Studies of 2-substituted 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones as precursors for the synthesis of N-alkyl-β-amino acids

Article abstract of DOI:10.1080/00397910802369612

1,3-Oxazolidin-5-ones and 1,3-oxazinan-6-ones have been shown to be useful precursors for the synthesis of N-methyl α- and β-amino acids, respectively. The methodology has now been expanded to allow for the synthesis of N-alkyl-β-amino acids. Copyright Ta

Full text of DOI:10.1080/00397910802369612

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Studies of 2-Substituted 1,3-
Oxazolidin-5-ones and 1,3-
Oxazinan-6-ones as Precursors
for the Synthesis of N-Alkyl-β-
Amino Acids
Andrew B. Hughes a & Brad E. Sleebs a b
a Department of Chemistry, La Trobe University,
Melbourne, Australia
b Walter and Eliza Hall Institute of Medical Research,
Bundoora, Australia
Version of record first published: 15 Feb 2011.
To cite this article: Andrew B. Hughes & Brad E. Sleebs (2008): Studies of 2-
Substituted 1,3-Oxazolidin-5-ones and 1,3-Oxazinan-6-ones as Precursors for the
Synthesis of N-Alkyl-β-Amino Acids, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:1, 48-60
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Synthetic Communications1, 39: 48–60, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369612
Studies of 2-Substituted 1,3-Oxazolidin-5-ones
and 1,3-Oxazinan-6-ones as Precursors for
the Synthesis of N-Alkyl-b-Amino Acids
Andrew B. Hughes1 and Brad E. Sleebs1,2
1Department of Chemistry, La Trobe University, Melbourne, Australia
2Walter and Eliza Hall Institute of Medical Research, Bundoora, Australia
Abstract: 1,3-Oxazolidin-5-ones and 1,3-oxazinan-6-ones have been shown to be
useful precursors for the synthesis of N-methyl a- and b-amino acids, respectively.
The methodology has now been expanded to allow for the synthesis of N-alkyl-b-
amino acids.
Keywords: b-Amino acids, Arndt–Eistert homologation, 1,3-oxazolidin-5-ones,
1,3-oxazinan-6-ones
INTRODUCTION
N-Alkyl-b-amino acid and a-amino acid residues are of particular inter-
est in peptidomimetics. a-Amino acid–derived peptides readily undergo
proteolysis and possess poor membrane permeability. However, incor-
poration of N-alkyl-a- and b-amino acid residues, into a peptidomi-
metic may enhance its lipophilic character and confer proteolytic
stability.[1] Hence, N-alkyl-b-amino residues have the capability to be
useful entities in the area of peptidomimetics and therefore, potentially,
the drug industry.
Received April 30, 2008.
Address correspondence to Andrew B. Hughes, Department of Chemistry,
La Trobe University, 3086 Melbourne, Australia. E-mail: a.hughes@latrobe.
edu.au
48

1,3-Oxazolidin-5-ones and 1,3-Oxazinan-6-ones
49
Scheme 1. Synthesis of N-methyl-a-amino acids 2 and N-methyl-b-amino acids
3 via 1,3-oxazolidin-5-ones 1.
Such is the interest in N-methyl-amino acids that there is now a
plethora of methods available for their synthesis.[2] Many of these
methods can be applied to the synthesis of N-alkyl-amino acids. The most
popular method is the use of a strong base in an N-alkylation reaction.
However, potential exists when using a strong base for racemization of
the chiral center.[3]
In previous studies, we have shown that 1,3-oxazolidin-5-ones 1 are
useful substrates for the synthesis of N-methyl-a-amino acids 2 and N-
methyl-b-amino acids 3 (Scheme 1).[4–9] In addition, we have also shown
that the homologous 1,3-oxazinan-6-ones 4 are versatile precursors for
gaining access to a range of N-methyl-b-amino acids 3 (Scheme 2).[7–9]
Further, we provided one example of an N-alkyl-a-residue.[10] Herein
we expand on this methodology to enable facile access to N-alkyl-
b-amino acids.
Scheme 2. Synthesis of N-methyl-b-amino acids 3 via 1,3-oxazinan-6-ones 4.

