A new synthetic method for the preparation of α,β-didehydroamino acid derivatives by means of a wittig-type reaction. Syntheses of (2S, 4S)- and (2R, 4R)-4-hydroxyprolines

Article abstract of DOI:10.1246/bcsj.75.2517

Ethyl N-Boc- and N-Z-α-tosylglycinates were reacted with a variety of aldehydes in the presence of tributylphosphine and a base to afford the corresponding α,β-didehydroamino acid derivatives with high (Z)-selectivity in good yields. Moreover, ethyl (4S)- and (4R)-2-(N-Boc-amino)-4,5-isopropylidenedioxy-2-pentenoates prepared by the present method were converted to (2S, 4S)- and (2R, 4R)-4-hydroxyprolines, respectively.

Full text of DOI:10.1246/bcsj.75.2517

c. Jpn.
© 2002 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 75, 2517–2525 (2002) 2517
e Chemical
ciety of Ja-
n
e Chemical
ciety of Ja-
n
α β
A New Synthetic Method for the Preparation of , -Didehydroamino
Acid Derivatives by Means of a Wittig-Type Reaction. Syntheses of
(2S, 4S)- and (2R, 4R)-4-Hydroxyprolines
Synthesis of Dehydroamino Acid
R. Kimura et al.
02
17
Rumi Kimura, Tanemasa Nagano, and Hideki Kinoshita*
25
Department of Chemistry, Faculty of Science, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192
(Received June 12, 2002)
SJA8
09-2673
163
Ethyl N-Boc- and N-Z-α-tosylglycinates were reacted with a variety of aldehydes in the presence of tributylphos-
phine and a base to afford the corresponding α,β-didehydroamino acid derivatives with high (Z)-selectivity in good
yields. Moreover, ethyl (4S)- and (4R)-2-(N-Boc-amino)-4,5-isopropylidenedioxy-2-pentenoates prepared by the present
method were converted to (2S, 4S)- and (2R, 4R)-4-hydroxyprolines, respectively.
02
02
.4
Increasing interest in α,β-didehydroamino acids has devel-
oped in recent years based both on their importance as chemi-
cal products and on their existence in biologically active natu-
ral products.1a–g Many reports related to the preparation of
α,β-didehydroamino acids have been published.2a–i Moreover,
intensive studies on the asymmetric hydrogenation of α,β-di-
dehydroamino acid derivatives have also been established
since they would provide a quite efficient route to optically ac-
tive usual and unusual amino acid derivatives,3a–d which are
widely used in various fields. Therefore, the development of a
new and effective method for the preparation of α,β-didehy-
droamino acid derivatives is one of the important and attractive
subjects in organic chemistry.
In previous papers, we reported that 3,4-disubstituted 5-to-
syl-1,5-dihydro-2H-pyrrole-2-one reacted with 2-formyl pyr-
roles in the presence of tributylphosphine (Bu3P) and a base to
afford the corresponding C/D ring component of phycobi-
lins,4a–c and ethyl N-t-butoxycarbonyl (Boc)- and N-benzylox-
ycarbonyl (Z)-α-tosylglycinates (1a and 1b) were reacted with
a variety of nitro compounds in the presence of a base to afford
the corresponding α,β-didehydroamino acid derivatives with
high (Z)-selectivity in good yields.5
carried out in toluene in the presence of 2.0 molar amounts of
tetraethyl orthotitanate [Ti(OEt)4], the yield of 6a could be im-
proved up to 70% yield (Entry 6). With 4-nitrobutanal (13)
bearing both nitro- and aldehyde groups, only the aldehyde
group reacted with 1a chemoselectively to provide 7a in good
yield (Entry 7). Furthermore, the reaction of 1a with N,Nꢀ,Nꢁ-
protected 3-guanidinopropanal (14) underwent very smoothly
at 60 °C for 1.5 h under the same reaction conditions to afford
the desired product 8a as a single isomer with (Z)-configura-
tion in good yield.
Similarly, the reaction of 1a with 1-Z-indole-3-carboxalde-
hyde (15), 1-Boc-indole-3-carboxaldehyde (16), and 1-Boc-
Imidazole-4-carboxaldehyde (17) afforded the corresponding
9a, 10a, and 11a with only the (Z)-configuration in good
yields, respectively (Entries 9–11). With (R)-isopropylideneg-
lyceraldehyde,6 compound 12a with predominantly the (Z)-
configuration (Z/E = 95/5 ) was obtained in 94% yield (Entry
12). In the same way, a variety of α,β-didehydroamino acid
derivatives 2b–11b were successfully synthesized by the reac-
tion of 1b and various aldehydes in good yields, respectively
(except for Entry 19).
Although the precise mechanism of the present coupling re-
action is still an open question, one possible reaction pathway
is shown in Scheme 1. Initially, the Schiff base was generated
from 1a or 1b and Na2CO3; a subsequent addition of the Bu3P
to the resulting base resulted in the formation of the ylide,
which was reacted with aldehyde and converted into a four-
In this paper, we now wish to report on a new method for
preparing α,β-didehydroamino acid derivatives starting from
1a or 1b and a variety of aldehydes in the presence of Bu3P
and a base. The results are summarized in Table 1.
First, compound 1a was treated with 2.0 molar amounts of
acetaldehyde in the presence of 1.5 molar amounts of Bu3P, 1.2
molar amounts of sodium carbonate, and a catalytic amount of
tetrabutylammonium bromide in THF at room temperature to
afford the desired ethyl 2-(N-Boc)amino-2-butenoate (2a) as a
mixture of (Z)- and (E)-isomers in 96% yield, in which the (Z)-
isomer was predominantly formed (Entry 1). The reaction of
1a with simple aldehydes succeeded in the formation of a vari-
ety of N-Boc-α,β-didehydroamino acid derivatives (3a, 4a,
and 5a) in satisfactory yields, respectively (Entries 2–4). Upon
the treatment of 1a with p-methoxybenzaldehyde, 6a was ob-
tained in unsatisfactory yield (Entry 5). When the reaction was
membered cyclic intermediate.
Finally, elimination of
Bu3PwO through transition state T2 with less steric repulsion
than that of transition state T1 occurred to provide a product
with predominantly the (Z)-configuration.
In the past, it had been reported that (2S, 4S)-4-hydroxypro-
line (28a) has biological activities,7a–c and that 28a and 28b8
are also useful as chiral building blocks for the syntheses of a
variety of valuable substances. Concerning synthetic studies
of 28, the interconversion of (2S, 4R)-4-hydroxyproline and its
enantiomer to 28 has been positively developed;9a–c however,
there are only a few reports concerning asymmetric synthesis,

2518 Bull. Chem. Soc. Jpn., 75, No. 11 (2002)
Synthesis of Dehydroamino Acid
Table 1. Preparation of Dehydroamino Acid Derivatives
Entry
Substrate
R1
a
Temp
Time
Solvent
Product
Yield/%
Z/Ea)
1
2
3
1a
1a
1a
1a
1a
1a
1a
Me
Et
2.0
2.0
2.0
2.0
1.5
1.5
2.0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
overnight
overnight
48 h
overnight
24 h
THF
THF
THF
THF
THF
2a
3a
4a
5a
6a
6a
7a
96
82
84
79
55
70
84
89/11
90/10
93/7
100/0
86/14
89/11
89/11
iPr
4
Ph
5
p-MeOC6H4
p-MeOC6H4
O2N(CH2)3
6b)
7
24 h
48 h
PhCH3
THF
8
9c)
1a
1a
1a
2.0
3.0
3.0
60 °C
r.t.
1.5 h
67 h
67 h
THF
8a
9a
84
73
77
100/0
100/0
100/0
PhCH3
PhCH3
10c)
r.t.
