Memory of chirality in the stereoselective synthesis of β-lactams: Importance of the starting amino acid derivative

Article abstract of DOI:10.1016/S0957-4166(03)00398-7

The enantioselectivity of the base-promoted cyclization of N-alkyl-N-chloroacetyl amino acid derivatives to β-lactams is dependent on the substituents on the starting material. While ^tBu esters are preferred over Me esters, and N-Bzl-, N-Pmb, N-Nph and N-Mom groups gave similar e.e. values, only amino acid derivatives with branched side-chains at the γ-position were able to show a good memory of chirality.

Full text of DOI:10.1016/S0957-4166(03)00398-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2161–2169
Memory of chirality in the stereoselective synthesis of b-lactams:
importance of the starting amino acid derivative
Ma6 Angeles Bonache,a Guillermo Gerona-Navarro,a Carlos Garc´ıa-Aparicio,a Miriam Al´ıas,b
Mercedes Mart´ın-Mart´ınez,a Ma6 Teresa Garc´ıa-Lo´pez,a Pilar Lo´pez,b Carlos Cativielab and
Rosario Gonza´lez-Mun˜iza,*
aInstituto de Qu´ımica Me´dica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
bDepartamento de Qu´ımica Orga´nica, ICMA, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Received 16 April 2003; accepted 14 May 2003
Abstract—The enantioselectivity of the base-promoted cyclization of N-alkyl-N-chloroacetyl amino acid derivatives to b-lactams
t
is dependent on the substituents on the starting material. While Bu esters are preferred over Me esters, and N-Bzl-, N-Pmb,
N-Nph and N-Mom groups gave similar e.e. values, only amino acid derivatives with branched side-chains at the g-position were
able to show a good memory of chirality.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
the base and solvent.21 Focused on the search for the
appropriate reaction conditions, we have recently per-
formed a more detailed study, which has allowed us to
determine the critical importance of the base and sol-
vent for the final enantiomer distribution.22
In recent years some chemical transformations have
been described to proceed in a selective manner without
using any external chiral source, a phenomenon that
has been explained in terms of a new asymmetric
concept known as ‘memory of chirality’.1 Most of these
transformations are found in the chemistry of a-amino
acids,2–16 although a few examples involve a-alkoxycar-
bonyl derivatives and axially chiral o-haloacryl-
anilides.17–19 Although the initial stereogenic center (or
chiral axis) is destroyed during the generation of the
corresponding reactive intermediates (radicals, carbe-
nium cations, enolates), these intermediates are able to
‘remember’ the configuration of their precursors to
transfer the chirality to the final compounds. The alkyl-
ation of a number of a-amino acid derivatives has been
extensively studied by Fuji’s group, and determined to
proceed with a high degree of asymmetric induction.12–16
A chiral non racemic enolate with restricted rotation
around the CꢀN axis has been proposed as the crucial
intermediate.13 We used a similar rationale to explain
the stereoselectivity found in the intramolecular alkyla-
tion of several N-benzyl-N-chloroacetyl amino acids I
to the corresponding 2-azetidinones II.20,21 From the
initial results, we envisaged a certain dependence of the
enantioselectivity on the amino acid side-chain and on
Now, to gain further insight into the factors governing
the phenomenon of the memory of chirality, herein we
have investigated the influence of R1, R2 and R3 sub-
stituents on the selectivity of the b-lactam ring
formation.
2. Results and discussion
As shown in Scheme 1, the starting chloroacetyl deriva-
tives 20–38 were conveniently prepared by reaction
of chloroacetyl chloride with the R2-substituted
compounds 1–8, and 10–19, previously synthesized
by reductive amination of commercially available a-
amino esters and the appropriate aldehyde.21 In the
particular case of compound 28, the sequence of reac-
tions was reversed to allow the incorporation of the
* Corresponding author. Tel.: +34-915-622-900; fax: +34-915-644-853;
e-mail: iqmg313@iqm.csic.es
0957-4166/03/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00398-7

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Ma A. Bonache et al. / Tetrahedron: Asymmetry 14 (2003) 2161–2169
Scheme 1.
cyclization of tert-butyl, methyl and benzyl esters
derived from phenylalanine derivatives 20–22 was
checked on a series of defined reaction conditions, and
the enantiomeric ratio of the resulting 2-azetidinones
was then measured by chiral HPLC (Table 1).22 With
methoxymethyl (Mom) group by N-alkylation of the
chloroacetyl derivative 9.23
To assess the contribution of the nature of the car-
boxylic ester on the observed enantioselectivity, the
Table 1. Influence of the R1 group on the selectivity of the cyclization of
L-Phe derivatives.
Entry
Starting compd
R1
Base
Solvent
Final compd
Yield (%)a
a:bb
e.e.
1
2
3
4
5
6
7
8
20
21
22
20
21
22
20
20
21
20
21
20
21
20
21
tBu
Me
Bzl
tBu
Me
Bzl
tBu
tBu
Me
tBu
Me
tBu
Me
tBu
Me
Cs2CO3
Cs2CO3
Cs2CO3
BTPP
BTPP
BTPP
BEMP
BTPP
BTPP
BEMP
BEMP
BTPP
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
DCM
DCM
DCM
NMP
39
40
41
39
40
41
39
39
40
39
40
39
40
39
40
71
74
75
73
68
58
81
58
65
65
68
56
79
52
81
78:22c
78:22d
79:21e
76:24c
67:33d
57:43e
76:24c
74:26c
67:33d
75:25c
68:32d
43:57c
34:66d
51:49c
43:57d
56
56
58
52
34
14
52
48
34
50
36
14f
32f
2
9
10
11
12
13
14
15
BTPP
BEMP
BEMP
NMP
NMP
NMP
14f
a Isolated yield.
b Measured by chiral HPLC (Column: OL-389).
c Hexane/acetone (96:4), 1.5 ml/min.
d Hexane/EtOH (95:5), 1 ml/min.
e OL-321, hexane/EtOH (97:3), 1 ml/min.
f Major isomer has R configuration.

