Synthesis of all four stereoisomers of 3-amino-2-hydroxybutanoic acids

Article abstract of DOI:10.1271/bbb.68.714

All four stereoisomers of 3-amino-2-hydroxybutanoic acids were been obtained as single enantiomers via stereospecific reactions from D-gulonic acid γ-lactone and D-glucono-δ-lactone.

Full text of DOI:10.1271/bbb.68.714

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Synthesis of All Four Stereoisomers of 3-Amino-2-
hydroxybutanoic Acids
Jin Hwan LEEa, Min Suk YANGa, Kuy Young KANGa, Yea Hwang MOONb & Ki Hun PARKa
a Division of Applied Life Science (BK21 program), Department of Agricultural Chemistry,
Gyeongsang National University
b Department of Animal Science & Biotechnology, Jinju National University
Published online: 22 May 2014.
To cite this article: Jin Hwan LEE, Min Suk YANG, Kuy Young KANG, Yea Hwang MOON & Ki Hun PARK (2004) Synthesis of All
Four Stereoisomers of 3-Amino-2-hydroxybutanoic Acids, Bioscience, Biotechnology, and Biochemistry, 68:3, 714-720, DOI:
10.1271/bbb.68.714
To link to this article: http://dx.doi.org/10.1271/bbb.68.714
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Biosci. Biotechnol. Biochem., 68 (3), 714–720, 2004
Synthesis of All Four Stereoisomers of 3-Amino-2-hydroxybutanoic Acids
y
1;
Jin Hwan LEE,1 Min Suk YANG,1 Kuy Young KANG,1 Yea Hwang MOON,2 and Ki Hun PARK
1Division of Applied Life Science (BK21 program), Department of Agricultural Chemistry,
Gyeongsang National University, Jinju 660-701, Korea
2Department of Animal Science & Biotechnology, Jinju National University, RAIRC, Jinju 660-758, Korea
Received October 27, 2003; Accepted December 3, 2003
All four stereoisomers of 3-amino-2-hydroxybutanoic
NH2
O
NH2
OH
acids were been obtained as single enantiomers via
stereospecific reactions from D-gulonic acid ꢀ-lactone
and D-glucono-ꢁ-lactone.
H
N
H NH2
Me
O
O
HO
HO H
Key words: isothreonine; alloisothreonine; simultaneous
dealkoxyhalogenation; D-gulonic acid ꢀ-
lactone; D-glucono-ꢁ-lactone
OH
O
NH2
O
HO
ꢂ-Hydroxy-ꢃ-amino acid natural products exhibit a
wide range of biological activity which includes anti-
biotic, antifungal and anti-tumor agents, as well as
displaying protease inhibition.1–5) The synthesis of
homochiral ꢂ-hydroxy-ꢃ-amino acids has therefore
attracted a considerable amount of interest in recent
years, and accordingly, a number of synthetic method-
ologies including Lewis acid-promoted cyanation have
been published.6) These methodologies are ideally suited
to the preparation of one stereoisomer of a target ꢂ-
hydroxy-ꢃ-amino acid, but they still represent a limited
stereodivergent approach. We have recently reported the
synthesis of (2S,3R)- and (2S,3S)-3-amino-2-hydroxy-4-
phenylbutanoic acid from a carbohydrate source.7) This
present report describes the transformation of sugars by
a homochiral synthetic technique to obtain all 3-amino-
2-hydroxybutanoic acid stereoisomers (1–4) with optical
purity. (2S,3R)-3-Amino-2-hydroxybutanoic acid (L-iso-
threonine, 1) is the key component of the glycopeptide,
1-N-(D-threo-3-amino-2-hydroxybutanoyl-20,30-dideoxy-
kanamycin A,8,9) which is known as to be a good
antibacterial agent.8,10) The derivatives of dideoxykana-
mycin A having (2S,3S)- and (2R,3R)-configuration (2
and 3) have shown potent antibacterial activity, similar
to that of dideoxykanamycin A (Fig. 1).8) Furthermore,
L-leucyl peptides 1 and 3 have similar activity to that of
bestatin-related compounds.11)
OH
Fig. 1. Structure of Dideoxykanamycin A.
O
O
OH
OH
3
2
HO
HO
HO
HO
R
S
S
OH OH
S
OH
OH
O
O
NH2
O
O
NH2
1
2
D-gulonic acid γ-lactone
HO
O
OH
OH
OH
R
O
S
R
R
2
3
HO
NH2
NH2
OH
3
4
D-glucono-δ-lactone
Scheme 1. Retrosynthesis of Target Molecules 1–4.
tions (Scheme 1).
Results and Discussion
The directly asymmetric conversion of ꢂ-hydroxy-ꢃ-
amino acid is a highly desirable synthetic transforma-
tion, although this methodology suffers from the
practical problem of a relatively low yield or limitated
stereodivergence. Our objective is to obtain enantio-
merically pure ꢂ-hydroxy-ꢃ-aminoacids from the well-
defined absolute configuration of carbohydrates which
have two stereocenters as required for the target
Our approach to the synthesis of the target molecules
(1–4) envisaged the use of epoxides and chiral amino-
alcohols (13, 17, 18 and 20) which can be obtained from
sugars (D-gulonic acid ꢀ-lactone and D-glucono-ꢁ-lac-
tone, respectively) via a series of selective transforma-
y
To whom correspondence should be addressed. Fax: +82-55-757-0178; E-mail: khpark@gshp.gsnu.ac.kr
Abbreviations: 10% Pd/C, palladium 10 wt.% on activated carbon; Pf-Br, 9-phenyl-9-fluorenyl bromide; Tf2O, trifluoromethanesulfonic anhydride

Synthesis of 3-Amino-2-hydroxybutanoic Acids
715
molecules (1–4). Thus, the stereochemistry at C2 and C3
O
O
O
O
of D-gulonic acid ꢀ-lactone was used as a basis for
compounds 1 and 2, whilst the stereochemistry at C2
and C3 of D-glucono-ꢁ-lactone was used for compounds
3 and 4.
