Enantioselective synthesis of 2-substituted 3-aminopropanoic acid (β-alanine) derivatives which are β-analogues of aromatic amino acids

Article abstract of DOI:10.1039/a706163c

3-Aminopropanoic acid derivatives with a phenyl, 4-hydroxyphenyl, benzyl or indol-3-yl substituent at C-2 can be prepared enantioselectively by routes involving electrophilic attack of synthetic equivalents of [H₂NCH₂]⁺ upon enolates derived from chiral 3-acyl-1,3-oxazolidin-2-ones. tert-Butyl bromoacetate may be used as the electrophile, with subsequent introduction of nitrogen through the Curtius reaction, using the sequence of reagents (i) CF₃CO₂H; (ii) (PhO)₂P(O)N₃, Et₃N, PhCH₂OH; alternatively, direct electrophilic reaction with 1-[N-(benzyloxycarbonyl)aminomethyl]benzotriazole 4c or benzyl N-(acetoxymechyl)carbamate 2d introduces a protected aminomethyl group in a single step.

Full text of DOI:10.1039/a706163c

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Enantioselective synthesis of 2-substituted 3-aminopropanoic acid
(â-alanine) derivatives which are â-analogues of aromatic amino acids
Elena Arvanitis, Holger Ernst, Alice A. Ludwig (née D’Souza),
Andrew J. Robinson and Peter B. Wyatt*,†
Department of Chemistry, Queen Mary and Westfield College, University of London,
Mile End Road, London, UK E1 4NS
3-Aminopropanoic acid derivatives with a phenyl, 4-hydroxyphenyl, benzyl or indol-3-yl substituent at
C-2 can be prepared enantioselectively by routes involving electrophilic attack of synthetic equivalents
of [H2NCH2]؉ upon enolates derived from chiral 3-acyl-1,3-oxazolidin-2-ones. tert-Butyl bromoacetate
may be used as the electrophile, with subsequent introduction of nitrogen through the Curtius reaction,
using the sequence of reagents (i) CF3CO2H; (ii) (PhO)2P(O)N3, Et3N, PhCH2OH; alternatively, direct
electrophilic reaction with 1-[N-(benzyloxycarbonyl)aminomethyl]benzotriazole 4c or benzyl N-(acetoxy-
methyl)carbamate 2d introduces a protected aminomethyl group in a single step.
Evans et al. have reported the use of N-(chloromethyl)-
Introduction
benzamide 2a to amidomethylate the titanium enolate of the
acyl oxazolidinone 3a, leading to the stereoselective formation
of the protected amino acid 3b in high yield.8 However, the
reagent 2a is known to be somewhat unstable.9 Furthermore,
the removal of the N-benzoyl group normally involves heating
with mineral acid. These hydrolysis conditions could cause
racemisation, particularly when enolisation is facilitated by the
presence of an α-aryl group, and they are likely to destroy sensi-
tive aromatic groups such as the indolyl moiety.
1-(Aminomethyl)benzotriazoles and their N-acyl derivatives
can also function as aminomethylating agents.10 Work by Page
et al.11 has shown that the reagents 4a and 4b, with N-benzoyl
and N-benzyl protecting groups respectively, may be used to
effect the stereoselective aminoalkylation of ketone enolates
containing the 1,3-dithiane-1-oxide auxiliary. 2-(Bromomethyl)-
phthalimide is commercially available and has been used for
enolate alkylation, but again harsh conditions (e.g. refluxing
40% HBr) are needed for the N-deprotection.12 We favoured the
N-benzyloxycarbonyl (Z) protecting group for use in the syn-
thesis of the amino acids 1. The Z group survives the conditions
for removal of common chiral auxiliaries, but may be cleaved
by catalytic hydrogenolysis under mild conditions; because all
the by-products of this deprotection are volatile, the final iso-
lation of the amino acids is made extremely straightforward.
There is considerable interest in the enantioselective synthesis
of β-amino acids, compounds which can have biological activ-
ity in their own right and which are useful building blocks for
the preparation of modified peptides and other potential
pharmaceuticals.1 However, there have been few reports of
asymmetric routes to β-alanine derivatives of general structure
1, substituted only at the α-carbon. The known methods include
CO2H
H2N
RNHCH2X
R
2a R = PhCO; X = Cl
R = PhCH OCO = Z; X = OH
2b
2c
2d
1
2
R = Z; X = Cl
R = Z; X = OAc
O
O
N
N
N
CO2Me
O
N
R
CH2Ph
NHR
3a R = H
4a R = PhCO
4b
4c
R = CH NHCOPh
R = PhCH
R = Z
3b
2
2
stereoselective alkylations of chiral enolates that are synthetic-
ally equivalent to the enolate from β-alanine2–4 and the con-
jugate addition of a carbon nucleophile to an α-methylene
β-alanine derivative.5 However, such approaches are unsuitable
for the preparation of the β-amino acids 1 where R is an aryl
group. In 1995 we described, in preliminary form, the first
enantioselective synthesis of 3-amino-2-phenylpropanoic acid
(α-phenyl-β-alanine, 13).6 Our key step was the asymmetric
Mannich reaction of the benzotriazole derivative 4c with the
lithium enolate of the acyl oxazolidinone 6a. Recently Williams
and co-workers reported that α-aryl-β-alanines may also be
prepared by sequences involving asymmetric Pd-catalysed reac-
tions of allylic acetates with dimethyl malonate,7 which in this
context are equivalent to the [RCHCO2H]ϩ and [H2NCH2]Ϫ
synthons respectively. Here we provide a full account of our
complementary approaches to α-substituted-β-alanines 1, in
which chiral enolates undergo electrophilic attack by synthetic
equivalents of the [H2NCH2]ϩ cation.
Results and discussion
We elected to make use of the Evans oxazolidinone chiral
auxiliary 5 to achieve stereoselectivity in attack upon the enol-
ates (Scheme 1, Table 1). By analogy with simple alkylation,13
this was predicted to lead to the preferential formation of pre-
cursors to the (R)-β-amino acids 13–16; if the (S)-isomers of the
amino acids were required, then they could be prepared using
the enantiomer of 5, which is readily available.
We decided to protect the phenolic hydroxy group of the
tyrosine analogue 14 as a benzyl ether and so used the known14
[4-(benzyloxy)phenyl]acetyl chloride in the acylation step. We
also considered it appropriate to protect the indolyl system in
tryptophan analogue 16 against deprotonation and electrophilic
attack by using a group which could be cleaved by hydrogen-
olysis: we chose to use the N-(indolyl) benzyloxycarbonyl group.
This protecting group has occasionally been used in tryptophan
chemistry,15 but the indole-3-acetic acid derivative 18 has
not been described before and little has been said about the
† E-Mail: p.b.wyatt@qmw.ac.uk
J. Chem. Soc., Perkin Trans. 1, 1998
521

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Table 1 Percentage yields obtained in transformations depicted in Scheme 1 and diastereoselectivities (ds) observed in Mannich reactions.
Yields (%)
Ds 10:11 from
Mannichreaction
5 → 6
6 → 8
8 → 10
6 → 10a
6 → 10b
10 → 12
12 → (13–15)
a
b
c
d
e
80
55
48
83
84
67
56
49
69
—
58
40
52
47
—
65
59
58
62
—
—
38
34
65
69
84
67
—
68d
91
—
81
—
96:4a,e
95:5a,e
93:7;a,e 95:5a,f
>90:10b,f
<10f
ca. 0
1
a Using 4c. b Using 2d. c Yield based on 10a. d Based on isolated yields of 10 and 11. e Based on 250 MHz H NMR spectrum of crude reaction
mixture.
