Synthesis of functionalised oxazoles and bis-oxazoles

Article abstract of DOI:10.1039/a704093h

A new method for the synthesis of oxazoles, and in particular chiral non-racemic oxazoles derived from amino acids, has been developed. Thus, rhodium(II) catalysed reaction of diazocarbonyl compounds 6 and 11 in the presence of amides 8 and 10 results in regioselective insertion of the carbenoid into the amide N-H bond with formation of the β-carbonyl amides 9 and 12. Cyclodehydration of amides 9 and 12 using triphenylphosphine-iodine-triethylamine gives functionalised oxazoles 7 and 13. The oxazoles 13c and 13f were converted into the bis-oxazoles 17a and 17b by a second rhodium(II) catalysed regioselective N-H insertion reaction on the amides 15, followed by cyclodehydration.

Full text of DOI:10.1039/a704093h

View Article Online / Journal Homepage / Table of Contents for this issue
Synthesis of functionalised oxazoles and bis-oxazoles1
Mark C. Bagley, Richard T. Buck, S. Lucy Hind and Christopher J. Moody*,†
Department of Chemistry, University of Exeter, Stocker Road, Exeter, Devon, UK EX4 4QD
A new method for the synthesis of oxazoles, and in particular chiral non-racemic oxazoles derived from
amino acids, has been developed. Thus, rhodium(II) catalysed reaction of diazocarbonyl compounds 6
and 11 in the presence of amides 8 and 10 results in regioselective insertion of the carbenoid into the amide
N᎐H bond with formation of the â-carbonyl amides 9 and 12. Cyclodehydration of amides 9 and 12 using
triphenylphosphine–iodine–triethylamine gives functionalised oxazoles 7 and 13. The oxazoles 13c and 13f
were converted into the bis-oxazoles 17a and 17b by a second rhodium(II) catalysed regioselective N᎐H
insertion reaction on the amides 15, followed by cyclodehydration.
with nitriles,35,36 as exemplified by our recent syntheses of the
5-(indol-3-yl)oxazole alkaloids 1 (Scheme 1).37 Although this
Introduction
The isolation of many structurally diverse oxazole containing
natural products has resulted in a renewed interest in the chem-
istry of oxazoles.2–9 Naturally occurring oxazoles range in
structure from relatively simple 2,5-disubstituted derivatives
such as the 5-(indol-3-yl)oxazole alkaloids pimprinine 1a and
pimprinethine 1b,10 to the more complex 2,4-disubstituted
compounds such as phenoxan 2,11–14 calyculin A15–17 and rhiz-
oxin.18,19 The oxazole (and thiazole) ring systems also occur in
biologically active cyclic peptides;4 examples include nosto-
cyclamide 320 and bistratamide C.21 Bis-oxazoles such as
H
N2
O
N
O
R
RC≡N
NaOMe
MeOH
1
Rh2(OAc)4
N
Boc
N
Boc
Scheme 1
method works well for simple nitriles, it is less satisfactory for
complex nitriles containing additional functional groups.
Therefore we have developed an alternative strategy based on
the N᎐H insertion reactions of rhodium carbenoids.38,39 This
has proved an effective strategy, particularly for the synthesis
of chiral, non-racemic oxazoles derived from α-amino acids,
and the results are described in detail herein.1 The following
paper reports an application of this methodology in the total
synthesis of (ϩ)-nostocyclamide 3.
O
N
O
R
Et
Me
Me
N
O
O
OMe
N
H
Ph
2
1a R = Me
1b R = Et
Me
N
Me
O
Results and discussion
S
N
H
S
It was in a projected synthesis of phenoxan 2 that the reaction
of diazocarbonyl compounds with nitriles proved somewhat
unsatisfactory. Thus reaction of the cyano acetal 5 with diazo-
malonates 6, prepared by diazo transfer to the corresponding
malonates,40 gave poor yields of the oxazoles 7a (33%) and 7b
(7%) (Scheme 2).
N
O
NH
HN
N
Me
O
O
Me
3
N2
O
CO2R
OR
OR
OR
O
EtO
EtO
N
O
N
EtO
EtO
N
N
O
O
Me
6
NH
Me
Me
Me
O
CN
Rh2(OAc)4
CHCl3, heat
O
Me
O
Me
Me
7
5
Me
Scheme 2 (a, R = Me; b, R = But)
4
The rhodium() catalysed addition of diazocarbonyl com-
pounds to N-protected α-aminonitriles, derived by dehydration
of α-amino acid amides (Path A, Scheme 3), also proved
unsatisfactory. Therefore we investigated the possibility of
reversing the order of steps by carrying out a rhodium carb-
enoid N᎐H insertion reaction on the amide followed by cyclo-
dehydration to give the oxazole (Path B, Scheme 3).
muscoride A 4,22–24 hennoxazole A25,26 and tris-oxazoles such as
the ulapualides and kabiramides are also known.27–31
From the many synthetic methods available for the construc-
tion of the heteroaromatic oxazole ring,32–34 we have focused on
the rhodium() catalysed reaction of diazocarbonyl compounds
Insertion reactions of metallocarbenoids are widely used in
synthesis,41–52 although, with the exception of the intra-
molecular insertion into the N᎐H bond of a β-lactam
† A substantial part of this work was carried out by the authors in the
Department of Chemistry, Loughborough University, Loughborough,
Leics., UK LE11 3TU.
J. Chem. Soc., Perkin Trans. 1, 1998
591

View Article Online
Table 1
N2
Z
O
R2
H
N
R1
Z
R1
NH2
6, 11
O
Rh2(OAc)4
CHCl3 or toluene
O
O
R2
10
12
Amide
R1
Diazo compound
R2
Z
Keto amide
Yield (%)
10a
10b
10c
10d
10d
10e
10e
10e
10e
10e
10f
CbzNHCH2
11a
11a
6a
Me
Me
OMe
OMe
Me
OMe
Me
CH2Cl
Et
Ph
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
12a
12b
12c
12d
12e
12f
12g
12h
12i
71
71
38
47
30
61
68
67
48
72
74
(S)-CbzNHCHMe
(S)-PhthNCHPri
(S)-BocNHCHPri
(S)-BocNHCHPri
(S)-CbzNHCHPri
(S)-CbzNHCHPri
(S)-CbzNHCHPri
(S)-CbzNHCHPri
(S)-CbzNHCHPri
6a
11a
6a
11a
11b
11c
11d
11a
12j
(S)-N-Cbz-pyrrolidin-2-yl
Me
CO2Me
12k
Table 2
H
R1
N
Z
Z
N
Ph3P, I2
R1
O
Et3N, CH2Cl2
R2
R2
O
O
12
13
Keto amide
R1
CbzNHCH2
(S)-CbzNHCHMe
(S)-CbzNHCHPri
(S)-CbzNHCHPri
(S)-CbzNHCHPri
R2
Z
Oxazole
Yield (%)
12a
12b
12g
12i
12j
12k
Me
Me
Me
Et
Ph
Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
13a
13b
13c
13d
13e
13f
56
66
65
88
31
73
(S)-N-Cbz-pyrrolidin-2-yl
R1
NH2
N2
CO2R
Path A
– H2O
OEt
R1
C
N
H
N
O
CO2R
OR
OEt
O
OR
EtO
6
O
EtO
CONH2
O
Rh2(OAc)4
toluene, heat
N2
Z
8
9
'cycloaddition'
Path A
Path B
N–H insertion
O
R2
Ph3P, Et3N
I2, CH2Cl2
cat. Rh2+
7a, 7b
H
N
R1
Z
Z
Scheme 4 (a, R = Me; b, R = But)
N
Path B
– H2O
R1
O
R2
R2
O
O
The reaction was then extended to the N-protected amino
acid amides 10 derived from glycine, (S)-alanine, (S)-valine and
(S)-proline, and to other diazocarbonyl compounds 11. The
amides 10 were prepared from the corresponding N-protected
amino acids by mixed anhydride formation with ethyl chloro-
formate followed by reaction with aqueous ammonia. The
α-diazo β-keto esters 11 were prepared by diazo transfer
reaction on the corresponding β-keto esters. The rhodium()
acetate catalysed N᎐H insertion reactions proceeded readily in
boiling chloroform and gave the desired products 12 in reason-
able yield (Table 1). In the case of amides 10a, 10b, 10d and 10e
no competing insertion into the carbamate N᎐H bond was
observed.55
Scheme 3
developed by Merck as a route to carbapenems and related
compounds,53 the N᎐H insertion reaction has found little use to
date.38,39 The initial substrate we investigated was the amide 8
which underwent reaction with the rhodium carbenoids derived
from diazomalonates 6a and 6b to give the corresponding N᎐H
insertion products 9a and 9b in 81 and 60% yield respectively
(Scheme 4). Various methods, e.g. POCl3, SOCl2, PCl5, P2O5,
were tried to effect the cyclodehydration of the β-carbonyl
amides 9 to the oxazoles 7, but the triphenylphosphine–iodine–
triethylamine protocol reported by Wipf proved the most satis-
factory.54 Using this method, the oxazoles 7a and 7b were
obtained in 84 and 79% yield respectively from the amides 9a
and 9b (Scheme 4).
Cyclodehydration of the β-carbonylamides 12 gave the
oxazoles 13 in modest to good yield (Table 2); the enantiomeric
purity of the oxazoles 13b, 13c and 13f was checked by HPLC
592
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
[Chiracel OD, hexane:propan-2-ol (19:1), 2 ml minϪ1] and
found to be >99%. The structure of oxazole 13c was also
confirmed by X-ray crystallography as reported previously.1
Amide 12h failed to give any oxazole under the cyclodehydra-
tion conditions, presumably because of competing attack of the
triphenylphosphine on the CH2Cl group.
Finally the method was extended to the synthesis of bis-
oxazoles. The oxazole-4-carboxylates 13c and 13f, derived from
N-Cbz (S)-valine and (S)-proline respectively were converted
into the corresponding acids 14 and hence amides 15 (Scheme
5). The amides 15 underwent regioselective N᎐H insertion in
modest yield on treatment with methyl diazoacetoacetate and
rhodium() acetate to give the insertion products 16, cyclo-
dehydration of which gave the bis-oxazoles 17 in good yield
(Scheme 5).
and ether refers to diethyl ether. Reactions were routinely
carried out under a nitrogen atmosphere. Analytical thin layer
chromatography was carried out using aluminium-backed
plates coated with Merck Kieselgel 60 GF254. Plates were visual-
ised under UV light (at 254 and/or 360 nm). Flash chrom-
atography was carried out using Merck Kieselgel 60 H silica or
Matrex silica 60.
Fully characterised compounds were chromatographically
homogeneous. IR spectra were recorded in the range 4000–600
cmϪ1 using Nicolet FT-205 or Perkin-Elmer Paragon 1000
1
FT-IR spectrometers. H and 13C NMR spectra were recorded
using Bruker AC-250 and Bruker DPX-400 instruments;
J values were recorded in Hz. High and low resolution mass
spectra were recorded on a Kratos MS80 instrument. Rotations
were recorded on an Optical Activity PolAAR 2001 polar-
imeter; [α]D values are given in units of 10Ϫ1 deg cm2 gϪ1
.
CO2Me
Me
COZ
Me
N
O
N
O
NaOH, aq. THF
(79, 87%)
Preparation of diazo compounds
General method for diazo transfer
R
R
To a solution of the substrate (37.8 mmol) and 4-acetamido-
benzenesulfonyl azide56 (10.0 g, 41.6 mmol) in acetonitrile (100
ml) at 0 ЊC was added triethylamine (15.8 ml, 113.4 mmol)
dropwise. After stirring at room temperature for 16 h the reac-
tion mixture was concentrated in vacuo and the resultant solid
was triturated with ether–light petroleum. The filtrate was con-
centrated in vacuo and purified by flash chromatography on
silica gel eluting with ether–light petroleum (1:4) to yield the
desired product.
