Synthesis of α-amino acids using amino acid γ-anion equivalents: Synthesis of 5-oxo α-amino acids, homophenylalanine derivatives and pentenylglycines

Article abstract of DOI:10.1039/a802142b

Treatment of protected iodohomoalanine 7 with Rieke copper leads to the formation of an organocopper reagent 10 which reacts with electrophiles in moderate yield to give enantiomerically pure α-amino acid derivatives 11, 12 and 13. Alternatively, reaction of the fully protected iodohomoalanine derivative 15 with activated zinc gives the corresponding alkylzinc iodide 14, which reacts under palladium catalysis with a range of electrophiles (aryl iodides and acid chlorides) to give the corresponding adducts 19 and 22. While the reactions with aryl iodides provide acceptable yields in THF as solvent, the corresponding reactions with acid chlorides requires dimethoxyethane or, preferably, a combination of toluene and dimethylacetamide under ultrasonication, for good results. The alkylzinc iodide 14 can be transformed into a zinc-copper reagent 16 which reacts with allylic halides, and with reactive acid chlorides, to give the corresponding adducts 221, 24-26 in reasonable yields.

Full text of DOI:10.1039/a802142b

View Article Online / Journal Homepage / Table of Contents for this issue
Synthesis of á-amino acids using amino acid ã-anion equivalents:
synthesis of 5-oxo á-amino acids, homophenylalanine derivatives
and pentenylglycines
Richard F. W. Jackson,*,a Joanne L. Fraser,a Neil Wishart,a Barry Porterb
and Martin J. Wythesc
a Department of Chemistry, Bedson Building, The University of Newcastle,
Newcastle upon Tyne, UK NE1 7RU
b Dagenham Research Centre, Rhône-Poulenc Rorer Ltd., Rainham Road South, Dagenham,
Essex, UK RM10 7XS
c Pfizer Central Research, Sandwich, Kent, UK CT13 9NJ
Treatment of protected iodohomoalanine 7 with Rieke copper leads to the formation of an organocopper
reagent 10 which reacts with electrophiles in moderate yield to give enantiomerically pure á-amino acid
derivatives 11, 12 and 13. Alternatively, reaction of the fully protected iodohomoalanine derivative 15 with
activated zinc gives the corresponding alkylzinc iodide 14, which reacts under palladium catalysis with
a range of electrophiles (aryl iodides and acid chlorides) to give the corresponding adducts 19 and 22.
While the reactions with aryl iodides provide acceptable yields in THF as solvent, the corresponding
reactions with acid chlorides requires dimethoxyethane or, preferably, a combination of toluene and
dimethylacetamide under ultrasonication, for good results. The alkylzinc iodide 14 can be transformed
into a zinc–copper reagent 16 which reacts with allylic halides, and with reactive acid chlorides, to give the
corresponding adducts 22l, 24–26 in reasonable yields.
Over recent years, we have developed the use of iodoalanine-
derived organometallic reagents for the synthesis of non-
proteinogenic amino acids in enantiomerically pure form. For
example, the organozinc reagent 1, prepared by treatment of
appropriately protected iodoalanine with activated zinc in
benzene–dimethylacetamide using sonochemical activation,
reacts under palladium catalysis with acid chlorides to give
4-oxo α-amino acids 2, and also with aryl iodides to give 3-aryl
α-amino acids 3 (Scheme 1).1
Efficient access to a synthetic equivalent for the amino acid
γ-anion synthon 5 would allow the direct preparation of enan-
tiomerically pure 5-oxo α-amino acids by reaction with acid
chlorides, homophenylalanine derivatives by coupling with aryl
iodides, and pentenylglycines by reaction with allylic halides.
Previous routes to 5-oxo α-amino acids have included reaction
of nucleophiles with pyroglutamic acid derivatives,6–10 treat-
ment of activated glutamic acid derivatives with diazo-
alkanes11,12 and acylation of glutamic acid derived enolates.13,14
Homophenylalanines, which are important as components of
ACE inhibitors (e.g. Enalapril), have been prepared by a variety
of methods. These include use of the chiral pool, for example
by reaction of diarylcopper lithium reagents with analogues of
iodohomoalanine 7.15,16 Use of chiral glycine anion equiva-
lents17 and of chiral glycine cation equivalents18 has also been
explored. An indirect approach, based on catalytic asymmetric
reduction of trichloromethyl ketones followed by reaction with
azide anion and hydrogenation, has been developed,19 and
catalytic asymmetric hydrogenation has also been exploited.20
Pentenylglycines have been prepared by both chemical21 and
enzymatic methods.22
R
NHBoc
CO2Bn
NHBoc
CO2Bn
NHBoc
CO2Bn
RCOCl
Pd0
ArI
IZn
Ar
Pd0
O
2
1
3
Scheme 1
The synthetic applicability of this approach has been signifi-
cantly extended by the demonstration that the zinc–copper
reagent 4, prepared from 1 by transmetallation, can react with
NHBoc
IZn(NC)Cu
NH2
CO2H
X
NHBoc HO2C
CO2Bn
NHBoc
CO2Bn
CO2Bn
4
5
6 X = ZnI
7 X = I
8 X = H
9
allylic halides (and a range of other electrophiles) to give
enantiomerically pure amino acid derivatives.2 The successful
demonstration that the zinc reagent 1 and the zinc–copper
reagent 4 behave as direct synthetic equivalents for the simple
unstabilised amino acid β-anion synthon prompted us to
explore the generality of this approach. In this paper we report
in full the results of our initial efforts to generate synthetic
equivalents for the amino acid γ-anion synthon 5.†
Earlier indirect approaches to the γ-anion equivalent 5 have
relied on the use of differentially protected glutamic acid
derivatives23–25 or the use of pyroglutamic acid.26,27 Since the
reagent 1 is viable,1 despite the presence of an acidic proton on
nitrogen,28 we decided to investigate whether a similarly pro-
tected homologous reagent 6 could be prepared using the con-
ditions that we had developed for the preparation of zinc
reagent 1. The required iodohomoalanine derivative 7 was pre-
pared from commercially available Boc-glutamic acid α-benzyl
† The work described in this paper has been published in preliminary
form.3–5
J. Chem. Soc., Perkin Trans. 1, 1998
1903

View Article Online
Table 1 Reactions of organocopper reagent 10 with electrophiles
ester 9 in 68% overall yield by the use of the Barton decarb-
oxylative iodination procedure.29 Photolytic decomposition of
the intermediate N-hydroxy-2-thiopyridone ester,30,31 rather
than the use of thermolysis, resulted in slightly higher yields.
Unfortunately, reaction of iodide 7 with zinc–copper couple
under the sonochemical conditions1 which we have developed
for preparation of the serine derived reagent 1, resulted in the
formation not only of the zinc reagent 6 but also significant
amount of protected 2-aminobutanoic acid 8, formed by pro-
tonation of the carbon᎐zinc bond. Similarly, use of activated
zinc in THF as solvent was also inefficient. After we had com-
pleted these preliminary experiments, it was reported that
provided a four-fold excess of the zinc reagent 6 is used, satis-
factory yields of coupled product may be obtained in the
palladium catalysed reaction with an iodohistidine derivative,
provided the yield is based on the iodohistidine derivative.32
Given the higher cost, in general, of the amino acid derived-
iodide compared with most simple electrophiles, we have
chosen to explore alternatives which make more efficient use of
the amino acid component.
We have therefore pursued two strategies for the development
of alternative synthetic equivalents for the amino acid γ-anion
synthon 5. The first of these involved direct formation of an
organocopper reagent 10 by treatment of the iodide 7 with
Rieke copper at low temperature,33 under which conditions we
hoped that protonation of the carbon᎐metal bond would be
less likely to occur. The second strategy involved complete
nitrogen protection, so as to prevent protonation of the carbon᎐
zinc bond by the acidic NH.
Electrophile
Product
R
Yield (%)
PhCOCl
MeCOCl
n-C5H11COCl
c-C5H9COCl
2-furylCOCl
CH2᎐᎐CHCH2Cl
11a
11b
11c
11d
11e
12a
12b
Ph
Me
n-C5H11
c-C5H9
2-furyl
H
46
52
44
55
40
42
62
PhCH᎐CHCH2Cl
Ph
᎐
protected 2-aminobutanoic acid 8. In two cases, 11c and 11d,
the enantiomeric purity of the products could be established by
direct comparison with literature data. Use of allylic halides
gave the corresponding allylated derivatives 12a and 12b. Isol-
ation of 12b established that the predominant reaction pathway
of the copper reagent with allylic substrates was SN2Ј. Our
results are summarised in Table 1. Consistent with this observ-
ation, reaction of 10 with prop-2-ynyl chloride gave the
terminal allene 13 (36%).12 A differently protected analogue of
this allene has been prepared previously by means of radical
chemistry,35 as well as by conventional enzymatic resolution.36
Having established that it was possible to prepare the organo-
copper reagent 10, attention was then directed towards the
formation of an organozinc reagent so as to explore its pal-
ladium catalysed coupling reactions with a range of electro-
philes. At the outset of our work in this area, the fully protected
organozinc reagent 14 had been prepared from the correspond-
ing iodide 15, and two examples of an efficient copper-catalysed
Preparation of an amino acid derived copper reagent
Z
Z
X
IZn(NC)Cu
N
N
The alkylcopper reagent 10 was prepared by treatment of the
iodide 7 with Rieke copper, prepared by reduction of the THF-
soluble salt CuCNؒ2 LiCl.33,34 After significant experiment-
ation, it was established that the most effective conditions
involved the use of an excess of Rieke copper (6 equiv.) at
Ϫ78 ЊC, which allowed conversion of the iodide 7 into the cop-
per reagent 10 within 30 minutes.‡ Reaction of 10 with acid
chlorides gave 5-oxo α-amino acids 11a–e in moderate yield
(Scheme 2). In all cases, the only isolated by-product was
O
O
O
O
14 X = IZn
15 X = I
17 X = HO2C
18 X = H
16
conjugate addition reaction of reagent 14 with enones had been
reported.37 This reagent therefore appeared to be an ideal
choice for exploring the scope of palladium catalysed coupling
reactions with a range of electrophiles. It was also clear that a
stoichiometric transmetallation into the zinc–copper reagent 16
would broaden the scope of the amino acid derivatives which
were accessible.38 The iodide 15 was prepared in an analogous
manner to the iodide 7, using the protected glutamic acid
derivative 17 as starting material, using the general literature
procedure29 which had been applied to this particular substrate
and reported in preliminary form.37
O
NHBoc
R
ii
CO2Bn
11a–e
R
iii
iv
i
NHBoc
CO2Bn
Cu
NHBoc
CO2Bn
7
12a,b
Synthesis of homophenylalanine derivatives
10
The zinc reagent 14 was prepared by treatment of the iodide 15
with zinc dust under the conditions developed by Knochel.39
This allowed the preparation of the reagent under more con-
venient conditions than those previously reported.37 Coupling40
of the zinc reagent 14 with aryl iodides in the presence of the
palladium(0) catalyst prepared by reaction of tris(dibenzyl-
ideneacetone)dipalladium with tri-o-tolylphosphine, proceeded
as expected to give the homophenylalanine derivatives 19 in
moderate yields (Scheme 3). The major by-product in all cases
NHBoc
CO2Bn
13
Scheme 2 Reagents and conditions: i, Rieke Cu (6 equiv.), THF,
Ϫ78 ЊC, 30 min; ii, RCOCl (6 equiv.), THF, Ϫ30 ЊC, 3 h; iii, RCH᎐
᎐
᎐
CHCH2Cl (6 equiv.), THF, Ϫ30 ЊC, 3 h; iv, HC᎐CCH2Cl (6 equiv.),
᎐
Z
N
Z
N
THF, Ϫ30 ЊC, 3 h
Ar
IZn
i
O
O
‡ The precise structure of the organocopper reagent 10 is a matter for
further investigation. One can speculate that the reagent is a lower order
lithiocyanocuprate [RCu(CN)Li], since Rieke has established that free
LiCN is not present in simpler cases.33 The reactivity of this reagent
towards electrophiles is substantially higher than the analogous zinc–
copper reagent 16.