50
A. B. Hughes and B. E. Sleebs
RESULTS AND DISCUSSION
In an extension of our previous work (Schemes 1 and 2)[7–9] it was envi-
saged that both 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones could
provide access to N-alkyl-b-amino acids by replacing formaldehyde with
an aliphatic aldehyde. We first concentrated efforts on the synthesis of
2-substituted-1,3-oxazinan-6-ones to provide access to N-alkyl-b-amino
acids.
The Cbz-N-b-amino acid 5 was subjected to condensation conditions
used previously,[6] only varying paraformaldehyde to benzaldehyde
(Scheme 3). However, under these conditions, no 2-substituted-1,3-oxazi-
nan-6-one 6 was formed. An alternative route was therefore sought.
Hiskey and Jung[11] demonstrated utilization of an amino acid Schiff’s
base to provide access to 2-oxazolidinones. Applying this methodology,
initial condensation of benzaldehyde with a sodium salt of b-alanine 7
to form a Schiff’s base and subsequent benzoylation allowed ring closure
to provide the 2-substituted-1,3-oxazinan-6-one 8 in low yield (14%)
(Scheme 3).
This methodology was then applied using pivaldehyde. Again a low
yield (10%) of the 2-substituted-1,3-oxazinan-6-one 9 was obtained. It
1
was found in H NMR analysis of the 2-t-butyl-1,3-oxazinan-6-one 9,
that over time the ring underwent hydrolysis back to its parent aldehyde
and the N-protected-b-alanine 10 (Scheme 3). Thus, the poor yields
obtained could be attributed to the degradation of the 2-substituted-
1,3-oxazinan-6-ones 6 and 9 once they had formed. Given these results,
it was decided not to access N-alkyl-b-amino acids via this route.
1,3-Oxazolidin-5-ones 1 have already been used to great effect in
the synthesis of N-methyl-a-amino acids 2.[4–8] Ben-Ishai[12] originally
demonstrated formaldehyde can be condensed with an amino acid
Scheme 3. Synthesis of 2-substituted-1,3-oxazinan-6-ones.

1,3-Oxazolidin-5-ones and 1,3-Oxazinan-6-ones
51
to form a 1,3-oxazolidin-5-one. Similarly, Freidinger et al.[13] produced 2-
substituted oxazolidinones that could be subsequently reduced to N-alkyl
residues. It was proposed to exploit this procedure to obtain the N-alkyl
a-amino acids. The Arndt–Eistert homologation could then be applied to
allow access to N-alkyl-b-amino acids.
Following the methodology of Freidinger et al.,[13] the 2-substituted
oxazolidinone 12 was formed by refluxing the aldehyde, the N-
carbamoyl-protected amino acid 11, and a catalytic amount of camp-
horsulfonic acid in toluene, with azeotropic removal of water using
a Dean–Stark trap. This resulted in a poor yield of the 2-alkyl-1,3-
oxazolidin-5-one 12 (30%). However, addition of a catalytic amount of
acetic acid to the reaction mixture resulted in the yield of the 2-
alkyl-1,3-oxazolidin-5-one 12 increasing two-fold (70%) (Scheme 4).
As a comparison, the approach described by Hiskey and Jung[11] was
also attempted to gain access to 2-substituted-1,3-oxazolidin-5-ones. The
procedure involved condensing the amino acid sodium salt 13 with ben-
zaldehyde to form the Schiff’s base 14. Subsequent N-acylation of 14
afforded the 2-substituted oxazolidinone 15 in a mediocre yield (55%)
(Scheme 4).
The N-carbamoyl 2-substituted oxazolidinones 12 and 15 were then
subjected to reductive cleavage to afford the N-alkyl a-residues 16 and
19 in good yields (71 and 75%, respectively) (Scheme 5). The Arndt–
Eistert homologation was then applied.[14] Activation of 16 and 19 to
their mixed anhydrides and subsequent reaction with diazomethane pro-
duced the diazoketones 17 and 20 in 60 and 50% yields, respectively.
Wolff rearrangement, using ultrasound in the presence of silver trifluoro-
acetate, produced the desired N-alkyl-b-residues 18 and 21 in good yields
(66 and 83%, respectively) (Scheme 5).
In conclusion, a facile method was developed to access N-alkyl-b-
residues. It was found that 2-substituted-1,3-oxazinan-6-ones could not
be utilized in the synthesis of N-alkyl-b-residues, because of their instab-
ility. However, 1,3-oxazolidin-5-ones were successfully utilized as
Scheme 4. Synthesis of 2-substituted-1,3-oxazolidin-5-ones.