10a
11
12
1a
1a
2.0
2.0
r.t.
r.t.
overnight
6 h
THF
THF
11a
12a
79
94
100/0
95/5
13
14
15
1b
1b
1b
1b
1b
1b
Me
Et
2.0
2.0
2.0
2.0
1.5
2.0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
overnight
overnight
48 h
overnight
24 h
THF
THF
THF
THF
PhCH3
THF
2b
3b
4b
5b
6b
7b
78
79
76
71
77
73
85/15
90/10
84/16
100/0
93/7
iPr
16
Ph
17b)
18
p-MeOC6H4
O2N(CH2)3
48 h
90/10
19
20
1b
1b
1b
2.0
2.0
3.0
r.t.
60 °C
r.t.
70 h
1.5 h
67 h
THF
THF
8b
8b
9b
< 25
76
—
100/0
100/0
21c)
PhCH3
60
22c)
23
1b
1b
3.0
2.0
r.t.
r.t.
67 h
PhCH3
THF
10b
11b
77
85
100/0
100/0
overnight
a) Determined by NOE measurement. b) In cases of entries 6 and 17, 2.0 molar amounts of Ti(OEt)4 were added. c) In cases of
entries 9, 10, 21, and 22, 3.0 molar amounts of Ti(OEt)4 were added.
in which an α-amino acid derivative is used as the starting ma-
terial.10a,b We are thus interested in the asymmetric synthesis
of 28 using compound 12 (Scheme 2).
First, the hydrolysis of the isopropylidene protecting group
of 12a was carried out with 0.5 M HCl aq in ethanol at room
temperature overnight to afford the corresponding diol deriva-
tive 18a and a by-product 19a in 85% and 11% yields, respec-
tively. Subsequently, conversion of the diol compound 18a to
27a was attempted under Mitsunobu reaction conditions in
CH2Cl2. Unfortunately, only the epoxide derivative 20 was ob-
tained in 97% yield11 instead of the expected 27a. Therefore,
we examined the conversion of 18a to 23a and the following

R. Kimura et al.
Bull. Chem. Soc. Jpn., 75, No. 11 (2002) 2519
Scheme 1.
cyclization of 23a to compound 25a. Thus, in order to protect
the primary hydroxy group of 18a selectively, compound 18a
was treated with t-butylchlorodimethylsilane (TBDMS-Cl, 1.1
equiv) in the presence of 1.2 equivalents of triethylamine
(TEA) and a catalytic amount of 4-dimethylaminopyridine
(DMAP) in CH2Cl2. Compound 21a was obtained in 84%
yield, which was furthermore converted into compound 22a in
quantitative yield by protection of the secondary hydroxy
group by means of t-butylchlorodiphenylsilane (TBDPS-Cl,
1.2 equiv) and imidazole (3 equiv) in DMF. Deprotection of
the TBDMS group of 22a was easily achieved with 1.5 M HCl
aq in ethanol at room temperature for 2 h to give compound
23a in 98% yield. The cyclization reaction was crucially de-
pendent on the reaction temperature. Namely, when the cy-
clization of 23a to 25a was carried out at room temperature for
2 d using 2 equivalents of diethyl azodicarboxylate (DEAD)
and 2 equivalents of Ph3P in CH2Cl2, ethyl 2-pyrrolecarboxy-
late (24) was obtained exclusively in 52% yield, whereas the
reaction at 0 °C provided the desired product 25a in 61% yield,
which was subsequently hydrogenated over 5% Pd–C in etha-
nol under a hydrogen atmosphere. Consequently, hydrogena-
tion took place with over 99% diastereoselectivity to give the
desired (2S,4S)-4-hydroxyproline derivative 26a in quantita-
tive yield, whose recrystallization from hexane gave optically
pure 26a. The stereochemistry of 26a was determined by com-
paring the specific rotation value of compound 28a derived
from 26a with that of an authentic sample.12 Deprotection of
the TBDPS group of 26a with tetrabutylammonium fluoride
(TBAF) in THF afforded 27a in 91% yield. Subsequent hy-
drolysis of the ester group with lithium hydroxide, and depro-
tection of the N-Boc group with hydrogen chloride, followed
by neutralization with TEA, afforded optically pure 28a12 in
83% yield based on 27a.
In the same pathway as described for compound 28a, opti-
cally pure (2R,4R)-4-hydroxyproline (28b) was synthesized
starting from compound 12b, as shown in Scheme 2.
We developed a new method for preparing a variety of α,β-
didehydroamino acid derivatives starting from 1a or 1b and
various aldehydes by a Wittig-type reaction using Bu3P and a
base. Also, compounds 12a and 12b, prepared by the present
coupling method, proved to be useful as starting material for
the asymmetric syntheses of 4-hydroxyprolines, respectively.
Experimental
All of the melting points were determined with a micro melting
apparatus (Yanagimoto Seisakusho) and were uncorrected. The
1H NMR, IR, and MS spectra were recorded on JEOL JNM-LA
400FT (400 MHz) and LA 300FT (300 MHz) NMR spectrome-
ters, a JASCO FT/IR-230 infrared spectrometer, and a JEOL SX-
102A mass spectrometer, respectively. The chemical shifts of
NMR are reported in the δ-scale relative to TMS as an internal
standard. All of the solvents were distilled and stored over a dry-
ing agent. Thin-layer chromatography (TLC) and flash column
chromatography were performed using Merck’s silicagel 60 PF254
(Art. 7749) and Cica-merck’s silicagel 60 (No. 9385-5B), respec-
tively.
α β
A General Procedure for Synthesis of , -Didehydroamino
Acid Derivatives: To a solution of acetaldehyde (18 mg, 0.40
mmol), 1a (72 mg, 0.20 mmol), and Bu3P (61 mg, 0.30 mol) in
THF (5 mL) was added a mixture of Na2CO3 (26 mg, 0.24 mmol)
and Bu4N+Br− (cat.) at room temperature under a N2 atmosphere.
After the mixture was stirred at this temperature overnight, the
solvent was removed in vacuo to afford a residue, which was parti-
tioned between ethyl acetate and water. The aqueous layer was
extracted with ethyl acetate, and the combined extracts were
washed with brine, dried over anhydrous MgSO4, and concentrat-

2520 Bull. Chem. Soc. Jpn., 75, No. 11 (2002)
Synthesis of Dehydroamino Acid

R. Kimura et al.
Bull. Chem. Soc. Jpn., 75, No. 11 (2002) 2521
ed under reduced pressure. The residue was subjected to prepara-
tive TLC (SiO2, hexane:ethyl acetate = 5:1, v/v) to afford ethyl
2-(N-Boc-amino)-2-butenoate (2a); 44 mg, 96%: (Z)- and (E)-iso-
mers were separable.
The physical and spectral data of compounds 2a–6a and 2b–6b
were in agreement with those of products prepared previously.5
Those of prepared compounds 7a–12a and 7b–11b are given in
the following.
(Z/E = 100/0): Compound 10a was prepared from 1a and 1-
Boc-indole-3-carboxaldehyde (15) in the same way as described
for compound 9a. (Z)-form; Mp 125.0–126.0 °C (ethyl acetate-
hexane); IR (KBr) 3324, 2979, 1731, 1714, 1644, 1585, 1455,
1372, 1282, 1239, 1161, 1084, 1048, 918, 895, 842, 768 cm−1; 1H
NMR (400 MHz; CDCl3) δ 1.38 (t, J = 7.1 Hz, 3H), 1.45 (s, 9H),
1.68 (s, 9H), 4.33 (q, J = 7.1 Hz, 2H), 6.10–6.30 (br, 1H), 7.27–
7.40 (m, 1H + 1H), 7.57 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.93 (s,
1H), 8.15 (d, J = 8.1 Hz, 1H). Found: C, 64.00; H, 7.14;
N,6.11%. Calcd for C23H30N2O6: C, 64.17; H, 7.14; N, 6.11%.
When the proton at the 2-position of the indole ring was irradiat-
ed, 3.6% and 2.2% of NOE were observed for the NH proton and
the olefinic proton, respectively. When the olefinic proton was ir-
radiated, 2.3% and 12.4% of NOE were observed for the proton at
the 2-position of the indole ring and the proton at the 4-position of
the indole ring, respectively.