O
O
O
O
3
2
O
O
O
5
a
OH OH
OH
OH
D-gulonic acid γ-lactone
(2S,3R)-3-Amino-2-hydroxybutanoic acid (L-isothreo-
nine) (1)
O
Diisopropylidene-D-glucitol (5) was synthesized in a
high yield via a four-step process from D-gulonic acid ꢀ-
lactone.7) Epoxide 5 was reacted with LiAlH4 to give
secondary alcohol 7 in an 81% yield, with no evidence
of any product arising from an endoreductive cleavage
pathway. Protected amine 8 was prepared in a 57% yield
from the secondary alcohol according to our recently
published methodology,7,12) in which the addition of a
pre-cooled solution of Tf2O in CH2Cl2 at ꢀ10ꢁC
suppressed epimerization in the triflation step. The 9-
phenyl-9-fluorenyl (Pf) group was chosen to protect the
amino moiety as it has been shown to be not only stable
under basic conditions but also stable to organometallic
reagents (Scheme 2).13) The terminal isopropylidene
group was selectively cleaved by treating diisopropyli-
dene 8 with Dowex 50-X8 resin to give diol 9 in a 91%
yield.14)
6
O
O
O
O
b
c
O
O
5
O
7
OH
O
O
8
NHPf
NHPf
d
OH
O
O
f
e
HO
RO
I
O
O
NHPf
O
12
NHPf
10: R = H
11: R = Ms
9
g
OBn
OH
OR
i
h
HO
HO
Compound 9 was then treated with NaIO4, and the
resulting aldehyde was reduced with NaBH4, leading to
the formation of alcohol 10 in a 91% overall yield.
Mesylation of alcohol 10 with MsCl in THF generated
mesylate 11, and subsequent treatment with LiI at 80ꢁC
gave iodide 12 in an 88% yield. Treatment of iodide 12
with n-BuLi at ꢀ40ꢁC generated (3R,4R) aminoalcohol
O
NHPf
O
NH2
NHPf
13: R = H
14: R = Bn
15
1
Scheme 2. Synthetic Route to the (2S,3R)-3-Amino-2-hydroxybuta-
noic Acid (1).
a: ref. 7; b: LAH, THF, 0ꢁC (81% yield); c: i) Tf2O, pyridine,
CH2Cl2, ꢀ10ꢁC (90% yield); ii) NaN3, DMF, rt (94% yield); iii) H2,
Pd/C, EtOAc, rt (85% yield); iv) Pf-Br, Pb(NO3)2, Et3N, CH2Cl2, rt
(79% yield); d: Dowex 50W-X8, MeOH, rt (91% yield); e: i) NaIO4,
EtOH-H2O (2:1), rt, NaBH4, 0ꢁC (91% yield); ii) MsCl, Et3N, THF,
0ꢁC (96%, yield); f: LiI, DMF, 80ꢁC (88% yield); g: i) n-BuLi, THF,
ꢀ40ꢁC (89% yield); ii) BnBr, 60% NaH, Bu4NI, THF, 0ꢁC (91%
yield); h: O3, MeOH, ꢀ78ꢁC , 30% H2O2, rt (90% yield); i: H2, 10%
Pd/C, MeOH, 70ꢁC (83% yield).
20
13 {½ꢂꢂD ꢀ287:6ꢁ (c 4.00, CHCl3)} in an 89% yield
through simultaneous dealkoxyhalogenation.12,15) The
secondary hydroxyl group of 13 was easily protected
with BnBr to give benzylate 14 in a 91% yield.
Ozonolysis of benzylate 14 and subsequent H2O2
oxidation afforded protected (2S,3R)-3-amino-2-hydrox-
ybutanoic acid 15. To remove the Pf and Bn protecting
groups, compound 15 was treated with H2 and 10% Pd/
C in MeOH. Subsequent purification by ion-exchange
chromatography (Dowex 50W-X8) yielded the base
form of (2S,3R)-3-amino-2-hydroxybutanoic acid (L-
resulting benzylate was subjected to ozonolysis and
hydrogenolysis by a similar procedure to that for
compound 1 to give (2S,3S)-3-amino-2-hydroxybutanoic
acid 2. The physical properties and 1H- and 13C-spectral
data for compound 2 were identical to those previously
reported.10,17)
1
isothreonine) 1 as a solid. H- and 13C-NMR data and
the optical rotation for 1 are consistent with those
reported.8,9,16)
(2R,3R)- and (2R,3S)-3-Amino-2-hydroxybutanoic
acid (D-alloisothreonine and D-isothreonine; 3 and 4)
To further demonstrate the versatility of this synthetic
strategy, we prepared the (2R,3R)- and (2R,3S)-3-amino-
2-hydroxybutanoic acids (3 and 4). The aminoalcohols
(18 and 20) were obtained as single stereoisomers from
D-glucono-ꢁ-lactone by the same procedure as that
already described (5!13). After benzylating the chiral
aminoalcohols (18 and 20), the resulting chiral benzy-
lates were sequentially subjected to ozonolysis and
hydrogenolisis to afford either (2R,3R)- or (2R,3S)-3-
amino-2-hydroxybutanoic acid (3 or 4) as a single
(2S,3S)-3-Amino-2-hydroxybutanoic acid (L-alloiso-
threonine) (2)
Epoxide 6 was prepared from D-gulonic acid ꢀ-
lactone.7) To prepare (2S,3S)-3-amino-2-hydroxybuta-
noic acid (2), called L-alloisothreonine, epoxide 6 was
converted to compound 16 through triflation, azidation,
hydrogenation, and an N-protection step. N-Protected 16
was subjected to the same reaction conditions as those
already described above (8!13) to afford (3R,4S)
20
aminoalcohol 17 {½ꢂꢂD +290.7ꢁ (c 1.00, CHCl3)}
(Scheme 3). After benzylating aminoalcohol 17, the

716
J. H. LEE et al.
tively). These compounds are important precursors for
O
O
the asymmetric synthesis of bioactive ꢂ-hydroxy-ꢃ-
amino acids. We additionally report that all four
stereoisomers of 3-amino-2-hydroxybutanoic acids (1–
4) could be obtained in enantiomerically pure form from
the respective chiral aminoalcohol.
a
O
6
O
16
NHPf
b
Experimental
OH
OH
All non-aq. reactions were carried out in an inert
nitrogen atmosphere. THF was distilled from Na/
benzophenone, and 2,2-dimethoxypropane, DMF, and
methylene chloride were distilled from CaH2. Column
chromatography was carried out with 230–400 mesh
silica gel. The final solution before evaporation was
washed with brine and dried over anhydrous Na2SO4.
