Stereoselective syntheses of (E)-α,β-didehydroamino acid and peptide containing its residue utilizing oxazolidinone derivative

Article abstract of DOI:10.1246/bcsj.82.364

Reaction of methyl N-Boc-N-phenoxycarbonylglycinate with various aldehydes afforded the corresponding cis-4,5-oxazolidinone derivatives, which were effectively converted to (E)-α,β-didehydroamino acids by means of a base. Furthermore, N-deprotection of the oxazolidinone derivatives and subsequent coupling reaction with Boc-amino acid furnished the corresponding dipeptides, which were transformed to dipeptide containing α,α- didehydroamino acid with high E selectivity.

Full text of DOI:10.1246/bcsj.82.364

364
Bull. Chem. Soc. Jpn. Vol. 82, No. 3, 364–380 (2009)
© 2009 The Chemical Society of Japan
Stereoselective Syntheses of (E)-¡,¢-Didehydroamino Acid and Peptide
Containing Its Residue Utilizing Oxazolidinone Derivative
Miki Kometani, Kohki Ihara, Rumi Kimura, and Hideki Kinoshita*
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa 920-1192
Received April 17, 2008; E-mail: khideki@p2223.nsk.ne.jp
Reaction of methyl N-Boc-N-phenoxycarbonylglycinate with various aldehydes afforded the corresponding cis-4,5-
oxazolidinone derivatives, which were effectively converted to (E)-¡,¢-didehydroamino acids by means of a base.
Furthermore, N-deprotection of the oxazolidinone derivatives and subsequent coupling reaction with Boc-amino acid
furnished the corresponding dipeptides, which were transformed to dipeptide containing ¡,¢-didehydroamino acid with
high E selectivity.
Much attention has been focused on naturally occurring
required for preparation of the starting material as mentioned
above,3b,6 we now wish to report a new and effective
stereoselective synthesis of (E)-¡,¢-didehydroamino acid de-
rivative 1 via cis-4,5-oxazolidinone derivative 2 starting from
methyl N-Boc-N-phenoxycarbonylglycinate 3f and a variety of
aldehydes 4 according to retrosynthetic analysis as shown in
Scheme 1. The present method is characterized by stereo-
specific formation of erythro-¢-hydroxy-¡-amino acid deriva-
tive in situ through aldol reaction of 3f with a variety of
aldehydes 4, simultaneous conversion to cis-4,5-oxazolidinone
derivative 2, which is stereoselectively transformed into (E)-
¡,¢-didehydroamino acid derivative 1, and the simplicity of
experimental procedure for the preparation.
First, we prepared methyl N,N-diprotected glycinates 3a-3f
by the reaction of methyl N-monoprotected glycinate 5a-5f
with di-t-butyl dicarbonate (Boc2O). Methyl Boc-glycinate (5a)
was treated with 2 molar equivalents of Boc2O in the presence
of 0.3 molar equivalents of 4-(dimethylamino)pyridine
(DMAP) in dry acetonitrile to afford the desired methyl N,N-
bis(t-butoxycarbonyl)glycinate (3a)7 in quantitative yield
(Entry 1 in Table 1). Similarly, methyl N,N-diprotected glyci-
nates 3b-3f were also prepared in good yields as shown in
Table 1 (Entries 2-6).
peptides containing ¡,¢-didehydroamino acids1 and their
derivatives from the view point of both synthetic interest and
the relationship between their structure and bioactivities.2
Therefore, much work related to the preparation of ¡,¢-
didehydroamino acids has been reported in which the products
bearing thermodynamically controlled alkene geometry, (Z)-
¡,¢-didehydroamino acids were predominantly formed.3 In
previous papers, we have reported that N-t-butoxycarbonyl
(Boc)- or N-benzyloxycarbonyl (Z)-¡-tosylglycine ester was
reacted with either a variety of nitro alkanes in the presence
of base or various aldehydes in the presence of base and
tributylphosphine to afford the corresponding ¡,¢-didehydro-
amino acid derivatives with high Z selectivity in good yields.4
The latter procedure was successfully applied to the synthesis
of optically active 4-hydroxyprolines.5
On the contrary, there are few reports6 concerning stereo-
selective synthesis of (E)-¡,¢-didehydroamino acid since its
stereochemistry is not always thermodynamically favored, for
example, 1) stereoselective elimination of hydrogen chloride
from erythro-¢-chloro-¡-amino acid derived from threo-¢-
hydroxy-¡-amino acid derivative,6a 2) stereospecific dehydra-
tion of erythro-¢-hydroxy-¡-amino acid derivative using
DAST [(diethylamino)sulfur trifluoride],6b 3) formation of
cyclic cis-sulfamidite starting from erythro-¢-hydroxy-¡-
amino acid derivative and thionyl chloride, and subsequent
elimination of sulfur dioxide,6c 4) Suzuki coupling of ¢-
bromo-¡,¢-didehydroamino acid derivative with monosub-
stituted boronic acid,6d 5) stereospecific dehydration of erythro-
¢-hydroxy-¡-amino acid derivative using Martin’s sul-
furane [diphenylbis(1,1,1,3,3,3-hexafluoro-2-phenyl-2-propyl)-
sulfurane],6e 6) stereospecific dehydration of threo-¢-hydroxy-
¡-amino acid derivative with EDC [1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide],6f 7) oxidation of 3-S-benzylthio-
amino acid derivative to the sulfoxide, followed by thermolysis
to form ¡,¢-didehydroamino acid.3b
Next, formation of cis-4,5-oxazolidinone derivatives through
the reaction of ester enolates of 3a-3f with benzaldehyde (4i)
was examined as a preliminary experiment. The results are
X
N
X
N
4
XHN
H
CO2CH3
CO2CH3
CO2CH3
O
O
PhO
O
R
5 R
HO
R
1
2
X
H
CO2CH3
O
N
O
R
PhO
3f
4
Although enantiomerically pure ¢-hydroxy-¡-amino acid
derivative or ¢-bromo-¡,¢-didehydroamino acid derivative is
Scheme 1. Retrosynthetic analysis of (E)-dehydroamino acid
derivative.
Published on the web March 12, 2009; doi:10.1246/bcsj.82.364

M. Kometani et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
365
Table 1. Preparation of Various N,N-Diprotected Glycine Methyl Esters
Boc2O , DMAP
PG(Boc)NCH2CO2CH3
PG-NHCH2CO2CH3
CH3CN, Temp, Time
5a-f
3a-f
Reaction conditions
Product/%
Boc2O
DMAP
Entry Substrate
PG
/mol equiv /mol equiv
Temp/°C
Time/h
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Boc
Z
Cl3CH2CO2C
H3CO2C
H3CH2CO2C
PhO2C
2.0
1.5
1.1
1.5
1.2
1.1
0.3
0.2
0.1
0.2
0.1
0.1
55
rt
rt
rt
rt
22
2
0.3
2
0.3
3
3a
3b
3c
3d
3e
3f
quant
77
98
90
quant
quant
¹5
Table 2. Preparation of cis-4,5-Oxazolidinone Derivatives
formation of 6 through a five-membered cyclic intermediate.
Namely, it reveals that N, O migration of the Boc group took
place during the reaction as shown in Scheme 2. Accordingly,
in Entry 1, quenching the reaction mixture afforded only 6 in
85% yield, while a mixture of 6 and 1i¤ due to elimination of
carbon dioxide and lithium tert-butoxide for longer reaction
time as shown in Entry 2, and a mixture of 1i and 1i¤ at
elevated temperature in Entry 3 (in Table 2) were furnished,
respectively. Reversibly, in the cases of the substrates 3d-3f,
the desired product 2i as a single isomer was obtained in 32%,
40%, and 63% yields, respectively (Entries 6-8 in Table 2).
Although the difference between the results using 3a-3f is
now not clear, the result in Entry 8 may be attributed to
stabilities of 3f under these reaction conditions and of the
leaving phenoxide anion. The structure of product 2i was
LDA (1.1 mol equiv)
PG(Boc)NCH2CO2CH3
THF, -78 °C, 1 h
3a-f
Boc
N
PhCHO (4i)
(1.1 mol equiv)
Temp, Time
CO2CH3
Ph
O
O
2i
Yield of
2i/%
Entry Substrate PG
Temp/°C Time/h
a)
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3c
3d
3e
3f
Boc
Boc
Boc
Z
Cl3CH2CO2C
H3CO2C
H3CH2CO2C
PhO2C
¹78
¹78
¹78-rt
¹78
rt
¹78
¹78-rt
¹78
0.5
2
4.5
6
1
3
®
®
b)
c)
®
traced)
tracee)
32f)
1
confirmed by comparison of its H NMR data with those of
the known compound reported by Naito et al.9a and NOE
measurement. The chemical shifts and coupling constant
(J = 8.90 Hz) between the hydrogens at the C4-C5 position
of 2i are fully in agreement with those of the reported values
(J = 9.0 Hz).9a,9b Eventually, it was found that the stereo-
chemical relationship between the hydrogens at the C4-C5
position is a cis configuration. As compound 3f among 3a-3f
examined was found to be a useful starting material for
construction of the cis-4,5-oxazolidinone system, the reaction
of compound 3f with a variety of aldehydes 4a-4h and 4j-4l
was examined. The results are listed in Table 3. When the
lithium ester enolate derived from 3f at ¹40 °C for 1 h in THF
was reacted with 1.1 molar equivalents of acetaldehyde (4a) at
¹40 °C for 4 h, no product was obtained at all (Entry 1 in
Table 3). After formation of the lithium ester enolate of 3f at
¹78 °C 4a was reacted at ¹40 or ¹78 °C for 4 h to furnish the
desired product 2a in moderate yields (Entries 2 and 3 in
Table 3). In a similar manner, the products 2b and 2c were
obtained in moderate yields by treating the reaction mixture at
¹78 to ¹40 °C for 4 h (Entries 4 and 5 in Table 3). In the
absence of additive, 2e, 2g, and 2h were produced only in 43%,
42%, and 31% yields, respectively (Entries 7, 9, and 10). In
order to improve the yields by activation of the aldehydes 4e,
4g, and 4h Lewis acids such as Ti(OiPr)4 and Cl2Ti(OiPr)2 were
used as an additive to produce the corresponding 2e, 2g, and 2h
in 66%, 51%, and 45% yields, respectively (Entries 7, 9, and
10 in Table 3). In the cases of aromatic aldehydes 4j-4l the
desired products 2j-2l were also obtained in moderate yields
(Entries 11-13 in Table 3).
1.5
1
40
63
a) Methyl 2-(t-butoxycarbonylamino)-3-(t-butoxycarbonyloxy)-
3-phenylpropanoate (6) was obtained in 85% yield. b) 56% of
compound 6 and 11% of methyl (Z)-N-Boc-¡,¢-didehydro-
phenylalaninate (1i¤) were obtained. c) A mixture of 1i¤ and
methyl (E)-N-Boc-¡,¢-didehydrophenylalaninate (1i) was ob-
tained in 36% and 25% yields, respectively. d) Recovery of 3b
in 38% yield. e) Recovery of 3c in 45% yield along with 37% of
5c. f) Recovery of 3d in 16% yield.
summarized in Table 2. Lithiation of 3a with 1.1 molar
equivalents of lithium diisopropylamide (LDA) in tetrahydro-
furan (THF) at ¹78 °C for 1 h followed by the reaction of the
lithium ester enolate thus prepared with 1.1 molar equivalents
of benzaldehyde (4i) at ¹78 °C for 30 min did not afford the
desired product 2i, but methyl 2-(t-butoxycarbonylamino)-3-
(t-butoxycarbonyloxy)-3-phenylpropanoate (6) in 85% yield
(Entry 1 in Table 2). Although the substrates 3b and 3c
were treated with benzaldehyde (4i) under similar reaction
conditions, no product 2i was obtained (Entries 4 and 5 in
Table 2). A plausible reaction mechanism for formation of 6
and methyl (Z)- or (E)-N-Boc-¡,¢-didehydrophenylalaninate
(1i¤3b,3h,8 and 1i) may be explained as follows: the lithium ester
enolate derived from 3a was reacted with benzaldehyde (4i) to
afford the lithium alkoxide of methyl N,N-diBoc-¢-phenyl-
serinate. Subsequently, the lithium alkoxide anion attacked
the carbonyl carbon atom of the N-Boc group resulting in

366
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
Syntheses of (E)-¡,¢-Didehydroamino Acid
Boc
Boc
N
OCH3
Boc
tBuO
CO2CH3
N
C6H5CH=O (4i)
-78 °C, 40 min
LDA, -78 °C, 1 h
N
CO2CH3
Boc
O Li
O
Boc
C6H5
O
Li
H
3a
OCH3
OCH3
Li
Li
Boc
N
C
BocNH
C
CO2CH3
C6H5
BocNH
BocN
tBuO
CO2CH3
O
O
Li
C6H5
tBuO–C–O
O
tBuO2CO
tBuO–C–O
O
C6H5
O
Li
O
C6H5
-CO2
-LiOtBu
H3O
CO2CH3
C6H5
CO2CH3
C6H5
BocNH
H
BocNH
tBuO2CO
6
(E)-1i, (Z)-1i'
Scheme 2.
Table 3. Preparation of Various Oxazolidinone Derivatives
Boc
Boc
CO2CH3
RCHO (1.1 mol equiv)
Additive (1.1 mol equiv)
N
LDA (1.1 mol equiv)
O
PhO2CNCH2CO2CH3
Temp, Time
N2, THF, -78 °C, 1 h
O
R
3f
2a-h, j-l
Entry Aldehyde
R
Additive
Temp/°C
Time/h Product Yield/%
1a)
2
3
4
5
6
4a
4a
4a
4b
4c
4d
CH3-
CH3-
CH3-
CH3CH2-
(CH3)2CH-
PhCH2CH2-
®
®
®
®
®
®
¹40
¹40
¹78
4
4
4
4
4
4
2a
2a
2a
2b
2c
2d
0
51
61
52
46
72
¹78- ¹40
¹78- ¹40
¹78
7
4e
Ti(OiPr)4
¹78
¹78
4
3
2e
66
41
R' = Z
N
8b)
4f
®
2f
R'
R' = Boc
9
4g
Cl2Ti(OiPr)2
¹78
3
2g
51
BocN
N
10
4h
4j
4k
4l
Boc(Z)NCH2CH2CH2-
p-BrC6H4-
p-CH3C6H4-
Cl2Ti(OiPr)2
¹78
¹78
¹30
¹30
3
48
48
48
2h
2j
2k
2l
45
51
55
60
11
12
13
®
®
®
p-CH3OC6H4-
a) The lithium ester enolate was prepared at ¹40 °C. b) LiHMDS was used as base.
Stereoselective formation of 4,5-cis-oxazolidinone deriva-
TS 1 to TS 4 to afford the lithium alkoxide of the correspond-
ing erythro-¢-hydroxy-¡-amino acid ester.11 Subsequently,
nucleophilic attack of the alkoxide anion thus formed onto
the carbonyl carbon atom of the N-phenoxycarbonyl group
might proceed and the subsequent elimination of the lithium
phenoxide gives the desired cis-4,5-oxazolidinone derivative 2
as shown in Scheme 3.
As synthetic route to cis-4,5-oxazolidinone derivatives 2a-2l
starting from 3f and aldehydes 4 was achieved, conversion of
diastereomerically pure compounds 2a-2l into (E)-¡,¢-dide-
tive 2 might be explained as follows. The silyl enol ester and
the O-alkylated enol ester were first isolated to determine
configuration of the lithium ester enolate formed in the
solution. Namely, the lithium ester enolate derived from 3a
or 3f with LDA at ¹78 °C in THF was treated with excess of
chlorotrimethylsilane, t-butyldimethylsilyl trifluoromethane-
sulfonate, t-butyldiphenylsilyl chloride (TBDPS-Cl), or benzyl
bromide.10 Unfortunately all attempts failed. The reaction
might proceed via TS 1 with the least steric hindrance among

M. Kometani et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
367
Boc
N
OCH3
O Li
Boc O Li
Boc
N
PhO
PhO
N
CO2CH3 LDA
PhO
OCH3
O
H
O
H
O
3f
RCHO
RCHO
OCH3
O
H
OCH3
O
H
OCH3
O
NXY
Li
R
OCH3
O
R
H
NXY
Li
H
H
R
R
H
Li
Li
NXY
O
O
O
O
H
H
NXY
TS 4
TS 1
TS 2
TS 3
Boc
N
Boc
N
H
Boc
N
NXY OCH3
Li
CO2CH3
R
CO2CH3
PhO
PhO
CO2CH3
R
4
R
O
5
- PhOLi
O
O
O
O
O
O
O
R
H
Li
2
X : Boc
Y : CO2Ph
Li
Scheme 3. A plausible reaction mechanism.
Table 4. Conversion of Oxazolidinone Derivatives to (E)-Dehydroamino Acid Derivatives
Boc
CO2CH3
R
BocHN
H
CO2CH3
R
N
LiHMDS (3.0 mol equiv)
THF, Temp, 5 min
O
O
1a-l'
2a-l
Yield/%
Entry
Substratea)
R
Temp/°C
E form
1a 57
Z form
1
2a
2a
2a
2a
2b
2c
2d
CH3-
CH3-
CH3-
CH3-
CH3CH2-
(CH3)2CH-
PhCH2CH2-
¹40
¹78
¹100
¹78
¹78
¹78
¹78
1a¤
1a¤
1a¤
1a¤
1b¤
1c¤
1d¤
41
27
<24
<13
<9
2b)
3c)
4
1a
1a
1a
1b
1c
1d
68
76
85
91
96
96
5
6
7
<4
<4
8d)
2e
¹10
1e
93
1e¤
<7
R'=Z
N
R'=Boc
9
10
11
2f
2g
2g
¹78
¹10
¹78
1f
1g
1g
82
48
83
1f¤
1g¤
1g¤
<8
25
R'
BocN
N
<4
12
13
14
15
16
2h
2i
2j
2k
2l
Boc(Z)NCH2CH2CH2-
Ph-
p-BrC6H4-
p-CH3C6H4-
p-CH3OC6H4-
¹10
¹20
¹20
¹20
¹20
1h
1i
1j
1k
1l
62
92
89
92
91
1h¤
1i¤
1j¤
1k¤
1l¤
25
6
9
6
7
a) Diastereomerically pure substrates 2a-2l were used. b) HMPA (3.0 mol equiv) was added. c) Reacted for
30 min. d) Reacted for 10 min.
hydroamino acid derivatives 1a-1l was examined under basic
conditions. The results are listed in Table 4. Various bases such
as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU), KOtBu, KOH, and lithium hexa-
methyldisilazide (LiHMDS) in THF were used. Eventually,
LiHMDS was base of choice among bases tested in THF to
afford ¡,¢-didehydroamino acid derivatives 1a-1l predomi-
nantly accompanied by ¡,¢-didehydroamino acid derivatives
1a¤-1l¤. Compound 2a was treated with 3.0 molar equivalents of
LiHMDS at ¹40 °C for 5 min to afford methyl 2-(t-butoxy-
carbonylamino)-2-butenoate as a separable mixture of 1a and
1a¤ in 57% and 41% yields, respectively (Entry 1 in Table 4).