52
A. B. Hughes and B. E. Sleebs
Scheme 5. Synthesis of N-alkyl-b-amino acids.
precursors to afford N-alkyl-b-amino acids in overall good yields. The
effective nature of this pathway underpins the viability of such methodol-
ogy being applied to other a-amino acids to produce various functiona-
lized N-alkyl-b-amino acids.
EXPERIMENTAL
General
All melting points are uncorrected and were recorded on a Reichert
Thermopan microscope hot-stage apparatus. Infrared spectra 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. Optical rotations were recorded on a
Perkin-Elmer 141 polarimeter. NMR were performed in (D)-chloroform
at 300 K unless otherwise stated on a Bruker Avance DRX-300 spectro-
¨
meter. Electrospray mass spectrometry (ESMS) was performed on a
Fission VG Bio-Q electrospray mass spectrometer, in the Department
of Chemistry, La Trobe University. Low- and high-resolution mass spec-
tra (LSIMS) were also measured at the University of Tasmania by Noel
Davies and coworkers on a Kratos Concept mass spectrometer at 70 eV,
all using water=methanol=acetic acid (0:99:1 or 50:50:1) mixtures as the

1,3-Oxazolidin-5-ones and 1,3-Oxazinan-6-ones
53
mobile phase. Microanalyses were performed by E. Mocellin and
coworkers from Chemical and Microanalytical Services in Belmont,
Victoria. Flash chromatography was carried out using silica-gel 60,
particle size 0.040–0.063 mm (230–400 mesh ASTM), supplied by Merck
Chemicals. Ethyl acetate and hexane used for chromatography were dis-
tilled prior to use. All solvents were purified by distillation. Thin-layer
chromatography (TLC) was performed on Merck kieselgel 60 F254 plates
and visualized with a UV lamp or by staining. Permanganate stain con-
sists of potassium permanganate (1% v=w), potassium carbonate (20%
v=w), and sodium hydroxide (1% v=w) in water. Ammonium molybdate
stain consists of 7% ammonium molybdate and 10% sulfuric acid in etha-
nol. Molybdenum polyphosphoric acid stain consists of 10% molybde-
num polyphosphoric acid in ethanol. For dry solvents, procedures from
Perrin and Armarego[15] were followed. All other reagents and solvents
were purified or dried as described by Perrin and Armarego.[15] All syn-
thetic yields reported are unoptimized.
2-Substituted-1,3-oxazinan-6-ones
N-Benzoyl-2-phenyl-6-oxo-1,3-oxazinane 8
b-Alanine 7 (0.03 mol) was dissolved in a 1 N sodium hydroxide solution
(0.03 mol), and the solution was evaporated to dryness under reduced
pressure. The residue was suspended in methylene chloride (40 mL),
and benzaldehyde (0.036 mol) was added. The solution was refluxed for
6 h, removing water azeotropically using a Dean–Stark trap under an
inert atmosphere. The solution was allowed to cool, and benzoyl chloride
(0.03 mol) was added at 0 ꢀC. The solution was allowed to warm to room
temperature, and it was stirred for 20 h. The mixture was diluted with
dichloromethane (30 mL), and the organic layer was washed successively
with water (50 mL), saturated sodium hydrogen carbonate (50 mL), 10%
citric acid solution (50 mL), and brine (50 mL). The organic layer was
dried (MgSO4) and concentrated in vacuo. Column chromatography
was performed eluting with 5–15% ethyl acetate–hexane to afford the
oxazinanone 8 as a solid (14% yield). Found: C, 72.49; H, 5.32; N,
4.87. C17H15NO3 requires C, 72.58; H, 5.37; N, 4.98%. Mp 99–103 ꢀC.
1H NMR (300 MHz, CDCl3) d 7.55–7.42 (10H, m, ArCH), 7.11 (1H,
bs, H-2), 4.30 (1H, bs, H-4A), 3.46–3.38 (1H, m, H-4B), 2.88–2.72 (1H,
m, H-5A), 2.51–2.41 (1H, m, H-6A). 13C NMR (75 MHz, CDCl3) d
171.14, 167.54 (CO), 136.17, 133.19 (Aryl C), 130.84, 129.38, 129.04,
128.59, 125.2 (aryl CH), 86.11 (C-2), 36.36 (C-4) 29.32 (C-5).

