Chemistry and X-ray crystallographic structure of N-protected (5-oxo-1,3-oxazolidin-4-yl)acetic acids: Versatile intermediates in the synthesis of peptidomimetics

Article abstract of DOI:10.1039/a608165g

The X-ray crystal structures of [(2′R,4′S)-3′-benzoyl-4′-benzyl-5′-oxo-2′- phenyloxazolidin-4′-yl]acetic acid 16 and [(2′S,4′R)-3′-acetyl-4′-benzyl-5′-oxo-2′- phenyloxazolidin-4′-yl]acetic acid 19 have been determined and their conformations compared to those of related oxazolidinones. Compounds of the type 16 and 19 have also been shown to be useful precursors to succinimide-based peptidomimetics possessing conformational restriction and latent reactivity.

Full text of DOI:10.1039/a608165g

View Article Online / Journal Homepage / Table of Contents for this issue
Chemistry and X-ray crystallographic structure of N-protected
(5-oxo-1,3-oxazolidin-4-yl)acetic acids: versatile intermediates in
the synthesis of peptidomimetics
Andrew D. Abell,* Ross A. Edwards and Mark D. Oldham
Department of Chemistry, University of Canterbury, Christchurch, New Zealand
The X-ray crystal structures of [(2ЈR,4ЈS)-3Ј-benzoyl-4Ј-benzyl-5Ј-oxo-2Ј-phenyloxazolidin-4Ј-yl]acetic
acid 16 and [(2ЈS,4ЈR)-3Ј-acetyl-4Ј-benzyl-5Ј-oxo-2Ј-phenyloxazolidin-4Ј-yl]acetic acid 19 have been
determined and their conformations compared to those of related oxazolidinones. Compounds of the
type 16 and 19 have also been shown to be useful precursors to succinimide-based peptidomimetics
possessing conformational restriction and latent reactivity.
O
Introduction
O
ZHN
AcHN
Bn
In recent years enormous effort has gone into the design and
synthesis of peptidomimetics. These compounds maintain
important structural features found in biologically active pep-
tides while offering the advantage of increased bio-availability,
bio-stability, bio-efficiency and bio-selectivity against the
natural biological target of the parent peptide.1 In extreme
cases, peptidomimetics bear only a scant resemblance to the
original parent peptide. Peptidomimetics can either inhibit (i.e.
act as an antagonist or inhibitor) or enhance (i.e. act as an
agonist) the effects of the original peptide and as a result they
offer a high potential as medicinal agents.
The introduction of rings into peptidomimetics results in
structures of well-defined conformation that can be used as
biological probes to mimic and test the biological conform-
ations adopted by peptides.1,2 Examples of this include potent
peptidomimetic inhibitors of renin 3 (e.g. 1) and the HIV
N
CO2Et
Br
CO2Et
NOSO2Me
O
Bn
5
4
R = Bn
R = Bn
O
Bn
ZHN
N
CO2Et
Bn
R1
R = Bn
O
O
6
ZN
O
R
COR2
R = H
O
Bn
3
ZHN
N
CO2Et
H
O
R = Me
R = Bn
O
OH
O
7
H
H
N
N
N
ZHN
N
N
H
Bn
CO2Me
COR2
O
O
ZHN
O
Bn
Me
ZHN
N
CO2Et
9
Bn
1
8
Scheme 1
H
N
O
potent mechanism-based inactivators of serine proteases.9,10
These compounds function by an enzyme-mediated hydrolysis
with subsequent Lossen rearrangement to release a highly
reactive isocyanate which results in irreversible enzyme inacti-
vation. We have attempted to increase the peptidic nature of
these simple amino acid analogues, with a view to increasing
potency and selectivity towards a given protease, by incorporat-
ing them into a peptidic sequence as in 5. Amino succinimides
of the type 7 have been reported to display anticonvulsant activ-
ity11 and also to play a critical role in protein splicing and other
post-translational protein modifications.12 Amino succinimdes
of the type 6, reported for the first time here, are phenylalanine
analogues of the known peptidomimetics 7. Peptidomimetic
lactams 8 have found wide application as conformationally
restricted inhibitors of renin 3 (e.g. compound 1) and other bio-
logical targets,13,14 while α-methylated amino acids 9 display
helix-inducing properties.15
MeOSuc-Ala-Ala
Br
O
O
2
protease.4 Functional groups possessing latent reactivity have
also been incorporated into peptidomimetics to provide select-
ive mechanism-based inactivators of enzymes.5 For example,
peptidomimetic halogeno enol lactones of the type 2 are potent
inactivators of serine proteases.6
We and others have used N-protected (5-oxo-1,3-oxazolidin-
4-yl)acetic acids7,8 and their derivatives (see Scheme 1, structure
3) as key synthetic intermediates to peptidomimetics with latent
reactivity (e.g. 4 and 5) and conformational restriction (e.g.
6–9). Acylated enamino esters 4 are inactivators of serine pro-
teases, a class of enzyme that catalyses the cleavage of peptides.8
N-Methylsulfonyloxysuccinimides have been shown to be
J. Chem. Soc., Perkin Trans. 1, 1997
1655

View Article Online
Here we detail the synthesis and X-ray crystallographic struc-
ture analysis of N-protected (5-oxo-1,3-oxazolidin-4-yl)acetic
acids and also their application to the preparation of imide-
based peptidomimetics of the type 5, 6 and 7.
This allowed the preparation of 5 and 6 with the same configur-
ation, a requirement for our biological studies.18
The unsubstituted oxazolidinone 10 was prepared by reac-
tion of N-Z--aspartic acid with paraformaldehyde and
toluene-p-sulfonic acid (PTSA) according to the method of
Scholtz and Bartlett (Scheme 2).19
Results and discussion
The required N-protected (5-oxo-1,3-oxazolidin-4-yl)acetic
acids 13,8b 16 and 19 were prepared (Scheme 2) using an exten-
Synthesis of peptidomimetics
Amino succinimides, e.g. 7, are traditionally prepared by reac-
tion of an N-protected aspartic acid anhydride with an amine
or an amino acid ester. The intermediate ring-opened α- and
β-acid amides are then cyclised by reaction with acetic
anhydride.20 Alternatively, side chain-protected aspartyl-
containing peptides can be cyclised with triethylamine to give
amino succinyl peptides.21 Amino succinimide formation of the
second type is also involved in the biochemistry of a number
of post-translational protein modification procedures.12 Here,
attack of a peptide amide nitrogen on an asparaginyl or
aspartyl side chain gives an amino succinimde that can undergo
ring opening to give two products, containing either an α- or
β-linkage.
O
ref. 18
ZN
N-Z-Asp
O
H
CO2H
10
Ph
Ph
O
O
ZN
ZN
O
i
ii
O
L-Phe
In the present study, an N,N-dicyclohexylcarbodiimide
(DCC)-catalysed coupling of the Z-protected aspartic acid
oxazolidinone 10 with -phenylalanine ethyl ester, in the pres-
ence of 1-hydroxybenzotriazole (HOBT), gave a mixture of 20
and 21 which was separable by chromatography (Scheme 3).
