Synthesis of new β-amino acids via 5-oxazolidinones and the arndt-eistert procedure

Article abstract of DOI:10.1071/CH05199

N-Methyl β-amino acids are potentially useful amino acid derivatives for incorporation in lead peptide therapeutics. The syntheses of five such compounds are presented. Their synthesis via 6-oxazinanones was low yielding. Alternatively, reductive cleavage of a 5-oxazolidinone gave the N-methyl β-amino acid, which was then homologated via an Arndt-Eistert procedure in high yield to give the N-methyl α-amino acid. CSIRO 2005.

Full text of DOI:10.1071/CH05199

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2005, 58, 778–784
www.publish.csiro.au/journals/ajc
Synthesis of New β-Amino Acids via 5-Oxazolidinones
and the Arndt–Eistert Procedure
Andrew B. HughesA,C and Brad E. SleebsB
A Department of Chemistry, La Trobe University, Melbourne VIC 3086, Australia.
B Walter and Eliza Hall Institute of Medical Research, Melbourne VIC 3086, Australia.
C Corresponding author. Email: a.hughes@latrobe.edu.au
N-Methyl β-amino acids are potentially useful amino acid derivatives for incorporation in lead peptide therapeutics.
The syntheses of five such compounds are presented. Their synthesis via 6-oxazinanones was low yielding. Alter-
natively, reductive cleavage of a 5-oxazolidinone gave the N-methyl α-amino acid, which was then homologated via
an Arndt–Eistert procedure in high yield to give the N-methyl β-amino acid.
Manuscript received: 10 August 2005.
Final version: 20 September 2005.
Introduction
diazomethane to effect formation of a diazoketone. A Wolff
rearrangement of the diazoketone then forms the homolo-
gated acid.
The homologation of amino acids via acid chlorides is
complicated by the formation of side-products.[5,7] This prob-
lem has been overcome by the use of the ‘mixed anhydride
method’, which allows the use of amides and urethanes.[8]
Previously, we reported the synthesis of N-methyl α-
amino acids by reductive cleavage of 5-oxazolidinones
(Scheme 1).[1] This chemistry sought to provide an efficient
and general approach to the preparation of N-methyl amino
acids, which have been found to be useful or even critical
structural motifs in numerous biologically active peptides.
Other authors have also recognized the need for improved
methods in this area.[2] In the interest of extending our
methodology, β-amino acids were considered as synthetic
targets. β-Amino acids are present in a relatively small num-
ber of natural products but they are known to confer useful
properties on structures in which they are present. There are
many approaches to the synthesis of β-amino acids and their
derivatives and these are described and reviewed in detail by
Juaristi.[3] The use of α-amino acids as starting materials was
the focus of our plans as they include a structurally diverse
range of sidechains. The α-amino acids require one-carbon
homologation of their backbones to become β-amino acids.
An established procedure for the homologation of car-
boxylic acids is the Arndt–Eistert method,[4] which has also
been applied to amino acids.[5,6] The original homologa-
tion procedure involves reaction of an acid chloride with
Results and Discussion
Herein we describe the syntheses of five novel N-methyl
β-amino acids derived from valine, glutamine, cysteine, tryp-
tophan, and histidine. In a first attempt, N-Cbz-l-valine 1 was
converted into the diazoketone 2 (Scheme 2). This reaction is
an example of the ‘mixed anhydride’method employing ethyl
chloroformate and N-methyl morpholine (NMM). Treatment
of the diazoketone with silver(i) trifluoroacetate gave the
β-amino acid 3 by Wolff rearrangement. Reaction of the acid
3 with paraformaldehyde and a mixed catalyst, consisting
of camphorsulfonic acid and acetic acid, gave the key oxaz-
inanone 4 but only in 45% yield. The following reductive
cleavage, effected with triethylsilane and trifluoroacetic acid,
worked and a moderate yield (63%) of the N-methyl amino
acid 5 was isolated.
It appeared that the ring closure to give the 6-
oxazinanone was disfavoured compared to the corresponding
5-oxazolidinone. It was decided to attempt preparation of the
oxazinanone derived from aminoisobutyric acid.All attempts
to effect a Wolff rearrangement of the diazoketone 6 failed
to form the expected β-amino acid 9. Instead, urea and
dimethylacrylic acid were condensed to form the pyrimidine-
2,4-dione 7 (Scheme 3).[9] Base hydrolysis then gave the
amino acid 8, which was protected as the benzyl carba-
mate 9. The carbamate 9 reacted under acidic conditions
with paraformaldehyde to give the 6-oxazinanone 10 (95%).
R
R
(CH2O)n, Hϩ
Cbz
Cbz
Cbz
O
N
H
CO2H
N
O
R
R
Et3SiH,
Cbz
O
O
N
CO2H
N
CF3CO2H
Me
Scheme 1. 5-Oxazolidinone strategy for the synthesis of N-methyl
α-amino acids via reductive cleavage.[1]
© CSIRO 2005
10.1071/CH05199
0004-9425/05/110778

Synthesis of New β-Amino Acids via 5-Oxazolidinones
779
(a)
(c)
(b)
(a)
Cbz
Cbz
CHN2
Cbz
Cbz
Cbz
Cbz
O
N
H
CO2H
N
H
N
H
CO2H
N
O
O
1
2
1
12
(b)
(c)
Cbz
CO2H
N
H
CHN2
N
CO2H
N
3
Me
Me
O
13
14
Cbz
(d )
Cbz
CO2H
N
N
(d)
Me
Cbz
CO2H
O
O
N
4
5
Me
5
Scheme 2. Reagents and conditions: (a) (i) ClCO2Et, NMM;
(ii) CH2N2. (b) AgO2CCF3, H2O, sonicate. (c) (CH2O)n, CSA (cat.),
CH3CO2H (cat.), C6H6, reflux, 3 h, 45%. (d) CF3CO2H, Et3SiH,
CH2Cl2, 63%.
Scheme 4. Reagents and conditions: (a) (CH2O)n, CSA (cat.), toluene,
reflux. (b) CF3CO2H, Et3SiH, CH2Cl2. (c) (i) ClCO2Et, NMM;
(ii) CH2N2, 50%. (d) AgO2CCF3, H2O, sonicate, 86%.