54
A. B. Hughes and B. E. Sleebs
N-Benzoyl-2-tert-butyl-6-oxo-1,3-oxazinane 9
b-Alanine 7 (0.03 mol) was dissolved in a 1 N sodium hydroxide solution
(0.03 mol), and the solution was evaporated to dryness under reduced
pressure. The residue was suspended in methylene chloride (40 mL),
and pivaldehyde (0.036 mol) was added. The solution was refluxed for
6 h, removing water azeotropically using a Dean–Stark trap under an
inert atmosphere. The solution was allowed to cool, and benzoyl chloride
(0.03 mol) was added at 0 ꢀC. The solution was allowed to warm to room
temperature and stirred for 20 h. The mixture was diluted with dichloro-
methane (30 mL), and the organic phase was washed successively with
water (50 mL), saturated sodium hydrogen carbonate (50 mL), 10% citric
acid solution (50 mL), and brine (50 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. Column chromatography was per-
formed eluting with 5–15% ethyl acetate–hexane to afford the oxazina-
none 9 as an oil (10% yield) (this compound degraded over time to N-
1
benzoyl-b-alanine 10 and pivaldehyde). H NMR (300 MHz, CDCl3) d
7.38–7.34 (5H, m, ArH), 6.24 (1H, bs, H-2), 4.01 (1H, bs, H-4A), 3.62–
3.52 (1H, m, H-4B), 2.48 (2H, bs, H-5), 1.01 [9H, s, C(CH3)3]. 13C
NMR (75 MHz, CDCl3) d 171.46, 167.10 (CO), 134.20 (aryl C), 130.28,
128.47, 126.52 (aryl CH), 89.91 (C-2), 39.49 (C-4), 38.49 [C(CH3)3],
30.43 [C-5), 25.72 (C(CH3)3].
2-Alkyl-1,3-Oxazolidin-5-ones
3-Benzyloxycarbonyl-2-nonyl-1,3-oxazolidin-5-one 12
Camphorsulfonic acid (1.0 mmol), acetic acid (1.0 mmol), and decanal
(0.015 mol) were added to the glycine benzylcarbamate 11 (0.01 mol) in
toluene (80 mL). The solution was refluxed with azeotropic removal of
water using a Dean–Stark trap for 20 h. The solution was concentrated
under reduced pressure, and the residue was dissolved in ethyl acetate
(70 mL). The organic layer was washed with saturated sodium bicarbo-
nate (70 mL); the organic layer was dried (MgSO4) and concentrated in
vacuo. The residue was purified using column chromatography eluting
with 5% ethyl acetate–hexane to furnish the oxazolidinone 12 as an oil
(70% yield), nmax(NaCl)=cmꢁ13034, 2926, 2855 (CH), 1807, 1714 (CO),
1416, 1360, 1253, 1080, 766, 698. 1H NMR (300 MHz, CDCl3) (rotamers)
d 7.34 (5H, s, ArH), 5.80–5.77 (1H, m, H-2), 5.18 and 5.13 (2H, q, JAB
12.2 Hz, ArCH2O), 4.21–4.16 (1H, m, H-4), 3.92–3.87 (1H, m, H-2),
1.88–1.71 (2H, m, CHCH2), 1.23 (14H, bs, (CH2)7), 0.86 (3H, t, J
6.3 Hz, CH2CH3). 13C NMR (75 MHz, CDCl3) d 169.26, 152.62 (CO),