Ma A. Bonache et al. / Tetrahedron: Asymmetry 14 (2003) 2161–2169
2163
43. In agreement with these results, the decrease in
selectivity was particularly marked for the 2,4,6-Tmb
derivative 44, with two o-methoxy groups, which was
obtained in almost racemic form. The presence of OMe
groups in meta-position had minor influence on the
selectivity (compare Table 1: entry 2 with Table 2: entry
5). From these results, it could be rationalized that the
o-methoxy groups at the benzyl substituent contribute
to destabilize the anionic intermediates responsible for
the preservation of the information of chirality of the
starting amino acid. The detrimental effect of this ortho
group does not seem to be related to its steric hin-
drance, since an increase in the volume of the benzyl
moiety, as in the 1-Nph derivative 46, resulted in a
slight increase in the selectivity. Surprisingly, a clearly
different group, as Mom, was also able to induce good
selectivities, comparable to those previously obtained
for the Pmb substituted derivative 39 under the indi-
cated conditions.22 Mom has previously been found to
be a good stereodirecting element in the intermolecular
a-alkylation of amino acid derivatives.13
the hindered phosphazene bases in MeCN or in DCM,
the (S)-selectivity was higher for the bulky tert-butyl
derivative than for the methyl ester, with a 13–18%
increase in e.e. for both BTPP and BEMP. Still lower
selectivity was found in the BTPP-assisted cyclization
of the Bzl derivative 22, which afforded b-lactam 41 in
only 14% e.e. In contrast, the type of alkyl ester did not
have any influence in the reactions carried out with
cesium carbonate, probably as a consequence of similar
E/Z enolate distribution and/or to close aggregate spe-
cies in all cases. As previously observed,22 the sense of
the asymmetric induction was reversed when NMP was
used as solvent, and better results were obtained for the
methyl ester derivative. The enhancement in (R)-selec-
t
tivity (Me versus Bu) was independent of the sterical
hindrance of the organic base, BTPP or BEMP.
Phenylalanine derivatives 23–28, bearing
dimethoxybenzyl group (2,4-Dmb),
a
2,4-
different
trimethoxybenzyls (Tmb), a 1-naphthylmethyl group
(Nph), and a methoxymethyl moiety (Mom) have been
prepared to gain further information about the influ-
ence of the R2 substituent on the degree of stereocon-
trol (Table 2).24 Previously, we had observed that Bzl
and Pmb groups give similar asymmetric inductions,
indicating that the p-methoxy group has not any effect
on the selectivity.21 However, the appendage of an
additional methoxy group in ortho-position of the
phenyl ring, as in 23 and 24, gave to remarkable
decreases in the e.e.’s of the resultant b-lactams 42 and
In our preliminary studies,20,21 Trp, Phe and Leu
derivatives gave the b-lactam ring stereoselectively,
while racemic azetidinones were obtained from Ala
analogues. To extend this study, the enantiomeric ratio
obtained in the cyclization of representative amino acid
derivatives, such as Tyr, Trp(Boc), Orn, Lys, Asp, and
Glu, was measured (Table 3). In those cases where the
efforts to determine the e.e.’s by chiral HPLC were
Table 2. Influence of R2 substituents on the selectivity of the cyclization of
L-Phe chloroacetyl derivatives

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Ma A. Bonache et al. / Tetrahedron: Asymmetry 14 (2003) 2161–2169
Table 3. Influence of the amino acid side-chain (R3) on the selectivity of the corresponding b-lactam (MeCN as solvent)
Entry
Starting compd
R1
R2
R3
Base
Final compd
Yield (%)a
a:bb
e.e.
1
2
3
4
5
6
7
8
29
29
30
31
32
32
33
34
34
35
36
37
38
38
Me Pmb
Me Pmb
tBu Pmb
tBu Bzl
CH2C6H4(p-O-di-Cl-Bzl)
CH2C6H4(p-O-di-Cl-Bzl)
CH2In(N-Boc)
CH2In
(CH2)3-NHZ
(CH2)3-NHZ
Cs2CO3 48
77
68
90
24
81
76
82
46
61
65
19
42
69
53
74:28c
63:37
46
26
42
30
14
10
8
BTPP
BTPP
BTPP
48
49
50
71:29d
65:35d
57:43e
55:45
Me Pmb
Me Pmb
Me Pmb
Me Pmb
Me Pmb
Me Pmb
Me Pmb
tBu Pmb
tBu Bzl
Cs2CO3 51
BTPP 51
(CH2)4-NHZ
Cs2CO3 52
Cs2CO3 53
Cs2CO3 53
Cs2CO3 54
Cs2CO3 55
54:46f
CH2CO2 Bu
77:23g,h 54
40:60g,h,i 20
t
t
9
CH2CO2 Bu
t
10
11
12
13
14
(CH2)2CO2 Bu
50:50g
71:29g
78:22g
50:50g
50:50g
0
42
56
0
CH2CH(CH3)2
CH2CH(CH3)2
CH3
BTPP
Cs2CO3 57
BTPP 57
56
tBu Bzl
CH3
0
a Isolated compounds.
b Measured by chiral HPLC (Column: OL-389).
c Hexane/acetone/EtOH (95:4:1), 1.2 ml/min.
d Hexane/acetone (96:4), 1.2 ml/min.
e Hexane/EtOH (90:10), 1 ml/min.
f Hexane/EtOH (94:6), 1 ml/min.
g Diastereoisomeric excesses measured after derivatization to the corresponding Azn-
L-Phe-OMe dipeptide derivatives (Refs. 21 and 22).
h Major compound a has R configuration.
i Reaction in THF.
unproductive, the diastereoisomeric ratio was measured
after derivatization to dipeptide derivatives.21,22 All aro-
matic amino acid derivatives tested were able to induce
memory of chirality effects with the selectivity following
the order Phe>Tyr:Trp. Compared to Phe-OMe-
derived b-lactam 40, Tyr-OMe analogue 48 was
obtained with slightly lower selectivity when both
Cs2CO3 and BTPP were used as base. For Trp deriva-
tives, the incorporation of a Boc group at position 1 of
the indole ring resulted in a 12% increase in the e.e.
value with respect to the NH analogue (compare entries
3 and 4). Concerning amino acids with basic side-
chains, only marginal enantioselectivities were found
for Orn and Lys derivatives. In contrast, a good asym-
metric induction was found in the Cs2CO3-assisted
intramolecular alkylation of the Asp derivative 34,†
although a lot of non-identified side products were also
formed in this reaction, probably due to competition
between a- and b-enolate formation. In good agreement
with this, the yield in the b-lactam 53 was increased by
lowering the polarity of the solvent (THF versus
MeCN), but as expected the selectivity decreased in this
solvent.22 In the acidic amino acid series, lengthening
the side-chain (Glu derivative 54), had a detrimental
effect on the selectivity leading to the complete loss of
the asymmetric induction. For aliphatic amino acids,
the alkylation of ramified Leu derivatives resulted in
good selectivities, comparable to those found for Phe
analogues, while not branched Ala derivative gave
racemic products.
From these results, it seems that the presence of amino
acids with branched side chains at the g position is
crucial for the stereoselectivity. Aromatic (Phe, Tyr)
and heteroaromatic (Trp) rings, aliphatic chains (Leu),
as well as carboxylate groups (Asp) can be considered
as useful branched moieties at this point. All these
results can be rationalized in terms of the existence of
enolate intermediates possessing axial chirality, by
restricted rotation around the CaꢀNa bond (Fig. 1).
