield with some partial epimerization even at 0 °C
(Scheme 6) while the b-lactam was not formed in the reaction
at ꢀ30 °C.
4. Conclusion
In conclusion, the chiral b-amino esters 8, 9, 12–18 were ob-
tained in moderate to good yields with good selectivity by the
asymmetric Mannich-type reaction of menthyl ester and imines
using the TiCl4/Et3N reagent system. The readily accessible syn-b-
amino acid ester 8a is useful for the resolution of racemic mandelic
acid 10 in >99% ee in a single step and it is a promising resolving
agent for the resolution of racemic carboxylic acids. The N-deben-
zylation of the syn-b-amino acid ester 8a was carried out using a

M. Periasamy et al. / Tetrahedron: Asymmetry 21 (2010) 385–392
389
1. Na2CO3/Ether
2. 3M HCl/Ether
N2 atmosphere, followed by the slow addition of triethylamine
(1.31 g, 1.81 mL, 13 mmol) in CH2Cl2 (10 mL) using a dropping fun-
nel over a period of 10 min. The reaction mixture was slowly
warmed to 25 °C and stirred at the same temperature for further
6 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and
washed successively with 5% NaHCO3 (20 mL), water (20 mL),
and brine solution (10 mL). The organic layer was separated, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash silica gel column
10a
(R)-(-)-
Precipitate
(>99%ee)
OH
CO2H
Yield = 28%
8a,
25 ºC, 12 h
Acetone/CH2Cl2
(11:5 v/v)
( )-10
1. Na2CO3/Ether
2. 3M HCl/Ether
(S)-(+)-10b
Filtrate
(42%ee)
Yield = 61%
(230–400 mesh) to isolate pure (L)-(ꢀ)-menthyl esters using hex-
ane/EtOAc (99:1) as an eluent.
Scheme 5.
5.2.1.
L
-(ꢀ)-Menthyl butyrate 5
Yield: 2.01 g (89%); IR (neat): 2961, 2872, 1726 cmꢀ1
;
1H NMR
Pd–C/HCOOH reagent system. The syn-b-amino acid 20 was syn-
thesized by the hydrolysis of syn-b-amino ester 8a with a glacial
CH3COOH/HCl reagent system. The b-lactam product 21 was ob-
tained by the reaction of a C2H5MgBr reagent with syn-b-amino es-
ter 8a. Accordingly, the method described here for the synthesis
and the application of the syn-b-amino esters has considerable po-
tential for further exploitation.
(400 MHz, CDCl3, d ppm): 0.76 (d, J = 6.8 Hz, 3H), 0.88–1.08 (m,
12H), 1.34–1.50 (m, 2H), 1.62–1.68 (m, 4H), 1.85–2.10 (m, 2H),
2.26 (t, J = 7.3 Hz, 2H), 4.68 (dt, J = 10.8 Hz, J = 4.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3, d ppm): 13.7, 16.3, 18.7, 20.8, 22.1, 23.5,
26.3, 31.4, 34.4, 36.7, 41.0, 47.1, 73.9, 173.3; ½a D25
¼ ꢀ74:7 (c 1.1,
ꢂ
C2H5OH). {Lit.12
½
a 2D5
ꢂ
¼ ꢀ75:8 (c 1, C2H5OH)}.
5. Experimental section
5.2.2.
Yield: 2.25 g (82%); IR (neat): 3065, 3032, 2955, 1730,
1454 cmꢀ1 1H NMR (400 MHz, CDCl3, d ppm): 0.70 (d, J = 6.8 Hz,
L
-(ꢀ)-Menthylphenyl acetate 6
5.1. Materials and methods
;
3H), 0.85 (d, J = 7.1 Hz, 3H), 0.90–0.93 (m, 4H), 0.96–1.10 (m,
2H), 1.33–1.50 (m, 2H), 1.64–1.79 (m, 3H), 1.98–2.0 (m, 1H), 3.61
(s, 2H), 4.69 (dt, J = 10.9 Hz, J = 4.4 Hz, 1H), 7.26–7.34 (m, 5H);
13C NMR (100 MHz, CDCl3, d ppm): 16.3, 20.7, 22.0, 23.5, 26.2,
31.4, 34.3, 40.8, 41.9, 47.1, 74.7, 126.9, 128.5, 129.2, 134.4, 171.2;
The melting points reported in this Letter are uncorrected and
were determined using a Superfit capillary point apparatus. IR spec-
tra were recorded on a JASCO FT-IR spectrophotometer Model 5300.
1H NMR and 13C NMR spectra were recorded on a Bruker Avance-400
Spectrometer with chloroform-d as a solvent and TMS as reference.
Optical rotations were measured in an AUTOPOL-IV digital polarim-
eter (readability 0.001o). Liquid chromatography (LC) and mass
analysis (LC–MS) were performed on SHIMADZU-LCMS-2010A. Ele-
mental analyses were carried out using a Perkin–Elmer elemental
analyzer model-240C and a Thermo Finnigan analyzer series Flash
EA 1112. HPLC analyses were performed on an SCL-10ATVP SHIMA-
DZU instrument. The ee values were determined using CHIRALCEL
OD-H column (4.6 ꢁ 250 mm) with eluents: hexane, 2-propanol, tri-
fluoroacetic acid at a rate 0.5 mL/min, with the monitoring wave
length 254 nm.