1,3-Oxazolidin-5-ones and 1,3-Oxazinan-6-ones
55
135.4 (Aryl C), 128.49, 128.36, 128.20, 128.06, 127.89 (Aryl CH), 90.44
(C-2), 67.69 (ArCH2), 44.67 (C-4), 34.81, 31.67, 29.25, 29.22, 29.07,
28.88, 22.69, 22.49 (CH2), 13.93 (CH2CH3).
(4S)-Benzyl 4-Methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate 15
L-Alanine (0.03 mol) was dissolved in a 1 N sodium hydroxide solution
(0.03 mol), and the solution was evaporated to dryness under reduced
pressure. The residue was suspended in methylene chloride (40 mL),
and benzaldehyde (0.036 mol) was added. The solution was refluxed for
6 h, removing water azeotropically using a Dean–Stark trap under an
inert atmosphere. The solution was allowed to cool, and benzyl chloro-
formate (0.03 mol) was added at 0 ꢀC. The solution was allowed to warm
to room temperature, and it was stirred for 20 h. The mixture was diluted
with dichloromethane (30 mL) and washed successively with water
(50 mL), saturated sodium hydrogen carbonate (50 mL), 10% citric acid
solution (50 mL), and brine (50 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. Column chromatography was per-
formed on the residue, eluting with 15% ethyl acetate–hexane to afford
the oxazolidinone 15 as an oil (55% yield), which was identical in all
respects with previously reported material.[16]
N-Alkyl-a-amino Acids
N-Benzyloxycarbonyl-N-decyl-acetic Acid 16
Triethylsilane (10 mmol) was added to the oxazolidinone 12 (5 mmol)
dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL).
The solution was allowed to stand for 3 days. The mixture was evapo-
rated under reduced pressure; the residue was dissolved in toluene
(10 mL) and reduced in vacuo (2ꢂ). The resulting oil was purified using
column chromatography, eluting with 20% ethyl acetate–hexane, to
afford the acid 16 as a clear colorless oil (71% yield). Found: M þ H,
350.2332. C20H31NO4 requires M þ H, 350.2331. nmax(NaCl)=cmꢁ1
3300 (OH), 3034, 2925, 2854 (CH), 1714, 1696, 1681 (CO), 1429, 1367,
1
1226, 1107, 696. H NMR (300 MHz, CDCl3) d 7.90 (1H, s, COOH),
7.33–7.29 (5H, m, ArH), 5.15–5.12 (2H, m, ArCH2), 4.03–3.98 (2H, m,
NCH2CO), 3.35–3.29 (2H, m, NCH2), 1.51–1.23 [16H, m, (CH2)8], 0.87
(3H, t, J 6.6 Hz, CH2CH3). 13C NMR (75 MHz, CDCl3) (rotamers) d
174.80, 174.42, 156.83, 155.91 (CO), 136.31 (aryl C), 128.40, 127.96,
127.88, 127.70 (aryl CH), 67.61, 67.40 (ArCH2), 48.79, 48.29 (NCH2CO),