O
O
O
a R = Ph
R
b R = 4-(benzyloxy)phenyl
c R = 1-benzyloxycarbonylindol-3-yl
d R = PhCH2
N
O
i, ii
HN
Me
O
e R = Me
Ph
Me
Ph
6a–e
5
iii
vi or vii
O
O
O
O
O
O
O
O
R
R
R
R
N
O
N
O
N
O
N
O
ButO2CCH2
ButO2CCH2
ZNHCH2
ZNHCH2
Ph
Ph
Ph
Ph
Me
7a–d
Me
Me
Me
11a–e
8a–d
10a–e
v
iv
viii
O
O
R
CO2H
R
N
O
HO2CCH2
ZNHCH2
Ph
Me
9a–d
12a–d
ix
OH
H
N
Ph
H2N
Ph
CO2H
H2N
H2N
H2N
CO2H
CO2H
CO2H
16
13 (from 12a)
14 (from 12b)
15 (from 12d)
Scheme 1 Reagents and conditions: i, BuLi, THF, Ϫ78 ЊC; ii, RCH2COCl; iii, NaN(SiMe3)2, THF, Ϫ78 ЊC, then BrCH2CO2But; iv, CF3CO2H, 20 ЊC,
1 h; v, (PhO)2P(O)N3, Et3N, PhCH2OH, PhMe, 20 ЊC, then reflux; vi, LDA or LiN(SiMe3)2, THF, Ϫ78 ЊC, then 4c; vii, TiCl4, EtNPri2, ZNHCH2OAc,
CH2Cl2, 20 ЊC; viii, LiOH, H2O2, H2O, 0 ЊC; ix, H2, Pd–C, AcOH
compatibility of 1-(benzyloxycarbonyl)indole derivatives with
strongly basic and nucleophilic reagents. The dilithium salt of
indole-3-acetic acid was acylated with benzyl chloroformate,
thus introducing a Z group onto the indole nitrogen (Scheme 2).
It has been reported that sodium and lithium enolates bear-
ing chiral auxiliaries such as 5 undergo alkylation by α-halo-
acetate esters with diastereoselectivity (ds) values usually
у95:5 (ref. 16). We used this general method to convert the acyl
oxazolidinones 6 into the tert-butyl esters 8, all of which were
highly crystalline compounds that could easily be obtained in
isomerically pure form. We did not isolate the minor diastereo-
isomers 7, but in each case the 250 MHz NMR spectrum of the
crude reaction mixture was studied and it was concluded that
the amount of the by-product 7 could not have exceeded 10%
of the amount of the major product 8. Treatment of the esters 8
with trifluoroacetic acid led to smooth deprotection to form the
corresponding carboxylic acids 9, which were transformed into
the urethanes 10, using diphenylphosphoryl azide, triethyl-
amine and benzyl alcohol in the general procedure of Shioiri
et al.17 In this variant of the Curtius rearrangement the inter-
mediate acyl azides and isocyanates need not be isolated. Com-
ClOC
HO2C
HO2C
ii
i
N
Z
N
Z
N
H
19
17
18
Scheme 2 Reagents and conditions: i, BuLi (2.2 equiv.), THF, Ϫ45 ЊC,
then PhCH2OCOCl (1 equiv.); ii, SOCl2, 20 ЊC, 14 h
The protected acid 18 was then converted into the acyl chloride
19, prior to coupling with the chiral auxiliary 5 in the usual way.
522
J. Chem. Soc., Perkin Trans. 1, 1998

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parison of the 250 MHz 1H NMR spectrum of crude 10a from
the Curtius reaction with an authentic sample of the diastereo-
isomer ent-11a (formed by the Mannich reaction as described
below) demonstrated that no detectable epimerisation had
occurred during the former reaction. Having obtained reference
samples of the N-(benzyloxycarbonyl)-β-amino acid derivatives
10, we then sought methods for preparing these compounds
directly from the acyloxazolidinones 6.
performed under Evans’ usual hydrolytic conditions (LiOH,
H2O2, H2O) and gave the carboxylic acids 12a–d in yields of
у65% after recrystallisation; if mild conditions were used for
the hydrolysis then the Z group on the indole system was not
affected. Finally the free amino acids 13, 14 and 15 were pre-
pared by catalytic hydrogenolysis.
The specific rotation of the (R)-3-amino-2-phenylpropanoic
acid 13 was equal in both sign and magnitude of that of
resolved material which had been assigned the (S)-absolute
configuration on the basis of a lengthy series of chemical
correlations.20 However, a single crystal X-ray diffraction
study6 of the salt of 13 with (1S)-(ϩ)-camphor-10-sulfonic acid
showed that we had indeed synthesised (R)-13 and that the
earlier assignment of absolute configuration by Garbarino and
Nuñez was incorrect.
In our hands (R)-15 had [α]D ϩ19 in 1  HCl. This is some-
what larger than the literature value of ϩ11.3, which has been
reported by Juaristi et al.2 Juaristi has observed that the specific
rotations of free β-amino acids are rather sensitive to the condi-
tions of measurement.21 We wondered if it might be possible
that partial racemisation occurred in the final step of Juaristi’s
synthesis (hydrolysis by 6  HCl, 90–100 ЊC, 8 h). When we
heated a sample of 15 in 6  DCl in an NMR tube at 93–97 ЊC
for 7 days and studied the 600 MHz NMR spectrum, we found
that no decomposition of 15 had occurred, but that the changes
in integration and appearance of the peaks in the region δH 2.5–
3.2 were consistent with ca. 35% deuterium incorporation at the
chiral centre. Thus there is a real possibility that small amounts
of racemisation may occur when α-substituted β-alanine
derivatives are exposed to hot hydrochloric acid.
The Mannich reagent 4c was found to be stable, crystalline
and easily prepared by refluxing commercially available 1-
(hydroxymethyl)benzotriazole and benzyl carbamate together
in toluene with a catalytic amount of toluene-4-sulfonic acid,
using a Dean and Stark trap to remove water. The benzo-
triazolide anion is a relatively poor leaving group (pKa of
benzotriazole = 8.2)18 and 4c does not show high reactivity as
an electrophile. Thus 4c completely failed to react with the
titanium enolate of 6a at 20 ЊC. Reaction of 4c with the Li and
Na enolates of 6a, which were quenched at temperatures of
Ϫ10 and Ϫ5 ЊC respectively, gave Mannich product 10a in
yields of only 31 and 45%; again much of the acyl oxazol-
idinone 6a remained unchanged. The highest yield (65%) of the
desired product 10a was obtained when a mixture containing 4c
and the lithium enolate of 6a was allowed to warm up to 25 ЊC
before being quenched; under these conditions the major
oxazolidinone-containing by-product was the deacylated chiral
auxiliary 5, which can arise by the known decomposition of
enolates at higher temperatures through a ketene mechanism.13
1
Analysis of the crude product by 250 MHz H NMR spec-
troscopy indicated that 10a, 5 and unreacted 6a were present in
the approximate molar ratio 8:2:1. Very little of the diastereo-
isomeric Mannich product 11a was formed and the similarity in
the chemical shifts of 11a to those of the main products made it
difficult to detect 11a in the NMR spectrum of the crude prod-
uct. When we performed the Mannich reaction using ent-6a we
were able to isolate the minor product ent-11a in 2% yield.
Reagent 4c was also successfully employed to effect the direct
conversion of the lithium enolates of 6b and 6c into the
urethanes 10b and 10c (yields 59 and 58% respectively). Again
only small amounts (ca. 3%) of the minor diastereoisomers 11b
and 11c were formed. Cleavage of the Z group from the indole
nitrogen did not occur under these conditions. Attempted reac-
tions of lithium enolates from the (3-phenylpropanoyl)oxazol-
idinone 6d and the propanoyloxazolidinone 6e with the benzo-
triazole derivative 4c did not yield synthetically useful amounts
of Mannich products 10 and 11: the acyl oxazolidinones 6 were
mainly recovered unchanged, although some of the chiral
auxiliary 5 was observed as a minor product. Thus the Mannich
reaction was successful in cases where R was an aryl group,
but not when R was alkyl. This suggested that those lithium
enolates which are not stabilised by conjugation with an α-aryl
group may be sufficiently basic to abstract the N-H proton
from the benzotriazole reagent 4c. We therefore examined the
possibility of introducing the ZNHCH2 group in Lewis acid-
promoted Mannich reactions.
The benzotriazole-derived reagent 4c was found to be unreac-
tive towards the titanium enolate of 6a. Benzyl N-(hydroxy-
methyl)carbamate (ZNHCH2OH) 2b was easily prepared,19 but
our attempts to convert it into the chloride ZNHCH2Cl 2c,
using PCl5, by analogy with the preparation of 2a, led only to
decomposition. However, the acetate 2d is readily available and
comparatively stable. We found that this reagent was able to
bring about the stereoselective Mannich reactions on titanium
enolates both when R was aryl (6a → 10a, 62%) and when R
was alkyl. In the latter cases the yields were rather low
(6d → 10d, 38%; 6e → 10e, 34%) and much of the starting
acyl oxazolidinone remained unconverted, even when the reac-
tion mixture was allowed to warm up to room temperature (e.g
42% of the starting acyl oxazolidinone 6d was recovered after
1 h at 20 ЊC).