Bn
H
(ref. 8)
(ref. 8)
Bn
CO2R
11
12 R = CHPh2
13 R = H
iii (ref. 8)
Ph
Ph
i
(ref. 9)
O
O
O
O
BzN
Bn
BzN
Bn
i
O
O
Bn
ii
ZN
ZN
O
O
C
(ref. 9)
CO2R
H
H
CO2H
H
N
CO2Et
H
O
14
15 R = CHPh2
16 R = H
10
20
iii (ref. 9)
Ph
+
ii
iii
Ph
O
H
O
OH
ZN
O
Bn
O
Bn
AcN
Bn
AcN
Bn
O
O
i
ii
ZHN
D-Phe
N
CO2Et
N
CO2Et
CO2R
H
ii
H
O
O
7
21
17
18 R = CHPh2
19 R = H
iii
Scheme 3 Reagents and conditions: i, -PheOEtؒHCl, Et3N, DCC,
HOBT, CH2Cl2; ii, excess Et3N, CH2Cl2, reflux; iii, Et3N, CH2Cl2
Scheme 2 Reagents and conditions: i, NaOH, PhCHO, then RCOX,
Ϫ20 to 4 ЊC; ii, LiHMDS, THF, Ϫ78 ЊC, then BrCH2CO2CHPh2; iii,
TFA
The reaction was carried out a number of times giving variable
ratios of 20 and 21. Treatment of 20 with triethylamine at room
temp. gave compound 21 while the reaction of either a mixture
of 20/21, or a separate sample of 21, with an excess of triethyl-
amine at reflux gave the desired amino succinimide 7 and
recovered starting material (Scheme 3).
sion of the methods pioneered by Seebach for the stereo-
selective preparation of α,α-disubstituted amino acids.16
The starting oxazolidinones 11, 14 and 17 were prepared
from - and -phenylalanine under standard conditions8,16
(Scheme 2), i.e. treatment of the Schiff base sodium salt of the
amino acid/benzaldehyde with either benzyl chloroformate (to
give 11), benzoyl chloride (to give 14) or acetyl chloride (to give
17). It is interesting to note that the reaction conditions gave
either the syn (e.g. 11) or the anti (e.g. 14 and 17) isomers as the
major products depending on the nature of the acylating agent.
The configurations of 11,8 147 and 1717 were assigned as shown
based on NOE data and/or X-ray crystallographic studies. In
addition, the X-ray crystal structure of 13 has been published 8
and the structures of 16 and 19 are reported here.
The precursor oxazolidinones 11, 14 or 17 were deprotonated
with lithium hexamethyldisilazide at Ϫ78 ЊC, and the resulting
C4 anion was treated with diphenylmethyl bromoacetate to give
12, 15 and 18 respectively. Hydrolysis then gave the desired
compounds 13, 16 and 19.
The syn and anti oxazolidinones 11 and 14, both derived
from -phenylalanine, gave rise to products (12 and 15) of
opposite configuration on alkylation (Scheme 2). For this
reason, -phenylalanine was used in the N-acetyl series to give
17 and hence 18, which then has the same configuration as 12.
The advantage of the current procedure over the existing
literature procedures is not just that compounds of the type 7
can be prepared, but also that it can be extended to the prepar-
ation of substituted succinimides of the type 6, a Phe-Phe
dipeptidomimetic (Scheme 4). In this case, the phenylalanine-
derived oxazolidinone 13 was coupled to -phenylalanine ethyl
ester to give 22 in 65% yield, which was either cyclised directly
to give the dipeptidomimetic 6 (73%) or treated with toluene-p-
sulfonic acid (PTSA) to give the amino succinimide 23 (58%). A
DCC-catalysed coupling of 23 with N-acetyl--leucine then
gave the tripeptidomimetic 24 (67%). An intermediate of the
type 21 was not observed in this case, unlike the example given
in Scheme 3. A complementary preparation of amino suc-
cinimides has been reported (Scheme 5).11 Here the oxazo-
lidinone ring, rather than the acid side chain of 10, is reported
to react with an amine to give 25 (step i, Scheme 5). Methyl-
ation (step ii) and cyclisation (step iii) then gave the succinimde
27.
A related sequence to that given in Scheme 4 was used to
prepare peptidomimetics of the type 5 (Scheme 6). To this end,
1656
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Ph
Ph
O
O
i
Bn
ZN
ZN
O
O
C
Bn
CO2H
Bn
N
CO2Et
H
O
22
13
ii
iii
O
O
Bn
Bn
H2N
Bn
ZHN
N
CO2Et
N
CO2Et
Bn
O
O
23
6
iv
O
Bn
AcLeuHN
Bn
N
CO2Et
Fig. 1 X-Ray molecular structure of compound 16 with crystallo-
graphic numbering scheme
O
24
Scheme 4 Reagents and conditions: i, -PheOEtؒHCl, Et3N, DCC,
HOBT, CH2Cl2; ii, Et3N, CH2Cl2, room temp.; iii, 4-MeC6H4SO3H,
toluene, reflux; iv, N-Ac--Leu, DCC, HOBT, CH2Cl2, 0 ЊC to room
temp.
O
ZN
ZHN
CONHR
CO2H
i
O
H
CO2H
H
25
10
ii
O
iii
ZHN
ZHN
CONHR
CO2Me
NR
O
H
H
27
26
Scheme 5 Reagents and conditions: i, RNH2, MeOH, reflux; ii, H2SO4,
MeOH, reflux; iii, 4-MeC6H4SO3H, toluene, reflux
reaction of the phenylalanine-derived oxazolidinone acid 19
with O-benzylhydroxylamine in the presence of benzotriazol-1-
yloxytris(dimethylamino)phosphonium hexafluorophosphate
(BOP) gave a separable mixture of 28 (26%) and 29 (56%). The
reaction of 28 with an excess of triethylamine at room temp.
gave a quantitative conversion to 29. Catalytic hydrogenation
of 29 gave the hydroxysuccinimide 30 (96%) which was reacted
with methanesulfonyl chloride, in the presence of diisopropyl-
ethylamine, to give the desired pseudo dipeptide 5 in 83% yield
(Scheme 6).
Fig. 2 X-Ray molecular structure of compound 19 with crystal-
lographic numbering scheme
Ph
Ph
O
O
AcN
Bn
AcN
Bn
O
O
i
CONHOBn
CO2H
19
28
+
X-Ray molecular structures
O
O
Perspective drawings of compounds 16 and 19, with atom label-
ling, are presented in Figs. 1 and 2. The phenyl and benzyl ring
substituents are syn, as would be expected from the alkylation
of precursor oxazolidinones 11 and 14, respectively. The abso-
lute configurations follow from the configuration of the starting
amino acids (Scheme 2). The conformations adopted by 16, 19,
the previously reported derivatives 13, 31–337 and related
examples22 are very similar. In particular, the oxazolidinone
rings adopt a shallow envelope conformation (e.g. see Fig. 3)
such that the phenyl substituent occupies a quasi-equatorial
position. In this conformation the phenyl-substituted carbon
atom is slightly out of the plane formed by the other four ring
atoms. This is supported by the fact that the angles between the
least-squares plane of O(1)–C(5)–C(4)–N(3) and the plane of
ii
AcHN
Bn
AcHN
Bn
NOSO2Me
NOR
iv
O
O
5
29 R = Bn
30 R = H
iii
Scheme 6 Reagents and conditions: i, NH2OBn, Et3N, BOP, CH2Cl2; ii,
Et3N, CH2Cl2, room temp.; iii, 10% Pd–C, H2; iv, Pri2EtN, MeSO2Cl,
CH2Cl2, 0 ЊC
O(1)–C(2)–N(3) (see Figs. 1 and 2 for atom numbering) of 13,
16, 19 and 31–33 are in the range of 9–12Њ (Table 1).
