Reagent-controlled diastereoselective synthesis of (2S,3R)- and (2R,3R)-2,3-diaminobutanoic acid derivatives using proline-catalyzed α-hydrazination reaction

Article abstract of DOI:10.1016/j.tet.2009.08.064

(2S,3R)- and (2R,3R)-2,3-Diaminobutanoic acid (Dab) derivatives were efficiently synthesized from Cbz-(R)-alanine using the proline-catalyzed diastereoselective α-hydrazination reaction and the SmI₂-promoted reductive cleavage of the N-N bond a

Full text of DOI:10.1016/j.tet.2009.08.064

Tetrahedron 65 (2009) 9468–9473
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reagent-controlled diastereoselective synthesis of (2S,3R)-
and (2R,3R)-2,3-diaminobutanoic acid derivatives using
proline-catalyzed a-hydrazination reaction
Kazuishi Makino, Sayaka Kubota, Sousuke Hara, Masaru Sakaguchi, Akinari Hamajima,
*
Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2009
Received in revised form 24 August 2009
Accepted 25 August 2009
Available online 31 August 2009
(2S,3R)- and (2R,3R)-2,3-Diaminobutanoic acid (Dab) derivatives were efficiently synthesized from Cbz-
(R)-alanine using the proline-catalyzed diastereoselective
a-hydrazination reaction and the SmI2-pro-
moted reductive cleavage of the N–N bond as the key steps.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diaminobutanoic acid
Alanine
Proline
Organocatalyst
Asymmetric synthesis
a
-Hydrazination
1. Introduction
2. Results and discussion
Chiral 2,3-diamino acids and their derivatives are an important
class of structurally unusual amino acids broadly found in nature
as a component of biologically active natural products and me-
dicinal agents.1 In connection with our ongoing synthetic studies
on papuamides,2 cyclodepsipeptides with a potent inhibitory ac-
tivity against the infection of human T-lymphoblastoid cells by
HIV-1RF, we needed a practical method for the synthesis of chiral
2,3-diaminobutanoic acids (1). Several attractive synthetic ap-
proaches to the 2,3-diaminobutanoic acids have been reported in
past years.3 However, there is a need for the simple and secure
construction of each 2,3-diaminobutanoic acid diastereomer. Re-
cently, we have been engaged in the organocatalytic synthesis of
structurally unusual amino acids and dihydroquinolines.4 We now
describe the reagent-controlled diastereoselective synthesis of
(2S,3R)- and (2R,3R)-2,3-diaminobutanoic acid derivatives from
Our plan for the synthesis of chiral 2,3-diaminobutanoic acid is
shown in Scheme 1. The stereoselective construction of the 2,3-
diamino structure is achieved by the organocatalytic asymmetric
a
-hydrazination reaction5 of the chiral aldehyde 2 derived from (R)-
alanine and the subsequent reductive cleavage of the hydrazine N–N
bond. This strategy would provide both diastereomeric isomers from
a common chiral starting material. Although the asymmetric
a-hydrazination of achiral aldehydes catalyzed by proline has been
originally reported by List, to the best of our knowledge, the reagent-
controlled diastereoselective synthesis of a 2,3-diamino acid from
a chiral aldehyde at C3 has never been reported.
organocatalyst
R'
R'
NH O
NH O
(NCO2R")2
H
H
''RO2CN
N
CO2R''
2
Cbz-(R)-alanine using the proline-catalyzed
a
-hydrazination re-
H
action as the key step.
NH2O
NH2O
OH
NH2
OH
NH2
(2S,3R)-1
Scheme 1.
(2R,3R)-1
* Corresponding author. Tel.: þ81 43 290 2987.
E-mail address: hamada@p.chiba-u.ac.jp (Y. Hamada).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.064

K. Makino et al. / Tetrahedron 65 (2009) 9468–9473
9469
The required (R)-3-(benzyloxycarbonylamino)butanal (5) was
readily prepared from Cbz-(R)-alanine (3) (Scheme 2). The one-
carbon homologation of 3 was carried out by the routine four-step
manipulation. The carboxylic acid 3 was esterified with iodo-
methane and potassium hydrogen carbonate in dimethylforma-
mide, and the resulting ester was reduced with NaBH4/LiCl in
ethanol/tetrahydrofuran to give the aminoalcohol, which was
tosylated with tosyl chloride and pyridine. The cyanation of the
tosylate with potassium cyanide provided the homologated nitrile
46 in 76% yield from 3. The following reduction of 4 with diisobu-
tylaluminum hydride (DIBAL-H) afforded the aldehyde 57 in 55%
yield. The yield was moderate due to the unexpected deprotection
of the Cbz group as a side reaction.
a-hydrazination reaction. At this point, the diastereoselectivity was
still unsatisfactory. In order to improve the diastereoselectivity, we
examined the temperature effect. The reaction at ꢀ20 ꢁC enhanced
the diastereoselectivity from 87/13 to 95/5 (Table 1, entries 2 and 8).