½
a 2D5
ꢂ
¼ ꢀ71:8 (c 0.62, CHCl3).
5.3. General procedure for the synthesis of chiral syn-b-amino
esters derived from menthyl ester and imines
To a stirred solution of menthyl ester (5.5 mmol) and imine
(5 mmol) in CH2Cl2 (40 mL) at ꢀ45 °C, a solution of TiCl4 (12 mmol,
2.28 g, 1.3 mL) in 15 mL of CH2Cl2 was slowly added through an
addition funnel over a period of 10 min under an N2 atmosphere.
After stirring for 0.5 h, triethylamine (0.70 mL, 5 mmol) was added
and the reaction mixture was stirred at ꢀ45 °C for a further 6 h.
The reaction was quenched with saturated aq K2CO3 (15 mL) solu-
tion, brought to room temperature, and filtered through a Buckner
funnel. The organic layer was separated and the aqueous layer was
counter extracted with CH2Cl2 (2 ꢁ 25 mL). The combined organic
extracts were washed with brine (15 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
5.2. General procedure for the synthesis of
5 and 6
L
-(ꢀ)-menthyl ester
To a stirred solution of (
CH2Cl2 (30 mL), acid chloride was added (11 mmol) at 0 °C under
L
)-(ꢀ)-menthol (1.56 g, 10 mmol) in
Ph
Ph
Pd/C
glacial CH3COOH/HCl
O
NH2
Ph
MeOH/HCOOH
(4:1 v/v)
O
HN
O
HN
(1:1 v/v)
RO
HO
Ph
Reflux, 24 h
RO
Ph
50 ºC, 2 h
Et
19
Yield = 86%
Et
20
Yield = 44%
Et
8a
EtMgBr, THF
0 ºC, 3 h
R = L-(-)-menthyl
Ph
Ph
Ph
Ph
N
N
O
Et
O
Et
21b
21a
Yield = 56%
21a:21b = 71:29
Scheme 6.

390
M. Periasamy et al. / Tetrahedron: Asymmetry 21 (2010) 385–392
residue was purified by flash column chromatography on silica gel
(230–400 mesh) column using hexane/EtOAc (98:2) as an eluent.
140.6, 174.0; LC–MS m/z 436 (M+1). Anal. Calcd: C, 79.95; H, 9.49;
N, 3.22. Found: C 80.07; H, 9.47; N, 3.28; ½a D25
¼ ꢀ8:0 (c 1, CHCl3).
ꢂ
5.3.1. Product mixture 8
5.3.4. Product mixture 13
Yield: 1.51 g (72%); dr = 92:8; The syn:anti diastereomeric ratio
was calculated on the basis of 1H NMR analysis of –CH proton adja-
cent to the menthyl oxygen moiety [For syn (d 4.49 ppm, dt,
J = 11 Hz, J = 4.4 Hz, 1H) and for anti products (d 4.73–4.80 ppm,
m, 0.09H)]. The syn:anti mixture was crystallized from hexane to
obtain compound 8a in pure form.
Yield: 1.44 g (64 %); dr = 83:17; The syn:anti diastereomeric ra-
tio was calculated on the basis of 1H NMR analysis of –CH proton
adjacent to menthyl oxygen moiety [For syn (d 4.48 ppm, dt,
J = 11 Hz, J = 4.4 Hz, 1H) and for anti products (d 4.68 ppm, dt,
J = 11 Hz, J = 4.3 Hz, 0.21 H)]. The syn:anti mixture was crystallized
from hexane to obtain compound 13a in pure form.
5.3.1.1. Compound 8a. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-
(2R)-2-[(R)-1-benzylamino-1-phenylmethyl]butanoate: Yield 1.30 g
5.3.4.1. Compound 13a. (1R,2S,5R)-2-Isopropyl-5-methylcyclohex-
yl(2R)-2-[(R)-1-benzylamino-1-(4-methoxyphenyl)methyl]butanoate:
Yield: 1.15 g (51%); mp 150–152 °C; IR (KBr): 3346, 3026, 2951,
(62%); mp 124–126 °C; IR (KBr): 3321, 3061, 2962, 1712 cmꢀ1 1H
;
NMR (400 MHz, CDCl3, d ppm): 0.44 (d, J = 6.8 Hz, 3H), 0.71 (d,
J = 6.8 Hz, 3H), 0.76–0.92 (m, 9H), 1.18–1.27 (m, 2H), 1.32–1.42 (m,
1H), 1.54–1.80 (m, 5H), 1.90–2.0 (m, 1H), 2.56–2.62 (m, 1H), 3.44 (d,
J = 13.2 Hz, 1H), 3.59 (d, J = 13.2 Hz, 1H), 3.80 (d, J = 8.3 Hz, 1H), 4.49
(dt, J = 11.0 Hz, J = 4.4 Hz, 1H), 7.21–7.30 (m, 10H); 13C NMR
(100 MHz, CDCl3, d ppm): 12.0, 15.9, 20.9, 22.1, 22.7, 23.0, 25.4, 31.4,
34.3, 41.0, 46.8, 51.5, 55.1, 63.7, 74.0, 126.9, 127.3, 128.0, 128.2,
128.4, 140.6, 141.9, 174.0; LC–MS: m/z 422 (M+1). Anal. Calcd: C,
79.76; H, 9.32; N, 3.32. Found: C, 79.45; H, 9.32; N, 3.49;
2860, 1718 cmꢀ1 1H NMR (400 MHz, CDCl3, d ppm): 0.44 (d,
;
J = 6.8 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H), 0.77–0.91 (m, 9H), 1.17–1.23
(m, 2H), 1.36–1.41 (m, 1H), 1.54–1.79 (m, 5H), 1.92–1.98 (m, 1H),
2.52–2.58 (m, 1H), 3.43 (d, J = 13.4 Hz, 1H), 3.59 (d, J = 13.9 Hz, 1H),
3.74 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 4.48 (dt, J = 11.0 Hz, J = 4.4 Hz,
1H), 6.84 (d, J = 8.3 Hz, 2H), 7.20–7.29 (m, 7H); 13C NMR (100 MHz,
CDCl3, d ppm): 11.9, 15.8, 20.8, 22.0, 22.9, 25.4, 31.3, 34.2, 41.0,
46.8, 51.3, 55.1, 55.3, 63.0, 73.9, 113.6, 126.8, 128.2, 128.3, 129.0,
133.9, 140.6, 158.8, 174.0; LC–MS: m/z 452 (M+1). Anal. Calcd: C,
77.12; H, 9.15; N, 3.10. Found: C, 77.16; H, 9.17; N, 3.29;
½
a 2D5
ꢂ
¼ ꢀ11:2 (c 1, CHCl3).
