Efficient synthesis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-ω- iodoalkanoates

Article abstract of DOI:10.1016/j.tetasy.2011.03.002

The efficient synthesis of four benzyl 2-(S)-[(tert-butoxycarbonyl)amino]- ω-iodoalkanoates {benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-3- iodopropanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-iodobutanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-

Full text of DOI:10.1016/j.tetasy.2011.03.002

Tetrahedron: Asymmetry 22 (2011) 580–586
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient synthesis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-x-
iodoalkanoates
⇑
Yohei Koseki, Haruka Yamada, Toyonobu Usuki
Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient synthesis of four benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-x-iodoalkanoates {benzyl
2-(S)-[(tert-butoxycarbonyl)amino]-3-iodopropanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-iod-
obutanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-5-iodopentanoate, benzyl 2-(S)-[(tert-butoxycar-
Received 3 February 2011
Accepted 7 March 2011
Available online 12 April 2011
bonyl)amino]-6-iodohexanoate} from natural or protected
L-amino acids is described.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
CO2H
HO2C H2N
x
-Iodoalkylated L-glycines equipped with protecting groups are
H
OH
NH2
CO2H
N
widely used as building blocks for the preparation of numerous or-
ganic molecules. For example, naturally occurring fluorescent
crosslinking amino acids, such as deoxypyridinoline 1 (Fig. 1)1
and pentosidine 2 (Fig. 1)2 are attractive synthetic target molecules
H
N
NH2
H2N
N
CO2H
N
N
H2N
CO2H
pentosidine 2
Figure 1. Structures of deoxypyridinoline 1 and pentosidine 2.
for utilizing
x-iodoalkylated L-glycines. The collagen crosslink in 1
is formed from the adjacent lysine, and is a useful biomarker of
bone resorption, and thus can be correlated with diseases such as
bone cancer, osteoporosis, and arthropathies.3 Pentosidine 2 iso-
lated from human extracellular matrix, contains lysine and argi-
nine side chains connected to an imidazopyridinium ring, and is
found on tissue and circulating proteins from patients with renal
failure.4 The key steps in the synthesis of 1 and 2 are the palla-
dium-catalyzed cross-coupling reaction between
-glycine segments and haloaryl groups, and the introduction of
-iodoalkylated -glycine moieties onto the nitrogen atom of the
pyridine ring.5,6 Jackson et al. reported the synthesis of several
types of -iodoalkylated -glycines in order to study the Negishi
deoxypyridinoline 1
2. Results and discussion
Our synthetic strategy took advantage of naturally derived
-amino acids (>99% ee) with the -configuration as starting
materials. In order to prevent racemization, derivatization of
-iodoalkylated -glycines must be conducted under mild condi-
tions due to the acidity of the -proton of the amino acids. The for-
x-haloalkylated
a
L
L
x
L
x
L
a
x
L
mation of iodoalkyl groups from the respective primary alcohol in
cross-coupling with haloaryl groups for the synthesis of phenylal-
amino acid systems was achieved with iodine, triphenylphosphine,
anine and its analogues.7
and imidazole in CH2Cl2.8 Thus,
L-serine, 4-benzoxyl-(S)-3-[(tert-
The convergent synthesis of protected
cines is a critical point for the synthetic study of such organic mol-
ecules. Jackson et al. synthesized some protected -iodoalkylated
-glycines based on the derivatization from natural -amino acids
in a couple of steps.7 Herein, we report the efficient unified synthe-
sis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]- -iodoalkanoates
3–6 (or -iodoalkylated -glycines) from commercially available
-amino acids (Fig. 2).
x-iodoalkylated L-gly-
butoxycarbonyl)amino]-4-oxobutanoic acid, and 5-benzoxyl-(S)-
4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid were selected
as the promising starting materials to be converted into the respec-
x
L
L
tive protected
x
-iodoalkylated
L-amino acids 3–6.
-serine into benzyl 2-(S)-[(tert-butoxycar-
The conversion of
L
x
bonyl)amino]-3-iodopropanoate 3 is described in Scheme 1. Pro-
tection of the carboxylic acid as the benzyl group and the amine
as the t-butoxycarbonyl group was achieved by treatment with
benzyl alcohol and di-tert-butyl dicarbonate ((Boc)2O), respec-
tively, to obtain alcohol 7.7b The desired iodide 3 was then ob-
tained from 7.8 The yield from commercially available 7 to 3 was
88% in one step, an improvement over the literature yield of 67%
over two steps.7b
x
L
natural or protected
L
⇑
Corresponding author. Tel.: +81 3 3238 3446; fax: +81 3 3238 3361.
E-mail address: t-usuki@sophia.ac.jp (T. Usuki).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.03.002

Y. Koseki et al. / Tetrahedron: Asymmetry 22 (2011) 580–586
NHBoc NHBoc
CO2Bn CO2Bn
581
NHBoc
CO2Bn
I
I
NHBoc
CO2Bn
I
I
3
4
5
6
Figure 2. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-x-iodoalkanoates 3–6.
1) PhSO3H, BnOH
benzene, reflux
I2, PPh3
NHBoc
CO2Bn
NH2
CO2H
L-serine
NHBoc
CO2Bn
I
HO
HO
5 h
imidazole
2) (Boc)2O, NaOH
THF, rt, 2 h
CH2Cl2, 0 °C
2 h, 88%
3
57% (2 steps)
7
[α]D = −22.1
Scheme 1. Synthesis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-3-iodopropanoate 3.
alcohol in the presence of the benzyl ester. Our approach to the
reduction was to first introduce an activated ester, such as a suc-
cinimide or formic ester, onto the carboxylic acid, and then to re-
duce this activated ester selectively into the primary alcohol by
treatment with sodium borohydride (NaBH4) (Table 1).7d When a
succinimide ester was introduced to the carboxylic acid of 4-benz-
oxyl-(S)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoic acid using
N-hydroxysuccinimide (NHS) and N,N0-dicyclohexylcarbodiimide
(DCC) in ethyl acetate (EtOAc), the desired benzyl 2-(S)-[(tert-
butoxycarbonyl)amino]-4-hydroxybutanoate 8 was obtained in
64% yield (entry 1).7e,f When the reduction was attempted with
the chloroformate ester in the presence of N-methylmorpholine
(NMM) as a base (entries 2–4) in tetrahydrofuran (THF),9 the yields
were improved. Ethylchloroformate was found to be the best re-
agent for the formation of the activated ester.