Under the optimized conditions, the reaction using (S)-proline in-
stead of (R)-proline as the catalyst mainly produced the anti-6 with
a syn/anti ratio of 3/97 (entry 9). These results show that the
present diastereoselective reaction proceeds in a reagent-con-
trolled manner to exclusively give the syn or anti product.
In our efforts to improve the diastereoselectivity (Table 1,
entry 2), we observed the partial epimerization of the newly
formed C2 stereocenter in syn-6 under the conditions of a longer
reaction time at 0–4 ꢁC. As shown in Table 2 and Figure 1, the
noticeable decrease in the diastereoselectivity from the syn/anti
ratio of 96/4 to 87/13 during 24 h was observed. These results
i) MeI, KHCO3, DMF
Cbz
indicate that this
a
-hydrazination reaction at 0–4 ꢁC competes
NH
ii) NaBH
4, LiCl, THF, EtOH
OH
with the proline-catalyzed epimerization of the product. Al-
though this epimerization was an inherent problem for the
iii) TsCl, pyridine
iv) KCN, DMSO
O
3
proline-catalyzed
a-hydrazination, fortunately, lowering the
76% (4 steps)
temperature to ꢀ20 ꢁC solved this problem and proved to pro-
Cbz
Cbz
duce the product with no or little epimerization.
DIBAL-H (2.1 eq),
NH
NH O
CN
H
toluene, -40 °C , 1 h
55%
Table 2
The epimerization of 6
5
4
Scheme 2. Preparation of b-aminoaldehyde 5 from (R)-alanine.
(R)-proline
Cbz
Cbz
(30 mol%)
NH O
NH O
With the starting aldehyde 5 in hand, we initially investigated
the optimization of the -hydrazination reactions. The reaction was
(NBoc)2 (1.2 equiv.)
H
H
a
CH3CN (0.2 M)
0-4 °C, time
BocN
NHBoc
5
carried out using (R)-proline (30 mol %) and three dialkyl azodi-
carboxylates in acetonitrile according to the literature5 as shown in
Table 1. The syn/anti ratio of the products was determined by the
integration of the aldehyde protons (anti-isomer: 9.63 ppm, syn-
isomer: 9.70 ppm, starting material: 9.76 ppm) in the 1H NMR
spectra. Although dibenzyl and diethyl azodicarboxylates have
a moderate diastereoselectivity, di-tert-butyl azodicarboxylate was
of excellent diastereoselectivity to give syn-6 as the major isomer
(entries 1–3). The choice of the protecting group at the C3-amino
group of 5 was critical for the yield. The protection with the Boc
group instead of the Cbz one resulted in a complex mixture (entry
4). Since the diastereoselectivity was insufficient, the effect of sol-
vents was examined again. The use of THF or DMF decreased the
syn/anti selectivity. On the other hand, dichloromethane showed
a good stereoselectivity (entries 5–7). In terms of the yield and
diastereoselectivity, acetonitrile was the most suitable for this
6
Time (h)
Yielda (%)
syn/antia
de (%)
1
3
6
9
11
15
19
24
39
66
88
93
95
96
98
100
96/4
96/4
94/6
91/9
90/10
89/11
87/13
87/13
92
92
88
82
80
78
74
74
a
Determined by 1H NMR.
100
90
80
70
60
50
Table 1
The optimization of reaction conditions
(NCO2R)2 (1.2 equiv.)
(R)-proline (30 mol%)
Cbz
Cbz
%
NH O
NH O
H
H
40
30
20
10
0
solvent (0.2 M),
0 - 4 °C, 19-24 h
RO2CN
5
NCO2R
H
yield
de
6
Entry
R
Solvent
Yielda (%)
syn/antia
1
2
Bn
t-Bu
Et
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
DMF
CH3CN
CH3CN
100
100
83
57/43
87/13
69/31
d
3b
4c
5
0
5
10
15
20
25
dd
h
96
58
96
69
83/17
63/37
44/56
95/5
6
7
Figure 1.
8b
9b,e
Using the optimized conditions, the synthesis of the Dab de-
rivatives was carried out as shown in Schemes 3 and 4. After the
(R)-proline-catalyzed a-hydrazination reaction of 5, the obtained
syn-6 with a small amount of anti-6 (syn/anti¼95/5) was oxidized
with sodium chlorite, and the resulting carboxylic acid was ester-
ified to afford the ester syn-7 in 75% yield in three steps.
93
3/97
Determined by 1H NMR.
The reaction was carried out at ꢀ20 ꢁC.
a
b
c
N-tert-Butoxycarbonylaminobutanal was used instead of 5.
Multi-spots reaction.
d
e
(S)-Proline was used.