½
a 2D5
ꢂ
¼ ꢀ5:8 (c 1, CHCl3).
5.3.2. Product mixture 9
Yield: 1.26 g (54%); dr = 86:14; the diastereomeric ratio of the
product mixture was calculated on the basis of the 1H NMR analy-
sis of the –CH proton adjacent to the –NH moiety [for minor prod-
uct (d 4.16 ppm, d, J = 10.8 Hz, 0.17H) and for major product (d
4.23 ppm, d, J = 10.5 Hz, 1H)]. The diastereomeric mixture was
crystallized from hexane to obtain compound 9a in pure form.
5.3.5. Product mixture 14
Yield: 1.55 g (71%); dr = 96:4; The syn:anti diastereomeric ratio
was calculated on the basis of 1H NMR analysis of a methyl proton
[For syn (d 0.72 ppm, d, J = 6.8 Hz, 3H) and for anti products (d
0.65 ppm, d, J = 6.8 Hz, 0.13 H)]. The syn:anti mixture was crystal-
lized from hexane to obtain compound 14a in pure form.
5.3.2.1. Compound 9a. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-
(2R,3R)-3-benzylamino-2,3-diphenyl propanoate: Yield: 1.0 g (43%);
5.3.5.1. Compound 14a. (1R,2S,5R)-2-Isopropyl-5-methylcyclohex-
yl(2R)-2-[(R)-1-benzyl amino-1-(3-methylphenyl)methyl]butanoate:
Yield: 1.45 g (67%); mp 112–114 °C; IR (KBr): 3319, 3024, 2957,
mp 136–138 °C; IR (KBr): 3323, 3061, 3028, 2953, 1711 cmꢀ1 1H
;
NMR: (400 MHz, CDCl3, d ppm): 0.29 (d, J = 6.8 Hz, 3H), 0.60 (d,
J = 6.8 Hz, 3H), 0.74–0.77 (m, 4H), 0.83–0.90 (m, 3H), 1.06–1.13 (m,
1H), 1.23–1.27 (m, 1H), 1.47–1.56 (m, 3H), 1.81 (br s, 1H), 3.28 (d,
J = 13.9 Hz, 1H), 3.52 (d, J = 13.7 Hz, 1H), 3.82 (d, J = 10.5 Hz, 1H),
4.23 (d, J = 10.5 Hz, 1H), 4.32–4.39 (m, 1H), 6.96 (d, J = 6.4 Hz, 2H),
7.19–7.22 (m, 3H), 7.26–7.35 (m, 6H), 7.45 (d, J = 6.8 Hz, 2H), 7.48
(d, J = 7.3 Hz, 2H); 13C NMR: (100 MHz, CDCl3, d ppm): 15.9, 20.8,
21.9, 23.0, 25.2, 31.3, 34.2, 40.3, 46.7, 50.8, 60.2, 63.6, 74.0, 126.8,
127.7, 127.9, 128.0, 128.2, 128.3, 128.6, 128.7, 128.8, 136.3, 140.1,
2868, 1718 cmꢀ1 1H NMR (400 MHz, CDCl3, d ppm): 0.43 (d,
;
J = 6.8 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H), 0.76–0.92 (m, 9H), 1.18–1.24
(m, 2H), 1.34–1.41 (m, 1H), 1.55–1.78 (m, 5H), 1.95–2.10 (m, 1H),
2.34 (s, 3H), 2.55–2.60 (m, 1H), 3.44 (d, J = 13.2 Hz, 1H), 3.59 (d,
J = 13.2 Hz, 1H), 3.74(d, J = 8.6 Hz, 1H), 4.48 (dt, J = 10.3 Hz,
J = 3.9 Hz, 1H), 7.04–7.10 (m, 3H), 7.17–7.31 (m, 6H); 13C NMR
(100 MHz, CDCl3, d ppm): 12.0, 15.8, 20.9, 21.5, 22.1, 22.8, 23.0,
25.4, 31.3, 34.2, 41.0, 46.8, 51.4, 55.1, 63.7, 73.9, 125.1, 126.9, 128.1,
128.2, 128.3, 128.6, 137.7, 140.5, 141.8, 173.9; LC–MS: m/z 436
(M+1). Anal. Calcd: C, 79.95; H, 9.49; N, 3.22. Found: C, 79.99; H,
141.1, 171.3; LC–MS: m/z 470 (M+1); ½a D25
¼ ꢀ12:8 (c 0.25, CHCl3).