CO2H
O
CONBn2
O
(a)
R
Cbz
Cbz
CO2H
Cbz
Cbz
N
H
N
H
N
N
O
O
O
9
15
16
R ϭ OH
6
R ϭ CHN2
CONBn2
(b)
(c)
O
Cbz
N
CO2H
H2N
NH2
Me
(a)
(c)
(b)
NH
17
ϩ
O
N
O
H
CONBn2
CHN2
CONBn2
CO2H
CO2H
(d)
Cbz
Cbz
7
N
N
Me
O
Me
CO2H
Cbz
CO2H
18
19
H2N
N
H
8
9
Scheme 5. Reagents and conditions: (a) (i) SOCl2; (ii) 2 eq. Bn2NH,
CH2Cl2, 52%. (b) CF3CO2H, Et3SiH, CH2Cl2, 90%. (c) (i) ClCO2Et,
NMM; (ii) CH2N2, 65%. (d) AgO2CCF3, H2O, sonicate, 85%.
Cbz
(d )
(e)
Cbz
CO2H
N
N
Me
O
O
prepare the N-methyl α-amino acid,[1] and then homologate
those compounds by the Arndt–Eistert procedure to afford
the required N-methyl β-amino acids.
10
11
Scheme 3. Reagents and conditions: (a) (CH2OH)2, 190◦C, 1 h.
(b) (i) NaOH, H2O; (ii) HCl, H2O. (c) Cbz-succinimide, Et3N, DMF.
(d) (CH2O)n, CSA (cat.), CH3CO2H (cat.), C6H6, reflux, 3 h, 95%.
(e) CF3CO2H, Et3SiH, CH2Cl2, 71%.
Accordingly, the l-valine carbamate 1 was converted into
its 5-oxazolidinone 12 (Scheme 4)[1] and this was reduc-
tively cleaved to give N-methyl valine 13. Treatment of the
acid 13 with ethyl chloroformate and NMM gave the mixed
anhydride, which was exposed to diazomethane to afford the
diazoketone 14 (50%).AWolff rearrangement of the diazoke-
tone using silver(i) trifluoroacetate proceeded in high yield
(86%) to give the expected β-amino acid 5. The efficiency
of this approach is higher than that in Scheme 2 and so the
synthesis in Schemes 5–8 was attempted.
It can be seen that compound 9 is more highly substituted
at the β-carbon than the carbamate 3. Presumably, it is the
steric compression caused by the gem-dimethyl group, the
Thorpe–Ingold effect[10] that is the reason for the improved
yield of the 6-oxazinanone 10 compared with the formation
of compound 4. Reductive cleavage then gave the expected N-
methyl β-amino acid 11. This β-amino acid was conveniently
purified and characterized as its dicyclohexylammonium salt
(71% yield).
At this point it was apparent that the approach to N-
methyl β-amino acids via the chemistry shown in Scheme 2
was low yielding, at least in the key oxazinanone formation
and reductive cleavage steps. An alternative strategy was to
The oxazolidinone 15[1] was treated with thionyl chloride
to make an acid chloride, which was quenched with diben-
zylamine to give the amide 16 (52%) (Scheme 5). Reductive
cleavage proceeded in high yield (90%) to provide the glu-
tamine derivative 17.The diazoketone 18 was isolated in 65%
yield and underwent smooth rearrangement to the desired
β-amino acid 19 (85%).

780
A. B. Hughes and B. E. Sleebs
SBn
SBn
CHN2
the Wolff rearrangement, but in practice the reaction was
uneventful. The β-amino acid 22 was isolated in 87% yield.
The conversions of the tryptophan derivative 23[1]
(Scheme 7) were similarly effective.The anhydride procedure
afforded the diazoketone 24 (56%) and the Wolff rearrange-
ment gave the β-amino acid 25 in moderate yield (68%).
Lastly, the 2,4-dinitrophenyl (DNP) protected histidine
26[1] (Scheme 8) was converted into the diazoketone 27
(50%). The Wolff rearrangement with silver(i) trifluoroac-
etate catalyst, as before, gave the expected acid 28 but the
acidwasdifficulttohandleandpurify.Alternatively, theWolff
rearrangement of the diazoketone 27 can be conducted in a
dioxane/methanol solvent mixture. The ketene intermediate
formed in the reaction is intercepted by methanol giving the
methyl ester 29 in good yield (82%).
(a)
Cbz
Cbz
N
CO2H
N
Me
Me
O
20
21
SBn
CO2H
(b)
Cbz
N
Me
22
Scheme 6. Reagents and conditions: (a) (i) ClCO2Et, NMM;
(ii) CH2N2, 50%. (b) AgO2CCF3, H2O, sonicate, 87%.
CHO
N
CHO
N
(a)
Conclusion
Cbz
Cbz
CHN2
N
CO2H
N
In conclusion, we report the elaboration, via Arndt–Eistert
homologation, of five N-methyl α-amino acids to the cor-
responding β-amino acids. This approach to β-amino acids
was compared with an approach via 6-oxazinanone interme-
diates, and these were found to be low yielding. A larger
range of these β-amino acids will be reported in due course.
The 6-oxazinanone intermediates, while being formed in low
yields, are still valuable for the formulation of novel sub-
stituted β-amino acids and our efforts in the future will be
focused on this area. In this way it is hoped a range of
novel monomeric units of high biological activity potential
and structural diversity will be made available to medicinal
and combinatorial chemists particularly those interested in
peptidomimetic compounds.
Me
Me
O
23
24
CHO
N
(b)
Cbz
CO2H
N
Me
25
Scheme 7. Reagents and conditions: (a) (i) ClCO2Et, NMM;
(ii) CH2N2, 56%. (b) AgO2CCF3, H2O, sonicate, 68%.