9470
K. Makino et al. / Tetrahedron 65 (2009) 9468–9473
Fortunately, the minor diastereoisomer anti-7 could be separated
by silica gel column chromatography. The conversion to the N-
benzohydrazide syn-8 for the N–N bond cleavage was easily ach-
ieved in two steps. The Boc groups of syn-7 were deprotected with
trifluoroacetic acid, and the resulting hydrazine was selectively N-
benzoylated with benzoic anhydride to produce syn-8 in 99% yield
(Scheme 3). Although the direct exposure of syn-7 to SmI2 in
MeOH/THF at room temperature only gave the undesired N-
deprotected product, the cleavage of the N–N bond of the N-ben-
zohydrazide syn-8 rapidly occurred under the same conditions to
afford the Dab derivative, which was directly protected with di-
Infrared spectra were recorded on SIMADZU FT IR-8100 and JASCO
FT/IR-230 spectrometers. NMR spectra were recorded on JEOL JNM-
GSX-400A and JNM-ECP-400 spectrometers with tetramethylsilane
as an internal standard, unless otherwise indicated. Mass spectra
were measured on a JMX-AX-500 spectrometer. Column chromato-
graphy was performed with silica gel BW-820MH or BW-200 (Fuji
Davison Co.). HPLC analyses were carried out on the chiral column
indicated in each experiment. All commercially available reagents
were used as received.
4.2. (R)-3-(N-Benzyloxycarbonylamino)butanenitrile (4)
tert-butyl dicarbonate to furnish the N,N0-diprotected (2S,3R)-2,3-
23
diaminobutanoic acid derivative 9 (mp 107 ꢁC, [
a
]
D
þ55.0 (c 1.49,
To a stirred suspension of Cbz-(R)-Ala-OH (71.7 g, 0.321 mol)
and KHCO3 (64.3 g, 0.642 mol) in DMF (535 mL) at room temper-
ature was added dropwise iodomethane (36.0 mL, 0.578 mol). After
5 h, the reaction mixture was diluted with water, and extracted
with ethyl acetate/n-hexane (4/1). The organic layer was washed
with water and 5% aqueous sodium sulfite. The combined organic
layers were dried over Na2SO4, filtered, and concentrated in vacuo
to give the ester as white solids. This crude product was used for the
next step without further purification.
CHCl3))3f,8 in 64% yield in two steps. The overall yield of the pure
(2S,3R)-9 was 47.5% from 5.
Cbz
Cbz
Cbz
Cbz
NH O
NH O
NH O
HN
NH O
a
d,e
f,g
R
H
OMe
OMe
NHBoc
BocN
N Boc
N Bz
5
H
H
(2S,3R)-9
syn-6: R = H
syn-7: R = OMe
syn-8
b,c
To a stirred suspension of the crude ester (ca. 0.321 mol), lith-
ium chloride (27.2 g, 0.64 mol), and NaBH4 (24.3 g, 0.64 mol) in THF
(350 mL) at room temperature was added dropwise ethanol
(800 mL). After 19 h, the reaction mixture was acidified with 10%
aqueous citric acid (500 mL) and concentrated in vacuo. The resi-
due was diluted with water and extracted with CH2Cl2. The com-
bined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to give the alcohol as white solids. This crude
product was used for the next step without further purification.
To a stirred solution of the crude alcohol (ca. 0.321 mol) in
pyridine (642 mL) at 0 ꢁC was added portionwise tosyl chloride
(91.8 g, 0.482 mol). After stirring the mixture for 6.5 h with grad-
ually warming to room temperature, the reaction mixture was di-
luted with water. The whole was extracted with ethyl acetate. The
combined organic layers were washed with aqueous HCl (4 M in
H2O), water, and saturated aqueous NaHCO3, dried over Na2SO4,
filtered, and concentrated in vacuo to give the tosylate as a pale
yellow oil. This crude product was used for the next step without
further purification.
Scheme 3. Diastereoselective synthesis of the (2S,3R)-Dab derivative from (R)-alanine.
Reagents and conditions: (a) (N-Boc)2 (1.2 equiv), (R)-proline (30 mol %), CH3CN
(0.2 M), ꢀ20 ꢁC, 39 h, 100% conversion, anti/syn¼5/95; (b) NaClO2; (c) MeI, KHCO3, 75%
yield (three steps); (d) CF3CO2H; (e) Bz2O, 99% (two steps); f) SmI2, MeOH/THF; g)
(Boc)2O, 64% yield (two steps).
On the other hand, pure anti-9 was obtained using (S)-proline
instead of (R)-proline. The a-hydrazination reaction of 5 using (S)-
proline at ꢀ20 ꢁC for 24 h afforded the anti-6 with an anti/syn ratio
of 97/3 in 93% yield. The obtained anti-6 was converted to the
(2R,3R)-2,3-diaminobutanoic acid derivative 9 with a similar effi-
ciency through a similar route (Scheme 4). A chromatographic
23
purification furnished the pure (2R,3R)-9 (mp 78–79 ꢁC, [
(c 0.50, CHCl3)).3f,9
a]
þ1.1
D
Cbz
Cbz
Cbz
Cbz
NH O
HN
NH O
NH O
NH O
a
d,e
f,g
OMe
OMe
R
H
NHBoc
BocN
N Bz
N Boc
H
H
5
To a stirred solution of the crude tosylate (ca. 0.321 mol) in
DMSO (486 mL) at room temperature was added powdered KCN
(31.4 g, 0.482 mol). After stirring the mixture at 60 ꢁC for 17 h, the
reaction mixture was diluted with water, and the resulting mixture
was extracted with ethyl acetate/n-hexane (4/1). The combined
organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane/ethyl acetate¼5/2) to give the
(2R,3R)-9
anti-6: R = H
anti-7: R = OMe
anti-8
b,c
Scheme 4. Diastereoselective synthesis of the (2R,3R)-Dab derivative from (R)-alanine.