ꢂ
9.46; N, 3.42; ½a D25
¼ ꢀ7:4 (c 1, CHCl3).
ꢂ
5.3.3. Product mixture 12
Yield: 1.5 g (69%); dr = 82:18; The syn:anti diastereomeric ratio
was calculated on the basis of 1H NMR analysis of the –CH proton
adjacent to the menthyl oxygen moiety [for syn (d 4.48 ppm, dt,
J = 11 Hz, J = 4.4 Hz, 1H) and for anti products (d 4.68 ppm, dt,
J = 11 Hz, J = 4.3 Hz, 0.22H)]. The syn:anti mixture was crystallized
from hexane to obtain compound 12a in pure form.
5.3.6. Product mixture 15
Yield: 1.50 g (78%); dr = 80:20; The syn:anti diastereomeric ratio
was calculated on the basis of 1H NMR analysis of a –CH proton
adjacent to the –NH moiety (cf. Fig. 3) [for syn (d 3.74 ppm, d,
J = 8.4 Hz, 1H) and for anti products (d 3.65 ppm, d, J = 2.8 Hz,
0.13H and d 3.68 ppm, d, J = 2.4 Hz, 0.12H)]. The syn:anti mixture
was separated by flash column chromatography on silica gel
(230–400 mesh) column using hexane/EtOAc (98:2) as an eluent.
5.3.3.1. Compound 12a. (1R,2S,5R)-2-Isopropyl-5-methylcyclohex-
yl(2R)-2-[(R)-1-benzylamino-1-(4-methyl phenyl)methyl]butanoate:
Yield: 1.15 g (53%); mp 126–128 °C; IR(KBr): 3348, 2947, 2922,
5.3.6.1. Compound 15a. (1R,2S,5R)-2-Isopropyl-5-methylcyclo-
hexyl (2R)-2-[(R)-1-butylamino-1-phenylmethyl]butanoate: Yield:
2866, 1718 cmꢀ1 1H NMR (400 MHz, CDCl3, d ppm): 0.43 (d,
;
J = 6.8 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H), 0.75–0.91 (m, 9H), 1.17–1.19
(m, 2H), 1.33–1.38 (m, 1H), 1.54–1.78 (m, 5H), 1.93–2.0 (m, 1H),
2.33 (s, 3H), 2.54–2.59 (m, 1H), 3.43 (d, J = 13.1 Hz, 1H), 3.59 (d,
J = 13.1 Hz, 1H,), 3.75 (d, J = 8.8 Hz, 1H), 4.48 (dt, J = 10.8, J = 4.4,
1H), 7.10–7.28 (m, 9H); 13C NMR (100 MHz, CDCl3, d ppm): 12.0,
15.8, 20.9, 21.2, 22.0, 22.8, 23.0, 25.4, 31.3, 34.2, 41.0, 46.8, 51.4,
55.2, 63.4, 73.9, 126.8, 127.9, 128.2, 128.3, 129.0, 136.7, 138.9,
1.22 g (63%); mp 78–80 °C. IR (KBr): 3323, 2959, 2868, 1712 cmꢀ1
;
1H NMR (400 MHz, CDCl3, d ppm): 0.48 (d, J = 6.8 Hz, 3H), 0.74 (d,
J = 6.8 Hz, 3H), 0.78–0.92 (m, 12H), 1.21–1.41 (m, 8H), 1.55–1.87
(m, 5H), 2.33–2.39 (m, 2H), 2.54 (br s, 1H), 3.74 (d, J = 8.4 Hz,
1H), 4.51 (dt, J = 11.0 Hz, J = 4.2 Hz, 1H), 7.20–7.28 (m, 5H); 13C
NMR (100 MHz, CDCl3, d ppm): 12.0, 14.0, 15.8, 20.4, 20.9, 22.0,
22.4, 23.0, 25.4, 31.3, 32.3, 34.2, 40.9, 46.8, 47.3, 55.0, 64.4, 73.9,

M. Periasamy et al. / Tetrahedron: Asymmetry 21 (2010) 385–392
391
127.1, 127.8, 128.1, 142.3, 174.0; LC–MS: m/z 389 (M+1). Anal.
5.4. Procedure for the preparation of mandelic acid complexes
Calcd: C, 77.47; H, 10.66; N, 3.61. Found: C, 77.47; H, 10.63; N,
11 of syn-b-amino esters 8a
3.52; ½a 2D5
¼ ꢀ27:3 (c 1, CHCl3).
ꢂ
The syn-b-amino ester 8a (0.42 g, 1 mmol) was taken in CH2Cl2/
acetone mixture (3 mL, 1:1 v/v ratio) and stirred for 10 min till
complete dissolution occurs. To that mixture, (R)-(ꢀ)-mandelic
acid 10a (0.152 g, 1 mmol) was added and the contents were stir-
red at 25 °C for 3 h. The precipitate formed was filtered off and
crystallized from toluene–isopropanol mixture to obtain the crys-
tals of complex 11 suitable for X-ray structure analysis.