From our previous results,25 and those reported by
Fuji,1b,13 the pro-S Z-enolate is supposed to be the
main responsible of the observed selectivity. This pro-
posal is in agreement with the increase in selectivity
observed for bulky tert-butyl esters versus methyl
esters, and for large Trp(Boc) derivative 49 compared
with Trp analogue 50. The need for enolates with
restricted mobility about CꢀN bond is in concordance
with the lack of memory of chirality in Ala and Glu
derivatives, and with the marginal selectivity in Orn
and Lys analogues, all possessing linear side-chains that
facilitate free rotation of the CꢀN bond and, therefore,
† Taking into account that the 4-CH2CO2 Bu group has preference
t
over the CH2CON branch of the b-lactam ring, major diastereoiso-
mer 53a has R configuration, and the corresponding dipeptide
derivative 58a is heterochiral.
Figure 1. Proposed enolate intermediates (Z-geometry).

Ma A. Bonache et al. / Tetrahedron: Asymmetry 14 (2003) 2161–2169
2165
t
the formation of the corresponding racemic mixtures.
The complete lack of asymmetry found for Glu and Ala
derivatives also discards the involvement of complex
intermediates consisting of achiral enolates and remain-
ing optically active starting materials.
174.30 (COO), 137.97–124.27 (16C, Ar), 81.46 (C, Bu),
63.50 (a-CH), 50.32 (N-CH2), 40.17 (b-CH2), 28.32
t
(CH3, Bu). Anal calcd for C24H27NO2: C, 79.74; H,
7.53; N, 3.87. Found: C, 79.76; H, 7.65; N, 3.99.
3.1.2. N-(p-Methoxybenzyl)-L-Tyr(O-di-Cl-Bzl)-OMe
In conclusion, we have demonstrated that the stereose-
lectivity, due to memory of chirality, in the cyclization
of amino acid derivatives to b-lactams is highly depen-
dent on the substituents of the starting N-chloroacetyl
amino acid derivative. Among these substituents, the
amino acid side-chain (R3) appears the principal
stereodirecting element, offering additional support for
the explanation that the memory of chirality is caused
by a hindered rotation around the CꢀN bond.
10. Syrup. Yield: 71%. Eluent AcOEt:hexano (1:9).
HPLC: tR=8.91 min (A:B=40:60). 1H NMR (300
MHz, CDCl3): l 7.32–6.76 (m, 11H, C6H5 and C6H4),
5.20 (s, 2H, CH2, OBzl), 3.73 (s, 3H, OMe), 3.70 (d,
1H, J=13.0, N-CH2), 3.61 (s, 3H, OMe), 3.53 (d, 1H,
J=13.0, N-CH2), 3.46 (t, 1H, J=7.0, a-CH), 2.87 (d,
2H, J=7.0, b-CH2), 1.78 (br s, 1H, a-NH). 13C NMR
(75 MHz, CDCl3): l 175.53 (COO), 159.08 (4-C, C6H4),
158.12 (4-C, Pmb), 137.41–114.13 (16C, Ar), 65.68
(CH2, OBzl), 62.42 (a-CH), 55.65 (OMe), 52.04 (OMe),
51.81 (N-CH2), 39.23 (b-CH2). Anal calcd for
C25H25Cl2NO4: C, 63.30; H, 5.31; N, 2.95; Cl, 14.95.
Found: C, 63.25; H, 5.33; N, 2.88; Cl, 14.87.
3. Experimental
All reagents were of commercial quality. Solvents were
dried and purified by standard methods. Amino acid
derivatives were obtained from Bachem AG or Neosys-
tem. 1H NMR spectra were recorded with a Varian
Gemini 200 or a Varian Unity 300 spectrometers oper-
ating at 200 and 300 MHz, respectively, using TMS as
internal standard. 13C NMR spectra were registered on
a Varian Gemini 200 (50 MHz) or a Varian Unity 300
(75 MHz). Electrospray mass spectra (positive mode)
were recorded with a Hewlett–Packard 1100SD spec-
trometer. Elemental analyses were obtained on a CHN-
O-RAPID instrument. Analytical TLC was performed
on aluminum sheets coated with a 0.2 mm layer of
silica gel 60 F254 (Merck). Silica gel 60 (230–400 mesh,
Merck) was used for column chromatography. Analyti-
cal HPLC was performed on a Waters Nova-pak C18
(3.9×150 mm, 4 mm) column, with a flow rate of 1
ml/min, using a tuneable UV detector set at 214 nm.
Mixtures of MeCN (solvent A) and 0.05% TFA in H2O
(solvent B) were used as mobile phase. Trp, Phe, Leu
and Ala derivatives not described below were prepared
as described.20,21,24
3.1.3. N-(p-Methoxybenzyl)-L-Orn(Z)-OMe 13. Syrup.
Yield: 90%. Eluent EtOAc:hexane (2:1). HPLC: tR=
1
6.59 min (A:B=30:70). H NMR (300 MHz, CDCl3): l
7.34 (s, 5H, C6H5), 7.22 (d, 2H, J=8.7, C6H4), 6.82 (d,
2H, J=8.7, C6H4), 5.25 (br s, 1H, d-NH), 5.09 (s, 2H,
CH2, Z), 3.78 (s, 3H, OMe), 3.72 (d, 1H, J=12.6,
N-CH2), 3.71 (s, 3H, OMe), 3.54 (d, 1H, J=12.6,
N-CH2), 3.24 (m, 1H, a-CH), 3.17 (m, 2H, d-CH2), 1.85
(br s, 1H, a-NH) , 1.64 (m, 4H, b-CH2 and g-CH2). 13C
NMR (75 MHz, CDCl3): l 175.63 (COO), 158.64 (4-C,
Pmb), 156.30 (CO, Z), 136.57–113.67 (11C, Ar), 66.45
(CH2, Z), 60.09 (a-CH), 55.14 (OMe), 51.69 (N-CH2),
51.46 (OMe), 40.64 (d-CH2), 30.63 (b-CH2), 26.31 (g-
CH2). Anal calcd for C22H28N2O5: C, 65.98; H, 7.08; N,
7.00. Found: C, 65.90; H, 7.00; N, 6.82.
3.1.4. N-(p-Methoxybenzyl)-L-Lys(Z)-OMe 14. Syrup.
Yield: 65%. Eluent AcOEt:hexano (1:2). HPLC: tR=
1
4.11 min (A:B=35:65). H NMR (300 MHz, CDCl3): l
7.34 (s, 5H, C6H5), 7.23 (d, 2H, J=8.6, C6H4), 6.85 (d,
2H, J=8.6, C6H4), 5.09 (s, 2H, CH2, Z),4.91 (br s, 1H,
d-NH), 3.78 (s, 3H, OMe), 3.73 (d, 1H, J=12.7, N-
CH2), 3.72 (s, 3H, OMe), 3.55 (d, 1H, J=12.7, N-CH2),
3.24 (t, 1H, J=6.6, a-CH), 3.16 (m, 2H, o-CH2), 1.81
(br s, 1H, a-NH), 1.62 (m, 2H, b-CH2), 1.42 (m, 4H,
g-CH2 and d-CH2). 13C NMR (75 MHz, CDCl3): l
175.84 (COO), 158.59 (4-C, Pmb), 156.26 (CO, Z),
136.52–113.62 (11C, Ar), 66.44 (CH2, Z), 60.17 (a-CH),
55.13 and 51.60 (OMe), 51.43 (N-CH2), 40.68 (o-CH2),
32.92 (d-CH2), 29.49 (b-CH2), 22.80 (g-CH2). Anal
calcd for C23H30N2O5: C, 66.65; H, 7.30; N, 6.76.