13c, 13f
EtO2CCl
Et3N;
aq. NH3
(96, 98%)
14 Z = OH
15 Z = NH2
11a
Rh2(OAc)4
(50, 38%)
CO2Me
Me
CO2Me
Me
Dimethyl diazomalonate 6a. Prepared in 96% yield according
to the literature procedure.56
N
HN
Ph3P, Et3N
Di-tert-butyl diazomalonate 6b. Prepared in 95% yield accord-
ing to the literature procedure.57
N
O
O
O
N
O
R
I2, CH2Cl2
(94, 81%)
R
Methyl 2-diazo-3-oxobutanoate 11a. According to the general
procedure the title compound was obtained as a yellow oil
(91%) (lit.,58 no data given) (Found: Mϩ, 142.0377. C5H6N2O3
requires M, 142.0378); νmax(neat)/cmϪ1 2143, 1721, 1659 and
1367; δH(250 MHz; CDCl3) 3.85 (3 H, s, OMe) and 2.48 (3 H, s,
Me); δC(62.9 MHz; CDCl3) 189.9, 161.7, 52.1 and 28.0; diazo
carbon not observed; m/z (EI) 142 (Mϩ, 20%), 83 (15) and 43
(100).
Methyl 4-chloro-2-diazo-3-oxobutanoate 11b. According to
the general procedure the title compound was obtained as a
yellow oil (56%) (Found: Mϩ, 175.9987. C5H5ClN2O3 requires
M, 175.9989); νmax(neat)/cmϪ1 2140, 1719, 1658 and 1439;
δH(250 MHz, CDCl3) 4.62 (2 H, s, CH2) and 3.87 (3 H, s, OMe);
δC(100.6 MHz; CDCl3) 184.0, 161.3, 75.8, 52.9 and 46.7; m/z
(EI) 176 (Mϩ, 4%), 178 (Mϩ, 2), 127 (55), 119 (5), 117 (15), 113
(85) and 85 (42).
Methyl 2-diazo-3-oxopentanoate 11c. According to the gen-
eral procedure the title compound was obtained as a yellow oil
(90%) (lit.,59 no data given) (Found: Mϩ, 156.0536. C6H8N2O3
requires M, 156.0535); νmax(neat)/cmϪ1 2982, 2145, 1725, 1660,
1438, 1365, 1309, 1220, 1139, 1081 and 1025; δH(250 MHz;
CDCl3) 3.84 (3 H, s, OMe), 2.86 (2 H, q, J 7.3, CH2) and 1.14 (3
H, t, J 7.3, Me); δC(62.9 MHz; CDCl3) 193.2, 161.7, 52.0, 33.6
and 8.1; diazo carbon not observed; m/z (EI) 156 (Mϩ, 15%),
128 (13), 113 (25), 69 (45) and 57 (100).
Me
O
Me
16
17
Scheme 5 (13c, 14–17a; R = (S)-CbzNHCHPri; 13f, 14–17b; R = (S)-
N-Cbz-pyrrolidin-2-yl)
The proline derived bis-oxazole 17b comprises the hetero-
cyclic core of the naturally occurring bis-oxazole muscoride A
4,22 and therefore 17b was a key intermediate in our projected
synthesis of the natural product (Scheme 6). However, our
work was curtailed when Wipf,23 and subsequently Pattenden24
reported total syntheses of muscoride A.
O
N
N
N
OMe
Cbz
O
O
Me
Me
17b
O
Ethyl 2-diazo-3-oxo-3-phenylpropanoate 11d. Prepared in
N
O
N
N
O
Me
NH
98% yield according to the literature procedure.57
Me
Me
Me
O
Me
O
Me
Oxazole formation from nitriles
Me
Me
4
Methyl 2-(3,3-diethoxypropyl)-5-methoxyoxazole-4-carboxylate
7a
Scheme 6
To a stirred boiling solution of 3-cyanopropionaldehyde diethyl
acetal 5 (1.00 g, 6.36 mmol) and rhodium() acetate (2 mol%)
in ethanol-free chloroform (15 ml) was added a solution of
dimethyl diazomalonate (1.51 g, 9.54 mmol) in ethanol-free
chloroform (10 ml) dropwise over a period of 24 h. After heat-
ing for a further 24 h the solvent was removed under reduced
Experimental
Commercially available reagents were used throughout without
further purification; solvents were dried by standard pro-
cedures. Light petroleum refers to the fraction with bp 40–60 ЊC
J. Chem. Soc., Perkin Trans. 1, 1998
593

View Article Online
pressure to yield a dark brown oil. The crude product was sub-
jected to flash silica gel column chromatography using ethyl
acetate and light petroleum (1:1) as eluent to yield the title
compound as a golden yellow oil (0.61 g, 2.13 mmol, 33%), data
given below.
J 7, exch. D2O, NH), 5.13 (1 H, d, J 12, OCHH), 5.09 (1 H, d,
J 12, OCHH), 4.27 (1 H, m, NCH) and 1.40 (3 H, d, J 7, Me);
δC(100.6 MHz; CDCl3), 176.9, 158.2, 138.2, 130.7, 130.4, 130.2,
69.3, 52.2 and 20.6; m/z (EI) 222 (Mϩ, 2%), 178 (22), 134 (18), 107
(9) and 91 (100).
(S)-N 2-(Phthaloyl)valinamide 10c
tert-Butyl 2-(3,3-diethoxypropyl)-5-tert-butoxyoxazole-4-carb-
oxylate 7b
To a stirred solution of (S)-N-phthaloylvaline (1.0 g, 5.04
mmol) and triethylamine (0.56 ml, 4.04 mmol) at 0 ЊC was
added ethyl chloroformate (0.39 ml, 4.04 mmol) rapidly. The
reaction mixture was stirred at 0 ЊC for 15 min. Aqueous
ammonia (35%; 1 ml) was added and the reaction was stirred
for 5 min and then concentrated in vacuo. Ethyl acetate (50 ml)
was added to the crude residue and the resulting slurry was
filtered. The filtrate was washed with saturated aqueous sodium
hydrogen carbonate (50 ml), brine (50 ml), aqueous citric acid
(1 ; 50 ml) and brine respectively. Concentration in vacuo
followed by recrystallisation from dichloromethane–light pet-
roleum yielded colourless needles (0.485 g, 30%), mp 191–
192 ЊC (lit.,62 mp 186–187 ЊC); [α]D19 76.0 (c 0.28, CHCl3)
(Found: C, 63.0; H, 5.4; N, 11.1. Calc. for C13H14N2O3: C, 63.4;
H, 5.7; N, 11.4%) (Found: Mϩ, 246.1009. C13H14N2O3 requires
M, 246.1004); νmax(Nujol)/cmϪ1 3399, 3197, 1773, 1711, 1692
and 1648; δH(250 MHz; CDCl3) 7.87 (2 H, m, ArH), 7.53 (2 H,
m, ArH), 6.91 (1 H, s, NH), 5.52 (1 H, s, NH), 4.41 (1 H, d,
J 11.3, CH), 2.83 (1 H, m, J 6.5, 11.3, PriCH), 1.14 (3 H, d, J
6.5, Me) and 0.87 (3 H, d, J 6.5, Me); δC(62.9 MHz; CDCl3)
171.5, 168.4, 134.4, 131.4, 123.6, 62.8, 27.6, 19.9 and 19.4; m/z
(EI) 247 (MHϩ, 30%), 202 (100) and 160 (34).
To a stirred boiling solution of 3-cyanopropionaldehyde diethyl
acetal 5 (1.00 g, 6.36 mmol) and rhodium() acetate (2 mol%)
in ethanol-free chloroform (15 ml) was added di-tert-butyl
diazomalonate (2.31 g, 9.54 mmol) in ethanol-free chloroform
(10 ml) dropwise over a period of 24 h. After heating for a
further 24 h the solvent was removed under reduced pressure to
yield a dark brown oil. The crude product was subjected to flash
silica gel column chromatography using ethyl acetate and light
petroleum (1:2) as eluent to yield the title compound as a
golden yellow oil (0.156 g, 0.42 mmol, 7%), data given below.
Preparation of amides
N 2-Benzyloxycarbonylglycinamide 10a‡
To a stirred solution of N-benzyloxycarbonylglycine (8.4 g, 40
mmol) and triethylamine (5.6 ml, 40 mmol, 1.0 equiv.) in dry
THF (65 ml) was added ethyl chloroformate (3.85 ml, 40 mmol,
1.0 equiv.) dropwise at Ϫ10 ЊC. The reaction was stirred for 30
min, after which aqueous ammonia (35%; 10 ml) in THF (5 ml)
was added and the resultant mixture was stirred at Ϫ10 ЊC for
45 min. The white precipitate was filtered, washed sequentially
with water (25 ml), saturated aqueous sodium hydrogen car-
bonate (25 ml) and water (25 ml) and dried in vacuo to afford
N-benzyloxycarbonylglycinamide (7.1 g, 85%) as colourless
crystals, mp 136.5–137.5 ЊC (ethyl acetate) (lit.,60 mp 136–
138 ЊC) (Found: C, 57.3; H, 5.8; N, 13.3. Calc. for C10H12N2O3:
C, 57.7; H, 5.8; N, 13.5%) (Found: Mϩ, 208.0849. C10H12N2O3
requires M, 208.0848); νmax(KBr)/cmϪ1 3379, 3325, 3189, 3063,
3037, 2979, 2943, 2775, 1693, 1651, 1537, 1455, 1410, 1344,
1290, 1266, 1150, 1117, 1058, 1003, 878, 818, 783, 733 and 695;
δH(400 MHz; [2H6]DMSO) 7.38 (5 H, m, ArH), 7.36 (2 H, s,
exch. D2O, NH2), 7.00 (1 H, m, exch. D2O, NH), 5.04 (2 H, s,
OCH2) and 3.57 (2 H, d, J 6, NCH2); δC(100.6 MHz;
[2H6]DMSO) 172.0, 157.3, 137.9, 129.2, 128.6, 128.5, 66.3 and
44.1; m/z (EI) 208 (Mϩ, 5%), 108 (55) and 91 (100).
(S)-N 2-(tert-Butoxycarbonyl)valinamide 10d
To a stirred solution of (S)-N-(tert-butoxycarbonyl)valine (10.0
g, 46.0 mmol) and triethylamine (6.42 ml, 46.0 mmol) in dry
THF (100 ml) at 0 ЊC was added ethyl chloroformate (4.40 ml,
46.0 mmol) rapidly. The reaction was stirred at 0 ЊC for 30 min
and aqueous ammonia (35%; 10 ml) in THF (5 ml) was added.
After stirring at 0 ЊC for a further 30 min the reaction mixture
was partitioned between ethyl acetate (75 ml) and water (50 ml).
The aqueous layer was extracted with ethyl acetate (2 × 75 ml).
The combined organic fractions were washed with saturated
aqueous sodium hydrogen carbonate (150 ml), brine (150 ml),
aqueous citric acid (1 ; 150 ml) and brine respectively and
dried over sodium sulfate. Concentration in vacuo yielded a col-
ourless solid (8.85 g, 89%), mp 158–159 ЊC (dichloromethane–
light petroleum) (lit.,63 mp 160–161 ЊC); [α]D19 17.7 (c 1.33,
DMF) {lit.,63 [α]D25 Ϫ4.73 (c 0.66, CHCl3)} (Found: C, 55.5; H,
9.4; N, 12.7. Calc. for C10H20N2O3: C, 55.5; H, 9.3; N, 12.95%);
νmax(Nujol)/cmϪ1 3385, 3346, 3200, 1678, 1638, 1528 and 1459;
δH(250 MHz; [2H6]DMSO) 7.24 (1 H, s, NH2), 6.98 (1 H, s,
NH2), 6.48 (1 H, d, J 8.8, NH), 3.72 (1 H, dd, J 7.0, 8.8, CH),
1.91 (1 H, m, J 6.7, 7.0, PriCH), 1.38 (9 H, s, But), 0.85 (3 H, d,
J 6.7, Me) and 0.81 (3 H, d, J 6.7, Me); δC(100.6 MHz;
[2H6]DMSO) 176.0, 158.0, 80.4, 62.0, 32.8, 30.7, 21.8 and 20.5;
m/z (EI) 217 (MHϩ, 35%), 172 (35), 161 (75), 117 (64) and 72
(100).