All melting point(mp) data were measured by Thomas
Scientific capillary melting point apparatus and are
uncorrected. IR spectra were recorded by a Bruker
IFS66 infrared Fourier transform spectrophotometer,
and 1H-NMR and 13C-NMR experiments were con-
ducted with a Brucker AW-500 spectrometer. Optical
rotation values were measured with a Jasco DIP-1000
polarimeter, and ½ꢂꢂD values are given in units of
HO
c
NHPf
17
O
NH2
2
Scheme 3. Synthetic Route to the (2S,3S)-3-Amino-2-hydroxybuta-
noic Acid (2).
a: i) LAH, THF, 0ꢁC; ii) Tf2O, pyridine, CH2Cl2, ꢀ10ꢁC; iii)
NaN3, DMF, rt; iv) H2, Pd/C, EtOAc, rt; v) Pf-Br, Pb(NO3)2, Et3N,
CH2Cl2, rt (58% yield, 5 steps); b: i) Dowex 50W-X8, MeOH, rt; ii)
NaIO4, EtOH-H2O (2:1), rt, NaBH4, 0ꢁC; iii) MsCl, Et3N, THF,
0ꢁC; iv) LiI, DMF, 80ꢁC; v) n-BuLi, THF, ꢀ40ꢁC (63% yield, 5
steps); c: i) BnBr, 60% NaH, Bu4NI, THF, 0ꢁC; ii) O3, MeOH,
ꢀ78ꢁC, 30% H2O2, rt; iii) H2, 10% Pd/C, MeOH, 70ꢁC (65% yield,
3 steps).
10ꢀ1 deg cm2gꢀ1
.
HO
OH
OH
O
1,2-Anhydro-3,4;5,6-di-O-isopropylidene-D-gulitol (5).
This compound was prepared from D-gulonic acid ꢀ-
lactone as previously described.7)
OH
a
a
O
2
HO 3
NHPf
18
NHPf
20
OH
D-glucono-δ-lactone
1-Deoxy-3,4;5,6-di-O-isopropylidene-D-gulitol (7).To
an ice-cooled solution of LiAlH4 (0.31 g, 8.19 mmol) in
THF (14 ml) was added a solution of epoxide compound
5 (1.00 g, 4.09 mmol) in THF (6 ml). The reaction
mixture was warmed to room temperature, stirred for
25 min, and then quenched by the sequential addition of
water (1.0 ml), 15% aq. NaOH (1.0 ml), and water
(3.0 ml). The mixture was filtered and evaporated. The
resulting residue was chromatographed on silica gel
(EtOAc-hexane, 1:3) to give compound 7 (0.82 g, 81%)
b
d
OBn
OBn
HO
HO
HO
HO
O
O
NHPf
O
O
NHPf
19
21
c
e
20
as an oil; ½ꢂꢂD ¼ þ7:8ꢁ (c 4.00, CHCl3); NMR ꢁH
OH
OH
(CDCl3): 1.27 (d, J ¼ 6:0 Hz, 3H), 1.38 (s, 3H), 1.40 (s,
3H), 1.43 (s, 3H), 1.44 (s, 3H), 2.24 (d, J ¼ 3:1 Hz, 1H),
3.87 (m, 2H), 3.94 (t, J ¼ 7:5 Hz, 1H), 4.06 (m, 2H), and
4.23 (m, 1H); NMR ꢁC (CDCl3): 19.4, 25.5, 26.1, 27.0,
27.3, 65.9, 68.3, 75.6, 77.7, 80.8, 109.4, and 109.7; IR
ꢄmax (KBr) cmꢀ1: 3477, 2998, 2940, 2904. Anal. Found:
C, 58.51; H, 9.01%. Calcd. for C12H22O5: C, 58.52; H,
9.00%.
NH2
NH2
3
4
Scheme 4. Synthetic Route to the (2R,3R)- and (2R,3S)-3-Amino-2-
hydroxybutanoic Acids (3 and 4).
a, b, c, d, e: i) ref. 7; ii) (2R,3R)- and (2R,3S)-3-amino-2-
hydroxybutanoic acids (3 and 4) were obtained by the same
procedure as that used for the conversion of 5 to 1.
1,2-Dideoxy-3,4;5,6-di-O-isopropylidene-2-[(9-phen-
yl-9-fluorenyl)-amino]-D-iditol (8). To a solution of
gulitol 7 (0.70 g, 2.84 mmol) in CH2Cl2 (10 ml) at
ꢀ10ꢁC was added pyridine (0.70 ml, 8.53 mmol), before
an ice-cooled solution of Tf2O (0.72 ml, 4.26 mmol) in
CH2Cl2 (6 ml) was dropped for 5 min at the same
temperature. The reaction mixture was stirred for 10 min
at ꢀ10ꢁC, and then quenched with saturated aq.