Reagents and conditions: (a) (N-Boc)2 (1.2 equiv), (S)-proline (30 mol %), CH3CN
(0.2 M), ꢀ20 ꢁC, 24 h, 93% conversion yield, anti/syn¼97/3; (b) NaClO2; (c) MeI, KHCO3,
79% yield (three steps); (d) CF3CO2H; (e) Bz2O, 95% (two steps); (f) SmI2; (g) (Boc)2O,
MeOH/THF, 82% yield (two steps).
product (53.2 g, 76% in four steps) as white solids: mp 43–44 ꢁC
3. Conclusion
23
(diethyl ether/n-hexane) (lit.6 mp 46–47); [
a]
þ68.2 (c 1.00,
D
23
CHCl3) (lit.6 [
a
]
D
ꢀ76.0 (c 0.5, CHCl3) for (S)-4); IR (ATR) 3328, 2987,
In conclusion, we have developed a new and practical route to
the (2S,3R)- and (2R,3R)-2,3-diaminobutanoic acid derivatives from
2243, 1685, 1532, 1454, 1335, 1256, 1217 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
1.35 (d, J¼6.8 Hz, 3H), 2.56 (dd, J¼4, 16.8 Hz, 1H), 2.77 (dd,
J¼5.4, 16.6 Hz, 1H), 3.98–4.09 (m, 1H), 4.87 (br s, 1H), 5.06–5.15 (m,
2H), 7.31–7.40 (m, 5H); 13C NMR (100 MHz, CDCl3)
19.3, 24.9, 43.6,
d
(R)-alanine using the reagent-controlled diastereoselective
a-
hydrazination reaction as the key step. This method will provide
a simple and secure procedure for the construction of 2,3-di-
aminobutanoic acid derivatives derived from readily available
d
66.9, 117.1, 128.0, 128.2, 128.3, 128.5, 136.0, 155.3; HRMS-FAB calcd
for C12H15N2O2 [MþH]þ 219.1134, found 219.1120. Anal. Calcd for
C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.93; H, 6.44; N,
12.58.
a
-amino acids.
4. Experimental
4.1. General
4.3. (R)-3-(N-Benzyloxycarbonylamino)butanal (5)
To a stirred solution of the nitrile 4 (7.40 g, 33.9 mmol) in tol-
uene (424 mL) at ꢀ40 ꢁC was added dropwise DIBAL-H (0.95 M in
hexane, 75.0 mL, 71.2 mmol) under argon atmosphere. After 1 h,
the reaction was quenched by a careful addition of diethyl ether
Melting points were measured with a SIBATA NEL-270 melting
point apparatus and are uncorrected. Optical rotations were mea-
sured on a JASCO P-1020 polarimeter with a sodium lamp (589 nm).

K. Makino et al. / Tetrahedron 65 (2009) 9468–9473
9471
(300 mL) and aqueous tartaric acid (2 M in H2O, 500 mL) at ꢀ40 ꢁC.
The resulting mixture was vigorously stirred at room temperature.
After 2 h, the mixture was separated and extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane/ethyl
acetate¼2/1) to give the product (3.90 g, 52%) as a colorless oil:
To a stirred solution of the crude trifluoroacetic acid salt (ca.
3.99 mmol) in CH2Cl2 (20 mL) at 0 ꢁC was added benzoic anhydride
(904 mg, 4.00 mmol) and diisopropylethylamine (2.8 mL,
16.1 mmol), and the resulting mixture was gradually warmed to
room temperature. After stirring the mixture for 2 h, the reaction
was quenched with saturated aqueous NaHCO3, and the resulting
mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
23
23
[
a]
þ14.6 (c 1.00, CHCl3) (lit.7 [
a]
þ16.9 (c 0.7, CH2Cl2)); IR (ATR):
D
D
3308, 2972, 1685, 1532, 1454, 1337, 1252 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
4.15–4.25 (m, 1H), 4.95 (br s, 1H), 5.04–5.15 (m, 2H), 7.30–7.38 (m,
5H), 9.76 (m, 1H); 13C NMR (100 MHz, CDCl3)
20.7, 42.8, 50.0, 66.6,
d
1.27 (d, J¼6.8 Hz, 3H), 2.66 (dq, J¼5.6, 17.2 Hz, 2H),
raphy (n-hexane/ethyl acetate¼1/2) to give the product syn-8
22
(1.52 g, 99%) as a colorless oil: [
a]
ꢀ57.8 (c 0.91, CHCl3); IR (ATR):
D
d
;
3313, 1699, 1646, 1523, 1454, 1213, 1054 cmꢀ1 1H NMR (400 MHz,
128.0, 128.1, 128.5, 136.2, 155.5, 200.8; HRMS-FAB calcd for
CDCl3)
d
1.29 (d, J¼6.8 Hz, 3H), 3.58 (d, J¼6.1 Hz, 1H), 3.74 (s, 3H,),
C12H16N1O3 [MþH]þ 222.1130, found 222.1112.