(S)-N 2-Benzyloxycarbonylalaninamide 10b
To a stirred solution of N-benzyloxycarbonylalanine (8.9 g, 40
mmol) and triethylamine (5.6 ml, 40 mmol, 1.0 equiv.) in dry
THF (65 ml) was added ethyl chloroformate (3.85 ml, 40 mmol,
1.0 equiv.) dropwise at 0 ЊC. The reaction was stirred for 30 min
and aqueous ammonia (35%; 10 ml) in THF (5 ml) was added.
The resultant mixture was stirred at 0 ЊC for 45 min and par-
titioned between ethyl acetate (75 ml) and water (50 ml). The
aqueous layer was further extracted with ethyl acetate (2 × 75
ml) and the organic extracts were combined, washed sequen-
tially with saturated aqueous sodium hydrogen carbonate (100
ml), brine (100 ml), hydrochloric acid (1 ; 100 ml) and brine
(2 × 100 ml), dried (Na2SO4) and evaporated in vacuo to afford
(S)-N-benzyloxycarbonylalaninamide (6.0 g, 68%) as colour-
less crystals, mp 131–131.5 ЊC (lit.,61 mp 129–130 ЊC), after
recrystallisation (chloroform–light petroleum) (Found: C, 59.3;
H, 6.4; N, 12.4. Calc. for C11H14N2O3: C, 59.45; H, 6.3;
N, 12.6%) (Found: Mϩ, 222.1005. C11H14N2O3 requires M,
222.1004); [α]D16.5 Ϫ12.8 (c 1.0, CHCl3); [α]D20 Ϫ3.1 (c 1.0, MeOH)
{lit.,61 [α]D16.5 Ϫ3.32 (c 2, MeOH)}; νmax(KBr)/cmϪ1 3393, 3312,
3198, 3067, 3034, 2982, 2955, 1699, 1653, 1539, 1455, 1251, 781
and 757; δH(400 MHz, CDCl3) 7.38 (5 H, m, ArH), 6.21 (1 H, s,
exch. D2O, NH2), 5.75 (1 H, s, exch. D2O, NH2), 5.46 (1 H, d,
(S)-N 2-(Benzyloxycarbonyl)valinamide 10e.
To a stirred solution of (S)-N-(benzyloxycarbonyl)valine (10.0
g, 40.0 mmol) and triethylamine (5.55 ml, 40.0 mmol) in dry
THF (100 ml) at 0 ЊC was added ethyl chloroformate (3.80 ml,
40.0 mmol) rapidly. The reaction was stirred at 0 ЊC for 30 min
and aqueous ammonia (35%; 10 ml) in THF (5 ml) was added.
After stirring at 0 ЊC for 30 min water (50 ml) was added and
the resulting precipitate was filtered. The precipitate was
washed with saturated aqueous sodium hydrogen carbonate
(100 ml), water (100 ml), hydrochloric acid (1 ; 100 ml) and
water (500 ml) respectively. The product was dried under vac-
uum over P2O5 to yield a colourless solid (7.20 g, 72%), mp 208–
209 ЊC (methanol) (lit.,64 mp 212 ЊC); [α]D19 24.3 (c 1.02, DMF)
{lit.,64 [α]D25 22.6 (c 1, DMF)} (Found: C, 61.9; H, 7.1; N, 10.8.
‡ In the names of amino acid amides, nitrogen atoms have the same
numbers as the carbon atoms to which they are attached.
594
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
Calc. for C13H18N2O3: C, 62.4; H, 7.2; N, 11.2%) (Found: Mϩ,
250.1326. C13H18N2O3 requires M, 250.1317); νmax(Nujol)/cmϪ1
3379, 3318, 1682, 1658 and 1250; δH(250 MHz; [2H6]DMSO)
7.35 (5 H, m, ArH), 7.16 (1 H, d, J 8.8, NH), 7.03 (2 H, s, NH2),
5.03 (2 H, s, OCH2), 3.80 (1 H, dd, J 6.5, 8.8, CH), 1.94 (1 H, m,
J 7.2, 6.5, PriCH), 0.86 (3 H, d, J 7.2, Me) and 0.83 (3 H, d, J
7.2, Me); δC(62.9 MHz; [2H6]DMSO) 178.4, 161.2, 142.1, 133.3,
132.7, 132.6, 70.6, 65.1, 35.4, 24.4 and 22.9; m/z (EI) 250 (Mϩ,
2%), 206 (30), 162 (35) and 91 (100).
H, m, CH2), 1.48 (18 H, s, But) and 1.20 (6 H, t, J 7.0, Me);
δC(100.6 MHz, CDCl3) 172.9, 167.2, 102.4, 83.1, 62.1, 58.1,
31.4, 29.6, 28.2 and 15.7; m/z (EI) 389 (Mϩ, 1%), 344 (31), 242
(13), 214 (14), 187 (36), 103 (30), 85 (22), 57 (100) and 41 (40).
General procedure for á-diazo â-keto ester reactions
A solution of the diazo keto ester (1.0 g, 7.0 mmol) in dry
chloroform (35 ml) was added dropwise over 6 h to a boiling
solution of the amide (5.0 mmol) and rhodium() acetate (2
mol%) in ethanol-free chloroform (130 ml). The mixture
was refluxed for a further 30 min, allowed to cool, evaporated
in vacuo and purified by flash chromatography on silica gel,
eluting with ethyl acetate–light petroleum (1:1).
(S)-N 2-Benzyloxycarbonylprolinamide 10f.
To a stirred solution of (S)-N-benzyloxycarbonylproline (10.0
g, 40 mmol) and triethylamine (5.6 ml, 40 mmol, 1.0 equiv.) in
dry THF (65 ml) was added ethyl chloroformate (3.85 ml, 40
mmol, 1.0 equiv.) dropwise at 0 ЊC. The reaction was stirred for
30 min and aqueous ammonia (35%; 10 ml) in THF (5 ml) was
added. The resultant mixture was stirred at 0 ЊC for 45 min and
partitioned between ethyl acetate (75 ml) and water (50 ml). The
aqueous layer was further extracted with ethyl acetate (2 × 75
ml) and the organic extracts were combined, washed sequen-
tially with saturated aqueous sodium hydrogen carbonate (100
ml), brine (100 ml), hydrochloric acid (1 ; 100 ml) and brine
(2 × 100 ml), dried (Na2SO4) and evaporated in vacuo to afford
(S)-N-benzyloxycarbonylprolinamide (6.0 g, 68%) as colourless
crystals, mp 93–94 ЊC (decomp.), after recrystallisation (ethyl
acetate–light petroleum) (lit.,65 mp 90–91 ЊC) (Found: C, 62.7;
H, 6.4; N, 11.2. Calc. for C13H16N2O3: C, 62.9; H, 6.5; N, 11.3%)
(Found: Mϩ, 248.1162. C13H16N2O3 requires M, 248.1161); [α]D16.5
Ϫ90.8 (c 1.0, CHCl3); [α]D20 Ϫ36.0 (c 1.0, MeOH) {lit.,65 [α]D16.5
Ϫ31.8 (c 1.12, EtOH)}; νmax(KBr)/cmϪ1 3390, 3202, 2982, 2953,
2892, 1698, 1666, 1417, 1361, 1300, 1208, 1185, 1133, 1087,
1030, 767, 727 and 693; δH(400 MHz; CDCl3) 7.38 (5 H, m,
ArH), 6.72 (1 H, s, exch. D2O, NHH), 5.81 (1 H, s, exch. D2O,
NHH), 5.22 (1 H, d, J 12, OCHH), 5.17 (1 H, d, J 12, OCHH),
4.39 (1 H, m, NCH), 3.52 (2 H, m, NCH2) and 2.48–1.80 (4 H,
m, CH2CH2); δC(100.6 MHz; CDCl3) 175.7, 174.8, 156.4, 155.4,
136.8, 128.9, 128.5, 128.2, 67.7, 61.0, 60.6, 47.8, 47.4, 31.5, 28.9,
24.9 and 24.1; m/z (EI) 248 (Mϩ, 1%), 204 (72), 160 (59) and
91 (100).
N 2-Benzyloxycarbonyl-N1-(1-methoxycarbonyl-2-oxopropyl)-
glycinamide 12a. According to the general procedure the title
compound was obtained as an off-white solid (71%), mp 81.5–
82 ЊC (ethyl acetate–light petroleum) (Found: C, 55.5; H, 5.6; N,
8.5. C15H18N2O6 requires C, 55.9; H, 5.6; N, 8.7%) (Found: Mϩ,
322.1166. C15H18N2O6 requires M, 322.1165); νmax(KBr)/cmϪ1
3401, 3325, 3035, 2958, 1744, 1721, 1656, 1529, 1284, 1265,
1233, 1223, 1156, 1135, 1047, 982, 784 and 724; δH(400 MHz,
CDCl3) 7.37 (5 H, m, ArH), 7.19 (1 H, m, exch. D2O, NH), 5.51
(1 H, m, exch. D2O, NH), 5.29 (1 H, d, J 6.5, NHCH), 5.17 (2
H, s, OCH2), 4.00 (2 H, d, J 6, NHCH2), 3.84 (3 H, s, OMe) and
2.40 (3 H, s, COMe); δC(100.6 MHz; CDCl3) 200.9, 171.9,
169.0, 159.2, 138.7, 131.0, 130.7, 130.6, 69.7, 65.4, 55.9, 46.6
and 30.4; m/z (EI) 322 (Mϩ, 1%), 280 (3), 162 (26), 91 (100) and
43 (22).
N 2-Benzyloxycarbonyl-N 1-(1-methoxycarbonyl-2-oxopropyl)-
alaninamide 12b. According to the general procedure the title
compound was obtained as colourless needles (71%), mp 122–
123 ЊC (ethyl acetate–light petroleum) as an inseparable mixture
of diastereomers (Found: C, 57.2; H, 6.0; N, 8.3. C16H20N2O6
requires C, 57.1; H, 6.0; N, 8.3%) (Found: Mϩ, 336.1322.
C16H20N2O6 requires M, 336.1321); νmax(KBr)/cmϪ1 3293, 3065,
2959, 1738, 1725, 1687, 1649, 1532, 1449, 1437, 1360, 1329,
1263, 1232, 1216, 1174, 1136, 1075, 1057 and 698; δH(400 MHz;
CDCl3) 7.43 (1 H, m, exch. D2O, NH), 7.31 (5 H, m, ArH), 5.73
(1 H, d, J 6.5, exch. D2O, NH), 5.26 (1 H, d, J 6.5, NHCH), 5.13
(1 H, d, J 12, OCHH), 5.06 (1 H, d, J 12, OCHH), 4.42 (1 H, m,
NHCHMe), 3.76 (3 H, s, OMe), 2.33 (3 H, s, COMe) and 1.35
(3 H, d, J 7, Me); δC(100.6 MHz; CDCl3) 197.8, 197.7, 171.9,
165.9, 165.8, 155.3, 135.7, 127.9, 127.6, 127.4, 66.4, 62.3, 52.6,
49.6, 27.2 and 17.8; m/z (EI) 336 (Mϩ, 0.5%), 294 (4), 178 (10),
162 (21), 134 (19), 91 (100) and 43 (23).