Conclusions
We have established synthetically useful routes to enantiomeri-
cally pure, α-substituted β-alanine derivatives. These methods
are especially attractive because they deliver the amino acids in
Z-protected form, convenient for further synthesis or for depro-
tection under mild conditions by hydrogenolysis. They avoid
the use of refluxing mineral acid for deprotection, thus minimis-
ing the risk of racemisation.
In cases where the α-substituent is an aryl group, the
protected aminomethyl group is conveniently introduced by
reaction of an appropriate chiral lithium enolate with the
benzotriazole-derived Mannich reagent 4c. This direct
approach fails when the α-substituent is an alkyl group, but
under such circumstances the alternative Mannich reagent 2d,
with acetate as the leaving group, can be used in conjunction
with a titanium enolate. There may be scope for increasing the
conversions obtained in these titanium-mediated reactions by
further changing the leaving group.
β-Alanine derivatives with either alkyl or aryl substituents at
the α-position are also available by reactions of chiral enolates
with tert-butyl bromoacetate, which can be rendered synthetic-
ally equivalent to a Mannich electrophile by a sequence of steps
including a Curtius rearrangement. This method is less direct
than the Mannich approach, but it tolerates a range of sub-
stituents (both alkyl and aryl) and the major diastereoisomer
from the asymmetric step tends to be amenable to purification
by crystallisation.
Experimental
General experimental procedures have been described by us in
an earlier publication.22 [α]D Values are given in units of 10Ϫ1
deg cm2 gϪ1. Hydrogenations were performed using balloons.
All reported compounds were homogeneous as judged by both
TLC and NMR spectroscopy. Mass spectra were obtained
by electron impact unless otherwise stated. The known acyl
oxazolidinones 6a (ref. 23), 6d (ref. 24) and 6e (ref. 25) were
prepared from the appropriate acyl chlorides and the lithium
Removal of the chiral auxiliaries from compounds 10a–d was
J. Chem. Soc., Perkin Trans. 1, 1998
523

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salt of 5, according to the general procedure of Evans et al.25
Petrol refers to light petroleum with bp 40–60 ЊC.
then added by cannula over 5 min. The mixture was stirred
during 30 min and then tert-butyl bromoacetate (1.65 ml, 10.2
mmol) was added by syringe. The mixture was allowed to attain
Ϫ20 ЊC over 2 h and was then quenched with saturated aqueous
NH4Cl (5 ml).
1-[N-(Benzyloxycarbonyl)aminomethyl]benzotriazole 4c
1-(Hydroxymethyl)benzotriazole (3.89 g, 26.1 mmol), benzyl
carbamate (3.94 g, 26.1 mmol), toluene-p-sulfonic acid mono-
hydrate (0.01 g) and toluene (70 ml) were refluxed together for
15 h in an apparatus fitted with a Dean and Stark water separ-
ator. The mixture was cooled and the crystals which separated
were filtered off. Recrystallisation from toluene gave the title
compound 4c (4.53 g, 62%) as a white crystalline solid, mp 119–
120 ЊC (Found: C, 64.0; H, 5.0; N, 20.0. C15H14N4O2 requires C,
63.8; H, 5.0; N, 19.85%); νmax(KBr)/cmϪ1 3255, 1725, 1531 and
1251; δH(80 MHz, CDCl3) 5.15 (2 H, s), 6.05 (2 H, d, J 7), 6.5 (1
H, br t, J 7), 7.2–7.6 (7 H, m) and 7.8–8.1 (2 H, m); m/z 282
(Mϩ, 15%), 119 (54) and 91 (100) (Found: Mϩ, 282.1115.
C15H14N4O2 requires M, 282.1117).
The mixture was extracted with ethyl acetate (100 ml),
washed with distilled water (100 ml), and the organic layer was
dried. The solvent was evaporated under vacuum to yield an
orange, viscous liquid, which was purified by flash chrom-
atography [CH2Cl2–petrol (80:20) to (90:10); gradient elution]
and crystallisation (EtOAc–petrol) to yield the title compound
8a (2.18 g, 67%) as white crystals, mp 125 ЊC; [α]D30 ϩ63.8 (c 0.5,
CHCl3); νmax(KBr)/cmϪ1 1767, 1722 and 1700; δH(80 MHz,
CDCl3) 0.97 (3 H, d, J 6), 1.45 (9 H, s), 2.60 (1 H, dd, J 17, 4.5),
3.28 (1 H, dd, J 17, 11), 4.70 (1 H, quintet, J 7), 5.4–5.7 (2 H, m)
and 7.2–7.5 (10 H, m); m/z 409 (Mϩ, 10%), 336 (10), 292 (10),
178 (100), 134 (11), 104 (10) and 57 (40) (Found: Mϩ, 409.1894.
C24H27NO5 requires M, 409.1889).
(4S,5R)-3-[4-(Benzyloxy)phenylacetyl]-4-methyl-5-phenyl-1,3-
oxazolidin-2-one 6b
(4S,5R,2ЈS)-3-[2-(4-Benzyloxyphenyl)-3-(tert-butoxycarbonyl)-
propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one 8b
A solution of (4S,5R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one
(5.10 g, 28.8 mmol) in THF (30 ml) was cooled to Ϫ78 ЊC and
treated over 2 min with 2.5  BuLi in hexane (12.7 ml, 31.7
mmol), followed by a solution of 4-(benzyloxy)phenylacetyl
chloride14 (7.52 g, 28.8 mmol) in THF (30 ml), which was added
during 2 min. The reaction mixture was allowed to warm to
0 ЊC over 1 h, then was quenched with saturated aqueous
NH4Cl (5 ml) and partitioned between CH2Cl2 (100 ml) and
water (100 ml). The organic phase was washed with aqueous
NaHCO3 (2 × 100 ml), dried (MgSO4), and evaporated to leave
an orange oil. Flash chromatography [CH2Cl2–petrol (1:1) to
CH2Cl2–Et2O (9:1); gradient elution] followed by recrystallis-
ation from Et2O–petrol gave (4S,5R)-3-[4-(benzoyloxy)phenyl-
acetyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one 6b (6.36 g, 55%)
as white crystals, mp 97–98 ЊC (Found: C, 74.8; H, 5.7; N, 3.4.
C25H23NO4 requires C, 74.8; H, 5.7; N, 3.5%); [α]D30 ϩ6.3 (c 1.0,
CH2Cl2); νmax(KBr)/cmϪ1 1778 and 1698; δH(250 MHz, CDCl3)
0.88 (3 H, d, J 7), 4.21 (1 H, d, J 15), 4.28 (1 H, d, J 15), 4.75 (1
H, quintet, J 7), 5.05 (2 H, s), 5.64 (1 H, d, J 7), 6.92–6.98 (2 H,
m) and 7.22–7.45 (14 H, m); m/z 401 (Mϩ, 4%), 224 (55) and 91
(100) (Found: Mϩ, 401.1638. C25H23NO4 requires M, 401.1627).
This was prepared by analogy with 8a, starting from (4S,5R)-3-
[4-(benzyloxy)phenylacetyl]-4-methyl-5-phenyl-1,3-oxazolidin-
2-one 6b (1.60 g, 4.0 mmol). The title compound 8b (1.18 g, 56%)
was obtained as white crystals, mp 158–160 ЊC (from EtOAc–
petrol); νmax(KBr)/cmϪ1 1783, 1732 and 1701; δH(250 MHz,
CDCl3) 0.93 (3 H, d, J 7), 1.40 (9 H, s), 2.56 (1 H, dd, J 17.5, 5),
3.21 (1 H, dd, J 17.5, 11), 4.67 (1 H, quintet, J 7), 5.40 (2 H, s),
5.45 (1 H, dd, J 11, 5), 5.50 (1 H, d, J 7), 6.90–6.97 (2 H, m) and
7.25–7.45 (12 H, m); m/z 515 (Mϩ, 1%), 282 (21), 178 (15)
and 91 (100) (Found: Mϩ, 515.2314. C31H33NO6 requires M,
515.2308).