368
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
Syntheses of (E)-¡,¢-Didehydroamino Acid
Boc
BocHN
1) LDA
N
CO2CH3
BocHN CO2CH3
1M HCl
MeOH
LiHMDS
3f
OH
O
O
O
O
H
O
O
O
O
2)
O
O
O
H
10, 61%
9
8a, 8a'
(E)- and (Z)-mixture
BocHN
O
BocHN
(S)
TBDPS-Cl
Imidazole
H2, Pd(OH)2/C
10 h, EtOH
(S)
OTBDPS
OTBDPS
O
O
O
12(cis-form), 89%
11, 80%
H
H2N
H
O
CO2H
(S)
ZHN
O
(S)
(S)
1) TFA
NH2
(S) (S)
HO
(S)
N
O
OTBDPS
H
HO
2) Et3N
Z-ONSu
O
CO2H
clavalanine
7, 80%
Scheme 4. Synthesis of (3S,5S)-3-(Z-amino)-5-(TBDPS-oxymethyl)-£-lactone 7.
Major product 1a was assigned to be (E)-2-(t-butoxycarbonyl-
Table 5. Preparation of Oxazolidinone 8
1
amino)-2-butenoate by comparison with the reported H NMR
O
data3b and by NOE measurement. Minor product 1a¤ proved to
be methyl (Z)-2-(t-butoxycarbonylamino)-2-butenoate by com-
O
H
(1.5 mol equiv)
Boc
O
1
parison with the reported H NMR data.3b,3c,3i,8a On treatment
LDA (1.1 mol equiv)
Additive (X mol equiv)
Temp, Time
PhO2CNCH2CO2CH3
N2, THF, -78 °C, 30 min
of 2a with 3.0 molar equivalents of LiHMDS at ¹100 °C for
30 min, stereoselectivity of E and Z isomers (1a/1a¤) was
improved considerably (Entry 3 in Table 4). Moreover, 2a was
reacted at ¹78 °C for 5 min to afford compound 1a in 85%
yield (Entry 4). Predominant formation of 1a from 2a might be
due to trans elimination by deprotonation with base at the ¡-
position of the ester group.3h In a similar manner, compounds
(E)-1b-1l were stereoselectively prepared in moderate to high
yields (Entries 5-16). Stereochemistry of 1b, 1d-1g, and 1i-1l
were assigned by NOE measurement without 1c and 1h, whose
stereochemistry were determined by isomerization to the
corresponding 1c¤ and 1h¤ using a catalytic amount of I2
(Entries 6 and 12 in Table 4).12 The 1H NMR spectra of
1a¤,3b,3c,3i,8a 1b¤,8a 1c¤,8a 1d¤,13 1i¤,3b,8a-8c 1k¤,14 and 1l¤15 were
satisfactorily in accordance with the reported data of Z isomer.
Because it was found that compounds 2 could be stereo-
selectively converted into (E)-¡,¢-didehydroamino acid deriv-
atives 1 the present method was employed for synthesis
of (3S,5S)-3-(benzyloxycarbonylamino)-5-(t-butyldiphenylsil-
oxy)-£-lactone (7),16 known as a key synthetic intermediate
of the antibiotic clavalanine17 isolated from streptomyces
clavuligerus according to Scheme 4. First, compound 8 was
prepared as the starting material as shown in Table 5. After 3f
was treated with 1.1 molar equivalents of LDA at ¹78 °C for
30 min, the resulting lithium ester enolate was reacted with 1.5
molar equivalents of (R)-O-2,3-isopropylideneglycelaldehyde
at ¹78 °C for 4 h to afford a separable mixture of two
diastereomers, of which 8a was produced as an oil and 8a¤ in
crystalline form in 22% and 30% yields, respectively (Entry 1
in Table 5). As 15.2% and 11.4% NOE between the hydrogens
at C4-C5 in irradiation of the proton at C4 in products 8a and
8a¤ were observed, the stereochemistry between the hydrogens
at C4-C5 of the oxazolidinone ring is assigned to be cis
configuration. To improve the total yield various reaction
3f
Boc
O
Boc
O
CO2CH3
CO2CH3
N
N
O
O
O
O
O
O
8a (oily form)
8a' (crystalline form)
Yield/%
8a 8a¤
X
Temp
/°C
Time
/h
Entry
Additive
/mol equiv
1
2
3
4
5
6
7
8
9
®
®
®
®
¹78
¹78- ¹10
4
3
22
10
30
24
®
®
¹78- ¹20 24 <22 <28
TiCl4¢2THF
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
1.5
0.5
0.5
1.1
1.1
1.5
2.0
¹78
¹78
¹78
¹78
¹78
¹78
¹78
2
2
4
4
6
2
4
26
24
<28
32
30
40 <25
38 19
®
20
13
16
21
10
conditions were examined. Accordingly, the ratio of two
diastereomers was found to be dependent on reaction con-
ditions (Entries 2-10 in Table 5).
Each of diastereomerically pure compounds 8a and 8a¤ thus
obtained was individually exposed to the conditions for
preparation of ¡,¢-didehydroamino acid via elimination of
carbon dioxide as described for preparation of compound 1.
The results are summarized in Table 6. Thus, treatment of 8a
(oily form) with 3.0 molar equivalents of LiHMDS at ¹10 °C
for 5 min furnished compound 9 in a ratio of 78:22 as a mixture
of E and Z isomers18 in 70% yield (Entry 2 in Table 6).
Similarly, 8a¤ (crystalline form) was reacted with 3.0 molar
equivalents of LiHMDS at ¹30 °C for 90 min in THF to afford

M. Kometani et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
369
the desired product 9 in a ratio of 85:15 as a mixture of E and Z
isomers in 87% yield (Entry 5 in Table 6). Formation of a
mixture of (E)- and (Z)-9 might be explained as follows: the
carbanion generated by deprotonation with LiHMDS under-
goes trans elimination of carbon dioxide with retention of
stereochemistry to afford (E)-9, however, (Z)-9 is produced due
to formation of the ester enolate.
Next, conversion of the mixture of diastereomers 9 into
compound 7 was performed according to Scheme 4. Treatment
of the mixture of diastereomers 9 (E/Z = 78:22) with 1 M HCl
in MeOH at room temperature for 1 day gave the desired £-
butenolide derivative 1019 and methyl (4S)-(Z)-2-(N-Boc-
amino)-4,5-dihydroxy-2-pentenoate in 61% and 19% yields,
respectively. Formation of the latter product was probably
attributed to deacetalization of the starting Z isomer 9 since the
authentic Z isomer 9 prepared by an alternative way5 afforded
only the deacetalization product in 90% yield under the same
reaction conditions. Therefore, E isomer 9 was cyclized to the
oxazolidinone derivative 10, whereas Z isomer 9 underwent
deacetalization. Next, compound 10 was reacted with 1.2
molar equivalents of TBDPS-Cl in the presence of 3 molar
equivalents of imidazole at room temperature for 4 h in
dimethylformamide (DMF) to afford O-protected product 11
in 80% yield. Hydrogenation of the resulting compound 11
over 20% Pd(OH)2-carbon in EtOH under hydrogen atmo-
sphere at room temperature for 10 h took place stereospecifi-
cally from the less hindered side due to the bulky TBDPS-
oxymethyl substituent at position 5 to afford exclusively cis
3,5-disubstituted £-lactone derivative 12 as a single isomer in
89% yield,5 whereas in the case of longer (overnight) reaction
time, a mixture of cis and trans isomers was obtained in 62%
and 13% yields, respectively. N-Deprotection of the resulting
compound 12 by trifluoroacetic acid (TFA) at 0 °C to room
temperature for 1 h in dichloromethane and subsequent cou-
pling reaction with 1.1 molar equivalents of N-(benzyloxycar-
bonyloxy)succinimide (Z-ONSu) in the presence of 3 molar
equivalents of triethylamine (TEA) at 0 °C to room temperature
for 2 h in THF afforded the desired compound 7 in 80% yield.
In a previous paper,12 we reported that isomerization of
dipeptide containing (E)-N-Boc-¡,¢-didehydroamino acid res-
idue to the corresponding Z isomer could be readily performed
by means of a catalytic amount of iodine. Indeed, stereochemi-
cally pure methyl (E)-2(N-t-butoxycarbonylamino)-2-butenoate
(1a) was treated with a catalytic amount of iodine at room
temperature for 19 h in THF to furnish the corresponding Z
isomer 1a¤ in 90% yield (Entry 1 in Table 7). In a similar way,
pure E isomers 1b-1h were smoothly isomerized to the
1
corresponding Z isomers 1b¤-1h¤ in high yields. The H NMR
data of the products 1a¤-1h¤ produced by isomerization were
satisfactorily identical with those of the minor products
obtained in Entries 4-12 in Table 4. The results are summa-
rized in Table 7.
Table 6. Conversion of Oxazolidinone 8 to Dehydroamino
Acid Derivative 9
BocNH
CO2CH3
LiHMDS (3.0 mol equiv)
N2, THF, Temp, Time
8a (oily form) or
8a' (crystalline form)
We next tried to prepare the amide compounds 13a-13k¤ by
the reaction of diastereomerically pure cis-4,5-oxazolidinoes
2a, 2d, and 2i with N-Boc amino acid derivatives as shown in
Table 8. Thus, after N-deprotection of 2i with 99% formic acid
at room temperature for 40 min, the resulting oxazolidinone
derivative was treated with 1.1 molar equivalents of LDA at
¹78 °C for 5 min in dry THF followed by reaction with 1.1
molar equivalents of the N-hydroxysuccinimide (HONSu)
ester of Boc-alanine at ¹78 to ¹10 °C for 3 h to afford the
corresponding amide product 13i as a major product and 13i¤
as a minor one in 96% total yields as a separable mixture of
O
O
H
9
Entry Substratea) Temp/°C Time/min Yield/% E/Z
1
2
3
4
5
8a
8a
8a
8a¤
8a¤
¹10
¹10
¹30
¹10
¹30
3
5
60
5
50
70
61
73
87
76/24
78/22
77/23
89/11
85/15
90
a) Stereoisomerically pure substrates 8a and 8a¤ were used.
Table 7. Isomerization of E to Z Isomer by Iodine
BocHN
H
CO2CH3
R
BocHN
R
CO2CH3
H
cat. I2
THF, rt, Time
(E)-1a-h
(Z)-1a'-h'
Entry
Substratea)
R
Time/h
Yield/%
E/Z
1
2
3
4
1a
1b
1c
1d
CH3-
19
17
21
12
1a¤
90
91
96
98
4/96
3/97
5/95
3/97
CH3CH2-
(CH3)2CH¹
PhCH2CH2-
1b¤
1c¤
1d¤
5
6
1e
24
43
1e¤
1f¤
97
93
4/96
9/91
R' = Z
N
R'
1f
R' = Boc
7
8
1g
1h
16
9
1g¤
1h¤
quant
96
0/100
0/100
BocN
N
Boc(Z)NCH2CH2CH2-
a) A stereochemically pure E isomer of 1a-1h was used.

370
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
Syntheses of (E)-¡,¢-Didehydroamino Acid
Table 8. Coupling of Boc-Amino Acid with cis-4,5-Oxazo-
lidinone Derivative
Table 9. Conversion of Compounds 13a-13k¤ to the
Corresponding Dehydropeptides 14a-14k¤
Boc
CO2CH3
Boc-AA-NH
LiHMDS (4.0 mol equiv)
13a-k'
CO2CH3
N
1) HCO2H
THF, -45 °C, 50 min
O
R
H
2)
LDA (1.1 mol equiv), -78 °C, 5 min
Boc-AA-ONSu (1.1 mol equiv)
O
R
14a-k'
racemic mixture
DMAP (0.1 mol equiv)
2a, d, i
Entry Substrate R
AA Product
Yield/% E/Z
-78 °C
Boc-AA
-10 °C, 3 h, THF
1
2
3
4
5
6
7
13a
13b
13b¤
13c
CH3
Gly 14a/14a¤
Ala 14b/14b¤
Ala 14b/14b¤
Val 14c/14c¤
Val 14c/14c¤
Leu 14d/14d¤
Leu 14d/14d¤
56
88
92
95
85
61
52
81/19
84/16
81/19
85/15
85/15
88/12
75/25
Boc-AA
CO2CH3
R
CO2CH3
R
N
N
O
+
O
O
O
13c¤
13d
13d¤
13a-k'
Total
yield/%
Entry Substratea)
R
AAb) Product
drc)
8
9
13e
13f
PhCH2CH2 Gly 14e/14e¤
Ala 14f/14f¤
52
80
75
72
80
88/12
85/15
84/16
89/11
87/13
1
2
3
4
2a
CH3
Gly 13a
82
68
60
78
®
10
11
12
13f¤
13g
13g¤
Ala 14f/14f¤
Val 14g/14g¤
Val 14g/14g¤
Ala 13b/13b¤
Val 13c/13c¤
Leu 13d/13d¤
53/47
52/48
51/49
13
14
15
16
17
18
19
13h
13i
13i¤
13j
13j¤
13k
13k¤
Ph
Gly 14h/14h¤
Ala 14i/14i¤
Ala 14i/14i¤
Val 14j/14j¤
Val 14j/14j¤
Leu 14k/14k¤
Leu 14k/14k¤
53
78
82
70
74
59
60
85/15
87/13
87/13
89/19
91/9
5
6
7
2d
PhCH2CH2 Gly 13e
Ala 13f/13f¤
94
60
62
®
52/48
52/48
Val 13g/13g¤
8
9
10
11
2i
Ph
Gly 13h
92
96
92
98
®
Ala 13i/13i¤
Val 13j/13j¤
Leu 13k/13k¤
53/47
51/49
55/45
89/11
88/12
a) A diastereomerically pure isomer of 2a, 2d, and 2i was used.
b) Means amino acid abbreviated by three letters. c) Means the
ratio of the two diastereomers.
isomerization to the minor product 14e¤ by means of I2.12
The minor products, 14a¤,3h,3i,20 14h¤,3h and 14i¤3b,3c were found
to be the dipeptide containing (Z)-¡,¢-didehydroamino acid
1
two diastereomers with a ratio of 53:47 as shown in Table 8
(Entry 9). Similarly, compounds 13a-13h (Entries 1-8) and
13j-13k¤ (Entries 10 and 11) were prepared in satisfactory
yields as a separable mixture of two diastereomers without
Entries 1, 5, and 8.
residue according to the reported H NMR data.
As mentioned above, the reaction of compound 3f derived
from glycine with a variety of aldehydes 4 afforded various
kinds of cis-4,5-oxazolidinone derivatives 2, which were
readily transformed to the corresponding ¡,¢-didehydroamino
acid derivatives with high E selectivity in good yields under
basic conditions. Thus, 3f was found to be a very useful
building block for the preparation of (E)-¡,¢-didehydroamino
acid. Moreover, (E)-¡,¢-didehydroamino acid derivatives thus
prepared were satisfactorily isomerized to the corresponding
(Z)-¡,¢-didehydroamino acid derivatives by using iodine.
Eventually, the present method will supply a convenient
preparation method for both (E)- and (Z)-¡,¢-didehydroamino
acid derivatives. In addition, the amide compounds 13 were
easily transformed to the corresponding dipeptides 14 contain-
ing (E)-¡,¢-didehydroamino acid residue under basic condi-
tions.
We next tried to prepare the dipeptide containing (E)-¡,¢-
didehydroamino acid residue as shown in Table 9. Compound
13b, the major product, thus obtained was treated with 4.0 molar
equivalents of LiHMDS at ¹45 °C for 50 min in THF to afford
the corresponding dipeptide 14b and 14b¤ in a ratio of 84:16 in
88% yield (Entry 2 in Table 9). Treatment of 13b¤, the minor
product, with LiHMDS under the same reaction conditions also
resulted in the formation of 14b and 14b¤ in a ratio of 81:19 in
92% yield (Entry 3 in Table 9). The major product 14b was
found to be methyl (E)-2-(Boc-alanylamino)-2-butenoate, and
14b¤ to be (Z)-2-(Boc-alanylamino)-2-butenoate compared with
the reported data3i,6f,20 and NOE measurement of 14b. From
these results, it was found that treatment of both 13b and 13b¤
bearing cis-4,5-oxazolidinone moiety with base afforded the
dipeptide 14b bearing (E)-¡,¢-didehydroamino acid residue
predominantly with high stereoselectivity accompanied by Z
isomer 14b¤ as in the case described for conversion of 2 to 1. In
the same way, compounds 14a and 14c-14k containing ¡,¢-
didehydroamino acid with high E selectivity were prepared in
good yields. The results are listed in Table 9. Stereochemistry
of the major products, 14a, 14c, 14d, and 14f-14k was
assigned to be E configuration by NOE measurement. Stereo-
chemistry of the major product 14e was determined by
Experimental
All of the melting points were determined with a micro melting
apparatus (Yanagimoto Seisakusyo) and are uncorrected. The
1H NMR, IR, and MS spectra were recorded on JEOL JNM-LA
400FT (400 MHz) and LA 300FT (300 MHz) NMR spectrometers,
a JASCO FT/IR-230 infrared spectrometer, and a JEOL SX-102A
mass spectrometer, respectively. The chemical shifts of the NMR
spectra are reported in ¤-relative to TMS as an internal standard.
All solvents were distilled and stored over a drying agent. Thin-
layer chromatography (TLC) and flash-column chromatography