Carbenoid N᎐H insertion reactions
General procedure for dialkyl diazomalonate reactions
A solution of the amide (12.65 mmol), the diazomalonate (6.32
mmol) and rhodium() acetate (2 mol%) in dry toluene (30 ml)
was heated under reflux overnight under a nitrogen atmosphere.
The solvent was then removed under reduced pressure to yield a
dark oil. This crude product was purified by flash chrom-
atography on silica gel, eluting with ethyl acetate–light pet-
roleum (1:15).
4,4-Diethoxy-N-[bis(methoxycarbonyl)methyl]butanamide 9a.
According to the general method the title compound was
obtained as a colourless solid (81%), mp 59–60 ЊC (ethyl
acetate–light petroleum) (Found: Mϩ, 305.1460. C13H23NO7
requires M, 305.1474); νmax(CH2Cl2)/cmϪ1 3307, 2976, 1748,
1667, 1438 and 1127; δH(250 MHz; CDCl3) 6.78 (1 H, br d,
J 6.9, NH), 5.21 (1 H, d, J 7.0, NCH), 4.54 (1 H, t, J 5.4,
OCHO), 3.82 (6 H, s, OMe), 3.66 (2 H, m, OCH2), 3.52 (2 H, m,
OCH2), 2.40 (2 H, t, J 7.3, CH2), 1.97 (2 H, m, CH2) and 1.20 (6
H, t, J 7.1, Me); δC(100.6 MHz; CDCl3) 172.9, 167.2, 102.3,
62.2, 56.5, 53.7, 31.2, 29.5 and 15.6; m/z (EI) 305 (Mϩ, 1%), 214
(63), 103 (100), 85 (78) and 57 (33).
N-[Bis(tert-butoxycarbonyl)methyl]-4,4-diethoxybutanamide
9b. According to the general method the title compound was
obtained as a colourless solid (60%), mp 70–71 ЊC (light pet-
roleum) (Found: Mϩ, 389.2415. C19H35NO7 requires M,
389.2413); νmax(CH2Cl2)/cmϪ1 3307, 2980, 1750, 1677, 1449 and
1144; δH(250 MHz, CDCl3) 6.56 (1 H, br d, J 6.9, NH), 4.95 (1
H, d, J 7.0, NCH), 4.54 (1 H, t, J 5.4, OCHO), 3.65 (2 H, m,
OCH2), 3.51 (2 H, m, OCH2), 2.40 (2 H, t, J 7.3, CH2), 1.97 (2
(S)-N 2-Phthaloyl-N 1-[bis(methoxycarbonyl)methyl]valin-
amide 12c. According to the general procedure the title com-
pound was obtained as a colourless solid (38%), mp 98–99 ЊC
(ethyl acetate–light petroleum) (Found: C, 56.1; H, 5.2; N, 7.1.
C18H20N2O7ؒ0.4H2O requires C, 56.4; H, 5.5; N, 7.3%) (Found:
Mϩ, 376.1273. C18H20N2O7 requires M, 376.1270); νmax(Nujol)/
cmϪ1 3354, 2960, 1762, 1721 and 1527; δH(250 MHz; CDCl3)
8.08 (1 H, d, J 6.5, NH), 7.88 (2 H, m, ArH), 7.76 (2 H, m,
ArH), 5.16 (1 H, d, J 6.5, CH), 4.49 (1 H, d, J 11.3, CH),
3.81 (3 H, s, OMe), 3.78 (3 H, s, OMe), 2.91 (1 H, m, J 11.3,
6.5, PriCH), 1.12 (3 H, d, J 6.5, Me) and 0.88 (3 H, d, J 6.5,
Me); δC(62.9 MHz; CDCl3) 168.7, 168.3, 166.30, 166.26,
134.5, 131.3, 123.8, 62.6, 56.4, 53.5, 53.4, 27.7, 19.6 and 19.5;
m/z (EI) 377 (MHϩ, 2%), 334 (40), 202 (100), 160 (25), 148
(33) and 130 (25).
(S)-N 2-tert-Butoxycarbonyl-N 1-[bis(methoxycarbonyl)-
methyl]valinamide 12d. According to the general procedure the
title compound was obtained as a colourless solid (47%), mp
118–118.5 ЊC (ethyl acetate–light petroleum) (Found: C, 51.7;
H, 7.6; N, 8.1. C15H26N2O7 requires C, 52.0; H, 7.6; N, 8.1%)
(Found: Mϩ, 346.1741. C15H26N2O7 requires M, 346.1740);
νmax(Nujol)/cmϪ1 3315, 1759, 1747, 1687, 1656, 1539 and 1527;
δH(250 MHz; CDCl3) 7.00 (1 H, d, J 6.5, NH), 5.19 (1 H, d,
J 6.5, CH), 5.02 (1 H, d, J 8.5, NH), 4.06 (1 H, dd, J 5.3, 8.5,
CH), 3.81 (6 H, s, OMe), 2.17 (1 H, m, J 7.0, 5.3, PriCH), 1.45
J. Chem. Soc., Perkin Trans. 1, 1998
595

View Article Online
(9 H, s, But), 0.98 (3 H, d, J 7.0, Me) and 0.93 (3 H, d, J 7.0,
Me); δC(62.9 MHz; CDCl3) 171.6, 166.5, 155.8, 83.2, 59.5, 56.1,
53.5, 30.9, 28.3, 19.2 and 17.5; m/z (EI) 347 (MHϩ, 10%), 291
(25), 172 (40), 116 (75) and 72 (100).
N 2-(Benzyloxycarbonyl)-N 1-(1-methoxycarbonyl-2-oxobutyl)-
valinamide 12i. The title compound was obtained as a solid
(48%), mp 144–145 ЊC (dichloromethane–light petroleum), as a
mixture of diastereomers (Found: C, 59.9; H, 6.8; N, 7.25.
C19H26N2O6 requires C, 60.3; H, 6.9; N, 7.4%) (Found: Mϩ,
378.1795. C19H26N2O6 requires M, 378.1791); νmax(Nujol)/cmϪ1
3298, 1749, 1725, 1687, 1649 and 1536; δH(250 MHz; CDCl3)
7.35 (5 H, m, ArH), 7.05 (1 H, d, J 6.3, NH), 5.32 (1 H, d, J 8.8,
NH), 5.22 (1 H, d, J 6.3, CH), 5.12 (1 H, s, OCH2), 5.11 (1 H, s,
OCH2), 4.16 (1 H, dd, J 6.0, 8.8, CH), 3.79 (3 H, s, OMe), 2.75
(2 H, m, CH2Me), 2.18 (1 H, m, J 7.0, 6.0, PriCH), 1.10 (3 H, t,
J 7.5, CH2Me), 0.97 (3 H, d, J 7.0, Me), 0.93 (3 H, d, J 7.0, Me)
and 0.91 (3 H, d, J 7.0, Me); δC(100.6 MHz; [2H6]DMSO) 203.2,
203.1, 172.1, 172.0, 167.9, 156.6, 137.5, 128.8, 128.2, 128.07,
128.05, 65.9, 62.3, 60.4, 60.3, 52.98, 52.97, 33.3, 33.2, 30.8, 30.7,
19.52, 19.48, 18.5, 18.3, 7.8 and 7.7; m/z (EI) 378 (Mϩ, 1%), 206
(7), 162 (20) and 91 (100).
N 2-(tert-Butoxycarbonyl)-N 1-(1-methoxycarbonyl-2-oxo-
propyl)valinamide 12e. According to the general procedure the
title compound was obtained as a colourless solid (30%), mp
111–113 ЊC (ethyl acetate–light petroleum), as a mixture of
diastereomers (Found: C, 54.5; H, 7.8; N, 8.5. C15H26N2O6
requires C, 54.5; H, 7.9; N, 8.5%); νmax(Nujol)/cmϪ1 3323, 1751,
1727, 1687 and 1520; δH(250 MHz; CDCl3) 7.13 (1 H, d, J 6.3,
NH), 7.06 (1 H, d, J 6.3, NH), 5.24 (1 H, d, J 6.3, CH), 5.01
(1 H, br d, J 6.0, NH), 4.04 (1 H, br dd, J 6.0, CH), 3.85 (3 H, s,
OMe), 3.82 (3 H, s, OMe), 2.38 (3 H, s, Me), 2.35 (3 H, s, Me),
2.19 (1 H, m, J 7.0, PriCH), 1.43 (9 H, s, But), 0.97 (3 H, d, J
7.0, Me) and 0.91 (3 H, d, J 7.0, Me); δC(100.6 MHz; CDCl3)
198.1, 198.0, 171.5, 166.4, 166.3, 155.8, 80.1, 62.94, 62.89, 59.5,
53.3, 30.9, 30.7, 28.3, 28.2, 28.0, 19.2, 19.1, 17.5 and 17.3; m/z
(EI) 331 (MHϩ, 100%), 275 (30), 231 (30), 116 (25) and 72
(100).
N2-(Benzyloxycarbonyl)-N 1-(1-benzoyl-1-ethoxycarbonyl-
methyl)valinamide 12j. According to the general procedure the
title compound was obtained as a colourless solid (72%), mp
128–129 ЊC (dichloromethane–light petroleum), as a mixture of
diastereomers (Found: C, 65.1; H, 6.2; N, 6.3. C24H28N2O6
requires C, 65.4; H, 6.4; N, 6.4%) (Found: Mϩ, 440.1947.
C24H28N2O6 requires M, 440.1947); νmax(Nujol)/cmϪ1 3380,
3320, 1736, 1724, 1718, 1694, 1651, 1556, 1538, 1504 and 1454;
δH(250 MHz, CDCl3, rotamers) 8.11 (2 H, d, J 7.3, ArH), 7.64
(1 H, m, ArH), 7.51 (2 H, t, J 6.5, ArH), 7.35 (5 H, m, ArH),
7.22 (1 H, d, J 7.0, NH), 6.15 (1 H, d, J 7.0, CH), 6.13 (1 H, d,
J 7.0, CH), 5.32 (1 H, d, J 7.3, NH), 5.12 (2 H, s, OCH2), 4.21 (1
H, br dd, J 7.3, 5.8, CH), 4.16 (2 H, q, J 6.5, CH2), 2.19 (1 H, m,
J 6.8, 5.8, PriCH), 1.13 (3 H, t, J 6.5, Me) and 0.90–1.01 (6 H,
m, Me); δC(100.6 MHz; CDCl3) 191.2, 171.2, 166.2, 156.4,
136.3, 134.1, 130.1, 129.6, 129.2, 128.7, 128.5, 128.4, 128.1,
67.2, 62.6, 62.5, 60.1, 58.3, 31.4, 31.2, 19.1, 17.7, 17.5, 14.0 and
13.8; m/z (EI) 440 (Mϩ, 2%), 425 (5), 162 (15), 105 (55) and 91
(100).
(S)-N 2-Benzyloxycarbonyl-N 1-[bis(methoxycarbonyl)methyl]-
valinamide 12f. According to the general procedure the title
compound was obtained as a colourless solid (61%), mp 161–
162 ЊC (dichloromethane–light petroleum) (Found: C, 56.4; H,
6.3; N, 7.3. C18H24N2O7 requires C, 56.8; H, 6.4; N, 7.4%)
(Found: Mϩ, 380.1582. C18H24N2O7 requires M, 380.1583);
νmax(Nujol)/cmϪ1 3293, 1758, 1745, 1687, 1651, 1537 and 1249;
δH(250 MHz, CDCl3) 7.35 (5 H, m, ArH), 6.88 (1 H, d, J 6.8,
NH), 5.32 (1 H, d, J 8.8, NH), 5.18 (1 H, d, J 6.8, CH), 5.12 (2
H, s, OCH2), 4.15 (1 H, dd, J 8.8, 5.5, CH), 3.81 (6 H, s, OMe),
2.17 (1 H, m, J 7.0, 5.5, PriCH), 0.99 (3 H, d, J 7.0, Me) and
0.94 (3 H, d, J 7.0, Me); δC(62.9 MHz; CDCl3) 171.1, 166.3,
156.2, 128.4, 128.1, 128.0, 67.0, 60.0, 56.0, 53.4, 53.3, 31.2, 19.0
and 17.4; m/z (EI) 380 (Mϩ, 4%), 206 (20), 162 (35) and 91
(100).