diastereomer in each case. The spectroscopic data
for 3 and 4 are consistent with those reported
(Scheme 4).9,10,17)
In conclusion, we report here the stereospecific
synthesis of chiral aminoalcohols 13, 17, 18, and 20
via simultaneous dealkoxyhalogenation from sugars (D-
gulonic acid ꢀ-lactone and D-glucono-ꢁ-lactone, respec-

Synthesis of 3-Amino-2-hydroxybutanoic Acids
717
NaHCO3 (16 ml). The organic layer was washed with
saturated aq. CuSO4 (16 ml) and then evaporated to give
a triflate (0.97 g, 90%) which was used without further
purification. A mixture of this triflate (0.97 g, 2.57
mmol) and NaN3 (0.50 g, 7.70 mmol) in DMF (10 ml)
was stirred for 2 h at room temperature. The reaction
mixture was quenched with H2O (50 ml) and extracted
with EtOAc (90 ml). After evaporating the organic layer,
the remaining residue was subjected to flash column
chromatography to give an azide compound (0.65 g,
94%). This compound was directly hydrogenated with
10% Pd/C (0.07 g) in EtOAc (10 ml) to the correspond-
ing free amine (0.50 g, 85%). To a solution of this free
amine (0.50 g, 2.04 mmol) in CH2Cl2 (10 ml) were
added Pf-Br (0.98 g, 3.06 mmol), Pb(NO3)2 (1.01 g, 3.06
mmol), and Et3N (0.60 ml, 4.08 mmol). After stirring for
24 h at room temperature, the mixture was filtered,
poured into an excess of H2O, and extracted with
CH2Cl2 (60 ml). After concentrating the combined
extracts, the resulting residue was chromatographed on
silica gel (EtOAc-hexane, 1:6) to give N-protected
compound 8 (0.78 g, 79%) as a solid, mp 40–42ꢁC;
added NaIO4 (1.44 g, 6.73 mmol) at room temperature.
After stirring for 3 h, the mixture was cooled to 0ꢁC,
NaBH4 (0.25 g, 6.73 mmol) was added, and the resulting
mixture was stirred for 10 min. After evaporating EtOH,
the mixture was poured into an excess of H2O and
extracted with EtOAc (120 ml). After concentrating the
combined extracts, the residue was chromatographed on
silica gel (EtOAc-hexane, 1:3) to give alcoholic com-
20
pound 10 (1.70 g, 91%) as a solid, mp 49–51ꢁC; ½ꢂꢂD
¼
ꢀ79:5ꢁ (c 2.00, CHCl3); NMR ꢁH (CDCl3): 0.81 (d,
J ¼ 6:8 Hz, 3H), 1.20 (s, 3H), 1.32 (s, 3H), 2.46 (m,
1H), 3.38 (dd, J ¼ 4:1; 8:3 Hz, 3H), 3.62 (m, 1H), 3.74
(dd, J ¼ 4:4, 11.0 Hz, 1H), 4.05 (m, 1H), and 7.02–7.72
(m, 13H); NMR ꢁC (CDCl3): 17.9, 27.2, 27.2, 27.4, 48.8,
63.7, 73.5, 76.7, 82.9, 108.6, 120.6, 120.7, 125.1, 126.1,
126.3, 126.3, 127.8, 128.3, 128.4, 128.8, 128.9, 129.0,
129.0, 129.1, 140.7, 141.4, 144.6, 149.1, and 150.2; IR
ꢄmax (KBr) cmꢀ1: 3436, 3319, 3070, 3019, 2990, 2931,
2873, 1739, 1607. Anal. Found: C, 78.04; H, 7.02; N,
3.36. Calcd. for C27H29NO3: C, 78.04; H, 7.03; N,
3.37%.
20
½ꢂꢂD ¼ ꢀ103:7ꢁ (c 1.00, CHCl3); NMR ꢁH (CDCl3):
1,2-Dideoxy-3,4-O-isopropylidene-5-O-methanesul-
fonyl-2-[(9-phenyl-9-fluorenyl)-amino]-L-xylitol (11). To
a solution of alcohol 10 (1.50 g, 3.60 mmol) in THF
(16 ml) were added triethylamine (1.00 ml, 7.21 mmol)
and methanesulfonyl chloride (0.56 ml, 7.21 mmol) at
0ꢁC. The reaction mixture was stirred for 10 min at the
same temperature, before being quenched with saturated
aq. NaHCO3 (35 ml). The organic phase was separated,
and the aq. phase was extracted with EtOAc (105 ml).
After concentrating the combined extracts, the resulting
residue was chromatographed on silica gel (EtOAc-
hexane, 1:5) to give mesylate 11 (1.70 g, 96%), mp 48–
0.62 (d, J ¼ 6:6 Hz, 3H), 1.35 (s, 3H), 1.36 (s, 3H), 1.40
(s, 3H), 1.48 (s, 3H), 2.19 (br, 1H), 2.31 (m, 1H), 3.69
(m, 2H), 3.90 (m, 2H), 4.18 (dd, J ¼ 3:5, 7.9 Hz, 1H),
and 7.18–7.68 (m, 13H); NMR ꢁC (CDCl3): 20.9, 26.2,
26.7, 27.4, 28.0, 48.5, 66.2, 72.9, 76.1, 82.5, 109.4,
109.8, 120.3, 120.4, 125.8, 126.1, 126.5, 127.5, 128.0,
128.2, 128.6, 128.7, 128.7, 140.7, 140.9, 146.0, 149.5,
and 152.0; IR ꢄmax (KBr) cmꢀ1: 3319, 3070, 2991, 2940,
2904, 1728. Anal. Found: C, 76.68; H, 7.26; N, 2.87%.
Calcd. for C31H35NO4: C, 76.67; H, 7.26; N, 2.88%.