56
A. B. Hughes and B. E. Sleebs
31.81 (NCH2), 29.46, 29.22, 28.17, 27.97, 26.60 (CH2), 22.60 (CH2CH3),
14.04 (CH2CH3).
(2S)-N-(Benzyloxycarbonyl)-2-aminobenzyl-propanoic Acid 19
Triethylsilane (10 mmol) was added to the oxazolidinone 15 (5 mmol)
dissolved in dichloromethane (5 mL) and trifluroacetic acid (5 mL). The
solution was allowed to stand for 3 days. The mixture was evaporated
under reduced pressure, the residue was dissolved in toluene (10 mL),
and the solution was concentrated in vacuo (2ꢂ). The resulting oil was
purified using column chromatography eluting with 20% ethyl acetate–
hexane to furnish the acid 19 as a clear colorless oil (75% yield). (Found:
M þ H, 314.1396. C18H20NO4 requires M þ H, 314.1392. [a]D20-29.2 (c,
0.68 in CH2Cl2). nmax(NaCl)=cmꢁ1 3089, 2946 (CH), 1703 (CO), 1454,
1
1238, 1015, 735, 698. H NMR (300 MHz, CDCl3) (rotamers) d 9.39
(1H, bs, COOH), 7.30 (10H, s, ArH), 5.18 (2H, s, ArCH2), 4.73–4.24
(3H, m, NCH, NCH2), 1.41–1.39 (3H, d, J 7.0 Hz, CHCH3). 13C NMR
(75 MHz, CDCl3) (rotamers) d 177.26, 156.45 (CO), 137.95, 136.08 (aryl
C), 128.49, 128.40, 127.98, 127.78, 127.26, 127.06 (aryl CH), 67.71
(ArCH2), 55.45, 54.99 (NCH), 51.03, 50.05 (NCH2), 15.76, 15.10
(CHCH3).
N-Alkyl-diazoketones
N-Benzyloxycarbonyl-3-aminodecyl-1-diazo-propan-2-one 17
The N-alkyl residue 16 (1 mmol) was dissolved in anhydrous THF
(5 ml=mmol), and the solution was cooled to ꢁ15 ꢀC. To the solution,
ethyl chloroformate (1.05 mmol) and N-methylmorpholine (1.05 mmol)
were added successively, and the mixture was stirred for 15 min before
an anhydrous dichloromethane solution of diazomethane (5 mmol)
(CAUTION!) was added slowly to the mixture. The yellow solution
was allowed to warm to room temperature, and it was stirred for 1 h.
Excess diazomethane was destroyed by addition of acetic acid. The mix-
ture was concentrated under reduced pressure, and the residue was dis-
solved in ethyl acetate (30 mL). The organic phase was washed
successively with saturated sodium bicarbonate (25 mL), 10% citric acid
solution (25 mL), and brine (25 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was of sufficient purity
to be used in the following reaction. If required for analysis, compounds

1,3-Oxazolidin-5-ones and 1,3-Oxazinan-6-ones
57
were purified using column chromatography, eluting with 5–10% ethyl
acetate–hexane to afford the diazoketone 17 as a clear yellow oil (60%
yield). Found: M þ H, 374.2444. C21H32N3O3 requires M þ H, 374.2441.
n
max(NaCl)=cmꢁ1 3089, 2925, 2854 (CH), 2107 (CHN2) 1701, 1654,
(CO), 1497, 1466, 1362, 1226, 1107, 770, 697. 1H NMR (300 MHz, CDCl3)
(rotamers) d 7.23–7.20 (5H, m, ArH), 5.33–5.22 (1H, m, CHN2), 5.04–5.01
(2H, m, ArCH2), 3.87–3.82 (2H, m, NCH2CO), 3.22–3.18 (2H, m, NCH2),
1.42–1.17 [16H, m, (CH2)8], 0.79 (3H, t, J 6.2 Hz, CH2CH3). 13C NMR
(75 MHz, CDCl3) (rotamers) d 191.03, 190.83, 156.00, 155.19 (CO),
136.06 (aryl C), 128.39, 127.99, 127.81, 127.57, 127.41, 127.34 (aryl
CH), 66.97, 66.87 (ArCH2), 54.30, 54.01 (CHN2), 48.51, 47.96
(NCH2CO), 31.43 (NCH2), 29.08, 28.84, 27.82, 27.45, 26.24 (CH2),
22.27 (CH2CH3), 13.65 (CH2CH3).
(3S)-N-Benzyloxycarbonyl-3-aminobenzyl-1-diazo-butan-2-one 20
The N-alkyl residue 19 (1 mmol) was dissolved in anhydrous THF
(5 ml=mmol) and the solution was cooled to ꢁ 15 ꢀC. To the solution,
ethyl chloroformate (1.05 mmol) and N-methylmorpholine (1.05 mmol)
were added successively, and the mixture was stirred for 15 min before
an anhydrous dichloromethane solution of diazomethane (5 mmol)
(CAUTION!) was added slowly to the mixture. The yellow solution
was allowed to warm to room temperature, and it was stirred for 1 h.
Excess diazomethane was destroyed by addition of acetic acid. The mix-
ture was concentrated under reduced pressure, and the residue was dis-
solved in ethyl acetate (30 mL). The organic phase was washed
successively with saturated sodium bicarbonate (25 mL), 10% citric acid
solution (25 mL), and brine (25 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was of sufficient purity
to be used in the following reaction. If required for analysis, compounds
were purified using column chromatography, eluting with 5–10% ethyl
acetate–hexane to afford the diazoketone 20 as a clear yellow oil
(50% yield). Found: M þ H, 338.1508. C19H20N3O3 requires M þ H,
338.3805). [a]D ꢁ 106.1 (c, 2.6 in CH2Cl2). nmax(NaCl)=cmꢁ1 3065,
20
2943 (CH), 2106 (CHN2), 1697, 1645 (CO), 1496, 1454, 1358, 1244,
1
770, 699. H NMR (300 MHz, CDCl3) d 7.26 (10H, s, ArH), 5.39–5.15
(3H, m, CHN2, ArCH2), 4.90–4.30 (3H, m, NCH, NCH2), 1.27 (3H, d,
J 4.3 Hz, CHCH3). 13C NMR (75 MHz, CDCl3) d 192.70, 155.91 (CO),
137.94, 135.95 (aryl C), 128.20, 128.12, 127.78, 127.72, 127.06 (aryl
CH), 67.39 (ArCH2), 58.97 (CHN2), 52.82 (NCH), 49.40 (NCH2),
14.08 (CHCH3).