Table 1
Optimization of the reduction of 4-benzoxyl-(S)-3-[(tert-butoxycarbonyl)amino]-4-
oxobutanoic acid
reagents, solvent
NHBoc
CO2Bn
HO
NHBoc
CO2Bn
(seeTable)
HO2C
then, NaBH4, H2O
0 °C
8
Entry
Reagents
Solvent
Temp (°C)
Time (h)
Yield (%)
1a
2b
3b
4b
NHS, DCC
EtOAc
THF
THF
rt
6
1
1
1
64
80
89
94
iBuOCOCl, NMM
MeOCOCl, NMM
EtOCOCl, NMM
ꢀ15
ꢀ15
ꢀ15
THF
a
1.1 equiv each of NHS and DCC were used. When the solution of the ester was
not washed with saturated NaHCO3, 8 was obtained in 58% yield. When 1-ethyl-3-
Next, the iodination of alcohol 8 was performed, which gave the
desired iodide 4 in 76% yield (Scheme 2). When the hydroxyl group
(3-dimethylaminopropyl)carbodiimide (EDC) in CH2Cl2 was used, the yield was
36%.
of 8 was converted into the corresponding
a-methoxy-a-trif-
b
1.1 equiv each of chloroformate and NMM were used for the reaction. When
luoromethylphenylacetate (MTP) ester 80, nuclear magnetic
resonance (NMR) analysis demonstrated that it was a single isomer
(>99% ee). In the same manner, the optimal chemoselective
triethylamine (Et3N) was used as a base, the yield was 50%.
The key step to prepare both benzyl 2-(S)-[(tert-butoxycar-
bonyl)amino]-4-iodobutanoate 4 and benzyl 2-(S)-[(tert-butoxy-
reduction
of
5-benzoxyl-(S)-4-[(tert-butoxycarbonyl)amino]-
5-oxopentanoic acid gave benzyl 2-(S)-[(tert-butoxycarbonyl)-
amino]-5-hydroxypentanoate 9 in 92% yield (Scheme 2). This
alcohol 9 was again converted into the corresponding MTP ester 90
carbonyl)amino]-5-iodopentanoate
5 was the chemoselective
reduction of the carboxylic acid into the corresponding primary
I2, PPh3
R1O
NHBoc
I
NHBoc
CO2Bn
imidazole
CH2Cl2, 0 °C
2 h, 76%
CO2Bn
8: R1 = H
4
(R)-Mosher's acid
DCC, DMAP, CH2Cl2
rt, 20 h, 45%
[α]D = −32.4
1
8'
: R = MTP
EtOCOCl, NMM
THF, -15 °C, 1 h
HO2C
NHBoc
CO2Bn
NHBoc
R2O
then, NaBH4, H2O
0 °C, 92%
CO2Bn
2
9
: R = H
(R)-Mosher's acid
DCC, DMAP, CH2Cl2
rt, 20 h, 68%
9': R2 = MTP
I2, PPh3
NHBoc
CO2Bn
imidazole
I
CH2Cl2, 0 °C
2 h, 82%
5
[α]D = −20.4
Scheme 2. Synthesis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-iodobutanoate 4 and benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-5-iodopentanoate 5.

582
Y. Koseki et al. / Tetrahedron: Asymmetry 22 (2011) 580–586
MeOCOCl
(Boc)2O
DMAP
HO2C
NHBoc
CO2Bn
MeO2C
NHBoc
CO2Bn
Et3N, DMAP
MeCN, rt
CH2Cl2
20 h, 99%
0 °C to rt, 0.5 h
92%
10
NaBH4
BF3·Et2O, THF
0 °C to rt, 21 h
1) DIBAL-H, Et2O
-78 °C, 5 min
MeO2C
N(Boc)2
CO2Bn
N(Boc)2
CO2Bn
2) MePPh3Br
nBuLi, THF
then, NaOH
H2O2, 0 °C
1.5 h, 77%
0 °C, 1 h, 47%
11
12
[α]D = −18.9
1) I2, PPh3
imidazole, CH2Cl2
R3O
N(Boc)2
CO2Bn
I
NHBoc
CO2Bn
0 °C, 2 h, 92%
2) CF3CO2H, CH2Cl2
rt, 3 h, 95%
6
3
13
: R = H
(R)-Mosher's acid
[α]D = −11.6
DCC, DMAP, CH2Cl2
rt, 21 h, 90%
13': R3 = MTP
Scheme 3. Synthesis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-6-iodohexanoate 6.
indicating that it was a single isomer (>99% ee). Iodination of alcohol
9 was performed and gave iodide 5 in moderate yield. According to
the literature, the yields of 4 (from 4-benzoxyl-(S)-3-[(tert-butoxy-
carbonyl)amino]-4-oxobutanoic acid) and 5 (from 5-benzoxyl-(S)-
4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid) were 40%
and 37%, respectively.7d We have thus achieved an improvement
in the synthesis of 4 and 5 in 71% and 75% over two steps, respec-
tively, utilizing efficient chemoselective reduction.
3. Conclusion
In conclusion, the efficient synthesis of benzyl 2-(S)-[(tert-butox-
ycarbonyl)amino]-x-iodoalkanoates {benzyl 2-(S)-[(tert-butoxy-
carbonyl)amino]-3-iodopropanoate 3, benzyl 2-(S)-[(tert-butox-
ycarbonyl)amino]-4-iodobutanoate 4, benzyl 2-(S)-[(tert-butoxy-
carbonyl)amino]-5-iodopentanoate 5, benzyl 2-(S)-[(tert-butoxy-
carbonyl)amino]-6-iodohexanoate 6} with enantiomeric retention
is reported starting from commercially available natural or pro-
Our synthesis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-6-
iodohexanoate 6 was based on extending the carbon chain via an
oxidation-Wittig reaction (Scheme 3).10 First, esterification of 5-
benzoxyl-(S)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid
using methylchloroformate was carried out to give 10 in 92% yield.
Adamczyk et al. suggested the direct reduction of 10 produced a
complex mixture due to interference from the NH group and insta-
bility of the aldehyde.10 A bis-Boc group was thus introduced to 10
and then 11 was reduced with diisobutylaluminium hydride (DI-
BAL-H) to give the aldehyde. When the Wittig reaction of this alde-
hyde was carried out immediately with the ylide generated from
methyl triphenylphosphonium bromide and potassium tert-butox-
ide (tBuOK) as a base, alkene 12 was obtained in good yield. How-
ever, the specific rotation of the product was found to be
tected L-amino acids. The overall yields for all syntheses were im-
proved compared with literature yields. The synthesis described
couldbe used not onlyfor preparation of the fluorescent crosslinking
amino acids 1 and 2, but also for the synthesis of related natural
products accordingly.
4. Experimental
4.1. General
Melting points were measured by an AS one ATM-01 apparatus.
Optical rotations were measured on a JASCO P-2200 digital polar-
imeter at the sodium lamp (k = 589 nm) D line and were recorded
a 2D0
ꢁ
¼ ꢀ6:8 (c 0.14, MeOH), indicating partial racemization at the
as follows: ½a TD
ꢁ
(c g/100 mL, solvent). Infrared (IR) spectra were re-
½
corded on a JASCO FT-IR 4100 spectrometer. 1H and 13C NMR spec-
tra were recorded on a JEOL Lambda 300 spectrometer (300 MHz)
and a JEOL Lambda 500 spectrometer (500 MHz) in deuterated sol-
vents. 1H NMR data are reported as follows: chemical shift (d,
ppm), integration, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet or unresolved), coupling constants (J) in Hz,
assignments. 13C NMR data are reported in terms of chemical shift
(d, ppm). EI-MS spectra were recorded on a Shimadzu GCMS
QP-5050 instrument or on a JEOL JMS-700 instrument. ESI-HRMS
spectra were recorded on a JEOL JMS-T100LC instrument or on a
Thermo Exactive spectrometer. FAB-MS spectra were observed on
a JEOL JMS-700 instrument. Elemental analysis was performed by
a Perkin Elmer PE2400 II apparatus.