4.24–4.30 (m, 1H), 5.09 (d, J¼12.2 Hz, 1H), 5.13 (d, J¼12.2 Hz, 1H),
5.14 (d, J¼8.8 Hz, 1H), 5.44 (br s, 1H), 7.29–7.36 (m, 5H), 7.44 (t,
J¼7.6 Hz, 2H), 7.52 (d, J¼7.6 Hz,1H), 7.75 (d, J¼7.6 Hz, 2H), 8.23 (br s,
4.4. Methyl (2S,3R)-2-(N-tert-butyloxycarbonyl-N0-tert-
butyloxycarbonylhydrazino)-3-benzyloxycarbonylamino
butyrate (syn-7)
1H); 13C NMR (100 MHz, CDCl3)
d 17.9, 47.0, 52.3, 66.6, 66.7, 126.9,
127.9, 128.0, 128.4, 128.5, 131.8, 132.3, 136.2, 156.2, 167.2, 171.2;
HRMS-FAB calcd for C20H24N3O5 [MþH]þ 386.1716, found 386.1689.
To a stirred mixture of di-tert-butyl azodicarboxylate (2.82 g,
12.2 mmol) and 5 (2.26 g, 10.2 mmol) in acetonitrile (51 mL) at
ꢀ20 ꢁC was added (R)-proline (353 mg, 3.07 mmol). After stirring the
mixture at ꢀ20 ꢁC for 39 h under argon atmosphere, the reaction
mixture was diluted with ethyl acetate and brine. The mixture was
separated, and the organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo to give syn-6 (syn/anti¼95/5, >99% conver-
sion) as a yellow oil. This crude product was used for the next step
without further purification. The diastereomeric ratio was de-
termined by the aldehyde proton of the 1H NMR (CDCl3 at 55 ꢁC, syn:
9.70 ppm, anti: 9.63 ppm, starting material: 9.76 ppm) spectrum.
To a stirred mixture of syn-6 (ca.10.2 mmol), 2-methyl-2-butene
(5.4 mL, 51.0 mmol), NaH2PO4 (2.45 g, 20.4 mmol) in tert-butyl al-
cohol (41 mL) and water (14 mL) at 0 ꢁC was added dropwise a so-
lution of NaClO2 (purity 79%, 4.67 g, 40.8 mmol) in water (14 mL).
After stirring the mixture at room temperature for 3 h, the reaction
mixture was diluted with water and extracted with ethyl acetate.
The combined organic layers were washed with aqueous Na2S2O3
(0.5 M in H2O) and brine, dried over Na2SO4, filtered, and concen-
trated in vacuo to give the carboxylic acid. This crude product was
used for the next step without further purification.
4.6. Methyl (2S,3R)-3-benzyloxycarbonylamino-2-tert-
butoxycarbonylamino butyrate (syn-9)
To a stirred solution of syn-8 (92.5 mg, 0.240 mmol) in MeOH
(1.8 mL) at 0 ꢁC was added SmI2 (0.1 M in THF, 14.4 mL, 1.44 mmol)
under argon atmosphere and the resulting mixture was stirred at
room temperature. After 20 min, an additional SmI2 (0.1 M in THF,
5.0 mL, 0.5 mmol) was added at room temperature. After additional
30 min, the reaction was quenched with aqueous Na2S2O3 solution
(10% in H2O, 30 mL), and the resulting mixture was extracted with
ethyl acetate. The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo to give the amine as a brown oil. This crude
product was used for the next step without further purification.
To a stirred solution of the crude amine (ca. 0.240 mmol) and
NaHCO3 (65.1 mg, 0.775 mmol) in 1,4-dioxane (1 mL) and H2O
(1 mL) at 0 ꢁC was added Boc2O (71.1 mg, 0.326 mmol) and the
resulting mixture was gradually warmed to room temperature.
After 10 h, the reaction was quenched with 10% aqueous citric acid,
and the resulting mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane/ethyl acetate¼3/1 to 2/1) to
To a stirred mixture of the crude carboxylic acid (ca. 10.2 mmol)
and KHCO3 (3.06 g, 30.6 mmol) in DMF (20.4 mL) at room tem-
perature was added dropwise iodomethane (1.3 mL, 20.9 mmol).