The conformations adopted by the ring substituents of 16
J. Chem. Soc., Perkin Trans. 1, 1997
1657

View Article Online
Table 1 Selected bond angles and bond lengths
The amide nitrogens of 13, 16, 19 and 31–33 show a very
slight pyramidalisation, with the angles at the nitrogen atom
summing to a value slightly less than 360Њ (Table 1). This is
further supported by small, but significant, τ1 and τ2 angles
(Table 1). The limited pyramidalisation observation is consist-
ent with electron delocalisation between the nitrogen and car-
Angle
between
Torsion angles (Њ)
Compound planes (Њ)a ΣαN (3)b (Њ) τ1
τ2
N(3)–C(7)/Å
c
d
13
16
19
31
32
33
11.9
10.3
10.9
9.5
12.4
9.2
358.6
359.1
358.8
359.2
359.0
358.8
Ϫ9.6
6.5
1.346
1.343
1.352
1.359
1.356
1.407
0.9
10.6
bonyl centre (see N᎐C᎐O bond lengths, Table 1). A number of
᎐
2.9 Ϫ11.4
syn N-acylated oxazolidinones, e.g. 34, and N-acylated imidazo-
lidinones, e.g. 35, are reported to show significantly greater
pyramidalisation of the amide nitrogen.24 In these cases, the
acyl group and the other ring substituents are located on
opposite sides of the ring and the tert-butyl group occupies a
quasi-axial, rather than a quasi-equatorial, position.24 Non-
acylated analogues are reported to show even greater ring
puckering.24 This pyramidalisation is thought to contribute
strongly to the steric bias between the two faces of the ring and
hence influence the stereoselectivity of reactions of these
heterocycles.
10.4
Ϫ7.5
Ϫ8.8
Ϫ1.7
6.5
4.4
a
Angle between least-squares plane through atoms O(1)–C(5)–C(4)–
N(3) and the plane of O(1)–C(2)–N(3). b Sum of the bond angles about
N(3). c Torsion angle C(2)–N(3)–C(7)–C(8)/C(71). d Torsion angle
C(4)–N(3)–C(7)–O(7).
The N-acyl carbonyl oxygen atom [O(7)] of 16 and 19 occu-
pies an approximate s-trans position with the phenyl substituent
of the acetal carbon atom [C(2), Figs. 1–3]. A similar conform-
ation was noted in the structures of 13 and 31–33 all of which,
like 16 and 19, are geminally disubstituted at C(4).7 The X-ray
crystal structures of less congested examples, which are mono-
substituted at C(4), reveal the alternative s-cis conformation.24
The work described here gives an analysis of the X-ray struc-
tures of N-protected (5-oxo-1,3-oxazolidin-4-yl)acetic acids
and provides a platform for their application to the synthesis of
peptidomimetics with conformational restriction and latent
reactivity.
Experimental
Mps were obtained using a Hot Stage Microscope and are
uncorrected. NMR Spectra were obtained in CDCl3 (unless
1
otherwise stated) at 300 MHz for H and 75 MHz for 13C; J
values are given in Hz. Infrared spectra were obtained using a
Perkin-Elmer 1600 FTIR spectrophotometer. Mass spectra
were obtained on a Kratos MS80RFA magnetic sector double
focusing mass spectrometer. Optical rotations were measured on
a JASCO J-20C recording spectropolarimeter, and [α]D values
are given in units of 10Ϫ1 degrees cm2 gϪ1. Preparative chrom-
atography was carried out using a Chromatotron (Harrison
Research Inc.) using glass plates coated with silica gel (P.F. 254
60). Lithium hexamethyldisilazide (LiHMDS) was obtained as
a 1.0  solution in THF from the Aldrich chemical company.
Fig. 3 X-Ray molecular structure of compound 16 showing ring
conformation
Ph
Ph
O
O
O
BzN
R
O
BzN
Pri
Ph
Ph
NHBz
NHBz
31 R = Bn
32 R = Pri
33
(2S,4R)-(؊)-3-Acetyl-4-benzyl-2-phenyl-1,3-oxazolidin-5-one 17
-Phenylalanine (2.50 g, 15.1 mmol) was dissolved in 1  aq.
NaOH (15.2 cm3, 15.2 mmol), with slight warming, to give the
corresponding sodium salt. The solvent was removed under
reduced pressure to give a white sticky solid. To this was added
benzaldehyde (2.3 cm3, 22.6 mmol) and cyclohexane (60 cm3)
and the mixture was refluxed for 23 h using a Dean and Stark
apparatus for the azeotropic removal of water. The solvent was
evaporated under reduced pressure and to the resultant white
solid residue was added dichloromethane (50 cm3) and the mix-
ture was cooled to Ϫ20 ЊC under N2. Acetyl chloride (1.5 cm3,
21.1 mmol) was added and the mixture was stirred at Ϫ20 ЊC
for a further 2 h and then at 4 ЊC for 4 days. The mixture was
allowed to warm to room temp. over 3.5 h before the solvent
was removed under reduced pressure. The pale orange oil resi-
due was taken up into a mixture of ethyl acetate (60 cm3) and
5% aq. NaHCO3 (50 cm3). The organic phase was separated
and washed with 5% aq. KHSO4 (50 cm3) and water (50 cm3).
The organic phase was separated and after the addition of solid
NaCl, dried (Na2SO4) and the solvent removed. The anti oxazo-
lidinone 17, which crystallised from the residue, was recrystal-
lised from ethyl acetate and light petroleum (1.64 g, 37%), mp
148–150 ЊC (Found: C, 73.3; H, 5.9; N, 4.5. C18H17NO3 requires
OEt
But
BzN
O
But
O
O
O
N
ZN
SMe
34
35
and 19 (and the previously reported examples 13 and 31–33)7
are also very similar. The C(21)–C(26) and C(61)–C(66) aro-
matic rings of 16 (Fig. 1) and 19 (Fig. 2) show an edge-on π–π
interaction 23 [the distance between C(22)/C(26) and the plane
of C(61)–C(66) is 3.336 and 3.444 Å for 16 and 19, respectively].
The C(21)–C(26) and C(71)–C(76) aromatic rings in the struc-
ture of 16 also show some evidence of π–π stacking23 [angle
between the aromatic ring planes defined by C(21)–C(26) and
C(71)–C(76) is 23.8Њ and the distance between C(26) and the
plane defined by C(71)–C(76) is 3.162 Å]. The structures of 16
and 19 also revealed intermolecular hydrogen bonds between
the carboxylic acid group [O(11)] and the N-acyl carbonyl
group [O(7)] of a second molecule [O(7)–O(11) distance is 2.604
and 2.625 Å for 16 and 19, respectively].
1658
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
C, 73.2; H, 5.8; N, 4.7%); [α]D20 Ϫ182 (c 1.3, dichloromethane);
νmax(KBr)/cmϪ1 3447, 3032, 1798 and 1666; δH ([2H6]DMSO,
100 ЊC) 1.78 (3 H, br s, CH3), 3.21 (1 H, A part of ABX, JAB 14.1,
JAX 2.7, CH2Ph), 3.60 (1 H, B part of ABX, JAB 14.1, JBX 5.9,
CH2Ph), 5.20 (1 H, X part of ABX, H4), 6.08 (1 H, s, H2), 7.18
(2 H, m, ArH), 7.29 (3 H, m, ArH) and 7.42 (5 H, s, ArH); δC
23.4, 34.2, 58.6, 90.5, 126.8, 127.6, 128.8, 129.4, 129.7, 130.8,
134.9, 136.1, 168.3 and 171.0.
atotron plate eluting with ethyl acetate–light petroleum (1:1).