a-carbon. When the ylide was prepared from methyl triphenyl-
phosphonium bromide and n-butyl lithium (nBuLi), the specific
rotation of the obtained 12 was ½a D20
¼ ꢀ18:9 (c 0.14, MeOH). Hyd-
ꢁ
roboration–oxidation of 12 then gave the primary alcohol 13. In or-
der to investigate the racemization of the synthetic amino acid,
alcohol 13 was again converted into the corresponding MTP ester
130. The NMR analysis suggested that no racemization (>99% ee)
of 130 occurred. The iodination followed by removal of one of the
Boc groups using trifluoroacetic acid gave the desired benzyl 2-
(S)-[(tert-butoxycarbonyl)amino]-6-iodohexanoate 6. Adamczyk
et al. synthesized tert-butyl 2-(S)-[(tert-butoxycarbonyl)amino]-
6-iodohexanoate from 5-(tert-butoxyl)-(S)-4-[(tert-butoxycar-
bonyl)amino]-5-oxopentanoic acid in 13% yield in seven steps.10
We achieved the synthesis of 6 from 5-benzoxyl-(S)-4-[(tert-
butoxycarbonyl)amino]-5-oxopentanoic acid in seven steps with
29% overall yield.
All reactions were conducted under a nitrogen atmosphere with
magnetic stirring using freshly distilled solvents unless otherwise
indicated. Tetrahydrofuran (THF) was dried by distillation from

Y. Koseki et al. / Tetrahedron: Asymmetry 22 (2011) 580–586
583
sodium/benzophenone ketyl or stored over molecular sieves.
Dichloromethane (CH2Cl2) and diethylether (Et2O) were dried by
distillation from calcium hydride or stored over molecular sieves.
Acetonitrile (MeCN) was dried by distillation from calcium hy-
dride. All reagents were obtained from commercial suppliers un-
less otherwise stated. Analytical thin layer chromatography (TLC)
was performed on Silica Gel 60 F254 plates produced by Merck.
Visualization was accomplished with UV light and phosphomolyb-
dic acid followed by heating. Column chromatography was per-
formed with acidic or neutral Silica Gel 60 (spherical) produced
by Kanto chemicals. The enantiomeric purities (ee values) of com-
mercially available amino acids as starting materials were >99.5%.
was concentrated. Purification on silica gel column chromatogra-
phy (hexane/EtOAc = 10:1?1:1) yielded benzyl 2-(S)-[(tert-butox-
ycarbonyl)amino]-3-iodopropanoate 3 as a yellow solid (3.57 g,
8.8 mmol, 88%); mp = 80–81 °C;
½
a 2D0
ꢁ
¼ ꢀ18:9 (c 0.1, EtOH),
½
a 2D5
ꢁ
¼ ꢀ22:1 (c 0.1, MeOH) (lit. value:
½ ꢁ
a 2D0
¼ ꢀ18:6 (c 1.0,
EtOH))7b; IR (KBr, cmꢀ1) 3494, 3361, 2986, 2652, 2448, 2294,
1957, 1902, 1760, 1684, 1511, 1155, 957, 918, 860, 819, 783,
486, 453; 1H NMR (CDCl3, 300 MHz) d 7.34–7.39 (5H, m, Bn),
5.36 (1H, br d, J = 7.5 Hz, NH), 5.24 (1H, d, J = 12.3 Hz, Bn), 5.18
(1H, d, J = 12.3 Hz, Bn), 4.55 (1H, m, CH), 3.61 (1H, dd, J = 10.2,
3.6 Hz, CH2I), 3.55 (1H, dd, J = 10.2, 3.6 Hz, CH2I), 1.45 (9 H, s,
tBu); 13C NMR (75 Hz, CDCl3) d 169.6, 155.0, 135.0, 128.8, 128.7,
80.6, 68.1, 53.8, 28.4, 7.9; EI-MS (m/z) calcd for C7H13INO2
[MꢀCO2Bn]+ 270.00, found 270.05; Anal. Calcd: C, 44.46; H, 4.97;
N, 3.46. Found: C, 44.46; H, 5.19; N, 3.38.
4.2. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-3-hydroxy-
propanoate 7
A mixture of
L-serine (5.25 g, 50 mmol, 1.0 equiv), benzenesulf-
4.4. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-
onic acidꢂhydrate (10.84 g, 62 mmol, 1.2 equiv), and benzyl alcohol
(25 mL) was stirred in benzene (50 mL) with a Dean–Stark appara-
tus for 5 h. After removal of the remaining solvent by distillation,
Et2O (100 mL) was added to the reaction mixture with vigorous
shaking for 2 h until the mixture gave a solid. Storage of the result-
ing mixture at 4 °C overnight yielded a solid product. After filtra-
tion, the residue was washed with cold Et2O, and then dried.
hydroxybutanoate 8
4-Benzoxyl-(S)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoic
acid (96.8 mg, 0.30 mmol, 1.0 equiv) was dissolved in THF (1.5 mL)
and stirred. The solution was cooled to ꢀ15 °C, and N-methylmor-
pholine (36 lL, 0.33 mmol, 1.1 equiv) and EtOCOCl (31 lL,
0.37 mmol, 1.2 equiv) were added. The reaction mixture was then
stirred for 1 h. The precipitated N-methylmorpholine hydrochlo-
ride was removed by filtration and washed with THF (5 mL). The
filtrate was cooled to 0 °C and NaBH4 (17.0 mg, 0.45 mmol,
1.5 equiv) was added, followed by the dropwise addition of water
(0.3 mL). The reaction mixture was stirred at 0 °C for 0.5 h. The
resulting solution was quenched with saturated aqueous NH4Cl,
stirred for 10 min, and extracted with EtOAc. The combined ex-
tracts were washed with brine, and dried over Na2SO4. Purification
on silica gel column chromatography (hexane/EtOAc = 2:1?1:1)
yielded benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-hydroxybut-
Recrystallization in hot EtOH gave L-serine benzyl ester benzene-
sulfonate (14.94 g, 42 mmol, >85%); 1H NMR (300 MHz, CDCl3) d
8.12 (3H, m, NH3þ), 7.83 (2H, d, J = 7.2 Hz, o-PhSO3ꢀ), 7.18–7.39
(8H, m, Bn, m,p-PhSO3ꢀ), 5.08 (1H, d, J = 12.3 Hz, Bn), 5.02 (1H, d,
J = 12.3 Hz, Bn), 4.30 (1H, s, OH), 4.16 (1H, s, CH), 4.02 (1H, dd,
J = 12.3, 4.5 Hz, CH2), 3.90 (1H, dd, J = 12.3, 4.5 Hz, CH2).