N 2-(Benzyloxycarbonyl)-N 1-(1-methoxycarbonyl-2-oxo-
propyl)valinamide 12g. According to the general procedure the
title compound was obtained as a colourless solid (68%), mp
148–149.5 ЊC (dichloromethane–light petroleum), as a mixture
of diastereomers (Found: C, 58.7; H, 6.6; N, 7.6. C18H24-
N2O6ؒ0.25H2O requires C, 58.6; H, 6.7; N, 7.6%) (Found: Mϩ,
364.1624. C18H24N2O6 requires M, 364.1634); νmax(Nujol)/cmϪ1
3299, 2923, 2854, 2360, 1725, 1692 and 1646; δH(250 MHz,
CDCl3) 7.34 (5 H, m, ArH), 7.01 (1 H, d, J 6.3, NH), 5.30 (1 H,
d, J 8.5, NH), 5.23 (1 H, d, J 6.3, CH), 5.13 (2 H, s, OCH2), 5.12
(2 H, s, OCH2), 4.14 (1 H, dd, J 6.0, 8.5, CH), 3.81 (3 H, s,
OMe), 2.39 (3 H, s, Me), 2.38 (3 H, s, Me), 2.17 (1 H, m, J 6.0,
7.0, PriCH), 0.97 (3 H, d, J 7.0, Me), 0.93 (3 H, d, J 7.0, Me)
and 0.92 (3 H, d, J 7.0, Me); δC(62.9 MHz; CDCl3) 171.14,
171.09, 166.2, 156.3, 136.1, 128.4, 128.1, 128.0, 67.0, 62.9, 62.8,
59.8, 53.3, 53.2, 31.2, 31.0, 28.0, 27.8, 19.1, 18.9, 17.5 and 17.3;
m/z (EI) 365 (MHϩ, 40%), 322 (15), 206 (45), 162 (75) and 91
(100).
N2-Benzyloxycarbonyl-N 1-(1-methoxycarbonyl-2-oxopropyl)-
prolinamide 12k. According to the general procedure the title
compound (74%) was obtained as a pale yellow oil as an
inseparable mixture of diastereomers (Found: Mϩ, 362.1486.
C18H22N2O6 requires M, 362.1478); νmax(film)/cmϪ1 3307, 3063,
3033, 2955, 2884, 1755, 1726, 1703, 1680, 1500, 1415, 1357,
1273, 1210, 1119, 1090, 1029, 984, 919, 770, 737 and 699; δH(400
MHz; CDCl3) 7.60 (1 H, m, exch. D2O, NH), 7.35 (5 H, m,
ArH), 5.18 (3 H, m, OCH2 and NHCH), 4.43 (1 H, m, NCH),
3.79 (3 H, s, OMe), 3.60 (2 H, m, NCH2), 2.33 (3 H, s, COMe)
and 2.25–1.86 (4 H, m, CH2CH2); δC(100.6 MHz; CDCl3) 198.6,
172.6, 172.2, 166.8, 156.3, 155.3, 136.9, 136.7, 129.0, 128.9,
128.6, 128.4, 128.3, 128.2, 67.71, 67.69, 63.4, 63.1, 60.9, 60.8,
53.9, 53.6, 47.9, 47.4, 31.4, 29.4, 28.2, 24.9 and 24.0; m/z (EI)
362 (Mϩ, 0.5%), 204 (15), 160 (23), 91 (100), 70 (13) and 43 (26).
Oxazole formation by cyclodehydration
General procedure54
N 2-(Benzyloxycarbonyl)-N 1-(3-chloro-1-methoxycarbonyl-2-
oxopropyl)valinamide 12h. According to the general procedure
the title compound was obtained as a colourless solid (67%),
Triethylamine (4.1 equiv.) and a solution of the keto amide
substrate (~3 mmol, 1.0 equiv.) in dry dichloromethane (10 ml)
were added sequentially to a stirred solution of triphenyl-
phosphine (2.0 equiv.) and iodine (2.0 equiv.) in dry dichloro-
methane (40 ml) at room temperature under N2. The mixture
was stirred until TLC analysis indicated that the reaction was
complete, evaporated in vacuo, purified by flash chrom-
atography on silica eluting with ethyl acetate–light petroleum.
Methyl 2-(3,3-diethoxypropyl)-5-methoxyoxazole-4-carboxyl-
ate 7a. According to the general procedure the title compound
was obtained as a golden yellow oil (84%) (Found: Mϩ,
287.1363. C13H21NO6 requires M, 287.1369); νmax(neat)/cmϪ1
2976, 1721, 1637, 1598, 1454 and 1126; δH(250 MHz, CDCl3)
4.54 (1 H, t, J 5.4, OCHO), 4.15 (3 H, s, OMe), 3.87 (3 H, s,
OMe), 3.66 (2 H, m, OCH2), 3.49 (2 H, m, OCH2), 2.76 (2 H, t,
mp 146–147 ЊC (dichloromethane–light petroleum), as
a
mixture of diastereomers (Found: C, 53.7; H, 5.7; N, 7.0.
C18H23ClN2O6 requires C, 54.2; H, 5.8; N, 7.0%) (Found: Mϩ,
398.1253. C18H23ClN2O6 requires M, 398.1244); νmax(Nujol)/
cmϪ1 3292, 3036, 1761, 1737, 1687, 1650 and 1538; δH(250
MHz, CDCl3) 7.36 (5 H, m, ArH), 7.02 (1 H, d, J 6.5, NH), 5.41
(1 H, d, J 6.5, CH), 5.26 (1 H, d, J 8.0, NH), 5.13 (2 H, s,
OCH2), 5.12 (2 H, s, OCH2), 4.48 (2 H, s, CH2Cl), 4.14 (1 H, dd,
J 8.0, 5.5, CH), 3.83 (3 H, s, OMe), 2.17 (1 H, m, J 7.0, 5.5,
PriCH), 0.99 (3 H, d, J 7.0, Me) and 0.94 (3 H, d, J 7.0, Me);
δC(100.6 MHz; [2H6]DMSO) 194.2, 194.1, 171.7, 166.5, 156.0,
136.8, 127.6, 127.5, 127.4, 65.3, 60.0, 59.9, 59.7, 52.6, 47.59,
47.55, 30.0, 29.9, 18.8, 17.9 and 17.7; m/z (EI) 400 (Mϩ, 1%),
398 (Mϩ, 1), 206 (14), 162 (25) and 91 (100).
596
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
J 7.8, CH2), 2.06 (2 H, m, CH2) and 1.19 (6 H, t, J 7.0, Me);
δC(100.6 MHz; CDCl3) 162.3, 162.1, 154.0, 106.3, 102.1, 62.0,
60.1, 52.0, 31.0, 23.8 and 15.6; m/z (EI) 287 (Mϩ, 1%), 242 (21),
214 (41), 85 (53), 69 (100) and 57 (48).
OMe), 3.04 (2 H, q, J 7.5, CH2), 2.20 (1 H, m, J 6.5, 6.8, PriCH),
1.26 (3 H, t, J 7.5, Me), 0.94 (3 H, d, J 6.8, Me) and 0.91 (3 H, d,
J 6.8, Me); δC(62.9 MHz; CDCl3) 162.5, 161.5, 161.1, 155.9,
136.1, 128.4, 128.0, 127.9, 126.3, 67.0, 54.7, 51.9, 32.8, 19.5,
18.6, 17.9 and 11.9; m/z (EI) 360 (MHϩ, 5%), 317 (6), 273 (10),
210 (10), 178 (12) and 91 (100).
tert-Butyl
2-(3,3-diethoxypropyl)-5-tert-butoxyoxazole-4-
carboxylate 7b. According to the general procedure the title
compound was obtained as a golden yellow oil (79%) (Found:
Mϩ, 371.2317. C19H33NO6 requires M, 371.2308); νmax(neat)/
cmϪ1 2978, 1718, 1626, 1582, 1445 and 1142; δH(250 MHz;
CDCl3) 4.54 (1 H, t, J 5.4, OCHO), 3.66 (2 H, m, OCH2), 3.50
(2 H, m, OCH2), 2.74 (2 H, t, J 8.1, CH2), 2.05 (2 H, m, CH2),
1.57 (9 H, s, But), 1.48 (9 H, s, But) and 1.20 (6 H, t, J 7.0, Me);
δC(100.6 MHz; CDCl3) 161.3, 158.6, 156.0, 114.4, 102.3, 85.6,
81.4, 62.0, 31.0, 28.9, 28.7, 24.2 and 15.6; m/z (EI) 371 (Mϩ, 1%),
242 (18), 214 (15), 187 (64), 84 (37), 57 (100), 41 (56) and 29 (46).
(S)-Ethyl 2-[1-(benzyloxycarbonylamino)-2-methylpropyl]-5-
phenyloxazole-4-carboxylate 13e. According to the general pro-
cedure the title compound was obtained as an off white sticky
solid (31%) (Found: Mϩ, 422.1813. C24H26N2O5 requires M,
422.1842); νmax(Nujol)/cmϪ1 3321, 1723, 1693, 1589, 1572, 1547
and 1513; δH(250 MHz; CDCl3) 7.97 (2 H, t, ArH), 7.46 (3 H,
m, ArH), 7.35 (5 H, m, ArH), 5.54 (1 H, d, J 9.3, NH), 5.13 (2
H, s, OCH2), 4.93 (1 H, dd, J 6.3, 9.3, CH), 4.41 (2 H, q, J 7.3,
OCH2Me), 2.27 (1 H, m, J 6.3, 6.8, PriCH), 1.38 (3 H, t, J 7.3,
Me), 1.00 (3 H, d, J 6.8, Me) and 0.98 (3 H, d, J 6.8, Me);
δC(100.6 MHz; CDCl3) 163.1, 162.3, 157.0, 155.0, 137.8, 131.2,
129.3, 129.2, 129.1, 128.7, 128.5, 127.4, 127.2, 66.5, 61.6, 55.9,
32.0, 19.8, 19.5 and 14.8; m/z (EI) 422 (Mϩ, 15%), 335 (14), 287
(20), 105 (25) and 91 (100).
(S)-Methyl 2-(1-benzyloxycarbonyltetrahydropyrrol-2-yl)-5-
methyloxazole-4-carboxylate 13f. According to the general pro-
cedure the title compound was obtained as light brown prisms
(73%), mp 84–85 ЊC (decomp.) (ethyl acetate–light petroleum)
(Found: C, 62.9; H, 5.8; N, 8.1. C18H20N2O5 requires C, 62.8; H,
5.85; N, 8.1%) (Found: Mϩ, 344.1371. C18H20N2O5 requires M,
344.1372); [α]D16.5 Ϫ79.2 (c 1.0, CHCl3); νmax(KBr)/cmϪ1 2977,
2957, 2879, 1710, 1698, 1620, 1429, 1351, 1210, 1195, 1120,
1100, 770, 755, 699 and 608; δH(400 MHz; CDCl3, 50 ЊC) 7.19 (5
H, m, ArH), 5.09 (1 H, d, J 12.4, OCHH), 4.91 (2 H, m, OCHH
and NCH), 3.80 (3 H, s, OMe), 3.65–3.40 (2 H, m, NCH2), 2.39
(3 H, s, Me), 2.30–1.78 (4 H, m, CH2CH2); δC(100.6 MHz;
CDCl3) 163.2, 163.1, 162.9, 162.8, 156.8, 156.6, 155.2, 154.7,
137.0, 136.8, 128.9, 128.7, 128.43, 128.36, 128.32, 128.29, 127.9,
127.6, 67.4, 67.3, 55.3, 55.0, 52.3 (2 carbons), 47.4, 47.0, 32.9,
31.9, 24.7, 24.0, 12.5 and 12.3; m/z (EI) 344 (Mϩ, 15%), 209
(12), 168 (27), 91 (100) and 51 (17).