5.3.6.2. Compound 15b. (1R,2S,5R)-2-Isopropyl-5-methylcyclo-
hexyl (2R)-2-[(S)-1-butylamino-1-phenylmethyl]butanoate (1:1
mixture of anti diastereomers): Yield: 0.28 g (14%), Gummy liquid.
1H NMR (400 MHz, CDCl3, d ppm): 0.76–0.83 (m, 18H), 0.90–0.93
(m, 14H), 1.03–1.53 (m, 22H), 1.68–1.71 (m, 4H), 1.96–2.11 (m,
4H), 2.26–2.31 (m, 4H), 2.43–2.49 (m, 2H), 3.65 (d, J = 2.8 Hz,
1H), 3.68 (d, J = 2.4 Hz, 1H), 4.74–4.83 (m, 2H), 7.23–7.26 (m,
6H), 7.31–7.34 (m, 4H). 13C NMR (100 MHz, CDCl3, d ppm): 11.7,
13.9, 15.9, 16.0, 20.3, 20.4, 20.8, 20.9, 22.0, 22.1, 23.0, 23.1, 23.5,
25.7, 25.8, 31.3, 31.4, 32.2, 32.3, 34.3, 40.9, 41.0, 46.8, 46.9, 47.0,
55.4, 55.5, 65.2, 65.6, 74.0, 74.1, 127.1, 127.2, 127.5, 127.6, 128.4,
142.2, 174.7, 174.9.
5.5. Procedure for the resolution of racemic mandelic acid 10
using syn-b-amino esters 8a
The syn-b-amino ester 8a (2.1 g, 5 mmol) was taken in acetone–
CH2Cl2 mixture (16 mL, 11:5 v/v ratio) and stirred for 10 min until
complete dissolution occurs. Racemic mandelic acid 10 (0.765 g,
5 mmol) was added and the contents were stirred at 25 °C for
12 h and the precipitate was filtered. The precipitate was sus-
pended in a mixture of ether and 2 M Na2CO3 and stirred until dis-
solution occurred. The aqueous layer was treated with dilute HCl
(3 M)/ether and the mandelic acid was extracted with ether
(3 ꢁ 25 mL). The combined organic extracts were washed with
brine (30 mL), dried over anhydrous Na2SO4, and the solvent was
evaporated to obtain the (R)-(ꢀ)-10a mandelic acid enantiomer
(>99% ee, 28% yield). The filtrate part was concentrated and the res-
idue was treated as outlined above to obtain the (S)-(+)-10b enan-
tiomer (42% ee, 61% yield). After decomposition: Precipitate: Yield
5.3.7. Product mixture 16
Yield: 1.23 g (54%); dr = 79:21; The syn:anti diastereomeric ratio
was calculated on the basis of 1H NMR analysis of a –CH proton
adjacent to the menthyl oxygen moiety [For syn (d 4.48, dt,
J = 11 Hz, J = 4.4 Hz, 1H) and for anti products (d 4.75–4.84 ppm,
m, 0.27 H)]. The syn:anti mixture was crystallized from hexane to
obtain compound 16a in pure form.
5.3.7.1. Compound 16a. (1R,2S,5R)-2-Isopropyl-5-methylcyclohex-
yl(2R)-2-[(R)-1-benzylamino-1-(4-chlorophenyl)methyl]butanoate:
Yield: 0.8 g (35%); mp 128–130 °C; IR (KBr): 3321, 3061, 2962,
1712 cmꢀ1
;
1H NMR (400 MHz, CDCl3, d ppm): 0.45 (d, J = 6.8 Hz,
0.215 g (28%); ½a D25
ꢂ
¼ ꢀ147:0 (c 0.5, ethanol) [Lit13
½
a 2D5
ꢂ
¼ ꢀ145:6
3H), 0.70–0.92 (m, 12H), 1.10–1.23 (m, 2H), 1.34–1.42 (m, 1H),
1.55–1.80 (m, 5H), 1.89–1.97 (m, 1H), 2.56–2.59 (m, 1H), 3.36–3.46
(m, 1H), 3.52–3.61 (m, 1H), 3.72–3.81 (m, 1H), 4.48 (dt, J= 11 Hz,
J = 4.4 Hz, 1H), 7.22–7.31 (m, 9H); 13C NMR (100 MHz, CDCl3, d
ppm): 12.0, 15.9, 20.9, 22.1, 22.7, 23.0, 25.4, 31.4, 34.2, 40.9, 46.7,
51.4, 55.0, 63.6, 73.9, 126.9, 127.3, 128.0, 128.2, 128.3, 140.5, 141.9,
173.9; LC–MS m/z 456 (M+). Anal. Calcd: C, 73.74; H, 8.40; N,
(c 0.43, ethanol, For >99% ee (R)-(ꢀ)-mandelic acid); enantiomeric
purity >99% ee (Determined by HPLC using chiral column, chiralcel
OD-H14 solvent system, hexane/2-propanol/trifluoroacetic acid =
900:100:2.5, v/v flow rate 0.5 mL/min, 254 nm, Retention times:
16.2 min for minor (S) and 19.8 min for major (R) isomer). From fil-
trate: Yield 0.470 g (61%); ½a D25
¼ þ60:4 (c 1, ethanol); enantio-
ꢂ
meric purity 42% ee, retention times: 15.7 min for major (S)
isomer and 20.1 min for minor (R) isomer.