20
1,2-Dideoxy-3,4-O-isopropylidene-2-[(9-phenyl-9-flu-
orenyl)-amino]-D-iditol (9). To a solution of N-protected
compound 8 (3.00 g, 6.18 mmol) in 90% MeOH (30 ml)
was added Dowex 50W-X8 resin (0.30 g) at room
temperature. After stirring for 24 h, the reaction mixture
was filtered, and then the filtrate was evaporated. The
resulting residue was chromatographed on silica gel
(EtOAc-hexane, 1:2) to give diol 9 (2.50 g, 91%) as a
50ꢁC; ½ꢂꢂD ¼ ꢀ98:6ꢁ (c 1.00, CHCl3); NMR ꢁH
(CDCl3): 0.66 (d, J ¼ 6:6 Hz, 3H), 1.33 (s, 3H), 1.42
(s, 3H), 2.13 (br, 1H), 2.36 (dd, J ¼ 3:9, 6.6 Hz 1H),
3.05 (s, 3H), 3.52 (dd, J ¼ 3:9, 8.2 Hz, 1H), 4.12 (dd,
J ¼ 6:1, 11.2 Hz, 1H), 4.37 (m, 1H), 4.46 (dd, J ¼ 2:6,
11.2 Hz, 1H), and 7.18–7.71 (m, 13H); NMR ꢁC
(CDCl3): 19.1, 26.8, 27.0, 27.3, 37.8, 48.2, 69.8, 72.7,
75.1, 81.0, 109.5, 120.0, 120.1, 120.2, 125.2, 125.4,
126.1, 127.2, 127.8, 127.9, 128.4, 128.4, 128.5, 140.3,
20
solid, mp 66–68ꢁC; ½ꢂꢂD ¼ ꢀ120:5ꢁ (c 1.00, CHCl3);
NMR ꢁH (CDCl3): 0.66 (d, J ¼ 6:6 Hz, 3H), 1.33 (s,
3H), 1.42 (s, 3H), 2.37 (m, 1H), 2.56 (br, 1H), 3.50 (m,
1H), 3.69 (m, 2H), 3.75 (dd, J ¼ 3:6, 8.2 Hz, 1H), 4.16
(dd, J ¼ 2:8, 8.2 Hz, 1H), and 7.19–7.69 (m, 13H);
NMR ꢁC (CDCl3): 19.8, 27.4, 27.8, 48.6, 65.5, 70.0,
73.1, 78.7, 81.6, 109.3, 120.4, 120.5, 125.7, 125.9,
126.4, 127.6, 128.1, 128.2, 128.7, 128.8, 128.9, 140.8,
140.6, 145.2, 149.0, and 151.0; IR ꢄmax (KBr) cmꢀ1
:
3346, 2983, 2933, 1735, 1662. Anal. Found: C, 68.14; H,
6.33; N, 2.85%. Calcd. for C28H31NO5S: C, 68.13; H,
6.33; N, 2.84%.
1,2,5-Trideoxy-3,4-O-isopropylidene-5-iodo-2-[(9-
phenyl-9-fluorenyl)-amino]-L-xylitol (12). To a solution
of mesylate 11 (1.50 g, 3.04 mmol) in DMF (15 ml) was
added LiI (1.22 g, 9.12 mmol) over 12 h at 80ꢁC. To the
reaction mixture was added saturated aq. NaHCO3
(40 ml), before extracting with EtOAc (90 ml). The
extract was evaporated and chromatographed on silica
gel (EtOAc-hexane, 1:12) to give iodonate 12 (1.40 g,
140.9, 145.5, 149.3, and 151.4; IR ꢄmax (KBr) cmꢀ1
:
3429, 3341, 3070, 2990, 2931, 1600. Anal. Found: C,
75.50; H, 7.00; N, 3.14%. Calcd. for C28H31NO4: C,
75.48; H, 7.01; N, 3.14%.
1,2-Dideoxy-3,4-O-isopropylidene-2-[(9-phenyl-9-flu-
orenyl)-amino]-L-xylitol (10). To a solution of diol 9
(2.00 g, 4.49 mmol) in EtOH-H2O (30 ml:15 ml) was
20
88%) as a solid, mp 51–54ꢁC; ½ꢂꢂD ¼ ꢀ103:2ꢁ (c 2.00,
CHCl3); NMR ꢁH (CDCl3): 0.62 (d, J ¼ 6:6 Hz, 3H),

718
J. H. LEE et al.
1.40 (s, 3H), 1.46 (s, 3H), 2.15 (br, 1H), 2.34 (m, 1H),
3.09 (dd, J ¼ 6:0, 10.6 Hz, 1H), 3.27 (dd, J ¼ 4:0,
10.6 Hz, 1H), 3.41 (dd, J ¼ 3:4, 7.5 Hz, 1H), 4.11 (m,
1H), and 7.17–7.69 (m, 13H); NMR ꢁC (CDCl3): 7.9,
20.4, 27.9, 28.0, 48.7, 73.0, 76.6, 86.1, 109.3, 120.4,
120.5, 125.8, 126.0, 126.5, 127.6, 128.2, 128.3, 128.7,
128.7, 128.8, 140.7, 140.9, 145.8, 149.5, and 151.7; IR
ꢄmax (KBr) cmꢀ1: 3341, 3078, 2990, 2939, 1607. Anal.
Found: C, 61.72; H, 5.36; N, 2.67%. Calcd. for
C27H28INO2: C, 61.72; H, 5.37; N, 2.67%.
(2S,3R)-2-O-Benzyl-3-[(9-phenyl-9-fluorenyl)-amino]-
butanoic acid (15). A solution of benzylate 14 (0.80 g,
1.85 mmol) in CH3OH (16 ml) was ozonized at ꢀ78ꢁC
until the solution turned blue, the residual ozone then
being removed by purging with N2 gas. The reaction
mixture was left to reach room temperature, 30% H2O2
(16 ml) was added, and the mixture was stirred over-
night. After concentrating the combined extracts, the
residue was chromatographed on silica gel (EtOAc-
hexane, 1:1) to give compound 15 (0.75 g, 90%) as a
20
solid, mp 76–78ꢁC; ½ꢂꢂD ¼ ꢀ59:4ꢁ (c 2.00, CHCl3);
(3R,4R)-3-Hydroxy-4-[(9-phenyl-9-fluorenyl)-amino]-
1-pentene (13). To a solution of iodinate 12 (1.30 g,
2.47 mmol) in THF (15 ml) was dropped 2.5 M n-BuLi
(1.98 ml, 4.95 mmol, 200 mol%) over 10 min via a
syringe at ꢀ40ꢁC. The reaction mixture was stirred for
an additional 15 min at the same temperature and then
quenched with saturated aq. NH4Cl (20 ml). The mixture
was extracted with EtOAc (60 ml) and concentrated. The
resulting residue was chromatographed on silica gel
(EtOAc-hexane, 1:4) to give allylic alcohol 13 (0.75 g,
NMR ꢁH (CDCl3): 0.89 (d, J ¼ 6:7 Hz, 3H), 2.57–2.62
(m, 1H), 3.26 (d, J ¼ 3:7 Hz, 1H), 4.13 (d, J ¼ 12:2 Hz,
1H), 4.56 (d, J ¼ 12:2 Hz, 1H), and 7.04–7.74 (m, 19H);
NMR ꢁC (CDCl3): 17.6, 50.0, 72.6, 72.8, 78.7, 120.5,
120.5, 124.2, 125.4, 125.7, 127.7, 127.7, 127.9, 128.3,
128.4, 128.5, 128.9, 129.2, 129.3, 137.4, 139.9, 141.2,
142.9, 146.9, 148.3, and 171.8; IR ꢄmax (KBr) cmꢀ1
:
3331, 3062, 3010, 2920, 1708, 1603. Anal. Found: C,
80.15; H, 6.04; N, 3.12%. Calcd. for C30H27NO3: C,
80.15; H, 6.05; N, 3.12%.