(4S,5R,2ЈS)-3-[2-(1-Benzyloxycarbonylindol-3-yl)-3-(tert-
butoxycarbonyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-
one 8c
This was prepared by analogy with 8a, starting from (4S,5R)-3-
[(1-benzyloxycarbonylindol-3-yl)acetyl]-4-methyl-5-phenyl-1,3-
oxazolidin-2-one 6c (0.72 g, 1.53 mmol). Purification of the
crude product by flash chromatography [CH2Cl2–petrol (4:1)]
and recrystallisation (Et2O–petrol) yielded the title compound
8c (0.439 g, 49%) as white crystals, mp 145 ЊC (Found: C, 70.1;
H, 5.9; N, 4.8. C34H34N2O7 requires C, 70.1; H, 5.9; N, 4.8%);
[α]D30 ϩ78.5 (c 1.0, CH2Cl2); νmax(KBr)/cmϪ1 1765, 1734 and 1705;
δH(250 MHz, CDCl3) 0.95 (3 H, d, J 7), 1.41 (9 H, s), 2.65 (1 H,
dd, J 17, 5), 3.40 (1 H, dd, J 17, 11), 4.69 (1 H, quintet, J 7),
5.38–5.50 (3 H, m), 5.74 (1 H, dd, J 11, 5), 7.25–7.50 (12 H, m),
7.66 (1 H, s), 7.80 (1 H, d, J 8) and 8.20 (1 H, d, J 8); m/z 582
(Mϩ, 0.5%), 526 (3), 349 (7), 278 (3), 233 (5) and 91 (100).
(4S,5R)-3-[(1-Benzyloxycarbonylindol-3-yl)acetyl]-4-methyl-5-
phenyl-1,3-oxazolidin-2-one 6c
[1-(Benzyloxycarbonyl)indol-3-yl]acetic acid 18 (1.17 g, 3.79
mmol) was dissolved in SOCl2 (11 ml) and the mixture was
allowed to stir overnight. The excess of SOCl2 and the side
products were evaporated under vacuum to leave a dark
coloured oil (1.27 g), considered to be [1-(benzyloxycarbonyl)-
indol-3-yl]acetyl chloride 19 on the basis of the following data:
νmax(film)/cmϪ1 1798 and 1737; δH(60 MHz, CDCl3) 4.2 (2 H, s),
5.4 (2 H, s), 7.2–7.5 (8 H, m), 7.6 (1 H, s) and 8.1–8.3 (1 H, m). A
portion of crude compound 19 (1.24 g, 3.79 mmol) was used to
acylate the oxazolidinone 5 by analogy with the preparation of
6b. Flash chromatography [CH2Cl2–petrol (7:3)] gave the title
compound 6c (0.854 g, 48%) as a white solid, mp 52–54 ЊC; [α]D35
Ϫ0.4 (c 1.0, CHCl3); νmax(film)/cmϪ1 1778, 1732 and 1705;
δH(250 MHz, CDCl3) 0.90 (3 H, d, J 7), 4.36 (1 H, dd, J 17, 1),
4.44 (1 H, dd, J 17, 1), 4.77 (1 H, quintet, J 7), 5.45 (2 H, s), 5.67
(1 H, d, J 7), 7.24–7.64 (13 H, m), 7.70 (1 H, s) and 8.20 (1 H, d,
J 8); m/z 468 (Mϩ, 19%), 291 (6), 247 (27), 220 (7), 157 (11), 91
(100), 65 (6) and 44 (11) (Found: Mϩ, 468.1683. C28H24N2O5
requires M, 468.1685).
(4S,5R,2ЈR)-3-[2-Benzyl-3-(tert-butoxycarbonyl)propanoyl]-4-
methyl-5-phenyl-1,3-oxazolidin-2-one 8d
This was prepared by analogy with 8a, starting from (4S,5R)-
4-methyl-5-phenyl-3-(3-phenylpropanoyl)-1,3-oxazolidin-2-one
6d24 (2.50 g, 8.1 mmol). Recrystallisation from Et2O–petrol
yielded the title compound 8d as white crystals (2.35 g, 69%), mp
79 ЊC; [α]D30 ϩ45 (c 0.2, CH2Cl2); νmax(KBr)/cmϪ1 1766 and 1706;
δH(250 MHz, CDCl3) 0.87 (3 H, d, J 7), 1.38 (9 H, s), 2.37 (1 H,
dd, J 17, 5), 2.71 (1 H, dd, J 13, 8), 2.82 (1 H, dd, J 17, 11), 2.99
(1 H, dd, J 13, 7), 4.48–4.59 (1 H, m), 4.60 (1 H, quintet, J 7),
5.30 (1 H, d, J 7) and 7.20–7.45 (10 H, m); m/z 423 (Mϩ, 3%),
367 (94), 308 (86), 178 (68), 117 (72) and 57 (100) (Found: Mϩ,
423.2040. C25H29NO5 requires M, 423.2046).
(4S,5R,2ЈS)-3-(3-tert-Butoxycarbonyl-2-phenylpropanoyl)-4-
methyl-5-phenyl-1,3-oxazolidin-2-one 8a
A 1  solution of NaN(SiMe3)2 in THF (Aldrich; 10.2 ml, 10.2
mmol) was diluted with dry THF (10 ml) and cooled to Ϫ72 ЊC.
A solution of (4S,5R)-4-methyl-5-phenyl-3-phenylacetyl-1,3-
oxazolidin-2-one 6a23 (2.50 g, 8.5 mmol) in THF (20 ml) was
(4S,5R,2ЈS)-3-(3-Carboxy-2-phenylpropanoyl)-4-methyl-5-
phenyl-1,3-oxazolidin-2-one 9a
(4S,5R,2ЈS)-3-(3-tert-Butoxycarbonyl-2-phenylpropanoyl)-4-
methyl-5-phenyl-1,3-oxazolidin-2-one 8a (103 mg, 0.25 mmol)
was dissolved in trifluoroacetic acid (1 ml) at room temperature.
After 1 h, the pale pink solution was evaporated under vacuum.
524
J. Chem. Soc., Perkin Trans. 1, 1998

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The residue was dissolved in diethyl ether and was then re-
evaporated. Recrystallisation from Et2O–petrol yielded the title
compound 9a (101 mg, 98%) as white crystals, mp 151 ЊC;
νmax(KBr)/cmϪ1 2700–3500, 1765, 1734 and 1694; δH(80 MHz,
CDCl3) 0.95 (3 H, d, J 7), 2.7 (1 H, dd, J 18, 4), 3.45 (1 H, dd,
J 18, 12), 4.75 (1 H, quintet, J 7), 5.4–5.7 (2 H, m), 7.3–7.6 (10
H, m) and 8.4 (1 H, br s); m/z 353 (Mϩ, 30%), 177 (21), 148 (6)
and 107 (100) (Found: Mϩ, 353.1259. C20H19NO5 requires M,
353.1263).
(8), 295 (100), 177 (4) and 118 (25) (Found: Mϩ, 458.1854.
C27H26N2O5 requires M, 458.1842).
A similar procedure to the above was used to convert ent-6a
(414 mg, 1.40 mmol) into ent-10a (347 mg, 54%). Also isolated
were: unreacted ent-6a (27 mg, 7%), ent-5 (51 mg, 20%) and
(4R,5S,2ЈR)-3-(3-benzyloxycarbonylamino-2-phenylpropanoyl)-
4-methyl-5-phenyl-1,3-oxazolidin-2-one ent-11a (14 mg, 2%),
isolated as a colourless oil and purified by flash chrom-
atography in CH2Cl2–Et2O (97.5:2.5); [α]D25 ϩ96 (c 0.49, EtOAc);
νmax(KBr)/cmϪ1 3359, 1781, 1721 and 1696; δH(250 MHz,
CDCl3) 0.75 (3 H, d, J 7), 3.58–3.80 (2 H, m), 4.81 (1 H, quintet,
J 7), 5.05–5.13 (4 H, m), 5.62 (1 H, d, J 7) and 7.15–7.40 (15 H,
m); m/z 458 (Mϩ, 1%), 414 (0.3), 367 (1), 295 (100) and 91 (54)
(Found: Mϩ, 458.1843. C27H26N2O5 requires M, 458.1842).