DNP
N
DNP
N
Experimental
N
N
(a)
Melting points (mp) were recorded on a Reichert ‘thermopan’ hot-
stageapparatusandareuncorrected. Elementalanalyseswereperformed
by Chemical and Microanalytical Services, Melbourne. Unless other-
wise specified, 1H and 13C NMR spectra were recorded on a Bruker
Avance 300 MHz spectrometer operating at 300 MHz for proton and
75 MHz for carbon nuclei. Chemical shifts were recorded as δ values
in parts per million (ppm). Spectra were acquired in deuterated chlo-
roform (CDCl3) at 20◦C unless otherwise stated. For 1H NMR spectra
recorded in CDCl3, the peak due to residual CHCl3 (δH 7.24) was used
as the internal reference, while the central peak (δC 77.0) of the CDCl3
triplet was used as the reference for proton-decoupled 13C NMR spec-
tra. Solvents were dried over standard drying agents[11] and freshly
distilled before use. Reactions were monitored by TLC on silica gel
60 F254 plates with detection by UV fluorescence or charring with a
basic potassium permanganate stain. Flash-column chromatography[12]
was performed on silica gel 60 (230–400 mesh). Optical rotations were
measured at the stated temperatures in the stated solvent on a Perkin–
Elmer 141 polarimeter at the sodium d-line (589 nm); [α]D values are
given in 10−1 deg cm2 g−1. Infrared spectra (νmax) were recorded on a
Bruker Vector 22 Fourier-Transform Spectrometer or a Perkin–Elmer
1720-X FT-IR Spectrometer using a diffuse reflectance accessory
with KBr background. Samples were analysed as KBr Disks (for
solids) or as thin films on NaCl plates (for liquids/oils). Low- and
high-resolution mass spectra (LSIMS) were measured on a Kratos Con-
cept mass spectrometer at 70 eV using a mobile phase consisting of
water/methanol/acetic acid in a ratio of 0/99/1 or 50/49/1 in the posi-
tive mode unless otherwise indicated. Diazomethane[13] was prepared
by the usual method from N-methyl-N-nitroso-p-toluenesulfonamide
(Diazald) and used immediately.
Cbz
Cbz
CHN2
N
CO2H
N
Me
Me
O
26
27
(b)
(c)
DNP
DNP
N
N
N
N
Cbz
CO2H
Cbz
CO2Me
N
N
Me
Me
28
29
Scheme 8. Reagents and conditions: (a) (i) ClCO2Et, NMM;
(ii) CH2N2, 50%. (b) AgO2CCF3, H2O, sonicate. (c) AgO2CCF3,
MeOH/dioxane, sonicate, 82%.
N-Methyl-S-benzyl cysteine 20 formed the expected anhy-
dride with ethyl chloroformate and then the desired diazoke-
tone 21 (50%) in reaction with diazomethane. There was
concern the sulfur would poison the silver catalyst used in

Synthesis of New β-Amino Acids via 5-Oxazolidinones
781
Benzyl (4R)-4-Isopropyl-6-oxo-1,3-oxazinane-3-carboxylate 4
3-{[(Benzyloxy)carbonyl](methyl)amino}-3-methylbutanoic Acid 11
To the β-amino acid 3 (1 mmol) in toluene (150 mL) was added cam-
phorsulfonic acid (0.1 mmol) and acetic acid (0.1 mmol). The reaction
mixture was heated to 90◦C for 5 h during which time paraformaldehyde
(excess) was added in small portions down the condenser. The reaction
was monitored by TLC. The mixture was filtered, while warm, through
a glass frit, and the filtrate was reduced under vacuum. The residue
was taken up in ethyl acetate and the organic phase was washed with
saturated NaHCO3 solution. The organic layer was dried (MgSO4) and
evaporated under reduced pressure.The residue was purified via column
chromatography with 20–45% ethyl acetate–hexane as eluent to afford
the 6-oxazinanone 4 as a clear colorless oil (45% yield). [α]2D0 + 147.8
(c 1.0 in MeOH). νmax (NaCl)/cm−1 2964, 2800, 1761, 1714, 1455,
1262, 1155, 1130, 1009, 990, 772, 738, 698. δH (rotamers) 7.37–7.24
(5H, m), 5.89 (1H, br s), 5.16 (2H, s), 4.89 (1H, d, J 10.8), 4.12–4.05 (1H,
m), 2.72 (1H, dd, J 7.0, 16.1), 2.54 (1H, dd, J 10.5, 16.1), 2.10–1.99 (1H,
m), 0.92–0.88 (6H, m). δC (rotamers) 170.2, 155.0, 135.4, 128.5, 128.4,
128.0, 73.0, 68.2, 54.7, 32.0, 31.5, 18.4, 16.5. m/z (LSIMS) (Found:
M+ 277.1309. C15H19NO4 requires M+ 277.3157).
The oxazinanone 10 (1 mmol) was dissolved in dichloromethane (min.
vol.)/trifluoroaceticacid(50/50, v/v).Triethylsilane(3 mmol)wasadded
and the mixture was stirred for 24–48 h, until no oxazinanone remained
(monitored by TLC). Toluene was added to the solution and the sol-
vent was then evaporated under vacuum. This procedure was repeated
three times to remove any trace of trifluoroacetic acid. The residue was
taken up in diethyl ether and washed with saturated NaHCO3 solu-
tion (three times). The combined aqueous layers were washed with
diethyl ether. The pH of the aqueous fraction was adjusted to pH 2
with dilute HCl solution, and the aqueous layers were extracted with
ethyl acetate (three times). The combined organic phases were dried
(MgSO4) and evaporated under reduced pressure. If there was any trace
of trifluoroacetic acid, a silica plug filtration was performed, with5–10%
methanol–dichloromethane as eluent. For analysis and ease of handling
the free acid could be converted into a dicyclohexyl ammonium salt
in the usual manner. The free acid was taken up in anhydrous diethyl
ether (min. vol.) and treated with dicyclohexylamine (1.05 mmol). A
precipitate was slowly formed. The dropwise addition of hexane some-
times aided the precipitation process. Stirring was generally continued
for 16 h. The solid was filtered off at the pump and washed with a cold
diethyl ether/hexane solution to give the dicyclohexylammonium salt
of compound 11 as a white solid (71% yield), mp 102–105◦C. νmax
(KBr)/cm−1 2937, 2859, 2538, 2454, 2361, 1685, 1622, 1544, 1457,
1391, 1337, 1267, 1120, 1074, 857, 741, 709. δH (rotamers) 8.43 (2H,
br s), 7.27 (5H, br s), 5.03–4.97 (2H, m), 2.95–2.68 (7H, m), 1.93–
1.12 (26H, m). δC (rotamers) 176.7, 176.4, 155.8, 155.2, 137.2, 128.2,
128.0, 127.9, 127.7, 127.5, 127.5, 66.3, 65.7, 57.0, 52.4, 51.3, 50.9,
47.3, 31.8, 29.3, 27.6, 26.4, 25.1, 24.7. m/z (LSIMS) (Found: 264.1243.
