A novel synthesis of N-but-3-enyl-α- and β-amino acids

Article abstract of DOI:10.1055/s-0028-1088072

N-But-3-enyl-α- and β-amino acids can be prepared by cleaving 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones in the presence of allylsilanes and boron trifluoride etherate at room temperature in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088072

PAPER
1991
A Novel Synthesis of N-But-3-enyl-a- and b-Amino Acids
N
-But-3-enylam
.
inoAcids T. Van Nguyen, Robert T. C. Brownlee, Andrew B. Hughes*
Department of Chemistry, La Trobe University, Victoria 3086, Australia
Fax +61(3)94791399; E-mail: a.hughes@latrobe.edu.au
Received 19 January 2009
intermediate 1,3-oxazolidin-5-ones and 1,3-oxazin-6-
ones were also attempted.
Abstract: N-But-3-enyl-a- and b-amino acids can be prepared by
cleaving 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones in the
presence of allylsilanes and boron trifluoride etherate at room tem-
perature in good to excellent yields.
N-But-3-enyl-a- and b-Amino Acids
Key words: 1,3-oxazolidin-5-ones, 1,3-oxazinan-6-ones, amino
acids, allylations, Lewis acids
Protected amino acids 1 were reacted with paraformalde-
hyde [(CH2O)n] in acetonitrile in the presence of p-tolu-
enesulfonic acid (PTSA) as catalyst. This reaction was
conducted in a microwave reactor at 130 °C for 3 minutes,
as previously described by Govender and Arvidsson6 to
form 1,3-oxazolidin-5-ones 2 (Scheme 1). The intermedi-
ate 2 gave spectra identical to those of an authentic sam-
ple.1,3,7,8
Aurelio et al.1,3,4,7,8 were successful in preparing N-pro-
tected N-methylated amino acids through the reductive
opening of 1,3-oxazolidin-5-ones in the presence of trieth-
ylsilane and TFA or BF3·OEt2. By similar methodology,
N-but-3-enyl-a-amino acids 3 were successfully synthe-
sized by cleaving intermediates 2 via treatment with
ATMS and BF3·OEt2 in dichloromethane at room temper-
ature. A range of uncommon amino acids with different
types of N-protecting groups were made by this method-
ology to form compounds 3 in good to excellent yields
(Table 1). We also trialed the cleavage of 1,3-oxazolidin-
5-ones through the use of ATMS and TFA, however,
these conditions failed to form the expected N-but-3-enyl-
a-amino acids.
N-Substituted amino acids have been found in proteins,
peptides, enzymes, hormones as well as other secondary
metabolities.1 These uncommon amino acids have re-
ceived considerable attention from the scientific commu-
nity because of their useful pharmacological properties,
particularly when they are present in larger molecules.2
Thus, they have become sub-targets in the synthesis of bi-
ologically active substances in medicinal chemistry. Both
solution- and solid-phase synthesis of these compounds
and their derivatives have been reported for the develop-
ment of some leads in therapeutic peptide and peptidomi-
metic structures.
In previous publications,3–5 we have reported the success-
ful synthesis of N-methylated-a- and b-amino acids and
some N-alkylated b-amino acids via reductive cleavage of
1,3-oxazolidin-5-ones and 1,3-oxazin-6-ones in the pres-
ence of triethylsilane and trifluoroacetic acid (TFA).
These conditions have been modified to prepare ana-
logues of N-alkenylated a- and b-amino acids. Both 1,3-
oxazolidin-5-ones and 1,3-oxazin-6-ones were success-
fully cleaved using allyltrimethylsilane (ATMS) and bo-
ron trifluoride etherate (BF3·OEt2) at room temperature to
form N-but-3-enyl-a- and b-amino acids. A range of un-
common amino acids with different types of N-protecting
groups were successfully made by this methodology. Op-
timization studies to improve the yields and purities of the
It is worthwhile to emphasize that the use of BF3·OEt2 cat-
alyst in the reaction led to a rapid cleavage of acid sensi-
tive side chain protecting groups as well as cleavage of
Boc-protected 1,3-oxazolidin-5-ones and this led to puri-
fication problems via column chromatography.
TSA, (CH2O)n
MeCN
MW (200 W)
3 min, 130 °C
60 psi
R
BF3⋅Et2O (2 equiv)
CH2Cl2
ATMS (3 equiv)
R
PG
R
N
CO2H
PG
O
PG
N
N
CO2H
3
H
20–98%
O
1
2
PG = Cbz, Fmoc, Ts, Bz
R = H, Me, i-Pr, s-Bu, i-Bu, Ph, Bn, 4-BnOC6H4CH2, (CH2)2CO2(Troc), (CH2)2CO2(DCHA), CH2CO2(Troc)
Scheme 1 Microwave formation of oxazolidin-5-ones 2 and their Lewis acid mediated cleavage to afford N-but-3-enyl-a-amino acids 3
SYNTHESIS 2009, No. 12, pp 1991–1998
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Advanced online publication: 27.04.2009
DOI: 10.1055/s-0028-1088072; Art ID: P00809SS
© Georg Thieme Verlag Stuttgart · New York

1992
T. T. Van Nguyen et al.
PAPER
Table 1 ATMS Cleavage of 1,3-Oxazolidinones 2 Using BF3·OEt2 to N-But-3-enyl-a-amino Acids 3
Residue
N-But-3-enyl-a-
Yield (%)
Residue
N-But-3-enyl-a-
Yield (%)
amino acid
amino acid
Cbz-L-Gly
Ts-L-Gly
3a
3b
3c
3d
3e
3f
89
95
80
94
82
76
98
80
85
98
Bz-L-Leu
3k
3l
60
84
98
95
92
20
54
43
65
64
Cbz-L-Ile
Cbz-L-Ala
Cbz-D-Ala
Fmoc-L-Ala
Troc-L-Ala
Cbz-L-Val
Fmoc-L-Val
Cbz-L-Leu
Fmoc-L-Leu
Cbz-L-Phg
3m
3n
3o
3p
3q
3r
3s
Cbz-L-Phe
Fmoc-L-Phe
Cbz-L-Tyr(OBn)
Cbz-L-Asp(DCHA)
Cbz-L-Glu(DCHA)
Fmoc-L-Glu(Troc)
Cbz-L-Glu(Troc)
3g
3h
3i
3j
3t
It is shown clearly from Table 1 that N-but-3-enyl-a-ami-
Different Allyl-Substituted Silanes
no acids with simple aliphatic or aromatic side chains
3a–o were obtained in good to excellent yields (60–98%). Allyltriphenylsilane (ATPS) was also applied to cleave
However, the five other compounds 3p–t were obtained in 1,3-oxazolidin-5-ones under the same reaction conditions
lower yields (20–65%). It may be due to the complexity or as ATMS (see Scheme 1). Although results show the
reactivity of the side chains, resulting in unwanted side re- spectra for the product 3 to be identical, ATMS gave bet-
actions that gave these lower yields. The dicyclohexyl- ter yields than those obtained from the reaction of 1,3-ox-
amine (DCHA) salt was also cleaved to give free side azolidin-5-ones and ATPS (Table 3).
chains for compounds 3q and 3r.
Table 3 Yields of N-But-3-enyl-a-amino Acids Using Different
Allyl-Substituted Silanes
Lewis Acids
Residue
Allyl-substituted N-But-3-enyl-a- Yield
silane
amino acid
(%)
80
55
95
60
98
55
Several Lewis acids were trialed in the cleavage of 1,3-ox-
azolidin-5-ones. It was shown from the study that
BF3·OEt2 is the best Lewis acid for the novel cleavage of
2 (Table 2). This is thought to be as a result of the stronger
Lewis acidity of BF3·OEt2 relative to the other Lewis ac-
ids tried though the use of AlCl3 was uniformly unsuc-
cessful.