3.07; Cl, 7.77. Found: C 73.70; H, 8.47; N, 3.19; ½a D25
¼ ꢀ3:2 (c 1,
ꢂ
CHCl3).
5.6. Procedure for the N-debenzylation of syn-b-amino ester 8a
5.3.8. Compound 17a
(1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl (2S)-2-[(S)-1-ben-
zylamino-1-phenylmethyl]butanoate: The crystallization of 17
was carried out in a similar manner to 8. Yield: 1.40 g (66%); mp
To a stirred solution of syn-b-amino ester 8a (0.42 g, 1 mmol)
in a mixture of methanol and formic acid (100%) (20 mL, 4:1 v/v),
Pd/C (50 mg, 5% by weight) was added under a nitrogen atmo-
sphere. The reaction mixture was heated to 50 °C for 2 h. The
reaction mixture was brought to room temperature, filtered,
and neutralized slowly by adding 3 M NaOH solution until the
solution became slightly basic. The reaction mixture was ex-
tracted with ether (3 ꢁ 20 mL) and the combined organic extracts
were washed with water (20 mL), brine (15 mL), dried over anhy-
drous K2CO3, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on sil-
ica gel (230–400 mesh) column using hexane/EtOAc (95:5) as an
eluent.
124–126 °C; ½a 2D5
¼ þ11:4 (c 1, CHCl3).
ꢂ
5.3.9. Product mixture 18
Yield: 0.91 g (45%); dr = 72:28; The syn:anti diastereomeric ratio
was calculated on the basis of 1H NMR analysis of a methyl proton
[For syn (d 0.42 ppm, d, J = 6.8 Hz, 3H) and for anti products (d
0.49 ppm, d, J = 6.8 Hz, 1.2 H)]. The syn:anti mixture was crystal-
lized from hexane to obtain compound 18a in pure form.
5.3.9.1. Compound 18. (1R,2S,5R)-2-Isopropyl-5-methylcyclohex-
yl(2R)-2-[(R)-1-anilino-1-phenylmethyl]butanoate: Yield: 0.50 g
(25%); mp 174–176 °C; IR (KBr): 3389, 3051, 2953, 1703 cmꢀ1
;
1H
5.6.1. Compound 19 (1R,2S,5R)-2-isoproyl-5-methylcyclohexyl-
(2R)-2-[(R)-1-amino-1-phenyl methyl]butanoate
NMR: (400 MHz, CDCl3, d ppm): 0.42 (d, J = 6.8 Hz, 3H), 0.66 (d,
J = 6.8 Hz, 3H), 0.83–0.92 (m, 9H), 1.25–1.42 (m, 3H), 1.56–1.65
(m, 3H), 1.75–1.89 (m, 2H), 2.69–2.75 (m, 1H), 4.31 (br s, 1H),
4.60–4.66 (m, 2H), 6.48 (d, J = 8 Hz, 2H), 6.62 (t, J = 7.4 Hz, 1H),
7.05 (t, J = 7.8 Hz, 2H), 7.18–7.34 (m, 5H); 13C NMR (100 MHz,
CDCl3, d ppm): 12.4, 15.6, 20.8, 20.9, 22.1, 23.0, 25.7, 31.5, 34.3,
41.1, 47.0, 54.8, 59.5, 74.6, 113.5, 117.6, 127.2, 127.3, 128.5, 129.1,
141.2, 147.2, 173.3; LC–MS: m/z 408 (M+1). Anal. Calcd: C, 79.56;
Yield: 0.28 g (86%); mp 96–98 °C; IR (KBr): 3371, 3308, 3061,
2955, 1714 cmꢀ1 1H NMR: (400 MHz, CDCl3, d ppm): 0.43 (d,
;
J = 6.8 Hz, 3H), 0.69–0.96 (m, 12H), 1.16–1.37 (m, 3H), 1.57–1.85
(m, 7H), 2.54–2.60 (m, 1H), 4.07 (d, J = 8.6 Hz, 1H), 4.50 (dt,
J = 10.8 Hz, J = 4.2 Hz, 1H), 7.21–7.32 (m, 5H); 13C NMR (100 MHz,
CDCl3, d ppm): 11.9, 15.8, 20.8, 22.0, 22.6, 23.0, 25.3, 31.3, 34.2,
40.9, 46.7, 55.9, 57.6, 73.9, 127.0, 127.3, 128.4, 144.1, 173.9; LC–
MS: m/z 332 (M+1). Anal. Calcd: C, 76.09; H, 10.03; N, 4.23. Found:
H, 9.15; N, 3.44. Found: C 79.58; H, 9.17; N, 3.48; ½a D25
¼ ꢀ21:4 (c
ꢂ
0.5, CHCl3).
C, 76.20; H, 10.02; N, 4.29. ½a D25
¼ ꢀ61:7 (c 0.5, CHCl3).
ꢂ

392
M. Periasamy et al. / Tetrahedron: Asymmetry 21 (2010) 385–392
5.7. Procedure for the hydrolysis of syn-b-amino ester 8a
facilities in the School of Chemistry, University of Hyderabad.
The award of the JC Bose Fellowship grant to M.P. is gratefully
acknowledged.