Next, (Boc)2O (9.16 g, 42.0 mmol, 1.3 equiv) was added to a
cooled solution of L-serine benzyl ester benzenesulfonate (11.4 g,
32.3 mmol, 1.0 equiv) in THF (65 mL) and aqueous NaOH (32 mL,
1 M). The solution was stirred at room temperature for 2 h. The
solution was then concentrated, and acidified with KHSO4
(100 mL; 10% w/v) to pH 2–3. The aqueous phase was extracted
with EtOAc (2 ꢃ 50 mL) and the combined organic layer was
washed with water (3 ꢃ 33 mL). After drying over Na2SO4, purifica-
tion on silica gel column chromatography (hexane/EtOAc =
1:0?1:1) yielded benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-3-
anoate
8
as
a
colorless oil (87.2 mg, 0.28 mmol, 94%);
¼ ꢀ39:9 (c 1.0,
½
a 2D7
ꢁ
¼ ꢀ40:2 (c 0.1, MeOH), lit. value:
½ ꢁ
a 2D7
MeOH)7e; IR (KBr, cmꢀ1) 3355, 2935, 1684, 1511, 1369, 1261,
1155, 1053, 912, 856, 787, 745, 696, 607, 474, 444; 1H NMR
(300 MHz, CDCl3) d 7.30–7.41 (5H, m, Bn), 5.38 (1H, d, J = 6.6 Hz,
NH), 5.19 (2H, dd, J = 13.4, 12.4 Hz, Bn), 4.50–4.60 (1H, m, CH),
3.59–3.74 (2H, m, CH2O), 2.04–2.21 (1H, m, CH2), 1.57–1.65 (1H,
m, CH2), 1.44 (9H, s, tBu); 13C NMR (75 MHz, CDCl3) d 172.8,
156.6, 135.3, 128.8, 128.6, 128.4, 80.6, 67.4, 58.4, 50.8, 36.2, 28.4;
ESI-HRMS (m/z) calcd for C16H23NO5Na [M+Na]+ 332.1468, found
332.1454.
hydroxypropanoate
7 as a white crystalline solid (6.42 g,
21.7 mmol, 57% (2 steps)); mp = 69–71 °C; ½a D21
ꢁ
¼ ꢀ14:0 (c 0.1,
EtOH), ½a 2D5
ꢁ
¼ ꢀ18:4 (c 0.1, MeOH) (lit. value: ½a D21
ꢁ ¼ ꢀ13:5 (c 1.0,
EtOH))7b; IR (KBr, cmꢀ1) 3442, 3373, 3091, 3066, 3034, 2960,
2927, 2856, 2179, 1949, 1748, 1717, 1500, 1456, 1367, 1344,
1250, 1164, 1051, 759, 698, 641; 1H NMR (300 MHz, CDCl3) d
7.31–7.41 (5H, m, Bn), 5.44 (1H, br s, NH), 5.24 (1H, d,
J = 12.0 Hz, Bn), 5.19 (1H, d, J = 12.0 Hz, Bn), 4.42 (1H, s, CH),
3.88–4.02 (2H, m, CH2), 2.21 (1H, s, OH), 1.44 (9H, s, tBu); 13C
NMR (75 Hz, CDCl3) d 170.8, 155.9, 135.3, 128.7, 128.6, 128.3,
80.5, 67.5, 63.7, 56.0, 28.4; EI-MS (m/z) calcd for C7H14NO3
[MꢀCO2Bn]+ 160.10, found 160.15.
4.5. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-(
a-methoxy-
a
-trifluoromethyl-acetoxy)-butanoate 80
At first, (R)-(+)-a-methoxy-a-trifluoromethylphenylacetic acid
(47.5 mg, 0.20 mmol, 2.1 equiv) in CH2Cl2 (1.0 mL) was added to
a solution of 2-(S)-[(tert-butoxycarbonyl)amino]-4-hydroxybut-
anoate 8 (30.2 mg, 0.098 mmol, 1.0 equiv) dissolved in CH2Cl2
(1.3 mL) at room temperature. Next, DCC (41.2 mg, 0.20 mmol,
2.1 equiv) and DMAP (7.7 mg, 0.063 mmol, 0.6 equiv) were added
to the reaction mixture. After stirring for 20 h, the mixture was fil-
tered and the filtrate was concentrated on a rotary evaporator.
Purification on silica gel column chromatography (hexane/EtOAc =
4.3. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-3-iodo-
propanoate 3
Triphenylphosphine (3.95 g, 15.1 mmol, 1.5 equiv) and imidaz-
ole (1.04 g, 15.3 mmol, 1.5 equiv) were dissolved in CH2Cl2 with
stirring. Next, I2 (3.81 g, 1.50 mmol, 1.5 equiv) was added to the
solution at 0 °C. The solution was warmed to room temperature
with stirring for 10 min and then cooled to 0 °C. A solution of ben-
3:1) yielded 2-(S)-[(tert-butoxycarbonyl)amino]-4-(a-methoxy-a-
trifluoromethyl-acetoxy)-butanoate 80 as a colorless oil (22.9 mg,
0.044 mmol, 45%); 1H NMR (500 MHz, CDCl3) d 7.48–7.52 (2H, m,
Ph), 7.30–7.41 (8H, m, Ph, Bn), 5.13 (2H, s, Bn), 5.09–5.11 (1H, m,
NH), 4.38–4.44 (1H, m, CH), 4.31–4.38 (2H, m, CH2O), 3.53 (3H, s,
OMe), 2.22–2.30 (1H, m, CHCH2CH2), 2.00–2.09 (1H, m,
CHCH2CH2), 1.42 (9H, s, tBu); FAB-MS (m/z) C21H23F3NO5
[M+2HꢀBoc]+ 426.15, found 426.21.
zyl 2-(S)-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate
7
(2.95 g, 10.0 mmol, 1.0 equiv) in CH2Cl2 (10 mL, washed with
8 mL) was also added to the solution. After stirring for 2 h, the
reaction mixture was filtered through a short column of neutral sil-
ica gel eluting with hexane/Et2O (=1:1, ca. 300 mL) and the filtrate

584
Y. Koseki et al. / Tetrahedron: Asymmetry 22 (2011) 580–586
4.6. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-
iodobutanoate 4
yielded 2-(S)-[(tert-butoxycarbonyl)amino]-5-(a-methoxy-a-tri-
fluoromethyl-acetoxy)-pentanoate 90 as a colorless oil (40.2 mg,
0.075 mmol, 68%); 1H NMR (300 MHz, CDCl3) d 7.45–7.51 (2H, m,
Ph), 7.36–7.42 (3H, m, Ph), 7.28–7.36 (5H, m, Bn), 5.15 (2H, dd,
J = 16.8, 12.0 Hz, Bn), 4.95–5.03 (1H, m, NH), 4.21–4.38 (3H, m,
CHCH2CH2CH2), 3.51 (3H, s, OMe), 1.81–1.94 (1H, m,
CHCH2CH2CH2), 1.57–1.81 (3H, m, CHCH2CH2CH2), 1.43 (9H, s,
tBu); FAB-MS (m/z) calcd for C22H25F3NO5 [M+2HꢀBoc]+ 440.17,
found 440.24.
Triphenylphosphine (306.7 mg, 0.99 mmol, 1.7 equiv) and imid-
azole (73.9 mg, 1.1 mmol, 1.9 equiv) were dissolved in CH2Cl2
(1.8 mL) with stirring. The solution was cooled to 0 °C and I2
(302.1 mg, 1.2 mmol, 2.1 equiv) was added. The solution was
warmed to room temperature and cooled to 0 °C. A solution of
benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate 8
(179.8 mg, 0.58 mmol, 1.0 equiv) in CH2Cl2 (0.6 mL) was also added.