Found: C, 66.75; H, 7.55; N, 6.98.
3.1. Synthesis of N-Benzyl-type amino acids
General procedure: A solution of H-Xaa-OR1·HCl (19.4
mmol) in MeOH (30 ml) was treated with TEA (2.7 ml,
19.40 mmol) and the corresponding aldehyde (29.09
mmol). The reaction was stirred at rt for 1.5 h, cooled
to 0°C, and NaBH4 (1.47g, 38.79 mmol) was added in
portions. After stirring at rt for additional 2 h, the
solvent was evaporated to dryness, and the residue was
extracted with EtOAc and washed with H2O and brine.
The organic layer was dried over Na2SO4 and, after
evaporation, the residue was purified on a silica gel
column as specified in each case.
3.1.5. N-(p-Methoxybenzyl)-L
-Asp(OtBu)-OMe 15.
Syrup. Yield: 79%. Eluent AcOEt:hexano (1:8). HPLC:
tR=4.00 min (A:B=35:65). 1H NMR (300 MHz,
CDCl3): l 7.23 (d, 2H, J=8.4, C6H4), 6.83 (d, 2H,
J=8.4, C6H4), 3.79 (d, 1H, J=12.7, N-CH2), 3.77 (s,
3H, OMe), 3.72 (s, 3H, OMe), 3.64 (d, 1H, J=12.7,
N-CH2), 3.60 (t, 1H, J=4.8, a-CH), 2.60 (dd, 2H,
J=4.8, 6.0, b-CH2), 2.00 (br s, 1H, a-NH), 1.40 (s, 9H,
CH3, tBu). 13C NMR (75 MHz, CDCl3): l 174.20
(COO), 169.92 (COO), 158.61 (4-C, Pmb), 131.65–
3.1.1. N-(1-Naphthyl)methyl-L
-Phe-OtBu 8. Syrup.
Yield: 75%. Eluent EtOAc:hexane (1:8). HPLC: tR=
1
6.13 min (A:B=45:55). H NMR (300 MHz, CDCl3): l
8.12–7.22 (m, 12H, Ar), 4.31 (d, 1H, J=12.9, N-CH2),
3.57 (d, 1H, J=12.9, N-CH2), 3.57 (t, 1H, J=6.9,
a-CH), 2.97 (m, 2H, b-CH2), 1.97 (br s, 1H, a-NH),
t
1.44 (s, 9H, CH3, Bu). 13C NMR (75 MHz, CDCl3): l

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Ma A. Bonache et al. / Tetrahedron: Asymmetry 14 (2003) 2161–2169
t
113.62 (5C, Ar), 80.89 (C, Bu), 56.94 (a-CH), 55.13
and 51.85 (OMe), 51.24 (N-CH2), 39.27 (b-CH2), 27.92
55.24 (OMe), 52.19 (OMe), 50.83 (N-CH2), 41.56
(CH2Cl), 40.42 (d-CH2), 26.81 (b-CH2), 26.33 (g-CH2).
EM (ES positive mode): 477.3 (M+1)+. Anal calcd for
C24H29ClN2O6: C, 60.44; H, 6.13; N, 5.87; Cl, 7.43.
Found: C, 60.55; H, 6.10; N, 5.75; Cl, 7.65.
t
(CH3, Bu). Anal calcd for C17H25NO5: C, 63.14; H,
7.79; N, 4.33. Found: C, 63.00; H, 7.55; N, 4.51.
3.2. Synthesis of N-alkyl-N-chloroacetyl amino acids
3.2.4. N-Chloroacetyl-N-(p-methoxybenzyl)-L-Lys(Z)-
General procedure: A solution of the corresponding
N-alkyl amino acid derivative (4 mmol) in THF (20 ml)
was treated with propylene oxide (4.2 ml, 60 mmol) and
chloroacetyl chloride (0.47 ml, 6 mmol). After stirring
at rt for 1–2 h, the solvents were evaporated and the
resulting residue was purified on a silica gel column,
using the solvent system specified in each case.
OMe 33. Syrup. Yield: 87%. Eluent AcOEt:hexano
(2:1). HPLC: tR=12.20 min (A:B=40:60). [h]D=−35.3
1
(c 1.04, CHCl3). Rotamer ratio 2.7:1. H NMR (300
MHz, CDCl3): l 7.31 (s, 5H, C6H5), 7.17 (d, 2H,
J=8.6, C6H4), 6.85 (d, 2H, J=8.6, C6H4), 5.05 (s, 2H,
CH2, Z), 4.88 (br s, 1H, d-NH), 4.51 (m, 2H, N-CH2),
4.44 (t, 1H, J=7.1, a-CH), 4.05 (d, 1H, J=12.3,
CH2Cl), 3.99 (d, 1H, J=12.3, CH2Cl), 3.76 (s, 3H,
OMe), 3.58 (s, 6H, OMe), 3.09 (m, 2H, o-CH2), 1.97
(m, 1H, b-CH2), 1.73 (m, 1H, b-CH2), 1.34 (m, 4H,
d-CH2 and g-CH2). 13C NMR (75 MHz, CDCl3): l
170.83 (COO), 167.40 (CON), 159.23 (4-C, Pmb),
156.27 (CO, Z), 136.49–113.52 (11C, Ar), 66.38 (CH2,
Z), 58.39 (a-CH), 55.17 and 52.05 (OMe), 50.50 (N-
CH2), 41.57 (CH2Cl), 40.47 (o-CH2), 29.31 (d-CH2),
28.57(b-CH2), 23.36 (g-CH2). EM (ES positive mode):
513.2 (M+Na)+. Anal calcd for C25H31ClN2O6: C,
61.16; H, 6.36; N, 5.71; Cl, 7.22. Found: C, 61.35; H,
6.06; N, 5.83; Cl, 7.05.