Ethyl 2-(N-Boc-amino)-6-nitro-2-hexenoate (7a) (Z/E = 89/
11): A pale-yellow oil; IR of a mixture of isomers (neat) 3341,
2980, 2935, 1715, 1660, 1554, 1493, 1368, 1265, 1164, 1096,
1048, 1029, 860, 777 cm−1; (Z)-form; 1H NMR (400 MHz;
CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H), 1.47 (s, 9H), 2.21 (quintet, J =
7.1 Hz, 2H), 2.33 (dt, J = 7.1, 7.3 Hz, 2H), 4.24 (q, J = 7.1 Hz,
2H), 4.42 (t, J = 7.1 Hz, 2H), 6.10–6.20 (br, 1H), 6.45 (t, J =
7.3 Hz, 1H); When γ-methylene protons were irradiated, 2.3% and
9.3% of NOE were observed for the NH proton and the olefinic
α
im
α β
Ethyl N -Boc-N -Boc- , -didehydrohistidinate (11a) (Z/E
= 100/0): Compound 11a was prepared from 1a and 1-Boc-imi-
dazole-4-carboxaldehyde (16). (Z)-form; An oil; IR (neat) 3289,
2979, 2930, 1758, 1717, 1652, 1557, 1507, 1457, 1372, 1253,
1152, 1065, 1013, 910, 839, 771, 745 cm−1; 1H NMR (400 MHz;
CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 1.49 (s, 9H), 1.62 (s, 9H), 4.30
(q, J = 7.1 Hz, 2H), 6.43 (s, 1H), 7.38 (s, 1H), 8.09 (s, 1H), 7.91
(s, 1H), 8.96-9.06 (br, 1H). When tBu protons of the Boc group of
the imidazole ring were irradiated, 6.4% of NOE was observed for
1
proton, respectively. (E)-form; H NMR (400 MHz; CDCl3) δ
1.34 (t, J = 7.1 Hz, 3H), 1.47 (s, 9H), 2.20 (quintet, J = 7.1 Hz,
2H), 2.67 (dt, J = 7.1, 7.3 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 4.42
(t, J = 7.1 Hz, 2H), 6.65–6.75 (m, 1H + 1H). EI-MS m/z 302
(M+; 0.6%).
α
α β
Ethyl N -Boc-Nꢀ-benzyl-Nꢀ,Nꢁ,Nꢁꢀ-tris(Boc)- , -didehydro-
argininate (8a) (Z/E = 100/0): (Z)-form; An oil; IR (neat)
3345, 2979, 2932, 1731, 1713, 1659, 1496, 1455, 1371, 1245,
1
t
1134, 1078, 1047, 977, 918, 854, 813, 767, 732, 701 cm−1; H
the Bu protons of the Nα-Boc group. EI-MS m/z 381 (M+;
NMR (400 MHz; CDCl3) δ 1.28 (t, J = 7.1Hz, 3H), 1.37 (s, 9H),
1.46 (s, 9H + 9H), 1.50 (s, 9H), 2.43 (dt, J = 6.8, 7.3 Hz, 2H),
3.41 (t, J = 6.8 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 4.83 (s, 2H),
6.26 (t, J = 7.3 Hz, 1H), 6.40–6.60 (br, 1H), 7.22–7.40 (m, 5H).
When γ-methylene protons were irradiated, 4.0% and 11.8% of
NOE were observed for the NH proton and the olefinic proton, re-
12.4%).
Ethyl (4S)-2-(N-Boc-amino)-4,5-isopropylidenedioxy-2-pen-
tenoate (12a) (Z/E = 95/5): Recrystallization from hexane
gave pure Z-isomer. (Z)-form; Mp 81.9–83.0 °C (hexane); [α]2D5
=
−11.4 ° (c 0.77, CHCl3); IR (KBr) 3329, 2983, 2936, 1730, 1715,
1666, 1504, 1455, 1370, 1318, 1247, 1160, 1057, 1030, 849,
spectively. EI-MS m/z 690 (M+; 19.9%).
771 cm−1; (Z)-form; H NMR (400 MHz; CDCl3) δ 1.32 (t, J =
1
α
α β
Ethyl N -Boc-Nꢀ-Z- , -didehydrotryptophanate (9a) (Z/E
7.1 Hz, 3H), 1.39 (s, 3H), 1.45 (s, 9H), 1.47 (s, 3H), 3.84 (dd, J =
6.6, 8.5 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.34 (dd, J = 6.6,
8.5 Hz, 1H), 4.84 (ddd, J = 6.6, 8.1, 8.5 Hz, 1H), 6.39 (d, J =
8.1 Hz, 1H), 6.30–6.50 (br, 1H). When the γ-methine proton of
the major product was irradiated, 1.5% and 3.6% of NOE were
observed for the NH proton and the olefinic proton, respectively.
Found: C, 57.02; H, 8.19; N, 4.35%. Calcd for C15H25NO6: C,
57.13; H, 7.99; N, 4.44%. (E)-form; 1H NMR (400 MHz; CDCl3)
δ 1.32 (t, J = 7.1 Hz, 3H), 1.39 (s, 3H), 1.45 (s, 9H), 1.47 (s, 3H),
3.63–3.70 (m, 1H), 4.20–4.35 (m, 2H + 1H), 5.30–5.38 (m, 1H),
6.74–6.87 (m, 1H). A mixture of 12a could be used in a subse-
quent reaction without recrystallization.
= 100/0): To a solution of Ti(OEt)4 (68 mg, 0.30 mmol) in tolu-
ene (5 mL) was added a suspension of Bu3P (61 mg, 0.30 mmol),
1-Z-indole-3-carboxaldehyde (14) (90 mg, 0.3 mmol), Na2CO3
(26 mg, 0.24 mmol), and Bu4N+Br− (cat.) in toluene (2 mL) at
room temperature under a N2 atmosphere; the mixture was stirred
for 67 h. Then, after the addition of a saturated aqueous solution
of NaHCO3 to the reaction mixture, an insoluble substance was
filtered and washed with ethyl acetate. The filtrate was concen-
trated in vacuo to afford a residue, which was partitioned between
ethyl acetate and water. The aqueous layer was extracted with eth-
yl acetate, and the combined extracts were washed with brine,
dried over anhydrous MgSO4, and concentrated under reduced
pressure. The residue was subjected to preparative TLC (SiO2,
hexane:ethyl acetate = 5:1, v/v) to afford 9a in 73% yield
(102 mg): An oil ; IR (neat) 3329, 2979, 2933, 1731, 1707, 1642,
Ethyl 2-(N-Z-Amino)-6-nitro-2-hexenoate (7b) (Z/E = 90/
10): An oil; IR of a mixture of isomers (neat) 3320, 3065, 3033,
2981, 1707, 1660, 1549, 1499, 1455, 1378, 1227, 1149, 1097,
1049, 905, 864, 772, 753, 699 cm−1; (Z)-form; 1H NMR
(400 MHz; CDCl3) δ 1.30 (t, J = 7.1 Hz, 3H), 2.23 (quintet, J =
6.8 Hz, 2H), 2.33 (dt, J = 6.8 Hz, 7.3 Hz, 2H), 4.22 (q, J =
7.1 Hz, 2H), 4.38 (t, J = 6.8 Hz, 2H), 5.14 (s, 2H), 6.30–6.40 (br,
1H), 6.53 (t, J = 7.3 Hz, 1H), 7.30–7.38 (m, 5H). When γ-methyl
protons were irradiated, 2.1% and 9.0% of NOE were observed
for the NH proton and the olefinic proton, respectively. (E)-form;
1H NMR (400 MHz; CDCl3) δ 1.33 (t, J = 7.1 Hz), 2.19 (quintet,
J = 6.8 Hz, 2H), 2.69 (dt, J = 6.8, 7.3 Hz, 2H), 4.28 (q, J = 7.1
Hz, 2H), 4.42 (t, J = 6.8 Hz, 2H), 5.14 (s, 2H), 6.80 (t, J = 7.3
Hz, 1H), 6.90–7.00 (br, 1H), 7.30–7.40 (m, 5H). EI-MS m/z 336
1485, 1456, 1393, 1367, 1244, 1163, 1087, 1047, 1028, 759 cm−1
;
1H NMR (400 MHz; CDCl3) δ 1.37 (t, J = 7.1 Hz, 3H), 1.37 (s,
9H), 4.32 (q, J = 7.1 Hz, 2H), 5.46 (s, 2H), 6.20–6.30 (br, 1H),
7.27–7.50 (m, 5H + 2H), 7.56 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H),
7.91 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H). When the proton at the 2-
position of the indole ring was irradiated, 3.8% and 1.3% of NOE
were observed for the NH proton and the olefinic proton, respec-
tively. When the olefinic proton was irradiated, 1.8% and 12.9%
of NOE were observed for the proton at the 2-position of the in-
dole ring and the proton at the 4-position of the indole ring, re-
spectively. EI-MS m/z 464 (M+; 3.0%).