58
A. B. Hughes and B. E. Sleebs
N-Alkyl-b-amino Acids
N-Benzyloxycarbonyl-3-aminodecyl-propanoic Acid 18
The diazoketone 17 (1 mmol) was dissolved in a solution of dioxane=
water (9:1, v=v, 15 mL). On addition of silver trifluoroacetate
(0.01 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). The mixture was concentrated in vacuo.
The resulting residue was purified using column chromatography eluting
with 20% ethyl acetate–hexane to afford the acid 18 as a clear colorless oil
(66% yield). Found: C, 69.37; H, 9.17; N, 3.76. C21H33NO4 requires C,
69.39; H, 9.15; N, 3.85% nmax(NaCl)=cmꢁ1 3034, 2926, 2855 (CH),
1736, 1706, (CO), 1408, 1424, 1283, 1137, 1101, 770, 697. 1H NMR
(300 MHz, CDCl3) (rotamers) d 9.60 (1H, bs, COOH), 7.31 (5H, s,
ArH), 5.12 (2H, s, ArCH2), 3.55–3.51 (2H, m, NCH2), 3.27–3.30 (2H,
m, CH2CO), 2.66–2.62 (2H, m, NCH2), 1.50–1.23 [16H, m, (CH2)8],
0.87 (3H, t, J 6.5 Hz, CH2CH3). 13C NMR (75 MHz, CDCl3) (rotamers)
d 176.58, 156.14 (CO), 136.44 (aryl C), 128.29, 127.80, 127.63, 126.84
(aryl CH), 67.07 (ArCH2), 48.00, 47.81 (NCH2), 43.46, 42.65 (CH2CO),
33.52, 32.92 (NCH2CH2), 31.72, 29.37, 29.13, 28.49, 28.00, 26.56
(CH2), 22.51 (CH2CH3), 13.94 (CH2CH3).
(3S)-N-Benzyloxycarbonyl-3-aminobenzyl-butanoic Acid 21
The diazoketone 20 (1 mmol) was dissolved in a solution of dioxane=
water (9:1, v=v, 15 mL). On addition of silver trifluoroacetate
(0.01 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). The mixture was concentrated in vacuo.
The resulting residue was purified using column chromatography eluting
with 20% ethyl acetate–hexane, to afford the acid 21 as a clear colorless
oil (83% yield). Found: M þ H, 328.1547. C19H22NO4 requires M þ H,
20
328.1549). [a]D þ 23.6 (c, 1.2 in CH2Cl2). nmax(NaCl)=cmꢁ1 3065,
2977 (CH), 1713, 1681 (CO), 1454, 1338, 1215, 1170, 735, 698.
1H NMR (300 MHz, CDCl3) (323 K) d 10.46 (1H, bs, CO2H), 7.31–
7.27 (10H, m, ArH), 5.21 (2H, s, ArCH2), 4.64–4.32 (3H, m, NCH2,
NCH), 2.76–2.54 (2H, m, CH2CO), 1.23 (3H, bs, CHCH3). 13C NMR
(75 MHz, CDCl3) d 176.62, 156.82 (CO), 138.07, 136.09 (aryl C),
128.50, 128.44, 128.07, 127.92, 127.32 (aryl CH), 67.82 (ArCH2), 50.80
(NCH), 49.68 (NCH2), 39.45 (CH2CO), 18.71 (CHCH3).