After 12 h, the reaction mixture was diluted with water and
extracted with diethyl ether. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo to give
the crude ester syn-7 as a red oil. This crude product was purified by
give syn-9 (55.8 mg, 64%) as colorless needles: mp 107 ꢁC (diethyl
23
ether/n-hexane); [
a
]
þ55.0 (c 1.49, CHCl3); IR (ATR): 1719, 1680,
D
1501, 1253, 1154 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.20 (d,
J¼6.8 Hz, 3H), 1.44 (s, 9H), 3.75 (s, 3H), 4.23–4.27 (m, 1H), 4.33 (dd,
J¼8.4, 3.7 Hz, 1H), 4.92 (d, J¼8.4 Hz, 1H), 5.05 (d, J¼14.7 Hz, 1H),
5.08 (d, J¼12.1 Hz, 1H), 5.36 (d, J¼7.3 Hz, 1H), 7.30–7.38 (m, 5H); 13C
silica gel column chromatography (CHCl3/diethyl ether¼30/1) to
24
give pure syn-7 (3.68 g, 75%, syn/anti >99/1) as a colorless oil: [
a]
NMR (100 MHz, CDCl3) d 18.3, 28.2, 49.3, 52.6, 57.6, 66.8, 80.2,128.0,
D
þ4.3 (c 0.28, CHCl3); IR (ATR) 3342, 2979, 1697, 1540, 1456, 1393,
128.1, 128.5, 136.3, 155.6, 171.3; HRMS-FAB calcd for C18H27N2O6
[MþH]þ 367.1869, found 367.1833. Anal. Calcd for C18H26N2O6: C,
59.00; H, 7.15; N, 7.65. Found: C, 58.75; H, 7.37; N, 7.43. The HPLC
analysis of the crude syn-9 was carried out using CHIRALCEL OJ-H
(n-hexane/i-PrOH¼95/5, 1.0 mL/min, tR¼12.0 min (major) and
16.6 min (minor)). The optical purity of the syn-9 was >99% ee.8
1367, 1311, 1234 cmꢀ1; 1H NMR (400 MHz, CDCl3 at 55 ꢁC)
d
1.30 (d,
J¼6.8 Hz, 3H), 1.44 (s, 18H), 3.71 (s, 3H), 4.36–4.41 (m, 1H), 4.69 (d,
J¼5.6 Hz, 1H), 5.02–5.11 (m, 2H), 7.25–7.35 (m, 5H); 13C NMR
(100 MHz, CDCl3 at 55 ꢁC)
d 18.2, 28.0 28.1, 46.9, 52.1, 62.9, 66.6,
81.2, 82.1,126.8, 127.8,127.9,128.3, 136.5, 155.2, 155.9, 169.2; HRMS-
FAB calcd for C23H36N3O8 [MþH]þ 482.2502, found 482.2471.
4.7. Methyl (2R,3R)-2-(N-tert-butyloxycarbonyl-N0-tert-
butyloxycarbonylhydrazino)-3-benzyloxycarbonylamino
butyrate (anti-7)
4.5. Methyl (1R,2S)-2-(N0-benzoylhydrazino)-3-
benzyloxycarbonylaminobutyrate (syn-8)
To a stirred solution of syn-7 (1.92 g, 3.99 mmol) in CH2Cl2
(15 mL) at room temperature was added trifluoroacetic acid
(0.5 mL). After stirring the mixture for 12 h, the reaction mixture
was concentrated in vacuo to give the trifluoroacetic acid salt as
a yellow oil. This crude product was used for the next step without
any further purification.
To a stirred mixture of di-tert-butyl azodicarboxylate (3.92 g,
17.0 mmol) and 5 (3.14 g, 14.2 mmol) in acetonitrile (43 mL) at
ꢀ20 ꢁC was added (S)-proline (490 mg, 4.26 mmol). After stirring
the mixture at ꢀ20 ꢁC for 24 h under argon atmosphere, the re-
action mixture was diluted with ethyl acetate and brine. The mix-
ture was separated, and the organic layer was dried over Na2SO4,

9472
K. Makino et al. / Tetrahedron 65 (2009) 9468–9473
filtered, and concentrated in vacuo to give anti-6 (anti/syn¼97/3,
93% conversion yield) as a yellow oil. This crude product was used
for the next step without any further purification. The di-
astereomeric ratio was determined by the aldehyde proton of 1H
NMR (CDCl3 at 55 ꢁC, syn: 9.70 ppm, anti: 9.63 ppm, starting ma-
terial: 9.76 ppm) spectrum.
under argon atmosphere. After 15 min, the reaction was quenched
with aqueous Na2S2O3 solution (1.0 M in H2O), and the resulting
mixture was filtered through a pad of Celite. The filtrate was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo to give
the amine as a brown oil. This crude product was used for the next
step without further purification.
To a stirred mixture of anti-6 (ca. 14.2 mmol), 2-methyl-2-bu-
tene (7.6 mL, 71.8 mmol), NaH2PO4 (3.41 g, 28.4 mmol) in tert-butyl
alcohol (53 mL) and H2O (18 mL) at 0 ꢁC was added dropwise
a solution of NaClO2 (purity 79%, 6.50 g, 56.9 mmol) in H2O (18 mL).
After stirring the mixture for 3 h at room temperature, the reaction
mixture was diluted with water and extracted with ethyl acetate.
The combined organic layers were washed with aqueous Na2S2O3
(0.5 M in H2O) and brine, dried over Na2SO4, filtered, and concen-
trated in vacuo to give the carboxylic acid as a yellow oil. This crude
product was used for the next step without further purification.