C14H18NO4 requires [M − H]+ 264.2971).
(3R)-3-{[(Benzyloxy)carbonyl](methyl)amino}-4-methylpentanoic
Acid 5
The diazoketone 14 (1 mmol) was dissolved in
a solution of
dioxane/water (9/1 v/v, 50 mL). On addition of silver trifluoroacetate
(0.1 mmol), the mixture was sonicated in an ultrasound bath for 30 min
or until no presence of the diazoketone remained as indicated by TLC
(ethyl acetate–hexane). To the mixture was added saturated NaHCO3
solution. A precipitate was formed and was filtered off through a bed
of celite and the filter cake was washed with saturated NaHCO3 solu-
tion and diethyl ether. The filtrate was placed in a separating funnel
and the aqueous layer was washed with diethyl ether (two times). The
ethereal layer was back-washed with saturated NaHCO3 solution. The
combined aqueous layers were acidified to pH 2 with dilute HCl solu-
tion, and extracted with ethyl acetate (3×).The organic extract was dried
(MgSO4) and evaporated under vacuum. The residue was subjected to
column chromatography for analysis, but for ease of handling a tert-
butyl ammonium salt can be made in the usual manner. The compound
5 was isolated as a clear colorless oil (86% yield), and it was then con-
verted into a tert-butylammonium salt, mp 99–101◦C. [α]D20 −7.5 (c 1.1
in MeOH). νmax (KBr)/cm−1 3408, 2937, 2928, 2742, 2635, 2361, 2341,
2224, 1689, 1638, 1543, 1406, 1324, 969, 700, 672. δH (D2O, rotamers)
7.31–7.11 (5H, m), 5.20–4.93 (2H, m), 4.12–4.08 (1H, m), 2.85–2.71
(3H, m), 2.50–2.32 (2H, m), 1.75–1.71 (1H, m), 1.26 (9H, s), 0.92–0.77
(6H, m). δC (D2O, rotamers) 180.2, 180.1, 158.2, 157.7, 136.5, 136.3,
128.4, 128.3, 127.9, 127.5, 127.2, 67.2, 66.9, 60.6, 51.6, 38.8, 38.7,
29.9, 28.5, 26.3, 18.7, 18.6, 18.5. m/z (LSIMS−) (Found: 278.1396.
Benzyl (1S)-3-Diazo-1-isopropyl-2-oxopropyl(methyl)carbamate 14
The N-carbonylbenzyloxy-l-N-methyl-α-amino acid 13 (1 mmol) was
dissolved in anhydrous THF (5 mL) and the solution was cooled to
−15◦C. To the solution, ethyl chloroformate (1.05 mmol) and N-methyl
morpholine (1.05 mmol) were added successively and the solution was
then stirred for 15 min before an anhydrous dichloromethane solution
containing diazomethane (5 mmol; CAUTION!)[13] was added slowly,
dropwise, to the mixture. The yellow solution was then allowed to warm
to room temperature and stirring was continued until there was no acid
remaining, as indicated by TLC. Excess diazomethane was destroyed
by addition of acetic acid. The mixture was concentrated under reduced
pressure and the residue was taken up in ethyl acetate. The organic
phase was washed successively with saturated NaHCO3 solution, 10%
citric acid solution, and brine. The organic layer was dried (MgSO4) and
evaporated to dryness under vacuum. The diazoketone 14 was isolated
as a clear yellow oil (50% yield). [α]2D0 −306.7 (c 1.2 in CH2Cl2). νmax
(NaCl)/cm−1 3106, 3068, 3034, 2964, 2875, 2102, 1696, 1644, 1470,
1399, 1371, 1338, 1226, 1170, 978, 791, 698. δH (rotamers) 7.15–7.10
(5H, m), 5.31 (1H, br s), 4.98–4.92 (0.5H, m), 4.14–3.92 (2H, m), 2.64
(3H, s), 2.16–2.03 (1H, m), 0.76 (3H, d, J 6.5), 0.66 (3H, d, J 5.2). δC
(rotamers) 190.9, 190.5, 156.3, 155.2, 136.1, 127.8, 127.6, 127.5, 127.3,
127.0, 66.8, 66.0, 54.4, 29.8, 29.3, 25.3, 25.0, 19.2, 19.0, 18.1, 17.9.
The product was of sufficient purity to be used in the following
reaction.
•
C15H21NO4 requires [M − H]+ 278.1392).
Benzyl 4,4-Dimethyl-6-oxo-1,3-oxazinane-3-carboxylate 10
To the β-amino acid 9 (1 mmol) in toluene (150 mL) was added cam-
phorsulfonic acid (0.1 mmol) and acetic acid (0.1 mmol). The reaction
mixture was heated to 90◦C for 5 h during which time paraformaldehyde
(excess) was added in small portions down the condenser. The reaction
was monitored by TLC. The mixture was filtered, while warm, through
a glass frit, and the filtrate was reduced under vacuum. The residue
was taken up in ethyl acetate and the organic phase was washed with
saturated NaHCO3 solution. The organic layer was dried (MgSO4) and
evaporated under reduced pressure.The residue was purified via column
chromatography with 20–45% ethyl acetate–hexane as eluent to afford
the 6-oxazinanone 10 as a white solid (95% yield), mp 70–71◦C. νmax
(KBr)/cm−1 3030, 2970, 1769, 1712, 1410, 1359, 1312, 1265, 1116,
1026, 698. δH (rotamers) 7.29–7.20 (5H, m), 5.40 (2H, s), 5.08 (2H, s),
2.65–2.60 (2H, m), 1.44 (6H, s). δC (rotamers) 170.0, 153.0, 135.4,
128.3, 128.1, 128.0, 127.9, 127.6, 127.6, 72.9, 67.4, 54.8, 44.6, 26.9,
26.8. m/z (LSIMS) (Found: 264.1231. C14H18NO4 requires [M + H]+
264.1236).