(M+; 1.1%).
α
α
in
α β
Ethyl N -Boc-N -Boc- , -didehydrotryptophanate (10a)
α β
Ethyl N -Z-Nꢁ-Benzyl-Nꢀ,Nꢁ,Nꢁꢀ-tris(Boc)- , -didehydro-

2522 Bull. Chem. Soc. Jpn., 75, No. 11 (2002)
Synthesis of Dehydroamino Acid
argininate (8b) (Z/E = 100/0): (Z)-form; An oil; IR (neat)
was obtained in 47% yield (56 mg). IR (neat) 2935, 1720, 1548,
1436, 1381, 1271, 1221, 1077, 988, 947, 872, 830, 759 cm−1; 1H
NMR (400 MHz; CDCl3) δ 2.31 (quintet, J = 6.8 Hz, 2H), 2.68
(t, J = 6.8 Hz, 2H), 4.47 (t, J = 6.8 Hz, 2H), 9.80 (S, 1H).
3-[Nꢁ-Benzyl-Nꢀ,Nꢁ,Nꢁꢀ-tris(Boc)guanidino]-1-propanal
(14): To a solution of Nꢀ,Nꢁ,Nꢁꢀ-tris(Boc)guanidine (3.769 g,
10.49 mmol),13 Ph3P (4.126 g, 15.73 mmol), and benzyl alcohol
(1.699 g, 15.73 mmol) in dry toluene (20 mL) was slowly added
DEAD (2.740 g, 15.73 mmol, 40% toluene solution) at room tem-
perature under a N2 atmosphere. The solution was warmed at 60
°C for 2 h and evaporated under reduced pressure to give a resi-
due, which was treated with CH3OH. An insoluble substance was
filtered and the filtrate was concentrated in vacuo. The residual oil
was purified by silica-gel column chromatography (eluent,
hexane:ethyl acetate = 20:1 v/v) to give Nꢁ-benzyl-Nꢀ,Nꢁ,Nꢁꢀ-
tris(Boc)guanidine in 81% yield (a pale yellow oil, 3.832 g). IR
(neat) 3240, 2970, 2931, 1718, 1655, 1458, 1076, 980, 948, 855,
700 cm−1; 1H NMR (400 MHz; CDCl3) δ 1.33 (s, 9H), 1.49 (s, 9H
+ 9H), 5.02 (s, 2H), 7.20–7.40 (m, 5H), 10.6–10.70 (br, 1H); EI-
MS m/z 449 (M+; 3.6%).
3331, 2979, 2934, 1731, 1715, 1651, 1498, 1455, 1369, 1247,
1
1141, 1078, 1050, 978, 916, 854, 813, 734, 699 cm−1; H NMR
(400 MHz; CDCl3) δ 1.28 (t, J = 7.1 Hz, 3H), 1.36 (s, 9H), 1.44
(s, 9H), 1.47 (s, 9H), 2.30 (dt, J = 6.8, 7.3 Hz, 2H), 3.43 (t, J =
6.8 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 4.82 (s, 2H), 5.14 (s, 2H),
6.37 (t, J = 7.3 Hz, 1H), 6.80–6.90 (br, 1H), 7.20–7.40 (m, 5H +
5H). When the γ-methylene protons were irradiated, 5.7% and
12.4% of NOE were observed for the NH proton and the olefinic
proton, respectively. EI-MS m/z 724 (M+; 6.6%)
α
in
α β
Ethyl N -Z-N -Z- , -Didehydrotryptophanate (9b) (Z/E =
100/0): Compound 9b was prepared from 1b and 1-Z-indole-3-
carboxaldehyde (14) in the same way as described for compound
9a. (Z)-form; Mp 91.0–92.0 °C (ethyl acetate-hexane); IR (KBr)
3313, 2929, 2853, 1738, 1715, 1643, 1586, 1498, 1455, 1394,
1
1308, 1245, 1141, 1088, 757, 698 cm−1; H NMR (400 MHz;
CDCl3) δ 1.33 (t, J = 7.1 Hz, 3H), 4.29 (q, J = 7.1 Hz, 2H), 5.15
(s, 2H), 5.44 (s, 2H), 6.36–6.44 (br, 1H), 7.30–7.41 (m, 5H + 5H
+ 2H), 7.61 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 8.17
(d, J = 8.1 Hz, 1H). When the proton at the 2-position of the in-
dole ring was irradiated, 4.1% and 2.5% of NOE were observed
for the NH proton and the olefinic proton, respectively. When the
olefinic proton was irradiated, 2.6% and 11.9% of NOE were ob-
served for the proton at the 2-position of the indole ring and the
proton at the 4-position of the indole ring, respectively. Found: C,
69.58; H, 5.28; N, 5.39%. Calcd for C29H26N2O6: C, 69.87; H,
5.26; N, 5.62%.
To a solution of the foregoing Nꢁ-benzyl-Nꢀ,Nꢁ,Nꢁꢀ-tris-
(Boc)guanidine (5.008 g, 11.14 mmol), PPh3 (5.843 g, 22.28
mmol), and 1,3-propanediol (2.050 g, 22.28 mmol) in dry toluene
(20 mL) was slowly added DEAD (7.760 g, 44.56 mmol, 40% tol-
uene solution) with vigorous stirring at room temperature under a
N2 atmosphere. The solution was warmed at 60 °C for 4 h and
evaporated under reduced pressure. The residue was treated with
ether, and an insoluble substance was filtered. Evaporation of the
filtrate and purification of the residual oil by silica-gel column
chromatography (eluent, hexane:ethyl acetate = 5:1, v/v) gave
the desired alcohol derivative in 60% yield (a pale-yellow oil,
3.390 g); IR (neat) 3504, 2977, 2934, 1737, 1654, 1476, 1368,
α
in
α β
Ethyl N -Z-N -Boc- , -didehydrotryptophanate (10b) (Z/E
= 100/0): Compound 10b was prepared from 1b and 1-Boc-in-
dole-3-carboxaldehyde (15) in the same way as described for
compound 9a. (Z)-form; An oil; IR (neat) 3036, 2927, 2933,
1732, 1706, 1642, 1545, 1497, 1455, 1370, 1329, 1308, 1251,
1153, 1088, 1052, 1027, 907, 861, 842, 747, 698 cm−1; 1H NMR
(400 MHz; CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 1.66 (s, 9H), 4.30
(q, J = 7.1 Hz, 2H), 5.15 (s, 2H), 6.25–6.40 (br, 1H), 7.28–7.50
(m, 5H + 2H), 7.65 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.95 (s, 1H),
8.19 (d, J = 8.1 Hz, 1H). When the proton at the 2-position of the
indole ring was irradiated, 4.7% and 2.3% of NOE were observed
for the NH proton and the olefinic proton, respectively. When the
olefinic proton was irradiated, 2.5% and 12.0% of NOE were ob-
served for the proton at the 2-position of the indole ring and the
proton at the 4-position of the indole ring, respectively. EI-MS
m/z 464 (M+; 9.8%).