3.2.1. N-Chloroacetyl-N-(1-naphthyl)methyl-L
-Phe-OtBu
27. Foam. Yield: 92%. Eluent EtOAc:hexane (1:8).
HPLC: tR=17.41 min (A:B=60:40). [h]D=−117.1 (c
1.05, CHCl3). Rotamer ratio 6.3:1. 1H NMR (300
MHz, CDCl3): l 7.90–7.18 (m, 12H, Ar), 4.93 (d, 1H,
J=18.0, N-CH2), 4.42 (d, 1H, J=18.0, N-CH2), 4.34 (t,
1H, J=6.3, a-CH), 3.98 (s, 2H, CH2Cl), 3.30 (m, 2H,
t
b-CH2), 1.46 (s, 9H, CH3, Bu). 13C NMR (75 MHz,
CDCl3): l 168.58 (COO) 167.31 (CON), 137.79–121.71
t
(16C, Ar), 82.06 (C, Bu), 62.92 (a-CH), 49.82 (CH2Cl),
t
41.15 (N-CH2), 35.18 (b-CH2), 27.84 (CH3, Bu). EM
(ES positive mode): 460.1 (M+Na)+. Anal calcd for
C26H28ClNO3: C, 71.30; H, 6.44; N, 3.20; Cl, 8.09.
Found: C, 71.35; H, 6.48; N, 3.15; Cl, 8.15.
3.2.5.
N-Chloroacetyl-N-(p-methoxybenzyl)-L-
Asp(OtBu)-OMe 34. Syrup. Yield: 98%. Eluent
AcOEt:hexano (1:4). HPLC: tR=8.69 min (A:B=
40:60). [h]D=−62.3 (c 1.96, CHCl3). Rotamers ratio
4.2:1. 1H NMR (300 MHz, CDCl3): l 7.25 (d, 2H,
J=8.5, C6H4), 6.86 (d, 2H, J=8.5, C6H4), 4.64 (d, 1H,
J=14.4, N-CH2), 4.46 (t, 1H, J=6.7, a-CH), 4.44 (d,
1H, J=14.4, N-CH2), 4.09 (d, 1H, J=12.7, CH2Cl),
4.01 (d, 1H, J=12.7, CH2Cl), 3.77 (s, 6H, OMe), 3.68
(s, 3H, OMe), 3.16 (dd, 1H, J=6.7, 16.9, b-CH2), 2.58
3.2.2. N-Chloroacetyl-N-(p-methoxybenzyl)-L-Tyr(O-di-
Cl-Bzl)-OtBu 29. Syrup. Yield: 92%. Eluent
AcOEt:hexano (1:2). HPLC: tR=16.03 min (A:B=
50:50). [h]D=−43.4 (c 1.47, CHCl3). Rotamer ratio
1
9.5:1. H NMR (300 MHz, CDCl3): l 7.40–6.82 (m,
11H, C6H4, C6H3 and C6H4), 5.31 (s, 2H, CH2, OBzl),
4.45 (d, 1H, J=16.4, N-CH2), 4.19 (m, 1H, a-CH), 4.15
(d, 1H, J=16.4, N-CH2), 4.09 (d, 1H, J=12.4, CH2Cl),
4.03 (d, 1H, J=13.9, b-CH2), 3.81 (m, 4H, N-CH2 and
OMe), 3.70 (s, 3H, OMe), 3.35 (dd, 1H, J=5.5, 13.9,
b-CH2), 3.25 (dd, 1H, J=9.7, 13.9, b-CH2). 13C NMR
(75 MHz, CDCl3): l 170.67 (COO), 167.33 (CON),
159.77 (4-C, C6H5), 158.20 (4-C, Pmb), 137.38–115.74
(16C, Ar), 65.83 (CH2, OBzl), 61.91 (a-CH), 55.69
(OMe), 52.97 (CH2Cl), 52.66 (OMe), 41.92 (N-CH2),
34.44 (b-CH2). EM (ES positive mode): 550.1 (M+1)+.
Anal calcd for C27H26Cl3NO5: C, 58.87; H, 4.76; N,
2.54; Cl, 19.31. Found: C, 59.05; H, 4.51, N, 2.75; Cl,
19.65.
t
(dd, 1H, J=6.7, 16.9, b-CH2), 1.39 (s, 9H, CH3, Bu).
13C NMR (75 MHz, CDCl3): l 170.11 (COO), 169.70
(COO), 166.74 (CON), 159.31 (4-C, Pmb), 128.68–
t
114.11 (5C, Ar), 81.00 (C, Bu), 56.87 (a-CH), 55.13
(OMe), 52.52 (N-CH2), 52.29 (OMe), 41.27 (CH2Cl),
35.37(b-CH2), 27.83 (CH3, tBu). EM (ES positive
mode): 422.1 (M+Na)+. Anal calcd for C19H26ClNO6:
C, 57.07; H, 6.55; N, 3.50; Cl, 8.87. Found: C, 57.35; H,
6.88; N, 3.15; Cl, 8.55.
3.2.6. N-Chloroacetyl-
L
-Phe-OtBu 9. A solution of H-
L-
Phe-OtBu (3 g, 11.64 mmol) in dry THF (48 ml) was
treated with TEA (1.62 ml, 11.64 mmol), and cooled to
0°C. Then, propylene oxide (12.2 ml, 174.6 mmol) and
chloroacetyl chloride (1.11 ml, 13.9 mmol) was added.
After stirring at rt for 1–2 h, the solvents were evapo-
rated and the resulting residue was purified on a silica
gel column using EtOAc:hexane (1:10). Foam. Yield:
86%. Eluent EtOAc:hexane (1:10). HPLC: tR=4.78 min
(A:B=45:55). 1H NMR (200 MHz, CDCl3): l 7.90–
7.18 (m, 5H, C6H5), 7.03 (d, 1H, J=7.1, a-NH), 4.76
(m, 1H, a-CH), 4.05 (s, 2H, CH2Cl), 3.13 (d, 2H,
3.2.3. N-Chloroacetyl-N-(p-methoxybenzyl)-L-Orn(Z)-
OMe 32. Syrup. Yield: 98%. Eluent EtOAc:hexane
(1:1). HPLC: tR=16.53 min (A:B=35:65). [h]D=−32.9
1
(c 2.19, CHCl3). Rotamer ratio 3.2:1. H NMR (300
MHz, CDCl3): l 7.36–6.77 (m, 9H, Ar), 5.08 (s, 2H,
CH2, Z), 4.82 (br s, 1H, d-NH), 4.60 (d, 1H, J=16.2,
N-CH2), 4.50 (d, 1H, J=16.2, N-CH2), 4.41 (t, 1H,
J=7.8, a-CH), 4.08 (m, 2H, CH2Cl), 3.79 (s, 3H,
OMe), 3.62 (s, 3H, OMe), 3.10 (m, 2H, d-CH2), 2.03
(m, 1H, b-CH2), 1.77 (m, 1H, b-CH2), 1.48 (m, 2H,
g-CH2). 13C NMR (75 MHz, CDCl3): l 170.73 (COO),
167.44 (CON), 159.39 (4-C, Pmb), 156.32 (CO, Z),
129.51–114.28 (11C, Ar), 66.55 (CH2, Z), 58.48 (a-CH),
t
J=5.8, b-CH2), 1.46 (s, 9H, CH3, Bu). 13C NMR (50
MHz, CDCl3): l 169.98 (COO), 165.52 (CON), 135.84–
t
127.22 (6C, Ar), 82.81 (C, Bu), 53.90 (a-CH), 42.54
t
(CH2Cl), 38.03 (b-CH2), 28.01 (CH3, Bu). EM (ES

Ma A. Bonache et al. / Tetrahedron: Asymmetry 14 (2003) 2161–2169
2167
1
positive mode): 320.1 (M+Na)+. Anal calcd for
C15H23ClNO3: C, 67.90; H, 8.74; N, 5.28; Cl, 11.91.