O
O
14
19a–h
Scheme 3 Reagents and conditions: i, ArI, Pd2(dba)3 (0.625 mol%),
P(o-tol)3 (2.5 mol%), THF, 50 ЊC, 1 h
1904
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
Table 2 Synthesis of homophenylalanine derivatives
was the 2-aminobutyric acid derivative 18 formed by proton-
ation of the zinc reagent 14. Our results are summarised in
Table 2.
Aryl iodide
Product
Ar
Yield (%)
Treatment of 19a with lithium methoxide in methanol12 gave
Z-protected homophenylalanine methyl ester 20 in excellent
yield, establishing the utility of these derivatives for the syn-
thesis of homophenylalanine derivatives. The enantiomeric pur-
ity of 20 was established by conversion into the corresponding
known Boc derivative 2115 using triethylsilane, di-tert-butyl
dicarbonate and catalytic palladium() acetate (Scheme 4).41
PhI
4-Br-C6H4I
4-F-C6H4I
2-MeO-C6H4I
3,4-(MeO)2-C6H3I
2-NO2-C6H4I
4-NO2-C6H4I
1-naphthyl iodide
19a
19b
19c
19d
19e
19f
19g
19h
Ph
4-Br-C6H4
4-F-C6H4
2-MeO-C6H4
3,4-(MeO)2-C6H3
2-NO2-C6H4
4-NO2-C6H4
1-naphthyl
61
42
65
26
41
28
54
53
Ph
Z
Ph
NHP
CO2Me
N
i
Table 3 Reaction of zinc reagent 14 with acid chlorides in DME
O
O
Acid chloride
Product
R
Yield (%)
20 P = Z
21 P = Boc
19a
ii
PhCOCl
22a
22b
22c
22d
22e
22f
22g
Ph
64
78
55
60
50
86
18
2-furylCOCl
m-Me-C6H4COCl
CH3COCl
C2H5COCl
C5H11COCl
AcOCH2COCl
2-furyl
m-Me-C6H4
CH3
C2H5
C5H11
Scheme 4 Reagents and conditions: i, LiOMe (1 equiv.), MeOH,
Ϫ10 ЊC, 1 h; ii, Et3SiH, Boc2O, Pd(OAc)2, Et3N, EtOH, 60 ЊC, 7 d
AcOCH2
Synthesis of 5-oxo á-amino acid derivatives by palladium-
catalysed cross-coupling reactions
Mindful of our previous observations concerning the
incompatibility of acid chlorides with alkylzinc iodides gener-
ated in THF, presumably due to the well-established tendency
of zinc salts to promote the cleavage of THF by acid chlor-
ides,42 we screened a range of solvents for the coupling of the
zinc reagent 14 with acid chlorides. We established that use of
dimethoxyethane (DME) as solvent allowed efficient formation
of the zinc reagent 14 from the iodide 15 using activated zinc
dust.39 Addition of a range of acid chlorides, together with
catalytic bis(triphenylphosphine)palladium() chloride, gave
the 5-oxo amino acid derivatives 22a–g in moderate to good
yields. Our results are summarised in Table 3 (Scheme 5). The
Table 4 Reaction of zinc reagent 14 with acid chlorides in benzene–
dimethylacetamide or toluene–dimethylacetamide
Acid chloride
Product
R
Yield (%)
PhCOCl
CH3COCl
AcOCH2COCl
CH2᎐᎐CHCOCl
ClCH2COCl
PhthNCH2COCl
22a
22d
22g
22h
22i
Ph
CH3
AcOCH2
CH2᎐᎐CH
ClCH2
PhthNCH2
PhthNCH(CH3)
76a
73a
77b
52b
49b
77b
73b
22j
PhthNCH(CH3)COCl 22k
a Benzene–DMA. b Toluene–DMA.
O
Z
Z
N
IZn
N
(specifically acetoxyacetyl chloride) gives the corresponding
adducts in poor yield. Given our success in coupling the serine-
derived organozinc reagent with functionalised acid chlorides,
provided the zinc reagent was prepared by sonication in
benzene–dimethylacetamide (DMA) (15:1) as solvent,1 we have
also employed these conditions. Zinc reagent 14 was prepared
efficiently in benzene–DMA using our sonochemical condi-
tions, and subsequent palladium catalysed reaction with func-
tionalised acid chlorides gave the expected functionalised 5-oxo
amino acid derivatives 22g and 22h in much improved yield,
emphasising the importance of proper choice of solvent in
reactions of organozinc reagents. Preparation of the zinc
reagent 14 in toluene–dimethylacetamide was also possible,
thus obviating the need to use benzene (Scheme 7). As further
R
i
O
O
O
O
22a–g
14
Scheme 5 Reagents and conditions: i, RCOCl, PdCl2(PPh3)2 (5 mol%),
DME, 35 ЊC, 1 h
adducts 22d11,12 and 22e11 have been prepared previously by
treatment of the acid chloride derived from protected glutamic
acid 17 with diazoalkanes11,12 or by palladium catalysed coup-
ling with organotin derivatives.11
A minimum value for the enantiomeric purity of 22a was
established by chiral phase HPLC analysis of the correspond-
ing methyl ester 23a, prepared by treatment of 22a with lithium
methoxide in methanol (Scheme 6).12 This analysis indicated
O
Z
N
Z
N
IZn
R
O
O
Z
N
O
O
NHZ
Ph
Ph
i
O
O
22a,d,g–k
14
CO2Me
O
O
Scheme 7 Reagents and conditions: i, RCOCl, PdCl2(PPh3)2 (5 mol%),
benzene–DMA or toluene–DMA, 35 ЊC, 1 h
23a
22a
Scheme 6 Reagents and conditions: i, LiOMe (1 equiv.), MeOH,
Ϫ10 ЊC, 1 h
examples, reaction with N-phthaloylglycine acid chloride, and
N-phthaloylalanine acid chloride, gave the corresponding
adducts 22j and 22k, respectively. Reaction of 14 with simple
acid chlorides also proceeded well in toluene–DMA. Thus,
reaction with benzoyl chloride gave ketone 22a (76%), while
reaction with acetyl chloride gave 22d (73%). Our results are
summarised in Table 4.
that 23a possessed an enantiomeric excess of 96%. We suspect
that the small amount of racemisation detected occurred
during the ring-cleavage process with lithium methoxide.
The main drawback to the use of DME as solvent is that
reaction of zinc reagent 14 with functionalised acid chlorides
J. Chem. Soc., Perkin Trans. 1, 1998
1905

View Article Online
Use of the zinc–copper reagent 16
acetate (10:1) as the eluent. The solvent was removed under
Given the success we had achieved using the zinc reagent 14 in
palladium-catalysed coupling reactions with aryl iodides, it was
appropriate to explore the reactivity of the zinc–copper reagent
16. This reagent was prepared from the zinc reagent 14 by add-
ition of CuCNؒ2 LiCl (as a solution in THF).2,39 Subsequent
reaction with ethyl oxalyl chloride gave the keto ester 22l in
reduced pressure. Purification was performed by initially apply-
ing the crude product to a silica gel pad and eluting with a
toluene–ethyl acetate (5:1) solvent system. The resulting yellow
crystalline solid was further purified by flash chromatography
over silica gel using toluene–ethyl acetate (20:1) as the eluent,
to afford a colourless oil which solidified on standing.
Recrystallisation from cyclohexane yielded benzyl (2S)-2-tert-
butoxycarbonylamino-4-iodobutanoate as white needles, mp
54–55 ЊC (from pentane) (lit.,29 54 ЊC) (2.87 g, 5 mmol, 68%)
(Found: C, 46.05; H, 5.05; N, 3.35. C16H22INO4 requires C,
45.85; H, 5.3; N, 3.35%); [α]D24 Ϫ33.4 (c 1.0 in MeOH) {lit.,29 [α]D24
Ϫ33.0 (c 1.0 in MeOH)}; νmax(KBr disc)/cmϪ1 3355, 1756, 1680
and 1516; δH(200 MHz, CDCl3) 1.44 [9 H, s, OC(CH3)3],
2.15–2.27 [1 H, m, C(3)H], 2.35–2.52 [1 H, m, C(3)H], 3.14 [2
H, t, J 8, C(4)H2], 4.34–4.40 [1 H, m, C(2)H], 5.12 (1 H, br d, J
8, NH), 5.14 (1 H, d, J 12, CHaHbPh), 5.20 (1 H, d, J 12,
CHaHbPh) and 7.36 (5 H, s, Ph); m/z (EI) 284 (Mϩ Ϫ CO2Bn,
O
R
Z
Z
N
N
EtO2C
O
O
O
O
24a R = H
24b R = CH2Cl
22l
Z
Z
Z
N
N
N
53.2%), 236 [72, Mϩ Ϫ (CH ) C᎐CH Ϫ HI] and 228 [73,
᎐
3
2
2
N
O
O
O
M
ϩ Ϫ CO Bn Ϫ (CH ) C᎐CH ].
O
O
᎐
2
3
2
2
26
25
General procedure for the preparation of the copper reagent 10
and subsequent reaction with electrophiles
good yield, indicating that, at least with very reactive acid chlor-
ides, good yields of adducts may be obtained even in the pres-
ence of THF. The zinc–copper reagent 16 also reacts with a
range of allylic halides to give the corresponding products of
SN2Ј substitution, specifically 24a (66%), 24b (52%), 25 (63%)
and 26 (18%).
In summary, we have established that the copper reagent 10,
the zinc reagent 14 and the zinc–copper reagent 16, which each
function as synthetic equivalents for the α-amino acid γ-anion
synthon, are useful intermediates for the preparation of non-
proteinogenic α-amino acids in enantiomerically pure form.
A solution of CuCN (0.417 g, 4.65 mmol) and anhydrous LiCl
(0.420 g, 9.9 mmol) in dry THF (4.5 cm3) at Ϫ40 ЊC was added
by syringe to a solution of lithium naphthalenide [prepared by
reaction of lithium (0.035 g, 5.0 mmol) and naphthalene (0.75
g, 5.85 mmol) in dry THF (5 cm3)] cooled to Ϫ100 ЊC under
argon. The resulting solution was stirred for 10 min at Ϫ100 ЊC,
warmed to Ϫ78 ЊC, when a solution of iodide 7 (0.314 g, 0.75
mmol) in THF (2.5 cm3) was added, during which the tempera-
ture of the reaction mixture rose transiently to Ϫ65 ЊC. The
mixture was stirred at Ϫ78 ЊC for 30 min, at which point TLC
analysis (5:1 light petroleum–ethyl acetate) indicated no
remaining iodide 7, and the electrophile (4.5 mmol, 6 equiv.)
was then added. The reaction mixture was warmed to Ϫ30 ЊC,
and stirred at this temperature for 3 h, and then treated with sat.
aq. NH4Cl (5 cm3). The mixture was extracted with EtOAc (60
cm3), and the organic extract was washed with sat. aq. NaHCO3
(2 × 40 cm3), distilled water (2 × 40 cm3), dried and solvent was
removed. The residue was then purified by flash chroma-
tography using gradient elution with toluene–EtOAc to give the
products 11, 12 or 13; protected 2-aminobutanoic acid 8 was
also isolated.