Methyl
2-(N-benzyloxycarbonylaminomethyl)-5-methylox-
azole-4-carboxylate 13a. According to the general procedure
the title compound was obtained as pale yellow needles (56%),
mp 86–87 ЊC (ethyl acetate–light petroleum) (Found: C, 59.2;
H, 5.1; N, 8.9. C15H16N2O5 requires C, 59.2; H, 5.3; N, 9.2%)
(Found: Mϩ, 304.1051. C15H16N2O5 requires M, 304.1059);
νmax(KBr)/cmϪ1 3323, 3067, 3036, 2954, 1719, 1690, 1622, 1545,
1439, 1345, 1273, 1217, 1198, 1154, 1098, 1055, 980, 786 and
698; δH(400 MHz; CDCl3) 7.26 (5 H, m, ArH), 5.30 (1 H, m,
exch. D2O, NH), 5.07 (2 H, s, OCH2), 4.43 (2 H, d, J 6, NCH2),
3.83 (3 H, s, OMe) and 2.53 (3 H, s, Me); δC(100.6 MHz;
CDCl3) 162.8, 159.2, 157.3, 156.5, 136.5, 128.9, 128.6, 128.5,
127.8, 67.7, 52.4, 38.6 and 12.3; m/z (EI) 304 (Mϩ 12%), 169
(14), 155 (18), 137 (11), 108 (15), 91 (83) and 43 (100).
(S)-Methyl 2-[1-(benzyloxycarbonylamino)ethyl]-5-methyl-
oxazole-4-carboxylate 13b. According to the general procedure
the title compound was obtained as colourless needles (66%),
mp 125.5–126 ЊC (ethyl acetate–light petroleum) (Found: C,
60.2; H, 5.7; N, 8.8. C16H18N2O5 requires C, 60.4; H, 5.7;
N, 8.8%) (Found: Mϩ, 318.1218. C16H18N2O5 requires M,
318.1216); [α]D16.5 Ϫ34.4 (c 1.0, CHCl3); νmax(KBr)/cmϪ1 3292,
3063, 2985, 2955, 2934, 1720, 1684, 1619, 1541, 1448, 1347,
1329, 1273, 1253, 1206, 1100, 1065, 782, 749, 698, 577 and 544;
δH(400 MHz, CDCl3) 7.26 (5 H, m, ArH), 5.41 (1 H, d, J 7,
exch. D2O, NH), 5.07 (1 H, d, J 12.3, OCHH), 5.02 (1 H, d,
J 12.3, OCHH), 4.94 (1 H, dq, J 7, 7, NCH), 3.82 (3 H, s, OMe),
2.53 (3 H, s, Me) and 1.49 (3 H, d, J 7, Me); δC(100.6 MHz,
CDCl3) 163.0, 162.9, 157.1, 155.9, 136.5, 128.9, 128.6, 128.5,
127.7, 67.4, 52.4, 45.5, 20.5 and 12.4; m/z (EI) 318 (Mϩ, 12%),
248 (5), 183 (20), 130 (22), 91 (100) and 70 (25).
(S)-Methyl 2-[1-(benzyloxycarbonylamino)-2-methylpropyl]-
5-methyloxazole-4-carboxylate 13c. According to the general
procedure the title compound was obtained as a colourless solid
(65%), mp 113–114 ЊC (ethyl acetate–light petroleum) (lit.,54 mp
110–110.5 ЊC); [α]D19 Ϫ53.7 (c 0.82, MeOH) {lit.,54 [α]D22 Ϫ35.9Њ
(c 0.4, CH2Cl2)} (Found: C, 62.0; H, 6.3; N, 8.1. Calc. for
C18H22N2O5: C, 62.4; H, 6.4; N, 8.1%) (Found: Mϩ, 346.1529.
C18H22N2O5 requires M, 346.1529); νmax(Nujol)/cmϪ1 3305,
2955, 2923, 2854, 1718, 1688, 1615 and 1536; δH(250 MHz;
CDCl3) 7.35 (5 H, m, ArH), 5.50 (1 H, d, J 9.3, NH), 5.11 (2 H,
s, OCH2), 4.80 (1 H, dd, J 6.0, 9.3, CH), 3.90 (3 H, s, OMe), 2.60
(3 H, s, Me), 2.20 (1 H, m, J 6.0, 7.5, PriCH), 0.86 (3 H, d, J 7.5,
Me) and 0.85 (3 H, d, J 7.5, Me); δC(62.9 MHz; CDCl3) 162.4,
161.5, 156.2, 155.9, 136.1, 128.4, 128.0, 127.9, 127.1, 67.0, 54.7,
51.8, 32.6, 18.7, 17.9 and 11.9; m/z (EI) 346 (MHϩ, 10%), 303
(8), 259 (12) and 91 (100).
(S)-Methyl 2-[1-(benzyloxycarbonylamino)-2-methylpropyl]-
5-ethyloxazole-4-carboxylate 13d. According to the general
procedure the title compound was obtained as a colourless solid
(88%), mp 73–74 ЊC (ethyl acetate–light petroleum); [α]D19 Ϫ43.2
(c 0.53, MeOH) (Found: C, 63.3; H, 6.7; N, 7.8. C19H24N2O5
requires C, 63.3; H, 6.7; N, 7.8%); νmax(Nujol)/cmϪ1 3305, 1713,
1691, 1603, 1547, 1296, 1250, 1207, 1098 and 1038; δH(250
MHz, CDCl3) 7.33 (5 H, m, ArH), 5.49 (1 H, d, J 9.3, NH), 5.11
(2 H, s, OCH2), 4.81 (1 H, dd, J 6.5, 9.3, CH), 3.90 (3 H, s,
Preparation of bis-oxazoles
(S)-2-[1-(Benzyloxycarbonylamino)-2-methylpropyl]-5-methyl-
oxazole-4-carboxylic acid 14a
To a stirred solution of the oxazole ester 13c (0.300 g, 0.866
mmol) in THF (15 ml) and water (5 ml) was added sodium
hydroxide (0.173 g, 4.33 mmol). After stirring overnight at
room temperature the reaction mixture was concentrated in
vacuo and partitioned between water and dichloromethane.
The aqueous layer was acidified to pH 1 with hydrochloric acid
and extracted with dichloromethane. The combined organic
extracts were washed with brine and dried over sodium sulfate.
Concentration in vacuo yielded an off white solid which was
recrystallised from ethyl acetate and light petroleum to give the
title compound as a colourless solid (0.227 g, 79%); mp 176–
177 ЊC; [α]D24 Ϫ54.6 (c 1.0, MeOH) (Found: C, 60.9; H, 5.9; N,
8.3. C17H20N2O5ؒ0.1H2O requires C, 61.1; H, 6.1; N, 8.4%)
(Found: Mϩ, 332.1371. C17H20N2O5 requires M, 332.1372);
νmax(Nujol)/cmϪ1 3413, 3281, 1713, 1543 and 1247; δH(250
MHz; CDCl3) 7.27 (5 H, m, ArH), 7.20 (1 H, br d, NH), 5.06
(2 H, s, OCH2), 4.86 (1 H, dd, J 6.5, 10.0, CH), 2.49 (3 H, s,
Me), 2.24 (1 H, m, J 6.8, 6.5, PriCH), 0.98 (3 H, d, J 6.8,
Me) and 0.95 (3 H, d, J 6.8, Me); δC(62.9 MHz; CDCl3)
164.2, 163.7, 157.1, 156.7, 136.2, 127.9, 128.2, 126.8, 66.9,
54.9, 32.6, 18.9, 18.1 and 11.6; 1 Ar C unobserved; m/z (EI)
332 (Mϩ, 10%), 289 (5), 245 (7), 197 (5), 164 (10), 108 (12)
and 91 (100).
(S)-2-[1-(Benzyloxycarbonylamino)-2-methylpropyl]-5-methyl-
oxazole-4-carboxamide 15a
To a stirred solution of the oxazole acid 14a (0.20 g, 0.602
mmol) and triethylamine (0.08 ml, 0.602 mmol) in THF (10 ml)
J. Chem. Soc., Perkin Trans. 1, 1998
597

View Article Online
at 0 ЊC was added ethyl chloroformate (0.06 ml, 0.602 mmol).
After stirring at 0 ЊC for 15 min, aqueous ammonia (30%; 5 ml)
in THF (5 ml) was added. The reaction was stirred for a further
15 min and then concentrated in vacuo. The crude residue was
partitioned between dichloromethane and water, the aqueous
layer was extracted with dichloromethane and the combined
organic extracts washed with saturated aqueous sodium hydro-
gen carbonate, brine and dried over sodium sulfate. Purification
by flash chromatography (ethyl acetate–light petroleum) gave
the title compound as a solid (0.191 g, 96%); mp 84–86 ЊC (ethyl
acetate–light petroleum) (Found: Mϩ, 331.1534. C17H21N3O4
requires M, 331.1519); νmax(CH2Cl2)/cmϪ1 3344, 3062, 2972,
2930, 1722 and 1265; δH(250 MHz; CDCl3) 7.36 (5 H, m, ArH),
6.62 (1 H, s, NH), 6.06 (1 H, s, NH), 5.74 (1 H, d, J 9.1, NH),
5.12 (2 H, s, OCH2), 4.71 (1 H, dd, J 6.0, 9.1, CH), 2.60 (3 H, s,
Me), 2.19 (1 H, m, J 6.8, 6.0, PriCH) and 0.94 (6 H, 2 d, J 6.8,
Me); δC(100.6 MHz; CDCl3) 166.7, 163.0, 158.5, 156.5, 138.7,
131.0, 130.8, 130.7, 130.6, 69.8, 57.3, 35.0, 21.2, 20.5 and 14.2;
m/z (EI) 331 (Mϩ, 15%), 288 (10), 244 (10), 196 (12), 136 (5),
115 (10) and 91 (100).
(S)-2-(1-Benzyloxycarbonyltetrahydropyrrol-2-yl)-5-methyl-
oxazole-4-carboxylic acid 14b
Sodium hydroxide (1.42 g, 35.6 mmol) was added in one por-
tion to a stirred solution of the oxazole ester 13f (2.13 g, 6.19
mmol) in THF–water (3:1) (52 ml) at room temperature. The
reaction was stirred overnight, the THF was evaporated in
vacuo and the mixture was partitioned between diethyl ether (50
ml) and water (50 ml). The aqueous layer was acidified to pH 2
with hydrochloric acid (1 ) and extracted with ethyl acetate
(2 × 100 ml). The combined organic extracts were washed with
brine (100 ml), dried (Na2SO4) and evaporated in vacuo to
afford the title compound (1.79 g, 87%) as a colourless solid,
mp 168–168.5 ЊC. A small portion was recrystallised to afford
the title compound as colourless prisms, mp 168.5–169.5 ЊC
(ethyl acetate); [α]D20 Ϫ80.0 (c 1.0, CHCl3) (Found: C, 61.7; H,
5.4; N, 8.5. C17H18N2O5 requires C, 61.8; H, 5.5; N, 8.5%)
(Found: Mϩ, 330.1215. C17H18N2O5 requires M, 330.1216);
νmax(KBr)/cmϪ1 3255, 2977, 2956, 2887, 1722, 1667, 1614, 1585,
1447, 1411, 1361, 1195, 1171, 1133, 1089, 768, 760, 729, 705,
677 and 612; δH(400 MHz; CDCl3, 20 ЊC) 9.15 (1 H, br s, exch.