(iii) Preparation of 10a via the Mannich reaction with benzyl
N-(acetoxymethyl)carbamate. TiCl4 (10% v/v in CH2Cl2; 0.97
ml, 0.88 mmol) was added to a solution of (4S,5R)-4-methyl-5-
phenyl-3-phenylacetyl-1,3-oxazolidin-2-one 6a (240 mg, 0.81
mmol) in CH2Cl2 (10 ml) at 0 ЊC. The pale orange mixture was
stirred at 0 ЊC for 10 min and then EtNPri2 (167 µl, 0.96 mmol)
was added. The purple solution was stirred at 0 ЊC for 1 h
before being cooled to Ϫ78 ЊC and treated with a solution pre-
pared from TiCl4 (10% v/v in CH2Cl2; 1.16 ml, 1.06 mmol),
benzyl N-(acetoxymethyl)carbamate19 (230 mg, 0.96 mmol)
and CH2Cl2 (10 ml) which had been kept at 0 ЊC for 30 min. The
reaction mixture was allowed to warm from Ϫ78 to 20 ЊC over
6 h and then was stirred at 20 ЊC for 1 h, before being quenched
with aqueous NH4Cl (10 ml). The product was extracted with
Et2O (3 × 30 ml). Drying and evaporation of the combined
Et2O extracts gave a yellow oil, which was subjected to flash
chromatography [EtOAc–petrol; gradient from 1:9 to 3:7] to
yield (4S,5R,2ЈR)-3-(3-benzyloxycarbonylamino-2-phenylprop-
anoyl)-4-methyl-5-phenyl-1,3-oxazolidin-2-one 10a (230 mg,
62%) as a pale yellow foam, identical by 1H NMR spectroscopy
(80 MHz, CDCl3) to the sample prepared in the preceeding
experiment.
(4S,5R,2ЈR)-3-(2-Benzyl-3-carboxypropanoyl)-4-methyl-5-
phenyl-1,3-oxazolidin-2-one 9d
By analogy with the preparation of 9a, (4S,5R,2ЈR)-3-[2-
benzyl-3-(tert-butoxycarbonyl)propanoyl]-4-methyl-5-phenyl-
1,3-oxazolidin-2-one 8d (1.00 g, 2.36 mmol) was converted
into the title compound 9d, which was obtained as a white
foam (682 mg, 79%), mp 62 ЊC; [α]D30 ϩ52 (c 0.2, CH2Cl2);
νmax(KBr)/cmϪ1 2800–3600 (br), 1781 and 1703; δH(250 MHz,
CDCl3) 0.84 (3 H, d, J 7), 2.47 (1 H, dd, J 17, 5), 2.68 (1 H,
dd, J 13, 9), 2.92 (1 H, dd, J 17, 10), 3.03 (1 H, dd, J 13, 7),
4.45–4.59 (1 H, m), 4.63 (1 H, quintet, J 7), 5.36 (1 H, d, J 7)
and 7.20–7.45 (10 H, m); m/z 367 (Mϩ, 15%), 308 (17), 177
(21), 148 (31) and 107 (100) (Found: Mϩ, 367.1420. C21H21-
NO5 requires M, 367.1420).
(4S,5R,2ЈR)-3-(3-Benzyloxycarbonylamino-2-phenylpropanoyl)-
4-methyl-5-phenyl-1,3-oxazolidin-2-one 10a
(i) Preparation of 10a via the Curtius reaction. (4S,5R,2ЈS)-3-
(3-Carboxy-2-phenylpropanoyl)-4-methyl-5-phenyl-1,3-oxazol-
idin-2-one 9a (404 mg, 1.14 mmol) was dissolved in toluene (5
ml). Triethylamine (320 µl, 2.3 mmol), diphenylphosphoryl
azide (300 µl, 1.4 mmol) and benzyl alcohol (241 µl, 2.3 mmol)
were added. The mixture was stirred for 1 h before being re-
fluxed for 1 h. Evaporation of the solvent left a brown residue,
which was dissolved in diethyl ether (14 ml) and washed with 2
 HCl (7 ml) and then with saturated aqueous NaHCO3 (7 ml).
The organic layer was dried and then evaporated under vacuum
to yield a brown oil, which was purified by repeated flash
chromatography [CH2Cl2–Et2O (99:1)] to yield the title com-
pound 10a (309 mg, 59%) as a white foam, mp 50–51 ЊC; [α]D29
ϩ79 (c 1, EtOAc). This material was identical by IR and 250
MHz 1H NMR spectroscopy to the major product 10a obtained
in the following experiment.
(ii) Preparation of 10a via the Mannich reaction with 1-[N-
(benzyloxycarbonyl)aminomethyl]benzotriazole 4c. A solution
of (4S,5R)-4-methyl-5-phenyl-3-phenylacetyl-1,3-oxazolidin-2-
one 6a (295 mg, 1.0 mmol) in THF (4 ml) was added to LDA in
THF (1.5 , 0.73 ml, 1.1 mmol) and the mixture was stirred for
20 min. A solution of 1-[N-(benzyloxycarbonyl)aminomethyl]-
benzotriazole 4c (311 mg, 1.1 mmol) in THF (4 ml) was added
and the mixture was stirred at Ϫ78 ЊC for 2 h, then allowed to
warm to 20 ЊC. Saturated aqueous NH4Cl (20 ml) was added
and the product was extracted with Et2O (3 × 30 ml). The Et2O
extracts were washed with 2  HCl (20 ml), aqueous NaHCO3
(2 × 20 ml) and brine (20 ml). Drying and evaporation of the
combined Et2O extracts gave a crude product whose 1H NMR
spectrum (250 MHz, CDCl3) was consistent with the presence
of (4S,5R,2ЈR)-3-(3-benzyloxycarbonylamino-2-phenylprop-
anoyl)-4-methyl-5-phenyl-1,3-oxazolidin-2-one 10a, (4S,5R)-
(4S,5R,2ЈR)-3-[3-Benzyloxycarbonylamino-2-(4-benzyloxy-
phenyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one 10b
(i) Preparation of 10b via the Curtius reaction. (4S,5R,2ЈS)-3-
[2-(4-Benzyloxyphenyl)-3-(tert-butoxycarbonyl)propanoyl]-4-
methyl-5-phenyl-1,3-oxazolidin-2-one 8b (1.21 g, 2.35 mmol)
was converted into the acid 9b (1.02 g, 95%) by analogy with the
preparation of 9a. A portion of the crude acid 9b (463 mg, ca. 1
mmol) was then transformed into the urethane 10b, by analogy
with the preparation of 10a using the Curtius reaction. Flash
chromatography [EtOAc–petrol (15:85) to EtOAc–petrol
(25:75); gradient elution], afforded the title compound 10b as a
white foam (241 mg, 40% from 8b), mp 50–51 ЊC; [α]D35 ϩ90 (c 1,
CHCl3); νmax(KBr)/cmϪ1 3417, 1782, 1721 and 1694; δH(250
MHz, CDCl3) 0.92 (3 H, d, J 7), 3.51–3.83 (2 H, m), 4.67 (1 H,
quintet, J 7), 5.01 (1 H, br s), 5.04 (2 H, s), 5.09 (2 H, s), 5.16 (2
H, dd, J 8, 6), 5.47 (1 H, d, J 7), 6.92–6.99 (2 H, m) and 7.24–
7.47 (17 H, m); m/z (FAB ex Et2O–nitrobenzyl alcohol) 565
(MHϩ, 54%), 521 (47), 413 (100), 401 (99) and 224 (52).
(ii) Preparation of 10b via the Mannich reaction with 1-
[N-(benzyloxycarbonyl)aminomethyl]benzotriazole 4c. A solu-
tion of (4S,5R)-3-[4-(benzyloxy)phenylacetyl]-4-methyl-5-
phenyl-1,3-oxazolidin-2-one 6b (803 mg, 2.0 mmol) in THF (10
ml) was added by cannula to a 0.35  solution of LiN(SiMe3)2
in THF (6.2 ml, 2.2 mmol) at Ϫ60 ЊC. The mixture was treated
with a solution of 1-[N-(benzyloxycarbonyl)aminomethyl]-
benzotriazole 4c (565 mg, 2.0 mmol) in THF (8 ml) and was
then allowed to warm up to 8 ЊC over 3 h. Saturated aqueous
NH4Cl (20 ml) was added, then the mixture was diluted with
Et2O (30 ml) and washed with 2  HCl (30 ml) followed by
aqueous NaHCO3 (30 ml). Drying and evaporation of the
organic phase gave a yellow oil (1.35 g). Flash chromatography
[CH2Cl2 to CH2Cl2–Et2O (96:4); gradient elution] gave two
diastereoisomeric Mannich products as follows.