Experimental
General experimental procedures and instrumentation are as
previously described.1 J Values are given in Hz. [α]D Values are
given in units of 10Ϫ1 deg cm2 gϪ1. Light petroleum refers to that
fraction with boiling point range 40–60 ЊC. All organic extracts
were dried over anhydrous MgSO4, and solvent was removed
using a rotary evaporator. Protected glutamic acid derivatives
17 and ent-17 were prepared by the literature method.43
Benzyl (2S)-tert-butoxycarbonylamino-4-iodobutanoate 7
N-Methylmorpholine (1.1 cm3, 10 mmol) and isobutyl chloro-
formate (1.4 cm3, 10 mmol) were added to a nitrogen purged
250 cm3 round bottomed flask, covered with aluminium foil,
Benzyl (2S)-2-tert-butoxycarbonylamino-5-oxo-5-phenyl-
pentanoate 11a
Treatment with benzoyl chloride (0.52 cm3, 4.5 mmol) yielded
the product as white crystals (0.138 g, 46%), mp 88–89 ЊC (from
EtOH) (Found: C, 69.6; H, 6.8; N, 3.5. C23H27NO5 requires C,
69.5; H, 6.85; N, 3.5%); [α]D24 Ϫ0.7 (c 1 in CH2Cl2); νmax(KBr
disc)/cmϪ1 3366, 2986, 1752, 1684, 1597 and 1514; δH(200 MHz,
CDCl3) 1.41 [9 H, s, OC(CH3)3], 2.01–2.22 [1 H, m, C(3)H],
2.25–2.38 [1 H, m, C(3)H], 2.88–3.16 [2 H, m, C(4)H2],
4.41–4.48 [1 H, m, C(2)H], 5.13 (1 H, d, J 12, CHaHbPh), 5.22
(1 H, d, J 12, CHaHbPh), 5.23 (1 H, br s, NH), 7.34 (5 H, s,
Ph), 7.43 (2 H, dd, J 8, 7, m-PhCO), 7.53 (1 H, dd, J 7, 1,
p-PhCO) and 7.88 (2 H, dd, J 8, 1, o-PhCO); m/z (EI)
containing
a
stirred solution of α-benzyl ()-N-(tert-
butoxycarbonyl)glutamic acid (3.37 g, 10 mmol) in dry THF
(50 cm3) at Ϫ15 ЊC. After stirring for 30 min at Ϫ15 ЊC the
mixed anhydride had formed, as judged by TLC analysis
using dichloromethane–methanol (10:1) as the eluent. A
solution of dry triethylamine (1.7 cm3, 12 mmol) and
N-hydroxythiopyridine (1.52 g, 12 mmol) in dry THF (20 cm3)
(prepared by stirring at room temperature, under an inert
atmosphere and in the absence of light) was added to the reac-
tion flask. The resulting solution was stirred for 1 h at Ϫ15 ЊC
to yield the 2-thiopyridyl ester [a yellow spot judged by TLC
analysis using toluene–ethyl acetate (1:1) as the eluent]. The
solution was filtered under reduced pressure in the absence of
light and concentrated under reduced pressure. The resulting
yellow liquid was dissolved in carbon tetrachloride (130 cm3)
and transferred to a 1000 cm3 round bottomed flask containing
a solution of iodoform (7.88 g, 20 mmol) in carbon tetra-
chloride (200 cm3) under a nitrogen atmosphere. The reaction
mixture was irradiated for approximately 3 h using a 150 W
tungsten bulb. This was carried out without the use of an
external cooling bath until all the 2-thiopyridyl ester had been
consumed, as judged by TLC analysis using toluene–ethyl
341 [Mϩ Ϫ (CH ) C᎐CH , 11%], 206 [67, MHϩ Ϫ (CH ) -
᎐
3
2
2
3 2
C᎐CH Ϫ PhCH3 Ϫ CO2] and 162 [85, MHϩ Ϫ (CH3)2-
᎐
2
C᎐CH Ϫ PhCH Ϫ 2CO ).
᎐
2
3
2
Benzyl (2S)-2-tert-butoxycarbonylamino-5-oxohexanoate 11b
Treatment with acetyl chloride (0.352 g, 0.32 cm3, 4.5 mmol)
yielded the product as an oil (0.130 g, 52%) (Found: C, 64.4; H,
7.5; N, 4.0. C18H25NO5 requires C, 64.45; H, 7.5; N, 4.2%); [α]D20
Ϫ5.3 (c 5.7 in CH2Cl2); νmax(film)/cmϪ1 3368, 2978, 2934, 1728,
1715 and 1514 (br); δH(200 MHz, CDCl3) 1.43 [9 H, s,
OC(CH3)3], 1.79–2.02 [1 H, m, C(3)H], 2.06–2.21 [1 H,
m, C(3)H], 2.09 [3 H, s, C(6)H3], 2.43–2.58 [2 H, m, C(4)H2],
1906
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
4.27–4.33 [1 H, m, C(2)H], 5.11 (1 H, d, J 12, CHaHbPh), 5.19
(1 H, d, J 12, CHaHbPh), 5.19 (1 H, br s, NH), and 7.34 (5 H, s,
Benzyl (2S,5RS)-2-tert-butoxycarbonylamino-5-phenylhept-6-
enoate 12b
Ph); m/z (EI) 336 (MHϩ, 1%), 280 [15, MHϩ Ϫ (CH ) C᎐CH ],
Treatment with cinnamyl chloride (0.687 g, 0.61 cm3, 4.5 mmol)
yielded the product as an inseparable mixture of diastereoi-
somers as an oil (0.189 g, 62%) (Found: C, 73.3; H, 7.15; N,
3.55. C25H31NO4 requires C, 73.3; H, 7.65; N, 3.4%); νmax(film)/
cmϪ1 3380, 3063, 3031, 2978, 2932, 1727, 1715 and 1499; δH(300
MHz, CDCl3) (both isomers, ratio not determined) 1.42 [9 H, s,
OC(CH3)3], 1.64–1.72 [4 H, m, C(3)H2 and C(4)H2], 3.16–3.29
[1 H, m, C(5)H], 4.30–4.40 [1 H, m, C(2)H], 4.94–5.26 [5 H, m,
NH, CH2Ph, C(7)H2], 5.81–5.94 [1 H, m, C(6)H], 7.10–7.40
(10 H, m, Ph); m/z (EI) 410 (MHϩ, 3%), 354 [13, MHϩ Ϫ
(CH3)2C᎐CH2], 310 [53, MHϩ Ϫ (CH3)2C᎐CH2 Ϫ CO2], and
᎐
3
2
2
236 [10, MHϩ Ϫ (CH ) C᎐CH Ϫ CO ], 200 (38, MHϩ Ϫ
᎐
3
2
2
2
PhCH Ϫ CO ), 144 [77, MHϩ Ϫ (CH ) C᎐CH Ϫ PhCH Ϫ
᎐
3
2
3
2
2
3
CO ] and 100 [84, MHϩ Ϫ (CH ) C᎐CH Ϫ PhCH Ϫ 2CO ].
᎐
2
3
2
2
3
2
Benzyl (2S)-2-tert-butoxycarbonylamino-5-oxodecanoate 11c
Treatment with hexanoyl chloride (0.606 g, 0.63 cm3, 4.5 mmol)
yielded the product as an oil (0.130 g, 44%) (Found: C, 67.25;
H, 8.55; N, 3.3. C22H33NO5 requires C, 67.5; H, 8.5; N, 3.6%);
[α]D18 Ϫ22.0 (c 2.0 in MeOH) {lit.,13 [α]D27 Ϫ22.3 (c 8.1 in MeOH)};
νmax(film)/cmϪ1 3368, 2959, 2934, 1728, 1713 and 1501 (br);
δH(200 MHz, CDCl3) 0.88 [3 H, t, J 6.7, C(10)H3], 1.10–1.35
[4 H, m, C(8)H2 and C(9)H2], 1.43 [9 H, s, OC(CH3)3], 1.46–1.60
[2 H, m, C(7)H2], 1.80–2.02 [1 H, m, C(3)H], 2.06–2.19 [1 H, m,
C(3)H], 2.33 [2 H, t, J 7.4, C(6)H3], 2.40–2.54 [2 H, m, C(4)H2],
4.24–4.35 [1 H, m, C(2)H], 5.11 (1 H, d, J 12, CHaHbPh), 5.12
(1 H, br s, NH), 5.20 (1 H, d, J 12, CHaHbPh) and 7.35 (5 H, s,
᎐
᎐
174 [74, MHϩ Ϫ (CH ) C᎐CH Ϫ PhCH Ϫ 2 CO ].
᎐
3
2
2
3
2
Benzyl (2S)-2-(tert-butoxycarbonylamino)hept-5,6-dienoate 13
Treatment with prop-2-ynyl chloride (0.335 g, 0.322 cm3, 4.5
mmol) yielded the product as an oil (0.090 g, 36%) (Found: C,
68.6; H, 7.6; N, 4.25. C19H25NO4 requires C, 68.85; H, 7.6; N,
4.25%); [α]D20 ϩ2.5 (c 3.7 in CH2Cl2); νmax(film)/cmϪ1 3370, 3067,
3034, 2978, 2932, 1735, 1716 and 1501; δH(200 MHz, CDCl3)
1.43 [9 H, s, OC(CH3)3], 1.65–1.80 [1 H, m, C(3)H], 1.92–2.10
[3 H, m, C(3)H and C(4)H2], 4.35–4.44 [1 H, m, C(2)H],
4.64–4.70 [2 H, m, C(7)H2], 5.01–5.09 [2 H, m, C(5)H and NH],
5.12 (1 H, d, J 12, CHaHbPh), 5.20 (1 H, d, J 12, CHaHbPh)
and 7.35 (5 H, s, Ph); δC(50 MHz, CDCl3) 24.07, 28.34, 31.96,
53.14, 67.04, 75.67, 79.93, 88.73, 128.27–128.64 (5 signals),
135.44, 155.09, 171.86 and 208.38; m/z (EI) 332 (MHϩ, 48%),
Ph); m/z (EI) 392 (MHϩ, 1.6%), 336 [12, MHϩ Ϫ(CH ) C᎐CH ],
᎐
3
2
2
256 [33, MHϩ Ϫ (CH ) C᎐CH Ϫ CO ], 200 [75, MHϩ Ϫ
᎐
3
2
2
2
(CH ) C᎐CH Ϫ PhCH Ϫ CO ] and 156 [87, MHϩ Ϫ
᎐
3
2
2
3
2
(CH ) C᎐CH Ϫ 2CO ].
᎐
3
2
2
2
Benzyl (2S)-2-tert-butoxycarbonylamino-5-oxo-5-cyclopentyl-
pentanoate 11d
Treatment with cyclopentanecarbonyl chloride (0.597 g, 0.55
cm3, 4.5 mmol) yielded the product as an oil (0.160 g, 55%)
(Found: C, 68.0; H, 8.05; N, 3.95. C22H31NO5 requires C, 67.85;
H, 8.0; N, 3.6%); [α]D18 Ϫ22.1 (c 6.7 in MeOH) {lit.,13 [α]D27 Ϫ23.3
(c 8.3 in MeOH)}; νmax(film)/cmϪ1 3370, 2961, 1728, 1713 and
1501; δH(200 MHz, CDCl3) 1.43 [9 H, s, OC(CH3)3], 1.53–1.79
[8 H, m, C(2Ј)H2, C(3Ј)H2, C(4Ј)H2 and C(5Ј)H2], 1.82–2.01
[1 H, m, C(3)H], 2.03–2.19 [1 H, m, C(3)H], 2.45–2.55 [2 H, m,
C(4)H3], 2.71–2.86 [1 H, m, C(1Ј)H2], 4.25–4.36 [1 H, m,
C(2)H], 5.12 (1 H, d, J 12, CHaHbPh), 5.18 (1 H, br s, NH), 5.20
(1 H, d, J 12, CHaHbPh) and 7.35 (5 H, s, Ph); m/z (EI) 390
276 [61, MHϩ Ϫ (CH ) C᎐CH ], 232 [95, MHϩ Ϫ (CH ) C-
᎐
3
2
2
3 2
᎐CH Ϫ CO ] and 140 [42, MHϩ Ϫ (CH ) C᎐CH Ϫ
᎐
᎐
2
2
3
2
2
PhCH3 Ϫ CO2].