M. Kometani et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
371
were performed using Merck’s silica gel 60PF254 (Art. 7749) and
Cica-Merck’s silica gel 60 (No. 9385-5B), respectively. All
crystalline products prepared in the present work were colorless.
A General Procedure for Conversion of Oxazolidinones 2a-
2l to (E)-¡,¢-Didehydroamino Acid Derivatives 1a-1l. To a
solution of 2a (81 mg, 0.31 mmol) in dry THF (5 mL) was added
LiHMDS (1.55 mmol) in THF at ¹78 °C under N2. The solution
was stirred for 5 min at that temperature and quenched with 1 M
AcOH in THF. The solvent was removed in vacuo to give a
residue, which was partitioned between ethyl acetate (EtOAc) and
water. The EtOAc solution was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
subjected to preparative TLC (SiO2, hexane/EtOAc = 4/1, v/v) to
afford methyl (E)-2-(Boc-amino)-2-butenoate (1a) in 85% (57 mg)
and Z isomer, 1a¤ in <13% yields, respectively. (E)-1a: oil; IR
(neat): 3457, 3420, 3358, 2979, 2954, 2932, 2394, 2287, 1728,
1651, 1511, 1439, 1365, 1254, 1200, 1163, 1116, 1051, 1013, 937,
Methyl 2-(N-Boc-amino)-5-phenyl-2-pentenoate (1d and
1d¤):
(E)-1d: oil; IR (neat): 3417, 3358, 3086, 3061, 3027,
2979, 2952, 2931, 2860, 2287, 1947, 1727, 1707, 1646, 1604,
1510, 1454, 1438, 1391, 1367, 1243, 1200, 1162, 1094, 1048,
¹1
1026, 897, 868, 836, 770, 750, 700 cm
;
1H NMR (400 MHz,
CDCl3): ¤ 1.47 (s, 9H), 2.76-2.81 (m, 2H), 2.81-2.88 (m, 2H),
3.79 (s, 3H), 6.58 (br, 1H), 6.76 (br, 1H), 7.19-7.28 (m, 5H).
HRMS (FAB+) (M+ + 1): Found: m/z 306.1709. Calcd for
C17H24NO4: 306.1705. When the methyl protons of the ester
group were irradiated, 1.3% and 1.8% NOE were observed for the
£,¤-methylene protons and the phenyl protons, respectively. (Z)-
1d¤; oil (Lit. mp 48 °C).14 IR (neat): 3339, 3086, 3062, 3027, 2978,
2952, 2931, 1725, 1657, 1604, 1496, 1454, 1437, 1391, 1367,
1269, 1246, 1165, 1085, 1049, 1031, 1003, 912, 882, 845, 798,
1
775, 749, 700 cm¹1; H NMR (400 MHz, CDCl3): ¤ 1.46 (s, 9H),
2.47 (q, J = 7.80 Hz, 2H), 2.77 (t, J = 7.80 Hz, 2H), 3.76 (s, 3H),
5.86 (br s, 1H), 6.58 (t, J = 7.80 Hz, 1H), 7.20-7.34 (m, 5H).
HRMS (FAB+) (M+ + 1): Found: m/z 306.1702. Calcd for
C17H24NO4: 306.1705.
1
888, 850, 829, 800, 771, 703 cm¹1; H NMR (400 MHz, CDCl3):
¤ 1.47 (s, 9H), 2.03 (d, J = 11.71 Hz, 3H), 3.86 (s, 3H), 6.57
(br, 1H), 6.78 (br, 1H). HRMS (FAB+) (M+ + 1): Found: m/z
216.1241. Calcd for C10H18NO4: 216.1236 When the ¢-methyl
protons were irradiated, 9.0% and 1.9% NOE were observed for
the olefinic proton and the protons of the methyl ester, respectively.
(Z)-1a¤: mp 72.5-73.5 °C (EtOAc-hexane) (Lit. mp 69-71 °C).8a
IR (KBr): 3330, 3168, 3007, 2978, 2952, 1722, 1642, 1608, 1586,
Methyl
¡-(N-Boc)-¢-(N¤-Z)-¡,¢-didehydrotryptophanate
(1e and 1e¤): (E)-1e; mp 113.0-113.5 °C (EtOAc-hexane). IR
(KBr): 3898, 3851, 3733, 3708, 3687, 3674, 3647, 3627, 3415,
2954, 2357, 1745, 1695, 1507, 1457, 1441, 1405, 1360, 1322,
¹1
1280, 1238, 1161, 1088, 1043, 910, 756, 704 cm
;
1H NMR
(400 MHz, CDCl3): ¤ 1.52 (s, 9H), 3.70 (s, 3H), 5.47 (s, 2H), 7.25-
7.41 (m, 6H), 7.48 (d, J = 7.81 Hz, 2H), 7.59 (d, J = 8.05 Hz, 1H),
7.74 (s, 1H), 8.07 (s, 1H), 8.17 (d, J = 8.07 Hz, 1H). HRMS
(FAB+) (M+ + 1): Found: m/z 451.1875. Calcd for C25H27N2O6:
451.1869. When the N-H proton of the carbamate was irradiated,
2.8% NOE was observed for the olefinic proton. (Z)-1e¤: mp
107.5-108.5 °C (EtOAc-hexane). IR (KBr): 3340, 2978, 2953,
2934, 1714, 1660, 1495, 1455, 1437, 1391, 1382, 1367, 1350,
1275, 1244, 1165, 1097, 1047, 1008, 949, 899, 835, 797, 774, 764,
1545, 1468, 1455, 1436, 1366, 1329, 1307, 1246, 1220, 1161,
¹1
1085, 1048, 1026, 985, 937, 910, 850, 793, 756, 698 cm
;
1H NMR (400 MHz, CDCl3): ¤ 1.47 (s, 9H), 1.81 (d, J = 7.32 Hz,
3H), 3.77 (s, 3H), 5.86-6.10 (br, 1H), 6.68 (q, J = 7.32 Hz, 1H).
Found: C, 55.60; H, 8.02; N, 6.51%. Calcd for C10H17NO4: C,
55.80; H, 7.96; N, 6.51%.
The physical and spectral data of compounds 1b-1l and 1b¤-1l¤
are shown in the following.
1
Methyl 2-(N-Boc-amino)-2-pentenoate (1b and 1b¤): (E)-1b:
oil; IR (neat): 3457, 3419, 3360, 2977, 2935, 2876, 2287, 1707,
1645, 1512, 1457, 1438, 1391, 1366, 1248, 1163, 1050, 1020, 978,
934, 876, 832, 816, 772, 702 cm¹1; 1H NMR (400 MHz, CDCl3): ¤
1.09 (t, J = 7.55 Hz, 3H), 1.47 (s, 9H), 2.54 (quintet, J = 7.55 Hz,
2H), 3.82 (s, 3H), 6.55 (br, 1H), 6.88 (br, 1H). HRMS (FAB+)
(M+ + 1): Found: m/z 230.1390. Calcd for C11H20NO4: 230.1392.
When the methyl ester protons were irradiated, 4.0% and 2.6%
NOE were observed for the methylene and the methyl protons of
the ethyl group. (Z)-1b¤: oil (Lit. oil);8a IR (neat): 3340, 3120, 2976,
2936, 2877, 1709, 1657, 1496, 1457, 1438, 1391, 1366, 1310,
728, 695 cm¹1; H NMR (400 MHz, CDCl3): ¤ 1.56 (s, 9H), 3.87
(s, 3H), 5.46 (s, 2H), 6.22 (br, 1H), 7.31-7.49 (m, 7H), 7.59 (s,
1H), 7.72 (d, J = 7.07 Hz, 1H), 7.92 (s, 1H), 8.20 (d, J = 7.79 Hz,
1H). Found: C, 66.60; H, 5.82; N, 6.26%. Calcd for C25H26N2O6;
C, 66.65; H, 5.82; N, 6.22%.
Methyl ¡-(N-Boc)-¢-(N¤-Boc)-¡,¢-didehydrotryptophanate
(1f and 1f¤): (E)-1f: mp 130.5-131.0 °C (EtOAc-hexane). IR
(KBr): 3854, 3735, 3650, 3452, 3188, 2980, 2359, 1727, 1712,
1629, 1519, 1455, 1435, 1398, 1339, 1309, 1257, 1237, 1212,
¹1
1148, 1093, 1045, 1028, 986, 922, 849, 765, 741, 725 cm
;
1H NMR (400 MHz, CDCl3): ¤ 1.52 (s, 9H), 1.68 (s, 9H), 3.75 (s,
3H), 6.85 (s, 1H), 7.25-7.32 (m, 2H), 7.57 (d, J = 7.56 Hz, 1H),
7.76 (s, 1H), 8.05 (s, 1H), 8.13 (d, J = 8.05 Hz, 1H). Found: C,
63.09; H, 6.85; N, 6.67%. Calcd for C22H28N2O6: C, 63.44; H,
6.78; N, 6.73%. When the olefinic proton was irradiated, 1.3% and
1.0% NOE were observed for the t-butyl protons of the Boc group
and the N-H proton of the carbamate, respectively. (Z)-1f¤: mp
145.0-146.0 °C (EtOAc-hexane). IR (KBr): 3324, 2978, 1734,
1247, 1160, 1110, 1049, 1020, 988, 917, 884, 848, 799, 776, 734,
¹1
692 cm
;
1H NMR (400 MHz, CDCl3): ¤ 1.06 (t, J = 7.56 Hz,
3H), 1.46 (s, 9H), 2.24 (quintet, J = 7.56 Hz, 2H), 3.77 (s, 3H),
6.02 (br, 1H), 6.53 (t, J = 7.56 Hz, 1H). HRMS (FAB+) (M+ + 1):
Found: m/z 230.1386. Calcd for C11H20NO4: 230.1392.
Methyl (N-Boc)-¡,¢-didehydroleucinate (1c and 1c¤): (E)-
1c: oil IR (neat): 3419, 3357, 2969, 2934, 2870, 1729, 1708, 1644,
1513, 1466, 1438, 1366, 1334, 1249, 1161, 1046, 1024, 855,
1641, 1584, 1545, 1482, 1454, 1435, 1370, 1330, 1308, 1250,
1153, 1086, 1049, 1019, 987, 935, 858, 839, 794, 741 cm ;
¹1
¹1
772 cm
;
1H NMR (400 MHz, CDCl3): ¤ 1.05 (d, J = 6.59 Hz,
6H), 1.47 (s, 9H), 3.22-3.31 (m, 1H), 3.82 (s, 3H), 6.37-6.50 (br,
2H). HRMS (FAB+) (M+ + 1): Found: m/z 244.1555. Calcd for
C12H22NO4: 244.1549. (Z)-1c¤: oil (Lit. mp 74-75 °C);8a IR (neat):
3340, 3119, 2964, 2933, 2871, 1710, 1657, 1495, 1438, 1366,
1H NMR (400 MHz, CDCl3): ¤ 1.45 (s, 9H), 1.68 (s, 9H), 3.64 (s,
3H), 6.17 (s, 1H), 7.29-7.36 (m, 2H), 7.59 (s, 1H), 7.70 (d,
J = 7.83 Hz, 1H), 7.94 (s, 1H), 8.15 (d, J = 8.03 Hz, 1H). Found:
C, 63.40; H, 6.84; N, 6.75%. Calcd for C22H28N2O6: C, 63.44; H,
6.78; N, 6.73%.
Methyl ¡-(N-Boc)-¢-(N¤-Boc)-¡,¢-didehydrohistidinate (1g
and 1g¤): (E)-1g: mp 147.5-149.0 °C (EtOAc-hexane). IR (KBr):
3389, 3137, 3124, 2983, 2949, 2359, 1736, 1656, 1545, 1496,
1478, 1435, 1390, 1374, 1352, 1308, 1276, 1256, 1225, 1159,
1315, 1258, 1161, 1119, 1049, 1028, 998, 958, 942, 915, 890, 843,
¹1
796, 778, 765, 742 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.05
(d, J = 7.87 Hz, 6H), 1.46 (s, 9H), 2.63-2.79 (m, 1H), 3.77 (s,
3H), 5.92 (br, 1H), 6.38 (d, J = 10.09 Hz, 1H). HRMS (FAB+)
(M+ + 1): Found: m/z 244.1559. Calcd for C12H22NO4: 244.1549.