Cbz-L-Ala
Cbz-L-Ala
Ts-L-Gly
ATMS
ATPS
ATMS
ATPS
ATMS
ATPS
3c
3c
3b
3b
3m
3m
Ts-L-Gly
Cbz-L-Phg
Cbz-L-Phg
Table 2 Yields of N-But-3-enyl-a-amino Acids Using Different
Lewis acids
Residue
Lewis Acid
BF3·OEt2
AlCl3
Product
Yield (%)
N-But-3-enyl-b-amino Acids
Cbz-L-Ala
3c
80
0
The homologation of commercially available crystalline,
optically pure a-amino acids to b-amino acids by the
Arndt–Eistert method9,10 has been accomplished employ-
ing a-amino acid derived diazoketones as the key interme-
diates.11,12 These optically active substrates have been
converted to the corresponding b-amino acids by Wolff
rearrangement13,14 in the presence of water, thermally,15–18
photochemically,10 by silver ion catalysis, and by using
ultrasound.19,20
EtAlCl2
Et2AlCl
BF3·OEt2
AlCl3
60
0
Fmoc-L-Phe
3o
92
0
EtAlCl2
Et2AlCl
65
0
For the synthesis of N-alkylated-a- and b-amino acids, di-
azomethane is a well-known reagent for diazoketone for-
mation, and is readily derived from N-nitroso-p-
Synthesis 2009, No. 12, 1991–1998 © Thieme Stuttgart · New York

PAPER
N-But-3-enylamino Acids
Table 4 Yields of N-But-3-enyl-b-amino acids
1993
toluenesulfonamide (Diazald).21 However, Diazald was
no longer commercially available to us.7,22 Less hazardous
trimethylsilyldiazomethane (TMSCHN2) was reacted
with protected amino acids 1 to produce diazoketones 4 in
the presence of EtOCOCl and Et3N under anhydrous con-
ditions (Scheme 2).23 The following Wolff rearrangement
using silver benzoate catylyst24 converted the diazoke-
tones 4 to N-protected-b-amino acids 5. The use of silver
benzoate catalyst was based on previous work by Seebach
et al.25 with some modifications to avoid time consuming
purification steps to remove benzoic acid as a by-product
in the reaction mixture.7 In addition, microwave irradia-
tion was also employed to reduce the reaction time from
3–12 hours18,25 (conventional method) to just 60 seconds
at 110 °C and 200 W (Scheme 2). 1,3-Oxazinan-6-ones 6
were synthesized using the same method as for the synthe-
sis of 1,3-oxazolidin-5-ones 2.6
Residue
N-But-3-enyl-b-amino acid Yield (%)
Cbz-L-Gly
Fmoc-L-Val
7a
7b
72
75
Mechanism
A mechanism for the cleavage of 1,3-oxazolidin-5-ones
by ATMS/ATPS and BF3·OEt2/EtAlCl2 is shown in
Scheme 3. The electrophilic C=O group in the ring is ac-
tivated by a Lewis acid to form an iminium ion 9 (Step A).
The nucleophilic double bond of ATMS/ATPS attacks the
iminium cation to generate a stabilized carbocation b to
the silicon atom (Step B). Subsequent loss of the silyl
group from 10 results in the transposition of the double
bond to form the N-but-3-enyl residue 3 (Step C).26
As an extension of the cleavage of 1,3-oxazolidin-5-ones
2 to N-but-3-enyl-a-amino acids 3, N-but-3-enyl-b-amino
acids 7 (Table 4) were successfully formed by the cleav-
age of 1,3-oxazinan-6-ones 6. The same conditions were
used as applied for the cleavage of 1,3-oxazolidin-5-ones;
using ATMS and BF3·OEt2 (Scheme 2).
(2-Buten-1-yl)triphenylsilane (15) was also trialed to
cleave (S)-3-benzyloxycarbonyl-4-methyl-5-oxazolidino-
ne (11) (Scheme 4). The proposed reaction mechanism is
the same as shown for the cleavage of 1,3-oxazolidin-5-
ones by ATMS/ATPS. The Lewis acid BF3·OEt2 activates
AgOBz, 1,4-dioxane–H2O
R
1. EtOCOCl, Et3N
R
MW (200 W), 60 s
110 °C, 60 psi
R
2. TMSCHN2
PG
CHN2
PG
CO2H
N
PG
N
H
N
CO2H
H
O
H
5
1
4
PTSA, (CH2O)n
MeCN, MW (200 W)
130 °C, 3 min, 60 psi
PG = Cbz, Fmoc
R = H, i-Pr
R
BF3⋅Et2O (2 equiv)
CH2Cl2
ATMS (3 equiv)
R
PG
CO2H
N
PG
N
72–75%
O
O
7
6
Scheme 2 Synthesis of N-but-3-enyl-b-amino acids
R
R
LA
R
LA
O
R
LA
(A)
(B)
(C)
PG
O
PG
PG
PG
O
N
N
N
N
CO2H
workup
O
O
O
γ
9
10
3
8
TMS
β
TMS
α
Scheme 3 Mechanism of the cleavage of 1,3-oxazolidinones using ATMS
BF3
BF3
O
BF3
(A)
(B)
(C)
PG
O
PG
PG
PG
O
N
N
N
CO2H
N
workup
O
O
O
γ
12
13
14
11
β
SiPh3
SiPh3
α
15
Scheme 4 Mechanism of the cleavage of (S)-benzyloxycarbonyl-4-methyl-1,3-oxazoldin-5-one by (2-buten-1-yl)triphenylsilane
Synthesis 2009, No. 12, 1991–1998 © Thieme Stuttgart · New York

1994
T. T. Van Nguyen et al.
PAPER
NaHCO3 (3 ꢀ 15 mL), dried (MgSO4), and evaporated under re-
duced pressure. The residue was purified by column chromatogra-
phy, eluting with 25–45% EtOAc–hexane to afford the title
products 2. Compounds 2a–t have spectra identical in all respects
with previously reported material.1,7,8,28
the ring in 11 to form an iminium cation 12 (Step A). Then
the nucleophilic double bond of 15 attacks the electro-
philic iminium ion to generate the intermediate 13 (Step
B). Acidic workup provides compound 14, as indicated by
NMR and mass spectrometry.
N-Protected N-But-3-enyl-a-amino Acids (3); General Proce-
dure
We have presented a simple and convenient method for
the cleavage of 1,3-oxazolidin-5-ones in the presence of
ATMS and BF3·OEt2 to form N-but-3-enyl-a-amino acids
in good to excellent yields. Optimization of this reaction
with different allyl-substituted silanes was tried and gave
good yields. N-But-3-enyl-b-amino acids were also suc-
cessfully synthesized through the cleavage of 1,3-oxazi-
nan-6-ones using ATMS and BF3·OEt2. A mechanism for
this reaction has been proposed.
1,3-Oxazolidin-5-ones 2 (1 mmol) were dissolved in CH2Cl2 (10
mL). BF3·OEt2 (2 mmol) and ATMS (3 mmol) were added to the re-
action mixture and the solution was stirred for 5 min–24 h with TLC
monitoring. The reaction solution was taken up in Et2O (20 mL) and
extracted with sat. aq NaHCO3 (3 ꢀ 15 mL). The aqueous layer was
adjusted to pH 2 with dil. HCl (10%), and extracted with EtOAc
(3 ꢀ 20 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The residual oils
were purified by silica gel column chromatography, eluting with
25–40% EtOAc–hexane to afford the title products 3.