To a stirred mixture of the crude carboxylic acid (ca. 14.2 mmol)
and KHCO3 (4.26 g, 42.6 mmol) in DMF (30 mL) at room temperature
was added dropwise iodomethane (1.8 mL, 28.9 mmol). After 12 h,
the reaction mixture was diluted with water and extracted with
diethyl ether. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo to give the crude ester as
a red oil. This crude product was purified by silica gel column
To a stirred solution of the crude amine (ca. 1.33 mmol) and
NaHCO3 (358 mg, 4.26 mmol) in 1,4-dioxane (3.0 mL) and H2O
(3.0 mL) at 0 ꢁC was added Boc2O (350 mg, 1.60 mmol) and the
resulting mixture was gradually warmed to room temperature.
After 12 h, the reaction was quenched by the addition of 10%
aqueous citric acid solution, and the resulting mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(n-hexane/ethyl acetate¼2/1) to give the product anti-9 (401 mg,
82%) as colorless needles: mp 78–79 ꢁC (diethyl ether/hexane);
23
[
a
]
þ1.1 (c 0.50, CHCl3); IR (ATR) 3348, 1744, 1687, 1528, 1319,
D
1266, 1228 cmꢀ1
; d 1.12 (3H, d,
1H NMR (400 MHz, CDCl3)
J¼6.8 Hz), 1.44 (9H, s), 3.76 (3H, s), 4.20 (1H, br s), 4.49 (1H, dd,
J¼8.0, 3.2 Hz), 5.07–5.15 (2H, m), 5.36 (1H, br s), 7.27–7.37 (5H,
m); 13C NMR (100 MHz, CDCl3)
d 16.5, 28.2, 28.3, 49.1, 52.6, 57.4,
chromatography (CHCl3/diethyl ether¼30/1) to give pure anti-7
66.8, 80.4, 128.1, 128.1, 128.5, 136.3, 155.8, 171.1; HRMS-FAB calcd
for C18H27N2O6 [MþH]þ 367.1869, found 367.1860. Anal. Calcd for
C18H26N2O6: C, 59.00; H, 7.15; N, 7.65. Found: C, 58.93; H, 7.03; N,
7.39. The HPLC analysis of the crude product was carried out
using CHIRALCEL AS-H (n-hexane/i-PrOH¼95/5, 1.0 mL/min,
tR¼13.9 min (minor) and 18.4 min (major)). The optical purity of
the anti-9 is >99% ee.9
24
(5.40 g, 79%, anti/syn >99/1) as a colorless oil: [
a
]
þ26.5 (c 0.89,
D
CHCl3); IR (ATR) 3337, 2979, 1712, 1515, 1392, 1367, 1311, 1234,
1148 cmꢀ1 1H NMR (400 MHz, CDCl3 at 55 ꢁC)
;
d
1.17 (d, J¼6.8 Hz,
3H),1.43 (s, 9H),1.47 (s, 9H), 3.74 (s, 3H), 4.47–4.52 (m,1H), 5.08–5.15
(m, 3H), 6.20 (br s, 1H), 6.68 (br s, 1H), 7.25–7.36 (m, 5H); 13C NMR
(100 MHz, CDCl3 at 55 ꢁC)
d 16.6, 28.0, 28.2, 29.7, 46.8, 52.2, 61.4,
66.6, 77.2, 81.7, 82.7, 127.8, 128.0, 128.4, 137.0, 155.0, 155.9, 169.9;
HRMS-FAB calcd for C23H36N8O3 [MþH]þ 482.2502, found 482.2480.
Acknowledgements
4.8. Methyl (1R,2R)-2-(N0-benzoylhydrazino)-3-
benzyloxycarbonylamino butyrate (anti-8)
This work was financially supported in part by a Grant-in-Aid for
Scientific Research (B) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
To a stirred solution of anti-7 (1.22 g, 2.53 mmol) in CH2Cl2
(10.5 mL) at room temperature was added trifluoroacetic acid
(3.5 mL). After stirring the mixture for 3 h, the reaction mixture was
concentrated in vacuo to give the trifluoroacetic acid salt as a yel-
low oil. This crude product was used for the next step without
further purification.
Supplementary data
The HPLC charts and 1H NMR spectra of (2R,3R)-9 and (2S,3R)-9.
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tet.2009.08.064.
To a stirred solution of the crude product (ca. 2.53 mmol) in
CH2Cl2 (12.6 mL) at 0 ꢁC was added benzoic anhydride (572 mg,
2.53 mmol) and diisopropylethylamine (1.8 mL, 10.1 mmol) and the
resulting mixture was gradually warmed to room temperature.
After 4 h, the reaction was quenched with saturated aqueous
NaHCO3, and the resulting mixture was extracted with ethyl ace-
tate. The organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
References and notes
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2005, 105, 3167–3196.