(4S)-3-Benzyloxycarbonyl-4-(2Ј-iodoethyl)oxazolidin-5-one 15
N-Methylmorpholine (1.9 cm3, 17.2 mmol) and isobutyl chloro-
formate (2.4 cm3, 17.2 mmol) were added to a nitrogen purged
250 cm3 round bottomed flask (covered with foil) containing a
stirred solution of 3-[(4S)-3-benzyloxycarbonyl-5-oxooxazol-
idin-4-yl]propanoic acid 17 (5.04 g, 17.2 mmol) in dry THF (50
cm3) at Ϫ15 ЊC. After stirring for 30 min at Ϫ15 ЊC the mixed
anhydride had formed as judged by TLC analysis using
dichloromethane–methanol (10:1) as the eluent. A solution of
triethylamine (2.9 cm3, 20.5 mmol) and N-hydroxythiopyridine
(2.6 g, 20.5 mmol) in dry THF (20 cm3) (prepared by stirring at
room temperature, under an inert atmosphere and in the
absence of light) was added to the reaction flask. The resulting
solution was stirred for 1 h at Ϫ15 ЊC to yield the 2-thiopyridyl
ester [a yellow spot judged by TLC analysis using toluene–ethyl
acetate (1:1) as the eluent]. The solution was filtered under
reduced pressure in the absence of light and concentrated under
reduced pressure. The resulting yellow liquid was dissolved in
1,1,1-trichloroethane (100 cm3) and transferred to a 1000 cm3
round bottomed flask containing a solution of iodoform (13.5
g, 34 mmol) in 1,1,1-trichloroethane (400 cm3) under a nitrogen
atmosphere. The reaction mixture was irradiated for approxi-
mately 3 h using a 150 W tungsten bulb. This was carried out
without the use of an external cooling bath until all the 2-
thiopyridyl ester had been consumed, as judged by TLC analy-
sis using toluene–ethyl acetate (10:1) as the eluent. The solvent
was removed under reduced pressure. Purification was per-
formed by initially applying the crude product to a silica gel pad
and eluting with a toluene–ethyl acetate (5:1) solvent system.
The resulting yellow crystalline solid was further purified by
flash chromatography over silica gel using toluene–ethyl acetate
(50:1) as the eluent, to afford a colourless oil which solidified
on standing. Recrystallisation from cyclohexane yielded (4S)-3-
benzyloxycarbonyl-4-(2Ј-iodoethyl)oxazolidin-5-one as white
needles, mp 80–81 ЊC (from cyclohexane) (3.31 g, 8.85 mmol,
51%) (Found: C, 41.6; H, 3.54; N, 3.7. C13H14INO4 requires C,
41.6; H, 3.76; N, 3.7%); [α]D17 ϩ86.5 (c 1.04 in CH2Cl2); νmax(KBr
disc)/cmϪ1 2922, 1778, 1718, 1415 and 501; δH(200 MHz,
(MHϩ, 11%), 334 [35, MHϩ Ϫ (CH ) C᎐CH ], 254 (59,
᎐
3
2
2
MHϩ Ϫ PhCH3 Ϫ CO2), 198 [76, MHϩ Ϫ (CH ) C᎐CH Ϫ
᎐
3
2
2
PhCH Ϫ CO ] and 154 [86, MHϩ Ϫ (CH ) C᎐CH Ϫ 2CO ].
᎐
3
2
3
2
2
2
Benzyl (2S)-2-tert-butoxycarbonylamino-5-oxo-5-(2Ј-furyl)-
pentanoate 11e
Treatment with 2-furoyl chloride (0.587 g, 0.444 cm3, 4.5 mmol)
yielded the product as white crystals (0.120 g, 40%), mp 118 ЊC
(from EtOH) (Found: C, 65.15; H, 6.45; N, 3.8. C21H25NO6
requires C, 65.1; H. 6.5; N, 3.6%); [α]D20 Ϫ9.8 (c 2.8 in CHCl2);
νmax(KBr disc)/cmϪ1 3368, 2978, 2932, 1738, 1713, 1672, 1501,
1254 and 1028; δH(200 MHz, CDCl3) 1.41 [9 H, s, OC(CH3)3],
1.99–2.19 [1 H, m, C(3)H], 2.21–2.33 [1 H, m, C(3)H], 2.75–2.99
[2 H, m, C(4)H], 4.34–4.45 [1 H, m, C(2)H], 5.00–5.24 (3 H, m,
CH2Ph and NH), 6.51 [1 H, dd, J 3.6, 1.7, C(4Ј)H], 7.13 [1 H,
dd, J 3.6, 0.7, C(3Ј)H], 7.34 (5 H, s, Ph) and 7.55 [1 H, dd,
J 1.7, 0.7, C(5Ј)H]; m/z (EI) 388 (MHϩ, 20%), 332 5, MHϩ Ϫ
(CH ) C᎐CH ], and 252 (64 MHϩ Ϫ PhCH Ϫ CO ).
᎐
3
2
2
3
2
Benzyl (2S)-2-(tert-butoxycarbonylamino)hept-6-enoate 12a
Treatment with allyl chloride (0.344 g, 0.37 cm3, 4.5 mmol)
yielded the product as an oil (0.104 g, 42%) (Found: MHϩ Ϫ Ph-
CH3 Ϫ CO2, 198.1496. C11H20NO2 requires 198.1494); [α]D20 Ϫ5.5
(c 1.4 in CH2Cl2); νmax(film)/cmϪ1 3370, 3067, 3034, 2978, 2932,
1732, 1717 and 1501; δH(200 MHz, CDCl3) 1.43 [9 H, s,
OC(CH3)3], 1.48–1.88 [4 H, m, C(3)H2 and C(4)H2], 1.97–2.09
[2 H, m, C(5)H2], 4.29–4.39 [1 H, m, C(2)H], 4.92–5.02 [3 H, m,
C(7)H2 and NH], 5.12 (1 H, d, J 12, CHaHbPh), 5.21 (1 H, d, J
12, CHaHbPh), 5.62–5.82 [1 H, m, C(6)H] and 7.35 (5 H, s, Ph);
m/z (FAB) 334 (MHϩ, 8%), 278 [48, MHϩ Ϫ (CH ) C᎐CH ],
᎐
3
2
2
and 234 [63, MHϩ Ϫ (CH ) C᎐CH Ϫ CO ]; m/z (EI) 198.
᎐
3
2
2
2
J. Chem. Soc., Perkin Trans. 1, 1998
1907

View Article Online
CDCl3) 2.38–2.52 [2 H, m, C(1Ј)H2], 3.20 [2 H, t, J 7, C(2Ј)H2],
4.35 [1 H, t, J 7, C(4)H], 5.15 (2 H, s, CH2Ph), 5.20 [1 H, d, J 4,
C(2)H], 5.60 [1 H, m, C(2)H] and 7.37 (5 H, s, Ph); m/z (EI) 375
(Mϩ, 4%), 240 (40, MHϩ Ϫ CO2 Ϫ PhCH3) and 91 (100,
C7H7ϩ).
yielded the product as a white solid (0.127 g, 0.31 mmol, 42%),
mp 73–74 ЊC (from cyclohexane) (Found: C, 56.1; H, 4.3; N,
3.3. C19H18BrNO4 requires C, 56.4; H, 4.5; N, 3.5%); [α]D22 ϩ62.6
(c 1.08 in CH2Cl2); νmax(KBr disc)/cmϪ1 2963, 1784, 1684, 1425
and 698; δH(200 MHz; CDCl3) 2.05–2.40 [2 H, m, C(1Ј)H2],
2.53–2.75 [2 H, m, C(2Ј)H2], 4.25–4.40 [1 H, m, C(4)H], 5.10–
5.23 [3 H, m, PhCH2 and C(2)H], 5.43–5.58 [1 H, m, C(2)H],
6.89–7.15 [2 H, m, C(2Љ)H and C(6Љ)H] and 7.36 [7 H, m, Ph,
C(3Љ)H and C(5Љ)H]; m/z (EI) 404 (Mϩ, 0.2%), 360 (52,
(4R)-3-Benzyloxycarbonyl-4-(2Ј-iodoethyl)oxazolidin-5-one
ent-15
The title compound was prepared from ent-17 using the
procedure described for the preparation of (4S)-3-benzyl-
oxycarbonyl-4-(2Ј-iodoethyl)oxazolidin-5-one 15. Recrystal-
lisation from cyclohexane yielded the product as white needles,
mp 80–81 ЊC (from cyclohexane), [α]D17 Ϫ86.9 (c 1.05 in CH2Cl2).
M
ϩ Ϫ CO2) and 268 (80, Mϩ Ϫ CO2 Ϫ PhCH3).
(4S)-3-Benzyloxycarbonyl-4-[2Ј-(4Љ-fluorophenyl)ethyl]-
oxazolidin-5-one 19c
Treatment with 1-fluoro-4-iodobenzene (115 µl, 1 mmol) yield-
ed the product as a white solid (0.167 g, 65%), mp 64–65 ЊC
(from cyclohexane) (Found: MHϩ, 344.1285. C19H19NO4F
requires 344.1298); [α]D22 ϩ100.8 (c 1.00 in CH2Cl2); νmax(KBr
disc)/cmϪ1 2937, 1778, 1687, 1521, 1423, 1223 and 1180; δH(200
MHz; CDCl3) 2.08–2.43 [2 H, m, C(1Ј)H2], 2.53–2.80 [2 H, m,
C(2Ј)H2], 4.25–4.40 [1 H, m, C(4)H], 5.09–5.26 [3 H, m, CH2Ph
and C(2)H], 5.43–5.60 [1 H, m, C(2)H], 6.85–6.97 [2 H, m,
C(3Љ)H and C(5Ј)H], 7.00–7.23 [2 H, m, C(2Љ)H and C(6Љ)H]
and 7.37 (5 H, s, Ph); m/z (EI) 344 (MHϩ, 0.2%), 300 (8,
MHϩ Ϫ CO2) and 208 (58, Mϩ Ϫ CO2 Ϫ PhCH3).
General procedure for the preparation of 4-aryl á-amino acids
19a–h
Zinc dust (325 mesh, 0.300 g, 4.5 mol) was added to a nitrogen
purged flask, to which distilled THF (0.34 cm3) and 1,2-
dibromoethane (19 µl, 0.225 mmol) were then added. The flask
was heated with a heat gun until reflux of the solvent was
observed, and the zinc suspension was stirred for a few minutes.
This process was repeated five times. The flask was allowed to
cool to room temperature, and trimethylsilyl chloride (6 µl,
0.046 mmol) was added. The resultant mixture was stirred
under nitrogen for 30 min. (4S)-3-Benzyloxycarbonyl-4-(2Ј-
iodoethyl)oxazolidin-5-one 15 (0.280 g, 0.75 mmol) in THF
(0.75 cm3) was added to the flask and the resultant mixture
stirred at 35 ЊC (typically 15 min) generating (4S)-3-benzyl-
oxycarbonyl-4-(2Ј-iodozincethyl)oxazolidin-5-one 14, in situ, as
judged by disappearance of the iodide using TLC with light
petroleum–ethyl acetate (5:1) as the eluent. The aromatic
iodide (1 mmol) was added, followed by tris(dibenzylideneace-
tone)dipalladium [Pd2(dba)3] (0.004 g, 0.005 mmol) and tri(o-
tolylphosphine) (0.006 g, 0.02 mmol) and the reaction mixture
was stirred for 1 h at 50 ЊC. After allowing the reaction mixture
to reach ambient temperature, ethyl acetate (50 cm3) was added
and the contents were filtered into a separating funnel. The
organic layer was washed with dilute hydrochloric acid (20 cm3,
1 ), washed with water (3 × 20 cm3), dried and concentrated
under reduced pressure to give the crude product as an oil.
Flash chromatography over silica gel (light petroleum–ethyl
acetate—gradient, typically 50:1 to 50:4) yielded the pure pro-
tected amino acid. In each case, the protonated zinc reagent 18
was isolated from each subsequent experiment employing zinc
reagent 14 in varying yields, together with the desired product.
(4S)-3-Benzyloxycarbonyl-4-[2Ј-(2Љ-methoxyphenyl)ethyl]-
oxazolidin-5-one 19d
Treatment with 2-iodoanisole (130 µl, 1 mmol) yielded the
product as an oil (0.069 g, 0.20 mmol, 26%) (Found: Mϩ,
355.1406. C20H21NO5 requires 355.1420); [α]D22 ϩ95.3 (c 1.14 in
CH2Cl2); νmax(film)/cmϪ1 2926, 1801, 1716, 1601 and 1417;
δH(200 MHz; CDCl3) 2.08–2.45 [2 H, m, C(1Ј)H2], 2.53–2.85 [2
H, m, C(2Ј)H2], 3.75 (3 H, s, OMe), 4.30–4.40 [1 H, m, C(4)H],
5.10–5.23 [3 H, m, CH2Ph and C(2)H], 5.45–5.58 [1 H, m,
C(2)H], 6.73–6.88, [2 H, m, C(3Љ)H and C(5Љ)H], 7.00–7.08
[1 H, m, C(4Љ)H], 7.13–7.23 [1 H, m, C(6Љ)H] and 7.35 (5 H,
s, PhCH2O); m/z (EI) 355 (Mϩ, 9%), 311 (2, Mϩ Ϫ CO2) and
219 (60, Mϩ Ϫ CO2 Ϫ PhCH3).