372
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
Syntheses of (E)-¡,¢-Didehydroamino Acid
¹1
¹1
1118, 1050, 1026, 1011, 986, 965, 895, 873, 837, 770 cm
;
775 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.49 (s, 9H), 2.33 (s,
1H NMR (400 MHz, CDCl3): ¤ 1.49 (s, 9H), 1.62 (s, 9H), 3.84 (s,
3H), 6.79 (s, 1H), 7.24 (s, 1H), 7.84 (s, 1H), 8.01 (s, 1H). Found:
C, 55.48; H, 6.96; N, 11.31%. Calcd for C17H25N3O6: C, 55.57; H,
6.86; N, 11.44%. When the N-H proton of the carbamate was
irraditated, 1.8% NOE was observed for the olefinic proton. (Z)-
1g¤: mp 120.5-121.5 °C (EtOAc-hexane). IR (KBr): 3300, 3134,
2981, 1755, 1738, 1718, 1649, 1550, 1466, 1393, 1368, 1331,
1257, 1234, 1214, 1156, 1063, 1013, 839, 805, 770 cm¹1; 1H NMR
(400 MHz, CDCl3): ¤ 1.48 (s, 9H), 1.63 (s, 9H), 3.84 (s, 3H), 6.42
(s, 1H), 7.37 (s, 1H), 8.09 (s, 1H), 9.04 (s, 1H). Found: C, 55.59;
H, 6.98; N, 11.27%. Calcd for C17H25N3O6: C, 55.57; H, 6.86; N,
11.44%.
3H), 3.66 (s, 3H), 6.62-6.70 (br, 1H), 7.09 (d, J = 8.34 Hz, 2H),
7.14 (d, J = 8.34 Hz, 2H), 7.38-7.48 (br, 1H). EI-MS m/z 291
(M+; 15.51%). When the N-H proton of the carbamate was
irradiated, 2.8% NOE was observed for the olefinic proton. (Z)-
1k¤: mp 88.0-89.0 °C (hexane) (Lit. 87-90 °C).8c IR (KBr): 3339,
2971, 1708, 1631, 1605, 1488, 1444, 1369, 1342, 1272, 1172,
¹1
1136, 1049, 1024, 987, 921, 820, 795, 775 cm
;
1H NMR
(300 MHz, CDCl3): ¤ 1.41 (s, 9H), 2.36 (s, 3H), 3.85 (s, 3H),
6.07-6.17 (br, 1H), 7.17 (d, J = 8.07 Hz, 2H), 7.25-7.48 (br, 1H),
7.44 (d, J = 8.07 Hz, 2H). Found: C, 65.66; H, 7.48; N, 4.71%.
Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81%.
Methyl
2-(N-Boc-amino)-3-(p-methoxyphenyl)propenoate
Methyl ¡-(N-Boc)-¾-(N¤-Boc-N¤-Z)-¡,¢-didehydrolysinate
(1h and 1h¤): (E)-1h: oil; IR (neat): 3365, 3065, 3033, 2979,
2935, 2401, 2291, 1790, 1738, 1588, 1500, 1479, 1456, 1369,
(1l and 1l¤): (E)-1l: oil; IR (neat): 3338, 2979, 1723, 1637,
1607, 1512, 1438, 1368, 1302, 1248, 1161, 1030, 985, 919,
¹1
824 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.49 (s, 9H), 3.68 (s,
1342, 1286, 1247, 1208, 1154, 1047, 973, 916, 854, 780, 753,
699 cm
3H), 3.81 (s, 3H), 6.60-6.70 (br, 1H), 6.83 (d, J = 8.90 Hz, 2H),
7.21 (d, J = 8.90 Hz, 2H), 7.34-7.44 (br, 1H). EI-MS m/z 307
(M+; 15.51%). When the N-H proton of the carbamate was
irradiated, 4.1% NOE was observed for the olefinic proton. (Z)-1l¤:
mp 111.0-112.0 °C (EtOAc-hexane). IR (KBr): 3338, 2979, 1703,
1638, 1604, 1515, 1442, 1360, 1321, 1259, 1181, 1145, 1055,
1030, 992, 826, 779 cm¹1; 1H NMR (400 MHz, CDCl3): ¤ 1.49 (s,
9H), 3.79 (s, 3H), 3.80 (s, 3H), 6.69-6.77 (br, 1H), 6.82 (d,
J = 8.80 Hz, 2H), 7.26-7.40 (br, 1H), 7.51 (d, J = 8.80 Hz, 2H).
Found: C, 62.32; H, 7.03; N, 4.47%. Calcd for C16H21NO5: C,
62.53; H, 6.89; N, 4.56%.
¹1
;
1H NMR (400 MHz, CDCl3): ¤ 1.46 (s, 9H), 1.47 (s,
9H), 1.75 (tt, J = 7.51, 7.69 Hz, 2H), 2.52 (dt, J = 7.70, 7.72 Hz,
2H), 3.68 (t, J = 7.70 Hz, 2H), 3.78 (s, 3H), 5.22 (s, 2H), 6.55 (br,
1H), 6.66 (br, 1H), 7.29-7.40 (m, 5H). HRMS (FAB+) (M+ + 1):
Found: m/z 493.2564. Calcd for C25H37N2O8: 493.2550. (Z)-1h¤:
oil; IR (neat): 3342, 2979, 1789, 1723, 1497, 1456, 1368, 1287,
1
1159, 1114, 1047, 915, 854, 778, 698 cm¹1; H NMR (400 MHz,
CDCl3): ¤ 1.45 (s, 9H), 1.47 (s, 9H), 1.75 (quintet, J = 7.52 Hz,
2H), 2.22 (dt, J = 7.15, 7.52 Hz, 2H), 3.66 (t, J = 7.52 Hz, 2H),
3.75 (s, 3H), 5.22 (s, 2H), 6.12 (br, 1H), 6.49 (t, J = 7.15 Hz, 1H),
7.30-7.40 (m, 5H). HRMS (FAB+) (M+ + 1): Found: m/z
493.2545. Calcd for C25H37N2O8: 493.2550.
A General Procedure for the Preparation of cis-4,5-Oxazo-
lidin-2-one Derivatives (2a-2l). To a solution of 3f (93 mg,
0.30 mmol) in dry THF (1.5 mL) was added 1.1 molar equivalents
of LDA at ¹78 °C under N2. After the solution was stirred at that
temperature for 1 h, a solution of benzaldehyde (4i) (35 mg,
0.33 mmol) in THF (1.5 mL) was added dropwise and the solution
was kept at ¹78 °C for 1 h. The reaction was then quenched with
1 M AcOH in MeOH and the solvent was concentrated under
reduced pressure. The residue was partitioned between EtOAc and
water. The aqueous layer was extracted with EtOAc and the
combined extracts were washed with brine, dried over MgSO4, and
evaporated in vacuo. The residual oil was subjected to preparative
TLC (SiO2, hexane/EtOAc = 5/1, v/v) to give 3-Boc-4-(meth-
oxycarbonyl)-5-phenyl-cis-4,5-oxazolidin-2-one (2i) in 63% yield
(203 mg). Mp 129.0-130.0 °C (EtOAc-hexane) (Lit, mp 114-
115 °C);9a IR (KBr): 2976, 1803, 1750, 1723, 1457, 1441, 1388,
1365, 1312, 1260, 1218, 1189, 1167, 1088, 1050, 1006, 927, 861,
Methyl 2-(N-Boc-amino)-3-phenylpropenoate (1i and 1i¤):
(E)-1i: oil; IR (neat): 3333, 2979, 1715, 1636, 1514, 1490, 1437,
¹1
1368, 1244, 1157, 1057, 1026, 984, 919, 857, 833, 754, 698 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.50 (s, 9H), 3.63 (s, 3H), 6.68-
6.74 (br, 1H), 7.21-7.32 (m, 5H), 7.40-7.60 (br, 1H). EI-MS m/z
277 (M+; 6.12%). When the N-H proton was irradiated, 3.1% and
1.0% NOE were observed for the olefinic proton and the protons of
the methyl ester. (Z)-1i: mp 76.0-77.0 °C (hexane) (Lit. mp 81-
82 °C,8a 77-79 °C8b); IR (KBr): 3327, 2990, 2946, 1721, 1700,
1644, 1488, 1445, 1369, 1287, 1242, 1206, 1163, 1143, 1079,
¹1
1063, 990, 841, 761, 690 cm
;
1H NMR (300 MHz, CDCl3): ¤
1.40 (s, 9H), 3.86 (s, 3H), 6.06-6.24 (br, 1H), 7.25 (s, 1H), 7.31-
7.40 (m, 3H), 7.52-7.55 (m, 2H). Found: C, 64.80; H, 6.97; N,
5.09%. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05%.
Methyl 3-(p-Bromophenyl)-2-(N-Boc-amino)propenoate (1j
and 1j¤): (E)-1j: oil; IR (neat): 3333, 2979, 1725, 1715, 1636,
1514, 1490, 1437, 1368, 1244, 1157, 1057, 1026, 984, 919, 857,
1
837, 786, 766, 699 cm¹1; H NMR (300 MHz, CDCl3): ¤ 1.51 (s,
9H), 3.25 (s, 3H), 4.95 (d, J = 8.90 Hz, 1H), 5.71 (d, J = 8.90 Hz,
1H), 7.28-7.40 (m, 2H), 7.50-7.55 (m, 3H). Found: C, 59.59; H,
6.19; N, 4.31%. Calcd for C16H19NO6: C, 59.81; H, 5.96; N,
4.36%. When the proton at C-4 was irradiated, 12.0% and 2.4%
NOE were observed for the proton at C-5 and both ortho protons of
the aromatic ring. When the proton at C-5 was irradiated, 15.1%
and 11.0% NOE were observed for the proton at C-4 and both
ortho protons of the aromatic ring.
1
833, 754, 698 cm¹1; H NMR (300 MHz, CDCl3): ¤ 1.50 (s, 9H),
3.65 (s, 3H), 6.72-6.82 (br, 1H), 7.10 (d, J = 8.44 Hz, 2H), 7.41
(d, J = 8.44 Hz, 2H), 7.45-7.55 (br, 1H). EI-MS m/z 355 (M+;
10.02%). When the N-H proton of the carbamate was irradiated,
3.5% and 1% NOE were observed for the olefinic proton and
both ortho protons of the aromatic ring, respectively. (Z)-1j¤: mp
121.0-122.0 °C (EtOAc-hexane). IR (KBr): 3327, 2990, 2946,
1721, 1700, 1644, 1488, 1445, 1369, 1287, 1242, 1206, 1163,
1143, 1063, 990, 841, 761, 690 cm¹1; 1H NMR (300 MHz, CDCl3):
¤ 1.40 (s, 9H), 3.86 (s, 3H), 6.20-6.30 (br, 1H), 7.19 (s, 1H), 7.39
(d, J = 8.62 Hz, 2H), 7.48 (d, J = 8.62 Hz, 2H). Found: C, 50.47;
H, 5.17; N, 3.85%. Calcd for C15H18NO4Br: C, 50.58; H, 5.09; N,
3.93%.
The physical and spectral data of compounds 2a-2h and 2j-2l
are shown in the following.
3-Boc-4-methoxycarbonyl-5-methyl-cis-4,5-oxazolidin-2-one
(2a): Mp 78.5-79.5 °C (EtOAc-hexane); IR (KBr): 3007, 2977,
2954, 2939, 2884, 1826, 1759, 1724, 1701, 1587, 1463, 1442,
1396, 1371, 1327, 1299, 1281, 1260, 1220, 1185, 1160, 1120,
1074, 1025 cm¹1; 1H NMR (400 MHz, CDCl3): ¤ 1.38 (d, J = 6.34
Hz, 3H), 1.51 (s, 9H), 3.83 (s, 3H), 4.72 (d, J = 8.78 Hz, 1H), 4.78
(dq, J = 6.34, 8.78 Hz, 1H). Found: C, 50.88; H, 6.67; N, 5.46%.
Methyl 2-(N-Boc-amino)-3-(p-tolyl)propenoate (1k and 1k¤):
(E)-1k: oil; IR (neat): 3355, 2979, 1725, 1708, 1637, 1607, 1507,
1485, 1438, 1368, 1248, 1159, 1050, 1023, 984, 845, 815,

M. Kometani et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
373
Calcd for C11H17NO6: C, 50.96; H, 6.61; 5.40%. When the protons
of the methyl ester were irradiated, 1.0%, 1.82%, and 1.34% NOE
were observed for the proton at C-4, both t-butyl protons of the
Boc group and the methyl protons at C-5, respectively.
3-Boc-5-ethyl-4-methoxycarbonyl-cis-4,5-oxazolidin-2-one
(2b): Mp 60.0-63.0 °C (EtOAc-hexane); IR (KBr): 3007, 2977,
2954, 2939, 2884, 1826, 1759, 1724, 1701, 1463, 1442, 1396,
C, 59.91; H, 6.25; N, 6.04%. Calcd for C23H28N2O8: C, 59.99; H,
6.13; N, 6.08%. When the proton at C-5 was irradiated, 15.9%
NOE was observed for the proton at C-4.
3-Boc-4-methoxycarbonyl-5-[(N¤-Boc)-4¤-imidazolyl]-cis-4,5-
oxazolidin-2-one (2g): Mp 138.0-139.0 °C (EtOAc); IR (KBr):
3003, 2979, 2935, 1819, 1802, 1750, 1725, 1399, 1368, 1328,
1312, 1276, 1248, 1219, 1190, 1156, 1091, 1069, 1020, 1006, 848,
¹1
1371, 1327, 1299, 1281, 1260, 1220, 1185, 1160, 1120, 1074,
776 cm ;
1H NMR (400 MHz, CDCl3): ¤ 1.51 (s, 9H), 1.61 (s,
¹1
925 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.08 (t, J = 7.34 Hz,
9H), 3.60 (s, 3H), 5.01 (d, J = 8.78 Hz, 1H), 5.70 (d, J = 8.78 Hz,
1H), 7.44 (s, 1H), 8.04 (s, 1H). Found: C, 52.61; H, 6.21; N,
10.04%. Calcd for C18H25N3O8: C, 52.55; H, 6.13; N, 10.21%.
3-Boc-4-methoxycarbonyl-5-{3-[(N¤-Boc-N¤-Z)aminopropyl]}-
3H), 1.51 (s, 9H), 1.59-1.68 (m, 2H), 3.81 (s, 3H), 4.51 (dt,
J = 4.56, 8.44 Hz, 1H), 4.72 (d, J = 8.44 Hz, 1H). Found: C,
52.62; H, 7.09; N, 5.07%. Calcd for C12H19NO6: C, 52.74; H, 7.01;
N, 5.13%.
cis-4,5-oxazolidin-2-one (2h):
Mp 83.5-84.5 °C (EtOAc-
3-Boc-4-methoxycarbonyl-5-isopropyl-cis-4,5-oxazolidin-2-
one (2c): Mp 82.0-84.0 °C (EtOAc-hexane); IR (KBr) 2982,
hexane); IR (KBr): 2979, 1810, 1740, 1654, 1559, 1542, 1508,
1458, 1363, 1339, 1279, 1251, 1164, 1129, 1088, 984, 846, 773,
1
1824, 1787, 1747, 1371, 1361, 1339, 1331, 1248, 1213, 1188,
743, 696 cm¹1; H NMR (400 MHz, CDCl3): ¤ 1.47 (s, 9H), 1.50
¹1
1161, 1125, 1096, 1050, 1026, 988 cm
;
1H NMR (300 MHz,
(s, 9H), 1.50-1.90 (m, 4H), 3.64-3.74 (m, 2H), 3.77 (s, 3H), 4.56
(dt, J = 3.84, 8.61 Hz, 1H), 4.66 (d, J = 8.61 Hz, 1H), 5.21 (s,
2H), 7.29-7.39 (m, 5H). Found: C, 58.09; H, 6.79; N, 5.33%.
Calcd for C26H36N2O10: C, 58.20; H, 6.76; H, 5.22%.
CDCl3): ¤ 1.02 (d, J = 6.40 Hz, 3H), 1.08 (d, J = 6.40, Hz, 3H),
1.51 (s, 9H), 1.72-1.79 (m, 2H), 3.81 (s, 3H), 4.15 (dd, J = 7.52,
10.09 Hz, 1H), 4.72 (d, J = 7.52 Hz, 1H). Found: C, 54.04; H,
7.35; N, 4.77%. Calcd for C13H21NO6: C, 54.35; H, 7.37; N,
4.88%.
3-Boc-5-(p-bromophenyl)-4-methoxycarbonyl-cis-4,5-oxazo-
lidin-2-one (2j): Mp 154.0-155.0 °C (EtOAc-hexane); IR (KBr):
2980, 1810, 1752, 1721, 1361, 1314, 1222, 1160, 1082, 1061,
1006, 846, 787, 774, 766, 694 cm¹1; 1H NMR (400 MHz, CDCl3):
¤ 1.51 (s, 9H), 3.32 (s, 3H), 4.96 (d, J = 8.90 Hz, 1H), 5.67 (d,
J = 8.90 Hz, 1H), 7.20 (d, J = 8.35 Hz, 2H), 7.53 (d, J = 8.35 Hz,
2H). Found: C, 48.03; H, 4.59; N, 3.42%. Calcd for C16H18NO6Br:
C, 48.02; H, 4.53; N, 3.50%. When the ¡-proton of the ester group
was irradiated, 13.8% NOE was observed for the ¢-proton.
3-Boc-4-methoxycarbonyl-5-(p-tolyl)-cis-4,5-oxazolidin-2-one
3-Boc-4-methoxycarbonyl-5-(2-phenylethyl)-cis-4,5-oxazo-
lidin-2-one (2d): Mp 123.0-125.0 °C (EtOAc-hexane); IR (KBr):
2979, 1810, 1746, 1702, 1383, 1371, 1352, 1207, 1166, 1060,
¹1
1017, 977, 785, 775, 770 cm
;
1H NMR (300 MHz, CDCl3): ¤
1.50 (s, 9H), 1.84-1.90 (m, 2H), 2.72-2.91 (m, 2H), 3.80 (s, 3H),
4.53 (dt, J = 4.95, 8.44 Hz, 1H), 4.68 (d, J = 8.44 Hz, 1H), 7.17-
7.31 (m, 1H). Found: C, 61.82; H, 6.77; N, 4.01%. Calcd for
C18H23NO6: C, 61.88; H, 6.64; N, 4.01%.
3-Boc-4-methoxycarbonyl-5-[(N¤-Z)-3¤-indolyl]-cis-4,5-oxazo-
lidin-2-one (2e): To a solution of 3f (93 mg, 0.30 mmol) in dry
THF (5 mL) was added 1.1 molar equivalents of LDA (0. 33 mmol)
at ¹78 °C under N2. After keeping at ¹78 °C for 1 h, a solution of
4e (84 mg, 0.30 mmol) in dry THF (2 mL) was added followed by
the addition of Ti(OiPr)4 (94 mg, 0.33 mmol). The solution was
stirred at ¹78 °C for 4 h and quenched with 1 M AcOH in THF.
After addition of a small amount of water, the mixture was passed
through celite. The THF was removed under reduced pressure to
give a residue, which was partitioned between EtOAc and water.
The EtOAc solution was washed with brine, dried, and evaporated
in vacuo to afford a residue, which was subjected to preparative
TLC (SiO2, hexane/EtOAc = 3/1, v/v). 98 mg of 2e was
obtained. Mp 173.0-173.5 °C (EtOAc-hexane); IR (KBr): 2979,
1804, 1742, 1609, 1573, 1457, 1407, 1370, 1357, 1315, 1258,
1243, 1220, 1172, 1131, 1102, 1055, 996, 756 cm¹1; 1H NMR (400
MHz, CDCl3): ¤ 1.52 (s, 9H), 3.16 (s, 3H), 5.05 (d, J = 8.78 Hz,
1H), 5.43 (d, J = 12.20 Hz, 1H), 5.47 (d, J = 12.20 Hz, 1H), 5.95
(dd, J = 0.98, 8.78 Hz, 1H), 7.29-7.50 (m, 8H), 7.70 (s, 1H), 8.19
(d, J = 8.29 Hz, 1H). Found: C, 63.08; H, 5.33; N, 5.67%. Calcd
for C26H26N2O8: C, 63.15; H, 5.30; H, 5.66%. When the proton at
C-4 was irradiated, 17.5%, 4.3%, and 3.3% NOE were observed
for the proton at C-5, 2-position of the indole ring and both the
t-butyl protons of the Boc group.
(2k):
Mp 128.0-129.0 °C (EtOAc-hexane); IR (KBr): 2979,
1801, 1749, 1721, 1365, 1318, 1216, 1186, 1171, 1091, 1048,
1007, 843, 810, 784, 767 cm
¹1
;
1H NMR (300 MHz, CDCl3): ¤
1.51 (s, 9H), 2.35 (s, 3H), 3.29 (s, 3H), 4.94 (d, J = 8.99 Hz, 1H),
5.67 (d, J = 8.99 Hz, 1H), 7.18 (br s, 4H). Found: C, 60.71; H,
6.41; N, 4.16%. Calcd for C17H21NO6: C, 60.89; H, 6.31; N,
4.18%. When the ¡-proton was irradiated, 13.3% NOE was
observed for the ¢-proton.
3-Boc-4-methoxycarbonyl-5-(p-methoxyphenyl)-cis-4,5-oxazo-
lidin-2-one (2l):
(KBr): 2979, 1802, 1747, 1721, 1614, 1518, 1447, 1367, 1314,
1251, 1225, 1177, 1161, 1090, 1052, 1034, 1002, 846, 776 cm
1H NMR (300 MHz, CDCl3): ¤ 1.50 (s, 9H), 3.32 (s, 3H), 3.81 (s,
3H), 4.92 (d, J = 8.99 Hz, 1H), 5.76 (d, J = 8.99 Hz, 1H), 6.89 (d,
J = 8.80 Hz, 2H), 7.23 (d, J = 8.80 Hz, 2H). Found: C, 57.88; H,
6.04; N, 3.86%. Calcd for C17H21NO7: C, 58.11; H, 6.02; N,
3.99%. When the ¡-proton of the ester group was irradiated,
12.4% NOE was observed for the ¢-proton.
A General Procedure for the Preparation of N,N-Diprotect-
ed Glycine Methyl Esters (3a-3f). A solution of methyl Boc-
glycinate (482 mg, 2.55 mmol), Boc2O (1.113 g, 5.10 mmol), and
DMAP (93 mg, 0.761 mmol) in dry acetonitrile (CH3CN) (5 mL)
was stirred at 55 °C for 22 h. The solvent was then removed in
vacuo to give a residue, which was partitioned between EtOAc and
a saturated solution of NH4Cl. The aqueous solution was extracted
with EtOAc. The combined extracts were washed with brine and
dried over MgSO4, and concentrated under reduced pressure. The
residue was subjected to silica gel column chromatography (eluent;
hexane/EtOAc = 10/1, v/v) to afford methyl N,N-diBoc-glycinate
(3a) in quantitative yield (734 mg). Mp 59.0-59.5 °C (hexane); IR
Mp 140.0-141.00 °C (EtOAc-hexane); IR
¹1
;
3-Boc-4-methoxycarbonyl-5-[(N¤-Boc)-3¤-indolyl]-cis-4,5-
oxazolidin-2-one (2f): Mp 152.0-153.0 °C (EtOAc); IR (KBr):
2981, 2367, 1800, 1742, 1655, 1596, 1559, 1542, 1508, 1458,
1356, 1318, 1258, 1224, 1154, 1131, 1101, 1051, 992, 844, 788,
1
770, 744 cm¹1; H NMR (400 MHz, CDCl3): ¤ 1.52 (s, 9H), 1.56
(s, 9H), 3.19 (s, 3H), 5.06 (d, J = 8.78 Hz, 1H), 5.98 (dd, J = 0.98,
8.78 Hz, 1H), 7.24-7.27 (m, 1H), 7.33-7.37 (m, 1H), 7.49 (d,
J = 7.81 Hz, 1H), 7.65 (s, 1H), 8.17 (d, J = 8.29 Hz, 1H). Found:
(KBr): 3001, 2978, 1756, 1731, 1694, 1435, 1412, 1383, 1368,
1335, 1231, 1146, 1127, 991, 962, 897, 862, 848, 788, 768 cm
¹1
;