4-methyl-5-phenyl-1,3-oxazolidin-2-one
5 and the starting
material 6a as the three main components in an approximate
molar ratio of 8:2:1.
Flash chromatography [EtOAc–petrol (1:4) to (2:3); gradi-
ent elution] gave (4S,5R,2ЈR)-3-(3-benzyloxycarbonylamino-2-
phenylpropanoyl)-4-methyl-5-phenyl-1,3-oxazolidin-2-one 10a
(297 mg, 65%) as a foam, [α]D30 ϩ84 (c 1.1, EtOAc); νmax(KBr)/
cmϪ1 3368, 1782, 1721 and 1698; δH(250 MHz, CDCl3) 0.92 (3
H, d, J 7), 3.56–3.67 (1 H, m), 3.74–3.85 (1 H, m), 4.68 (1 H,
quintet, J 7), 5.00–5.13 (3 H, m), 5.22 (1 H, dd, J 8, 6), 5.46
(1 H, d, J 7) and 7.21–7.44 (15 H, m); m/z 458 (Mϩ, 1%), 307
J. Chem. Soc., Perkin Trans. 1, 1998
525

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The title compound 10b (661 mg, 59%), mp 51–54 ЊC, was
(4S,5R,2ЈR)-3-(3-Benzyloxycarbonylamino-2-benzylpropanoyl)-
4-methyl-5-phenyl-1,3-oxazolidin-2-one 10d
obtained from the earlier chromatographic fractions and was
1
identical by H NMR spectroscopy to a sample of this com-
(i) Preparation of 10d via the Curtius reaction. This was per-
formed by analogy with the preparation of 10a by method (i),
starting from (4S,5R,2ЈR)-3-(2-benzyl-3-carboxypropanoyl)-
4-methyl-5-phenyl-1,3-oxazolidin-2-one 9d (336 mg, 0.9 mmol).
The crude product was purified by flash chromatography
[CH2Cl2–Et2O (19:1)] to give a colourless oil which was
recrystallised from diethyl ether and petrol to yield the title
compound 10d as white crystals (252 mg, 60%), mp 91–93 ЊC;
[α]D31 ϩ11.0 (c 1, CH2Cl2); νmax(KBr)/cmϪ1 3377, 1778, 1737 and
1690; δH(250 MHz, CDCl3) 0.83 (3 H, d), 2.86 (1 H, dd,
J 14, 7), 3.02 (1 H, dd, J 13, 8), 3.43–3.64 (2 H, m), 4.39 (1 H, br
quintet, J 7), 4.54 (1 H, quintet, J 7), 5.09 (2 H, s), 5.12–5.22 (1
H, br), 5.27 (1 H, d, J 7) and 7.20–7.45 (15 H, m); m/z 472 (Mϩ,
4%), 381 (6), 335 (10), 308 (59), 160 (30), 131 (46) and 91 (100)
(Found: Mϩ, 472.1997. C28H28N2O5 requires M, 472.1998).
(ii) Preparation of 10d via the Mannich reaction with benzyl
N-(acetoxymethyl)carbamate. This was performed analogously
to the preparation of 10a by method (iii), starting from 8d (691
mg, 2.23 mmol). The reaction mixture was allowed to warm up
from Ϫ78 to 0 ЊC over 3 h, then was kept at 0 ЊC for 3 h and at
20 ЊC for 1 h after which work up was performed as before.
pound prepared using the Curtius reaction, as described in
the preceding experiment. Evaporation of the later fractions
from the chromatography gave a colourless oil, which solidi-
fied upon standing and was considered to be (4S,5R,2ЈS)-3-
[3-benzyloxycarbonylamino-2-(4-benzyloxyphenyl)propanoyl]-4-
methyl-5-phenyl-1,3-oxazolidin-2-one 11b (36 mg, 3%), on the
basis of the following properties: mp 48–51 ЊC; [α]D34 Ϫ129.5
(c 0.93, CHCl3); νmax(film)/cmϪ1 3370, 1780, 1718 and 1700;
δH(250 MHz, CDCl3) 0.76 (3 H, d, J 7), 3.55–3.80 (2 H, m),
4.81 (1 H, quintet, J 7), 5.00–5.15 (6 H, m), 5.63 (1 H, d, J
7), 6.95 (2 H, d, J 8) and 7.17–7.46 (17 H, m); m/z (FAB ex
Et2O–nitrobenzyl alcohol) 565 (MHϩ, 31%), 520 (64), 412
(99) and 400 (100).
(4S,5R,2ЈR)-3-[3-Benzyloxycarbonylamino-2-(1-benzyloxycarb-
onylindol-3-yl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-
one 10c
(i) Preparation of 10c via the Curtius reaction. This was per-
formed by analogy with the preparation of 10b by the Curtius
reaction, starting from (4S,5R,2ЈS)-3-[2-(1-benzyloxycarbon-
ylindol-3-yl)-3-(tert-butoxycarbonyl)propanoyl]-4-methyl-5-
phenyl-1,3-oxazolidin-2-one 8c (192 mg, 0.33 mmol). Flash
chromatography [CH2Cl2–EtOAc (99:1)] gave a colourless oil
containing a mixture of 10c and benzyl alcohol. Reprecipit-
ation from diethyl ether with petrol afforded the title compound
(108 mg, 52% from 8c) as a white solid, mp 63–64 ЊC (Found: C,
70.4; H, 5.2; N, 6.4. C37H33N3O7 requires C, 70.35; H, 5.3; N,
6.65%); [α]D30 ϩ74.7 (c 0.79, CH2Cl2); νmax(KBr)/cmϪ1 3400,
1784, 1731, 1696 and 1678; δH(250 MHz, CDCl3) 0.93 (3 H,
d, J 7), 3.68–3.96 (2 H, m), 4.70 (1 H, quintet, J 7), 5.05–5.12
(3 H, m), 5.39–5.52 (4 H, m), 7.25–7.50 (17 H, m), 7.67 (1 H,
s), 7.76 (1 H, d, J 8) and 8.18 (1 H, d, J 8); m/z (FAB ex
Et2O–nitrobenzyl alcohol) 632 (MHϩ, 100%), 588 (85), 467
(39) and 306 (8).
1
Analysis of the crude product by 250 MHz H NMR spec-
troscopy indicated that the starting material 8d and the
Mannich product 10d were present in a ca. 1:1 molar ratio.
Flash chromatography [CH2Cl2–Et2O (97:3)] gave first 8d
(292 mg, 42% recovery) followed by 10d (446 mg) as an oil.
Recrystallisation of the latter compound from diethyl ether–
petrol gave 10d (400 mg, 38%; 66% based on recovered 8d) as
1
white crystals, mp 90–93 ЊC, identical by 250 MHz H NMR
spectroscopy with material prepared by the Curtius reaction
according to the preceding experiment.