(4S)-3-Benzyloxycarbonyl-4-[2Ј-(3Љ,4Љ-dimethoxyphenyl)ethyl]-
oxazolidin-5-one 19e
Treatment with 3,4-dimethoxyiodobenzene (0.246 g, 1 mmol)
yielded the product as an oil (0.118 g, 0.31 mmol, 41%) (Found:
C, 65.5; H, 6.0; N, 3.3. C21H23NO6 requires C, 65.4; H, 6.0; N,
3.6%); [α]D22 ϩ95.7 (c 0.985 in CH2Cl2); νmax(film)/cmϪ1 2924,
1802, 1717 and 1418; δH(200 MHz; CDCl3) 2.08–2.33 [2 H, m,
C(1Ј)H2], 2.50–2.73 [2 H, m, C(2Ј)H2], 3.84 (6 H, s, CH3O at 3Љ
and CH3O at 4Љ), 4.28–4.40 [1 H, m, C(4)H], 5.13–5.23 [3 H, m,
CH2Ph and C(2)H], 5.45–5.55 [1 H, m, C(2)H], 6.65–6.80 [3 H,
m, C(2Љ)H, C(5Љ)H and C(6Љ)H] and 7.36 (5 H, s, Ph); m/z (EI)
(4S)-3-Benzyloxycarbonyl-4-ethyloxazolidin-5-one 18
This compound was isolated as an oil (Found: Mϩ, 249.1007.
C13H15NO4 requires 249.1001); [α]D24 ϩ57.0 (c 0.8 in MeOH)
{lit.,44 [α]D24 ϩ58 (c 0.8 in MeOH)}; νmax(film)/cmϪ1 2972, 1805,
1716 and 1417; δH(200 MHz; CDCl3) 0.95 [3 H, t, J 8, C(2Ј)H3],
1.83–2.25 [2 H, m, C(1Ј)H2], 4.30–4.35 [1 H, m, C(4)H], 5.13–
5.26 [3 H, m, CH2Ph and C(2)H], 5.48–5.58 [1 H, m, C(2)H]
and 7.36 (5 H, s, Ph); m/z (EI) 249 (Mϩ, 24%).
385 (Mϩ, 100%), 341 (44,
ϩ Ϫ CO2 Ϫ PhCH3).
M
ϩ Ϫ CO2) and 249 (62,
M
(4S)-3-Benzyloxycarbonyl-4-[2Ј-(2Љ-nitrophenyl)ethyl]-
oxazolidin-5-one 19f
Treatment with 1-iodo-2-nitrobenzene (0.249 g, 1 mmol) yield-
ed the product as an oil (0.079 g, 0.21 mmol) (Found:
M
(4S)-3-Benzyloxycarbonyl-4-(2Ј-phenethyl)oxazolidin-5-one 19a
Treatment with iodobenzene (112 µl, 1 mmol) yielded the prod-
uct as a white solid (0.150 g, 0.46 mmol, 61%), mp 46–47 ЊC
(from cyclohexane) (Found: Mϩ, 325.1322. C19H19NO4 requires
325.1314); [α]D16 ϩ101.1 (c 0.19 in CH2Cl2); νmax(KBr disc)/cmϪ1
2924, 1802, 1717 and 1418; δH(200 MHz; CDCl3) 2.08–2.23
[2 H, m, C(1Ј)H2], 2.55–2.78 [2 H, m, C(2Ј)H2], 4.25–4.40 [1 H,
m, C(4)H], 5.10–5.20 [3 H, m, CH2Ph and C(2)H], 5.40–5.53
[1 H, m, C(2)H], 7.00–7.20 (5 H, m, Ar) and 7.36 (5 H, s, Ph);
m/z (EI) 325 (Mϩ, 1.9%), 281 (29, Mϩ Ϫ CO2) and 233 (61,
ϩ Ϫ CO2H, 325.1195. C18H17N2O4 requires 325.1188); [α]D22
ϩ79.8 (c 0.5 in CH2Cl2); νmax(film)/cmϪ1 2925, 1801, 1717, 1526,
1416 and 1355; δH(200 MHz; CDCl3) 2.15–2.48 [2 H, m,
C(1Ј)H2], 2.78–3.00 [1 H, m, C(2Ј)H2], 3.03–3.18 [1 H, m,
C(2Ј)H], 4.33–4.48 [1 H, m, C(4)H], 5.21 (2 H, s, CH2Ph), 5.08
[1 H, d, J 4, C(2)H], 5.55 [1 H, d, J 4, C(2)H], 7.36 [7 H, s, Ph,
C(4Љ)H and C(6Љ)H], 7.4–7.58 [1 H, m, C(5Љ)H] and 7.93 [1 H,
dd, J 8 and 1, C(3Љ)H]; m/z (EI) 325 (Mϩ Ϫ CO2H, 6.8%), 281
(18,
CO2 Ϫ PhCH3).
M M
ϩ Ϫ CO2H Ϫ CO2) and 189 (23, ϩ Ϫ CO2H Ϫ
M
ϩ Ϫ CO2 Ϫ PhCH3).
(4S)-3-Benzyloxycarbonyl-4-[2Ј-(4Љ-bromophenyl)ethyl]-
oxazolidin-5-one 19b
Treatment with 1-bromo-4-iodobenzene (0.283 g, 1 mmol)
(4S)-3-Benzyloxycarbonyl-4-[2Ј-(4Љ-nitrophenyl)ethyl]-
oxazolidin-5-one 19g
Treatment with 1-iodo-4-nitrobenzene (0.249 g, 1 mmol) yielded
1908
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
the product as a solid (0.154 g, 0.41 mmol, 54%), mp 82–84 ЊC
(from light petroleum and ethyl acetate) (Found: Mϩ Ϫ CO2H,
325.1176. C18H17N2O4 requires 325.1188); [α]D22 ϩ92.1 (c 1.0 in
CH2Cl2); νmax(KBr disc)/cmϪ1 2927, 1792, 1513, 1420 and 1350;
δH(200 MHz; CDCl3) 2.08–2.40 [2 H, m, C(1Ј)H2], 2.65–2.88
[2 H, m, C(2Ј)H2], 4.23–4.45 [1 H, m, C(4)H], 5.05–5.23 [3 H,
m, CH2Ph and C(2)H], 5.43–5.55 [1 H, m, C(2)H], 7.35 [7 H,
m, Ph, C(2Љ)H and C(6Љ)H] and 8.07 [2 H, m, C(3Љ)H and
C(5Љ)H]; m/z (EI) 325 (Mϩ Ϫ CO2H, 47%), 281 (31, Mϩ Ϫ
CO2H Ϫ CO2) and 189 (40, Mϩ Ϫ CO2H Ϫ CO2 Ϫ PhCH3).
(1 H, br d, J 8, NH) and 7.22–7.32 (5 H, m, Ph); m/z (EI)
237 [Mϩ Ϫ (CH ) C᎐CH , 18.5%] and 133 [93, Mϩ Ϫ (CH3)2-
᎐
3
2
2
C᎐CH Ϫ CO Ϫ CO Me).
᎐
2
2
2
General procedure for the preparation of 5-oxo á-amino acids 22
Method A. Zinc dust (325 mesh, 0.300 g, 4.5 mmol) was
added to a nitrogen purged flask to which distilled 1,2-
dimethoxyethane (0.34 cm3) and 1,2-dibromoethane (19 µl,
0.225 mmol) were then added. The flask was heated with a heat
gun until reflux of the solvent was observed and the zinc sus-
pension was stirred for a few minutes. This process was repeated
five times. The flask was allowed to cool to room temperature,
and trimethylsilyl chloride (6 µl, 0.046 mmol) was added. The
resultant mixture was stirred under nitrogen for 15 min. (4S)-3-
Benzyloxycarbonyl-4-(2Ј-iodoethyl)oxazolidin-5-one 15 (0.280
g, 0.75 mmol) in 1,2-dimethoxyethane (0.75 cm3) was added to
the flask and the resultant mixture stirred at 35 ЊC (typically 15
min) generating (4S-3-benzyloxycarbonyl-4-(2Ј-iodozincethyl)-
oxazolidin-5-one in situ, as judged by disappearance of the
iodide by TLC analysis using light petroleum–ethyl acetate (5:1)
as the eluent. The freshly distilled acid chloride (1 mmol) was
added, followed by bis(triphenylphosphine)palladium dichlor-
ide [(Pd(PPh3)2Cl2)] (0.028 g, 0.0375 mmol, 5 mol%) and the
reaction mixture was stirred for 1 h at 35 ЊC. After allowing the
reaction mixture to reach ambient temperature, ethyl acetate
(50 cm3) was added and the contents were filtered into a separ-
ating funnel. The organic phase was washed with dilute hydro-
chloric acid (20 cm3, 1 ), water (3 × 20 cm3), dried and concen-
trated under reduced pressure to give the crude product as an
oil. Flash chromatography over silica gel (light petroleum–ethyl
acetate–gradient, typically 50:1 to 50:16) yielded the pure
protected amino acid.
Method B. (4S)-3-Benzyloxycarbonyl-4-(2Ј-iodoethyl)oxazol-
idin-5-one15 (0.280 g, 0.75 mmol) and zinc–copper couple (0.090
g) were added to a nitrogen purged flask, to which dry toluene
(1.5 cm3) and anhydrous DMA (0.2 cm3) were then added. The
reaction mixture was irradiated in an ultrasonic cleaning bath
according to the procedure described previously,1 typically for
30 min, generating (4S)-3-benzyloxycarbonyl-4-(2Ј-iodozinc-
ethyl)oxazolidin-5-one, in situ, as judged by disappearance of
the iodide by TLC analysis using light petroleum–ethyl acetate
(5:1) as the eluent. Pd(PPh3)2Cl2 (0.028 g, 0.0375 mmol, 5
mol%) and the freshly distilled acid chloride were added and
the reaction mixture was sonicated for a further 1 h (25–35 ЊC).
Ethyl acetate (50 cm3) was added and the contents were filtered
into a separating funnel. The organic phase was washed with
dilute hydrochloric acid (20 cm3, 1 ), water (3 × 20 cm3), dried
and concentrated under reduced pressure to give the crude
product as an oil. Flash chromatography over silica gel (light
petroleum–ethyl acetate–gradient, typically 50:1 to 50:16)
yielded the pure protected amino acid.
(4S)-3-Benzyloxycarbonyl-4-[2Ј-(1Љ-naphthyl)ethyl]oxazolidin-
5-one 19h
Treatment with 1-iodonaphthalene (146 µl, 1 mmol) yielded the
product as an oil (0.149 g, 0.40 mmol, 53%) (Found: Mϩ,
375.1452. C23H21NO4 requires 375.1470); [α]D16 ϩ94.0 (c 0.705 in
CH2Cl2); νmax(film)/cmϪ1 3065, 2924, 1799, 1716 and 1415;
δH(200 MHz; CDCl3) 2.00–2.38 [2 H, m, C(1Ј)H2], 2.98–3.30
[2 H, m, C(2Ј)H2], 4.33–4.48 [1 H, m, C(4)H], 5.15 (2 H, s,
CH2Ph), 5.23 [1 H, d, J 4, C(2)H], 5.45–5.60 [1 H, m, C(2)H],
7.33 (5 H, s, Ph) 7.40–7.50 [3 H, m, C(2Љ)H, C(3Љ)H and C(4Љ)H]
and 7.70–8.00 [4 H, m, C(5Љ)H, C(6Љ)H, C(7Љ)H and C(8Љ)H];
m/z (EI) 375 (Mϩ, 8.8%), 331 (0.3, Mϩ Ϫ CO2) and 239 (7,
M
ϩ Ϫ CO2 Ϫ PhCH3).
Methyl (2S)-2-benzyloxycarbonylamino-4-phenylbutanoate 20
(4S)-3-Benzyloxycarbonyl-4-(2Ј-phenylethyl)oxazolidin-5-one
19a (0.060 g, 0.18 mmol) in methanol (1 cm3) was added to a
stirred solution of lithium methoxide (0.016 g, 0.41 mmol) in
methanol (2 cm3) at Ϫ10 ЊC under an atmosphere of nitrogen.