Crystallisation from ethyl acetate and light petroleum gave 28
as fine white splintery crystals (108 mg, 26%), mp 160–162 ЊC
(softens at 155 ЊC) (Found: C, 70.5; H, 5.6; N, 6.3. C27H26N2O5
requires C, 70.7; H, 5.7; N, 6.1%); [α]D20 Ϫ20 (c 1.1, dichloro-
methane); νmax(KBr)/cmϪ1 3196, 3031, 1793 and 1667; δH ([2H8]-
dioxane, 90 ЊC) 1.66 (3 H, s, CH3), 2.90 (1 H, d, J 16.1,
CH2CO), 3.43 and 3.84 (2 H, ABq, JAB 13.6, CH2Ph), 3.77 (1 H,
br, CH2CO), 4.99 and 5.02 (2 H, ABq, JAB 11.2, OCH2Ph),
6.55 (1 H, s, H2), 6.59 (2 H, d, J 7.3, ArH), 7.23 (2 H, t, J 7.3,
ArH), 7.36–7.58 (11 H, m, ArH) and 9.64 (1 H, br s, NH); δC
24.3, 38.3, 42.0, 66.7, 78.2, 90.9, 127.7, 127.9, 128.5, 128.7,
129.1, 129.3, 130.1, 130.6, 134.8, 135.0, 135.04 166.7, 170.9 and
172.9.
Further elution with ethyl acetate gave 29 (177 mg, 56%), mp
186–189 ЊC (softens at 182 ЊC) (Found: C, 68.1; H, 5.9; N, 8.1.
C20H20N2O4 requires C, 68.2; H, 5.7; N, 8.0%); [α]D20 ϩ80 (c 1.1,
dichloromethane); νmax(KBr)/cmϪ1 3344, 3033, 1790, 1729, 1651
and 1538; δH 2.02 (3 H, s, CH3), 2.96 and 2.98 (2 H, ABq, JAB
17.6, CH2CO), 3.00 and 3.13 (2 H, ABq, JAB 13.2, CH2Ph), 4.94
and 4.99 (2 H, ABq, JAB 9.7, OCH2Ph), 5.90 (1 H, s, NH), 7.16
(2 H, m, ArH), 7.35 (6 H, m, ArH) and 7.48 (2 H, m, ArH); δC
22.7, 37.4, 42.0, 57.3, 78.7, 128.3, 128.4, 129.09, 129.2, 129.7,
130.1, 132.0, 133.5, 168.5, 170.4 and 172.3.
Method B. Triethylamine (92 µl, 0.66 mmol) was added to a
solution of 28 (30 mg, 0.07 mmol) in dichloromethane (0.8 cm3)
and the mixture stirred at room temp. for 1 h. The solution was
diluted with dichloromethane (15 cm3) and washed with 5% aq.
HCl (10 cm3), followed by water (2 × 10 cm3). The organic
phase was dried (MgSO4) and the solvent removed to give a
residue that was purified by radial chromatography using a 1
mm silica gel chromatotron plate eluting with ethyl acetate–
light petroleum (3:1) to yield 29 as a clear colourless oil (23 mg,
100%).
(2ЈS,4ЈR)-(؉)-3Ј-Acetyl-4Ј-benzyl-5Ј-oxo-2Ј-phenyl-1Ј,3Ј-
oxazolidin-4Ј-yl)acetic acid 19
LiHMDS (3.75 cm3 of 1  solution in THF, 3.75 mmol, 1.1
equiv.) was added to oxazolidinone 17 (1.00 g, 3.39 mmol) dis-
solved in THF (40 cm3) at Ϫ78 ЊC under N2. The mixture was
stirred at Ϫ78 ЊC for 7 min, after which time a solution of
BrCH2CO2CHPh2 (1.50 g, 4.92 mmol) in dry THF (4 cm3) was
added. The mixture was stirred at Ϫ78 ЊC for a further 2 h and
then at room temp. for 20 h. The solvent was evaporated under
reduced pressure and the residue was taken up into a mixture of
diethyl ether (50 cm3) and saturated aq. NH4Cl (40 cm3). The
aqueous phase was extracted with diethyl ether (3 × 30 cm3)
and the diethyl ether fractions were combined, dried (Na2SO4)
and solvent removed. The resulting clear yellow oil was purified
by radial chromatography using a 4 mm silica gel plate and
eluting with ethyl acetate–light petroleum (1:4) to give 18 as
a clear colourless oil (1.47 g, 83%), which was used in sub-
sequent steps without further purification [HRMS: found (EI)
Mϩ, 519.2048. C33H29NO5 requires 519.2046]; [α]D20 ϩ10 (c 2.2,
dichloromethane); νmax(KBr)/cmϪ1 3065, 3032, 2928, 1794,
1734 and 1666; δH 1.30 (3 H, s, CH3), 3.17 and 4.09 (2 H,
ABq, JAB 17.1, CH2CO), 3.32 and 3.78 (2 H, ABq, JAB 13.7,
CH2Ph), 6.02 (1 H, s, H2), 6.05 (2 H, d, J 7.3, ArH), 6.89 (1
H, s, CHPh2), 7.00 (2 H, t, J 7.8, ArH), 7.19 (1 H, t, J 7.4,
ArH) and 7.22–7.39 (15 H, m, ArH); δC 24.2, 39.6, 41.9, 66.2,
77.9, 90.8, 126.7, 127.2, 127.6, 127.7, 127.9, 128.1, 128.5,
128.5, 128.5, 129.0, 129.9, 130.6, 134.8, 135.1, 139.1, 139.5,
169.3, 169.7 and 172.7.
(3R)-(؉)-3-Acetylamino-3-benzyl-1-hydroxysuccinimide 30
A mixture of 29 (105 mg, 0.30 mmol) and 10% Pd on C (10 mg)
in dry THF (5 cm3) was stirred under a H2 atmosphere for 2.5 h.
The reaction mixture was filtered, the filtrate evaporated and
the solid residue was washed with ethyl acetate to give 30 as a
white solid (75 mg, 96%), mp 182–188 ЊC (softens at 112 ЊC)
(Found: C, 55.6; H, 5.7; N, 9.8. C13H14N2O4.H2O requires C,
55.2; H, 5.8; N, 10.0%); [α]D20 ϩ90 (c 1.1, CH3OH); νmax(KBr)/
cmϪ1 3318, 1792, 1718, 1655 and 1543; δH (CD3OD) 1.98 (3 H, s,
CH3), 2.82 and 2.87 (2 H, ABq, JAB 17.6, CH2CO), 2.99 and
3.22 (2 H, ABq, JAB 13.2, CH2Ph), 7.17 (2 H, m, ArH) and 7.23
(3 H, m, ArH); δC(CD3OD) 22.4, 37.8, 42.6, 59.1, 129.2, 130.1,
131.6, 134.1, 171.9, 173.6 and 175.5.
The benzhydryloxazolidinone 18 (250 mg, 0.48 mmol) was
dissolved in dry THF (20 cm3), trifluoroacetic acid (0.74 cm3,
9.61 mmol) was added and the mixture was stirred for 3 h at
room temp. under N2. The mixture was evaporated under
reduced pressure and the residue was taken up into ethyl acetate
(75 cm3) and washed with dilute aq. HCl (100 cm3) and water
(50 cm3). The organic phase was dried (Na2SO4) and solvent
was removed to give a residue that was washed with dichlo-
romethane (3 cm3) to give 19 as a white solid (106 mg, 62%), mp
228–229 ЊC (Found: C, 68.0; H, 5.5; N, 3.9. C20H19NO5 requires
C, 68.0; H, 5.4; N, 4.0%); [α]D20 ϩ16 (c 1.0, methanol); νmax(KBr)/
cmϪ1 2932, 1794, 1726 and 1622; δH (CD3OD) 1.52 (3 H, s, CH3),
3.03 and 3.82 (2 H, ABq, JAB 7.6, CH2CO2), 3.26 and 3.73 (2 H,
ABq, JAB 13.2, CH2Ph), 6.25 (2 H, d, J 7.3, ArH) 6.49 (1 H, s,
H2), 7.09 (2 H, t, J 7.8, ArH) and 7.20–7.46 (6 H, m, ArH); δC
24.9, 40.9, 43.3, 68.5, 92.9, 129.3, 129.7, 130.2, 130.5, 131.6,
132.0, 137.0, 137.3, 172.6, 174.1 and 175.2.