There are several extra carbons and one double bond in
the N-protected-N-but-3-enyl-a- and b- amino acids as
compared to the protected N-methylamino acids. There
are numerous reactions that can be applied to these new
modified amino acids, such as epoxidation, addition reac-
tions and hydrogenation.
N-Benzyloxycarbonyl-2-aminobut-3-enylethanoic Acid (3a)
Yield: 243 mg (89%); light yellow oil; [a]D18 –0.4 (c 1.43, CH2Cl2).
IR (KBr): 3067, 3010, 2920–2849, 1701, 1477, 1430, 1367, 1290,
1227, 1148, 996, 952, 916, 770, 736, 698 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 9.68 (br s, 1 H, OH),
7.34–7.24 (m, 5 H, ArH), 5.80–5.66 (m, 1 H, CH2=CH), 5.16–5.10
(m, 2 H, ArCH2), 5.04–5.00 (m, 2 H, CH2CO2H), 4.05 (d, J = 16.3
Hz, 2 H, CH2=CH), 3.44–3.37 (m, 2 H, NCH2CH2), 2.34–2.24 (m,
2 H, NCH2CH2).
The bioactivities of N-but-3-enyl-a- and b-amino acids
have not been researched yet, but we believe that they will
have roles in peptidic natural products or peptidomimetic
compounds.
13C NMR (75 MHz, CDCl3, 315 K): d (rotamers) = 174.2, 174.0,
156.4, 155.6 (C=O), 135.9 (aryl C), 134.4 (CH2=CH), 128.1, 127.6,
127.4 (aryl CH), 116.7 (CH2=CH), 67.4 (ArCH2), 48.8, 48.4
(CH2CO2H), 48.1, 47.6 (NCH2CH2), 32.5, 31.9 (NCH2CH2).
HRMS (ESI): m/z [M + H]+ calcd for C14H17NO4: 264.1230; found:
264.1242.
Melting points are uncorrected and were recorded on a Reichert
‘Thermopan’ microscope hot-stage apparatus. IR spectra were re-
corded on a Bruker Vector 22 Fourier-Transform Spectrometer or a
Perkin-Elmer 1720-X FT-IR Spectrometer using a diffuse reflec-
tance accessory with KBr optics. Optical rotations were recorded on
a Perkin-Elmer 141 Polarimeter. NMR spectroscopy was performed
in CDCl3 at 300 K, unless otherwise stated, on a Bruker Avance
DRX-300 Spectrometer. Electrospray Ionization Mass Spectrome-
try (ESIMS) was carried out at the Mass Spectrometry & Proteom-
ics Facility at La Trobe University on a Bruker Daltonics
(Germany) Esquire 6000 ion trap mass spectrometer at 300 °C with
scan rate 5500 m/z/sec and MeOH was used as the mobile phase.
Low- and high-resolution mass spectra (LSIMS) were measured at
the University of Tasmania by Dr. Noel Davies and co-workers on
a Kratos Concept Mass Spectrometer at 70 eV; all using H2O–
MeOH–AcOH (0:99:1 or 50:50:1) mixtures as the mobile phase.
Microanalyses were performed by E. Mocellin and co-workers from
Chemical and Microanalytcial Services Pty Ltd in Belmont, Victo-
ria. Flash chromatography was carried out using silica gel 60 parti-
cle size 0.040–0.063 mm (230–400 mesh ASTM) supplied by Merck
Chemicals. EtOAc and hexane used for chromatography were dis-
tilled prior to use. CH2Cl2 was distilled and stored over Linde type
4 Å molecular sieves. TLC was performed on Merck Kieselgel 60
F254 plates and visualized with a UV lamp or by staining. Perman-
ganate stain consists of KMnO4 (1% v/w), K2CO3 (20% v/w), and
NaOH (1% v/w) in H2O. Molybdenum polyphosphoric acid stain
consists of 10% molybdenum polyphosphoric acid in EtOH. All
other reagents and solvents were purified or dried as described by
Perrin and Armarego.27
N-Toluenesulfonyl-2-aminobut-3-enylethanoic Acid (3b)
Yield: 268 mg (95%); white solid; mp 100–102 °C; [a]D –1.2
18
(c 1.04, CH2Cl2).
IR (KBr): 3300–3250, 3010–2926, 1732, 1495, 1338, 1158, 1090,
938, 814, 757, 668, 629 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 9.58 (br s, 1 H, OH),
7.71–7.66 (m, 2 H, ArH), 7.28–7.23 (m, 2 H, ArH), 5.66–5.59 (m,
1 H, CH2=CH), 5.05–4.97 (m, 2 H, CH2=CH), 4.08–4.03 (m, 2 H,
CH2CO2H), 3.29–3.24 (m, 2 H, NCH2CH2), 2.39 (s, 3 H, CH3),
2.29–2.21 (m, 2 H, NCH2CH2).
13C NMR (75 MHz, CDCl3): d (rotamers) = 174.2 (C=O), 143.4,
136.1 (aryl C), 133.9 (CH2=CH), 129.5, 129.3, 126.9 (aryl CH),
117.1 (CH2=CH), 47.8 (CH2CO2H), 47.6 (NCH2CH2), 32.1
(NCH2CH2), 21.1 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H17NO4S: 284.0950;
found: 284.0949.
(2S)-N-Benzyloxycarbonyl-2-aminobut-3-enylpropanoic Acid
(3c)
Yield: 221 mg (80%); light yellow oil; [a]D18 –21.5 (c 1.0, CH2Cl2).
IR (KBr): 3050, 3010, 3000–2943, 1704, 1683, 1652, 1475, 1422,
1368, 1293, 1199, 1157, 1066, 1015, 915, 771, 736, 697 cm–1.
1,3-Oxazolidin-5-ones 2; General Procedure
1H NMR (300 MHz, CDCl3): d (rotamers) = 10.80 (br s, 1 H, OH),
7.33–7.30 (m, 5 H, ArH), 5.79–5.68 (m, 1 H, CH2=CH), 5.15 (s, 2
H, ArCH2), 5.05–4.99 (m, 2 H, CH2=CH), 4.50–4.29 (m, 1 H,
CHCH3), 3.46–3.13 (m, 2 H, NCH2), 2.37–2.29 (m, 2 H,
NCH2CH2), 1.49–1.45 (m, 3 H, CH3).
N-Protected a-amino acids 1 (2 mmol), paraformaldehyde (400
mg), and PTSA (40 mg) were suspended in MeCN (10 mL). The
mixture was heated in a sealed microwave tube for 3 min at 130 °C,
200 W, and 60 psi. The mixture was hot-filtered through a glass frit,
and the filtrate was concentrated in vacuo. The residue was taken up
in EtOAc (20 mL), the organic phase was washed with sat. aq
13C NMR (75 MHz, CDCl3, 310 K): d (rotamers) = 176.6, 156.1
Synthesis 2009, No. 12, 1991–1998 © Thieme Stuttgart · New York

PAPER
N-But-3-enylamino Acids
1995
(C=O), 135.9 (aryl C), 134.7 (CH2=CH), 128.1, 127.6, 127.4 (aryl
CH), 116.3 (CH2=CH), 67.2 (ArCH2), 55.3 (CHCH3), 46.6, 45.8
(NCH2), 33.7, 32.9 (NCH2CH2), 15.5, 14.9 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C15H19NO4: 278.1387; found:
1682, 1651, 1538, 1455, 1290, 1229, 1151, 988, 916, 771, 752, 697,
668 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 10.20 (br s, 1 H, OH),
7.33–7.16 (m, 5 H, ArH), 5.72–5.16 (m, 1 H, CH2=CH), 5.17 (s, 2
H, ArCH2), 5.08–4.96 (m, 2 H, CH2=CH), 4.05–3.95 (m, 1 H,
CHCO2H), 3.48–3.18 (m, 2 H, NCH2), 2.37–2.30 [m, 3 H,
NCH2CH2 and CH(CH3)2], 1.02 (d, J = 6.0 Hz, 3 H, CH3), 0.90 (d,
J = 6.3 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3, 315 K): d (rotamers) = 174.0, 157.0
(C=O), 135.8 (aryl C), 134.3 (CH2=CH), 128.1, 127.8, 127.5 (aryl
CH), 116.6 (CH2=CH), 67.5 (CHCO2H), 47.1 (NCH2), 32.9
(NCH2CH2), 27.4 [CH(CH3)2], 19.5, 18.8 (CH3).