Benzyl (4S)-4-[3-(Dibenzylamino)-3-oxopropyl]-5-oxo-
1,3-oxazolidine-3-carboxylate 16
The oxazolidinone 15 (8.0 mmol) in thionyl chloride (6 mL) was
refluxed for 15 min under an inert atmosphere. The excess thionyl
chloride was removed at reduced pressure and the residue was dis-
solved in toluene and then the solvent was evaporated under vacuum.
This procedure was repeated another two times. The acid chloride
was then dissolved in dry methylene chloride and, at 0◦C, dry diben-
zylamine (16.0 mmol) was added slowly. The mixture was left to
stir for 30 min while warming to room temperature. The hydrochlo-
ride salt produced was filtered off and the organic layer was washed

782
A. B. Hughes and B. E. Sleebs
successively with dilute hydrochloric acid solution (two times), sat-
urated sodium carbonate solution, and water. The organic layer was
dried (MgSO4) and concentrated under vacuum. The glutamine deriva-
tive 16 was purified by column chromatography with 30% ethyl
acetate/hexane as eluent to give a clear colorless oil (52% yield).
[α]D20 +71.5 (c 1.1 in CH2Cl2). νmax (KBr)/cm−1 3063, 3031, 2921,
1799, 1715, 1650, 1645, 1416, 1359, 1212, 1028, 733, 699. δH
(rotamers) 7.37–7.09 (15H, m), 5.50 (1H, br s), 5.18–5.10 (3H, m),
4.67–4.36 (5H, m), 2.64–2.24 (4H, m). δC (rotamers) 172.0, 171.7,
153.0, 137.1, 136.2, 135.3, 128.9, 128.6, 128.5, 128.2, 128.2, 127.6,
127.4, 126.3, 77.4, 67.9, 53.9, 49.8, 48.3, 28.1, 26.2. m/z (LSIMS)
(Found: M+ 472.1996. C28H28N2O5 requires M+ 472.1998).
ethyl acetate (three times). The organic extract was dried (MgSO4) and
evaporated under vacuum. The residue was subjected to column chro-
matography for analysis, but for ease of handling a tert-butyl ammonium
salt can be made in the usual manner (see above). The compound 19
was isolated as a clear, colorless oil (85% yield), and was then converted
into a tert-butylammonium salt, mp 108–111◦C. [α]D20 +6.7 (c 3.2 in
MeOH) (Found: C 70.5, H 7.7, N 7.5. C33H43N3O5 requires C 70.6,
H 7.7, N 7.5%). νmax (KBr)/cm−1 2972, 2634, 2547, 2234, 1698, 1640,
1547, 1400, 1335, 1209, 1152, 736, 696. δH (rotamers) 7.70 (3H, s),
7.28–6.98 (15H, m), 5.12–4.87 (2H, m), 4.62–4.18 (5H, m), 2.69 (3H,
s), 2.42–2.27 (4H, m), 1.90 (2H, m), 1.24 (9H, s). δC (rotamers, 318 K)
176.7, 172.9, 156.6, 137.4, 137.0, 136.5, 128.9, 128.5, 128.4, 128.2,
127.8, 127.5, 127.3, 126.5, 66.9, 53.9, 50.9, 50.1, 48.4, 41.6, 29.9, 28.6,
28.0, 27.7.
(2S)-4-{[(Benzyloxy)carbonyl](methyl)amino}-5-dibenzylamino-
5-oxobutanoic Acid 17
This compound was prepared according to the procedure of Aurelio
et al.[1] This material was isolated as a white solid (90% yield). [α]2D0
−8.7 (c 2.0 in CH2Cl2). νmax (KBr)/cm−1 3064, 3031, 2942, 1733,
1703, 1650, 1605, 1453, 1361, 1212, 1171, 734, 698. δH (rotamers)
10.34 (1H, br s), 7.33–7.04 (15H, m), 5.10–5.08 (2H, m), 4.81–4.33 (5H,
m), 2.87–2.84 (3H, m), 2.57–2.01 (4H, m). δC (rotamers) 173.6, 172.7,
157.2, 156.9, 136.8, 136.3, 135.8, 129.1, 128.7, 128.5, 128.3, 128.1,
127.8, 127.6, 126.4, 67.7, 58.7, 50.0, 48.8, 31.6, 30.1, 29.6, 24.7. m/z
(LSIMS)(Found:[M + H]+ 475.2235. C28H31N2O5 requires[M + H]+
475.2233).
Benzyl (1R)-1-[(Benzylthio)methyl]-3-diazo-2-oxopropyl(methyl)-
carbamate 21
The N-carbonylbenzyloxy-l-N-methyl-α-amino acid 20 (1 mmol) was
dissolved in anhydrous THF (5 mL) and the solution was cooled to
−15◦C. To the solution, ethyl chloroformate (1.05 mmol) and N-methyl
morpholine (1.05 mmol) were added successively and the solution was
then stirred for 15 min before an anhydrous dichloromethane solution
containing diazomethane (5 mmol; CAUTION!)[13] was added slowly,
dropwise, to the mixture. The yellow solution was then allowed to warm
to room temperature and stirring was continued until there was no acid
remaining, as indicated by TLC. Excess diazomethane was destroyed
by addition of acetic acid. The mixture was concentrated under reduced
pressure and the residue was taken up in ethyl acetate. The organic
phase was washed successively with saturated NaHCO3 solution, 10%
citric acid solution, and brine. The organic layer was dried (MgSO4) and
evaporated to dryness under vacuum. The diazoketone 21 was isolated
as a clear yellow oil (50% yield). [α]2D0 −182.2 (c 1.0 in CH2Cl2). νmax
(NaCl)/cm−1 3064, 3031, 2930, 2108, 1697, 1643, 1494, 1479, 1355,
1133, 1071, 766, 699. δH (rotamers) 7.35–7.21 (10H, m), 5.39–5.16
(3H, m), 4.87–4.53 (1H, m), 3.70–3.59 (2H, m), 3.01–2.94 and 2.71–
2.60 (2H, 2m), 2.79 (3H, s). δC (rotamers) 191.0, 156.7, 137.6, 136.3,
128.7, 128.3, 127.9, 127.5, 126.9, 67.5, 62.0, 60.7, 54.0, 35.9, 30.8, 29.9,
29.5, 28.9. m/z (LSIMS) (Found: [M + H]+ 384.1381. C20H22N3O3S
requires [M + H]+ 384.1382).