1247, 1140, 1078, 977, 854, 815, 765, 700 cm−1 1H NMR
;
(400 MHz; CDCl3) δ 1.39 (s, 9H), 1.49 (s, 9H + 9H), 1.66 (tt, J =
5.6, 6.3 Hz, 2H), 3.38 (t, J = 6.3 Hz, 2H), 3.51 (t, J = 5.6 Hz,
2H), 4.82 (s, 2H), 7.22–7.40 (m, 5H). The proton of OH group
was not assigned. EI-MS m/z 507 (M+; 3.6%).
To a mixture of pyridinium chlorochromate (80 mg, 0.37 mmol)
and finely powdered molecular sieves 3A (185 mg) was added a
solution of the foregoing propanol derivative (127 mg, 0.25 mmol)
in dry CH2Cl2 (1 mL) at room temperature under a N2 atmosphere,
and the mixture was stirred for 2.5 h at this temperature. The sol-
vent was removed in vacuo to afford a residue, which was triturat-
ed with ether. An insoluble substance was filtered and the filtrate
was concentrated in vacuo. The resulting residue was purified by
silica-gel column chromatography (eluent, hexane:ethyl acetate =
4:1, v/v) to afford the product 14 in 68% yield (a pale-yellow oil,
86 mg); IR (neat) 2979, 2934, 1792, 1731, 1645, 1497, 1477,
1368, 1249, 1130, 1077, 977, 854, 814, 768, 701 cm−1; 1H NMR
(400 MHz; CDCl3) δ 1.37 (s, 9H), 1.46 (s, 9H), 1.50 (s, 9H), 2.64
(t, J = 7.0 Hz, 2H), 3.62 (t, J = 7.0 Hz, 2H), 4.87 (s, 2H), 7.20-
7.40 (m, 5H), 9.62 (s, 1H); EI-MS m/z 505 (M+; 9.6%).
α
im
α β
Ethyl N -Z-N -Boc- , -didehydrohistidinate (11b) (Z/E =
100/0): (Z)-form; An oil; IR (neat) 3274, 2982, 2943, 2917,
1766, 1732, 1652, 1555, 1473, 1371, 1253, 1149, 1061, 1014,
910, 840, 731 cm−1; H NMR (400 MHz; CDCl3) δ 1.29 (t, J =
1
7.1 Hz, 3H), 1.62 (s, 9H), 4.27 (q, J = 7.1 Hz, 2H), 5.18 (s, 2H),
6.46 (s, 1H), 7.30–7.40 (m, 5H + 1H), 8.06 (s, 1H), 9.42–9.48 (br,
t
1H). When Bu protons of the Boc group of the imidazole ring
were irradiated, 2.1% of NOE was observed for the benzylic pro-
tons of the Z-group. EI-MS m/z 415 (M+; 21.6%).
4-Nitrobutanal (13): To a suspension of pyridinium chloro-
chromate (405 mg, 2. 00 mmol) and molecular sieves 4A (1.00 g)
in 5 mL of CH2Cl2 was added a solution of 4-nitro-1-butanol
(119 mg, 1.0 mmol)5 in 0.3 mL of acetone at room temperature
with vigorous stirring. After 1 h the solvent was removed in vacuo
and the residue was triturated with ether. An insoluble substance
was filtered off and the filtrate was concentrated under reduced
pressure to afford a residue, which was subjected to preparative
TLC (SiO2; hexane:ethyl acetate = 2:1, v/v). An oily product
1-Z-Indole-3-carboxaldehyde (15): To a solid of indole-3-
carboxaldehyde (5.760 g, 40 mmol) placed in a flask was added a
solution of Na2CO3 (9.328 g, 88 mmol) in 88 mL of water, fol-
lowed by the addition of 50 mL of CH3CN, including a catalytic
amount of DMAP. Then, to the vigorously stirred solution was
dropwise added Z-Cl (6.823 g, 40 mmol) at room temperature un-
der an air atmosphere; the solution was allowed to be stirred for
24 h. After dilution with a large amount of water, the mixture was
extracted with ethyl acetate several times. The ethyl acetate solu-

R. Kimura et al.
Bull. Chem. Soc. Jpn., 75, No. 11 (2002) 2523
tion was washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure to afford the product in quan-
titative yield (11.161 g); mp 47.0–48.0 °C (ethyl acetate–hexane);
IR (KBr) 3141, 2822, 1753, 1608, 1546, 1454, 1402, 1376, 1346,
1264, 1230, 1167, 1125, 1095, 1043, 1031, 1015, 972, 781, 757,
732, 707, 691 cm−1; 1H NMR (400 MHz; CDCl3) δ 5.51 (s, 2H),
7.30–7.60 (m, 5H + 1H + 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.27
(s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 10.09 (s, 1H). Found: C, 73.23;
H, 4.72; N, 4.95%. Calcd for C17H13NO3: C, 73.11; H; 4.69; N,
5.02%.
hexane:ethyl acetate = 2:1, v/v) to afford 18a in 85% yield
(327 mg). Mp 67.0–68.0 °C (ethyl acetate–hexane); [α]2D5
=
+18.9 ° (c 0.15, CHCl3); IR (KBr) 3311, 2981, 2935, 1718, 1508,
1369, 1160, 1029, 857, 779 cm−1; 1H NMR (400 MHz; CDCl3) δ
1.32 (t, J = 7.1 Hz, 3H), 1.46 (s, 9H), 2.02-2.12 (br, 1H), 2.70–
2.80 (br, 1H), 3.63 (dd, J = 6.6, 11.2 Hz, 1H), 3.70 (dd, J = 3.9,
11.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.49 (ddd, J = 3.9, 6.6,
9.5 Hz, 1H), 6.37 (d, J = 9.5 Hz, 1H), 6.80–7.00 (br, 1H); Found:
C, 52.16; H, 7.73; N, 4.88%. Calcd for C12H21NO6: C, 52.35; H,
7.69; N, 5.09%.
1-Boc-Indole-3-carboxaldehyde (16): In the same way as
described for the preparation of 15 using di-t-butyl dicarbonate,
16 was obtained in quantitative yield. Mp 117.0–118.0 °C (ethyl
acetate–hexane); IR (KBr) 3002, 2814, 1742, 1678, 1558, 1482,
1472, 1398, 1359, 1330, 1309, 1277, 1242, 1157, 1102, 1046,
Ethyl 2-(N-Boc-amino)-4,5-epoxy-2-pentenoate (20): To a
solution of compound 18a (73 mg, 0.265 mmol) and Ph3P
(104 mg, 0.40 mmol) in dry CH2Cl2 (7 mL) was dropwise added a
solution of DEAD (70 mg, 0.40 mmol, 40% toluene solution) in
dry CH2Cl2 (2 mL) at room temperature under a N2 atmosphere;
the solution was stirred for 30 min. Then, the solvent was re-
moved in vacuo to afford a residue, which was partitioned be-
tween ethyl acetate and water. The aqueous layer was extracted
with ethyl acetate. The ethyl acetate solution was washed with
brine, dried over MgSO4, and concentrated under reduced pres-
sure. The residual oil was subjected to preparative TLC (SiO2,
hexane:ethyl acetate = 2:1, v/v) to afford the epoxide derivative
20 in 97% yield (an oil, 66 mg). IR (neat) 3340, 2980, 2934,
2871, 1731, 1714, 1505, 1392, 1368, 1257, 1161, 1102, 1075,
1024, 847, 780, 697 cm−1; 1H NMR (300 MHz; CDCl3) δ 1.28 (t,
J = 7.2 Hz, 3H), 1.44 (s, 9H), 4.21 (q, J = 7.2 Hz, 2H), 4.74–4.90
(m, 2H), 5.73–5.77 (m, 1H), 6.30 (d, J = 6.1 Hz, 1H), 6.40–6.62
(br, 1H); EI-MS m/z 257 (M+; 1.2%)
1
839, 786, 759, 668 cm−1; H NMR (400 MHz; CDCl3) δ 1.71 (s,
9H), 7.35-7.45 (m, 1H + 1H), 8.15 (d, J = 8.1 Hz, 1H), 8.23 (s,
1H), 8.29 (d, J = 8.1 Hz, 1H), 10.11 (s, 1H). Found: C, 68.62; H,
6.14; N, 5.65%. Calcd for C14H15NO3: C, 68.55; H, 6.36; N,
5.71%.