20
89%) as a solid, mp 51–52ꢁC; ½ꢂꢂD ¼ ꢀ287:6ꢁ (c 4.00,
CHCl3); NMR ꢁH (CDCl3): 0.55 (d, J ¼ 6:4 Hz, 3H),
2.12 (dt, J ¼ 6:5, 12.9 Hz, 1H), 2.90 (br, 1H), 3.58 (t,
J ¼ 6:7 Hz, 1H), 5.04–5.07 (m, 1H), 5.17–5.21 (m, 1H),
5.51–5.58 (m, 1H), and 7.19–7.71 (m, 13H); NMR ꢁC
(CDCl3): 19.1, 53.0, 72.5, 77.3, 117.0, 120.0, 120.0,
125.1, 125.6, 125.9, 127.2, 127.7, 128.1, 128.3, 138.4,
140.1, 140.6, 145.1, 148.7, and 151.0; IR ꢄmax (KBr)
cmꢀ1: 3404, 3317, 3078, 3027, 2933, 1815, 1735. Anal.
Found: C, 84.41; H, 6.79; N, 4.11%. Calcd. for
C24H23NO: C, 84.42; H, 6.79; N, 4.10%.
(2S,3R)-3-Amino-2-hydroxybutanoic acid [(1), L-iso-
threonine]. Protected butanoic acid 15 (0.50 g, 1.11
mmol) and 10% Pd/C (0.05 g) were stirred in CH3OH
(12 ml) under an atmosphere of hydrogen at 70ꢁC for
12 h. After filtering the catalyst off with Celite, to the
filtrate was added Dowex 50W-X8. The mixture was
filtered, and then washed with MeOH. The remaining
residue was eluted with 3 N NH4OH. The ammoniacal
solution was evaporated, and co-evaporation with
toluene gave L-isothreonine 1 (0.11g, 83%) as a solid,
20
mp 213–216ꢁC; ½ꢂꢂD ¼ ꢀ13:2ꢁ (c 0.70, H2O) {lit.16)
25
(3R,4R)-3-O-Benzyl-4-[(9-phenyl-9-fluorenyl)-amino]-
1-pentene (14). Allylic alcohol 13 (1.00 g, 2.93 mmol)
was dissolved in THF (15 ml) and treated with 60% NaH
(0.23 g, 5.86 mmol) and Bu4NI (0.32 g, 0.88 mmol) at
0ꢁC. After stirring for 10 min at the same temperature,
BnBr (0.70 ml, 5.86 mmol) was added. The reaction
mixture was stirred for 24 h at room temperature and
then quenched with saturated aq. NH4Cl (30 ml), before
the mixture was extracted with EtOAc (90 ml). After
concentrating the combined extracts, the residue was
purified by silica gel column chromatography (EtOAc-
hexane, 1:8) to give benzylate 14 (1.15 g, 91%) as an oil,
½ꢂꢂD ¼ ꢀ12:4ꢁ (c 0.75, H2O), mp > 225ꢁC (decomp.)};
NMR ꢁH (D2O): 1.27 (d, J ¼ 11:3 Hz, 3H), 3.59–3.63
(m, 1H), and 4.24 (d, J ¼ 7:9 Hz, 1H); NMR ꢁC (D2O):
14.5, 49.2, 70.8, and 174.1; IR ꢄmax (KBr) cmꢀ1: 3416,
3063, 2930, 1740. Anal. Found: C, 40.31; H, 7.62; N,
11.77%. Calcd. for C4H9NO3: C, 40.33; H, 7.62; N,
11.76%.
1,2-Anhydro-3,4;5,6-di-O-isopropylidene-D-iditol (6).
This compound was prepared from D-gulonic acid ꢀ-
lactone as previously described.7)
20
½ꢂꢂD ¼ ꢀ1:2ꢁ (c 4.00, CHCl3); NMR ꢁH (CDCl3): 0.56
1,2-Dideoxy-3,4;5,6-di-O-isopropylidene-2-[(9-phen-
yl-9-fluorenyl)-amino]-D-mannonate (16). N-protected
16 was obtained by the same procedure with the
conversion of 5 to 8; the overall yield for this conversion
(d, J ¼ 6:5 Hz, 3H), 2.43 (dt, J ¼ 6:4; 12:7 Hz, 1H), 3.48
(dd, J ¼ 6:3; 7:0 Hz, 1H), 4.14 (d, J ¼ 12:2 Hz, 1H),
4.36 (d, J ¼ 12:2 Hz, 1H), 5.23–5.29 (m, 2H), 5.74–5.81
(m, 1H), and 7.16–7.68 (m, 13H); NMR ꢁC (CDCl3):
18.5, 51.7, 70.5, 73.4, 84.9, 119.0, 120.2, 120.3, 125.8,
126.1, 126.5, 127.4, 127.7, 127.9, 128.0, 128.1, 128.4,
128.5, 128.6, 128.7, 136.1, 136.3, 139.2, 140.7, 140.9,
146.4, 150.2, and 151.6; IR ꢄmax (neat) cmꢀ1: 3334,
3070, 3026, 2975, 2939, 2873, 1951. Anal. Found: C,
87.56; H, 6.57; N, 2.76%. Calcd. for C31H29NO: C,
86.27; H, 6.77; N, 3.25%.