278.1385.
(2R)-N-Benzyloxycarbonyl-2-aminobut-3-enylpropanoic Acid
(3d)
18
Yield: 259 mg (94%); light yellow oil; [a]D +19.9 (c 1.15,
CH2Cl2).
IR (KBr): 3050, 3010, 3000–2943, 1698, 1682, 1423, 1372, 1292,
1008, 915, 770, 698 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 10.00 (br s, 1 H, OH),
7.33–7.30 (m, 5 H, ArH), 5.76–5.65 (m, 1 H, CH2=CH), 5.20 (s, 2
H, ArCH2), 5.05–4.99 (m, 2 H, CH2=CH), 4.50–4.29 (m, 1 H,
CHCH3), 3.46–3.44 (m, 1 H, NCH2), 3.23–3.13 (m, 1 H, NCH2),
2.37–2.29 (m, 2 H, NCH2CH2), 1.50–1.35 (m, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d (rotamers) = 176.8, 156.1, 155.4
(C=O), 135.9 (aryl C), 134.6 (CH2=CH), 128.1, 127.7, 127.4 (aryl
CH), 116.4 (CH2=CH), 67.2 (ArCH2), 55.3 (CHCH3), 46.7, 45.7
(NCH2), 33.7, 32.9 (NCH2CH2), 15.5, 14.9 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C17H23NO4: 306.1699; found:
306.1702.
(2S)-N-Fluorenylmethoxycarbonyl-2-aminobut-3-enyl(3-meth-
yl)butanoic Acid (3h)
Yield: 314 mg (80%); clear colorless oil; [a]D +13.3 (c 1.0,
23
CH2Cl2).
IR (KBr): 3067, 2970–2850, 1702, 1473, 1451, 1423, 1291, 1230,
1153, 1108, 1000, 918, 760, 738, 622 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 9.88 (br s, 1 H, OH),
7.75–7.25 (m, 8 H, ArH), 5.74–5.39 (s, 1 H, CH2=CH), 5.07–4.87
(m, 2 H, CH2=CH), 4.68–4.54 (m, 2 H, CHCH2O), 4.22 (t, J = 5.4
Hz, 1 H, CHCH2O), 3.88 (d, J = 10.3 Hz, 1 H, CHCO2H), 3.28–3.13
(m, 1 H, NCH2), 2.98–2.89 (m, 1 H, NCH2), 2,34–2.31 [m, 1 H,
CH(CH3)2], 2.08–2.01 (m, 2 H, NCH2CH2), 1.01–0.68 (m, 6 H,
2 ꢀ CH3).
(2S)-N-Fluorenylmethoxycarbonyl-2-aminobut-3-enylpropan-
oic Acid (3e)
Yield: 298 mg (82%); light yellow solid; mp 89 °C; [a]D23 –17.7
(c 1.67, CH2Cl2).
IR (KBr): 3050, 3010, 3000–2946, 1703, 1450, 1350, 1292, 1189,
1071, 759, 740 cm–1.
1H NMR (300 MHz, CDCl3, 310 K): d (rotamers) = 10.09 (br s, 1
H, OH), 7.75–7.27 (m, 8 H, ArH), 5.56 (s, 1 H, CH2=CH), 5.01 (d,
J = 9.3 Hz, 2 H, CH2=CH), 4.54–4.21 (m, 4 H, CHCH2O, CHCH3
and CHCH2O), 3.40–3.02 (m, 2 H, NCH2), 2.15–2.04 (m, 2 H,
NCH2CH2), 1.43–1.23 (m, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d (rotamers) = 174.2, 156.9 (C=O),
143.4, 143.2, 141.1 (aryl C), 134.1 (CH2=CH), 127.4, 126.8, 124.3,
119.7 (aryl CH), 116.6 (CH2=CH), 67.4, (CHCO2H), 67.0
(CHCH2O), 47.0 (CHCH2O), 32.6 (NCH2), 27.5, 27.2 (NCH2CH2),
25.5 [CH(CH3)2], 19.5, 18.8 (CH3).
13C NMR (75 MHz, CDCl3, 310 K): d (rotamers) = 176.7, 156.0
(C=O), 143.6, 141.1 (aryl C), 134.5 (CH2=CH), 127.3, 126.7, 124.4,
119.6 (aryl CH), 116.3 (CH2=CH), 67.0 (CHCH2O), 55.3, 54.7
(CHCH3), 47.0 (CHCH2O), 45.8 (NCH2), 33.3 (NCH2CH2), 14.8
(CH3).
HRMS (ESI): m/z [M + H]+ calcd for C24H27NO4: 394.2012; found:
394.2015.
(2S)-N-Benzyloxycarbonyl-2-aminobut-3-enyl(4-methyl)pen-
tanoic Acid (3i)
Yield: 271 mg (85%); light yellow oil; [a]D23 –19.9 (c 1.0, CH2Cl2).
HRMS (ESI): m/z [M + H]+ calcd for C22H23NO4: 366.1699; found:
366.1699.
IR (KBr): 3070, 3035, 2958–2870, 1739, 1705, 1499, 1456, 1388,
1369, 1264, 1154, 916, 771, 735, 698 cm–1.
(2S)-N-Trichloroethoxycarbonyl-2-aminobut-3-enylpropanoic
Acid (3f)
Yield: 29 mg (76%); light yellow oil.
1H NMR (300 MHz, CDCl3, 320 K): d (rotamers) = 10.83 (br s, 1
H, CO2H), 7.32–7.24 (m, 5 H, ArH), 5.72 (s, 1 H, CH2=CH), 5.16
(s, 2 H, ArCH2), 5.06–4.98 (m, 2 H, CH2=CH), 4.56 (s, 1 H,
CHCO2H), 3.47 (s, 0.6 H, NCH2), 3.17–3.07 (m, 0.4 H, NCH2),
2.41–2.30 (m, 2 H, NCH2CH2), 1.77–1.62 [m, 3 H, CH2CH(CH3)2],
0.94 (d, J = 5.7 Hz, 6 H, 2 ꢀ CH3).
13C NMR (75 MHz, CDCl3): d (rotamers) = 177.2, 156.8, 155.9
(C=O), 136.2 (aryl C), 135.1, 134.79 (CH2=CH), 128.4, 127.9,
127.8, 127.6 (aryl CH), 116.6 (CH2=CH), 67.5 (ArCH2), 58.3, 57.9
(CHCO2H), 46.9, 46.1 (NCH2), 38.7, 38.0 [CH2CH(CH3)2], 33.8,
32.9 (NCH2CH2), 24.7 [CH(CH3)2], 22.9, 21.7 (CH3).