Found: C, 67.85; H, 8.70; N, 5.35; Cl, 11.75.
45:55). H NMR (200 MHz, CDCl3): l 7.27–7.17 (m,
5H, C6H5), 4.61 (s, 2H, N-CH2), 3.39 (d, 1H, J=14.3,
3-H), 3.34 (s, 3H, OMe), 3.25 (d, 1H, J=15.0, 4-CH2),
3.11 (d, 1H, J=14.3, 3-H), 2.93 (d, 1H, J=15.0, 4-
t
3.2.7. N-Chloroacetyl-N-methoxymethyl-
L
-Phe-OtBu 28.
CH2), 1.38 (s, 9H, CH3, Bu). 13C NMR (50 MHz,
CDCl3): l 168.89 (COO), 167.19 (CON), 137.90–126.80
(6C, Ar), 82.17 (C, Bu), 80.36 (N-CH2) 62.32 (4-C),
55.84 (OMe), 41.03 (3-C), 35.22 (4-CH2), 28.00 (CH3,
tBu). EM (ES positive mode): 328.1 (M+Na)+. Anal
calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59.
Found: C, 66.75; H, 7.38, N, 4.32.
A solution of 9 (0.2 g, 0.67 mmol) in CH2Cl2 (2 ml) was
treated with tetrabutylammonium bromide (43.2 mg,
0.13 mmol), and cooled to 0°C. Then, a solution of 50%
NaOH (0.19 ml, 2.37 mmol) and chloromethylmethyl
ether (0.61 ml, 0.80 mmol) were added dropwise. After
stirring at rt for 4.5 h, the solvents were evaporated and
the resulting residue was partitioned between CH2Cl2
and H2O (1:1) and the phases were separated. The
organic layer was washed with brine and dried over
Na2SO4. After evaporation, the resulting residue was
purified on a silica gel column using EtOAc:hexane
(1:5). Syrup. Yield: 59%. Eluent EtOAc:hexane (1:5).
HPLC: tR=7.17 min (A:B=45:55). [h]D=−65.85 (c
0.56, CHCl3). Rotamer ratio 10.8:1. 1H NMR (200
MHz, CDCl3): l 7.24–7.16 (m, 5H, C6H5), 4.53 (d, 1H,
J=11.5, N-CH2), 4.07 (s, 2H, CH2Cl), 4.00 (d, 1H,
J=11.5, N-CH2), 3.25 (m, 5H, b-CH2 and OCH3), 1.42
t
3.3.3. 1-(p-Methoxybenzyl)-4-methoxycarbonyl-4-(p-2,6-
dichlorobenzyloxy)benzyl-2-azetidinone 48. Syrup. Elu-
ent AcOEt:hexano (1:2). HPLC: tR=12.69 min
(A:B=50:50). 1H NMR (300 MHz, CDCl3): l 7.29–
6.77 (m, 13H, C6H5, and C6H4), 5.15 (s, 2H, CH2,
OBzl), 4.32 (m, 2H, 1-CH2), 3.71 (s, 3H, OMe), 3.45 (s,
3H, OMe), 3.18 (d, 1H, J=14.7, 3-H), 3.14 (d, 1H,
J=14.1, 4-CH2), 2.84 (d, 1H, J=14.7, 3-H), 2.81 (d,
1H, J=14.1, 4-CH2).13C NMR (75 MHz, CDCl3): l
171.29 (COO), 166.26 (CON), 159.07 (4-C C6H5),
158.03 (4-C, Pmb), 136.96–113.89 (16C, Ar), 65.14
(CH2, OBzl), 62.96 (4-C), 55.24 (OMe), 52.28 (OMe),
45.32 (1-CH2), 44.36 (3-C), 38.75 (4-CH2), 40.36 (3%-C),
30.38. EM (ES positive mode): 514.1 (M++1). Anal
calcd for C27H25Cl2NO5: C, 63.04; H, 4.90; N, 2.72; Cl,
13.78. Found: C, 63.35; H, 4.92; N, 2.52; Cl, 13.87.
t
(s, 9H, CH3, Bu). 13C NMR (50 MHz, CDCl3): l
169.27 (COO), 167.46 (CON), 138.18–127.07 (6C, Ar),
82.45 (N-CH2), 80.64 (C, tBu), 62.59 (OMe) 56.12
(a-CH), 41.32 (CH2Cl), 35.49 (b-CH2), 28.28 (CH3,
tBu). EM (ES positive mode): 364.1 (M+Na)+. Anal
calcd for C17H24ClNO4: C, 59.73; H, 7.08; N, 4.10; Cl,
10.37. Found: C, 59.65; H, 6.89; N, 4.00; Cl, 10.15.
3.3.4.
1-(p-Methoxybenzyl)-4-methoxycarbonyl-4-[3-
51.