The reaction mixture was stirred at Ϫ10 ЊC of 1.5 h. After allow-
ing the reaction mixture to reach ambient temperature, ethyl
acetate (10 cm3) was added and the contents were filtered into a
separating funnel. The organic phase was washed with dilute
hydrochloric acid (10 cm3, 1 ) and water (3 × 10 cm3), dried
and concentrated under reduced pressure to give the crude
product as an oil. Flash chromatography over silica gel using
toluene–ethyl acetate (30:1) as the eluent yielded methyl (2S)-2-
benzyloxycarbonylamino-4-phenylbutanoate 20 as an oil (0.054
g, 0.16 mmol, 92%) (Found: MHϩ, 328.1542. C19H22NO4
requires 328.1549); [α]D22 ϩ14.4 (c 0.5 in CH2Cl2); νmax(film)/cmϪ1
3341, 2953, 1724, 1527 and 1498; δH(200 MHz; CDCl3) 1.83–
2.01 [1 H, m, C(3)H], 2.05–2.30 [1 H, m, C(3)H], 2.62 [2 H, t,
J 8, C(4)H2], 3.66 (3 H, s, OCH3), 4.38 [1 H, m, C(2)H], 5.07
(2 H, s, OCH2Ph), 5.33 (1 H, br d, J 8, NH), 7.00–7.27 (5 H, m,
Ph) and 7.31 (5 H, s, OCH2Ph); m/z (EI) 328 (MHϩ, 0.9%) and
284 (41, MHϩ Ϫ CO2).
Methyl (2S)-2-tert-butoxycarbonylamino-4-phenylbutanoate 21
A
solution of methyl (2S)-2-benzyloxycarbonylamino-4-
phenylbutanoate 20 (0.070 g, 0.215 mmol) in ethanol (1 cm3)
was added dropwise to a nitrogen purged flask, covered with
aluminium foil, containing a stirred solution of triethylsilane
(69 µl, 0.43 mmol), di-tert-butyl dicarbonate (59 µl, 0.26 mmol),
palladium acetate (0.005 g, 0.02 mmol) and triethylamine (10
µl, 0.07 mmol) in dry ethanol (1 cm3) at 60 ЊC. The reaction
mixture was stirred for 7 d at 60 ЊC. The reaction mixture was
then allowed to reach ambient temperature, filtered under
reduced pressure in the absence of light and concentrated under
reduced pressure to give the crude product as an oil. Flash
chromatography over silica gel using light petroleum–diethyl
ether (4:1) as the eluent yielded methyl (2S)-2-tert-butoxy-
carbonylamino-4-phenylbutanoate 21 as an oil (0.024 g, 0.08
(4S)-3-Benzyloxycarbonyl-4-(3Ј-oxo-3Ј-phenylpropyl)-
oxazolidin-5-one 22a
Treatment with benzoyl chloride (0.141 g, 116 µl, 1 mmol) using
Method B yielded the product as an oil (0.202 g, 0.57 mmol,
76%) (Found: MHϩ Ϫ PhCH3 Ϫ CO2, 218.0827. C12H12NO3
requires 218.0817); [α]D20 ϩ26.3 (c 0.695 in CH2Cl2); νmax(film)/
cmϪ1 2924, 1801, 1716, 1603, 1450 and 1417; δH(200 MHz;
CDCl3) 2.30–2.50 [2 H, m, C(1Ј)H2], 3.00–3.20 [2 H, m,
C(2Ј)H2], 4.45 [1 H, t, J 7, C(4)H], 5.10 (2 H, s, PhCH2), 5.20
[1 H, d, J 4, C(2)H], 5.60 [1 H, br s, C(2)H], 7.33 (5 H, s,
PhCH2O), 7.40–7.60 (3 H, m, m-PhCO and p-PhCO) and 7.90
(2 H, dd, J 7 and 1, o-PhCO); m/z (EI) 218 (MHϩ Ϫ
PhCH3 Ϫ CO2, 0.9%).
mmol, 38%) [Found: Mϩ Ϫ (CH ) C᎐CH , 237.1013 C H -
᎐
3
2
2
12 15
NO4 requires 237.1001]; [α]D22 Ϫ14.7 (c 1.2 in MeOH) [lit.,15 [α]D20
Ϫ15.0 (c 1.6 in MeOH)]; νmax(film)/cmϪ1 3362, 2977, 1744, 1716
and 1516; δH(200 MHz; CDCl3) 1.45 [9 H, s, OC(CH3)3], 1.87–
2.02 [1 H, m, C(3)H], 2.06–2.21 [1 H, m, C(3)H], 2.67 [2 H, t,
J 8, C(4)H2], 3.72 (3 H, s, OCH3), 4.36 [1 H, m, C(2)H], 5.08
(4R)-3-Benzyloxycarbonyl-4-(3Ј-oxo-3Ј-phenylpropyl)-
oxazolidin-5-one ent-22a
The above compound was prepared using Method B with
(4R)-3-benzyloxycarbonyl-4-(2Ј-iodoethyl)oxazolidin-5-one as
J. Chem. Soc., Perkin Trans. 1, 1998
1909

View Article Online
starting material. Treatment with benzoyl chloride (0.141 g, 116
µl, 1 mmol) yielded the product as an oil, [α]D20 Ϫ24.6 (c 0.88 in
CH2Cl2).
5.04–5.18 [3 H, m, C(2)H and PhCH2], 5.46 [1 H, br d, J 4,
C(2)H] and 7.29 (5 H, s, Ph); m/z (EI) 347 (Mϩ, 5.8%), 303 (37,
ϩ Ϫ CO2) and 211 (85, Mϩ Ϫ CO2 Ϫ PhCH3).
M
(4S)-3-Benzyloxycarbonyl-4-[3Ј-oxo-3Ј-(2Љ-furyl)propyl]-
oxazolidin-5-one 22b
(4S)-3-Benzyloxycarbonyl-4-(4Ј-acetoxy-3Ј-oxobutyl)-
oxazolidin-5-one 22g
Treatment with 2-furoyl chloride (0.131 g, 98 µl, 1 mmol) using
Method A yielded the product as an oil (0.203 g, 0.59 mmol,
78%) (Found: MHϩ, 344.1116. C18H18NO6 requires 344.1134);
[α]D16 ϩ74.6 (c 0.84 in CH2Cl2); νmax(film)/cmϪ1 2926, 1799, 1716,
1676, 1469, 1415; δH(200 MHz; CDCl3) 2.20–2.88 [2 H, m,
C(1Ј)H2], 2.96–2.98 [2 H, m, C(2Ј)H2], 4.42 [1 H, t, J 7, C(4)H],
5.15 (2 H, s, PhCH2), 5.22 [1 H, d, J 4, C(2)H], 5.51–5.60 [1 H,
m, C(2)H], 6.52 [1 H, dd, J 3.6 and 1.7, C(4Љ)H], 7.16 [1 H, br d,
J 3.6, C(3Љ)H], 7.35 (5 H, s, Ph) and 7.56 [1 H, dd, J 1.7 and 0.7,
C(5Љ)H]; m/z (EI) 344 (MHϩ, 4.4%), 300 (21, MHϩ Ϫ CO2), 252
(19, MHϩ Ϫ PhCH3) and 208 (63, MHϩ Ϫ CO2).
Treatment with acetoxyacetyl chloride (0.137 g, 107 µl, 1 mmol)
using Method B yielded the product as an oil (0.202 g, 0.58
mmol, 77%) (Found: Mϩ, 349.1168. C17H19NO7 requires
349.1161); [α]D16 ϩ78.0 (c 0.595 in CH2Cl2); νmax(film)/cmϪ1 3433,
1801, 1718, 1653 and 1419; δH(200 MHz; CDCl3) 2.15–2.19 [5
H, m, C(1Ј)H2 and CH3CO], 2.23–2.60 [2 H, m, C(2Ј)H2], 4.34
[1 H, t, J 7, C(4)H], 4.34–4.37 (2 H, m, AcOCH2CO), 5.18–5.22
[3 H, m, C(2)H and PhCH2], 5.50–5.58 [1 H, m, C(2)H] and
7.37 (5 H, s, Ph); m/z (EI) 349 (Mϩ, 2.0%), 305 (2.5, Mϩ Ϫ CO2)
and 213 (56, Mϩ Ϫ CO2 Ϫ PhCH3).
(4S)-3-Benzyloxycarbonyl-4-(3Ј-oxopent-4Ј-enyl)oxazolidin-5-
one 22h
(4S)-3-Benzyloxycarbonyl-4-[3Ј-oxo-3Ј-(3Љ-methylphenyl)-
propyl]oxazolidin-5-one 22c
Treatment with acryloyl chloride (0.091 g, 81 µl, 1 mmol) using
Method B yielded the product as an oil (0.118 g, 0.39 mmol,
52%) (Found: MHϩ Ϫ PhCH3, 212.0550. C9H10NO5 requires
212.0559); [α]D16 ϩ100.9 (c 1.06 in CH2Cl2); νmax(film)/cmϪ1 2901,
1802, 1722, 1653 and 1415; δH(200 MHz, CDCl3) 2.18–2.31 [2
H, m, C(1Ј)H2], 2.65–2.80 [2 H, m, C(2Ј)H2], 4.38 [1 H, t, J 6,
C(4)H], 5.20–5.22 [3 H, m, C(2)H and PhCH2], 5.48–5.58 [1 H,
m, C(2)H], 5.82 [1 H, dd, J 10 and 2, C(5Ј)H], 6.12–6.38 [2 H,
m, C(4Ј)H and C(5Ј)H] and 7.37 (5 H, s, Ph); m/z (EI) 212
(MHϩ Ϫ PhCH3, 6.9%) and 168 (83, Mϩ Ϫ CO2 Ϫ PhCH3).
Treatment with m-toluoyl chloride (0.155 g, 132 µl, 1 mmol)
using Method A yielded the product as an oil (0.151 g, 0.41
mmol, 55%) (Found: Mϩ, 367.1406. C21H21NO5 requires
367.1419); [α]D20 ϩ81.6 (c 0.3 in CH2Cl2); νmax(film)/cmϪ1 3034,
2922, 1799, 1718, 1604, 1587 and 1415; δH(200 MHz; CDCl3)
2.40 [5 H, m, C(1Ј)H2 and CH3], 3.01–3.18 [2 H, m, C(2Ј)H2],
4.45 [1 H, t, J 7, C(4)H], 5.22 [1 H, d, J 4, C(2)H], 5.29 (2 H, s,
PhCH2), 5.43–5.60 [1 H, m, C(2)H], 7.33–7.44 [7 H, m, C(4Љ)H,
C(5Љ)H and Ph] and 7.65–7.75 [2 H, m, C(2Љ)H and C(6Љ)H];
m/z (EI) 367 (Mϩ, 2.7%), 323 (2.0, Mϩ Ϫ CO2) and 231 (63,
M
ϩ Ϫ PhCH3 Ϫ CO2).
(4S)-3-Benzyloxycarbonyl-4-(4Ј-chloro-3Ј-oxobutyl)oxazolidin-
5-one 22i
(4S)-3-Benzyloxycarbonyl-4-(3Ј-oxobutyl)oxazolidin-5-one 22d
Treatment with acetyl chloride (0.0785 g, 71 µl, 1 mmol) using
Method B yielded the product as an oil (0.159 g, 0.55 mmol,
73%) (Found: MHϩ, 292.1199). C15H18NO5 requires 292.1185);
[α]D16 ϩ75.4 (c 0.19 in CH2Cl2); νmax(film)/cmϪ1 2924, 1802, 1717
and 1416; δH(200 MHz; CDCl3) 2.09 (3 H, br 2, CH3), 2.10–2.17
[2 H, m, C(1Ј)H2], 2.48–2.68 [2 H, m, C(2Ј)H2], 4.34 [1 H, t, J 7,
C(4)H], 5.19 [3 H, m, C(2)H and PhCH2], 5.43–5.52 [1 H, br d,
J 4, C(2)H] and 7.37 (5 H, s, Ph); m/z (EI) 292 (MHϩ, 1.9%),
248 (43, MHϩ Ϫ CO2) and 156 (81, MHϩ Ϫ CO2 Ϫ PhCH3).