The syn-b-amino ester 8a (0.42 g, 1 mmol) was taken in a mix-
ture of glacial acetic acid and hydrochloric acid (10 mL, 1:1 v/v)
and refluxed for 24 h. The solvents were distilled off and the resi-
due was taken in 5 mL of distilled water. A saturated sodium bicar-
bonate solution was added dropwise to the mixture until it became
slightly basic. The aqueous solution was extracted with ether
(3 ꢁ 15 mL) and the combined organic layer was washed with
brine (15 mL), dried over anhydrous Na2SO4, filtered, and the sol-
vents were removed under reduced pressure. The crude residue
was purified by flash column chromatography on silica gel (230–
400 mesh) column using hexane/EtOAc (90:10) as an eluent. Yield:
0.12 g (44%); mp 80–82 °C; IR (KBr): 3400, 3034, 2964, 1684, 1624,
References
1. (a) Werder, M.; Hauser, H.; Carreira, E. M. J. Med. Chem. 2005, 48, 6035; (b)
Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R.; Yumibe, N., Jr.; Clader, J.
W.; Burnett, D. A. J. Med. Chem. 1998, 41, 973; (c) Clader, J. W.; Burnett, D. A.;
Caplen, M. A.; Domalski, M. S.; Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M. E.;
Zhao, H.; Burrier, R. E.; Salisbury, B.; Davis, R., Jr. J. Med. Chem. 1996, 39, 3684;
(d) Durckheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 180.
2. (a) Shinagawa, S.; Kanamaru, T.; Harada, S.; Asai, M.; Okazaki, H. J. Med. Chem.
1987, 30, 1458; (b) Namikoshi, M.; Rinehart, K. L.; Dahlem, A. M.; Beasley, V. R.;
Carmichael, W. W. Tetrahedron Lett. 1989, 30, 4349; (c) Nussbaum, F.; Spiteller,
P.; Ruth, M.; Steglich, W.; Wanner, G. Angew. Chem., Int. Ed. 1998, 37, 3292; (d)
Spiteller, P.; Ruth, M.; Nussbaum, F.; Steglich, W. Angew. Chem., Int. Ed. 2000,
39, 2754; (e) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986, 27,
2797; (f) Shih, C.; Gossett, L. S.; Gruber, J. M.; Grossman, C. S.; Andis, S. L.;
Schultz, R. M.; Worzalla, J. F.; Corbett, T. H.; Metz, J. T. Bioorg. Med. Chem. Lett.
1999, 9, 69; (g) Roers, R.; Verdine, G. L. Tetrahedron Lett. 2001, 42, 3563. and
references cited therein.
3. (a) Cole, D. C. Tetrahedron 1994, 50, 9517; (b) Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991; (c) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117; (d)
Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833.
4. (a) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221; (b) Martin, S. F. Acc. Chem.
Res. 2002, 35, 895; (c) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am.
Chem. Soc. 2007, 129, 6756; (d) Hata, S. S.; Tomioka, K. Tetrahedron 2007, 63,
8514; (e) Hata, S.; Iguchi, M.; Iwasawa, T.; Yamada, K. I.; Tomioka, K. Org. Lett.
2004, 6, 1721; (f) Chowdari, N. S.; Suri, J. T.; Barbas, C. F. Org. Lett. 2004, 6, 2507.
5. (a) Fujisawa, T.; Ukaji, Y.; Noro, T.; Date, K.; Shimizu, M. Tetrahedron Lett. 1991,
32, 7563; (b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G. J. Org. Chem.
1992, 57, 4155; (c) Annunziata, R.; Bengalia, M.; Cozzi, F.; Raimondi, L.
Tetrahedron Lett. 1993, 34, 6921; (d) Ambhaikar, N. B.; Snyder, J. P.; Liotta, D. C.
J. Am. Chem. Soc. 2003, 125, 3690; (e) Barragan, E.; Olivo, H. F.; Ortega, M. R.;
Sarduy, S. J. Org. Chem. 2005, 70, 4214.
1583 cmꢀ1 1H NMR (400 MHz, CDCl3, d ppm): 0.74 (t, J = 7.2 Hz,
;
3H), 1.26–1.31 (m, 1H), 1.65–1.72 (m, 1H), 2.77 (br s, 1H), 3.80
(d, J = 13.2 Hz, 1H), 4.11–4.21 (m, 2H), 7.26–7.40 (m, 10H), 8.75
(br s, 2H); 13C NMR (100 MHz, CDCl3, d ppm): 12.3, 20.7, 49.0,
50.0, 61.5, 128.6, 128.9, 129.1, 129.3, 129.5, 129.8, 132.0, 133.4,
177.3; LC–MS m/z 284 (M+1). Anal. Calcd. C, 76.29; H, 7.47; N,
4.94. Found: C, 76.35; H, 7.48; N, 5.0; ½a D25
¼ þ43:4 (c 0.15, CHCl3).
ꢂ
5.8. Procedure for the synthesis of b-lactam 21
To a stirred solution of syn-b-amino ester 8a (0.42 g, 1 mmol) in
dry THF (10 mL), a solution of ethylmagnesium bromide (0.13 g,
1 mmol) in 5 mL of dry THF was added slowly at 0 °C under an
N2 atmosphere over a period of 10 min. The reaction mixture
was stirred at 0 °C for 3 h and then quenched with saturated NH4Cl
solution. The reaction mixture was diluted with ether (20 mL) and
the organic layer was separated. The aqueous layer was extracted
with ether (2 ꢁ 15 mL) and the combined organic extracts were
washed with brine (15 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The crude residue was
purified by column chromatography on silica gel (230–400 mesh)
using hexane/EtOAc (95:5) as an eluent. Yield 0.23 g (56%); dr
6. Periasamy, M.; Suresh, S.; Ganesan, S. S. Tetrahedron: Asymmetry 2006, 17,
1323.