IR (KBr): 3450–2900, 3050, 3010–2951, 1716, 1698, 1475, 1422,
1292, 1155, 1104, 919, 763, 718 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 8.85 (br s, 1 H, OH),
5.80–5.74 (m, 1 H, CH2=CH), 5.11–5.02 (m, 2 H, CH2=CH), 4.80–
4.70 (m, 2 H, CH2O), 4.47–4.45 (m, 1 H, CHCH3), 3.52–3.45 (m, 1
H, NCH2), 3.21–3.16 (m, 1 H, NCH2), 2.46–2.33 (m, 2 H,
NCH2CH2), 1.57–1.50 (m, 3 H, CH3).
13C NMR (75 MHz, CDCl3, 315 K): d (rotamers) = 176.6, 176.4,
154.2, 153.5 (C=O), 134.3 (CH2=CH), 116.7 (CH2=CH), 95.0
(CCl3), 75.0 (CH2O), 55.6 (CHCH3), 47.4, 46.2 (NCH2), 33.6, 32.6
(NCH2CH2), 15.5, 14.7 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H25NO4: 320.1856; found:
320.1849.
(2S)-N-Fluorenylmethoxycarbonyl-2-aminobut-3-enyl(4-meth-
yl)pentanoic Acid (3j)
HRMS (ESI): m/z [M + H]+ calcd for C10H14Cl3NO4: 318.0061;
found: 318.0059.
Yield: 398 mg (98%); clear glass; [a]D22 –19.9 (c 1.02, CH2Cl2).
(2S)-N-Benzyloxycarbonyl-2-aminobut-3-enyl(3-methyl)bu-
tanoic Acid (3g)
IR (KBr): 3090, 2960–2850, 1701, 1477, 1450, 1420, 1368, 1293,
1226, 1046, 917, 758, 738, 621 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 9.78 (br s, 1 H, OH),
7.75–7.30 (m, 8 H, ArH), 5.54–5.48 (s, 1 H, CH2=CH), 5.08–4.90
Yield: 299 mg (98%); light yellow oil; [a]D20 +5.1 (c 1.0, CH2Cl2).
IR (KBr): 3450–2900, 3050, 3010, 2970–2800, 1738, 1703, 1699,
Synthesis 2009, No. 12, 1991–1998 © Thieme Stuttgart · New York

1996
T. T. Van Nguyen et al.
PAPER
(m, 2 H, CH2=CH), 4.61–4.60 (d, J = 5.2 Hz, 2 H, CHCH2O), 4.54–
4.51 (m, 1 H, CHCH2O), 4.22 (d, J = 4.5 Hz, 1 H, CHCO2H), 3.44–
2.83 (m, 2 H, NCH2), 2.38–2.05 (m, 2 H, NCH2CH2), 1.79–1.53 [m,
3 H, CH2CH(CH3)2], 0.94–0.78 (m, 6 H, 2 ꢀ CH3).
13C NMR (75 MHz, CDCl3): d (rotamers) = 175.0, 156.9 (C=O),
135.8 (aryl C), 134.6 (CH2=CH), 133.7 (aryl C), 129.2, 128.5,
128.2, 127.8, 127.5 (aryl CH), 116.0 (CH2=CH), 67.6 (CHCO2H),
63.0 (ArCH2), 44.8 (NCH2), 33.3, 32.7 (NCH2CH2).
13C NMR (75 MHz, CDCl3): d (rotamers) = 176.9, 156.5 (C=O),
143.5, 141.1 (aryl C), 134.8, 134.5 (CH2=CH), 127.3, 126.7, 124.4,
119.6 (aryl CH), 116.3 (CH2=CH), 66.8 (CHCH2O), 58.1, 57.5
(CHCO2H), 47.1 (CHCH2O), 46.4, 45.8 (NCH2), 38.1, 37.7
[CH2CH(CH3)2], 33.1, 32.7 (NCH2CH2), 24.4 [CH(CH3)2], 22.6,
21.4 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C20H21NO4: 340.1543; found:
340.1544.
(2S)-N-Benzyloxycarbonyl-2-aminobut-3-enyl(3-phenyl)pro-
panoic Acid (3n)
Yield: 336 mg (95%); colorless oil; [a]D24 –118.3 (c 1.0, CH2Cl2).
HRMS (ESI): m/z [M + H]+ calcd for C25H29NO4: 408.2169; found:
408.2178.
IR (KBr): 3050, 3030, 3000–2900, 1701, 1479, 1474, 1454, 1291,
1222, 1028, 916, 752, 698 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 9.53 (br s, 1 H, OH),
7.33–7.06 (m, 10 H, ArH), 5.67–5.51 (m, 1 H, CH2=CH), 5.25–5.07
(m, 2 H, ArCH2O), 5.00–4.88 (m, 2 H, CH2=CH), 4.24–4.22 (m, 1
H, CHCO2H), 3.34–3.07 (m, 3 H, ArCH2CHCO2H and NCH2),
2.74–2.65 (m, 1 H, NCH2), 2.14–2.04 (m, 2 H, NCH2CH2).
13C NMR (75 MHz, CDCl3, 315 K): d (rotamers) = 174.8, 155.9
(C=O), 137.2, 136.0 (aryl C), 134.5 (CH2=CH), 128.8, 128.2, 128.1,
127.7, 127.5, 126.4 (aryl CH), 116.2 (CH2=CH), 67.2 (ArCH2O),
63.3 (CHCO2H), 48.6 (NCH2), 34.7 (ArCH2CHCO2H), 32.6
(NCH2CH2).
(2S)-N-Phenylcarbonyl-2-aminobut-3-enyl(4-methyl)pentan-
oic Acid (3k)
Yield: 173 mg (60%); light yellow oil; [a]D20 –3.2 (c 2.0, CH2Cl2).
IR (KBr): 3050, 2960–2850, 1733, 1594, 1446, 1350, 1250, 1234,
987, 700, 668 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 10.71 (br s, 1 H, OH),
7.42–7.33 (m, 5 H, ArH), 5.77–5.71 (m, 0.6 H, CH2=CH), 5.42–
5.40 (m, 0.4 H, CH2=CH), 5.07–4.78 (m, 2 H, CH2=CH), 4.52 (s,
0.4 H, CHCO2H), 4.26 (s, 0.6 H, CHCO2H), 3.45–3.13 (m, 2 H,
NCH2), 2.51–2.17 (m, 2 H, NCH2CH2), 1.98–1.43 [m, 3 H,
CH2CH(CH3)2], 0.97–0.52 (m, 6 H, 2 ꢀ CH3).
13C NMR (75 MHz, CDCl3): d (rotamers) = 173.4, 173.2 (C=O),
135.5, 135.2, 135.1 (aryl C), 133.4 (CH2=CH), 130.4, 129.4, 128.2,
128.1, 127.5, 126.8, 126.4 (aryl CH), 117.2, 116.6 (CH2=CH), 60.0
(CHCO2H), 43.9, 43.5 (NCH2), 38.2, 37.6, 36.9 [CH2CH(CH3)2],
33.2, 32.0 (NCH2CH2), 24.8, 24.6 [CH(CH3)2], 21.7, 21.2 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C15H19NO4: 354.1699; found:
354.1706.
(2S)-N-Fluorenylmethoxycarbonyl-2-aminobut-3-enyl(3-phe-
nyl)propanoic Acid (3o)
Yield: 405 mg (92%); clear glass; [a]D23 –79.6 (c 1.04, CH2Cl2).
IR (KBr): 3050, 3000–2900, 1701, 1478, 1450, 1423, 1223, 1001,
740, 701 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C17H23NO3: 290.1750; found:
290.1751.