1-Boc-imidazole-4-carboxaldehyde (17): To a solid of 4-
(hydroxymethyl)- imidazole hydrochloride (135 mg, 1.00 mmol)
was added a solution of Na2CO3 (117 mg, 1.10 mmol) in water
(2 mL), followed by the addition of a solution of a catalytic
amount of DMAP in THF (2 mL). A solution of di-t-butyl dicar-
bonate (240 mg, 1.1 mmol) in THF (3 mL) was slowly added to
the above-mentioned solution. After the solution was allowed to
stand overnight with vigorous stirring, and follwing the addition
of water, the mixture was extracted with ethyl acetate a couple of
times. The combined extracts were washed with brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure. To
a solution of oxalyl chloride (254 mg, 2.00 mmol) in dry CH2Cl2
(5 mL) was added 0.22 mL of dimethyl sulfoxide (DMSO,
3.00 mmol) at −78 °C under a N2 atmosphere; the solution was
kept at this temperature for 15 min. A solution of the foregoing
crude imidazole derivative in dry CH2Cl2 (3 mL) was added to the
above solution at −78 °C. After 15 min the mixture was gradually
warmed to room temperature and concentrated in vacuo to give a
residue, which was partitioned between ethyl acetate and water.
The aqueous layer was extracted with ethyl acetate. The com-
bined extracts were washed with brine, dried over anhydrous
MgSO4, and concentrated in vacuo. The residual oil was subject-
ed to silica-gel column chromatography (eluent, hexane:ethyl ace-
tate = 2:1, v/v) to give the product in 47% yield (a pale-yellow
crystalline, 202 mg); mp 80.0–81.0 °C (ethyl acetate–hexane); IR
(KBr) 3134, 3115, 3061, 2996, 2938, 1751, 1698, 1540, 1493,
1462, 1402, 1378, 1315, 1281, 1263, 1228, 1160, 1120, 1049,
Ethyl (4S)-2-(N-Boc-amino)-5- t - butyldimethylsiloxy- 4 -
hydroxy-2-pentenoate (21a): To a mixed solution of 18a
(440 mg, 1.60 mmol), TBDMS-Cl (270 mg, 1.8 mmol), and
DMAP (20 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added TEA
(202 mg, 2.00 mmol) at room temperature under a N2 atmosphere.
The solution was stirred at this temperature overnight. The sol-
vent was removed in vacuo to afford a residue, which was parti-
tioned between ethyl acetate and water. The aqueous layer was
extracted with ethyl acetate, and the combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concentrat-
ed in vacuo. The residue was purified by column chromatography
on silica gel (SiO2, hexane:ethyl acetate = 4:1, v/v) to afford 21a
in 84% yield (a pale-yellow oil, 843 mg). [α]2D5 = +15.2 ° (c 1.55,
CHCl3); IR (neat) 3394, 2955, 2930, 2858, 1730, 1661, 1473,
1392, 1368, 1320, 1254, 1164, 1112, 1050, 838, 779, 669 cm−1
;
1H NMR (400 MHz; CDCl3) δ 0.09 (s, 3H + 3H), 0.90 (s, 9H),
1.31 (t, J = 7.1 Hz, 3H), 1.46 (s, 9H), 3.34–3.46 (br, 1H), 3.69
(dd, J = 8.5, 9.3 Hz, 1H), 3.75 (dd, J = 5.4, 9.3 Hz, 1H), 4.24
(q, J = 7.1 Hz, 2H), 4.47 (ddd, J = 5.4, 8.1, 8.5 Hz, 1H), 6.29 (d,
J = 8.1 Hz, 1H), 6.68–6.72 (br, 1H); EI-MS m/z 389 (M+; 0.8%).
1
1017, 963, 891, 841, 771, 756, 668 cm−1; H NMR (400 MHz;
CDCl3) δ 1.65 (s, 9H), 8.03 (s, 1H), 8.14 (s, 1H), 9.94 (s, 1H).
Found: C, 54.94; H, 6.15; N, 14.28%. Calcd for C23H30N2O6: C,
55.09; H, 6.16; N, 14.28%.
Ethyl
(4S)-2-(N-Boc-amino)-5-t-butyldimethylsiloxy-4-t-
Compound 21a
butyldiphenylsiloxy-2-pentenoate (22a):
(514 mg, 1.30 mmol), TBDPS-Cl (726 mg, 2.60 mmol), and imi-
dazole (270 mg, 4.00 mmol) were dissolved in DMF (5 mL) at
room temperature under a N2 atmosphere. The solution was
stirred at this temperature overnight. The solution was diluted
with water and then extracted with ether. The combined organic
layers were washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was purified by preparative
TLC (SiO2, hexane:ethyl acetate = 10:1, v/v) to afford 22a in
quantitative yield (a pale-yellow oil). [α]2D5 = +37.2 ° (c 3.45,
CHCl3); IR (neat) 3406, 3071, 2930, 2858, 1731, 1662, 1589,
1473, 1428, 1391, 1367, 1255, 1161, 1112, 836, 778, 739, 702
Ethyl
(4S)-2-(N-Boc-amino)-4,5-dihydroxy-2-pentenoate
(18a): To a solution of the acetonide 12a (441 mg, 1.40 mmol)
in EtOH (2 mL) was added 0.5 M HCl (3 mL) at room tempera-
ture under an air atmosphere. The solution was stirred at this tem-
perature overnight and then neutralized with a saturated aqueous
solution of NaHCO3. The organic solvent was removed in vacuo.
The resulting aqueous layer was saturated with NaCl and then ex-
tracted with ethyl acetate. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concentrat-
ed in vacuo. The residue was purified by preparative TLC (SiO2,

2524 Bull. Chem. Soc. Jpn., 75, No. 11 (2002)
Synthesis of Dehydroamino Acid
1
cm−1; H NMR (300 MHz; CDCl3) δ 0.20 (s, 3H + 3H), 1.06
(dd, J = 7.7, 12.5 Hz, 1H), 3.82 (dd, J = 3.9, 12.5 Hz, 1H), 4.25
(q, J = 7.2 Hz, 2H), 4.82–4.91 (m, 1H), 5.46 (d, J = 2.8 Hz, 1H),
7.30–7.50 (m, 3H + 3H), 7.60–7.69 (m, 2H + 2H); EI-MS m/z
495 (M+; 11.9 %).
(s, 9H), 1.28 (s, 9H), 1.48 (t, J = 7.1 Hz, 3H), 1.59 (s, 9H), 3.75–
3.85 (m, 1H), 3.87 (dd, J = 5.0, 9.2 Hz, 1H), 4.41 (q, J = 7.1 Hz,
2H), 4.64–4.80 (m, 1H), 6.32 (d, J = 7.1 Hz, 1H), 6.58–6.80 (br,
1H), 7.48–7,65 (m, 3H + 3H), 7.84–7.90 (m, 2H + 2H). EI-MS
m/z 627 (M+; 0.4%).