374
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
Syntheses of (E)-¡,¢-Didehydroamino Acid
1H NMR (400 MHz, CDCl3): ¤ 1.50 (s, 18H), 3.75 (s, 3H), 4.34 (s,
2H). Found: C, 53.70; H, 7.95; N, 4.74%. Calcd for C13H23NO6: C,
53.97; H, 8.01; N, 4.84%.
The physical and spectral data of compounds 3b-3f are shown
in the following.
for 1 h, a solution of benzaldehyde (4i) (92 mg, 0.87 mmol) in THF
(4 mL) was added dropwise at ¹78 °C and the solution was
kept at ¹78 °C for 1 h. After quenching the reaction at that
temperature with 0.5 M HCl in MeOH, the solvent was removed in
vacuo to give a residue, which was partitioned between EtOAc
and water. The aqueous layer was extracted with EtOAc. The
combined extracts were washed with brine dried over MgSO4,
and evaporated in vacuo. The residue was subjected to preparative
TLC (SiO2, hexane/EtOAc = 7/1, v/v) to afford methyl 2-(Boc-
amino)-3-(t-butoxycarbonyloxy)-3-phenylpropanoate (6) in 85%
yield (265 mg). Mp 84.0-85.0 °C (EtOAc-hexane); IR (KBr):
Methyl N-Boc-N-Z-glycinate (3b):
Oil; IR (neat): 2979,
1801, 1761, 1699, 1456, 1439, 1415, 1370, 1343, 1258, 1217,
¹1
1182, 1153, 1107, 1004, 951, 916, 855, 780, 752, 698 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.46 (s, 9H), 3.71 (s, 3H), 4.41 (s,
2H), 5.24 (s, 2H), 7.30-7.40 (m, 5H). HRMS (FAB+) (M+ + 1):
Found: m/z 324.1451. Calcd for C16H22NO6: 324.1447.
Methyl
N-Boc-N-2,2,2-trichloroethoxycarbonylglycinate
3404, 2979, 1750, 1702, 1519, 1369, 1287, 1252, 1160, 1090,
¹1
(3c): Mp 51.0-51.5 °C (heptane); IR (KBr): 2982, 2957, 1812,
1756, 1708, 1439, 1416, 1371, 1346, 1255, 1221, 1156, 1062,
1019, 956, 855, 816, 778, 720 cm¹1; 1H NMR (400 MHz, CDCl3):
¤ 1.54 (s, 9H), 3.76 (s, 3H), 4.47 (s, 2H), 4.82 (s, 2H). Found: C,
35.99; H, 4.44; N, 3.82%. Calcd for C11H16NO6Cl3: C, 36.24; H,
4.42; N, 3.84%.
1029, 968, 872, 760, 709 cm ;
1H NMR (300 MHz, CDCl3): ¤
1.41 (s, 9H), 1.47 (s, 9H), 3.70 (s, 3H), 4.95-5.05 (m, 2H), 5.93 (d,
J = 4.03 Hz, 1H), 7.29-7.39 (m, 5H). Found: C, 60.58; H, 7.51; N,
3.45%. Calcd for C20H29NO7: C, 60.75; H, 7.39; N, 3.54%.
(3S,5S)-3-(N-Z-amino)-5-(t-butyldiphenylsiloxy)methyl-£-lac-
tone (7).
To compound 12 (180 mg, 0.38 mmol) in CH2Cl2
Methyl N-Boc-N-methoxycarbonylglycinate (3d): Oil; IR
(neat): 2980, 2958, 1804, 1764, 1703, 1444, 1410, 1369, 1347,
(0.5 mL) was added TFA (0.5 mL) at 0 °C under N2. The solution
was stirred for 1 h at room temperature, and the solvent was
removed in vacuo to afford a residue, which was dissolved in
THF (3 mL). To the solution was added a solution of TEA
(116 mg, 1.15 mmol) in THF (0.5 mL) followed by the addition
of N-benzyloxycarbonyloxysuccinimide (Z-ONSu) (144 mg,
0.58 mmol). The solution was allowed to stir for 2 h at room
temperature. After evaporation of the solvent the residue was
partitioned between EtOAc and water. The EtOAc was washed
with brine, dried over MgSO4, and evaporated in vacuo to give a
residue, which was subjected to preparative TLC (SiO2, hexane/
EtOAc = 3/1, v/v). The desired product 7 was obtained in 80%
1
1224, 1155, 1112, 1010, 948, 855, 783 cm¹1; H NMR (300 MHz,
CDCl3): ¤ 1.50 (s, 9H), 3.76 (s, 3H), 3.84 (s, 3H), 4.40 (s,
2H). HRMS (FAB+) (M+ + 1) Found: m/z 248.1134. Calcd for
C10H18NO6: 248.1134.
Methyl N-Boc-N-ethoxycarbonylglycinate (3e):
Oil; IR
(neat): 2981, 1803, 1736, 1724, 1700, 1478, 1439, 1418, 1371,
¹1
1344, 1223, 1156, 1108, 1025, 959, 926, 893, 856, 782 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.32 (t, J = 7.15 Hz, 3H), 1.50 (s,
9H), 3.76 (s, 3H), 4.28 (q, J = 7.15 Hz, 2H), 4.40 (s, 2H). HRMS
(FAB+) (M+ + 1): Found: m/z 262.1296. Calcd for C11H20NO6:
262.1291.
25
25
yield (155 mg). Oil; ½¡ꢀD +3.96° (c 0.88, EtOH) [Lit, ½¡ꢀD +3.9°
Methyl N-Boc-N-phenoxycarbonylglycinate (3f): Mp 56.5-
57.5 °C (hexane); IR (KBr): 2980, 1810, 1753, 1712, 1594, 1494,
(c 2.1, EtOH)];16 IR (neat): 3331, 3070, 2931, 2858, 1786, 1713,
1588, 1525, 1471, 1455, 1428, 1362, 1328, 1259, 1198, 1113,
¹1
1413, 1369, 1347, 1201, 1148, 1099, 1075, 1001, 959, 855, 777,
1058, 1027, 997, 935, 907, 823, 777, 742, 703 cm ;
1H NMR
¹1
754 cm
;
1H NMR (400 MHz, CDCl3): ¤ 1.54 (s, 9H), 3.79 (s,
(400 MHz, CDCl3): ¤ 1.05 (s, 9H), 2.06-2.18 (m, 1H), 2.66-2.74
(m, 1H), 3.74 (dd, J = 4.04, 11.55 Hz, 1H), 3.90 (dd, J = 2.38,
11.55 Hz, 1H), 4.53-4.59 (br, 2H), 5.13 (s, 2H), 5.30 (br, 1H), 7.30-
7.46 (m, 11H), 7.63-7.67 (m, 4H). HRMS (FAB+) (M+ + 1):
Found: m/z 504.2197. Calcd for C29H34NO5Si: 504.2206.
3H), 4.52 (s, 2H), 7.14-7.40 (m, 5H). Found: C, 57.94; H, 6.19; N,
4.54%. Calcd for C15H19NO6: C, 58.24; H, 6.19; N, 4.53%.
4-(N-Boc-N-Z-amino)butanal (4h).
4-(N-Boc-N-Z-amino)-
butanal (4h) in Table 3 was prepared starting from 4-amino-1-
butanol.
3-Boc-4-methoxycarbonyl-5-(2,2-dimethyl-[1,3]dioxolane-4-
yl)-cis-4,5-oxazolidin-2-one (8a and 8a¤). To a solution of 3f
(309 mg, 1.0 mmol) in dry THF (6 mL) was added 1.1 molar
equivalents of LDA (1.1 mmol) at ¹78 °C and the solution was
stirred for 30 min at that temperature. A solution of (R)-O-2,3-
isopropylideneglycelaldehyde (195 mg, 1.5 mmol) in dry THF
(5 mL) was added dropwise at ¹78 °C followed by the addition of
Ti(OiPr)4 (427 mg, 1.5 mmol). The resulting solution was allowed
to stir for 2 h at ¹78 °C and quenched with 1 M AcOH in THF at
that temperature. After evaporation of the solvent, the residue was
partitioned between EtOAc and water. The EtOAc solution was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure to afford a residue. The crude product was
separated by preparative TLC (SiO2, hexane/EtOAc = 3/1, v/v)
to afford the oxazolidinone derivatives 8a (oily form, 138 mg) in
40% and 8a¤ (crystalline form, <86 mg) in <25% yields, respec-
To a solution of oxalyl chloride (0.96 mL, 11 mmol) in dry
CH2Cl2 (25 mL) added DMSO (2.13 mL, 30 mmol)21 at ¹78 °C
under N2. After 15 min, a solution of 17 (3.24 g, 10 mmol) in
CH2Cl2 (10 mL) was added and the solution was stirred for 15 min
at that temperature. After addition of TEA (10.5 mL, 75 mmol) the
mixture was gradually warmed to room temperature and then
stirred for 1 h. The solvent was removed in vacuo to give a residue,
which was partitioned between EtOAc, Et2O, and water. The
organic layer was dried over MgSO4 and evaporated in vacuo to
afford a residual oil which was subjected to silica gel column
chromatography (eluent, hexane/EtOAc = 2/1, v/v). Compound
4h was obtained in 90% yield (2.90 g). Oil; IR (neat): 2979, 2936,
2823, 2723, 1790, 1724, 1498, 1455, 1369, 1342, 1294, 1264,
¹1
1202, 1154, 1119, 1065, 1031, 1003, 854, 779, 752, 669 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.47 (s, 9H), 1.86-1.95 (m, 2H),
2.43 (t, J = 7.33 Hz, 2H), 3.69 (t, J = 7.15 Hz, 2H), 5.22 (s, 2H),
7.33-7.38 (m, 5H), 9.71 (s, 1H). HRMS (FAB+) (M+ + 1): Found:
m/z 322.1656. Calcd for C17H24NO5: 322.1654.
tively. 8a: oil; IR (neat): 2985, 2937, 1828, 1758, 1730, 1479,
¹1
1457, 1438, 1372, 1333, 1255, 1215, 1157, 1068, 846, 771 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.31 (s, 3H), 1.42 (s, 3H), 1.50 (s,
9H), 3.81 (s, 3H), 3.99 (dd, J = 3.67, 8.62 Hz, 1H), 4.08-4.16 (m,
2H), 4.50 (m, 1H), 4.84 (d, J = 8.62 Hz, 1H). HRMS (FAB+)
(M+ + 1): Found: m/z 346.1505. Calcd for C15H24NO8: 346.1502.
When the proton at C-4 position was irradiated, 15.2% and 1.3%
Methyl
2-(Boc-amino)-3-(t-butoxycarbonyloxy)-3-phenyl-
propanoate (6). To a solution of 3a (277 mg, 0.79 mmol) in
dry THF (4 mL) was added 1.1 molar equivalents of LDA at
¹78 °C under N2. After the solution was stirred at that temperature