D2O, CO2H), 7.25 (5 H, m, ArH), 5.19 (1 H, m, NCHCH2), 5.01
(2 H, m, OCH2), 3.70 (1 H, m, NCHHCH2), 3.61 (1 H, m,
NCHHCH2), 2.61 (1.34 H, s, Me), 2.46 (1.66 H, s, Me) and
2.38–1.88 (4 H, m, NCHCH2CH2); δH(400 MHz, CDCl3,
50 ЊC) 7.28 (5 H, m, ArH), 6.60 (1 H, br s, exch. D2O, CO2H),
5.17 (1 H, m, NCHCH2), 5.11 (2 H, br s, OCH2), 3.67 (1 H, m,
NCHHCH2), 3.59 (1 H, m, NCHHCH2), 2.51 (3 H, s, Me) and
2.38–1.88 (4 H, m, NCHCH2CH2); δC(100.6 MHz; CDCl3)
165.7, 163.0, 157.5, 155.3, 154.7, 137.0, 136.7, 128.7, 128.4,
128.3, 127.2, 67.5, 55.3, 54.9, 47.4, 46.9, 32.7, 31.7, 24.7, 24.0,
12.6 and 12.4; m/z (EI) 330 (Mϩ, 8%), 149 (21), 91 (100) and 43
(50).
(S)-Methyl 2-{2-[1-(benzyloxycarbonylamino)-2-methylpropyl]-
5-methyloxazol-4-ylcarbonylamino}-3-oxobutanoate 16a
To a stirred solution of the oxazole amide 15a (0.242 g, 0.730
mmol) and rhodium() acetate (0.006 g, 0.015 mmol, 2 mol%)
in anhydrous chloroform (10 ml) heating under reflux was
added methyl diazoacetoacetate (0.156 g, 1.1 mmol) in chloro-
form (10 ml) dropwise via a syringe pump over 3 h. The reaction
mixture was heated under reflux overnight and then concen-
trated in vacuo. The crude residue was purified by flash chrom-
atography (ethyl acetate–light petroleum) to give the title com-
pound as an oily solid (0.163 g, 50%) (Found: Mϩ, 445.1847.
C22H27N3O7 requires M, 445.1849); νmax(Nujol)/cmϪ1 3392,
3326, 1727, 1669, 1634, 1504, 1234, 1159, 1095 and 1026; δH(250
MHz; CDCl3) 7.89 (1 H, d, J 6.6, NH), 7.35 (5 H, m, ArH), 5.35
(2 H, m, NH and CH), 5.15 and 5.14 (2 H, 2 × s, OCH2, both
diastereomers), 4.79 (1 H, dd, J 6.0, 9.3, CH), 3.85 (3 H, s,
OMe), 2.59 (3 H, s, Me), 2.42 (3 H, s, Me), 2.20 (1 H, m, J 6.8,
6.0, PriCH), 0.95 (3 H, d, J 6.8, Me) and 0.94 (3 H, d, J 6.8,
Me); δC(100.6 MHz; CDCl3) 199.1, 167.0, 161.2, 160.6, 156.1,
153.1, 136.9, 128.3, 127.8, 127.7, 127.6, 65.6, 62.5, 55.0, 52.9,
30.9, 27.6, 19.0, 18.7 and 11.3; m/z (EI) 446 (MHϩ, 5%), 445
(Mϩ, 3), 403 (15), 312 (17), 294 (12), 225 (20), 207 (5), 162 (7),
137 (5), 110 (12) and 91 (100).
(S)-2-(1-Benzyloxycarbonyltetrahydropyrrol-2-yl)-5-methyl-
oxazole-4-carboxamide 15b
To a stirred solution of the carboxylic acid 14b (1.79 g, 5.40
mmol) and triethylamine (0.90 ml, 6.46 mmol) in dry THF (15
ml) was added ethyl chloroformate (0.60 ml, 6.28 mmol) drop-
wise at 0 ЊC. The reaction was stirred for 30 min and aqueous
ammonia (35%; 1.5 ml) was added. The resultant mixture was
stirred at 0 ЊC for 45 min and partitioned between ethyl acetate
(100 ml) and water (50 ml). The aqueous layer was further
extracted with ethyl acetate (2 × 50 ml) and the organic extracts
were combined, washed sequentially with aqueous sodium
hydrogen carbonate (100 ml), brine (100 ml), hydrochloric acid
(1 ; 75 ml), and brine (100 ml), dried (Na2SO4), and evapor-
ated in vacuo to afford the title compound (1.75 g, 98%) as a pale
yellow foam that was used without further purification; [α]D19
Ϫ71.7 (c 1.0, CHCl3) (Found: Mϩ, 329.1378. C17H19N3O4
requires M, 329.1376); νmax(CHCl3)/cmϪ1 3522, 3404, 1680,
1633, 1575, 1418, 1357, 1119, 984 and 910; δH(400 MHz;
CDCl3, 20 ЊC) 7.33–7.00 (5 H, m, ArH), 6.75 (0.45 H, s, exch.
D2O, CONHH), 6.67 (0.55 H, s, exch. D2O, CONHH), 5.86 (1
H, s, exch. D2O, CONHH), 5.15–4.80 (3 H, m, NCHCH2 and
OCH2), 3.61 (1 H, m, NCHHCH2), 3.49 (1 H, m, NCHHCH2),
2.52 (1.35 H, s, OCCH3), 2.43 (1.65 H, s, OCCH3) and 2.30–
1.85 (4 H, m, NCHCH2CH2); δH(400 MHz, CDCl3, 50 ЊC) 7.27
(5 H, m, ArH), 6.66 (1 H, br s, exch. D2O, CONHH), 5.56 (1 H,
br s, exch. D2O, CONHH), 5.16 (1 H, m, NCHCH2), 4.95 (2 H,
br s, OCH2), 3.65 (1 H, m, NCHHCH2), 3.56 (1 H, m, NCH-
HCH2), 2.53 (3 H, s, Me) and 2.35–1.90 (4 H, m, NCH-
CH2CH2); δC(100.6 MHz; CDCl3) 165.1, 162.2, 162.1, 158.3,
155.6, 155.1, 154.4, 154.2, 129.64, 129.58, 129.2, 129.1, 128.8,
128.7, 128.5, 67.8, 55.6, 55.2, 47.7, 47.2, 35.0, 33.0, 24.9, 24.2,
12.5 and 12.4; m/z (EI) 329 (Mϩ, 13%), 194 (17), 153 (16), 91
(100), 70 (45) and 43 (46).
(S)-Methyl 2-{2-[1-(benzyloxycarbonylamino)-2-methylpropyl]-
5-methyloxazol-4-yl}-5-methyloxazole-4-carboxylate 17a
To a stirred solution of triphenylphosphine (0.148 g, 0.566
mmol) and iodine (0.144 g, 0.566 mmol) in anhydrous dichloro-
methane (10 ml) was added triethylamine (0.16 ml, 1.132 mmol)
followed by a solution of the oxazole 16a (0.126 g, 0.283 mmol)
in dichloromethane (10 ml). The reaction mixture was stirred
for 1 h at room temperature and then concentrated in vacuo.
The crude residue was purified by flash chromatography (ethyl
acetate–light petroleum) to yield the title compound (0.113 g,
94%); mp 163–164 ЊC (ethyl acetate–light petroleum); [α]D24
Ϫ40.0 (c 1.0, CHCl3) (Found: C, 61.2; H, 5.8; N, 9.6.
C22H25N3O6ؒ0.25H2O requires C, 61.2; H, 5.9; N, 9.7%)
(Found: Mϩ, 427.1742. C22H25N3O6 requires M, 427.1743);
νmax(Nujol)/cmϪ1 3289, 2957, 2937, 2860, 1734, 1694, 1545,
1300, 1264, 1202 and 1177; δH(400 MHz, CDCl3) 7.32 (5 H, m,
ArH), 5.48 (1 H, d, J 9.1, NH), 5.13 (2 H, s, OCH2), 4.83 (1 H,
dd, J 6.5, 9.1, CH), 3.92 (3 H, s, OMe), 2.70 (3 H, s, Me), 2.67 (3
H, s, Me), 2.21 (1 H, m, PriCH) and 0.95 (6 H, 2 overlapping d,
J 6.8, Me); δC(100.6 MHz; CDCl3) 162.7, 162.4, 156.0, 155.9,
154.0, 150.5, 136.2, 128.5, 128.3, 128.14, 128.08, 124.5, 67.1,
54.8, 51.9, 32.8, 18.8, 18.0, 12.0 and 11.7; m/z (EI) 427 (Mϩ,
2%), 340 (1), 319 (100), 276 (77), 259 (10), 244 (66), 222 (12),
190 (17), 162 (7), 135 (4), 108 (80), 107 (66), 91 (41), 79 (86), 77
(50) and 55 (41).
(S)-Methyl 2-[2-(1-benzyloxycarbonyltetrahydropyrrol-2-yl)-5-
methyloxazol-4-ylcarbonylamino]-3-oxobutanoate 16b
A solution of methyl 2-diazoacetoacetate (0.439 g, 3.07 mmol)
598
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
in dry chloroform (12 ml) was added dropwise over 6 h to a
refluxing solution of the amide 15b (0.715 g, 2.17 mmol) and
rhodium() acetate (19 mg, 0.044 mmol, 2 mol%) in dry chloro-
form (60 ml). The reaction mixture was allowed to cool,
evaporated in vacuo and purified by flash chromatography on
silica, eluting with ethyl acetate–light petroleum (1:1), to afford
the title compound (0.36 g, 38%) as a mixture of diastereomers
as a colourless oil (Found: Mϩ, 443.1691. C22H25N3O7 requires
M, 443.1692); νmax(CHCl3)/cmϪ1 3399, 2958, 2890, 1758, 1730,
1700, 1670, 1635, 1501, 1419, 1357, 1277, 1201, 1164 and 1119;
δH(400 MHz; CDCl3, 20 ЊC) 7.88 (1 H, m, exch. D2O, CONH),
7.40–7.05 (5 H, m, ArH), 5.36 (1 H, d, J 6.8, MeO2CCH), 5.19–
4.90 (3 H, m, NCHCH2 and OCH2), 3.74 (3 H, s, OMe), 3.68 (1
H, m, NCHHCH2), 3.58 (1 H, m, NCHHCH2), 2.58 (1.5 H, s,
Me), 2.45 (1.5 H, s, Me), 2.42 (3 H, s, Me) and 2.30–1.85 (4 H,
m, NCHCH2CH2); δH(400 MHz; CDCl3, 50 ЊC) 7.83 (1 H, m,
exch. D2O, CONH), 7.40–7.05 (5 H, m, ArH), 5.36 (1 H, d,
J 6.8, MeO2CCH), 5.19–4.90 (3 H, m, NCHCH2 and OCH2),
3.74 (3 H, s, CH3O), 3.68 (1 H, m, NCHHCH2), 3.58 (1 H, m,
NCHHCH2), 2.50 (3 H, br s, Me), 2.38 (3 H, s, Me) and 2.30–
1.85 (4 H, m, NCHCH2CH2); δC(100.6 MHz; CDCl3) 198.3,
198.1, 166.5, 161.7, 161.5, 154.8, 154.3, 153.8, 153.6, 136.6,
136.4, 128.4, 128.3, 127.9, 127.8, 67.0, 66.9, 62.5, 54.8, 54.4,
53.3, 46.9, 46.5, 32.2, 31.2, 27.9, 24.2, 23.5, 11.7 and 11.5; m/z
(EI) 443 (Mϩ, 3%), 401 (10), 310 (17), 223 (22), 160 (12), 91
(100), 70 (31) and 43 (55).