2. (a) Hara, S.; Makino, K.; Hamada, Y. Peptide Science 2005; 2006; p 39–42; (b) Hara,
S.; Makino, K.; Hamada, Y. Tetrahedron Lett. 2006, 47, 1081–1085; (c) Hara, S.;
Nagata, E.; Makino, K.; Hamada, Y. Peptide Science 2007; 2008; p 27–30; (d)
Makino, K.; Jiang, H.; Suzuki, T.; Hamada, Y. Tetrahedron: Asymmetry 2006, 17,
1644–1649; (e) Makino, K.; Nagata, E.; Hamada, Y. Tetrahedron Lett. 2005, 46,
8159–8162; (f) Makino, K.; Nagata, E.; Hamada, Y. Tetrahedron Lett. 2005, 46,
6827–6830.
silica gel column chromatography (n-hexane/ethyl acetate¼1/1) to
20
give anti-8 (1.09 g, 95%) as white solids: [
a]
þ37.3 (c 1.40, CHCl3);
D
IR (ATR): 3313, 1699, 1646, 1523, 1454, 1213, 1054 cmꢀ1
(400 MHz, CDCl3 at 55 ꢁC)
;
1H NMR
3. (a) Dunn, P. J.; Haener, R.; Rapoport, H. J. Org. Chem. 1990, 55, 5017–5025; (b)
Schmidt, U.; Mundinger, K.; Riedl, B.; Haas, G.; Lau, R. Synthesis 1992, 1201–1202;
(c) Gonda, J.; Helland, A.-C.; Ernst, B.; Bellus, D. Synthesis 1993, 729–733; (d)
Nakamura, Y.; Hirai, M.; Tamotsu, K.; Yonezawa, Y.; Shin, C. Bull. Chem. Soc. Jpn.
1995, 68, 1369–1377; (e) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T.
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Tejero, T. Tetrahedron: Asymmetry 1998, 9, 629–646; (g) Han, H.; Yoon, J.; Janda,
K. D. J. Org. Chem. 1998, 63, 2045–2048; (h) Kuwano, R.; Okuda, S.; Ito, Y. Tet-
rahedron: Asymmetry 1998, 9, 2773–2775; (i) Knudsen, K. R.; Risgarrd, T.;
Nishiwaki, N.; Gothelf, K. V.; Jorgensen, K. A. J. Am. Chem. Soc. 2001, 123,
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Chang, J. W.; Lee, W. K.; Dong, Y.; Yun, H. Tetrahedron 2001, 57, 8267–8276; (k)
Dumez, E.; Szeki, A.; Jackson, R. F. W. Synthesis 2001, 1214–1216; (l) Nishiwaki,
N.; Kundsen, K. R.; Gothelf, K. V.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2001, 40,
2992–2995; (m) Robinson, A. J.; Stanislawski, P.; Mulholland, D. J. Org. Chem.
2001, 66, 4148–4152; (n) Robinson, A. J.; Lim, C. Y. J. Org. Chem. 2001, 66,
4141–4147; (o) Ambroise, L.; Dumez, E.; Szeki, A.; Jackson, R. F. W. Synthesis
2002, 2296–2308; (p) Belllardi, L.; Gothelf, A. S.; Hazell, R. G.; Jorgensen, K. A.
d
1.24 (3H, d, J¼6.8 Hz), 3.77 (3H, s),
3.82–3.84 (1H, m), 4.23–4.28 (1H, m), 5.09 (1H, d, J¼12.4 Hz), 5.17
(1H, d, J¼12.4 Hz), 5.21 (1H, br s), 5.42 (1H, br s), 7.26–7.37 (5H, m),
7.42 (2H, t, J¼7.4 Hz), 7.50 (1H, m), 7.77 (2H, d, J¼7.2 Hz), 8.32 (1H,
br s); 13C NMR (100 MHz, CDCl3)
d 16.8, 46.3, 52.2, 65.8, 66.9, 126.9,
127.9, 128.0, 128.4, 128.6, 131.9, 132.3, 136.2, 156.7, 166.9, 170.6;
HRMS-FAB calcd for C20H24N3O5 [MþH]þ 386.1716, found 386.1699.
4.9. Methyl (2R,3R)-3-benzyloxycarbonylamino-2-tert-
butoxycarbonylamino butyrate (anti-9)
To a stirred solution of anti-8 (512 mg, 1.33 mmol) in CH3OH
(6.7 mL) at 0 ꢁC was added SmI2 (0.1 M in THF, 40 mL, 4.00 mmol)

K. Makino et al. / Tetrahedron 65 (2009) 9468–9473
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8. The physical data of our synthetic (2S,3R)-9 were inconsistent with the reported
value (oil, [
a
]
ꢀ26.3 (c 0.56, CHCl3) for (2R,3S)-isomer).3f This discrepancy was
D
solved by HPLC analysis of the synthetic (2S,3R)-9, and its optical purity was
unambiguously confirmed by the HPLC analysis of the synthetic (2R,3S)-9 and
(2S,3R)-9. See Supplementary data.
5. (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657; (b) Bogevig, A.; Juhl, K.;
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9. The physical data of our synthetic (2R,3R)-9 were inconsistent with the reported
value (oil, [
a
]D¼ꢀ19.8 (c 0.28, CHCl3)).3f The optical purity of the synthetic
(2R,3R)-9 was unambiguously confirmed by HPLC analysis of the synthetic
(2R,3R)-9 and (2S,3S)-9. See Supplementary data.