Benzyl (1S)-3-Diazo-1-[3-(dibenzylamino)-3-oxopropyl]-
2-oxopropyl(methyl)carbamate 18
The N-carbonylbenzyloxy-l-N-methyl-α-amino acid 17 (1 mmol) was
dissolved in anhydrous THF (5 mL) and the solution was cooled to
−15◦C. To the solution, ethyl chloroformate (1.05 mmol) and N-methyl
morpholine (1.05 mmol) were added successively and the solution was
then stirred for 15 min before an anhydrous dichloromethane solution
containing diazomethane (5 mmol; CAUTION!)[13] was added slowly,
dropwise, to the mixture. The yellow solution was then allowed to
warm to room temperature and stirring was continued until there was
no acid remaining, as indicated by TLC. Excess diazomethane was
destroyed by addition of acetic acid. The mixture was concentrated
under reduced pressure and the residue was taken up in ethyl acetate.
The organic phase was washed successively with saturated NaHCO3
solution, 10% citric acid solution, and brine. The organic layer was
dried (MgSO4) and evaporated to dryness under vacuum to give the
diazoketone 18 as a clear yellow oil (65% yield). [α]2D0 −69.1 (c 1.0
in CH2Cl2). νmax (NaCl)/cm−1 3088, 3063, 2948, 2106, 1738, 1700,
1646, 1495, 1467, 1348, 1192, 1080, 768, 734, 699. δH (rotamers)
7.29–7.05 (15H, m), 5.43–5.08 (3H, m), 4.79–4.32 (5H, m), 2.82–2.77
(3H, m), 2.44–2.30 (4H, m). δC (rotamers) 192.0, 171.8, 171.3, 170.7,
156.6, 155.7, 137.0, 136.1, 136.0, 128.6, 128.3, 128.2, 128.1, 128.0,
127.8, 127.7, 127.5, 127.4, 127.3, 126.0, 67.3, 67.0, 61.7, 61.2, 60.9,
60.0, 58.1, 53.8, 53.6, 49.5, 48.1, 30.7, 29.8, 29.0, 28.7, 23.1, 22.8. m/z
(LSIMS)(Found:[M + H]+ 499.2334. C29H31N4O4 requires[M + H]+
499.2345).
The product was of sufficient purity to be used in the following
reaction.
(3R)-3-{[(Benzyloxy)carbonyl](methyl)amino}-4-benzylthiobutanoic
Acid 22
The diazoketone 21 (1 mmol) was dissolved in a solution of dioxane/
water (9/1 v/v, 50 mL). On addition of silver trifluoroacetate (0.1 mmol)
the mixture was sonicated in an ultrasound bath for 30 min or until
no presence of the diazoketone remained as indicated by TLC (ethyl
acetate–hexane). To the mixture was added saturated NaHCO3 solution.
A precipitate was formed and was filtered off through a bed of celite and
the filter cake was washed with saturated NaHCO3 solution and diethyl
ether. The filtrate was placed in a separating funnel and the aqueous
layer was washed with diethyl ether (two times). The ethereal layer was
back-washed with saturated NaHCO3 solution. The combined aqueous
layers were acidified to pH 2 with dilute HCl solution, and extracted with
ethyl acetate (three times). The organic extract was dried (MgSO4) and
evaporated under vacuum. The residue was subjected to column chro-
matography for analysis, but for ease of handling a tert-butyl ammonium
salt can be made in the usual manner. The compound 22 was isolated
as a clear colorless oil (87% yield). A sample was converted into a
tert-butylammonium salt, mp 89–90◦C. [α]D20 −39.0 (c 1.6 in MeOH).
νmax (KBr)/cm−1 2976, 2919, 2629, 2529, 1697, 1682, 1557, 1455,
1398, 1329, 1273, 698. δH (rotamers) 7.31–7.18 (10H, m), 6.54 (3H,
br s), 5.18–5.00 (2H, m), 4.65–4.57 (1H, m), 3.70–3.65 (2H, m), 2.78–
2.75 (3H, m), 2.67–2.40 (4H, m), 1.25 (9H, s). δC (rotamers) 176.9,
176.8, 156.5, 138.2, 138.1, 136.8, 136.7, 128.9, 128.3, 127.8, 127.8,
127.4, 126.8, 67.1, 66.8, 53.6, 50.7, 41.2, 40.8, 36.1, 36.0, 34.1, 33.9,
The product was of sufficient purity to be used in the following
reaction.
(3S)-3-{[(Benzyloxy)carbonyl](methyl)amino}-
6-dibenzylamino-6- oxohexanoic Acid 19
The diazoketone 18 (1 mmol) was dissolved in a solution of dioxane/
water (9/1 v/v, 50 mL). On addition of silver trifluoroacetate (0.1 mmol)
the mixture was sonicated in an ultrasound bath for 30 min or until
no presence of the diazoketone remained as indicated by TLC (ethyl
acetate–hexane). To the mixture was added saturated NaHCO3 solution.