(3R)-(؉)-3-Acetylamino-3-benzyl–1-methylsulfonyloxysuccin-
imide 5
Methanesulfonyl chloride (27 µl, 0.35 mmol) was added to a
solution of 30 (60 mg, 0.30 mmol) and diisopropylethylamine
(44 µl, 0.25 mmol) in dichloromethane (1 cm3) at 0 ЊC and the
mixture was stirred at 0 ЊC for 20 min and then at room temp.
for 1 h. The mixture was diluted with dichloromethane (15 cm3)
and washed successively with cold water (10 cm3), cold 5% aq.
HCl (10 cm3) and cold 10% aq. NaHCO3 (10 cm3). The organic
phase was dried (Na2SO4) and the solvent removed to give 5 as
a clear colourless oil which crystallised from diethyl ether
(65 mg, 83%), mp 64–67 ЊC (Found: C, 47.6; H, 4.9.
C14H16N2O6Sؒ3/4H2O requires C, 47.5; H, 5.0%); [α]D20 ϩ36 (c 0.8,
dichloromethane); νmax(KBr)/cmϪ1 3269, 3036, 2936, 1809,
1747, 1661 and 1531; δH 2.03 (3 H, s, CH3CO), 3.04 and 3.11
(2 H, ABq, JAB 17.6, CH2CO), 3.06 and 3.23 (2 H, ABq, JAB
13.2, CH2Ph), 3.35 (3 H, s, SCH3), 5.95 (1 H, s, NH), 7.19 (2
H, m, ArH) and 7.39 (3 H, m, ArH); δC 22.2, 37.4, 39.6, 41.5,
57.8, 128.3, 129.0, 130.2, 131.4, 166.6, 170.5 and 171.1
[HRMS: found (EI) Mϩ, 340.0725. C14H16N2O6S requires
340.0729].
(2ЈS,4ЈR)-(؊)-2-(3Ј-Acetyl-4Ј-benzyl-5Ј-oxo-2Ј-phenyl-1Ј,3Ј-
oxazolidin-4Ј-yl)-N-benzyloxyacetamide 28 and (3R)-(؉)-3-
acetylamino-3-benzyl-1–benzyloxysuccinimide 29
Method A. Triethylamine (125 µl, 0.90 mmol, 1 equiv.) was
added to a stirred suspension of 19 (316 mg, 0.89 mmol), BOP
(442 mg, 0.10 mmol) and O-benzylhydroxylamine (142 mg, 1.15
mmol) in dichloromethane (12 cm3) under N2. After stirring at
room temp. for 80 min., a further equivalent of triethyl-
amine (125 µl, 0.9) was added and stirring was continued for a
further 80 min. The solvent was evaporated under reduced pres-
sure and the residue was taken up into ethyl acetate (20 cm3).
The organic phase was washed with 5% aq. HCl (20 cm3), water
(20 cm3), 5% aq. NaHCO3 (20 cm3) and water (20 cm3), and
dried (Na2SO4). The solvent was removed and the residue was
purified by radial chromatography on a 1 mm silica gel chrom-
J. Chem. Soc., Perkin Trans. 1, 1997
1659

View Article Online
(2S,4ЈS)-(؉)-Ethyl 2-[(3Ј-benzyloxycarbonyl-5Ј-oxo-1Ј,3Ј-
oxazolidin-4Ј-yl)methylcarbonylamino]-3-phenylpropanoate 20
and (2S,3ЈS)-(؊)-ethyl 2-{3Ј-[benzyloxycarbonyl(hydroxy-
methyl)amino]succinimido}-3-phenylpropanoate 21
acetate–light petroleum (1:1) to give 21 (4.3 mg, 33%) and 7
(5.1 mg, 42%) [HRMS: found (EI) Mϩ, 424.1634. C23H24N2O6
requires 424.1634]; [α]D20 Ϫ72 (c 0.5, dichloromethane);
νmax(KBr)/cmϪ1 3358, 2937, 1786, 1717 and 1526; δH 1.28 (3 H,
t, J 7.3, CH3), 2.56 (1 H, dd, J 6.3, 17.8, CH2CO), 3.04 (1 H, dd,
J 8.9, 17.8, CH2CO), 3.40 (1 H, A part of ABX, JAB 14.1, JAX
11.3, CHCH2Ph), 3.50 (1 H, B part of ABX, JAB 14.1, JBX 5.6,
CHCH2Ph), 4.24 (3 H, m, OCH2 and CHCH2CO), 5.00 (1 H, X
part of ABX, CHCH2Ph), 5.11 (2 H, s, OCH2Ph), 5.27 (1 H, br
d, J 4.8, NH) and 7.13–7.39 (10 H, m, ArH); δC 14.1, 34.0, 36.0,
50.0, 54.1, 62.2, 67.5, 127.2, 128.3, 128.4, 128.6, 129.0, 135.7,
136.3, 155.8, 167.9, 173.0 and 174.6.
Method A. -Phenylalanine ethyl ester hydrochloride (50 mg,
0.22 mmol), triethylamine (31 µl, 0.22 mmol) and HOBTؒ1H2O
(34 mg, 0.22 mmol) were added to 1018 (61 mg, 0.22 mmol)
dissolved in dichloromethane (0.45 cm3) and the solution was
cooled to 0 ЊC under N2. After stirring for 10 min, DCC (45 mg,
0.22 mmol) was added and the mixture was stirred for a further
10 min at 0 ЊC and then for 18 h at room temp. The mixture was
filtered and the filtrate diluted with dichloromethane (15 cm3)
and washed with 3.5% aq. HCl (20 cm3) and water (2 × 20 cm3).
The organic phase was dried (MgSO4) and the solvent was
removed under reduced pressure. The residue was taken up in
ethyl acetate, filtered and evaporated to give a mixture of 20 and
Method B. Triethylamine (0.5 cm3, 0.36 mmol) was added to
21 (11.5 mg, 0.03 mmol) dissolved in dichloromethane (0.5 cm3)
and the mixture was refluxed for 1 h. Work up and purification
as described above gave recovered 21 (7 mg, 61%) and 7 (4 mg,
38%).
1
21 (19:1 by H NMR spectroscopy) which was not purified
further (89 mg, 90%) [HRMS: found: (FAB) MHϩ, 455.1808.
C24H27N2O7 requires 455.1818]; [α]D20 ϩ71 (c 2.2, dichloro-
methane); νmax(KBr)/cmϪ1 3354, 2928, 1801, 1717 and 1531;
δH (for 20) ([2H6]DMSO, 60 ЊC) 1.08 (3 H, t, J 7.1, CH3), 2.71 (1
H, dd, J 2.9, 16.7, CHCH2CO), 2.92 (1 H, dd, J 8.4, 13.8,
CHCH2Ph), 3.01 (1 H, dd, J 6.2, 13.8, CHCH2Ph), 3.04 (1 H,
dd, J 4.7, 16.7, CHCH2CO), 4.02 (2 H, q, J 7.1, OCH2CH3),
4.42 (2 H, m, 2 × CH), 5.08 (1 H, dd, J 1.0, 3.4, NCH2O), 5.15
(2 H, s, OCH2Ph), 5.44 (1 H, d, J 3.4, NCH2O), 7.17–7.39 (10
H, m, ArH) and 8.45 (1 H, d, J 7.3, NH); δC 13.7, 35.0 (br),
37.2, 51.4, 53.1, 61.2, 67.4, 77.9 (br), 126.7, 127.7, 128.1, 128.2,
128.3, 128.9, 135.2, 135.4, 152.3, 168.4, 170.9 and 172.0.