References
1 Preliminary communication, M. C. Bagley, R. T. Buck, S. L. Hind,
C. J. Moody and A. M. Z. Slawin, Synlett, 1996, 825.
2 G. Pattenden, J. Heterocycl. Chem., 1992, 29, 607.
3 J. P. Michael and G. Pattenden, Angew. Chem., Int. Ed. Engl., 1993,
32, 1.
4 P. Wipf, Chem. Rev., 1995, 95, 2115.
5 J. R. Lewis, Nat. Prod. Rep., 1992, 9, 81.
6 J. R. Lewis, Nat. Prod. Rep., 1993, 10, 29.
7 J. R. Lewis, Nat. Prod. Rep., 1994, 11, 395.
8 J. R. Lewis, Nat. Prod. Rep., 1995, 12, 135.
9 J. R. Lewis, Nat. Prod. Rep., 1996, 13, 435.
10 Y. Koyama, K. Yokose and L. J. Dolby, Agric. Biol. Chem., 1981, 45,
1285.
11 R. Jansen, B. Kunze, V. Wray, H. Reichenbach, E. Jurkiewicz,
G. Hunsmann and G. Höfle, Liebigs Ann. Chem., 1991, 707.
12 B. Kunze, R. Jansen, L. Pridzun, E. Jurkiewicz, G. Hunsmann,
G. Höfle and H. Reichenbach, J. Antibiot., 1992, 45, 1549.
13 Y. Ishibashi, S. Ohba, S. Nishiyama and S. Yamamura, Tetrahedron
Lett., 1996, 37, 2997.
14 D. Garey, M. Ramirez, S. Gonzales, A. Wertsching, S. Tith,
K. Keefe and M. R. Peña, J. Org. Chem., 1996, 61, 4853.
15 Y. Kato, N. Fusetani, S. Matsunaga, K. Hashimoto, S. Fujita and
T. Furuya, J. Am. Chem. Soc., 1986, 108, 2780.
16 D. A. Evans, J. R. Gage and J. L. Leighton, J Am. Chem. Soc., 1992,
114, 9434.
17 N. Tanimoto, S. W. Gerritz, A. Sawabe, T. Noda, S. A. Filla and
S. Masamune, Angew. Chem., Int. Ed. Engl., 1994, 33, 673.
18 S. Iwasaki, M. Namikoshi, H. Kobayashi, J. Furukawa, S. Okuda,
A. Itai, A. Kasuya, Y. Iitaka and Z. Sato, J. Antibiot., 1986, 39,
424.
19 M. Nakada, S. Kobayashi, M. Shibasaki, S. Iwasaki and M. Ohno,
Tetrahdron Lett., 1993, 34, 1039.
(S)-Methyl 2-[(1-benzyloxycarbonyltetrahydropyrrol-2-yl)-5-
methyloxazol-4-yl]-5-methyloxazole-4-carboxylate 17b
20 A. K. Todorova, F. Jüttner, A. Linden, T. Plüss and W. von
Philipsborn, J. Org. Chem., 1995, 60, 7891.
21 E. Aguilar and A. I. Meyers, Tetrahedron Lett., 1994, 35, 2477.
22 A. Nagatsu, H. Kajitani and J. Sakakibara, Tetrahedron Lett., 1995,
36, 4097.
23 P. Wipf and S. Venkatraman, J. Org. Chem., 1996, 61, 6517.
24 G. Pattenden, personal communication.
25 T. Ichiba, W. Y. Yoshida, P. J. Scheuer, I. Higa and D. G. Gravalos,
J. Am. Chem. Soc., 1991, 113, 3173.
26 P. Wipf and S. Lim, J. Am. Chem. Soc., 1995, 117, 558.
27 J. A. Roesener and P. J. Scheuer, J. Am. Chem. Soc., 1986, 108, 846.
28 D. W. Knight, G. Pattenden and D. E. Rippon, Synlett, 1990, 36.
29 S. K. Chattopadhyay and G. Pattenden, Tetrahedron Lett., 1995, 36,
5271.
30 J. S. Panek and R. T. Beresis, J. Org. Chem., 1996, 61, 6496.
31 S. Matsunaga, N. Fusetani and K. Hashimoto, J. Am. Chem. Soc.,
1986, 108, 847.
32 T. L. Gilchrist, Contemp. Org. Synth., 1994, 1, 205.
33 T. L. Gilchrist, Contemp. Org. Synth., 1995, 2, 337.
34 G. V. Boyd, Prog. Heterocycl. Chem., 1996, 8, 192.
35 K. J. Doyle and C. J. Moody, Tetrahedron, 1994, 50, 3761.
36 C. J. Moody and K. J. Doyle, Prog. Heterocycl. Chem., 1997, 9, 1.
37 K. J. Doyle and C. J. Moody, Synthesis, 1994, 1021.
38 E. Aller, R. T. Buck, M. J. Drysdale, L. Ferris, D. Haigh, C. J.
Moody, N. D. Pearson and J. B. Sanghera, J. Chem. Soc., Perkin
Trans. 1, 1996, 2879.
Triethylamine (0.33 ml, 2.37 mmol) and a solution of the
oxazole 16b (252 mg, 0.568 mmol) in dry dichloromethane (5
ml) were added successively to a stirred solution of triphenyl-
phosphine (298 mg, 1.14 mmol) and iodine (289 mg, 1.14
mmol) in dry dichloromethane (12 ml) at room temperature.
The mixture was stirred overnight, evaporated in vacuo and
purified by flash chromatography on silica, eluting with ethyl
acetate–light petroleum (3:2) to afford the title compound (195
mg, 81%) as a colourless oil. A small portion was recrystallised
from ethyl acetate–light petroleum to afford the title compound
as colourless needles, mp 122–122.5 ЊC; [α]D19 Ϫ71.1 (c 1.0,
CHCl3) (Found: C, 61.8; H, 5.15; N, 9.7. C22H23N3O6 requires
C, 62.1; H, 5.45; N, 9.9%) (Found: Mϩ, 425.1592. C22H23N3O6
requires M, 425.1587); νmax(CHCl3)/cmϪ1 3011, 2977, 2895,
1702, 1618, 1442, 1420, 1353, 1108, 1058 and 985; δH(400
MHz, CDCl3, 20 ЊC) 7.33 (2 H, m, ArH), 7.15 (3 H, m,
ArH), 5.14 (1 H, d, J 12.4, NCHCH2), 4.99 (2 H, m, OCH2),
3.89 (3 H, s, OMe), 3.68 (1 H, m, NCHHCH2), 3.56 (1 H, m,
NCHHCH2), 2.67 (3 H, s, Me), 2.64 (1.3 H, s, Me), 2.52 (1.7
H, s, Me) and 2.37–1.88 (4 H, m, NCHCH2CH2); δH(400
MHz, CDCl3, 50 ЊC) 7.35–7.00 (5 H, m, ArH), 5.09 (1 H, d,
J 12.4, NCHCH2), 4.95 (2 H, s, OCH2), 3.84 (3 H, s, OMe),
3.61 (1 H, m, NCHHCH2), 3.53 (1 H, m, NCHHCH2), 2.61
(3 H, s, Me), 2.51 (3 H, s, Me) and 2.35–1.85 (4 H, m,
NCHCH2CH2); δC(100.6 MHz; CDCl3) 163.2, 162.7, 155.8,
154.8, 154.3, 154.1, 154.0, 150.4, 150.2, 136.6, 136.4, 128.4,
128.3, 128.2, 127.9, 127.8, 124.7, 124.5, 67.0, 66.9, 55.0, 54.6,
51.8, 47.0, 46.5, 32.4, 31.4, 24.3, 23.6, 12.0, 11.8 and 11.6;
m/z (EI) 425 (Mϩ, 11%), 290 (8), 237 (7), 160 (23), 91 (100) and
43 (32).
39 L. Ferris, D. Haigh and C. J. Moody, J. Chem. Soc., Perkin Trans. 1,
1996, 2885.
40 M. Regitz and G. Maas, Diazo Compounds. Properties and Synthesis,
Academic Press, London, 1986.
41 M. P. Doyle, Acc. Chem. Res., 1986, 19, 348.
42 M. P. Doyle, Chem. Rev., 1986, 86, 919.
43 G. Maas, Top. Curr. Chem., 1987, 137, 75.
44 J. Adams and D. M. Spero, Tetrahedron, 1991, 47, 1765.
45 A. Padwa and S. F. Hornbuckle, Chem. Rev., 1991, 91, 263.
46 A. Padwa and K. E. Krumpe, Tetrahedron, 1992, 48, 5385.
47 E. A. Shapiro, A. B. Dyatkin and O. M. Nefedov, Russ. Chem. Rev.,
1993, 62, 447.
Acknowledgements
48 A. Padwa and D. J. Austin, Angew. Chem., Int. Ed. Engl., 1994, 33,
1797.
49 T. Ye and M. A. McKervey, Chem. Rev., 1994, 94, 1091.
50 D. J. Miller and C. J. Moody, Tetrahedron, 1995, 51, 10811.
51 A. F. Khlebnikov, M. S. Novikov and R. R. Kostikov, Adv.
Heterocycl. Chem., 1996, 65, 93.
52 F. Zaragoza, Tetrahedron, 1997, 53, 3425.
53 L. D. Cama and B. G. Christensen, Tetrahedron Lett., 1978, 44,
4233.
We thank the Association of International Cancer Research
(studentship to S. L. H.) and the EPSRC (ROPA Award) for
support of this work, and the EPSRC for funds towards the
purchase of a 400 MHz NMR spectrometer at Loughborough.
We also thank Fisons Pharmaceuticals/Astra Charnwood for
their generous support of our research programmes initiated at
Loughborough University, and the EPSRC Mass Spectrometry
Service at Swansea for mass spectra.
54 P. Wipf and C. P. Miller, J. Org. Chem., 1993, 58, 3604.
J. Chem. Soc., Perkin Trans. 1, 1998
599

View Article Online
62 M. Bianchi and I. Barzaghi, Farmaco Ed. Sci., 1965, 20, 611.
63 P. Tavecchia, P. Gentili, M. Kurz, C. Sottani, R. Bonfichi, E. Selva,
S. Lociuro, E. Restelli and R. Ciabatti, Tetrahedron, 1995, 51, 4867.
64 E. Wunsch, G. Wendlberger and A. Hogel, Chem. Ber., 1971, 104,
2430.
55 S. N. Osipov, N. Sewald, A. F. Kolomiets, A. V. Fokin and
K. Burger, Tetrahedron Lett., 1996, 37, 615.
56 J. S. Baum, D. A. Shook, H. M. L. Davies and H. D. Smith, Synth.
Commun., 1987, 17, 1709.
57 J. C. Lee and J. Y. Yuk, Synth. Commun., 1995, 25, 1511.
58 A. M. P. Koskinen and L. Muñoz, J. Chem. Soc., Chem. Commun.,
1990, 652.
65 R. Appel and E. Hiester, Chem. Ber., 1983, 116, 2037.
59 T. Ibata and H. Nakano, Bull. Chem. Soc. Jpn., 1992, 65, 3088.
60 J. L. Abernethy, F. G. Howell, A. Ledesma, D. Doose and
R. Everett, Tetrahedron, 1975, 31, 2659.
Paper 7/04093H
Received 11th June 1997
Accepted 26th September 1997
61 S.-T. Chen, M.-K. Jang and K.-T. Wang, Synthesis, 1993, 858.
600
J. Chem. Soc., Perkin Trans. 1, 1998