A precipitate was formed and was filtered off through a bed of celite and
the filter cake was washed with saturated NaHCO3 solution and diethyl
ether. The filtrate was placed in a separating funnel and the aqueous
layer was washed with diethyl ether (two times). The ethereal layer was
back-washed with saturated NaHCO3 solution. The combined aqueous
layers were acidified to pH 2 with dilute HCl solution, and extracted with

Synthesis of New β-Amino Acids via 5-Oxazolidinones
783
29.5, 27.8. m/z (LSIMS) (Found: [M + H]+ 374.1442. C24H35N2O4S
requires [M + H]+ 374.1426).
slowly to the mixture. The yellow solution was allowed to warm to
room temperature and stirring was continued until there was no acid
remaining, as indicated by TLC. Excess diazomethane was destroyed
by addition of acetic acid. The reaction mixture was concentrated under
reduced pressure and the residue was dissolved in ethyl acetate. The
organic phase was washed with saturated NaHCO3 solution.The organic
layer was dried (MgSO4) and evaporated under vacuum. The residue
was then subjected to column chromatography with ethyl acetate as
eluent, followed by 95/5 ethyl acetate/methanol as an eluent to afford
the diazoketone 27 as a clear orange gum (50% yield). [α]2D0 −12.7
(c 0.38 in MeOH). νmax (NaCl)/cm−1 3100, 2943, 2108, 1694, 1641,
1609, 1537, 1348, 1141, 1081, 742. δH (rotamers, [D6]DMSO) 8.79–
8.78 (1H, m), 8.51–8.48 (1H, m), 7.63–7.51 (2H, m), 7.30–7.23 (6H, m),
6.83 and 6.70 (1H, 2s), 5.44–5.29 (1H, m), 5.15–4.86 (3H, m), 3.31–
2.85 (5H, m). δC (rotamers, [D6]DMSO) 191.8, 156.7, 155.8, 146.7,
144.2, 140.5, 136.4, 136.3, 134.9, 129.1, 128.4, 128.2, 128.0, 127.8,
121.2, 117.0, 67.6, 63.0, 61.7, 60.3, 54.3, 31.8, 30.7, 26.6, 26.0, 21.0. m/z
(LSIMS)(Found:[M + H]+ 494.1436. C22H20N7O7 requires[M + H]+
494.1424).
Benzyl (1S)-3-Diazo-1-[(1-formyl-1H-indol-3-yl)methyl]-2-
oxopropyl(methyl)carbamate 24
The N-carbonylbenzyloxy-L-N-methyl-α-amino acid 23 (1 mmol) was
dissolved in anhydrous THF (5 mL) and the solution was cooled to
−15◦C. To the solution, ethyl chloroformate (1.05 mmol) and N-methyl
morpholine (1.05 mmol) were added successively and the solution was
then stirred for 15 min before an anhydrous dichloromethane solution
containing diazomethane (5 mmol; CAUTION!)[13] was added slowly,
dropwise, to the mixture. The yellow solution was then allowed to
warm to room temperature and stirring was continued until there was
no acid remaining, as indicated by TLC. Excess diazomethane was
destroyed by addition of acetic acid.The mixture was concentrated under
reduced pressure and the residue was taken up in ethyl acetate. The
organic phase was washed successively with saturated NaHCO3 solu-
tion, 10% citric acid solution, and brine. The organic layer was dried
(MgSO4) and evaporated to dryness under vacuum. The diazoketone
24 was isolated as a clear yellow oil (56% yield). [α]2D0 −122.8 (c 0.5
in CH2Cl2). νmax (NaCl)/cm−1 3012, 2926, 2856, 2107, 1702, 1643,
1607, 1496, 1355, 1202, 1140, 792, 748, 698. δH (rotamers) 9.31–8.34
(2H, m), 7.58–6.87 (9H, m), 5.43–4.88 (4H, m), 3.39–2.83 (5H, m). δC
(rotamers) 192.4, 191.4, 159.1, 156.6, 155.5, 136.0, 135.7, 134.2, 131.0,
129.7, 128.5, 128.4, 127.7, 125.3, 124.5, 123.9, 123.0, 122.6, 121.9,
119.7, 119.3, 118.9, 118.7, 116.0, 110.8, 109.6, 67.8, 67.6, 62.1, 60.8,
60.2, 54.4, 31.8, 30.9, 30.1, 29.6, 29.2, 23.2, 22.7, 20.9. m/z (LSIMS)
(Found: [M − 28]+ 376.1421. C22H20N2O4 requires [M − 28]+
376.1423).
Methyl (3S)-3-{[(Benzyloxy)carbonyl](methyl)amino}-4-
[1-(2,4-dinitrophenyl)-1H-imidazol-4-yl]butanoate 29
The diazoketone 27 (0.1 mmol) was dissolved in a solution of
dioxane/MeOH (9/1 v/v, 5 mL). On addition of silver trifluoroacetate
(0.01 mmol) the mixture was sonicated in an ultrasound bath for 30 min
or until no diazoketone remained, as indicated by TLC. The reaction
mixture was concentrated under vacuum. The residue was dissolved in
ethyl acetate, and the organic phase was washed with saturated sodium
carbonatesolution.Theorganiclayerwasdried(MgSO4)andevaporated
under vacuum. The residue was subjected to column chromatography
with 95/5 ethyl acetate/methanol as eluent, to afford the ester 29 as
a clear yellow gum (82% yield). [α]2D0 0.00 (c 0.16 in MeOH). νmax
(NaCl)/cm−1 3116, 2952, 1735, 1695, 1610, 1542, 1343, 1213, 1145,
737. δH (rotamers, [D6]DMSO) 8.82–8.81 (1H, m), 8.52–8.48 (1H, m),
8.16–8.10 (1H, m), 7.70–7.63 (1H, m), 7.31–7.16 (6H, m), 6.90–6.88
(1H, m), 5.27 (2H, s), 4.75–4.68 (1H, m), 3.61 (3H, s), 3.05–2.49 (7H,
m). δC (rotamers, [D6]DMSO) 171.3, 156.1, 147.0, 144.5, 141.0, 137.1,
136.3, 135.0, 129.2, 128.4, 128.1, 121.2, 119.2, 117.1, 67.0, 54.7, 51.7,
37.6, 37.3, 31.5, 31.2, 30.8. m/z (LSIMS) (Found: [M + H]+ 498.1644.