There is a significant inconsistency in the reported mps for this
compound; lit.,11 mp 64–65 ЊC and lit.,12 mp 102–103 ЊC. Our
sample did not crystallise, but exhibited spectroscopic data
which were consistent with the data reported in the literature.12
Treatment with chloroacetyl chloride (0.113 g, 80 µl, 1 mmol)
using Method B yielded the product as an oil (0.120 g, 0.37
mmol, 49%) (Found: Mϩ, 325.0715. C15H16NO5Cl requires
325.0717); [α]D16 ϩ57.1 (c 0.14 in CH2Cl2); νmax(film)/cmϪ1 3034,
2934, 1798, 1716, 1454 and 1416; δH(200 MHz, CDCl3) 2.09–
2.21 [2 H, m, C(1Ј)H2], 2.44–2.57 [1 H, m, C(2Ј)H], 2.74–2.81
[1 H, m, C(2Ј)H], 4.03–4.27 (2 H, s, ClCH2CO), 4.35 [1 H, t,
J 7, C(4)H], 5.11–5.23 [3 H, m, C(2)H and PhCH2], 5.52–5.58
[1 H, m, C(2)H] and 7.37 (5 H, s, Ph); m/z (EI) 325 (Mϩ, 2.4%),
233 (3, Mϩ Ϫ PhCH3) and 189 (65, Mϩ Ϫ PhCH3 Ϫ CO2).
(4S)-3-Benzyloxycarbonyl-4-(3Ј-oxo-4Ј-phthalimidobutyl)-
oxazolidin-5-one 22j
Treatment with freshly prepared N-phthaloylglycine acid chlor-
ide (0.75 mmol) [prepared by adding oxalyl chloride (67 µl,
0.098 g, 0.717 mmol) to a stirred solution of N-phthaloylglycine
(0.154 g, 0.75 mmol) in dry toluene (2 cm3), followed by the
addition of dry N,N-dimethylformamide (25 µl) and stirring for
30 min] using Method B gave the crude product as an oil. Flash
chromatography over silica gel (light petroleum–ethyl acetate,
10:1 to 1:1) yielded the product as an oil (0.173 g, 0.41 mmol,
77%) (Found: MH Ϫ C9H6NO2, 277.0958. C14H15NO5 requires
277.0950; [α]D16 ϩ63.9 (c 1.04 in CH2Cl2); νmax(film)/cmϪ1 2926,
1800, 1717, 1686, 1449 and 1415; δH(200 MHz; CDCl3) 2.22–
2.29 [2 H, m, C(1Ј)H2], 2.60–2.80 [2 H, m, C(2Ј)H2], 4.53 [1 H, t,
J 7, C(4)H], 4.37–4.54 (2 H, m, NCH2CO), 5.16–5.21 [3 H, m,
C(2)H and PhCH2], 5.52 [1 H, br d, J 4, C(2)H], 7.36 (5 H, s,
Ph), 7.42 [2 H, dd, J 5.5 and 3.1, C(2Љ)H and C(3Љ)H phthaloyl]
and 7.82 [2 H, dd, J 5.5 and 3.1, C(1Љ)H and C(4Љ)H phthaloyl];
m/z (EI) 277 (MHϩ Ϫ C9H6NO2, 0.1%).
(4S)-3-Benzyloxycarbonyl-4-(3Ј-oxopentyl)oxazolidin-5-one 22e
Treatment with propanoyl chloride (0.0925 g, 87 µl, 1 mmol)
using Method A yielded the product as an oil (0.116 g, 0.38
mmol, 50%) (Found:
M
ϩ Ϫ CO2, 261.1357. C15H19NO3
requires 261.1365); [α]D16 ϩ34.8 (c 0.33 in CH2Cl2) {lit.,11 [α]D25
ϩ82.5 (c unspecified, MeOH)}; νmax(film)/cmϪ1 2922, 1801,
1716 and 1416; δH(200 MHz; CDCl3) 1.25 [3 H, t, J 8, C(5Ј)H3],
2.13–2.26 [2 H, m, C(4Ј)H2], 2.32–2.43 [2 H, m, C(1Ј)H2], 2.48–
2.63 [2 H, m, C(2Ј)H2], 4.33 [1 H, t, J 4, C(4)H], 5.17 (2 H, s,
PhCH2), 5.21 [1 H, br d, J 4, C(2)H], 5.50–5.59 [1 H, m, C(2)H]
and 7.36 (5 H, s, Ph); m/z (EI) 261 (Mϩ Ϫ CO2, 1.4%) and 169
(6, Mϩ Ϫ CO2 Ϫ PhCH3). This compound has reported mp
45–46 ЊC,11 but no spectroscopic data were included.
(4S)-3-Benzyloxycarbonyl-4-(3Ј-oxooctyl)oxazolidin-5-one 22f
Treatment with hexanoyl chloride (0.135 g, 171 µl, 1 mmol)
using Method A yielded the product as an oil (0.225 g, 0.65
mmol, 86%) (Found: Mϩ, 347.1744. C19H25NO5 requires
347.1733); [α]D16 ϩ70.0 (c 0.51 in CH2Cl2); νmax(film)/cmϪ1 2957,
2932, 1801, 1716 and 1415; δH(200 MHz; CDCl3) 0.81 [3 H, t, J
7, C(8Ј)H3], 1.17 [4 H, m, C(6Ј)H2 and C(7Ј)H2], 1.46 (2 H, m,
C(5Ј)H2], 2.09–2.16 [2 H, m, C(4Ј)H2], 2.24–2.31 [2 H, m,
C(1Ј)H2], 2.40–2.46 [2 H, m, C(2Ј)H2], 4.26 [1 H, t, J 6, C(4)H],
(4S)-3-Benzyloxycarbonyl-4-[(4ЈS)-3Ј-oxo-4Ј-phthalimido-
pentyl]oxazolidin-5-one 22k
Treatment with N-phthaloyl--alanine acid chloride45 (0.472 g,
2 mmol) according to Method B (double scale) gave the crude
product as an oil. Flash chromatography over silica gel (light
petroleum–ethyl acetate–gradient, 10:1 to 1:1) yielded the
product as an oil (0.494 g, 1.095 mmol, 73%) (Found: Mϩ,
1910
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
450.1417. C24H22N2O7 requires 450.1426); [α]D16 ϩ48.9 (c 1.115
in CH2Cl2); νmax(film)/cmϪ1 2922, 1799, 1778, 1714, 1414 and
1388; δH(200 MHz, CDCl3) 1.61 (3 H, d, J 6.5, CH3), 2.11–2.25
[2 H, m, C(1Ј)H2], 2.62–2.67 [2 H, m, C(2Ј)H2], 4.31 [1 H, t, J 4,
C(4)H], 4.70–4.98 [1 H, m, C(4Ј)H], 5.15–5.21 [3 H, m, PhCH2
and C(2)H], 5.43–5.58 [1 H, m, C(2)H], 7.36 (5 H, s, Ph), 7.63–
7.77 [2 H, m, C(2Љ)H and C(3Љ)H phthaloyl] and 7.78–7.87 [2 H,
m, C(1Љ)H and C(4Љ)H phthaloyl]; m/z (EI) 450 (Mϩ, 4.1%), 406
(12, Mϩ Ϫ CO2) and 314 (52, M Ϫ CO2 Ϫ PhCH3).
petroleum–ethyl acetate, 10:1 to 1:1) yielded the pure pro-
tected amino acid as an oil (0.186 g, 0.53 mmol, 71%) (Found:
Mϩ, 349.1150. C17H19NO7 requires 349.1162); [α]D16 ϩ64.8
(c 1.015 in CH2Cl2); νmax(film)/cmϪ1 3034, 2984, 2934, 1801,
1724, 1446 and 1415; δH(200 MHz, CDCl3) 1.36 (3 H, t, J 7.1,
OCH2CH3), 2.00–2.39 [2 H, m, C(1Ј)H2], 3.03–3.12 [2 H, m,
C(2Ј)H2], 4.25–4.35 [3 H, m, C(4)H and OCH2CH3], 5.00 [3 H,
m, C(2)H and PhCH2], 5.51–5.59 [1 H, m, C(2)H] and 7.36 (5
H, s, Ph); m/z (EI) 349 (Mϩ, 1.2%), 305 (31, Mϩ Ϫ CO2) and
213 (22, Mϩ Ϫ CO2 Ϫ PhCH3).
Methyl (2S)-2-[benzyloxycarbonylamino-5-oxo-5-phenyl-
pentanoate 23a
(4S)-3-Benzyloxycarbonyl-4-(pent-4-enyl)oxazolidin-5-one 24a
Treatment with allyl chloride (0.765 g, 81 µl, 1 mmol) yielded
the product as an oil (0.145 g, 0.50 mmol, 66%) (Found: Mϩ,
289.1302. C16H19NO4 requires 289.1314); [α]D24 ϩ101.5 (c 1.075
in CH2Cl2); νmax(film)/cmϪ1 3402, 3067, 3036, 2926, 1803, 1718
and 1417; δH(200 MHz, CDCl3) 1.30–1.63 [2 H, m, C(1Ј)H2],
1.75–2.18 [4 H, m, C(2Ј)H2 and C(3Ј)H2], 4.28–4.40 [1 H, m,
C(4)H], 4.90–5.05 [2 H, m, C(5Ј)H2], 5.11–5.29 [3 H, m, PhCH2
and C(2)H], 5.45–5.60 [1 H, m, C(2)H], 5.63–5.90 [1 H, m,
C(4Ј)H], and 7.37 (5 H, s, Ph); m/z (EI) 289 (Mϩ, 1.6%), 245
(6, Mϩ Ϫ CO2) and 153 (61, Mϩ Ϫ CO2 Ϫ PhCH3).
(4S)-3-Benzyloxycarbonyl-4-(3Ј-oxo-3Ј-phenylpropyl)oxazol-
idin-5-one 22a (0.120 g, 0.34 mmol) was added to a stirred
solution of LiOMe from lithium (0.030 g, 0.77 mmol) in
methanol (4 cm3) at Ϫ10 ЊC under an atmosphere of nitrogen.
The reaction mixture was stirred at Ϫ10 ЊC for 1 h. After
allowing the reaction mixture to reach ambient temperature,
ethyl acetate (10 cm3) was added and the contents were filtered
into a separating funnel. The organic phase was washed with
dilute hydrochloric acid (10 cm3, 1 ) and water (3 × 10 cm3),
dried and concentrated under reduced pressure to give the
crude product as an oil. Flash chromatography over silica gel
using toluene–ethyl acetate (10:1) as the eluent yielded methyl
(2S)-2-benzyloxycarbonylamino-5-oxo-5-phenylpentanoate as
a solid (0.095 g, 0.27 mmol, 79%), mp 74–75 ЊC (Found: C,
67.7; H, 6.13; N, 3.9. C20H21NO5 requires C, 67.6; H, 6.13;
N, 3.9%); [α]D17 ϩ4.5 (c 0.635 in CH2Cl2); νmax(film)/cmϪ1 3340,
3037, 2916, 1743, 1689, 1524 and 1446; δH(200 MHz, CDCl3)
2.01–2.20 [1 H, m, C(3)H], 2.26–2.43 [1 H, m, C(3)H], 2.94–3.22
[2 H, m, C(4)H2], 3.74 (3 H, s, OCH3], 4.45 [1 H, m, C(2)H],
5.08 (2 H, s, PhCH2), 5.57 (1 H, d, J 8, NH), 7.33 (5 H, s, Ph),
7.40–7.48 [2 H, m, C(3Ј)H and C(5Ј)H], 7.52–7.61 [1 H, m,
C(4Ј)H] and 7.92 [2 H, d, J 7, C(2Ј)H and C(5Ј)H]; m/z (EI) 296
(Mϩ Ϫ CO2Me, 17.1%), 252 (51, Mϩ Ϫ CO2Me Ϫ CO2) and
160 (10, Mϩ Ϫ CO2Me Ϫ CO2 Ϫ PhCH3).