After stirring for 2 h, the mixture was diluted with Et2O. The residue
was filtered through a short column of neutral silica gel eluting with
Et2O. Purification on silica gel column chromatography (hexane/
EtOAc = 2:1) yielded benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-
iodobutanoate 4 as a yellow oil (184.3 mg, 0.44 mmol, 76%);
4.9. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-5-iodo-
pentanoate 5
Triphenylphosphine (244.9 mg, 0.93 mmol, 2.0 equiv) and imid-
azole (63.1 mg, 0.93 mmol, 2.0 equiv) were dissolved in CH2Cl2
(1.35 mL) with stirring. The solution was cooled to 0 °C and I2
(237.4 mg, 0.94 mmol, 2.0 equiv) was added. The solution was
warmed to room temperature and cooled to 0 °C. A solution of ben-
½
a 2D0
ꢁ
¼ ꢀ32:4 (c 0.1, MeOH) (lit. value: ꢀ33.0 (c 1.0, MeOH))11; IR
(KBr, cmꢀ1) 3356, 2979, 1756, 1681, 1518, 1445, 1370, 1298,
1251, 1153, 1052, 1028, 946, 855, 824, 789, 753, 696; 1H NMR
(300 MHz, CDCl3) d 7.31–7.41 (5H, m, Bn), 5.18 (2H, dd, J = 15.2,
12.2 Hz, Bn), 5.10 (1H, m, NH), 4.37 (1H, m, CH), 3.11–3.17 (2H,
m, CH2I), 2.33–2.48 (1H, m, CH2), 2.10–2.25 (1H, m, CH2), 1.44
(9H, s, tBu); 13C NMR (75 MHz, CDCl3) d 171.5, 155.4, 135.2, 128.8,
128.7, 128.4, 80.4, 67.5, 54.5, 37.1, 28.4, ꢀ0.6; ESI-HRMS (m/z) calcd
for C16H22NO4INa [M+Na]+ 442.0486, found 442.0474.
zyl 2-(S)-[(tert-butoxycarbonyl)amino]-5-hydroxypentanoate
9
(150.8 mg, 0.47 mmol, 1.0 equiv) in CH2Cl2 (0.45 mL) was also
added. After stirring for 2 h, the mixture was diluted with Et2O.
The residue was filtered through a short column of neutral silica
gel eluting with Et2O. Purification on silica gel column chromatog-
raphy (hexane/EtOAc = 5:1) yielded benzyl 2-(S)-[(tert-butoxycar-
bonyl)amino]-5-iodopentanoate
5 as a yellow oil (165.0 mg,
4.7. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-5-hydroxy-
pentanoate 9
0.38 mmol, 82%);
½
a 2D7
ꢁ
¼ ꢀ20:4 (c 0.1, MeOH), lit. value:
½
a 2D7
ꢁ
¼ ꢀ19:9 (c 1.0, MeOH)7e; IR (neat, cmꢀ1) 3369, 2976, 1714,
1501, 1454, 1366, 1164, 1053, 1024, 864, 751, 698, 601, 501; 1H
NMR (300 MHz, CDCl3) d 7.31–7.40 (5H, m, Bn), 5.18 (2H, dd,
J = 20.9, 12.2 Hz, Bn), 5.04 (1H, m, NH), 4.38 (1H, m, CH), 3.08–
3.21 (2H, m, CH2I), 1.58–1.99 (4H, m, CH2CH2), 1.44 (9H, s, tBu);
13C NMR (75 MHz, CDCl3) d 172.3, 155.4, 135.3, 128.7, 128.6,
128.4, 80.1, 67.2, 52.7, 33.7, 29.2, 28.4, 21.1, 5.5; ESI-HRMS (m/z)
calcd for C17H24NO4INa [M+Na]+ 456.0642, found 456.0622.
At first, 5-benzoxyl-(S)-4-[(tert-butoxycarbonyl)amino]-5-oxo-
pentanoic acid (302.4 mg, 0.90 mmol, 1.0 equiv) was dissolved in
THF (4.5 mL) and stirred. The solution was cooled to ꢀ15 °C, and
N-methylmorpholine (109
(82
lL, 0.99 mmol, 1.1 equiv) and EtOCOCl
L, 0.99 mmol, 1.1 equiv) were added. The reaction mixture
l
was stirred for 1 h. The precipitated N-methylmorpholine hydro-
chloride was then removed by filtration and washed with THF
(10 mL). The filtrate was cooled to 0 °C and NaBH4 (51.7 mg,
1.37 mmol, 1.5 equiv) was added, followed by the dropwise addi-
tion of water (0.9 mL). The reaction mixture was stirred at 0 °C
for 0.5 h. The resulting solution was quenched with saturated
aqueous NH4Cl, stirred for 10 min, and extracted with EtOAc. The
combined extracts were washed with brine, and dried over Na2SO4.
Purification on silica gel column chromatography (hexane/
EtOAc = 5:1) yielded benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-
5-hydroxypentanoate 9 as a colorless oil (266.6 mg, 0.82 mmol,
4.10. 1-Benzyl-5-methyl-2-(S)-[(tert-
butoxycarbonyl)amino]pentanedioate 10
Triethylamine (3.14 mL, 22.5 mmol, 1.5 equiv) was added to a
solution of 5-benzoxyl-(S)-4-[(tert-butoxycarbonyl)amino]-5-oxo-
pentanoic acid (5.06 g, 15.0 mmol, 1.0 equiv) dissolved in CH2Cl2
(68 mL). The mixture was cooled to 0 °C, after which DMAP
(182.1 mg, 1.5 mmol, 0.1 equiv) followed by MeOCOCl (1.38 mL,
18.0 mmol, 1.2 equiv) were added sequentially. The solution was
warmed to room temperature and stirred for 0.5 h. The reaction
mixture was then diluted with CH2Cl2 (50 mL), washed with aque-
ous 1 M NaHCO3 (225 mL), and extracted with CH2Cl2
(100 mL ꢃ 3). The organic layer was dried over Na2SO4. Purification
on silica gel column chromatography (hexane/EtOAc = 2:1) yielded
1-benzyl-5-methyl-2-(S)-[(tert-butoxycarbonyl)amino]pentane-
92%); ½a 2D7
ꢁ
¼ 30:7 (c 0.1, MeOH), ½a D25
¼ ꢀ1:3 (c 0.1, CHCl3), lit. va-
ꢁ
lue: ½a 2D5
ꢁ
¼ ꢀ2:9 (c 1.0, CHCl3)12; IR (neat, cmꢀ1) 3371, 2976, 1711,
1523, 1454, 1367, 1165, 1049, 865, 752, 698; 1H NMR (300 MHz,
CDCl3) d 7.29–7.38 (5H, m, Bn), 5.24 (1H, m, NH) 5.15 (2H, dd,
J = 19.3, 12.4 Hz, Bn), 4.36 (1H, m, CH), 3.60 (2H, t, J = 6.2 Hz,
CH2I), 1.54–2.16 (4H, m, CH2CH2), 1.42 (9H, s, tBu); 13C NMR
(75 MHz, CDCl3) d 172.7, 155.6, 135.5, 128.7, 128.6, 128.4, 80.1,
67.2, 62.2, 60.5, 53.3, 29.5, 28.4; EI-MS (m/z) calcd for C9H18NO3
[MꢀCO2Bn]+ 188.13, found 188.25.