1H NMR (300 MHz, CDCl3): d (rotamers) = 9.47 (br s, 1 H, OH),
7.77–7.12 (m, 13 H, ArH), 5.63–5.39 (m, 1 H, CH2=CH), 4.93–4.83
(m, 2 H, CH2=CH), 4.68–4.62 (m, 1 H, CHCO2H), 4.58–4.46 (m, 1
H, CHCH2O), 4.27–4.10 (m, 2 H, CHCH2O), 3.39–2.91 (m, 2 H,
CH2Ar), 2.65–2.42 (m, 2 H, NCH2), 2.05–1.89 (m, 2 H, NCH2CH2).
13C NMR (75 MHz, CDCl3, 315 K): d (rotamers) = 174.9, 155.8
(C=O), 143.5, 141.1, 137.3 (aryl C), 134.4 (CH2=CH), 128.8, 128.2,
127.3, 126.8, 126.3, 124.4, 119.6 (aryl CH), 116.1 (CH2=CH), 66.9
(CH2O), 63.2 (CHCO2H), 48.5 (NCH2), 47.1 (CHCH2O), 34.7
(CH2Ar), 32.3 (NCH2CH2).
(2S,3S)-N-Benzyloxycarbonyl-2-aminobut-3-enyl(3-meth-
yl)pentanoic Acid (3l)
Yield: 268 mg (84%); clear colorless oil; [a]D +6.1 (c 1.0,
CH2Cl2).
25
IR (KBr): 3750–2850, 1699, 1683, 1456, 1418, 1292, 916, 748, 696,
668, 643, 612 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 10.5 (br s, 1 H, CO2H),
7.33–7.14 (m, 5 H, ArH), 5.69–5.64 (m, 2 H, CH2=CH), 5.17 (s, 2
H, ArCH2), 4.99 (d, J = 10.1 Hz, 2 H, CH2=CH), 4.17 (d, J = 9.7
Hz, 1 H, CHCO2H), 3.49–3.19 (m, 2 H, NCH2), 2.31–2.29 (m, 2 H,
NCH2CH2), 2.14–2.00 (m, 1 H, C2H5CHCH3), 1.45–1.35 (m, 1 H,
CH2CH3), 0.99–0.85 (m, 7 H, CH2CH3 and 2 ꢀ CH3).
13C NMR (75 MHz, CDCl3, 315 K): d (rotamers) = 174.3, 157.0
(C=O), 135.8 (aryl C), 134.4 (CH2=CH), 128.1, 127.8, 127.5 (aryl
CH), 116.6 (CH2=CH), 67.6 (CHCO2H), 66.0 (ArCH2), 46.5
NCH2), 33.5, (C2H5CHCH3), 33.0 (NCH2CH2), 24.9 (CH2CH3),
15.6 (CH3), 11.3, 10.4 (CH2CH3).
HRMS (ESI): m/z [M + H]+ calcd for C28H27NO4: 442.2018; found:
442.2015.
(2S)-N-Benzyloxycarbonyl-2-aminobut-3-enyl(3-benzyloxy-
phenyl)propanoic Acid (3p)
Yield: 48 mg (20%); clear colorless oil.
IR (KBr): 3400–2850, 3050, 3032, 1698, 1683, 1511, 1471, 1455,
1422, 1372, 1293, 1240, 1176, 1108, 1001, 917, 831, 736, 696, 668
cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 8.78 (br s, 1 H, OH),
7.42–6.83 (m, 14 H, ArH), 5.68–5.53 (m, 1 H, CH2=CH), 5.25–5.10
(m, 2 H, ArCH2O), 5.02 (s, 2 H, ArCH2OAr), 5.00–4.90 (m, 2 H,
CH2=CH), 4.17–4.12 (m, 2 H, CHCO2H), 3.32–3.06 (m, 3 H,
ArCH2CHCO2 and NCH2), 2.74 (d, J = 7.2 Hz, 1 H, NCH2), 2.18–
2.05 (m, 2 H, NCH2CH2).
13C NMR (75 MHz, CDCl3, 315 K): d (rotamers) = 175.1 (CO2H),
157.3 (aryl COCH2), 156.0 (C=O), 136.6, 136.0 (aryl CCH2), 134.9
(aryl CCH2CHCO2H), 134.5 (CH2=CH), 129.8, 129.4, 128.2,
128.1, 127.9, 127.8, 127.6, 127.5, 127.1 (aryl CH), 116.4, 116.2
(CH2=CH), 114.7 (aryl CHCO), 69.7 (ArCH2OAr), 67.2
(ArCH2OCO), 63.5, 62.2 (CHCO2H), 48.7 (NCH2), 34.8, 33.7
(ArCH2CHCO2H), 32.6, 32.1 (NCH2CH2).
HRMS (ESI): m/z [M + H]+ calcd for C18H25NO4: 320.1856; found:
320.1869.
(2S)-N-Benzyloxycarbonyl-2-aminobut-3-enyl(2-phenyl)eth-
anoic Acid (3m)
Yield: 333 mg (98%); white solid; mp 75–77 °C; [a]D20 +85.2 (c 1.3,
CH2Cl2).
IR (KBr): 3050, 3033, 3000–2900, 1743, 1696, 1479, 1455, 1416,
1366, 1291, 1187, 1144, 973, 917, 973, 917, 742, 698, 636 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 10.33 (br s, 1 H,
CO2H), 7.37–7.23 (m, 10 H, ArH), 5.96 (s, 1 H, CHCO2H), 5.48–
5.40 (m, 1 H, CH2=CH), 5.24 (s, 2 H, ArCH2), 4.88–4.76 (m, 2 H,
CH2=CH), 3.50–3.40 (m, 1 H, NCHH), 3.18–3.10 (m, 1 H, NCHH),
2.15 (s, 1 H, NCH2CHH), 1.74 (s, 1 H, NCH2CHH).
Synthesis 2009, No. 12, 1991–1998 © Thieme Stuttgart · New York

PAPER
N-But-3-enylamino Acids
1997
HRMS (ESI): m/z [M + H]+ calcd for C28H29NO5: 460.2118; found:
HRMS (ESI): m/z [M + H]+ calcd for C26H26Cl3NO6: 554.0898;
460.2133.
found: 554.0892.
(2S)-N-Benzyloxycarbonyl-2-aminobut-3-enylbutanedioic Acid
(2S)-N-Benzyloxycarbonyl-2-aminobut-3-enylpentanedioic
(3q)
Acid (3t)
20
20
Yield: 174 mg (54%); clear colorless oil; [a]D –43.7 (c 1.68,
Yield: 146 mg (43%); clear colorless oil; [a]D –60.4 (c 1.46,
CH2Cl2).
CH2Cl2).
IR (KBr): 3500–2700, 3030, 1714, 1699, 1683, 1746, 1423, 1373,
1227, 1080, 1003, 914, 772, 735, 699, 624 cm–1.
IR (KBr): 3450–2800, 3069, 1712, 1498, 1475, 1423, 1371, 1225,
1001, 915, 772, 735, 698 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 11.35 (br s, 2 H,
2 ꢀ OH), 7.33–7.16 (m, 5 H, ArH), 5.74–5.72 (m, 1 H, CH2=CH),
5.14–5.02 (m, 2 H, ArCH2), 4.95–4.93 (m, 2 H, CH2=CH), 4.46–
4.41 (m, 1 H, CHCO2H), 3.54–3.25 (m, 2 H, NCH2), 2.37–2.35 (m,
1 H, CH2CO2H), 2.06–2.03 (m, 1 H, CH2CO2H), 1.27–1.22 (m, 2 H,
NCH2CH2).