A separate large scale preparation as described above, using
-phenylalanine ethyl ester hydrochloride (247 mg, 1.08 mmol),
triethylamine (0.15 cm3, 1.08 mmol,) and HOBTؒ1H2O (165
mg, 1.08 mmol), gave a mixture of 20 and 21 in a ratio of 1:2 by
1H NMR spectroscopy (455 mg, 94%). A sample (395 mg) of
this was purified by radial chromatography using a 2 mm silica
plate and eluting with ethyl aetate–light petroleum (1:1) to give
20 (113 mg, 27%, data as recorded above).
Further elution gave 21 (207 mg, 50%) {HRMS: found (EI)
[M Ϫ CH2O]ϩ, 424.1630. C23H24N2O6 requires 424.163 42}; [α]D20
Ϫ64 (c 1.15, dichloromethane); νmax(KBr)/cmϪ1 3479, 2939, 1788
and 1715; δH ([2H8]-1,4-dioxane, 90 ЊC) 1.37 (3 H, t, J 7.3, CH3),
2.91 (1 H, A part of ABX, JAB 17.6, JAX 6.4, CH2CO), 3.02 (1 H,
B part of ABX, JAB 17.6, JBX 9.3, CH2CO), 3.44 (1 H, A part of
ABX, JAB 14.4, JAX 10.0, CHCH2Ph), 3.62 (1 H, B part of ABX,
JAB 14.4, JAX 5.7, CHCH2Ph), 4.33 (2 H, q, OCH2CH3), 4.42
(1 H, br s, OH), 4.56 (1 H, X part of ABX, CHCH2CO), 4.92
(2H, m, CH2OH), 5.17 (1 H, X part of ABX, CHCH2Ph), 5.24
and 5.30 (2 H, br ABq, J 12.3, OCH2Ph) and 7.30–7.48 (10 H,
m, ArH); δC(mixture of conformational isomers) 14.0, 33.8,
34.0, 34.3, 35.1, 53.9, 54.1, 54.8, 55.9, 62.2, 68.2, 72.2, 72.6,
127.0, 128.2, 128.5, 128.6, 128.6, 128.7, 129.0, 135.5, 136.4,
136.6, 154.7, 154.8, 168.0, 168.2, 173.2, 174.3 and 174.8.
(2S,2ЈS,4ЈR)-(؉)-Ethyl 2-[(4Ј-benzyl-3Ј-benzyloxycarbonyl-5Ј-
oxo-2Ј-phenyl-1Ј,3Ј-oxazolidin-4Ј-yl)acetamido]-3-phenyl-
propanoate 22
-Phenylalanine ethyl ester hydrochloride (93 mg, 0.41 mmol),
triethylamine (58 µl, 0.42 mmol) and HOBTؒH2O (62 mg, 0.41
mmol) were added to 138 (178 mg, 0.40 mmol) dissolved in
dichloromethane (1 cm3) and the solution was cooled to 0 ЊC
under N2. After stirring for 10 min at 0 ЊC, DCC (85 mg, 0.41
mmol) was added and the mixture was stirred for a further 40
min at 0 ЊC and then for 18 h at room temp. The mixture was
filtered and the filtrate diluted with dichloromethane (25 cm3),
washed with 5% aq. HCl (25 cm3) and water (2 × 20 cm3). The
organic phase was dried (MgSO4), evaporated under reduced
pressure and the residue was purified by radial chromatography
on a 1 mm silica gel chromatotron plate, eluting with ethyl
acetate–light petroleum (1:3) to give 22 as a clear colourless oil
(162 mg, 65%) [HRMS: found (EI) Mϩ, 620.2527. C37H36N2O7
requires 620.2522]; [α]D20 ϩ46 (c 0.5, dichloromethane);
νmax(KBr)/cmϪ1 3360, 3033, 2934, 1794, 1711, 1674 and 1527; δH -
([2H8]-1,4-dioxane, 90 ЊC) 0.95 (3 H, t, J 7.1, CH3), 3.05 (1 H, d,
J 16.2, CH2CO), 3.19 (2 H, m, CH2Ph), 3.36 and 3.59 (2 H,
ABq, J 13.2, C4Ј-CH2Ph), 3.64 (1 H, br, CH2CO), 4.27 (2 H,
q, J 7.3, OCH2CH3), 4.92 (1 H, q, J 6.8, 1 H, CH), 4.99 (1 H, br
s, OCH2Ph), 5.18 (1 H, d, J 12.7, OCH2Ph), 6.43 (1 H, s, H2Ј),
6.50 (2 H, d, J 7.3, ArH), 7.04 (2 H, br s, ArH), 7.10 (2 H, t, J
7.4, ArH) and 7.26–7.48 (14 H, m, ArH); δC 13.9, 37.9, 40.9,
53.2, 61.5, 65.4, 67.0, 90.2, 126.9, 127.3, 127.4, 127.7, 127.9,
128.0, 128.4, 128.8, 129.0, 129.1, 130.6, 134.9, 135.1, 135.7,
152.2, 168.2, 170.9 and 172.9.
(2S,3ЈR)-(؊)-Ethyl 2-(3Ј-benzyl-3Ј-aminosuccinimido)-3-
phenylpropanoate 23
Toluene-p-sulfonic acid (50 mg, 0.26 mmol) was added to a
solution of 22 (68 mg, 0.11 mmol) in toluene (2 cm3) and the
mixture was refluxed for 1 h under N2. The solvent was removed
under reduced pressure and the residue taken up into ethyl
acetate (20 cm3) and water (20 cm3). The organic phase was
separated and washed with water (2 × 20 cm3), dried (Na2SO4),
the solvent was evaporated under reduced pressure and the
residue was purified by radial chromatography on a 1 mm silica
gel chromatotron plate, eluting with ethyl acetate–light petrol-
eum (1:1) to give 23 as an oil (24 mg, 58%) [HRMS: found (EI)
Mϩ, 380.1734. C22H24N2O4 requires 380.1736]; [α]D20 Ϫ54 (c 0.1,
dichloromethane); νmax(KBr)/cmϪ1 3368, 2982, 2934, 1780, 1743
and 1711; δH 1.19 (3 H, t, J 7.1, CH3), 2.23 and 2.71 (2 H, ABq,
J 18.3, CH2CO), 2.77 and 2.88 (2 H, ABq, J 13.6, C3Ј-CH2Ph),
3.32 (1 H, A part of ABX, JAB 14.2, JAX 11.7, CHCH2Ph), 3.47
(1 H, B part of ABX, JAB 14.2, JBX 5.4, CHCH2Ph), 4.18 (2 H,
m, OCH2), 4.94 (1 H, X part of ABX, CH), 7.09 (5 H, m, ArH)
and 7.25 (5 H, m, ArH); δC 14.0, 33.8, 40.0, 42.8, 53.1, 59.1,
61.9, 127.0, 127.3, 128.5, 128.6, 129.1, 130.3, 134.7, 136.5,
168.04 173.7 and 180.4.
Method B. A solution of compound 20 (15 mg, 0.03 mmol) in
dichloromethane (0.4 cm3) was treated with triethylamine (46
cm3, 0.33 mmol, 10 equiv.) for 28 min at room temp. The mix-
ture was diluted with dichloromethane (10 cm3), washed succes-
sively with 5% aq. HCl (10 cm3) and water (2 × 10 cm3), dried
1
(MgSO4) and the solvent removed. H NMR spectral analysis
of the residue revealed the presence of 20 and 21 in an
approximate ratio of 1:2.