dioate 10 as a colorless oil (4.84 g, 13.8 mmol, 92%); ½a D20
¼ ꢀ31:3
ꢁ
(c 0.16, MeOH); IR (KBr, cmꢀ1) 3345, 2973, 1700, 1523, 1456, 1163,
1059, 954, 903, 865, 802, 784, 758, 699, 632, 506, 435; 1H NMR
(300 MHz, CDCl3) d 7.30–7.40 (5H, m, Bn), 5.17 (2H, dd, J = 13.2,
12.3 Hz, Bn), 5.10 (1H, m, NH), 4.37 (1H, m, CH), 3.66 (3H, s,
CO2CH3), 2.29–2.47 (2H, CH2), 2.14–2.25 (1H, m, CHCH2CH2),
1.90–2.04 (1H, m, CHCH2CH2), 1.43 (9H, s, tBu); 13C NMR
(75 MHz, CDCl3) d 173.3, 172.2, 155.5, 135.4, 128.8, 128.6, 128.4,
80.2, 67.4, 53.1, 51.9, 30.2, 28.4, 27.9; EI-MS (m/z) calcd for
4.8. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-5-(
a
a-methoxy-
-trifluoromethyl-acetoxy)-pentanoate 90
At first, (R)-(+)-a-methoxy-a-trifluoromethylphenylacetic acid
(25.0 mg, 0.11 mmol, 1.0 equiv) in CH2Cl2 (1.0 mL) was added to
a solution of 2-(S)-[(tert-butoxycarbonyl)amino]-5-hydroxypent-
anoate 9 (65.6 mg, 0.20 mmol, 1.8 equiv) dissolved in CH2Cl2
(1.3 mL) at room temperature. Next, DCC (44.7 mg, 0.22 mmol,
2.0 equiv) and DMAP (6.7 mg, 0.055 mmol, 0.5 equiv) were added
to the reaction mixture. After stirring for 20 h, the mixture was fil-
tered and the filtrate concentrated on a rotary evaporator. Purifica-
tion on silica gel column chromatography (hexane/EtOAc = 5:1)
C
10H18NO4 [MꢀCO2Bn]+ 216.12, found 216.20.
4.11. 1-Benzyl-5-methyl-2-(S)-[bis-(tert-
butoxycarbonyl)amino]pentanedioate 11
At first, DMAP (336.1 mg, 2.75 mmol, 0.2 equiv) was added to a
solution of 1-benzyl-5-methyl-2-(S)-[(tert-butoxycarbonyl)amino]

Y. Koseki et al. / Tetrahedron: Asymmetry 22 (2011) 580–586
585
pentanedioate 10 (4.81 g, 13.7 mmol, 1.0 equiv) dissolved in MeCN
(43 mL). To this mixture, a solution of (Boc)2O (11.97 g, 54.9 mmol,
4.0 equiv) in MeCN (9 mL) was added at room temperature, and
stirred for 20 h. Purification on silica gel column chromatography
(hexane/EtOAc = 3:1) yielded 1-benzyl-5-methyl-2-(S)-[bis-(tert-
butoxycarbonyl)amino]pentanedioate 11 as a colorless oil (6.09 g,
0 °C and NaBH4 (34.7 mg, 0.92 mmol, 1.3 equiv) was added. After
stirring for 10 min, BF3ꢂEt2O (115 L, 0.91 mmol, 1.3 equiv) was
l
added to the solution. The mixture was allowed to warm to room
temperature and then stirred for 21 h. The solution was then
cooled to 0 °C, after which 1 M NaOH (1.05 mL, 1.05 mmol,
1.5 equiv) was added followed by 30% H2O2 (0.86 mL), and stirred
for 1.5 h. The mixture was diluted with water (8.6 mL) and ex-
tracted with EtOAc (8.6 mL ꢃ 3). The combined organic layer was
dried over Na2SO4. Purification on silica gel column chromatogra-
phy (hexane/EtOAc = 1:1) yielded benzyl 2-(S)-[bis-(tert-butoxy-
13.5 mmol, 99%); ½a D20
ꢁ
¼ ꢀ29:5 (c 0.15, MeOH); IR (neat, cmꢀ1
)
2980, 2385, 2292, 1744, 1456, 1368, 1141, 1007, 855, 782, 753,
698, 461; 1H NMR (300 MHz, CDCl3) d 7.29–7.37 (5H, m, Bn), 5.16
(2H, dd, J = 12.8, 12.8 Hz, Bn), 4.97 (1H, dd, J = 9.6, 4.8 Hz, CH), 3.67
(3H, s, CO2CH3), 2.45–2.57 (1H, m, CHCH2CH2), 2.36–2.44 (2H, m,
CH2), 2.15–2.27 (1H, m, CHCH2CH2), 1.45 (18H, s, tBu); 13C NMR
(75 MHz, CDCl3) d 173.2, 170.3, 152.1, 135.7, 128.6, 128.2, 128.1,
83.4, 66.9, 57.6, 51.8, 30.7, 28.0, 24.9; EI-MS (m/z) calcd for
carbonyl)amino]-6-hydroxyhexanoate 13 as
a
colorless oil
(237.5 mg, 0.54 mmol, 77%); ½a D20
ꢁ
¼ ꢀ16:0 (c 0.13, MeOH); IR (neat,
cmꢀ1) 3540, 2979, 1744, 1457, 1368, 1143, 994, 854, 782, 755, 698,
602, 463; 1H NMR (300 MHz, CDCl3) d 7.29–7.35 (5H, m, Bn), 5.15
(2H, dd, J = 16.8, 12.3 Hz, Bn), 4.89 (1H, dd, J = 9.6, 5.1 Hz, CH), 3.64
(2H, t, J = 6.6 Hz, CH2O), 2.12–2.19 (1H, m, CHCH2CH2CH2CH2OH),
1.89–1.97 (1H, m, CHCH2CH2CH2CH2OH), 1.55–1.65 (2H, m,
CHCH2CH2CH2CH2OH), 1.40–1.50 (2H, m, CHCH2CH2CH2CH2OH),
1.47 (18H, s, tBu ꢃ 2); 13C NMR (75 MHz, CDCl3) d 170.9, 152.5,
135.8, 128.6, 128.2, 128.1, 83.2, 66.9, 62.7, 58.2, 32.4, 29.3, 28.1,
22.5.
C
15H26NO6 [MꢀCO2Bn]+ 316.18, found 316.30.