3.3. Synthesis of 2-azetidinones
(benzyloxycarbonyl)amino]propyl-2-azetidinone
Syrup. Yield: 81%. Eluent EtOAc:hexane (2:1). HPLC:
tR=10.45 min (A:B=35:65). 1H NMR (300 MHz,
CDCl3): l 7.32 (s, 5H, C6H5), 7.18 (d, 2H, J=8.1,
C6H4), 6.80 (d, 2H, J=8.1, C6H4), 5.06 (s, 2H, CH2, Z),
4.74 (m, 1H, 3%-NH), 4.43 (d, 1H, J=15.3, 1-CH2), 4.24
(d, 1H, J=15.3, 1-CH2), 3.73 (s, 3H, OMe), 3.58 (s, 3H,
OMe), 3.19 (d, 1H, J=14.7, 3-H), 2.98 (m, 2H, 3%-H),
2.83 (d, 1H, J=14.7, 3-H), 1.89 (m, 1H, 1%-H), 1.58 (m,
1H, 1%-H), 1.34 (m, 2H, 2%-H). 13C NMR (75 MHz,
CDCl3): l 171.64 (COO), 165.89 (CON), 159.02 (4-C,
Pmb), 156.19 (CO, Z), 136.38–113.82 (11C, Ar), 66.49
(CH2, Z), 62.04 (4-C), 55.09 (OMe), 52.31 (OMe), 45.46
(1-CH2), 44.10 (3-C), 40.36 (3%-C), 30.38 (1%-C), 24.22
(2%-C). EM (ES positive mode): 441.3 (M++1). Anal
calcd for C24H28N2O6: C, 65.44; H, 6.41; N, 6.36.
Found: C, 65.35; H, 6.29; N, 6.15.
General procedure: The corresponding chloroacetyl
derivative (0.38 mmol) was dissolved in the appropriate
solvent (1.5 ml) and treated, at rt and under Ar atmo-
sphere, with the base (0.56 mmol). The reaction was
monitored by TLC or HPLC until complete disappear-
ance of the starting material. The solution or suspen-
sion was evaporated, redissolved in EtOAc, washed
with H2O, and dried over Na2SO4. After evaporation,
the resulting residue was purified on a silica gel column.
The obtained 2-azetidinone was directly evaluated by
chiral HPLC, or transformed into the corresponding
dipeptide derivatives, as previously described.21
3.3.1.
4-Benzyl-4-tert-butoxycarbonyl-1-(1-naphthyl)-
methyl-2-azetidinone 46. Foam. Yield: 70%. Eluent
EtOAc:hexane (1:8). HPLC: tR=13.52 min (A:B=
1
50:50). H NMR (300 MHz, CDCl3): l 8.25–6.86 (m,
3.3.5.
1-(p-Methoxybenzyl)-4-methoxycarbonyl-4-[4-
12H, Ar), 5.14 (d, 1H, J=15.3, 1-CH2), 4.78 (d, 1H,
J=15.3, 1-CH2), 3.27 (d, 1H, J=14.8, 3-H), 3.10 (d,
1H, J=13.9, 4-CH2), 2.91 (d, 1H, J=14.8, 3-H), 2.62
(benzyloxycarbonyl)amino]butyl-2-azetidinone 52. Syrup.
Eluent AcOEt:hexano (2:1). HPLC: tR=8.04 min
(A:B=40:60). H NMR (300 MHz, CDCl3): l 7.26 (s,
1
t
(d, 1H, J=13.9, 4-CH2), 1.22 (s, 9H, CH3, Bu). 13C
5H, C6H5), 7.11 (d, 2H, J=8.7, C6H4), 6.75 (d, 2H,
J=8.7, C6H4), 5.00 (s, 2H, CH2, OBzl), 4.69 (br s, 1H,
3%-NH), 4.37 (d, 1H, J=15.3, 1-CH2), 4.17 (d, 1H,
J=15.3, 1-CH2), 3.68 (s, 3H, OMe), 3.51 (s, 3H, OMe),
3.13 (d, 1H, J=14.6, 3-H), 2.97 (m, 2H, 4%-H), 2.75 (d,
1H, J=14.6, 3-H), 1.81 (m, 1H, 1%-H), 1.48 (m, 1H,
1%-H), 1.19 (m, 2H, 3%-H), 1.05 (m, 2H, 2%-H). 13C NMR
(75 MHz, CDCl3): l 171.78 (COO), 166.06 (CON),
159.00 (4-C, Pmb), 156.12 (CO, Z), 136.50–113.82 (11C,
Ar), 66.51 (CH2, OBzl), 62.30 (4-C), 55.17 and 52.32
(OMe), 45.48 (1-CH2) 44.12 (3-C), 40.42 (4%-C), 33.00
NMR (75 MHz, CDCl3): l 169.73 (COO), 166.79
t
(CON), 135.09–123.93 (16C, Ar), 82.86 (C, Bu), 64.22
(4-C), 45.92 (1-CH2), 42.85 (3-C), 39.41 (4-CH2), 27.74
t
(CH3, Bu). EM (ES positive mode): 402.3 (M+1)+.
Anal calcd for C26H27NO3: C, 77.78; H, 6.78; N, 3.49.
Found: C, 77.56; H, 6.76; N, 3.20.
3.3.2. 4-Benzyl-4-tert-butoxycarbonyl-1-methoxymethyl-
2-azetidinone 47. Foam. Yield: 36% (Method A). Eluent
EtOAc:hexane (1:6). HPLC: tR=5.31 min (A:B=

2168
Ma A. Bonache et al. / Tetrahedron: Asymmetry 14 (2003) 2161–2169
(3%-C), 27.63 (1%-C). 20.94 (2%-C). EM (ES positive
mode): 455.1 (M+1)+. Anal calcd for C25H30N2O6: C,
66.06; H, 6.65; N, 6.16. Found: C, 66.45; H, 6.75; N,
6.25.
min (A:B=35:65). [h]D=−24.5 (c 0.69, CHCl3). 1H
NMR (300 MHz, CDCl3): l 7.21–6.74 (m, 9H, C6H5
and C6H4), 6.26 (d, 1H, J=7.5, a-NH), 4.58 (m, 1H,
a-CH), 4.37 (s, 2H, 1-CH2), 3.74 (s, 3H, OMe), 3.64 (s,
3H, OMe), 3.03 (dd, 1H, J=5.6, 14.1, b-Phe), 2.96 (d,
1H, J=16.2, 3-H), 2.80 (d, 1H, J=16.8, 4-CH2), 2.67
(dd, 1H, J=8.1, 13.1, b-Phe), 2.63 (d, 1H, J=16.2
3-H), 2.57 (d, 1H, J=16.8, 4-CH2), 1.33 (s, 9H, CH3,
tBu). EM (ES positive mode): 533.2 (M+Na)+. Anal
calcd for C28H34N2O7: C, 65.87; H, 6.71; N, 5.49.
Found: C, 65.95; H, 6.50; N, 5.65.