Ethyl(2S,4S)-N-Boc-4-t-butyldiphenylsiloxyprolinate (26a):
Compound 25a (1.096 g, 2.20 mmol) was hydrogenated over 5%
palladium on carbon (329 mg) in EtOH (15 mL) at room tempera-
ture under a H2 atmosphere for 1 d. The catalyst was filtered
through a pad of celite, and the filtrate was removed in vacuo to
afford the desired product in quantitative yield (ds; > 99%). The
crude product was subjected to a HPLC analysis to determine the
diastereoselectivity [column, CAPCELL PAK (Shiseido) UG-120
(4.6 Å–250 nm); buffer A, 0.1% aqueous TFA; B, 80% CH3CN
(0.1% TFA); linear gradient, 50–95% B over 40 min; flow rate, 1.0
mL/min, detection at 210 nm]. Recrystallization from hexane af-
forded pure 26a as a single isomer. Mp 93.5–94.5 °C (hexane);
[α]2D5 = −44.6 ° (c 1.00, CHCl3); IR (KBr) 2978, 2930, 2857,
1759, 1702 ,1588, 1471, 1429, 1395, 1220, 1191, 1157, 1111,
1083, 1054, 918, 822, 752, 742, 706 cm−1; 1H NMR (400
Ethyl (4S)-2-(N-Boc-amino)-4-t-butyldiphenylsiloxy-5-hy-
droxy-2-pentenoate (23a): To a solution of the starting material
22a (363 mg, 0.58 mmol) in EtOH (3.0 mL) was added dropwise
1.5 M HCl (0.6 mL) at room temperature under an air atmosphere.
The solution was stirred at this temperature for 2 h and then neu-
tralized with a saturated aqueous solution of NaHCO3. The organ-
ic solvent was removed in vacuo. The resulting aqueous layer was
saturated with NaCl and then extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over anhy-
drous MgSO4, and concentrated in vacuo. The residue was puri-
fied by preparative TLC (SiO2, hexane:ethyl acetate = 5:1, v/v)
to afford the desired product 23a in 98% yield (a pale-yellow oil,
297 mg). [α]2D5 = −27.1 ° (c 1.04, CHCl3); IR (neat) 3404, 2932,
2858, 1726, 1474, 1428, 1367, 1251, 1161, 1111, 822, 741,
703 cm−1; 1H NMR (400 MHz; CDCl3) δ 1.06 (s, 9H), 1.28 (t, J =
7.1 Hz, 3H), 1.34 (s, 9H), 3.69 (dd, J = 6.6, 10.8 Hz, 1H), 3.70–
3.81 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 4.52–4.56 (m, 1H), 4.64–
5.75 (br, 1H), 6.33 (d, J = 9.3 Hz, 1H), 7.60–7.64 (br, 1H), 7.32–
7.45 (m, 3H + 3H) 7.60–7.65 (m, 2H + 2H); EI-MS m/z 513
(M+; 0.1 %).
Ethyl 1-Boc-2-pyrrolecarboxylate (24): To a solution of
Ph3P (283 mg, 1.08 mmol) in dry CH2Cl2 (7 mL) was added
DEAD (188 mg, 1.08 mmol, 40% tuluene solution) at 0 °C under
a N2 atmosphere. To the solution was slowly added a solution of
23a (267 mg, 0.52 mmol) in dry CH2Cl2 (7 mL) over a period of
1.5 h at this temperature. After stirring for 20 h at room tempera-
ture the solvent was removed in vacuo to give a residue, which
was partitioned between ether and water. The aqueous layer was
extracted with ether and the combined extracts were washed with
brine, dried over anhydrous MgSO4, and concentrated under re-
duced pressure. The residual oil was subjected to preparative TLC
(SiO2, hexane:ethyl acetate = 10:1, v/v) to afford pyrrole com-
pound 24 in 52% yield (a pale-yellow oil, 65 mg). IR (neat) 2980,
2931, 1751, 1726, 1449, 1419, 1394, 1370, 1349, 1318,
1269,1213, 1194, 1159, 1094, 1064, 849, 775, 744, 705 cm−1; 1H
NMR (300 MHz; CDCl3) δ 1.35 (t, J = 7.2 Hz, 3H), 1.58 (s, 9H),
4.23 (q, J = 7.2 Hz, 2H), 6.16 ( dd, J = 1.7, 3.3 Hz, 1H), 6.83 (dd,
J = 1.5, 3.3 Hz, 1H), 7.31 (dd, J = 1.7, 2.8 Hz, 1H); EI-MS m/z
239 (M+; 6.6%).
t
MHz; CDCl3) δ 1.02 and 1.03 (s, 9H, rotamer, Bu) 1.30 (t, J =
7.2 Hz, 3H), 1.41 and 1.44 (s, 9H, rotamer, tBu), 2.12–2.24 (m, 1H
+ 1H), 3.37–3.46 (m, 1H), 3.52–3.57 (m, 1H), 4.16–4.33 (m, 2H
+ 1H + 1H), 7.35–7.46 (m, 3H + 3H), 7.60–7.65 (m, 2H + 2H);
Found: C, 67.36; H, 8.04; N, 2.81%. Calcd for C28H39NO5Si: C,
67.57; H, 7.90; N, 2.81%.
Ethyl (2S, 4S)-N-Boc-4-hydroxyprolinate (27a): To a solu-
tion of 26a (845 mg, 1.70 mmol) in THF (5 mL) was added 1 M
TBAF solution in THF (8.5 mL, 8.5 mmol) at room temperature
under an air atmosphere. The solution was stirred at the tempera-
ture overnight. The solvent was removed in vacuo to afford a resi-
due, which was partitioned between ethyl acetate and water. The
aqueous layer was extracted with ethyl acetate, and the combined
organic layers were washed with brine, dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was purified by
preparative TLC (SiO2, hexane:ethyl acetate = 1:1, v/v) to afford
the product 27a in 91% yield (a pale-yellow oil, 598 mg). [α]2D5
=
−6.91 ° (c 0.86, CHCl3); IR (neat) 3454, 2979, 2935, 1751, 1701,
1477, 1404, 1367, 1256, 1192, 1161, 1123, 1089, 1047, 972, 906,
858, 755 cm−1; 1H NMR (400 MHz; CDCl3) δ 1.27 and 1.28 (t, J
= 7.1 Hz, 3H, rotamer, CH3), 1.39 and 1.43 (s, 9H, rotamer, tBu),
2.00–2.07 (m, 1H), 2.24–2.35 (m, 1H), 3.28–3.44 (br, 1H) 3.46–
3.54 (m, 1H), 3.58–3.68 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.27–
4.33 (m, 1H + 1H); EI-MS m/z 257 (M+; 0.2 %).
(2S, 4S)-4-Hydroxyproline (28a): To a solution of 27a
(386 mg, 1.50 mmol) in EtOH (5 mL) was added 1.0 M LiOH aq
(3.0 mL)atroomtemperatureunderanairatmosphere. Thesolution
was stirred at room temperature for 2 h. The organic solvent was
removed in vacuo. The resulting aqueous layer was extracted with
ether once. The aqueous layer was acidified with 10% citric acid
(pH 3), saturated with NaCl, and then extracted with ethyl acetate.
The combined organic layers were dried over anhydrous MgSO4,
and concentrated in vacuo. The resulting crystalline was treated
with 10 equivalents of hydrogen chloride (2 M hydrogen chloride
in 1,4-dioxane, 5.0 mL) at room temperature for 19 h under an air
atmosphere. Then, the solvent was removed in vacuo to afford the
hydrogen chloride salt, which was treated with TEA (92 mg,
0.91 mmol) in cooled EtOH (3 mL). The resulting desired product
was filtered and recrystallization from H2O–EtOH afforded 28a in
α β
Ethyl (4S)-N-Boc-4-t-butyldiphenylsiloxy- , -didehydro-
prolinate (25a): To a solution of Ph3P (787 mg, 3.00 mmol) in
CH2Cl2 (15 mL) was added DEAD (323 mg, 3.04 mmol, 40% tol-
uene solution) at 0 ° C under a N2 atmosphere. Then, a solution of
23a (695 mg, 1.35 mmol) in CH2Cl2 (15 mL) was added dropwise
over a period of 2 h at 0 ° C. The solution was stirred at 0 ° C for
2 d. The solvent was removed in vacuo to afford a residue, which
was partitioned between ether and water. The aqueous layer was
extracted with ether, and the combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was subjected to preparative TLC (SiO2, hexane:ethyl
acetate = 10:1, v/v) to afford 25a in 59% yield (a pale-yellow oil,
20 mg). [α]2D5 = +55.5 ° (c 1.00, CHCl3); IR (neat) 3072, 2935,
2859, 1735, 1706, 1629, 1454, 1431, 1364, 1300, 1238, 1177,
1113, 1069, 1000, 915, 823, 736, 701 cm−1; 1H NMR (300 MHz;
CDCl3) δ 1.05 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H), 1.45 (s, 9H), 3.74
83% yield. Mp 250.0–252.0 ° C (decomp) (H2O–EtOH); [α]2D5
=
−57.7 ° (c 0.65, H2O); IR (KBr) 3215, 2995, 2938 1630. 1561,
1433, 1384, 1327, 1311, 1264, 1197, 1177, 1088, 1070, 1040,

R. Kimura et al.
Bull. Chem. Soc. Jpn., 75, No. 11 (2002) 2525
1001, 976, 920, 869, 831, 811, 735, 680 cm−1
;
1H NMR
Namikoshi, M. H. G. Munro, J. W. Blunt , P. E. Mulligan, Y. R.