4.12. Benzyl-2-(S)-[bis-(tert-butoxycarbonyl)amino]-5-hexe-
noate 12
Diisobutylaluminum hydride (DIBAL-H, 1 M solution in hexane,
0.84 mL, 0.84 mmol, 1.4 equiv) was added dropwise to a ꢀ78 °C
cooled solution of 1-benzyl-5-methyl-2-(S)-[bis-(tert-butoxycar-
bonyl)amino]pentanedioate 11 (271.9 mg, 0.60 mmol, 1.0 equiv)
in Et2O (7.2 mL) over 3 min. The reaction mixture was stirred for
4.14. Benzyl 2-(S)-[bis-(tert-butoxycarbonyl)amino]-6-(
methoxy-
-trifluoromethyl-acetoxy)-hexanoate 130
a-
a
5 min, then quenched with water (150 lL), and allowed to warm
to room temperature. The resulting white thick solution was filtered
through Celite powder and washed with Et2O (4 mL ꢃ 3). The filtrate
was concentrated and the remaining trace amounts of water were
removed by azeotrope using toluene. Purification on silica gel col-
umn chromatography (hexane/EtOAc = 5:1) gave benzyl-2-(S)-
[bis-(tert-butoxycarbonyl)amino]-5-oxopentanoate as a colorless
oil (216.3 mg, 0.51 mmol, 85%); IR (neat, cmꢀ1) 2980, 2723, 2384,
2291, 1746, 1456, 1368, 1146, 1003, 853, 782, 753, 698, 461; 1H
NMR (300 MHz, CDCl3) d 9.77 (1H, s, CHO), 7.30–7.35 (5H, m, Bn),
5.16 (2H, dd, J = 14.1, 12.3 Hz, Bn), 4.92 (1H, dd, J = 9.4, 5.0 Hz, CH),
2.44–2.69 (3H, m, CHCH2CH2), 2.13–2.24 (1H, m, CHCH2CH2), 1.45
(18H, s, tBu ꢃ 2); 13C NMR (75 MHz, CDCl3) d 201.1, 170.3, 152.2,
135.6, 128.6, 128.3, 128.1, 83.6, 67.0, 57.6, 40.6, 28.0, 22.3.
At first, (R)-(+)-a-methoxy-a-trifluoromethylphenylacetic acid
(23.0 mg, 0.096 mmol, 2.0 equiv) in CH2Cl2 (0.8 mL) was added to a
solution of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-6-hydroxy-
hexanoate 13 (21.1 mg, 0.048 mmol, 1.0 equiv) dissolved in CH2Cl2
(0.6 mL) at room temperature. Next, DCC (20.3 mg, 0.098 mmol,
2.0 equiv) and DMAP (4.2 mg, 0.072 mmol, 0.5 equiv) were added
to the reaction mixture. After stirring the reaction mixture for
21 h, the mixture was filtered and the filtrate was concentrated on
a rotary evaporator. Purification on silica gel column chromatogra-
phy (hexane/EtOAc = 5:1) yielded 2-(S)-[(tert-butoxycarbonyl)-
amino]-6-(a-methoxy-a-trifluoromethyl-acetoxy)-hexanoate 13’
as a colorless oil (28.3 mg, 0.043 mmol, 90%). 1H NMR (500 MHz,
CDCl3) d 7.48–7.53 (2H, m, Ph), 7.38–7.41 (3H, m, Ph), 7.28–7.36
(5H, m, Bn), 5.14 (2H, dd, J = 12.6, 7.5 Hz, Bn), 4.86 (1H, q,
J = 3.0 Hz, CH), 4.31 (2H, t, J = 4.0 Hz, CH2O), 3.54 (3H, s, OMe),
2.01–2.18 (1H, m, CHCH2), 1.88–1.97 (1H, m, CHCH2), 1.67–1.80
(2H, m, CHCH2CH2CH2), 1.38–1.50 (2H, m, CHCH2CH2CH2),
1.43 (18H, s, tBu ꢃ 2); FAB-MS (m/z) calcd for C23H27F3NO5
[M+3Hꢀ2Boc]+ 454.18, found 454.28.
nBuLi (2.69 M solution in hexane, 0.19 mL, 0.52 mmol,
1.1 equiv) was added dropwise to a suspension of methyl triphen-
ylphosphonium bromide (200.1 mg, 0.56 mmol, 1.2 equiv) in THF
(6.9 mL) at 0 °C. After stirring the mixture for 0.5 h, benzyl-2-(S)-
[bis-(tert-butoxycarbonyl)amino]-5-oxopentanoate
(197.5 mg,
0.47 mmol, 1.0 equiv) in THF was added to the resulting orange
ylide solution. The solution was stirred for 1 h at 0 °C and then
quenched with saturated aqueous NH4Cl (1.7 mL). The mixture
was diluted with water (8.5 mL) and extracted with EtOAc
(8.5 mL ꢃ 3). The combined organic layer was dried over Na2SO4.
Purification on silica gel column chromatography (hexane/EtOAc =
10:1) yielded benzyl-2-(S)-[bis-(tert-butoxycarbonyl)amino]-5-
hexenoate 12 as a colorless oil (107.5 mg, 0.26 mmol, 55%);
4.15. Benzyl 2-(S)-[bis-(tert-butoxycarbonyl)amino]-6-iodo-
hexanoate
Triphenylphosphine (1.23 g, 4.7 mmol, 2.0 equiv) and imidazole
(320.7 mg, 4.7 mmol, 2.0 equiv) were dissolved in CH2Cl2 (7.1 mL)
with stirring. Next, I2 (1.19 g, 4.7 mmol, 2.0 equiv) was added to
the solution at 0 °C. The solution was warmed to room
temperature and then cooled to 0 °C. A solution of benzyl 2-(S)-
[bis-(tert-butoxycarbonyl)amino]-6-hydroxyhexanoate 13 (1.03 g,
2.35 mmol, 1.0 equiv) in CH2Cl2 (4.3 mL) was then added to the
solution. After stirring for 2 h, the mixture was diluted with Et2O.
The residue was filtered through a short column of neutral silica
gel by eluting with Et2O. Purification on silica gel column chroma-
tography (hexane/EtOAc = 5:1) yielded benzyl 2-(S)-[bis-(tert-
butoxycarbonyl)amino]-6-iodohexanoate as a yellow oil (1.18 g,
½
a 2D0
ꢁ
¼ ꢀ18:9 (c 0.14, MeOH); IR (neat, cmꢀ1) 2981, 1740, 1456,
1366, 1227, 1126, 854, 752, 698; 1H NMR (300 MHz, CDCl3) d
7.29–7.34 (5H, m, Bn), 5.74–5.85 (1H, m, CH), 5.15 (2H, dd,
J = 15.4, 12.6 Hz, Bn), 4.89–5.08 (3H, m, CH=CH2), 2.20–2.29 (1H,
m, CHCH2CH2), 2.10–2.17 (2H, m, CHCH2CH2), 1.96–2.06 (1H, m,
CHCH2CH2), 1.45 (18H, s, tBu ꢃ 2); 13C NMR (75 MHz, CDCl3) d
170.9, 152.3, 137.5, 135.8, 128.6, 128.2, 128.1, 115.7, 83.2, 66.9,
57.8, 30.5, 29.0, 28.1; Anal. Calcd: C, 65.85; H, 7.93; N, 3.34. Found:
C, 66.01; H, 8.16; N, 3.28.