13C NMR (75 MHz, CDCl3, 315 K): d (rotamers) = 176.1, 174.9,
169.5, 155.7 (C=O), 135.8 (aryl C), 134.6 (CH2=CH), 128.5, 128.1,
127.8, 127.4 (aryl CH), 116.6, 116.5 (CH2=CH), 67.3, 67.1
(ArCH2), 57.7, 56.9 (CHCO2H), 48.8 (NCH2), 35.7 34.9
(CH2CO2H), 32.9, 32.3 (NCH2CH2).
1H NMR (300 MHz, CDCl3, 315 K): d (rotamers) = 11.53 (br s, 2
H, 2 ꢀ OH), 7.31 (s, 5 H, ArH), 5.73 (s, 1 H, CH2=CH), 5.14 (s, 2
H, ArCH2), 5.09–4.98 (m, 2 H, CH2=CH), 4.40–4.20 (m, 1 H,
CHCO2H), 3.51 (s, 1 H, NCH2), 3.20–3.11 (m, 1 H, NCH2), 2.59–
2.02 (m, 6 H, CH2CH2CO2H, NCH2CH2, CH2CH2CO2H).
13C NMR (75 MHz, CDCl3): d (rotamers) = 178.6, 176.3, 156.2,
155.5 (C=O), 135.8, 135.5 (aryl C), 134.5 (CH2=CH), 128.2, 127.8,
127.4 (aryl CH), 116.6 (CH2=CH), 67.4 (ArCH2), 59.4, 59.1
(CHCO2H), 48.2, 47.4 (NCH2), 33.2, 32.4 (CH2CO2H), 30.1
(NCH2CH2), 24.7, 24.0 (CH2CH2CO2H).
HRMS (ESI): m/z [M + H]+ calcd for C17H22NO6: 336.1441; found:
336.1448.
HRMS (ESI): m/z [M + H]+ calcd for C16H19NO6: 322.1295; found:
322.1285.
Diazoketones 4; General Procedure
(2S)-N-Benzyloxycarbonyl-2-aminobut-3-enyl-5-oxo-5-(2,2,2-
Ethyl chloroformate (3.1 mmol) in anhyd THF (5 mL) was added to
a solution of PG-N-a-amino acid (3 mmol) and Et3N (3.1 mmol) in
THF (15 mL) at –15 °C and the mixture was stirred for 30 min at
–5 °C under argon. The precipitated Et3NH+Cl– was filtered off.
MeCN (10 mL) and TMSCHN2 (6 mmol) were added to the filtrate
and the mixture was stirred for 48 h at 4 °C. After that, Et2O (30
mL) was added and the mixture was extracted sequentially with
10% aq citric acid (30 mL), sat. aq NaHCO3 (30 mL), and brine (30
mL). The organic layer was separated and then dried (Na2SO4). The
solvent was removed under reduced pressure and the crude product
was purified by chromatography (EtOAc–hexane, 1:3) to afford the
title compound. Products 4a and 4b had spectra identical with those
of an authentic sample.7,14,29–31
trichloroethoxy)pentanoic Acid (3r)
Yield: 296 mg (64%); clear colorless oil; [a]D –43.7 (c 1.91,
19
CH2Cl2).
IR (KBr): 3050, 3030, 3000–2850, 1747, 1704, 1474, 1422, 1371,
1223, 1143, 916, 722, 698 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 10.24 (br s, 1 H, OH),
7.33–7.28 (m, 5 H, ArH), 5.71–5.69 (m, 1 H, CH2=CH), 5.14 (d,
J = 11.4 Hz, 2 H, ArCH2), 5.04 (dd, J = 10.4, 7.1 Hz, 2 H,
CH2=CH), 4.74–4.67 (m, 2 H, CH2CCl3), 4.36–4.26 (m, 1 H,
CHCO2H), 3.56–3.46 (m, 1 H, NCH2), 3.17–3.07 (m, 1 H, NCH2),
2.59–2.15 (m, 6 H, NCH2CH2, CHCH2CH2, CHCH2CH2).
13C NMR (75 MHz, CDCl3): d (rotamers) = 175.5, 170.9, 156.1,
155.4 (C=O), 135.8, 135.5 (aryl C), 134.4 (CH2=CH), 128.2, 127.8,
127.7, 127.4 (aryl CH), 116.7 (CH2=CH), 94.5 (CCl3), 73.6
(CH2CCl3), 67.4 (ArCH2), 59.4, 58.9 (CHCO2H), 48.2, 47.5
(NCH2), 33.2, 32.4 (NCH2CH2), 30.0 (CH2CH2CO2), 24.7, 24.1
(CH2CH2CO2).
N-Protected b-Amino Acids 5; General Procedure
A mixture of N-a-aminoacyldiazomethane 4 (1 mmol), silver ben-
zoate (2 mg, 0.08 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was
prepared in a closed vessel. The reaction was performed for 60 sec
at 110 °C, 200 W, and 60 psi. The remaining solvent was filtered off
and evaporated under reduced pressure. The resulting residue was
redissolved in 10% aq NaHCO3 (20 mL). The aqueous layer was
washed with Et2O (2 ꢀ 20 mL) and acidified to pH 2 with aq 10%
HCl and then extracted using EtOAc (3 ꢀ 20 mL). The combined
organic layers were washed with H2O (2 ꢀ 15 mL), dried (Na2SO4),
and evaporated to obtain the title products 5. Products 5a and 5b had
spectra identical in all respects with the previously reported materi-
al.4
HRMS (ESI): m/z [M + H]+ calcd for C19H22Cl3NO6: 466.0585;
found: 466.0583.
(2S)-N-Fluorenylmethoxycarbonyl-2-aminobut-3-enyl-5-oxo-5-
(2,2,2-trichloroethoxy)pentanoic Acid (3s)
Yield: 360 mg (65%); clear colorless oil; [a]D –25.2 (c 1.98,
21
CH2Cl2).
IR (KBr): 3068, 3000–2900, 1749, 1703, 1698, 1478, 1450, 1422,
1372, 1289, 1223, 1142, 1047, 912, 799, 759, 740, 621 cm–1.
1,3-Oxazinan-6-ones 6; General Procedure
The method applied to synthesize 1,3-oxazinan-6-ones was the
same as the method for synthesizing 1,3-oxazolidin-5-ones. Prod-
ucts 6a and 6b have spectra identical in all respects with the previ-
ously reported material.7
1H NMR (300 MHz, CDCl3): d (rotamers) = 10.12 (br s, 1 H, OH),
7.77–7.23 (m, 8 H, ArH), 5.70–5.46 (m, 1 H, CH=CH2), 5.05–4.82
(m, 2 H, CH2=CH), 4.73 (s, 2 H, CH2CCl3), 4.60 (d, J = 5.0 Hz, 2
H, CH2O), 4.21–4.01 (m, 2 H, CHCH2O and CHCO2H), 3.44–2.87
(m, 2 H, NCH2), 2.46–2.02 (m, 6 H, NCH2CH2, CH2CH2CO2, and
CH2CH2CO2).
13C NMR (75 MHz, CDCl3): d (rotamers) = 175.4, 170.9, 156.0
(C=O), 143.4, 141.1 (aryl C), 134.5, 134.3 (CH2=CH), 127.4, 126.8,
124.4, 119.6 (aryl CH), 116.5 (CH2=CH), 94.5 (CCl3), 73.7
(CH2CCl3), 66.7 (CHCH2O), 60.2, 59.4, 58.7 (CHCO2H), 47.9
(CHCO2H), 47.4, 47.0 (NCH2), 32.8, 32.4 (NCH2CH2), 29.9
(CH2CH2CO2), 24.3, 23.9 (CH2CH2CO2).