Beasley, A. M. Dahlem, and W. W. Carmichael, J. Am. Chem.
Soc., 110, 8557 (1988). g) K. Nagaoka, M. Matsumoto, J. Oono,
K. Yokoi, S. Ishizeki, and T. Nakashima, J. Antibiot., 36, 1527
(1986).
(400 MHz; D2O) δ 2.22–2.28 (m, 1H), 2.50–2.55 (m, 1H), 3.36
(dd, J = 3.9, 12.5 Hz, 1H), 3.44–3.48 (m, 1H), 4.21 (dd, J = 3.9,
10.5 Hz, 1H), 4.56–4.67 (m, 1H); HRMS (FAB) (M+ + 1) Found:
m/z 132.0672. Calcd for C5H10NO3: 132.0660. [Lit,13 Mp 248 ° C
(decomp), [α]2D5 = −58.0 ° (c 2.00, H2O)]
2
a) H. E. Carter, “Organic Reactions,” John Wiley and Sons
The NMR and IR data of compounds 12b, 18b, 21b–23b, and
25b–28b were satisfactorily in accodance with those described for
the enantiomers obtained above.
Inc. (1949), Vol. 3, p. 198. b) I. Photaki, J. Am. Chem. Soc., 85,
1123 (1963). c) D. H. Rich and J. P. Tam, J. Org. Chem., 42, 3815
(1977). d) C. Shin, Y. Yonezawa, K. Unoki, and J. Yoshimura,
Tetrahedron Lett., 1979, 1049. e) S. Nomoto, A. Sano, and T.
Shiba, Tetrahedron Lett., 1979, 521. f) P. A. Manis and M. W.
Rathke, J. Org. Chem., 45, 4952 (1980). g) Y. Shimohigashi and
G. H. Stammer, J. Chem. Soc., Perkin Trans. 1, 1983, 803. h) U.
Schmidt, A. Lieberknecht, and J. Wild, Synthesis, 1984, 53. i) N.
M. Okeley, Y. Zhu, and W. A. van der Donk, Org. Lett., 2, 3603
(2000).
Ethyl
(4R)-2-(N-Boc-amino)-4,5-isopropylidenedioxy-2-
pentenoate (12b): 12b was prepared from 1a and (S)-isopropyl-
ideneglyceraldehyde.6 Yield: 94%; (Z/E = 95/5) ; Mp 75.0–76.5
° C (hexane); [α]2D5 = +12.3 ° (c 0.77, CHCl3).
Ethyl
(4R)-2-(N-Boc-amino)-4,5-dihydroxy-2-pentenoate
(18b): Yield: 85% ; Mp 67.0–68.0 ° C (ethyl acetate–hexane);
[α]2D5 = −18.2 ° (c 1.57, CHCl3).
Ethyl (4R)-2-(N-Boc-amino)-5-t-butyldimethylsiloxy-4-hy-
droxy-2-pentenoate (21b): Yield: 84%; a pale yellow oil; [α]2D5
= −15.1 ° (c 1.10, CHCl3).
3
a) W. S. Knowles, M. J. Sabacky, B. D. Vineyard, and D. J.
Weinkauff, J. Am. Chem. Soc., 97, 2567 (1975). b) A. Miyashita,
A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi, and R.
Noyori, J. Am. Chem. Soc., 102, 7932 (1980). c) R. Noyori,
“Asymmetric Catalysis in Organic Syntheses,” Wiley-inter-
science, NewYork (1994), p. 16. d) E. N. Jacobsen, A. Pfaltz, and
H. Yamamoto, “Comprehensive Asymmetric Catalysis,” Springer-
Verlag, Berlin and Heiderberg (1999), Vol. 1, p. 145.
Ethyl
(4R)-2-(N-Boc-amino)-5-t-butyldimethylsiloxy-4-t-
butyldiphenylsiloxy-2-pentenoate (22b): Yield: Quantitative;
a pale yellow oil; [α]2D5 = −37.0 ° (c 0.72, CHCl3).
Ethyl (4R)-2-(N-Boc-amino)-4-t-butyldiphenylsiloxy-5-hy-
droxy-2-pentenoate (23b): Yield: Quantitative; a pale-yellow
oil; [α]2D5 = +26.5 ° (c 1.04, CHCl3).
4
a) H. Kinoshita, H. Ngwe, K. Kohori, and K. Inomata,
α β
Ethyl (4R)-N-Boc-4-t-butyldiphenylsiloxy- , -didehydro-
Chem. Lett., 1993, 1441. b) T. Kakiuchi, H. Kato, K. P.
Jayasundera, H. Higashi, K. Watabe, D. Sawamoto, H. Kinoshita,
and K. Inomata, Chem. Lett., 1998, 1001. c) T. Kakiuchi, H.
Kinoshita, and K. Inomata, Synlett, 1999, 901.
prolinate (25b): Yield: 59%; a pale yellow oil; [α]2D5 = −55.9 °
(c 0.96, CHCl3).
Ethyl (2R, 4R)-N-Boc-4-t-butyldiphenylsiloxyprolinate
(26b): Yield: Quantitative. Recrystallization from hexane af-
forded pure 26b. Mp 94.0–95.0 ° C (hexane); [α]2D5 = +45.0 ° (c
1.85, CHCl3).
Ethyl (2R, 4R)-N-Boc-4-hydroxyprolinate (27b): Yield:
90%; a pale-yellow oil; [α]2D5 = +7.15 ° (c 0.95, CHCl3).
(2R, 4R)-4-hydroxyproline (28b): Yield: 63% ; Mp 245.0–
248.0 ° C (decomp) (H2O–EtOH); [α]2D5 = +58.6 ° (c 0.65, H2O)
[Lit,8b Mp 252–257 ° C (decomp), [α]2D5 = +58.6 ° (c 2.00, H2O)].
5
T. Nagano and H. Kinoshita, Bull. Chem. Soc. Jpn., 73,
1605 (2000).
6
(1986).
7
J. Jurczack, S. Pikul, and T. Bauer, Tetrahedron, 42, 447
a) W. M. Lewko, L. A. Liotta, M. S. Wicha, B. K. Vonder-
haar, and W. R. Kidwell Cancer Res., 41, 2855 (1981). b) E. M.
Tan, L. U. Ryhanen, and J. Uitto, J. Invest Delmatol., 80,
261(1983). c) W. D. Klohs, R. W. Steinkampf, M. S. Wicha, A. E.
Mertus, J. B. Tunas, and W. R. Leopold, J. Natl. Cancer Inst., 75,
353 (1985).
Authors express their sincere thanks to Prof. N. Sakura and
Dr. K. Ooki of Faculty of Pharmaceutical Sciences, Hokuriku
University, for their kind help for HPLC measurement.
8
J. C. Sheehan, H.G. Zachau, and W.B. Lawson, J. Am.
Chem. Soc., 80, 3348 (1958).
a) A. A. Patchett and B. Witkop, J. Am. Chem. Soc., 79, 185
9
(1957). b) G. L. Baker, S. J. Fritschel, J. R. Stille, and J. K. Stille,
J. Org. Chem., 46, 2954 (1981). c) M. Seki and K. Matsumoto,
Biosci. Biotech. Biochem., 59, 1161 (1995).
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