M. Kometani et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
375
NOE were observed for the proton at C-5 and the methyl protons
of the ester group, respectively. 8a¤: mp 189.0-191.0 °C (EtOAc-
hexane). IR (KBr): 2992, 2939, 2899, 1807, 1759, 1723, 1458,
1369, 1337, 1218, 1158, 1103, 1070, 1033, 992, 973, 916, 862,
1589, 1519, 1472, 1428, 1392, 1369, 1344, 1316, 1237, 1158,
¹1
1115, 1085, 1045, 1010, 937, 904, 857, 823, 772, 742, 703 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.03 (s, 9H), 1.50 (s, 9H), 3.76 (dd,
J = 4.95, 11.00 Hz, 1H), 3.89 (dd, J = 4.22, 11.00 Hz, 1H), 5.05-
5.09 (m, 1H), 6.77 (br, 1H), 6.97 (br, 1H), 7.36-7.42 (m, 5H),
7.62-7.66 (m, 5H). HRMS (FAB+) (M+ + 1): Found: m/z
468.2208. Calcd for C26H34NO5Si: 468.2206.
1
839, 785, 766 cm¹1; H NMR (400 MHz, CDCl3): ¤ 1.34 (s, 3H),
1.41 (s, 3H), 1.51 (s, 9H), 3.79 (s, 3H), 3.96 (dd, J = 6.24, 8.62 Hz,
1H), 4.12 (dd, J = 6.79, 8.62 Hz, 1H), 4.29 (ddd, J = 3.85, 6.24,
6.79 Hz, 1H), 4.58 (dd, J = 3.85, 8.80 Hz, 1H), 4.74 (d, J =
8.80 Hz, 1H). Found: C, 51.89; H, 6.77; N, 4.09%. Calcd for
C15H23NO8: C, 52.17; H, 6.71; N, 4.06%. When the proton at C-4
was irradiated, 11.4% and 1.0% NOE were observed for the proton
at C-5 and methyl protons of the ester group, respectively.
(3S,5S)-3-(N-Boc-amino)-5-(t-butyldiphenylsiloxy)methyl-£-
lactone (12).
Compound 11 (94 mg, 0.21 mmol) was hydro-
genated over 20% palladium hydroxide on carbon (12 mg) in
EtOH (3 mL) at room temperature under hydrogen atmosphere for
10 h. Then, the catalyst was filtered through a pad of celite, and the
filtrate was removed in vacuo. The residual oil was subjected
to preparative TLC (SiO2, hexane/EtOAc = 3/1, v/v) to afford
Methyl
(4S)-2-(N-Boc-amino)-4,5-isopropylidenedioxy-2-
To a solution of 8a
pentenoate (Mixture of E- and Z-9).
25
(65 mg, 0.188 mmol) in dry THF (4 mL) was added 3.0 molar
equivalents of LiHMDS (0.564 mmol) at ¹10 °C under N2 and the
solution was stirred for 5 min at that temperature. The reaction was
quenched with 1 M AcOH in THF and the solvent was removed in
vacuo to give a residue, which was partitioned between EtOAc and
water. The EtOAc solution was washed with brine, dried over
MgSO4, and evaporated in vacuo to afford a residue, which was
subjected to preparative TLC (SiO2, hexane/EtOAc = 3/1, v/v).
The desired product 9 was obtained as a mixture of E and Z
isomers in a ratio of 78:22 in 70% yield (40 mg). IR (neat): 3417,
3340, 2983, 2935, 2875, 1725, 1653, 1512, 1456, 1439, 1369,
1345, 1246, 1158, 1058, 1021, 845, 761 cm¹1; 1H NMR (300 MHz,
CDCl3): E isomer: ¤ 1.39 (s, 3H), 1.45 (s, 3H), 1.47 (s, 9H), 3.65
(dd, J = 7.52, 7.89 Hz, 1H), 3.85 (s, 3H), 4.25 (dd, J = 6.60,
8.05 Hz, 1H), 5.34 (dd, J = 6.60, 13.94 Hz, 1H), 6.70 (br s, 1H),
6.88 (d, J = 7.34 Hz, 1H). Z isomer: ¤ 1.39 (s, 3H), 1.45 (s, 3H),
1.46 (s, 9H), 3.80 (s, 3H), 3.81-3.86 (m, 1H), 4.34 (dd, J = 6.60,
8.62 Hz, 1H), 4.85 (dd, J = 6.60, 14.67 Hz, 1H), 6.40 (d, J =
8.25 Hz, 1H), 6.44 (br s, 1H). HRMS (FAB+) (M+ + 1) Found:
302.1599. Calcd for C14H24NO6: 302.1604.
compound 12 in 89% yield (88 mg). Oil; ½¡ꢀD +3.56° (c 1.25,
EtOH); IR (neat): 3351, 3071, 3050, 2964, 2931, 2894, 2859,
1962, 1894, 1784, 1713, 1589, 1510, 1473, 1456, 1428, 1391,
1367, 1328, 1291, 1254, 1164, 1114, 1051, 1030, 978, 936, 911,
1
871, 823, 742, 704 cm¹1; H NMR (400 MHz, CDCl3): ¤ 1.06 (s,
9H), 1.46 (s, 9H), 2.03-2.11 (m, 1H), 2.66-2.81 (br, 1H), 3.74 (dd,
J = 3.90, 11.50 Hz, 1H), 3.89 (dd, J = 2.93, 11.50 Hz, 1H), 4.44-
5.16 (br, 1H), 4.48-4.55 (m, 2H), 7.36-7.47 (m, 6H), 7.64-7.68
(m, 4H). HRMS (FAB+) (M+ + 1): Found: m/z 470.2360. Calcd
for C26H36NO5Si: 470.2363.
A General Procedure for Coupling Reaction of Boc-Amino
Acid with cis-4,5-Oxazolidinone Derivatives (13a-13k¤).
A
solution of 3-Boc-4-(methoxycarbonyl)-5-phenyl-cis-4,5-oxazol-
idin-2-one (2i) (321 mg, 1.0 mmol) in 99% formic acid (20 mL)
was allowed to stand for 40 min. Evaporation of the solvent
afforded the N-deprotected oxazolidinone derivative in quantita-
tive yield (mp 147-148 °C from EtOAc-hexane). To the resulting
oxazolidinone (221 mg, 1.0 mmol) in dry THF (5 mL) was added
dropwise 1.1 molar equivalents of LDA at ¹78 °C under N2. After
5 min a solution of Boc-Ala-ONSu (429 mg, 1.1 mmol) in THF
(5 mL) was added at ¹78 °C followed by the addition of a solution
of DMAP (12 mg, 0.1 mmol) in dry THF (2 mL). The solution was
then warmed to ¹10 °C and kept at that temperature for 3 h. After
quenching the reaction with 1 M AcOH in THF at ¹78 °C, the
solvent was removed in vacuo to give a residue, which was
partitioned between EtOAc and water. The aqueous layer was
extracted with EtOAc. The combined EtOAc extracts were washed
with a solution of 10% NaHCO3 and brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was subjected to
preparative TLC (SiO2, hexane/EtOAc = 2/1, v/v) to give 13i as
major product and 13i¤ as minor one in 51% (199 mg) and 45%
(177 mg) yields, respectively. 13i: mp 160.0-161.0 °C (EtOAc-
(4S)-2-(N-Boc-amino)-5-hydroxymethylbutenolide (10).
A
solution of compound 9 (E/Z = 78/22, 160 mg, 0.53 mmol) and
1 M HCl in MeOH (2.0 mL) was stirred for 1 d under air. After
neutralization with NaHCO3 solution at 0 °C, the solvent was
removed in vacuo to give a residue, which was partitioned between
EtOAc and water. The organic solution was washed with brine,
dried over MgSO4, and concentrated under reduced pressure. The
residue was purified with preparative TLC (SiO2, hexane/
EtOAc = 1/1, v/v) to afford the product 10 in 61% yield
25
(74 mg). Mp 123.0-124.0 °C (EtOAc-hexane); ½¡ꢀD +18.14° (c
0.19, CHCl3); IR (KBr): 3425, 2979, 1767, 1662, 1538, 1456,
1370, 1344, 1315, 1241, 1160, 1075, 1045, 1016, 934, 888, 849,
1
25
770 cm¹1; H NMR (300 MHz, CDCl3): ¤ 1.50 (s, 9H), 2.30-2.44
hexane); ½¡ꢀD ¹54.03° (c 0.74, EtOH); IR (KBr): 3423, 2985,
(br, 1H), 3.71 (dd, J = 5.69, 12.29 Hz, 1H), 3.97 (dd, J = 3.30,
12.29 Hz, 1H), 5.14 (m, 1H), 6.82-6.98 (br, 1H), 7.04-7.08 (br,
1H). Found: C, 52.12; H, 6.63; N, 6.05%. Calcd for C10H15NO5: C,
52.40; H, 6.60; N, 6.11%.
2953, 1806, 1748, 1722, 1702, 1503, 1368, 1340, 1243, 1216,
1
1196, 1143, 1020, 757, 701 cm¹1; H NMR (400 MHz, CDCl3): ¤
1.45 (s, 9H), 1.48 (d, J = 7.07 Hz, 3H), 3.20 (s, 3H), 5.02 (d,
J = 8.05 Hz, 1H), 5.14 (d, J = 9.03 Hz, 1H), 5.40 (dq, J = 7.07,
8.05 Hz, 1H), 5.82 (d, J = 9.03 Hz, 1H), 7.28-7.44 (m, 2H),
7.36-7.44 (m, 3H). Found: C, 58.08; H, 6.14; N, 7.10%. Calcd
for C19H24N2O7: C, 58.15; H, 6.17; N, 7.14%. 13i¤: mp 145.0-
(4S)-2-(N-Boc-amino)-5-(t-butyldiphenylsiloxy)methylbute-
nolide (11). A solution of 10 (85 mg, 0.37 mmol), TBDPS-Cl
(123 mg, 0.45 mmol), and imidazole (76 mg, 1.12 mmol) in DMF
(3 mL) was allowed to stir for 4 h at room temperature. The
reaction solution was diluted with water and extracted with ether.
The ethereal solution was washed with brine, dried over MgSO4,
and evaporated in vacuo to give a residue which was subjected to
preparative TLC (SiO2, hexane/EtOAc = 3/1, v/v). The desired
25
146.0 °C (EtOAc-hexane); ½¡ꢀD ¹38.59° (c 0.68, EtOH); IR
(KBr): 3374, 2981, 2934, 1784, 1747, 1725, 1692, 1627, 1521,
¹1
1359, 1249, 1215, 1200, 1166, 1140, 1012, 760, 701 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.42-1.50 (br, 3H), 1.44 (s, 9H),
3.24 (s, 3H), 5.03 (d, J = 8.78 Hz, 1H), 5.22-5.34 (br, 1H), 5.39-
5.58 (br, 1H), 5.81 (d, J = 8.78 Hz, 1H), 7.28-7.35 (m, 2H), 7.36-
7.43 (m, 3H). Found: C, 58.23; H, 6.31; N, 7.05%. Calcd for
C19H24N2O7: C, 58.15; H, 6.17; N, 7.14%.
25
product 11 was obtained as oil in 80% yield (132 mg). ½¡ꢀD
+25.84° (c 1.18, EtOH); IR (neat): 3421, 3317, 3134, 3071, 3049,
2959, 2931, 2893, 2858, 2741, 2344, 1961, 1768, 1734, 1667,

376
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
Syntheses of (E)-¡,¢-Didehydroamino Acid
The physical and spectral data of compounds 13a-13h¤ and
13j-13k¤ are shown in the following.
373.1975.
3-(Boc-glycyl)-cis-4-methoxycarbonyl-5-(2-phenylethyl)oxa-
zolidin-2-one (13e): Oil; IR (film): 3356, 3062, 3006, 2979,
2933, 1715, 1516, 1438, 1393, 1368, 1215, 1166, 1054, 1030, 754,
701, 667 cm¹1; 1H NMR (300 MHz, CDCl3): ¤ 1.45 (s, 9H), 1.84-
2.00 (m, 2H), 2.58-2.81 (m, 1H), 2.81-2.96 (m, 1H), 3.79 (s, 3H),
4.38-4.50 (m, 1H), 4.53-4.64 (m, 1H), 4.66 (dt, J = 4.22, 8.44 Hz,
1H), 4.82 (d, J = 8.44 Hz, 1H), 5.00-5.16 (br, 1H), 7.16-7.38 (m,
5H). HRMS (FAB+) (M+ + 1): Found: m/z 407.1814. Calcd for
C20H27N2O7: 407.1818.
3-(Boc-glycyl)-cis-4-methoxycarbonyl-5-methyloxazolidin-2-
one (13a): Oil; IR (film): 3355, 2979, 2925, 2852, 1749, 1521,
1393, 1368, 1218, 1164, 1099, 1054, 952, 862, 761 cm¹1; 1H NMR
(300 MHz, CDCl3): ¤ 1.42 (d, J = 6.24 Hz, 3H), 1.45 (s, 9H), 3.81
(s, 3H), 4.42-4.50 (m, 1H), 4.57-4.70 (m, 1H), 4.85 (d, J =
8.62 Hz, 1H), 4.91 (dq, J = 6.24, 8.62 Hz, 1H), 4.99-5.13 (br, 1H).
HRMS (FAB+) (M+ + 1): Found: m/z 317.1355. Calcd for
C13H21N2O7: 317.1349.
3-(Boc-alanyl)-cis-4-methoxycarbonyl-5-methyloxazolidin-2-
3-(Boc-alanyl)-cis-4-methoxycarbonyl-5-(2-phenylethyl)oxa-
25
25
one (13b and 13b¤): 13b: oil; ½¡ꢀD +21.08° (c 1.28, EtOH). IR
zolidin-2-one (13f and 13f¤): 13f: oil; ½¡ꢀD ¹63.78° (c 1.08,
(film): 3391, 2980, 2936, 1794, 1754, 1707, 1507, 1454, 1392,
EtOH); IR (film): 3626, 3393, 3026, 3006, 2979, 2935, 1825, 1793,
1367, 1217, 1166, 1099, 1071, 1054, 1020, 981, 953, 862,
1753, 1709, 1497, 1455, 1369, 1215, 1167, 1073, 1055, 1021, 757,
¹1
1
758 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.42 (d, J = 6.24 Hz,
701 cm¹1; H NMR (300 MHz, CDCl3): ¤ 1.42 (s, 9H), 1.44 (d,
3H), 1.43 (d, J = 6.97 Hz, 3H), 1.43 (s, 9H), 3.80 (s, 3H), 4.90 (d,
J = 8.80 Hz, 1H), 4.91 (dq, J = 6.24, 8.80 Hz, 1H), 4.98-5.12 (br,
1H), 5.33 (dq, J = 6.97, 8.07 Hz, 1H). HRMS (FAB+) (M+ + 1):
Found: m/z 331.1506. Calcd for C14H23N2O7: 331.1505. 13b¤: oil;
J = 6.79 Hz, 3H), 1.80-2.00 (m, 2H), 2.65-2.85 (m, 1H), 2.85-
3.00 (m, 1H), 3.77 (s, 3H), 4.66 (ddd, J = 4.04, 8.62, 9.72 Hz, 1H),
4.87 (d, J = 8.62 Hz, 1H), 4.96-5.10 (br, 1H), 5.32 (dq, J = 6.79,
7.15 Hz, 1H), 7.14-7.38 (m, 5H). HRMS (FAB+) (M+ + 1):
Found: m/z 421.1978. Calcd for C21H29N2O7: 421.1975. 13f¤: oil:
25
½¡ꢀD ¹118.63° (c 1.08, EtOH); IR (film): 3389, 2980, 2936, 1793,
25
1755, 1706, 1505, 1454, 1390, 1367, 1217, 1166, 1099, 1071,
1054, 1020, 953, 862, 758 cm¹1; 1H NMR (300 MHz, CDCl3): ¤
1.42 (d, J = 6.42 Hz, 6H), 1.44 (s, 9H), 3.81 (s, 3H), 4.80 (d,
J = 8.44 Hz, 1H), 4.89 (dq, J = 6.42, 8.44 Hz, 1H), 5.20-5.34 (br,
1H), 5.36-5.52 (m, 1H). HRMS (FAB+) (M+ + 1): Found: m/z
331.1498. Calcd for C14H23N2O7: 331.1505.
½¡ꢀD ¹119.94° (c 0.32, EtOH); IR (film): 3384, 2979, 2955, 2933,
1793, 1752, 1712, 1496, 1454, 1368, 1211, 1168, 1071, 1022, 756,
¹1
701 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.35 (d, J = 8.83 Hz,
3H), 1.36 (s, 9H), 1.82-2.04 (m, 2H), 2.70-2.82 (m, 1H), 2.86-
2.98 (m, 1H), 3.78 (s, 3H), 4.61 (ddd, J = 4.39, 8.29, 9.27 Hz, 1H),
4.75 (d, J = 8.29 Hz, 1H), 5.15-5.30 (br, 1H), 5.40-5.50 (m, 1H),
7.15-7.36 (m, 5H). HRMS (FAB+) (M+ + 1): Found: m/z
421.1965. Calcd for C21H29N2O7: 421.1975.
3-(Boc-valyl)-cis-4-methoxycarbonyl-5-methyloxazolidin-2-
one (13c and 13c¤): 13c: mp 101.5-102.5 °C (EtOAc-hexane);
25
½¡ꢀD ¹70.66° (c 1.17, EtOH); IR (KBr): 3440, 3004, 2973, 2870,
3-(Boc-valyl)-cis-4-methoxycarbonyl-5-(2-phenylethyl)oxa-
25
2840, 1795, 1760, 1718, 1698, 1509, 1458, 1366, 1212, 1164,
zolidin-2-one (13g and 13g¤): 13g: oil; ½¡ꢀD ¹53.38° (c 0.67,
¹1
1100, 882, 795 cm
;
1H NMR (300 MHz, CDCl3): ¤ 0.83 (d,
EtOH); IR (film): 3340, 2968, 2931, 1793, 1753, 1706, 1497,
¹1
J = 6.79 Hz, 3H), 1.05 (d, J = 6.79 Hz, 3H), 1.41 (d, J = 2.93 Hz,
3H), 1.45 (s, 9H), 2.30-2.38 (m, 1H), 3.80 (s, 3H), 4.87 (dq,
J = 6.42, 8.44 Hz, 1H), 4.90 (d, J = 8.44 Hz, 1H), 5.10-5.28 (br,
1H), 5.37 (dd, J = 3.67, 9.35 Hz, 1H). HRMS (FAB+) (M+ + 1):
Found: m/z 359.1825. Calcd for C16H27N2O7: 359.1818. 13c¤: oil;
1456, 1391, 1368, 1211, 1165, 1143, 1016, 756, 701 cm ;
1H NMR (300 MHz, CDCl3): ¤ 0.84 (d, J = 6.79 Hz, 3H), 1.09 (d,
J = 6.79 Hz, 3H), 1.44 (s, 9H), 1.86-1.98 (m, 2H), 2.24-2.38 (br,
1H), 2.68-2.82 (m, 1H), 2.84-2.98 (m, 1H), 3.76 (s, 3H), 4.64 (dt,
J = 4.04, 8.80 Hz, 1H), 4.88 (d, J = 8.80 Hz, 1H), 5.02 (d, J =
9.35 Hz, 1H), 5.36 (dd, J = 3.67, 9.35 Hz, 1H), 7.14-7.34 (m, 5H).
HRMS (FAB+) (M+ + 1): Found: m/z 449.2281. Calcd for
25
½¡ꢀD +61.48° (c 0.96, EtOH); IR (film): 3437, 3392, 2972, 2935,
2875, 1793, 1750, 1705, 1500, 1392, 1365, 1211, 1164, 1098,
1
25
1054, 1017, 758, 667 cm¹1; H NMR (300 MHz, CDCl3): ¤ 0.85
C23H33N2O7: 449.2288. 13g¤: oil: ½¡ꢀD +32.37° (c 0.50, EtOH);
(d, J = 6.79 Hz, 3H), 1.09 (d, J = 6.79 Hz, 3H), 1.40 (d,
J = 6.42 Hz, 3H), 1.44 (s, 9H), 2.20-2.24 (br, 1H), 3.79 (s, 3H),
4.77 (d, J = 8.44 Hz, 1H), 4.86 (dq, J = 6.42, 8.44 Hz, 1H),
5.11-5.25 (br, 1H), 5.36 (dd, J = 3.67, 9.35 Hz, 1H). HRMS
(FAB+) (M+ + 1): Found: m/z 359.1825. Calcd for C16H27N2O7:
359.1818.
IR (film): 3442, 3395, 3026, 2970, 2932, 2874, 1793, 1753, 1704,
¹1
1497, 1391, 1368, 1215, 1164, 1018, 756, 701 cm
;
1H NMR
(300 MHz, CDCl3): ¤ 0.80 (d, J = 6.79 Hz, 3H), 1.04 (d, J = 6.79
Hz, 3H), 1.45 (s, 9H), 1.86-1.98 (m, 2H), 2.06-2.24 (br, 1H),
2.69-2.82 (m, 1H), 2.86-2.98 (m, 1H), 3.78 (s, 3H), 4.59 (dt,
J = 4.77, 8.62 Hz, 1H), 4.73 (d, J = 8.62 Hz, 1H), 5.17 (d, J =
9.35 Hz, 1H), 5.44 (dd, J = 3.76, 9.35 Hz, 1H), 7.18-7.36 (m, 5H).
HRMS (FAB+) (M+ + 1): Found: m/z 449.2274. Calcd for
C23H33N2O7: 449.2288.
3-(Boc-leucyl)-cis-4-methoxycarbonyl-5-methyloxazolidin-2-
one (13d and 13d¤): 13d: mp 92.0-93.0 °C (EtOAc-hexane);
25
½¡ꢀD ¹84.34° (c 0.86, EtOH); IR (KBr): 3396, 3331, 2963, 2937,
2873, 1796, 1746, 1712, 1524, 1390, 1367, 1253, 1212, 1167,
3-(Boc-glycyl)-cis-4-methoxycarbonyl-5-phenyloxazolidin-2-
one (13h): Mp 118.0-119.0 °C (EtOAc-hexane); IR (KBr): 3397,
3025, 3008, 2978, 2955, 1794, 1742, 1732, 1697, 1523, 1394,
1381, 1338, 1270, 1249, 1233, 1195, 1168, 1143, 1051, 1018, 941,
¹1
1100, 1051, 1026, 951, 786, 759 cm
;
1H NMR (300 MHz,
CDCl3): ¤ 0.96 (d, J = 6.42 Hz, 3H), 1.03 (d, J = 6.42 Hz, 3H),
1.40 (d, J = 6.42 Hz, 3H), 1.43 (s, 9H), 1.55-1.90 (m, 3H), 3.80 (s,
3H), 4.84-4.96 (m, 2H), 4.91 (d, J = 8.80 Hz, 1H), 5.30-5.52 (m,
1H). HRMS (FAB+) (M+ + 1): Found: m/z 373.1972. Calcd for
1
795, 701 cm¹1; H NMR (300 MHz, CDCl3): ¤ 1.46 (s, 9H), 3.21
(s, 3H), 4.48 (dd, J = 4.40, 19.26 Hz, 1H), 4.71 (dd, J = 6.79,
19.26 Hz, 1H), 5.09 (d, J = 8.99 Hz, 1H), 5.04-5.12 (br, 1H), 5.82
25
C17H29N2O7: 373.1975. 13d¤: oil; ½¡ꢀD +31.83° (c 0.31, EtOH);
IR (film): 3352, 2960, 2872, 1793, 1756, 1708, 1507, 1456, 1439,
(d, J = 8.99 Hz, 1H), 7.28-7.46 (m, 5H). HRMS (FAB+) (M+
1): Found: m/z 379.1516. Calcd for C18H23N2O7: 379.1505.
+
¹1
1366, 1212, 1168, 1098, 1051, 1024, 757, 666 cm
;
1H NMR
(300 MHz, CDCl3): ¤ 0.93 (d, J = 6.60 Hz, 3H), 1.03 (d, J =
6.24 Hz, 3H), 1.42-1.48 (m, 12H), 1.70-1.88 (m, 3H), 3.80 (s,
3H), 4.77 (d, J = 8.44 Hz, 1H), 4.86 (dq, J = 6.42, 8.44 Hz,
1H), 5.09 (d, J = 8.49 Hz, 1H), 5.38-5.56 (m, 1H). HRMS
(FAB+) (M+ + 1): Found: m/z 373.1977. Calcd for C17H29N2O7:
3-(Boc-valyl)-cis-4-methoxycarbonyl-5-phenyloxazolidin-2-
one (13j and 13j¤): 13j: mp 113.5-1114.5 °C (EtOAc-hexane);
25
½¡ꢀD ¹19.66° (c 0.44, EtOH); IR (KBr): 3416, 2968, 1796, 1748,
1710, 1510, 1456, 1370, 1343, 1217, 1163, 1134, 1053, 1020,
¹1
1001, 874, 839, 756, 697 cm
;
1H NMR (300 MHz, CDCl3): ¤