(4S,5R,2ЈR)-3-(3-Benzyloxycarbonylamino-2-methylpropanoyl)-
4-methyl-5-phenyl-1,3-oxazolidin-2-one 10e via the Mannich
reaction with benzyl N-(acetoxymethyl)carbamate
(ii) Preparation of 10c via the Mannich reaction with 1-[N-
(benzyloxycarbonyl)aminomethyl]benzotriazole 4c. This was
performed by analogy with the preparation of 10b by method
(ii), starting from (4S,5R)-3-[(1-benzyloxycarbonylindol-3-
yl)acetyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one 6c (627 mg,
1.34 mmol). Evaporation of the crude product in vacuo left a
pale yellow foam (894 mg). A portion of this residue (13 mg)
was analysed by 250 MHz 1H NMR spectroscopy, on the
basis of which compounds 10c, 5, 6c and 11c were judged to
be present in the approximate molar ratio 80:10:6:4. The
remainder of the residue from the evaporation was purified
by flash chromatography [CH2Cl2 to CH2Cl2–EtOAc (96:4);
gradient elution] to yield the following three fractions. First
fraction: (4S,5R)-3-[(1-benzyloxycarbonylindol-3-yl)acetyl]-4-
methyl-5-phenyl-1,3-oxazolidin-2-one 6c (37.5 mg, 6%), iden-
This was prepared analogously to the preparation of 10a by
method (iii), starting from (4S,5R)-4-methyl-5-phenyl-3-
propanoyl-1,3-oxazolidin-2-one 6e.25 The reaction mixture was
allowed to warm from Ϫ78 to 20 ЊC over 8 h and then was
stirred at 20 ЊC for 1 h, before being worked up as before. Flash
chromatography [EtOAc–petrol; gradient from (2:1) to (1:1)]
yielded
(4S,5R,2ЈR)-3-(3-benzyloxycarbonylamino-2-methyl-
propanoyl)-4-methyl-5-phenyl-1,3-oxazolidin-2-one 10e (130 mg,
34%) as a clear glass. Recrystallisation from petrol gave white
crystals, mp 91–93 ЊC; [α]D29 Ϫ33.7 (c 2.1, CH2Cl2); δH(250 MHz,
CDCl3) 0.86 (3 H, d, J 7), 1.23 (3 H, d, J 7), 3.41–3.54 (2 H, m),
3.96 (1 H, sextet, J 7), 4.73 (1 H, quintet, J 7), 5.08 (2 H, s),
5.19–5.29 (1 H, br t), 5.65 (1 H, d, J 7) and 7.25–7.45 (10 H, m);
m/z 369 (Mϩ, 9%), 289 (5), 219 (8) and 91 (100) (Found: Mϩ,
396.1692. C22H24N2O5 requires M, 396.1685).
1
tical to the starting material by H NMR spectroscopy. Sec-
ond fraction: (4S,5R,2ЈR)-3-[3-(Benzyloxycarbonylamino)-2-
(1-benzyloxycarbonylindol-3-yl)propanoyl]-4-methyl-5-phenyl-
1,3-oxazolidin-2-one 10c as a pale yellow foam (484 mg,
(R)-3-Benzyloxycarbonylamino-2-phenylpropanoic acid 12a
(4S,5R,2ЈR)-3-(3-Benzyloxycarbonylamino-2-phenylpropan-
oyl)-4-methyl-5-phenyl-1,3-oxazolidin-2-one 10a (212 mg,
0.46 mmol) was dissolved in a mixture of THF (4 ml) and H2O
(1.3 ml) and cooled to 0 ЊC. LiOHؒH2O (49 mg, 1.16 mmol),
and aqueous H2O2 (30% solution, 0.25 ml) were added. The
reaction was quenched after 30 min with saturated aqueous
Na2SO3 (10 ml) and diluted with brine (10 ml).
The reaction mixture was extracted with CH2Cl2 (3 × 15 ml).
The aqueous layer was then acidified with 2  HCl (to pH 2)
and extracted into EtOAc (3 × 15 ml). The combined organic
layers were dried and evaporated under vacuum to yield a vis-
cous oil, which was recrystallised from diethyl ether and petrol
to yield the title compound as white crystals (89.4 mg, 65%),
mp 95–97 ЊC (lit.,26 100–102 ЊC); [α]D36 ϩ92.5 (c 1.0 in EtOH)
[lit.,26 ϩ93.6 (c 1.0, EtOH)]; νmax(KBr)/cmϪ1 3390, 1720 and
1654; δH(250 MHz, CDCl3) 3.65–4.15 (3 H, m), 5.15–5.35 (3 H,
1
58%), mp 59–65 ЊC, identical by H NMR spectroscopy (250
MHz, CDCl3) to material prepared by the Curtius reaction,
as described in the preceding experiment. Third fraction: con-
sidered to be (4S,5R,2ЈS)-3-[3-benzyloxycarbonylamino-2-(1-
benzyloxycarbonylindol-3-yl)propanoyl]-4-methyl-5-phenyl-1,3-
oxazolidin-2-one 11c (36 mg, 3%), on the basis of the follow-
ing data: off-white foam, mp 63–66 ЊC; [α]D34 Ϫ95 (c 0.73,
CHCl3); νmax(film)/cmϪ1 3378, 1780, 1726 and 1698 (shoul-
der); δH(250 MHz, CDCl3) 0.76 (3 H, d, J 7), 3.65–3.90 (2 H,
m), 4.80 (1 H, quintet, J 7), 5.06–5.18 (3 H, m), 5.39–5.50 (3
H, m), 5.66 (1 H, d, J 7), 7.16–7.52 (17 H, m), 7.60 (1 H, s),
7.78 (1 H, d, J 8) and 8.18 (1 H, d, J 8); m/z (FAB ex Et2O–
nitrobenzyl alcohol) 632 (MHϩ, 47%), 588 (51), 479 (82) and
467 (100).
526
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
m) and 7.35–7.55 (10 H, m). The broadness of the peaks in the
1H NMR spectrum was attributed to the presence of inter-
converting rotamers.
222–224 ЊC (lit.,20 224–225 ЊC, lit.,26 223–226 ЊC); [α]D30 ϩ94 (c
0.2, H2O) [lit.,20 ϩ95 (c 0.2 in H2O), lit.,26 ϩ85 (c 0.2 in H2O)];
δH(250 MHz, D2O) 3.30 (1 H, dd, J 12, 7), 3.49 (1 H, dd, J 12,
8), 3.81 (1 H, ‘t’, J 7) and 7.34–7.48 (5 H, m).
(R)-3-Benzyloxycarbonylamino-2-(4-benzyloxyphenyl)propanoic
acid 12b
(R)-3-Amino-2-phenylpropanoic acid, (1S)-(؉)-camphor-
sulfonate salt
This was prepared by analogy with 12a, starting from
(4S,5R,2ЈR)-3-[3-benzyloxycarbonylamino-2-(4-benzyloxy-
phenyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one 10b
(571 mg, 1.01 mmol). Recrystallisation from Et2O–petrol
yielded the title compound 12b as a white solid (283 mg,
69%), mp 105–108 ЊC (from Et2O–petrol) (Found: C, 71.0; H,
5.6; N, 3.3. C24H23NO5 requires C, 71.1; H, 5.7; N, 3.45%);
[α]D28 ϩ113 (c 1.1, CH2Cl2); νmax(KBr)/cmϪ1 3350, 2400–3500
(br) and 1697; δH(250 MHz; CDCl3, broad spectrum, prob-
ably as a result of the presence of interconverting rotamers)
3.5–3.9 (3 H, m), 5.05 (2 H, s), 5.05–5.20 (2 H, m), 6.05 (1 H,
br s, exchanges with D2O), 6.93 (2 H, d, J 8), 7.13–7.22 (2 H,
m) and 7.30–7.45 (10 H, m); m/z 405 (Mϩ, 0.1%), 254 (11)
and 91 (100) (Found: Mϩ, 405.1576. C24H23NO5 requires M,
405.1564).
A solution of (R)-3-amino-2-phenylpropanoic acid 13 (32.0
mg, 0.19 mmol) in water (4 ml) was treated with (1S)-(ϩ)-
camphor-10-sulfonic acid (49.0 mg, 0.21 mmol) in EtOH (1 ml).
The solvents were evaporated and the residue was twice
recrystallised from EtOH–Et2O to give the title compound (52.5
mg, 68%) as white needles, mp 183–189 ЊC (lit.,26 190–192 ЊC);
[α]D26 ϩ61 (c 0.5 in H2O) [lit.,26 ϩ63 (c 0.5, H2O)]. The relative
configuration of the title compound was proven by single
crystal X-ray diffraction.6
(R)-3-Amino-2-(4-hydroxyphenyl)propanoic acid 14
(R)-3-(Benzyloxycarbonylamino)-2-(4-benzyloxyphenyl)prop-
anoic acid 12b (107.7 mg) was dissolved in glacial acetic acid (2
ml) and hydrogenated over Pd black (15 mg) for 1 h, during
which time white crystals formed in the reaction mixture. Water
(2 ml) was added and the mixture was filtered through Celite,
which was then washed with 50% aqueous AcOH (10 ml).