3.3.6. 1-(p-Methoxybenzyl)-4-methoxycarbonyl-4-(tert-
butoxycarbonyl)methyl-2-azetidinone 53. Solid. Eluent
AcOEt:hexano (1:2). HPLC: tR=5.63 min (A:B=
40:60). [h]D=−2.3 (c 1.33, CHCl3 for 20% e.e.). 1H
NMR (300 MHz, CDCl3): l 7.11 (d, 2H, J=8.1, C6H4),
6.75 (d, 2H, J=8.7, C6H4), 4.31 (d, 1H, J=15.1, 1-
CH2), 4.23 (d, 1H, J=15.1, 1-CH2), 3.71 (s, 3H, OMe),
3.50 (s, 3H, OMe), 3.28 (d, 1H, J=14.8, 3-H), 2.93 (d,
1H, J=14.8, 3-H), 2.78 (d, 1H, J=16.6, 4-CH2), 2.56
3.4.2. 1-(p-Methoxybenzyl)-4-[N-(1%-methoxycarbonyl-
2% - phenyl)ethyl]carbamoyl - 4 - (2 - tert - butoxycarbonyl)-
ethyl-2-azetidinone 59. Isomer 4S,1%S 59a: Foam. Eluent
AcOEt:hexano (2:1). HPLC: tR=52.21 min (A:B=
30:70). [h]D=−4.8 (c 1.20, CHCl3). 1H NMR (300
MHz, CDCl3): l 7.30–6.81 (m, 9H, C6H5 and C6H4),
6.14 (d, 1H, J=8.3, a-NH), 4.68 (m, 1H, a-CH), 4.27
(s, 2H, 1-CH2), 3.76 (s, 3H, OMe), 3.71 (s, 3H, OMe),
3.08 (dd, 1H, J=5.2, 13.9, b-Phe), 2.81 (d, 1H, J=15.1,
3-H), 2.71 (dd, 1H, J=8.3, 13.9, b-Phe), 2.67 (d, 1H,
J=15.1, 3-H), 2.18 (m, 2H, 2%CH2), 1.97 (m, 2H,
t
(d, 1H, J=16.6, 4-CH2), 1.31 (s, 9H, CH3, Bu). 13C
NMR (75 MHz, CDCl3): l 171.36 (COO), 168.92
(COO), 166.19 (CON), 159.62 (4-C, Pmb), 130.12–
t
114.44 (5C, Ar), 82.14 (C, Bu), 59.63 (4-C), 55.63 and
52.76 (OMe), 48.00 (1-CH2) 44.85 (3-C), 40.82 (4-CH2),
t
28.31 (CH3, Bu). EM (ES positive mode): 364.2 (M+
1)+. Anal calcd for C19H25NO6: C, 62.80; H, 6.93; N,
3.85. Found: C, 62.45; H, 7.15; N, 3.95.
t
1%CH2), 1.38 (s, 9H, CH3, Bu). EM (ES positive mode):
3.4. Synthesis of dipeptide derivatives
547.2 (M+Na)+. Anal calcd for C29H36N2O7: C, 66.39;
H, 6.92; N, 5.34. Found: C, 66.75; H, 6.40; N, 5.15.
Isomer 4R,1%S 59b: Syrup. Eluent AcOEt:hexano (2:1).
HPLC: tR=47.84 min (A:B=30:70). [h]D=+22.8 (c
1.04, CHCl3). 1H NMR (300 MHz, CDCl3): l 7.32–6.80
(m, 9H, C6H5 and C6H4), 6.28 (d, 1H, J=7.9, a-NH),
4.71 (m, 1H, a-CH), 4.35 (d, 1H, J=15.3, 1-CH2), 4.07
(d, 1H, J=15.3, 1-CH2), 3.76 (s, 3H, OMe), 3.70 (s, 3H,
OMe), 3.06 (dd, 1H, J=6.0, 13.9, b-Phe), 2.98 (d, 1H,
J=14.9, 3-H), 2.84 (d, 1H, J=14.9, 3-H), 2.81 (dd, 1H,
J=7.6, 13.9, b-Phe), 2.01 (m, 4H, 1%CH2 and 2%CH2),
General procedure: A solution of the corresponding
4-alkoxycarbonyl 2-azetidinone (0.24 mmol) was
hydrolyzed with TFA (1 ml) in CH2Cl2 (2 ml), for
tert-butyl esters, or with 2N NaOH (0.18 ml, 0.36
mmol) in MeOH (3 ml), for methyl esters, and worked
up normally. A solution of the obtained 4-carboxy
derivative and H-L-Phe-OMe (0.48 mmol) in dry THF
(4 ml) was successively treated at rt with BOP (0.21 g,
0.48 mmol) and TEA (0.13 ml, 0.96 mmol). The stirring
was continued until complete disappearance of the
starting material (1–2 days). The isomers ratio was
determined by HPLC or by 1H NMR on the crude
reaction mixtures. To characterize the obtained dipep-
tide derivatives, the solvent was evaporated, the residue
was dissolved in EtOAc and washed with citric acid
(10%), NaHCO3 (10%) and brine. The organic layer
was dried (Na2SO4) and evaporated leaving a residue
that was purified on a silica gel column as specified in
each case.
t
1.38 (s, 9H, CH3, Bu). EM (ES positive mode): 547.3
(M+Na)+. Anal calcd for C29H36N2O7: C, 66.39; H,
6.92; N, 5.34. Found: C, 66.25; H, 6.90; N, 5.55.
Acknowledgements
This work was supported by CICYT (SAF 2000-0147).
M.A.B. and G.G.-N. are predoctoral fellows from the
Ramo´n Areces Foundation and Ministry of Science
and Technology, respectively.
3.4.1. 1-(p-Methoxybenzyl)-4-[N-(1%-methoxycarbonyl-
2%-phenyl)ethyl]carbamoyl-4-(tert-butoxycarbonyl)-meth-
yl-2-azetidinone 58. Isomer 4R,1%S 58a: Syrup. Eluent
AcOEt:hexano (2:1). HPLC: tR=29.92 min (A:B=
35:65). [h]D=+73.5 (c 1.07, CHCl3). 1H NMR (300
MHz, CDCl3): l 7.13 (m, 7H, C6H5 and C6H4), 6.74 (d,
2H, J=8.7, C6H4), 6.41 (d, 1H, J=7.8, a-NH), 4.63 (m,
1H, a-CH), 4.29 (d, 1H, J=14.9, 1-CH2), 4.16 (d, 1H,
J=14.9, 1-CH2), 3.70 (s, 3H, OMe), 3.58 (s, 3H, OMe),
3.01 (m, 2H, 3-H), 2.89 (dd, 1H, J=6.4, 13.9, b-Phe),
2.87 (d, 1H, J=16.9 4-CH2), 2.80 (dd, 1H, J=6.4, 13.9,
b-Phe), 2.54 (d, 1H, J=16.9 4-CH2), 1.33 (s, 9H, CH3,
tBu). EM (ES positive mode): 533.2 (M+Na)+. Anal
calcd for C28H34N2O7: C, 65.87; H, 6.71; N, 5.49.
Found: C, 65.45; H, 6.40; N, 5.75. Isomer 4S,1%S 58b:
Syrup. Eluent AcOEt:hexano (2:1). HPLC: tR=25.84
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