1,3-Oxazolidin-5-ones and 1,3-Oxazinan-6-ones
ACKNOWLEDGMENT
59
The authors thank La Trobe University for a post graduate scholarship
provided to B.E.S.
REFERENCES
1. Goodfellow, V. S.; Marathe, M. V.; Kuhlman, K. G.; Fitzpatrick, T. D.;
Cuadrado, D.; Hanson, W.; Zuzack, J. S.; Ross, S. E.; Wieczoreck, M.;
Burkard, M.; Whalley, E. T. Bradykinin receptor antagonists containing N-
substituted amino acids: in vitro and in vivo B2 and B1 receptor antagonist
activity. J. Med. Chem. 1996, 39, 1472–1484.
2. Aurelio, L.; Hughes, A. B. Synthetic preparation of N-methyl-a-amino acids.
Chem. Rev. 2004, 104, 5823–5846.
3. Cheung, S. T.; Benoiton, N. L. N-Methylamino acids in peptide synthesis,
VII: Studies on the enantiomeric purity of N-methylamino acids prepared
by various procedures. Can. J. Chem. 1977, 55, 916–921.
4. Aurelio, L.; Box, J. S.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, M. M. An
efficient synthesis of N-methyl amino acids by way of intermediate 5-oxazo-
lidinones. J. Org. Chem. 2003, 68, 2652–2667.
5. Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B. A novel synthesis of N-methyl
asparagine, arginine, histidine, and tryptophan. Org. Lett. 2002, 4,
3767–3769.
6. Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, B. E. The facile pro-
duction of N-methyl amino acids via oxazolidinones. Aust. J. Chem. 2000, 53,
425–433.
7. Sleebs, B. E.; Hughes, A. B. Effective methods for the synthesis of N-methyl
b-amino acids from all 20 common a-amino acids using 1,3-oxazolidin-5-ones
and 1,3-oxazinan-6-ones. Helv. Chim. Acta 2006, 89, 2611–2637.
8. Sleebs, B. E.; Hughes, A. B. Synthesis of new b-amino acids via 5-oxazolidi-
nones and the Arndt–Eistert procedure. Aust. J. Chem. 2005, 58, 778–784.
9. Sleebs, B. E.; Hughes, A. B. Diastereoselective synthesis of a-methyl and
a-hydroxy-b-amino acids via 4-substituted-1,3-oxazinan-6-ones. J. Org.
Chem. 2007, 72, 3340–3352.
10. Hughes, A. B.; Mackay, M. F.; Sleebs, M. M. (2R,4S)-3-N-(Fluoren-9-
ylmethoxycarbonyl)-4-methyl-2-nonyloxazolidin-5-one. Acta Cryst. Sect. E
2003, E59, o1079–o1081.
11. Hiskey, R. G.; Jung, J. M. Azomethine chemistry, II: Formation of peptides
from oxazolidin-5-ones. J. Am. Chem. Soc. 1963, 85, 578–582.
12. Ben-Ishai, D. Reaction of acylamino acids with paraformaldehyde. J. Am.
Chem. Soc. 1957, 79, 5736–5737.
13. Freidinger, R. M.; Hinkle, J. S.; Perlow, D. S.; Arison, B. H. Synthesis of
9-fluorenylmethyloxycarbonyl-protected N-alkyl amino acids by reduction
of oxazolidinones. J. Org. Chem. 1983, 48, 77–81.
14. See Ref. 6 and 7, and references therein.

60
A. B. Hughes and B. E. Sleebs
15. Perrin, D. D.; Armarego, W. L. F. Purification Of Laboratory Chemicals;
3rd ed.; Pergamon: Oxford, 1988.
16. Altmann, E.; Nebel, K.; Mutter, M. Versatile stereoselective synthesis of
completely protected trifunctional a-methylated a-amino acid starting from
alanine. Helv. Chim. Acta 1991, 74, 800–806.