N-Protected N-But-3-enyl-b-amino Acids 7; General Procedure
The procedure for synthesizing N-but-3-enyl-b-amino acids 7 was
the same procedure as for the preparation of N-but-3-enyl-a-amino
acids 3.
N-Benzyloxycarbonyl-3-aminobut-3-enylpropanoic Acid (7a)
Yield: 20 mg (72%); light yellow oil.
Synthesis 2009, No. 12, 1991–1998 © Thieme Stuttgart · New York

1998
T. T. Van Nguyen et al.
PAPER
IR (KBr): 3067, 3000–2900, 1730, 1704, 1480, 1423, 1368, 1291,
1218, 1189, 1138, 1028, 997, 916 cm–1.
Acknowledgment
The authors wish to thank the Vietnamese Government for the pro-
vision of a Post-Graduate Scholarship (to T.T.V.N.) and the CSIRO
for a Molecular and Health Technologies Aurora PhD Top-Up
scholarship (to T.T.V.N.).
1H NMR (300 MHz, CDCl3): d (rotamers) = 9.58 (br s, 1 H, OH),
7.31–7.15 (m, 5 H, ArH), 5.70 (br s, 1 H, CH2=CH), 5.11–5.08 (m,
2 H, ArCH2), 5.01 (d, J = 9.8 Hz, 2 H, CH2=CH), 3.55–3.45 (m, 2
H, CH2CH2CO2H), 3.36–3.32 (m, 2 H, NCH2), 2.71–2.59 (m, 2 H,
CH2CO2H), 2.34–2.27 (m, 2 H, NCH2CH2).
13C NMR (75 MHz, CDCl3): d (rotamers) = 175.8, 156.2 (C=O),
136.2 (aryl C), 134.6 (CH2=CH) 128.1, 127.9, 127.8, 127.5, (aryl
CH), 116.7 (CH2=CH), 66.9 (ArCH2), 47.3 (NCH2), 44.5
(CH2CH2CO2H), 32.9 (CH2CH2CO2H), 29.7 (NCH2CH2).
HRMS (ESI): m/z [M + H]+ calcd for C14H18NO4: 278.1392; found:
278.1397.
References
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A. Helv. Chim. Acta 1998, 81, 59.
(2S)-N-Fluorenylmethoxycarbonyl-3-aminobut-3-enyl(4-meth-
yl)pentanoic Acid (7b)
Yield: 23 mg (75%); amorphous solid.
IR (KBr): 3160, 3068, 3043, 3020, 3000–2850, 1698, 1667, 1463,
1450, 1388, 1291, 1149, 1000, 912 cm–1.
1H NMR (300 MHz, CDCl3): d (rotamers) = 9.71 (br s, 1 H, OH),
7.73–7.25 (m, 8 H, ArH), 5.73–5.40 (m, 1 H, CH2=CH), 5.01–4.85
(m, 2 H, CH2=CH), 4.61–4.55 (m, 2 H, CHCH2O), 4.19–4.12 (m, 1
H, CHCH2O), 3.20 (m, 1 H, NCH2), 2.66–2.63 (m, 1 H,
CHCH2CO2H), 2.20–1.69 (m, 4 H, CHCH2CO2H, NCH2CH2),
1.26–1.10 [m, 1 H, CH(CH3)2], 0.92–0.75 (m, 3 H, CH3), 0.57–0.46
(m, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d (rotamers) = 177.1, 176.7, 155.7
(C=O), 143.8, 141.1 (aryl C), 135.0, 134.7 (CH2=CH), 128.0, 127.2,
126.8, 126.7, 125.6, 124.4, 124.1, 119.5 (aryl CH), 116.1
(CH2=CH), 66.0 (CHCH2O), 61.8 (CHCH2CO2H), 47.2, 47.0
(CHCH2O), 46.4 (NCH2), 36.8, 36.4 (CH2CO2), 33.2, 32.5, 31.5
[CH(CH3)2], 30.9, 30.5 (NCH2CH2), 19.6, 19.3 (2 ꢀ CH3).
HRMS (ESI): m/z [M + H]+ calcd for C25H30NO4: 408.2169; found:
408.2175.
(18) Leggio, A.; Liguori, A.; Procopio, A.; Sindona, G. J. Chem.
Soc., Perkin Trans. 1 1997, 1969.
(19) Muller, A.; Vogt, C.; Sewald, N. Synthesis 1998, 837.
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Daineko, V. M.; Katser, S. B.; Churakov, A. V.; Kuz’mina,
L. G.; Howard, J. A. K. Inorg. Chim. Acta 2003, 350, 283.
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Oberer, L.; Hommel, V.; Widmer, H. Helv. Chim. Acta
1996, 79, 913.
(2S)-N-Benzyloxycarbonyl-2-aminobut-2-methyl-3-enylpro-
panoic Acid (14)
(S)-3-Benzyloxycarbonyl-4-methyl-1,3-oxazolidin-5-one (11; 0.15
mmol) was dissolved in CH2Cl2 (5 mL). BF3·OEt2 (0.3 mmol) and
ATMS (0.45 mmol) were added to the reaction mixture and the so-
lution was stirred for 18 h with TLC monitoring. The reaction solu-
tion was taken up in Et2O (10 mL) and extracted with aq sat.
NaHCO3 (3 ꢀ 10 mL). The aqueous layer was adjusted to pH 2 with
10% dil. HCl, and extracted with EtOAc (3 ꢀ 10 mL). The com-
bined organic layers were dried (MgSO4), filtered, and concentrated
under reduced pressure. The residual oils were purified via silica gel
column chromatography, eluting with 30% EtOAc–hexane to af-
ford the title product; yield: 17.5 mg (40%); light yellow oil.
IR (KBr): 3400–2900, 3068, 3033, 2980–2900, 1694, 1668, 1470,
1446, 1429, 1255, 1207, 1172, 1101, 1080, 1014, 917 cm–1.
(26) Pillot, J. P.; Dunogues, J.; Calas, R. Tetrahedron Lett. 1976,
1871.
1H NMR (300 MHz, CDCl3): d (rotamers) = 7.62–7.51 (m, 5 H,
ArH), 5.66 (br s, 1 H, CH2=CH), 5.12 (s, 2 H, ArCH2), 4.96 (br s, 2
H, CH2=CH), 4.13 (br s, 1 H, CH3CHCO2H), 3.34–3.09 (m, 2 H,
NCH2), 2.47 (br s, 1 H, NCH2CHCH3), 1.69–1.32 (m, 3 H,
CH3CHCO2H) 0.98–0.82 (m, 3 H, NCH2CHCH3).
13C NMR (75 MHz, CDCl3): d (rotamers) = 175.8, 156.4, 155.7
(C=O), 140.7 (aryl C), 135.8, 135.5, 135.3 (CH2=CH), 129.4, 128.6,
128.1, 127.7, 127.6 (aryl CH), 114.5 (CH2=CH), 67.2 (ArCH2),
57.0, 56.5 (CH3CHCO2H), 53.2, 52.8 (NCH2), 37.6, 37.4
(NCH2CHCH3), 17.1, 17.0 (NCH2CHCH3), 15.5, 14.8, 13.9
(CH3CHCO2H).
(27) Perrin, D. D.; Armarego, W. L. F. In Purification Of
Laboratory Chemicals; Pergamon: Oxford, 1988.
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1988, 31, 2199.
(31) Plucinska, K.; Liberek, B. Tetrahedron 1987, 43, 3509.
MS (ESI, 3000V): m/z (%) = 314 (100, [M + Na]), 292 (20,
[M + H]).
Synthesis 2009, No. 12, 1991–1998 © Thieme Stuttgart · New York