7. (a) Oertling, H.; Reckziegel, A.; Surburg, H.; Bertram, H. J. Chem. Rev. 2007, 107,
2136. and references cited therein; (b) Ezquerra, J.; Pedregal, C. J. Org. Chem.
1999, 64, 6554; (c) Emura, T.; Esaki, T.; Tachibana, K.; Shimizu, M. J. Org. Chem.
2006, 71, 8559; (d) Kumar, S.; Sobhia, M. E.; Ramachandran, U. Tetrahedron:
Asymmetry 2005, 16, 2599; (e) Xu, H. W.; Li, G. Y.; Wong, M. K.; Che, C. M. Org.
Lett. 2005, 7, 5349.
8. Crystal data: For complex 11: Molecular formula: C36H47NO5 [C28H40NO2,
C8H7O3], MW = 573.75, orthorhombic, space group: P2(1) 2(1) 2(1),
71:29; IR (neat): 3030, 2926, 1738 cmꢀ1 1H NMR: (400 MHz,
;
a = 9.694(3) Å, b = 16.116(6) Å, c = 21.580(12) Å,
a = 90°, b = 90°, c = 90°,
CDCl3, d ppm): (for the diastereomeric mixture) 0.69 (t, J = 7.3 Hz,
3H), 0.99–1.10 (m, 1H), 1.37–1.48 (m, 1H), 3.19–3.24 (m, 1H),
3.78 (d, 1H, J = 14.9 Hz), 4.51 (d, J = 5.4 Hz, 1H), 4.80 (d,
J = 14.6 Hz, 1H), 7.06–7.30 (m, 12H). Additional signals for the min-
or isomer: 0.90 (t, J = 7.3 Hz, 3H), 1.60–1.67 (m, 1H), 1.71–1.80 (m,
1H), 2.89–2.92 (m, 1), 3.64 (d, J = 14.9 Hz, 1H), 3.97 (s, 1H), 4.79–
4.80 (m, 1H); 13C NMR (100 MHz, CDCl3, d ppm): (for the diastereo-
meric mixture) 11.4, 11.7, 18.7, 21.7, 44.1, 44.2, 57.1, 57.7, 59.9,
62.0, 126.4, 127.5, 127.6, 127.7, 128.1, 128.2, 128.3, 128.4, 128.5,
128.6, 135.4, 135.7, 170.2, 170.7; mass m/z 266 (M+1).
V = 3371(3) Å3, Z = 4, c = 1.130 Mg Mꢀ3 = 0.074 mmꢀ1, T = 298(2) K. Of the
q
, l
9909 reflections collected, 5934 were unique (Rint = 0.0520). Refinement on all
data converged at R1 = 0.0552, wR2 = 0.0990. (CCDC deposition number:
677361).
9. (a) Hata, S.; Iwasawa, T.; Iguchi, M.; Yamada, K.; Tomioka, K. Synthesis 2004, 9,
1471; (b) Adrian, J. C.; Barkin, J. L.; Fox, R. J.; Chick, J. E.; Hunter, A. D.; Nicklow,
R. A. J. Org. Chem. 2000, 65, 6264; (c) Joffe, A. L.; Thomas, T. M.; Adrian, J. C.
Tetrahedron Lett. 2004, 45, 5087.
10. (a) Periasamy, M.; Suresh, S.; Ganesan, S. S. Tetrahedron Lett. 2005, 46, 5521; (b)
Silveria, C. C.; Vieira, A. S.; Braga, A. L.; Russowsky, D. Tetrahedron 2005, 61,
9312.
11. (a) Baar, M. R.; Cerrone-Szakal, A. L. J. Chem. Educ. 2005, 82, 1040; (b) Kozma,
D.; Nyeki, A.; Acs, M.; Fogassy, E. Tetrahedron: Asymmetry 1994, 5, 315; (c)
Tanaka, K.; Fukuoka, T.; Shiro, M. J. Chem. Res. (S) 2002, 446; (d) Acs, M.;
Bregger, E. N.; Simon, K.; Argay, G. J. Chem. Soc., Perkin Trans 2 1992, 2011; (e)
Ingersoll, A. W.; Babcock, S. H.; Burns, F. B. J. Am. Chem. Soc. 1933, 55, 411.
12. Xu, J. H.; Kawamoto, T.; Tanaka, A. Appl. Microbiol. Biotechnol. 1995, 43, 402.
13. Sato, F.; Kobayashi, Y.; Takahashi, O. Y.; Chiba, T.; Takeda, Y.; Kusakabe, M. J.
Chem. Soc., Chem. Commun. 1985, 22, 1636.
Acknowledgments
S. Selva Ganesan is thankful to the DST for the JC Bose research
fellowship. The UGC support under the ‘University with Potential
for Excellence (UPE)’ and ‘Centre for Advance Study (CAS-SAP)’ pro-
grammes is gratefully acknowledged. We are thankful to the DST
for a 400, 500 MHz NMR spectrometer and National XRD-CCD
14. Ebbers, E. J.; Ariaans, G. J. A.; Bruggink, A.; Zwanenburg, B. Tetrahedron:
Asymmetry 1999, 10, 3701.