M. Kometani et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
377
0.86 (d, J = 6.97 Hz, 3H), 1.13 (d, J = 6.79 Hz, 3H), 1.45 (s, 9H),
2.28-2.46 (br, 1H), 3.18 (s, 3H), 5.03 (d, J = 9.36 Hz, 1H), 5.16
(d, J = 9.35 Hz, 1H), 5.44 (dd, J = 3.85, 9.36 Hz, 1H), 5.81 (d,
J = 9.35 Hz, 1H), 7.65-7.75 (m, 5H). HRMS (FAB+) (M+ + 1):
Found: m/z 421.1989. Calcd for C21H29N2O7: 421.1975. 13j¤: mp
In a similar way, compounds 13a-13h¤ and 13j-13k¤ were
converted into 14a-14h¤ and 14j-14k¤, whose physical and
spectral data were shown in following.
Methyl 2-(Boc-glycylamino)-2-butenoate (14a and 14a¤):
(E)-14a: oil; IR (film): 3346, 2979, 2933, 1707, 1518, 1393,
25
¹1
128.5-129.5 °C (EtOAc-hexane); ½¡ꢀD ¹12.52° (c 0.54, EtOH);
1368, 1252, 1167, 1054, 1031, 950, 861, 757 cm ;
1H NMR
IR (KBr): 3405, 2970, 2934, 1784, 1749, 1699, 1512, 1357, 1277,
(300 MHz, CDCl3): ¤ 1.46 (s, 9H), 2.08 (d, J = 7.52 Hz, 3H),
3.82-3.88 (m, 5H), 5.24-5.38 (br, 1H), 5.44 (q, J = 7.52 Hz, 1H),
7.98-8.12 (br, 1H). HRMS (FAB+) (M+ + 1): Found: m/z
273.1444. Calcd for C12H21N2O5: 273.1451. When the amide
NH proton was irradiated, 2.0% NOE was observed for the olefinic
proton. (Z)-14a¤: oil (Lit. mp 100.0-101.5 °C,3h 100 °C,3i and 103-
104 °C20). IR (film) 3321, 2979, 2959, 2932, 1721, 1514, 1439,
1368, 1281, 1168, 1073, 1052, 1029, 949, 863, 756 cm¹1; 1H NMR
(300 MHz, CDCl3): ¤ 1.47 (s, 9H), 1.77 (d, J = 7.15 Hz, 3H), 3.76
(s, 3H), 3.92 (d, J = 5.50 Hz, 2H), 5.24-5.36 (br, 1H), 6.84 (q,
J = 7.15 Hz, 1H), 7.50-7.60 (br, 1H). HRMS (FAB+) (M+ + 1):
Found: m/z 273.1455. Calcd for C12H21N2O5: 273.1451.
1246, 1217, 1200, 1166, 1140, 1055, 1017, 891, 758, 722,
¹1
700 cm
;
1H NMR (300 MHz, CDCl3): ¤ 0.86 (d, J = 6.97 Hz,
3H), 1.08 (d, J = 6.79 Hz, 3H), 1.45 (s, 9H), 2.12-2.32 (br, 1H),
3.23 (s, 3H), 5.02 (d, J = 8.62 Hz, 1H), 5.22 (d, J = 9.35 Hz, 1H),
5.44 (dd, J = 3.85, 9.35 Hz, 1H), 5.81 (d, J = 8.62 Hz, 1H), 7.28-
7.44 (m, 5H). Found: C, 59.90; H, 6.79; N, 6.65%. Calcd for
C21H28N2O7: C, 59.98; H, 6.71; N, 6.66%.
3-(Boc-leucyl)-cis-4-methoxycarbonyl-5-phenyloxazolidin-2-
25
one (13k and 13k¤): 13k: oil; ½¡ꢀD ¹24.29° (c 0.63, EtOH); IR
(film): 3350, 2960, 2872, 1793, 1756, 1708, 1507, 1456, 1439,
¹1
1366, 1212, 1168, 1098, 1051, 1025, 757 cm
;
1H NMR (300
MHz, CDCl3): ¤ 0.98 (d, J = 6.11 Hz, 3H), 1.07 (d, J = 6.05 Hz,
3H), 1.30-1.42 (m, 1H), 1.45 (s, 9H), 1.72-1.94 (m, 2H), 3.18 (s,
3H), 4.95 (d, J = 8.44 Hz, 1H), 5.13 (d, J = 9.17 Hz, 1H), 5.40-
5.54 (br, 1H), 5.82 (d, J = 9.17 Hz, 1H), 7.28-7.44 (m, 5H).
HRMS (FAB+) (M+ + 1): Found: m/z 435.2124. Calcd for
Methyl 2-(Boc-alanylamino)-2-butenoate (14b and 14b¤):
(E)-14b: mp 96.5-97.0 °C (EtOAc-hexane) (Lit. mp 100-
25
101 °C);6f ½¡ꢀD ¹19.83° (c 1.10, EtOH); IR (KBr): 3319, 3047,
2982, 2955, 2935, 1738, 1677, 1662, 1531, 1367, 1345, 1254,
1
1167, 1116, 1070, 1043, 1026, 858, 788, 757, 715 cm¹1; H NMR
25
C22H31N2O7: 435.2121. 13k¤: oil; ½¡ꢀD ¹24.49° (c 0.71, EtOH);
(300 MHz, CDCl3): ¤ 1.38 (d, J = 7.15 Hz, 3H), 1.45 (s, 9H), 2.06
(d, J = 8.99 Hz, 3H), 3.82 (s, 3H), 4.35-4.60 (br, 1H), 4.90-5.15
(br, 1H), 7.17 (q, J = 8.99 Hz, 1H), 7.96-8.16 (br, 1H). HRMS
(FAB+) (M+ + 1): Found: m/z 287.1600. Calcd for C13H23N2O5:
287.1607. When the olefinic proton was irradiated, 2.0% NOE was
observed for the amide NH proton. (Z)-14b¤: mp 112.0-113.0 °C
(EtOAc-hexane) (Lit. Mp 114 °C,3i 115-116 °C,6f and 116 °C21);
IR (film): 3390, 2980, 2936, 1794, 1754, 1705, 1505, 1454, 1392,
1367, 1217, 1166, 1099, 758 cm¹1; 1H NMR (300 MHz, CDCl3): ¤
0.96 (d, J = 6.60 Hz, 3H), 1.06 (d, J = 6.60 Hz, 3H), 1.44 (s, 9H),
1.38-1.52 (m, 1H), 1.55-1.67 (m, 1H), 1.75-1.92 (m, 1H), 3.24 (s,
3H), 5.01 (d, J = 8.80 Hz, 1H), 5.07 (m, 1H), 5.55 (ddd, J = 3.49,
10.3, 10.4 Hz, 1H), 5.80 (d, J = 8.80 Hz, 1H), 7.28-7.42 (m, 5H).
HRMS (FAB+) (M+ + 1): Found: m/z 435.2135. Calcd for
C22H31N2O7: 435.2121.
25
½¡ꢀD ¹18.66° (c 0.42, EtOH); IR (KBr): 3336, 3292, 2980,
2948, 1720, 1673, 1524, 1323, 1281, 1166, 1050, 772, 705,
¹1
A General Procedure for Conversion of Compounds 13a-
13k¤ to the Corresponding Dehydropeptides 14a-14k¤. To a
solution of 13i (70 mg, 0.18 mmol) in dry THF (3 mL) was added
4.0 molar equivalents of LiHMDS in dry THF (2 mL) at ¹45 °C
under N2 and the solution was stirred for 50 min at that temper-
ature. After the reaction was quenched with 1 M AcOH in THF at
¹45 °C, the solvent was removed in vacuo to give a residue, which
was partitioned between EtOAc and water. The aqueous layer was
extracted with EtOAc and the combined extracts were washed with
brine, dried oner MgSO4, and concentrated in vacuo. The residual
oil was subjected to preparative TLC (SiO2, benzene/EtOAc =
4/1, v/v) to give methyl (E)-N-Boc-alanyldehydrophenylalaninate
(14i) in 68% (43 mg) and methyl (Z)-N-Boc-alanyldehydrophen-
ylalaninate (14i¤) in 10% (6 mg) yields, respectively. (E)-14i: oil;
673 cm ;
1H NMR (300 MHz, CDCl3): ¤ 1.42 (d, J = 6.97 Hz,
3H), 1.46 (s, 9H), 1.76 (d, J = 7.15 Hz, 3H), 3.76 (s, 3H), 4.20-
4.38 (br, 1H), 4.90-5.10 (br, 1H), 6.82 (q, J = 7.15 Hz, 1H), 7.46-
7.58 (br, 1H). HRMS (FAB+) (M+ + 1): Found: m/z 287.1610.
Calcd for C13H23N2O5: 287.1607.
Methyl 2-(Boc-valylamino)-2-butenoate (14c and 14c¤): (E)-
25
14c: mp 133.5-134.0 °C (EtOAc-hexane); ½¡ꢀD ¹5.20° (c 1.29,
EtOH); IR (KBr): 3330, 3276, 3022, 2976, 2955, 2871, 1735,
1685, 1666, 1523, 1434, 1369, 1353, 1248, 1172, 1045, 1021,
¹1
1000, 930, 880, 830, 808 cm
;
1H NMR (300 MHz, CDCl3): ¤
0.93 (d, J = 6.79 Hz, 3H), 0.98 (d, J = 6.79 Hz, 3H), 1.45 (s, 9H),
2.18-2.25 (m, 1H), 2.19 (d, J = 7.52 Hz, 3H), 3.84 (s, 3H), 3.90-
4.04 (br, 1H), 4.90-5.12 (br, 1H), 7.20 (q, J = 7.70 Hz, 1H), 7.75-
7.85 (br, 1H). Found: C, 57.10; H, 8.35; N, 8.89%. Calcd for
C15H26N2O5: C, 57.31; H, 8.34; N, 8.91%. When the olefinic
proton was irradiated, 1.1% NOE was observed for the amide
25
½¡ꢀD ¹2.10° (c 0.54, EtOH); IR (film): 3317, 3057, 2979, 2932,
2853, 1718, 1680, 1644, 1493, 1367, 1267, 1167, 1114, 1068,
¹1
25
1020, 858, 769, 737, 692 cm
;
1H NMR (300 MHz, CDCl3): ¤
NH proton. (Z)-14c¤: mp 99.5-100.5 °C (EtOAc-hexane); ½¡ꢀD
1.43 (d, J = 7.15 Hz, 3H), 1.47 (s, 9H), 3.64 (s, 3H), 4.22-4.42 (br,
1H), 5.16 (d, J = 7.34 Hz, 1H), 7.16-7.34 (m, 5H), 7.69 (s, 1H),
8.38-8.64 (br, 1H). HRMS (FAB+) (M+ + 1): Found: m/z
349.1759. Calcd for C18H25N2O5: 349.1764. When the olefinic
proton was irradiated, 3.9% NOE was observed for the amide
¹11.51° (c 0.66, EtOH); IR (KBr): 3326, 3284, 2955, 2871,
1732, 1685, 1660, 1525, 1508, 1300, 1278, 1247, 1169, 1070,
1045, 932, 876, 806 cm¹1; 1H NMR (300 MHz, CDCl3): ¤ 0.98 (d,
J = 6.79 Hz, 3H), 1.03 (d, J = 6.79 Hz, 3H), 1.17 (d, J = 7.34 Hz,
3H), 1.45 (s, 9H), 2.14-2.32 (m, 1H), 3.76 (s, 3H), 4.00-4.10 (m,
1H), 4.96-5.14 (br, 1H), 6.83 (q, J = 7.15 Hz, 1H), 7.26-7.35 (br,
1H). Found: C, 57.31; H, 8.45; N, 8.87%. Calcd for C15H26N2O5:
C, 57.31; H, 8.34; N, 8.91%.
25
NH proton. (Z)-14i¤: mp 116.0-117.0 °C (EtOAc-hexane); ½¡ꢀD
+66.06° (c 0.19, EtOH); IR (KBr): 3390, 3370, 3058, 2984, 2949,
1715, 1693, 1644, 1500, 1478, 1273, 1206, 1163, 1118, 1065,
¹1
1010, 771, 694 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.42 (d,
Methyl 2-(Boc-leucylamino)-2-butenoate (14d and 14d¤):
25
J = 7.08 Hz, 3H), 1.45 (s, 9H), 3.84 (s, 3H), 4.26-4.38 (br, 1H),
4.92-5.08 (br, 1H), 7.30-7.50 (m, 5H), 7.43 (s, 1H), 7.68-7.80 (br,
1H). Found: C, 61.88; H, 7.00; N, 7.90%. Calcd for C18H24N2O5:
C, 62.05; H, 6.94; N, 8.04%.
(E)-14d: mp 93.5-94.5 °C (EtOAc-hexane); ½¡ꢀD ¹20.08° (c
0.91, EtOH); IR (KBr): 3281, 3052, 2976, 2925, 2872, 1727, 1664,
¹1
1536, 1366, 1352, 1292, 1257, 1166, 1047, 1023, 850, 785 cm
;
1H NMR (300 MHz, CDCl3): ¤ 0.94 (d, J = 6.23 Hz, 3H), 0.96 (d,