Evaporation of the combined filtrate and washings, then crys-
tallisation from water, yielded the title compound 14 (43.7 mg,
91%) as a white solid, mp ca. 270 ЊC (decomp.) (Found: C, 59.2;
H, 6.0; N, 7.5. C9H11NO3 requires C, 59.7; H, 6.2; N, 7.6%); [α]D30
ϩ16.7 (c 1.2, HCO2H); νmax(KBr)/cmϪ1 3225, 2400–3300 (br),
1653, 1589 and 1510; δH(250 MHz, CF3CO2D) 3.62–3.76 (1 H,
m), 3.84–3.95 (1 H, m), 4.33 (1 H, t, J 7), 6.8 (2 H, d, J 8), 7.1 (1
H, br s) and 7.32 (2 H, d, J 8); m/z 181 (Mϩ, 2%), 164 (15), 152
(100) and 107 (64) (Found: Mϩ, 181.0737. C9H11NO3 requires
M, 181.0739).
(R)-3-Benzyloxycarbonylamino-2-(1-benzyloxycarbonylindol-3-
yl)propanoic acid 12c
(4S,5R,2ЈR)-3-[3-Benzyloxycarbonylamino-2-(1-benzyloxy-
carbonylindol-3-yl)propanoyl]-4-methyl-5-phenyl-1,3-oxazol-
idin-2-one 10c (50.2 mg, 0.079 mmol) was dissolved in THF (1
ml) and the solution was cooled to 0 ЊC; LiOHؒH2O (4.0 mg,
0.095 mmol), aqueous H2O2 (30%, 0.1 ml) and water (0.3 ml)
were then added. After 25 min aqueous Na2SO3 (1 ml) was
added followed by 2  HCl to pH 3. The mixture was par-
titioned between EtOAc (10 ml) and water (10 ml). Drying and
evaporation of the EtOAc phase gave an off-white solid which
was recrystallised from CH2Cl2–petrol to give the title com-
pound 12c (31.5 mg, 84%), mp 163–164 ЊC (Found: C, 68.5; H,
5.1; N, 5.9. C27H24N2O6 requires C, 68.6; H, 5.1; N, 5.9%); [α]D35
ϩ58 (c 1.0, acetone); νmax(KBr)/cmϪ1 3331, 2500–3300 (br),
1743, 1719 and 1684; δH(250 MHz, CDCl3) 3.5–3.8 (2 H, m),
4.0–4.3 (1 H, m), 5.0–5.3 (3 H, m), 5.4–5.5 (2 H, m), 7.05–7.7
(14 H, m) and 8.17 (1 H, d, J 8); m/z (FAB ex petrol–glycerol)
473 (MHϩ, 16%), 429 (17), 283 (17) and 214 (100).
(R)-3-Amino-2-benzylpropanoic acid 15
This was prepared by analogy with 13, starting from (R)-3-
benzyloxycarbonylamino-2-benzylpropanoic acid 12d (53.2
mg, 0.17 mmol). Crystallisation from H2O–EtOH yielded the
title compound 15 (24.6 mg, 81%) as white crystals, mp 227–
229 ЊC (lit.,2 225–226 ЊC); [α]D35 ϩ18.9 (c 0.88, 1  HCl), [α]D33
ϩ19.2 (c 0.65, 1  HCl) {lit.,2 [α]D29 ϩ11.3 (c 1, 1  HCl)}; δH(250
MHz, D2O) 2.90–3.27 (5 H, m) and 7.41–7.57 (5 H, m); δC(63
MHz, D2O) 39.2, 43.8, 50.1, 129.7, 131.8, 132.0, 141.7 and
182.7; m/z 179 (Mϩ, 53%), 162 (51), 144 (9), 117 (75), 103 (22),
91 (100), 78 (30) and 65 (29) (Found: Mϩ, 179.0947. C10H13NO2
requires M, 179.0946).
(R)-3-Benzyloxycarbonylamino-2-benzylpropanoic acid 12d
This was prepared by analogy with 12a, from (4S,5R,2ЈR)-3-
(3-benzyloxycarbonylamino-2-benzylpropanoyl)-4-methyl-5-
phenyl-1,3-oxazolidin-2-one 10d (225 mg, 0.5 mmol). The crude
product was crystallised from Et2O–petrol to yield the title
compound 12d (99.6 mg, 67%) as white crystals. After a further
recrystallisation from Et2O–petrol the crystals (61 mg) had mp
74–75 ЊC (Found: C, 68.8; H, 6.0; N, 4.4. C18H19NO4 requires C,
69.0; H, 6.1; N, 4.5%); [α]D27 ϩ9.7 (c 0.15, CH2Cl2); [α]D27 Ϫ1.4 (c
0.4, EtOH); νmax(KBr)/cmϪ1 3348, 2400–3600 (br), 1792 and
1695; δH(250 MHz, CDCl3) 2.62–3.55 (5 H, m), 5.02–5.22 (3 H,
m) and 7.10–7.40 (10 H, m); the peaks in the NMR spectrum
were broad, probably as a consequence of the presence of inter-
converting rotamers; m/z 313 (Mϩ, 0.3%), 222 (0.4), 131 (7), 91
(100) and 65 (21) (Found: Mϩ, 313.1317. C18H19NO4 requires
M, 313.1314).
(1-Benzyloxycarbonylindol-3-yl)acetic acid 18
Indole-3-acetic acid 17 (4.20 g, 24 mmol) was dissolved in dry
THF (100 ml) and the solution was cooled to Ϫ45 ЊC. A 2.2 
solution of BuLi in hexane (24 ml, 53 mmol) was added over
5 min. After a further 5 min benzyl chloroformate (3.6 ml, 24
mmol) was added and the reaction mixture was allowed to
attain Ϫ5 ЊC over 2 h before being quenched with saturated
aqueous NH4Cl (10 ml). Water (100 ml) was added and the
mixture was extracted with Et2O (2 × 60 ml). The aqueous
phase was acidified with 2  HCl to pH 3 and was then
extracted with diethyl ether (3 × 60 ml). The ether extracts from
after the acidification were combined, diluted with sufficient
EtOAc to dissolve any precipitate, dried, filtered and evapor-
ated. Recrystallisation from EtOAc–petrol, together with flash
chromatography [CH2Cl2–EtOAc (4:1) to CH2Cl2–EtOAc
(2:1); gradient elution] of the residue from evaporation of the
mother liquors, and further recrystallisation (CH2Cl2–petrol)
yielded the title compound 18 (5.14 g, 69%) as white crystals,
mp 153–154 ЊC (Found: C, 69.8; H, 4.9; N, 4.55. C18H15NO4
requires C, 69.9; H, 4.9; N, 4.5%); νmax(KBr)/cmϪ1 2400–3600
(br), 1733 and 1696; δH(250 MHz, CDCl3) 3.75 (2 H, s), 5.46
(2 H, s), 7.23–7.55 (8 H, m) and 8.17 (1 H, d, J 8); m/z 309
(R)-3-Amino-2-phenylpropanoic acid 13
(4S,5R,2ЈR)-3-(3-Benzyloxycarbonylamino-2-phenylpropan-
oyl)-4-methyl-5-phenyl-1,3-oxazolidin-2-one 10a (459 mg, 1
mmol) was hydrolysed using LiOHؒH2O (104 mg, 2.5 mmol) as
in the preparation of 12a. The crude (R)-3-benzyloxycarbonyl-
amino-2-phenylpropanoic acid 12a was not recrystallised, but
was dissolved in glacial acetic acid (10 ml). 10% Palladium on
carbon (300 mg) was added and the mixture was hydrogenated
overnight. Filtration through Celite, repeated evaporation with
water and recrystallisation from water–ethanol gave the title
compound 13 as white crystals (112 mg, 68% from 10a), mp
J. Chem. Soc., Perkin Trans. 1, 1998
527

View Article Online
(Mϩ, 18%), 265 (5), 220 (18) and 91 (100) (Found: Mϩ,
309.1000. C18H15NO4 requires M, 309.1001).
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Acknowledgements
We thank the EPSRC (formerly SERC) for studentships (held
by A. J. R. and A. A. D. S.), the European Union for assisting
H. E. to participate in an exchange scheme with the University
of Münster, the University of London Intercollegiate Research
Service for 600 MHz NMR spectroscopy and the University of
London Central Research Fund for financial support. We are
grateful to Mr P. Cook, Mr G. Coumbarides, Miss J. Isaacs and
Mr A. Roachford for recording spectra.
18 J. E. Fagel and G. W. Ewing, J. Am. Chem. Soc., 1951, 73, 4360.
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Paper 7/06163C
Received 22nd August 1997
Accepted 13th October 1997
528
J. Chem. Soc., Perkin Trans. 1, 1998