2.2 mmol, 92%); ½a D20
ꢁ
¼ ꢀ19:0 (c 0.1, MeOH), ½a D27
¼ ꢀ14:7 (c 0.1,
ꢁ
4.13. Benzyl-2-(S)-[bis-(tert-butoxycarbonyl)amino]-6-hydroxy-
hexanoate 13
MeOH); IR (neat, cmꢀ1) 2978, 1793, 1752, 1498, 1456, 1367,
1135, 996, 854, 754, 697, 597, 464; 1H NMR (300 MHz, CDCl3) d
7.31–7.34 (5H, m, Bn), 5.15 (2H, dd, J = 16.2, 12.6 Hz, Bn), 4.88
(2H, dd, J = 9.6, 5.1 Hz, CH), 3.18 (2H, t, J = 6.8 Hz, CH2I), 2.08–
2.17 (1H, m, CH2CH2CH2CH2I), 1.82–2.00 (3H, m, CHCH2-
Benzyl-2-(S)-[bis-(tert-butoxycarbonyl)amino]-5-hexenoate 12
(294.5 mg, 0.70 mmol, 1.0 equiv) in THF (3.4 mL) was cooled to

586
Y. Koseki et al. / Tetrahedron: Asymmetry 22 (2011) 580–586
CH2CH2CH2I), 1.41–1.48 (2H, m, CHCH2CH2CH2CH2I), 1.45 (18H, s,
tBu ꢃ 2); 13C NMR (75 MHz, CDCl3) d 170.7, 152.3, 135.8, 128.6,
128.2, 128.1, 83.3, 66.9, 58.1, 33.1, 28.5, 28.1, 27.3, 6.5; EI-MS
(m/z) calcd for C15H27INO4 [MꢀCO2Bn]+ 412.10, found 412.25.
Technology (MEXT) of Japan, EBARA Hatakeyama Memorial Fund
(EHMF), and Japan Gasoline Company—Saneyoshi (JGC-S) Scholar-
ship Foundation. We thank Professor Tony K. M. Shing (The Chi-
nese University of Hong Kong) and Dr. Yong Y. Lin (Columbia
University) for suggestions.
4.16. Benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-6-iodohexa-
noate 6
References
1. Ogawa, T.; Ono, T.; Tsuda, M.; Kawanishi, Y. Biochem. Biophys. Res. Commun.
1982, 107, 1252–1257.
Trifluoroacetic acid (44.5 lL, 0.58 mmol, 1.9 equiv) was added
to a solution of benzyl 2-(S)-[bis-(tert-butoxycarbonyl)amino]-6-
iodohexanoate (161.5 mg, 0.30 mmol, 1.0 equiv) dissolved in
CH2Cl2 (4 mL). The reaction mixture was stirred for 3 h at room
temperature. The mixture was then diluted with CH2Cl2 (15 mL)
and washed with 10% aqueous NaOH (8 mL), and extracted with
CH2Cl2 (8 mL ꢃ 3). The organic layer was dried over Na2SO4. Purifi-
cation on silica gel column chromatography (hexane/EtOAc = 5:1)
yielded benzyl-2-(S)-[(tert-butoxycarbonyl)amino]-6-iodohexano-
2. Sell, D. R.; Monnier, V. M. J. Biol. Chem. 1989, 264, 21597–21602.
3. Bilezikan, J. P.; Raisz, L. G.; Rogan, G. Principles of Bone Biology; Academic Press:
New York, 2001.
4. Friedlanger, M. A.; Wu, Y. C.; Schulak, J. A.; Monnier, V. M.; Hricik, D. A. Am. J.
Kidney Dis. 1995, 25, 445–451.
5. Total synthesis of 1: (a) Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetrahedron
1999, 55, 63–88; (b) Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetrahedron:
Assymmetry 2000, 11, 2289–2298; (c) Allevi, P.; Cribiù, R.; Giannini, E.;
Anastasia, M. J. Org. Chem. 2007, 72, 3478–3483.
6. Total synthesis of 2: (a) Sugiyama, H.; Yokokawa, F.; Shioiri, T.; Katagiri, N.;
Oda, O.; Ogawa, H. Tetrahedron Lett. 1999, 40, 2569–2572; (b) Yokokawa, F.;
Sugiyama, H.; Shioiri, T.; Katagiri, N.; Oda, O.; Ogawa, H. Tetrahedron 2001, 57,
4759–4766.
7. (a) Jackson, R. F. W.; Wythes, M. J.; Wood, A. Tetrahedron Lett. 1989, 30, 5941–
5944; (b) Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.; Wythe, M. J. J. Org.
Chem. 1992, 57, 3397–3404; (c) Dunn, M. L.; Jackson, R. F. W.; Pietruszka, J.;
Turner, D. J. Org. Chem. 1995, 60, 2210–2215; (d) Jackson, R. F. W.; Moore, R. J.;
Dexter, C. S.; Elliott, J.; Mowbray, C. E. J. Org. Chem. 1998, 63, 7875–7884l; (e)
Dexter, C. S.; Jackson, R. F. W. J. Org. Chem. 1999, 64, 7579–7585; (f) Rilatt, I.;
Jackson, R. F. W. J. Org. Chem. 2008, 73, 8694–8704.
8. Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599–4602.
9. (a) Lee, B. H.; Gerfen, G. J.; Miller, M. J. J. Org. Chem. 1984, 49, 2418–2423; (b)
Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J. Tetrahedron Lett.
1991, 32, 923–926; (c) Bowers, A. A.; Greshoch, T. J.; West, N.; Estiu, G.;
Schreiber, S. L.; Wiest, O.; Williams, R. M.; Bradner, J. E. J. Am. Chem. Soc. 2009,
131, 2900–2905.
ate 6 as a colorless oil (125.4 mg, 0.28 mmol, 95%); ½a D20
¼ ꢀ11:6
ꢁ
(c 0.1, MeOH), ½a D27
ꢁ
¼ ꢀ8:6 (c 0.1, MeOH); IR (neat, cmꢀ1) 3369,
2976, 1714, 1501, 1455, 1366, 1165, 1051, 1026, 867, 751, 698,
600, 498; 1H NMR (300 MHz, CDCl3) d 7.33–7.40 (5H, m, Bn),
5.18 (2H, dd, J = 25.4, 12.2 Hz, Bn), 5.04 (1H, m, NH), 4.35 (1H, m,
CH), 3.11 (2H, t, J = 6.9 Hz, CH2I), 1.73–1.87 (3H, m,
CHCH2CH2CH2CH2I), 1.57–1.70 (1H, m, CHCH2CH2CH2CH2I), 1.37–
1.50 (2H, m, CHCH2CH2CH2CH2I), 1.44 (9H, s, tBu); 13C NMR
(75 MHz, CDCl3) d 172.6, 155.4, 135.4, 128.7, 128.6, 128.5, 80.1,
67.2, 53.3, 32.9, 31.7, 28.4, 26.2, 6.2; ESI-HRMS (m/z) calcd for
C
18H26O4NINa [M+Na+] 470.0804, found 470.0796.
10. Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetrahedron: Asymmetry 1999, 10,
775–781.
Acknowledgments
11. Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, L. Tetrahedron 1988, 44, 5479–
5486.
12. Olsen, R. K.; Ramasamy, K.; Emery, T. J. Org. Chem. 1984, 49, 3527–3534.
This work was supported by a Grant-in-Aid for Young Scientists
(B) from the Ministry of Education, Culture, Sports, Science and