20
was 58%; mp 48–52ꢁC; ½ꢂꢂD ¼ þ0:4ꢁ (c 2.00, CHCl3);
NMR ꢁH (CDCl3): 0.77 (d, J ¼ 6:5 Hz, 3H), 1.30 (s,
3H), 1.32 (s, 3H), 1.33 (s, 3H), 1.34 (s, 3H), 2.23 (m,
2H), 3.28 (t, J ¼ 8:0 Hz, 1H), 3.45 (dd, J ¼ 6:5, 8.2 Hz,
1H), 3.55 (dd, J ¼ 5:4, 7.8 Hz, 1H), 3.62 (dd,
J ¼ 3:7; 7:8 Hz, 1H), 3.80–3.84 (m, 1H), and 7.17–
7.71 (m, 13H); NMR ꢁC (CDCl3): 17.6, 25.7, 26.3, 27.0,
27.1, 49.6, 65.2, 73.0, 76.8, 78.7, 81.4, 109.3, 109.4,
120.0, 120.0, 125.3, 125.5, 126.1, 127.1, 127.9, 127.9,

Synthesis of 3-Amino-2-hydroxybutanoic Acids
719
128.2, 128.3, 128.4, 140.3, 140.4, 145.3, 150.1, and
150.5; IR ꢄmax (KBr) cmꢀ1: 3303, 3063, 2991, 2896,
1598. Anal. Found: C, 76.67; H, 7.26; N, 2.86%. Calcd.
for C31H35NO4: C, 76.67; H, 7.26; N, 2.88%.
3017, 2931, 2870, 1729, 1624. Anal. Found: C, 80.14; H,
6.05; N, 3.12%. Calcd. for C30H27NO3: C, 80.15; H,
6.05; N, 3.12%.
(2R,3R)-3-Amino-2-hydroxybutanoic acid [(3), D-al-
loisothreonine]. (2R,3R)-Hydroxybutanoic acid 3 was
obtained by same procedure as that for the conversion of
15 to 1; the overall yield for this conversion was 62%;
(3R,4S)-3-Hydroxy-4-[(9-phenyl-9-fluorenyl)-amino]-
1-pentene (17). Allylic alcohol 17 was obtained by the
same procedure with the conversion of 8 to 13; the
overall yield for this conversion was 63%; mp 48–52ꢁC;
20
mp 239–240ꢁC; ½ꢂꢂD ¼ þ23:4ꢁ (c 0.90, H2O) {lit.9)
20
25
½ꢂꢂD ¼ þ290:7ꢁ (c 1.00, CHCl3); NMR ꢁH (CDCl3):
½ꢂꢂD ¼ þ23:0ꢁ (c 0.50, H2O), mp 238–239ꢁC}; NMR
0.66 (d, J ¼ 6:7 Hz, 3H), 2.29 (m, 1H), 3.12 (br, 1H),
3.52 (m, 1H), 5.01–5.10 (m, 2H), 5.59 (m, 1H), and
7.20–7.73 (m, 13H); NMR ꢁC (CDCl3): 17.6, 52.8, 73.0,
74.5, 115.7, 120.4, 120.5, 125.1, 125.7, 126.3, 127.7,
128.3, 128.5, 128.8, 128.9, 137.7, 140.3, 141.4, 145.5,
149.6, and 150.8; IR ꢄmax (KBr) cmꢀ1: 3462, 3027,
2933, 1735, 1644. Anal. Found: C, 84.40; H, 6.79; N,
4.12%. Calcd. for C24H23NO: C, 84.42; H, 6.79; N,
4.10%.
ꢁH (D2O): 1.24 (d, J ¼ 6:8 Hz, 3H), 3.80–3.85 (m, 1H),
and 4.52 (d, J ¼ 3:4 Hz, 1H); NMR ꢁC (D2O): 12.3,
49.5, 70.4, and 174.4; IR ꢄmax (KBr) cmꢀ1: 3429, 2930,
1634. Anal. Found; C, 40.35; H, 7.63; N, 11.76%. Calcd.
for C4H9NO3: C, 40.33; H, 7.62; N, 11.76%.
(3S,4S)-3-Hydroxy-4-[(9-phenyl-9-fluorenyl)-amino]-
1-pentene (20). Aminoalcohol 20 was obtained from D-
glucono-ꢁ-lactone by the same procedure as that
described for the preparation of 13, mp 48–52ꢁC;
20
(2S,3S)-3-Amino-2-hydroxybutanoic acid [(2), L-al-
loisothreonine]. Hydroxybutanoic acid 2 was obtained
by same procedure with the conversion of 13 to 1; the
overall yield for this conversion was 65%; mp 243–
½ꢂꢂD ¼ þ267:4ꢁ (c 1.00, CHCl3); NMR ꢁH (CDCl3):
0.55 (d, J ¼ 6:4 Hz, 3H), 2.12 (m, 1H), 3.58 (dd,
J ¼ 6:8, 7.5 Hz, 1H), 5.05–5.08 (m, 1H), 5.17–5.21 (m,
1H), 5.51–5.58 (m, 1H), and 7.20–7.71 (m, 13H); NMR
ꢁC (CDCl3): 19.1, 53.1, 72.5, 77.3, 117.1, 120.0, 120.1,
125.2, 125.6, 125.9, 127.2, 127.8, 128.1, 128.4, 138.5,
140.1, 140.7, 145.1, 148.7, and 151.1; IR ꢄmax (KBr)
cmꢀ1: 3426, 3310, 3078, 2933. Anal. Found: C, 84.42;
H, 6.78; N, 4.11%. Calcd. for C24H23NO: C, 84.42; H,
6.79; N, 4.10%.