(2S,3ЈS)-(؊)-Ethyl 2-[3Ј-(benzyloxycarbonylamino)succin-
imido]-3-phenylpropanoate 7
Method A. A solution of 20 (containing 5% 21, prepared as
described above) (13 mg, 0.03 mmol) and triethylamine (50 cm3,
0.36 mmol) in dichloromethane (0.5 cm3) was gently refluxed
for 1 h under N2. The mixture was cooled, diluted with dichloro-
methane (10 cm3) and washed with 5% aq. HCl (10 cm3) and
water (2 × 10 cm3), dried (MgSO4) and solvent removed. The
residue was purified by preparative silica TLC eluting with ethyl
1660
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
(2S,3ЈR)-(؊)-Ethyl 2-[3Ј-benzyl-3Ј-(N-acetyl-L-leucylamino)-
succinimido]-3-phenylpropanoate 24
tral scattering factors and anomalous dispersion corrections for
non-hydrogen atoms were taken from Ibers and Hamilton.26
Atomic coordinates, thermal parameters and bond lengths and
angles have been deposited at the Cambridge Crystallographic
Data Centre (CCDC). See Instructions for Authors, J. Chem.
Soc., Perkin Trans. 1, 1997, Issue 1. Any request to the CCDC
for this material should quote the full literature citation and the
reference number 207/107.
N-Acetyl--leucine (8.5 mg, 0.05 mmol) and HOBT (7.5 mg,
0.05 mmol) were added to a stirred solution of 23 (18 mg, 0.05
mmol) in dichloromethane (0.4 cm3) at 0 ЊC under N2. After 7
min, DCC (10 mg, 0.05 mmol) was added and the resulting
mixture was stirred for 15 min at 0 ЊC and then at room temp.
for 60 h. The reaction mixture was filtered, diluted with CH2Cl2
(15 cm3), washed with 5% aq. HCl (20 cm3) and water (2 × 20
cm3), the solvent was evaporated under reduced pressure and
the residue was purified by radial chromatography on a 1 mm
silica gel chromatotron plate, eluting with ethyl acetate–light
petroleum (3:2) to give 24 as a clear colourless oil (17 mg, 67%)
[HRMS: found (FAB) MHϩ, 536.2775. C30H38N3O6 requires
536.2761]; [α]D20 Ϫ75 (c 1.5, dichloromethane); νmax(KBr)/cmϪ1
3271, 2959, 1786, 1747, 1717, 1643 and 1549; δH 0.90 (3 H, d, J
5.9, CHCH3), 0.92 (3 H, d, J 5.9, CHCH3), 1.20 (3 H, t, J 7.1,
CH2CH3), 1.42 (1 H, m, CHCH2CH), 1.60 (2 H, m,
CH2CHMe2), 1.96 (3 H, s, CH3CO), 2.78 and 2.92 (2 H, ABq, J
13.7, C3Ј-CH2Ph), 2.85 and 2.94 (2 H, ABq, J 18.1, CH2CO),
3.21 (1 H, A part of ABX, JAB 14.5, JAX 9.2, CHCH2Ph), 3.53 (1
H, B part of ABX, JAB 14.5, JBX 6.6, CHCH2Ph), 4.16 (2 H, m,
OCH2), 4.34 (1 H, dt, J 5.8, 8.3, NHCH), 4.99 (1 H, X part of
ABX, CHCH2Ph), 5.71 (1 H, d, J 7.8, NHCH), 6.53 (1 H, s,
NH), 7.09 (2 H, m, ArH) and 7.18–7.33 (8 H, m, ArH); δC 14.0,
22.1, 22.8, 23.1, 24.6, 34.1, 39.1, 40.6, 41.9, 51.2, 53.4, 59.5,
61.8, 126.8, 127.9, 128.4, 128.9, 129.1, 130.2, 133.0, 136.8,
168.0, 170.3, 171.8, 173.1 and 176.0.
A second minor fraction (tentatively assigned as the leucine
epimer of 24) was obtained (1.6 mg, 6%) [HRMS: found (FAB)
MHϩ, 536.2761. C30H38N3O6 requires 536.2761]; [α]D20 Ϫ13 (c
0.13, dichloromethane); δH 0.86 (3 H, d, J 5.8, CHCH3), 0.88 (3
H, d, J 5.8, CHCH3), 1.21 (3 H, t, J 7.1, CH2CH3), 1.30–1.65 (3
H, m, CH2CHMe2), 2.03 (3 H, s, CH3CO), 2.60 and 2.92 (2 H,
ABq, J 13.9, C3Ј-CH2Ph), 2.81 and 2.96 (2 H, ABq, J 18.1,
CH2CO), 3.25 (1 H, A part of ABX, JAB 14.4, JAX 9.5,
CHCH2Ph), 3.54 (1 H, B part of ABX, JAB 14.4, JBX 6.6,
CHCH2Ph), 4.18 (2 H, m, OCH2), 4.35 (1 H, m, NHCH), 5.20
(1 H, X part of ABX, CHCH2Ph), 5.69 (1 H, d, J 7.8, NHCH),
6.79 (1 H, s, NH) and 7.10–7.34 (10 H, m, ArH).
Data for compound 16. C25H21NO5, M = 415.43, crystal
dimensions 0.60 × 0.28 × 0.22 mm, orthorhombic, a =
6.8350(10), b = 16.178(2), c = 19.308(2) Å, α = 90, β = 90,
γ = 90Њ, V = 2135.0(5) Å3, space group P212121, Z = 4, F(000) =
872, Dc = 1.292 Mg mϪ3, absorption coefficient = 0.090 mmϪ1, θ
range for data collection = 2.11–24.96, index ranges = 0 ≤ h ≤ 7,
0 ≤ k ≤ 19, 0 ≤ l ≤ 20, data/restraints/parameters = 1668/0/281,
goodness-of-fit on F2 = 1.084, final R indices [I > 2σ(I)]:
R1 = 0.0427, wR2 = 0.0904, R indices (all data): R1 = 0.0688,
wR2 = 0.1036, largest difference peak and hole = 0.225 and
Ϫ0.197 e ÅϪ3. The unit cell parameters were obtained by least-
squares refinement of the setting angles of 32 reflections with
2 ≤ 2θ ≤ 22.5Њ. A unique data set was measured at 130(2) K
within 2θmax = 57Њ limit (ω scans). Of the 1724 reflections
obtained, 1668 were unique (Rint = 0.0361) and were used in the
full-matrix least-squares refinement.27 The intensities of 3
standard reflections, measured every 97 reflections throughout
the data collection, showed 0% decay.
Data for compound 19. C20H19NO5, M = 353.36, crystal
dimensions 0.74 × 0.62 × 0.46 mm, orthorhombic, a =
7.3920(10), b = 15.1810(10), c = 15.7410(10) Å, α = 90, β = 90
γ = 90Њ, V = 1766.4(3) Å3, space group P212121, Z = 4, F(000)
744, Dc = 1.329 Mg mϪ3, absorption coefficient = 0.096 mmϪ1
,
θ
range for data collection = 2.59 to 30.00, index
ranges = Ϫ10 ≤ h ≤ 3, 0 ≤ k ≤ 21, 0 ≤ l ≤ 22, data/restraints/
parameters = 3932/0/237, goodness-of-fit on F2 = 0.890, final
R indices [I > 2σ(I)]: R1 = 0.0352, wR2 = 0.0710, R indices (all
data): R1 = 0.0517, wR2 = 0.0846, largest difference peak and
hole = 0.166 and Ϫ0.184 e ÅϪ3. The unit cell parameters were
obtained by least-squares refinement of the setting angles of 42
reflections with 9.563 ≤ 2θ ≤ 25.020Њ. A unique data set was
measured at 168(2) K within 2θmax = 57Њ limit (ω scans). Of the
4058 reflections obtained, 3933 were unique (Rint = 0.0222) and
were used in the full-matrix least-squares refinement.27 The
intensities of 3 standard reflections, measured every 97 reflec-
tions throughout the data collection, showed 6.18% decay for
which the data were scaled accordingly.