378
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
Syntheses of (E)-¡,¢-Didehydroamino Acid
J = 6.42 Hz, 3H), 1.45 (s, 9H), 1.46-1.52 (m, 1H), 1.66-1.78 (m,
2H), 2.09 (d, J = 7.70 Hz, 3H), 3.83 (s, 3H), 4.06-4.22 (br, 1H),
4.76-4.96 (br, 1H), 7.20 (q, J = 7.70 Hz, 1H), 7.90-8.10 (br, 1H).
HRMS (FAB+) (M+ + 1): Found: m/z 329.1984. Calcd for
C16H29N2O5: 329.2077. When the olefinic proton was irradiated,
2.1% NOE was observed for the amide NH proton. (Z)-14d¤: oil:
4.92-5.10 (br, 1H), 6.72 (t, J = 7.34 Hz, 1H), 7.06 (br s, 1H) 7.16-
7.34 (m, 5H). HRMS (FAB+) (M+ + 1): Found: m/z 405.2396.
Calcd for C22H33N2O5: 405.2390.
Methyl N-Boc-glycyldehydrophenylalaninate (14h and
14h¤): (E)-14h: mp 130.5-131.5 °C (EtOAc-hexane); IR (KBr):
3286, 3240, 2979, 2940, 1747, 1698, 1636, 1539, 1439, 1364,
25
1
½¡ꢀD +71.63° (c 0.20, EtOH); IR (neat): 3348, 2979, 2932, 2853,
1299, 1252, 1219, 1166, 982, 942, 760, 705 cm¹1; H NMR (300
1710, 1521, 1454, 1393, 1368, 1280, 1252, 1167, 1054, 950, 861,
MHz, CDCl3): ¤ 1.48 (s, 9H), 3.64 (s, 3H), 3.92 (d, J = 5.87 Hz,
2H), 5.34 (t, J = 5.89 Hz, 1H), 7.20-7.36 (m, 5H), 7.81 (s, 1H),
8.37 (br s, 1H). Found: C, 60.82; H, 6.59; N, 8.36%. Calcd for
C17H22N2O5: C, 61.06; H, 6.63; N, 8.38%. When the amide
NH proton was irradiated, 6.6% NOE was observed for the
olefinic proton. (Z)-14h¤: oil (Lit. mp 62.5-64 °C);3h IR (film):
3299, 2979, 2951, 2933, 1686, 1638, 1521, 1367, 1252, 1165,
¹1
760 cm
;
1H NMR (300 MHz, CDCl3): ¤ 0.95 (d, J = 6.05 Hz,
3H), 0.96 (d, J = 6.41 Hz, 3H), 1.46 (s, 9H), 1.55-1.80 (m, 6H),
3.76 (s, 3H), 4.05-4.30 (br, 1H), 4.80-5.00 (br, 1H), 6.81 (q,
J = 7.15 Hz, 1H), 7.46-7.58 (br, 1H). HRMS (FAB+) (M+ + 1):
Found: m/z 329.2079. Calcd for C16H29N2O5: 329.2077.
Methyl 2-(Boc-glycylamino)-5-phenyl-2-pentenoate (14e and
1
14e¤): (E)-14e: oil; IR (film): 3326, 2978, 2928, 2849, 1715,
1052, 1030, 865, 754, 697 cm¹1; H NMR (300 MHz, CDCl3): ¤
¹1
1681, 1520, 1455, 1367, 1249, 1165, 1066, 751, 700 cm
;
1.45 (s, 9H), 3.84 (s, 3H), 3.92 (d, J = 5.14 Hz, 2H), 5.16-5.28
(br, 1H), 7.31-7.52 (m, 5H), 7.44 (s, 1H), 7.69 (br s, 1H). HRMS
(FAB+) (M+ + 1): Found: m/z 335.1614. Calcd for C17H23N2O5:
335.1607.
1H NMR (300 MHz, CDCl3): ¤ 1.46 (s, 9H), 2.77 (t, J = 7.34 Hz,
2H), 2.82-2.93 (m, 2H), 3.80 (s, 3H), 3.86 (d, J = 5.87 Hz, 2H),
5.10-5.24 (br, 1H), 7.16-7.34 (m, 6H), 8.00-8.10 (br, 1H). HRMS
(FAB+) (M+ + 1): Found: m/z 363.1929. Calcd for C19H27N2O5:
363.1920. When the methylene protons at £-protons were irra-
diated, 1.1% NOE was observed for the methyl ester protons. (Z)-
Methyl N-Boc-valyldehydrophenylalaninate (14j and 14j¤):
25
(E)-14j: mp 143.5-144.5 °C (EtOAc-hexane); ½¡ꢀD +22.81° (c
1.11, EtOH); IR (KBr): 3287, 3050, 3040, 2972, 2880, 1734, 1678,
14e¤: oil; IR (film): 3316, 2979, 2933, 1712, 1518, 1454, 1367,
1661, 1532, 1392, 1367, 1299, 1252, 1222, 1167, 1045, 1021, 750,
¹1
¹1
1248, 1167, 1066, 859, 755, 700 cm
;
1H NMR (300 MHz,
697 cm ;
1H NMR (300 MHz, CDCl3): ¤ 0.98 (d, J = 6.83 Hz,
CDCl3): ¤ 1.45 (s, 9H), 2.47 (dt, J = 7.32, 7.56 Hz, 2H), 2.78 (t,
J = 7.56 Hz, 2H), 3.75 (s, 3H), 3.87 (d, J = 5.87 Hz, 2H), 5.09-
5.22 (br, 1H), 6.73 (t, J = 7.32 Hz, 1H), 7.15-7.35 (m, 6H). HRMS
(FAB+) (M+ + 1): Found: m/z 363.1920. Calcd for C19H27N2O5:
363.1920.
3H), 1.03 (d, J = 6.59 Hz, 3H), 1.45 (s, 9H), 2.18-2.32 (m, 1H),
3.64 (s, 3H), 3.98-4.14 (br, 1H), 4.96-5.18 (br, 1H), 7.20-7.34
(m, 5H), 7.76 (s, 1H), 8.16 (br s, 1H). HRMS (FAB+) (M+ + 1):
Found: m/z 377.2068. Calcd for C20H29N2O5: 377.2077. When the
olefinic proton was irradiated, 2.5% NOE was observed for the
amide NH proton. (Z)-14j¤: mp 146.0-147.0 °C (EtOAc-hexane);
Methyl 2-(Boc-alanylamino)-5-phenyl-2-pentenoate (14f and
25
25
14f¤): (E)-14f: oil; ½¡ꢀD ¹22.10° (c 0.17, EtOH): IR (film): 3311,
½¡ꢀD +45.37° (c 0.15, EtOH); IR (KBr): 3323, 3247, 3010, 2959,
2978, 2932, 1684, 1605, 1521, 1454, 1366, 1249, 1167, 1066,
2930, 2879, 1729, 1687, 1665, 1526, 1366, 1300, 1275, 1249,
¹1
1
1021, 749, 699 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.38 (d,
1202, 1172, 762, 681 cm¹1; H NMR (300 MHz, CDCl3): ¤ 0.97
J = 7.15 Hz, 3H), 1.45 (s, 9H), 2.72-2.84 (m, 2H), 2.84-2.96 (m,
2H), 3.80 (s, 3H), 4.14-4.28 (br, 1H), 4.90-5.08 (br, 1H), 7.14-
7.32 (m, 6H), 8.06-8.16 (br, 1H). HRMS (FAB+) (M+ + 1):
Found: m/z 377.2082. Calcd for C20H29N2O5: 377.2077. (Z)-14f¤:
(d, J = 6.79 Hz, 3H), 1.03 (d, J = 6.79 Hz, 3H), 1.46 (s, 9H), 2.18-
2.34 (m, 1H), 3.84 (s, 3H), 4.05 (dd, J = 5.87, 8.62 Hz, 1H),
4.92-5.10 (br, 1H), 7.30-7.38 (m, 3H), 7.40 (s, 1H), 7.48 (d,
J = 6.42 Hz, 2H), 7.54 (br s, 1H). Found: C, 63.77; H, 7.58; N,
7.28%. Calcd for C20H28N2O5: C, 63.81; H, 7.50; N, 7.44%.
25
oil; ½¡ꢀD ¹1.95° (c 0.44, EtOH); IR (film): 3299, 2979, 2931,
1790, 1684, 1650, 1498, 1366, 1269, 1249, 1164, 1065, 1023, 746,
Methyl N-Boc-leucyldehydrophenylalaninate (14k and
¹1
25
699 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.38 (d, J = 7.15 Hz,
14k¤):
(E)-14k: mp 151.5-152.5 °C (EtOAc-hexane); ½¡ꢀD
3H), 1.44 (s, 9H), 2.46 (q, J = 7.52 Hz, 2H), 2.78 (t, J = 7.52 Hz,
2H), 3.75 (s, 3H), 4.16-4.30 (br, 1H), 4.89-4.96 (br, 1H), 6.71 (t,
J = 7.33 Hz, 1H), 7.16-7.36 (m, 6H). HRMS (FAB+) (M+ + 1):
Found: m/z 377.2088. Calcd for C20H29N2O5: 377.2077.
+13.71° (c 0.18, EtOH); IR (KBr): 3276, 3051, 2953, 2870, 1738,
1670, 1636, 1541, 1436, 1397, 1368, 1318, 1297, 1254, 1221,
¹1
1171, 1052, 1030, 982, 758, 696 cm
;
1H NMR (300 MHz,
CDCl3): ¤ 0.96 (d, J = 6.05 Hz, 3H), 0.98 (d, J = 6.41 Hz, 3H),
1.47 (s, 9H), 1.49-1.62 (m, 1H), 1.67-1.84 (m, 2H), 3.64 (s, 3H),
4.14-4.32 (br, 1H), 4.90 (d, J = 7.32 Hz, 1H), 7.20-7.34 (m, 5H),
7.79 (s, 1H), 8.35 (br s, 1H). HRMS (FAB+) (M+ + 1): Found: m/
z 391.2231. Calcd for C21H31N2O5: 391.2233. When the olefinic
proton was irradiated, 4.0% NOE was observed for the amide NH
Methyl 2-(Boc-valylamino)-5-phenyl-2-pentenoate (14g and
25
14g¤):
(E)-14g: mp 114.0-115.0 °C (EtOAc-hexane); ½¡ꢀD
+3.55° (c 0.22, EtOH); IR (KBr): 3329, 3298, 3031, 2981, 2964,
2932, 2873, 1729, 1687, 1666, 1652, 1603, 1526, 1518, 1386,
¹1
1300, 1246, 1174, 1010, 744, 698 cm
;
1H NMR (300 MHz,
25
CDCl3): ¤ 0.93 (d, J = 6.79 Hz, 3H), 0.99 (d, J = 6.79 Hz, 3H),
1.45 (s, 9H), 2.14-2.25 (m, 1H), 2.73-2.84 (m, 2H), 2.81-2.93 (m,
2H), 3.79 (s, 3H), 3.90-4.06 (br, 1H), 4.98-5.14 (br, 1H), 7.14 (t,
J = 7.70 Hz, 1H), 7.18-7.32 (m, 5H), 7.88 (br s, 1H). HRMS
(FAB+) (M+ + 1): Found: m/z 405.2387. Calcd for C22H33N2O5:
405.2390. When the £-methylene protons were irradiated, 1.7%
NOE was observed for protons of the methyl ester. (Z)-14g¤: mp
proton. (Z)-14k¤: oil; ½¡ꢀD +10.31° (c 0.30, EtOH); IR (film):
3299, 2957, 2940, 2870, 1690, 1512, 1267, 1168, 918, 732,
¹1
692 cm
;
1H NMR (300 MHz, CDCl3): ¤ 0.94 (d, J = 6.10 Hz,
3H), 0.97 (d, J = 6.34 Hz, 3H), 1.46 (s, 9H), 1.48-1.52 (m, 1H),
1.67-1.84 (m, 2H), 3.82 (s, 3H), 4.18-4.32 (br, 1H), 4.92 (d,
J = 8.05 Hz, 1H), 7.26-7.38 (m, 3H), 7.40 (s, 1H), 7.48 (d,
J = 7.07 Hz, 2H), 7.77 (br s, 1H). HRMS (FAB+) (M+ + 1):
Found: m/z 391.2236. Calcd for C21H31N2O5: 391.2233.
25
99.0-100.0 °C (EtOAc-hexane); ½¡ꢀD +14.86° (c 0.07, EtOH); IR
(KBr): 3331, 3293, 3018, 2965, 2839, 1732, 1723, 1685, 1662,
4-(N-Z-amino)-1-butyl Acetate (15).
To a mixture of 4-
¹1
1524, 1507, 1294, 1169, 750, 699 cm
;
1H NMR (300 MHz,
amino-1-butanol (1.782 g, 20 mmol) and sodium carbonate
(2.332 g, 22 mmol) in water (46 mL) was added dropwise a
solution of Z-Cl (3.410 g, 20 mmol) in THF (40 mL) at 0 °C. The
mixture was allowed to stand overnight at room temperature and
CDCl3): ¤ 0.94 (d, J = 6.79 Hz, 3H), 1.00 (d, J = 6.79 Hz, 3H),
1.43 (s, 9H), 2.15-2.24 (m, 1H), 2.48 (q, J = 7.34 Hz, 2H), 2.79 (t,
J = 7.34 Hz, 2H), 3.75 (s, 3H), 3.97 (dd, J = 6.05, 8.07 Hz, 1H),

M. Kometani et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 3 (2009)
379
the THF was removed in vauo to give a residue, which was
partitioned between EtOAc and water. The EtOAc solution was
washed with brine, dried, and evaporated in vacuo to afford the
product in quantitative yield (4.46 g).
To a solution of the resulting alcohol (4.46 g, 20 mmol) in THF
(20 mL) was added a catalytic amount of DMAP followed by the
addition of acetic anhydride (3.77 mL, 40 mmol) at room temper-
ature. After stirring for 20 min, the reaction was quenched with a
saturated solution of aqueous NaHCO3 and the solvent was
removed in vacuo. The residue was dissolved in EtOAc and the
organic solution was washed with brine, dried over MgSO4, and
evaporated under reduced pressure to afford the desired product 15
References
a) T. Ueno, T. Nakashima, Y. Hayashi, H. Fukami, Agric.
1
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in 94% yield (4.98 g). Oil; IR (neat): 3344, 3033, 2951, 1723,
¹1
1603, 1530, 1455, 1366, 1247, 1138, 1038, 993, 741, 698 cm
;
1H NMR (300 MHz, CDCl3): ¤ 1.53-1.66 (m, 4H), 2.02 (s, 3H),
3.17-3.23 (m, 2H), 4.03-4.14 (m, 2H), 5.07 (s, 2H), 5.08 (br, 1H),
7.33 (br, 5H). HRMS (FAB+) (M+ + 1): Found: m/z 266.1393.
Calcd for C14H20NO4: 266.1392.
4-(N-Boc-N-Z-amino)-1-butyl Acetate (16). To a solution of
15 (4.98 g, 18.7 mmol) in dry THF (15 mL) was added a solution
of a catalytic amount of DMAP in dry THF (5 mL) at 0 °C
followed by the addition of a solution of Boc2O (6.22 g,
28.5 mmol) in dry THF at that temperature. The solution was
allowed to stand overnight at room temperature. After evaporation
of the solvent, the residue was partitioned between EtOAc and
water. The organic solution was washed with brine, dried over
MgSO4, and concentrated under reduced pressure to give com-
pound 16 in 81% yield (5.58 g). Oil; IR (neat): 2978, 1792, 1739,
1697, 1609, 1587, 1550, 1498, 1475, 1369, 1290, 1240, 1202,
1100, 1072, 852, 780, 753, 700 cm¹1; 1H NMR (300 MHz, CDCl3):
¤ 1.47 (s, 9H), 1.61-1.66 (br, 4H), 2.02 (s, 3H), 3.67 (t, J =
6.83 Hz, 2H), 4.04 (t, J = 6.10 Hz, 2H), 5.22 (s, 2H), 7.32-7.40
(m, 5H). HRMS (FAB+) (M+ + 1): Found: m/z 366.1916. Calcd
for C19H28NO6: 366.1916.
2
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3
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4-(N-Boc-N-Z-amino)-1-butanol (17).
Compound 16
(1.120 g, 3.07 mmol) was dissolved in 0.5 M HCl in MeOH
(63 mL) at 0 °C. The solution was gradually warmed to room
temperature and allowed to stand overnight. After neutralization
with a saturatated solution of NaHCO3 at 0 °C, the MeOH was
removed in vacuo to afford a residue, which was extracted with
EtOAc. The EtOAc solution was washed with brine, dried over
MgSO4, and evaporated in vacuo to give a residue, which was
subjected to silica gel column chromatography (eluent; hexane/
EtOAc = 1/1, v/v) giving the product 17 (765 mg, 77%). Oil; IR
(neat): 3487, 2977, 2938, 2870, 1782, 1736, 1455, 1369, 1294,
1253, 1119, 1065, 1030, 751 cm¹1; 1H NMR (300 MHz, CDCl3): ¤
1.47 (s, 9H), 1.51-1.68 (m, 4H), 2.02 (br, 1H), 3.59-3.69 (m, 4H),
5.21 (s, 2H), 7.31-7.38 (m, 5H). HRMS (FAB+) (M+ + 1): Found:
m/z 324.1811. Calcd for C17H26NO5: 324.1811.
Isomerization of the (E)-N-Boc-¡,¢-didehydroamino Acid
Methyl Ester 1 to the Corresponding Z Isomer 1¤ by Iodine.
To a solution of 1a (41 mg, 0.19 mmol) in dry THF (2 mL) was
added a catalytic amount of iodine at room temperature under N2.
The solution was stirred for 19 h at that temperature and quenched
with a saturated solution of NaHSO3. The solvent was removed in
vacuo to afford the residue, which was extracted with EtOAc. The
organic solution was washed with brine, dried over MgSO4, and
concentrated in vacuo to give a residue, which was subjected to
preparative TLC (SiO2, hexane/EtOAc = 4/1, v/v) to afford Z
isomer, 1a¤ (35 mg) and E isomer, 1a (<2 mg).
4
1605.
5
T. Nagano, H. Kinoshita, Bull. Chem. Soc. Jpn. 2000, 73,
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7
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9
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