C23H24N5O8 requires [M + H]+ 498.1625).
The product was of sufficient purity to be used in the following
reaction.
(3S)-3-{[(Benzyloxy)carbonyl](methyl)amino}-4-(1-formyl-1H-indol-
3-yl)butanoic Acid 25
The diazoketone 24 (1 mmol) was dissolved in a solution of diox-
ane/water (9/1 v/v, 50 mL). On addition of silver trifluoroacetate
(0.1 mmol) the mixture was sonicated in an ultrasound bath for 30 min
or until no presence of the diazoketone remained as indicated by TLC
(ethyl acetate/hexane). To the mixture was added saturated NaHCO3
solution. A precipitate was formed and was filtered off through a bed
of celite and the filter cake was washed with saturated NaHCO3 solu-
tion and diethyl ether. The filtrate was placed in a separating funnel
and the aqueous layer was washed with diethyl ether (two times). The
ethereal layer was back-washed with saturated NaHCO3 solution. The
combined aqueous layers were acidified to pH 2 with dilute HCl solu-
tion, and extracted with ethyl acetate (three times). The organic extract
was dried (MgSO4) and evaporated under vacuum.The residue was sub-
jected to column chromatography for analysis, but for ease of handling
a tert-butyl ammonium salt can be made in the usual manner. The com-
pound 25 was isolated as a clear, colorless oil (68% yield), and it was
then converted into a tert-butylammonium salt, mp 110–114◦C. [α]D20
−25.4 (c 1.8 in MeOH). (Found: C 66.7, H 7.0, N 8.9. C26H33N3O5
requires C 66.8, H 7.1, N 9.0%). νmax (KBr)/cm−1 3094, 2932, 2622,
2551, 2359, 2250, 1707, 1545, 1452, 1383, 1209, 1131, 762, 756, 733,
695. δH (D2O, rotamers, 318 K) 8.82–8.02 (2H, m), 7.44–6.86 (9H, m),
4.91–4.66 (3H, m), 2.84–2.69 (5H, m), 2.58–2.53 (2H, m) 1.37 (9H, s).
δC (rotamers, 318 K) 178.6, 157.4, 161.2, 156.7, 136.4, 135.9, 133.5,
131.1, 128.2, 127.3, 126.7, 124.6, 124.2, 123.6, 121.8, 121.2, 120.3,
119.0, 115.3, 109.9, 67.0, 66.4, 54.1, 53.9, 51.8, 40.6, 28.6, 28.3, 27.1,
26.6, 26.5.
Acknowledgment
We thank La Trobe University for the provision of a Post-
Graduate Scholarship awarded to B.E.S.
References
[1] (a) L. Aurelio, R. T. C. Brownlee, A. B. Hughes, B. E. Sleebs,
Aust. J. Chem. 2000, 53, 425. doi:10.1071/CH99082
(b) L. Aurelio, J. S. Box, R. T. C. Brownlee, A. B. Hughes,
M. M. Sleebs, J. Org. Chem. 2003, 68, 2652. doi:10.1021/
JO026722L
[2] (a) K. N. White, J. P. Konopelski, Org. Lett. 2005, 7, 4111.
doi:10.1021/OL051441W
(b) S. Zhang, T. Govender, T. Norstroem, P. Arvidsson, J. Org.
Chem. 2005, 70, 6918. doi:10.1021/JO050916U
(c) E. Biron, K.Yamada, H. Oku, R. Katakai, J. Org. Chem. 2005,
70, 5183. doi:10.1021/JO050477Z
[3] Enantioselective Synthesis of β-Amino Acids (Ed. E. Juaristi)
1997 (Wiley-VCH: New York).
[4] A. Hassner, C. Stumer, Organic Synthesis Based on Name
Reactions and Unnamed Reactions 1994 (Pergamon: Oxford).
[5] K. Plucinska, B. Liberek, Tetrahedron 1987, 43, 3509. doi:
10.1016/S0040-4020(01)81643-4
[6] T. Kimmerlin, D. Seebach, Helv. Chim. Acta 2003, 86, 2098.
doi:10.1002/HLCA.200390166
Benzyl (1S)-3-Diazo-1-{[1-(2,4-dinitrophenyl)-1H-imidazol-
4-yl]methyl}-2-oxopropyl(methyl)carbamate 27
The amino acid 26 (1 mmol) was dissolved in anhydrous THF (5 mL)
and the solution was cooled to −30◦C. To the solution, ethyl chlorofor-
mate (1.05 mmol) and collidine (1.05 mmol) were added successively
and the mixture was stirred for 15 min before an anhydrous solution of
diazomethane (5 mmol; CAUTION!)[13] in dichloromethane was added
[7] B. Penke, J. Czombos, L. Baláspiri, J. Petres, K. Kovács, Helv.
Chim. Acta 1970, 53, 1057. doi:10.1002/HLCA.19700530520

784
A. B. Hughes and B. E. Sleebs
[8] D. S.Tarbell, J.A. Price, J. Org. Chem. 1957, 22, 245. doi:10.1021/
[12] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.
doi:10.1021/JO00408A041
JO01354A005
[9] (a) K.-Y. Zee-Cheng, R. K. Robins, C. C. Cheng, J. Org. Chem.
1961, 26, 1877. doi:10.1021/JO01065A046
(b) D. Seebach, P. E. Ciceri, M. Overhand, B. Jaun, D. Rigo, Helv.
Chim. Acta 1996, 79, 2043. doi:10.1002/HLCA.19960790802
[10] E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds
1994, Ch. 11, p. 682 (Wiley: New York).
[13] Diazomethane is very toxic and potentially explosive. For proce-
dures on its preparation and safe handling see:
(a) T. J. de Boer, H. J. Baker, Org. Synth. Collect. Vol. 4 1963,
p. 250 (Wiley: New York, NY).
(b) M. Hudlicky, J. Org. Chem. 1980, 45, 5377. doi:10.1021/
JO01314A036
[11] W. L. F. Armarego, D. D. Perrin, Purification of Laboratory
Chemicals, 3rd edn 1988 (Pergamon Press: Oxford).