(2S,3ЈR)-(؊)-Ethyl 2-(3Ј-benzyl-3Ј-benzyloxycarbonylamino-
succinimido)-3-phenylpropanoate 6
A solution of 22 (25 mg, 0.04 mmol) in dichloromethane (0.55
cm3) was treated with triethylamine (0.06 cm3, 0.43 mmol) for 3
h at room temp. under N2. The reaction mixture was then
diluted with dichloromethane (15 cm3) and washed with 5% aq.
HCl (20 cm3) and water (20 cm3). The organic phase was dried
(MgSO4), the solvent was evaporated under reduced pressure
and the residue was purified by preparative silica TLC eluting
with ethyl acetate–light petroleum (1:2) to give 6 (15 mg, 73%)
[HRMS: found (EI) Mϩ, 514.2105. C30H30N2O6 requires
514.2104]; [α]D20 Ϫ46 (c 1.2, dichloromethane); νmax(KBr)/cmϪ1
3358, 3032, 2930, 1786 and 1715; δH 1.21 (3 H, t, J 7.3, CH3),
2.80 and 2.91 (2 H, ABq, J 13.8, C3Ј-CH2Ph), 2.89 and 3.06 (2
H, ABq, J 18.3, CH2CO), 3.26 (1 H, dd, J 10.2, 14.6,
CHCH2Ph), 3.53 (1 H, dd, J 6.3, 14.6, CHCH2Ph), 4.18 (2 H,
m, OCH2CH3), 5.04 (3 H, m, 3 H, CH and OCH2Ph), 7.02 (2 H,
m, ArH) and 7.15–7.39 (13 H, m, ArH); δC 14.0, 33.9, 39.4,
42.0, 53.4, 59.7, 62.0, 67.2, 126.9, 127.9, 128.3, 128.4, 128.5,
128.6, 128.9, 129.1, 130.2, 133.3, 135.8, 136.6, 154.7, 168.1,
173.2 and 176.6.
Acknowledgements
The authors acknowledge financial support from the New
Zealand Foundation for Research, Science and Technology
Public Good Science Fund. The authors are also grateful to
Professor Ward Robinson of the University of Canterbury
Department of Chemistry for his assistance with the X-ray
crystallography.
References
1 J. Gante, Angew. Chem., Int. Ed. Engl., 1994, 33, 1699.
2 D. P. Fairlie, G. Abbenante and D. R. March, Curr. Med. Chem.,
1995, 2, 654.
3 S. Thaisrivongs, D. T. Pals, S. R. Turner and L. T. Kroll, J. Med.
Chem., 1988, 31, 833.
4 M. L. West and D. P. Fairlie, Trends Pharm. Sci., 1995, 16, 67.
5 A. D. Abell, in Detailed Reaction Mechanisms: Mechanisms of
Biological Importance, ed. J. Coxon, JAI Press., London, 1992, vol.
2, pp. 243–260.
6 P. E. Reed and J. A. Katzenellenbogen, J. Org. Chem., 1991, 56,
2624.
7 A. D. Abell, J. M. Taylor and M. D. Oldham, J. Chem Soc., Perkin
Trans. 1, 1996, 1299.
8 (a) A. D. Abell and J. M. Taylor, J. Org. Chem., 1993, 58, 14;
X-Ray crystallographic determination for compounds 16 and 19
General. Intensity data were collected on a Siemens Four-
circle diffractometer, graphite monochromatised Mo-Kα radi-
ation (λ 0.7107 Å) being used. The structures were solved by
direct methods with the SHELXS86.25 Hydrogen atoms were
fixed in idealised positions. All non-hydrogen atoms were
refined with anisotropic atomic displacement parameters. Neu-
J. Chem. Soc., Perkin Trans. 1, 1997
1661

View Article Online
(b) A. D. Abell, M. D. Oldham and J. M. Taylor, J. Chem Soc.,
Perkin Trans. 1, 1995, 953; (c) A. D. Abell, M. D. Oldham and
J. M. Taylor, J. Org. Chem., 1995, 60, 1214.
20 D. T. Witiak, B. R. Vishnuvajjala, W. L. Cook, J. A. Minatelli,
T. K. Gupta and M. C. Gerald, J. Med. Chem., 1977, 20, 801.
21 S. Capasso, L. Mazzarella, F. Sica and A. Zagari, Int. J. Peptide
Protein Res., 1989, 33, 124.
22 A. C. Willis, A. L. J. Beckwith and M. J. Tozer, Acta Crystallogr.,
Sect. C, 1991, 47, 2276.
23 C. Chipot, R. Jaffe, B. Maigret, D. A. Pearlman and P. A. Kollman,
J. Am. Chem. Soc., 1996, 118, 11 217; C. A. Hunter, Angew. Chem.,
Int. Ed. Engl., 1993, 32, 1584.
24 D. Seebach, B. Lamatsch, R. Amstutz, A. K. Beck, M. Dobler,
M. Egli, R. Fitzi, M. Gautschi, B. Herradón, P. C. Hidber,
J. J. Irwin, R. Locher, M. Maestro, T. Maetzke, A. Mouriño,
E. Pfammatter, D. A. Plattner, C. Schickli, W. B. Schweizer,
P. Seiler, G. Stucky, W. Petter, J. Escalante, E. Juaristi, D. Quintana,
C. Miravitlles and E. Molins, Helv. Chim. Acta, 1992, 75, 913.
25 G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467.
26 International Tables for Crystallography, ed. J. A. Ibers and
W. C. Hamilton, Kynoch Press, Birmingham, 1992, vol. C.
27 G. M. Sheldrick, Program for Crystal Structure Solution, University
of Göttingen, 1993.
9 W. C. Groutas, M. J. Brubaker, M. A. Stanga, J. C. Castrisos,
J. P. Crowley and E. J. Schatz, J. Med. Chem., 1989, 32, 1607.
10 A. D. Abell and M. D. Oldham, J. Org. Chem., 1997, 62, 1509.
11 M. Park, J. Lee and J. Choi, Bioorg. Med. Chem. Lett., 1996, 6,
1297.
12 Y. Shao, M.-Q. Xu and H. Paulus, Biochemistry, 1995, 34, 10 844;
P. E. Thompson, N. L. E. Wijaya, F. M. Ng and M. T. W. Hearn,
Bioorg. Med. Chem. Lett., 1993, 3, 1625.
13 J.-P. Wolf and H. Rapoport, J. Org. Chem., 1989, 54, 3164;
T. M. Zydowsky, J. F. Dellaria, Jr. and H. N. Nellans, J. Org. Chem.,
1988, 53, 5607.
14 C. Toniolo, Int. J. Peptide Protein Res., 1990, 35, 287.
15 E. Altmann, K. Nebel and M. Mutter, Helv. Chim. Acta, 1991, 74,
800.
16 D. Seebach and A. Fadel, Helv. Chim. Acta, 1985, 68, 1243;
R. M. Williams, Synthesis of Optically Active α-Amino Acids,
Organic Chemistry Series, Vol 7, ed. J. Baldwin and P. D. Magnus,
Pergamon Press, Oxford, 1989.
17 A. D. Abell and M. D. Oldham, unpublished X-ray crystallographic
data.
18 A. D. Abell and M. D. Oldham, unpublished data
19 J. M. Scholtz and J. M. Bartlett, Synthesis, 1989, 542.
Paper 6/08165G
Received 3rd December 1996
Accepted 20th February 1997
1662
J. Chem. Soc., Perkin Trans. 1, 1997