(4S)-3-Benzyloxycarbonyl-4-[(3ЈRS)-3-(chloromethyl)pent-4Ј-
enyl]oxazolidin-5-one 24b
Treatment with 1,4-dichlorobut-2-ene (0.125 g, 106 µl, 1 mmol)
yielded the products (an inseparable mixture of diastereo-
isomers) as an oil (0.131 g, 0.39 mmol, 52%) (Found: Mϩ,
337.1095. C17H20NO4Cl requires 337.1081); νmax(film)/cmϪ1
3419, 3067, 3034, 2954, 2925, 1801, 1717 and 1417; δH(200
MHz, CDCl3) 1.18–2.10 [4 H, m, C(1Ј)H2 and C(2Ј)H2], 2.25–
2.48 [1 H, m, C(3Ј)H], 3.43 (2 H, d, J 6, CH2Cl), 4.28–4.38 [1 H,
m, C(4)H], 5.03–5.25 [5 H, m, C(5Ј)H2, PhCH2 and C(2)H],
5.43–5.70 [2 H, m, C(2)H and C(4Ј)H] and 7.37 (5 H, s, Ph);
m/z (EI) 337 (Mϩ, 1.3%), 293 (3, Mϩ Ϫ CO2) and 201 (58,
M
ϩ Ϫ CO2 Ϫ PhCH3).
Methyl (2R)-2-benzyloxycarbonylamino-5-oxo-5-phenyl-
pentanoate ent-23a
The compound was prepared from ent-22a using the above pro-
cedure, and the product was isolated as a solid, mp 74–75 ЊC;
[α]D18 Ϫ4.3 (c 0.9 in CH2Cl2). The enantiomeric purities of com-
pounds 23a and ent-23a were determined to be 96% ee by chiral
phase HPLC using a Daicel Chiralpak AS column.
(4S)-3-Benzyloxycarbonyl-4-(penta-3Ј,4Ј-dienyl)oxazolidin-5-
one 25
Treatment with prop-2-ynyl chloride (0.0745 g, 72 µl, 1 mmol)
yielded the product as an oil (0.136 g, 0.47 mmol, 63%) (Found:
M
ϩ Ϫ CO2H, 242.1187. C15H16NO2 requires 242.1181); [α]D24
ϩ67.6 (c 1.05 in CH2Cl2); νmax(film)/cmϪ1 3034, 2957, 2926,
1801, 1716 and 1525; δH(200 MHz, CDCl3) 1.95–2.25 [4 H, m,
C(1Ј)H2 and C(2Ј)H2], 4.30–4.38 [1 H, m, C(4)H], 4.66–4.73
[2 H, m, C(5Ј)H2], 5.00–5.13 [1 H, m, C(3Ј)H], 5.18–5.26 [3 H,
m, PhCH2 and C(2)H], 5.45–5.63 [1 H, m, C(2)H] and 7.37
(5 H, s, Ph); m/z (EI) 242 (Mϩ Ϫ CO2H, 7.7%), 198 (20, Mϩ Ϫ
CO2H Ϫ CO2) and 106 (60, Mϩ Ϫ CO2H Ϫ CO2 Ϫ PhCH3).
Reactions of the zinc–copper reagent 16
A solution of (4S)-3-benzyloxycarbonyl-4-(2Ј-iodozincethyl)-
oxazolidin-5-one 14 in dry THF (1.09 cm3) (prepared as
described previously) was cooled to Ϫ10 ЊC and a solution of
CuCNؒ2 LICl [prepared from reaction of anhydrous copper()
cyanide (0.67 g, 0.75 mmol) and anhydrous lithium chloride
(0.64 g, 1.5 mmol) in dry THF (2 cm3)] was added dropwise.
The reaction mixture was warmed to 0 ЊC and stirred for 10 min
prior to re-cooling to Ϫ25 ЊC, and the electrophile added. The
reaction mixture was then warmed to 0 ЊC and stirred for 3 h.
After allowing the reaction mixture to reach ambient tempera-
ture, ethyl acetate (50 cm3) was added and the contents were
filtered into a separating funnel. The organic phase was washed
with saturated aqueous sodium hydrogen carbonate (2 × 20
cm3), water (3 × 20 cm3), dried and concentrated under reduced
pressure to give a crude product as an oil. Flash chroma-
tography over silica gel using a light petroleum–ethyl acetate-
gradient, typically 50:1 to 50:4 as the eluent (except where
stated otherwise) yielded the pure protected amino acid.
1,7-Bis[(4ЈS)-3Ј-benzyloxycarbonyl-5Ј-oxooxazolidin-4Ј-yl]hept-
3-ene 26
Treatment with 1,3-dichloropropene (0.055 g, 46 µl, 0.5 mmol)
yielded the product as an oil (0.072 g, 0.14 mmol, 18%) (Found:
MHϩ Ϫ CO2 Ϫ PhCH3, 401.1730. C21H25N2O6 requires
401.1713); [α]D24 ϩ99.9 (c 0.99 in CH2Cl2); νmax(film)/cmϪ1 3403,
3065, 3033, 2925, 1801, 1717 and 1417; δH(200 MHz, CDCl3)
1.23–1.50 [4 H, m, C(1)H2 and C(7)H2], 1.65–2.50 [6 H, m,
C(2)H2, C(5)H2 and C(6)H2], 4.25–4.35 [2 H, m, 2 × C(4Ј)H],
5.11–5.26 [6 H, m, 2 × PhCH2 and 2 × C(2Ј)H], 5.30–5.40 [2 H,
m, C(3)H and C(4)H], 5.48–5.60 [2 H, m, 2 × C(2Ј)H] and 7.37
(10 H, s, Ph); m/z (EI) 401 (MHϩ Ϫ CO2 Ϫ PhCH3, 18.5%) and
357 (37, MHϩ Ϫ CO2 Ϫ PhCH3 Ϫ CO2).
Ethyl 2-oxo-4-[(4ЈS)-3Ј-benzyloxycarbonyl-5Ј-oxooxazolidin-
4-yl]butanoate 22l
Ethyl oxalyl chloride (0.137 g, 112 µl, 1 mmol) was used as the
electrophile, and the reaction was conducted according to the
general procedure. Flash chromatography over silica gel (light
Acknowledgements
We thank the EPSRC for CASE awards (N. W. and J. L. F.), and
Pfizer Central Research and Rhône-Poulenc Rorer for support
through the CASE scheme.
J. Chem. Soc., Perkin Trans. 1, 1998
1911

View Article Online
26 J. E. Baldwin, T. Miranda, M. G. Moloney and T. Hokelek,
References
Tetrahedron 1989, 45, 7459.
27 M. R. Attwood, M. G. Carr and S. Jordan, Tetrahedron Lett., 1990,
31, 283.
28 H. P. Knoess, M. T. Furlong, M. J. Rozema and P. Knochel, J. Org.
Chem., 1991, 56, 5974.
1 R. F. W. Jackson, N. Wishart, A. Wood, K. James and M. J. Wythes,
J. Org. Chem., 1992, 57, 3397.
2 M. J. Dunn, R. F. W. Jackson, J. Pietruszka and D. Turner, J. Org.
Chem., 1995, 60, 2210.
3 R. F. W. Jackson, N. Wishart and M. J. Wythes, Synlett, 1993, 219.
4 J. L. Fraser, R. F. W. Jackson and B. Porter, Synlett, 1994, 379.
5 J. L. Fraser, R. F. W. Jackson and B. Porter, Synlett, 1995, 819.
6 T. Ohta, A. Hosoi, T. Kimura and S. Nozoe, Chem. Lett., 1987,
2091.
7 T. Ohta, T. Kimura, N. Sato and S. Nozoe, Tetrahedron Lett., 1988,
29, 4303.
8 T. Ohta, N. Sato, T. Kimura, S. Nozoe and K. Izawa, Tetrahedron
Lett., 1988, 29, 4305.
9 J. Ackermann, M. Matthes and C. Tamm, Helv. Chim. Acta, 1990,
73, 122.
10 J. Ezquerra, J. de Mendoza, C. Pedregal and C. Ramirez,
Tetrahedron Lett., 1992, 33, 5589.
11 T. L. Ho, B. Gopalan and J. J. Nestor, J. Org. Chem., 1986, 51, 2405.
12 J. M. Scholtz and P. A. Bartlett, Synthesis, 1989, 542.
13 N. Aubry, R. Plante and R. Déziel, Tetrahedron Lett., 1990, 31,
6311.
14 H. H. Ibrahim and W. D. Lubell, J. Org. Chem., 1993, 58, 6438.
15 J. A. Bajgrowicz, A. El Hallaoui, R. Jacquier, C. Pigiere and
P. Viallefont, Tetrahedron, 1985, 41, 1833.
16 A. El Marini, M.-L. Roumestant, L. Pappalardo and P. Viallefont,
Bull. Soc. Chim. Fr., 1989, 4, 554.
29 D. H. R. Barton, Y. Hervé, P. Potier and J. Thierry, Tetrahedron,
1988, 44, 5479.
30 D. H. R. Barton, Y. Hervé, P. Potier and J. Thierry, Tetrahedron,
1987, 43, 4297.
31 W. G. Dauben, B. A. Kowalczyk and D. P. Bridon, Tetrahedron
Lett., 1989, 30, 2461.
32 D. A. Evans and T. Bach, Angew. Chem., Int. Ed. Engl., 1993, 32,
1326.
33 D. E. Stack, B. T. Dawson and R. D. Rieke, J. Am. Chem. Soc., 1992,
114, 5110.
34 D. E. Stack, B. T. Dawson and R. D. Rieke, J. Am. Chem. Soc., 1991,
113, 4672.
35 J. E. Baldwin, R. M. Adlington, A. Basak and H.-H. Ting, J. Chem.
Soc., Chem. Commun., 1986, 1280.
36 N. J. S. Huby, R. G. Kinsman, D. Lathbury, P. G. Vernon and
T. Gallagher, J. Chem. Soc., Perkin Trans. 1, 1991, 145.
37 Y. Tamaru, H. Tanigawa, T. Yamamoto and Z.-i. Yoshida, Angew.
Chem., Int. Ed. Engl., 1989, 28, 351.
38 P. Knochel and R. D. Singer, Chem. Rev., 1993, 93, 2117.
39 P. Knochel, M. C. P. Yeh, S. C. Berk and J. Talbert, J. Org. Chem.,
1988, 53, 2390.
40 E.-i. Negishi, A. O. King and N. Okukado, J. Org. Chem., 1977, 42,
1821.
17 R. Fitzi and D. Seebach, Tetrahedron, 1988, 44, 5277.
18 R. M. Williams, P. J. Sinclair, D. Zhai and D. Chen, J. Am. Chem.
Soc., 1988, 110, 1547.
41 M. Sakaitani, K. Hori and Y. Ohfune, Tetrahedron Lett., 1988, 29,
2983.
19 E. J. Corey and J. O. Link, J. Am. Chem. Soc., 1992, 114, 1906.
20 D. G. Melillo, R. D. Larsen, D. J. Mathre, W. F. Shukis, A. W. Wood
and J. R. Colleluori, J. Org. Chem., 1987, 52, 5143.
21 J. E. Baldwin, R. M. Adlington, A. Basak, S. L. Flitsch, A. K.
Forrest and H.-H. Ting, J. Chem. Soc., Chem. Commun., 1986, 273.
22 H. K. Chenault, J. Dahmer and G. M. Whitesides, J. Am. Chem.
Soc., 1989, 111, 6354.
42 S. Bhar and B. C. Ranu, J. Org. Chem., 1995, 60, 745.
43 M. Itoh, Chem. Pharm. Bull., 1969, 17, 1679.
44 D. H. R. Barton, Y. Hervé, P. Potier and J. Thierry, J. Chem. Soc.,
Chem. Commun., 1984, 1298.
45 K. Balenovic, D. Cerar and Z. Fuks, J. Chem. Soc., 1952, 3316.
23 J. E. Baldwin, M. North, A. Flinn and M. G. Moloney, Tetrahedron,
1989, 45, 1453.
24 J. E. Baldwin, M. North, A. Flinn and M. G. Moloney, Tetrahedron,
1989, 45, 1465.
25 M. Delbosco, A. N. C. Johnstone, G. Bazza, S. Lopatriello and
M. North, Tetrahedron, 1995, 51, 8545.
Paper 8/02142B
Received 18th March 1998
Accepted 20th April 1998
1912
J. Chem. Soc., Perkin Trans. 1, 1998