20
23
245ꢁC; ½ꢂꢂD ¼ ꢀ24:8ꢁ (c 1.00, H2O) {lit.17) ½ꢂꢂD
¼
ꢀ25:7ꢁ (c 1.10, H2O), mp 240–241ꢁC}; NMR ꢁH (D2O):
1.23 (d, J ¼ 6:8 Hz, 3H), 3.81–3.83 (m, 1H), and 4.51
(d, J ¼ 3:4 Hz, 1H); NMR ꢁC (D2O): 12.3, 49.5, 70.4,
and 174.4; IR ꢄmax (KBr) cmꢀ1: 3406, 3075, 2940, 1740,
1620. Anal. Found: C, 40.33; H, 7.61; N, 11.77%. Calcd.
for C4H9NO3: C, 40.33; H, 7.62; N, 11.76%.
(2R,3S)-2-O-Benzyl-3-[(9-phenyl-9-fluorenyl)-amino]-
butanoic acid (21). The procedure to obtain alcohol
compound 21 was the same as that described for the
(3S,4R)-3-Hydroxy-4-[(9-phenyl-9-fluorenyl)-amino]-
1-pentene (18). Compound 18 was obtained by the same
procedure with the conversion of D-gulonic acid ꢀ-
20
conversion of 13 to 15; mp 75–77ꢁC; ½ꢂꢂD ¼ þ50:3ꢁ (c
20
lactone to 13; mp 51–52ꢁC; ½ꢂꢂD ¼ ꢀ293:9ꢁ (c 1.00,
1.50, CHCl3); NMR ꢁH (CDCl3): 0.88 (d, J ¼ 6:3 Hz,
3H), 2.58 (t, J ¼ 5:2 Hz, 1H), 3.28 (d, J ¼ 3:4 Hz, 1H),
4.08 (m, 1H), 4.50 (br, 1H), and 7.03–7.73 (m, 19H);
NMR ꢁC (CDCl3): 17.5, 49.9, 72.6, 72.7, 78.3, 120.5,
120.5, 124.2, 125.3, 125.6, 127.6, 127.7, 128.0, 128.3,
128.4, 128.5, 128.9, 129.3, 129.4, 137.3, 139.7, 141.1,
CHCl3); NMR ꢁH (CDCl3): 0.66 (d, J ¼ 6:7 Hz, 3H),
2.27–2.44 (m, 1H), 3.51–3.54 (m, 1H), 5.02–5.10 (m,
2H), 5.51–5.62 (m, 1H), and 7.20–7.89 (m, 13H); NMR
ꢁC (CDCl3): 17.2, 52.4, 72.6, 74.1, 77.3, 115.3, 120.0,
120.1, 124.7, 125.3, 125.9, 127.3, 127.9, 128.1, 128.4,
128.5, 137.3, 139.8, 141.0, 145.1, 149.2, and 150.4; IR
ꢄmax (KBr) cmꢀ1: 3448, 3317, 3070, 2976, 1648. Anal.
Found: C, 84.42; H, 6.78; N, 4.10%. Calcd. for
C24H23NO: C, 84.42; H, 6.79; N, 4.10%.
142.6, 146.6, 147.9, and 172.1; IR ꢄmax (KBr) cmꢀ1
:
3280, 3060, 3017, 2931, 2870, 1729, 1624. Anal. Found:
C, 80.16; H, 6.03; N, 3.11%. Calcd. for C30H27NO3: C,
80.15; H, 6.05; N, 3.12%.
(2R,3R)-2-O-Benzyl-3-[(9-phenyl-9-fluorenyl)-amino]-
butanoic acid (19). The procedure to obtain alcohol
compound 19 was the same as that described for the
(2R,3S)-3-Amino-2-hydroxybutanoic acid [(4), D-iso-
threonine]. Compound 4 was obtained by same proce-
dure as that for the conversion of 15 to 1; the overall
yield for this conversion was 67%; mp 218–219ꢁC;
½ꢂꢂD ¼ þ14:1ꢁ (c 0.70, H2O) {lit.17) ½ꢂꢂD ¼ þ21:6ꢁ (c
1.10, H2O), mp 223–225ꢁC (decomp.)}; NMR ꢁH
(D2O): 1.12 (d, J ¼ 6:8 Hz, 3H), 3.44–3.47 (m, 1H),
and 4.08 (d, J ¼ 4:8 Hz, 1H); NMR ꢁC (D2O): 15.0,
49.8, 71.3, and 174.6; IR ꢄmax (KBr) cmꢀ1: 3410, 3070,
2932, 1612. Anal. Found: C, 40.33; H, 7.60; N, 11.75%.
Calcd. for C4H9NO3: C, 40.33; H, 7.62; N, 11.76%.
20
conversion of 13 to 15; mp 70–73ꢁC; ½ꢂꢂD ¼ þ48:6ꢁ (c
20
20
1.00, CHCl3); NMR ꢁH (CDCl3): 0.65 (d, J ¼ 6:7 Hz,
3H), 2.83–2.85 (m, 1H), 3.58 (d, J ¼ 4:1 Hz, 1H), 4.31
(dd, J ¼ 4:9, 11.5 Hz, 1H), 4.66 (t, J ¼ 11:3 Hz, 1H),
and 7.14–7.70 (m, 19H); NMR ꢁC (CDCl3): 17.1, 51.6,
72.5, 72.5, 80.9, 120.3, 120.3, 125.5, 125.7, 125.7,
127.6, 127.9, 128.1, 128.1, 128.2, 128.2, 128.4, 128.6,
128.9, 129.0, 129.0, 137.4, 140.2, 140.6, 143.4, 147.0,
148.4, and 173.4; IR ꢄmax (KBr) cmꢀ1: 3280, 3060,

720
J. H. LEE et al.
8) Umemura, E., Tsuchiya, T., and Umezawa, S., Synthesis
Acknowledgments
of 1-N-(D-threo-and racemic erythro-3-amino-2-hy-
droxybutanoyl)-20,30-dideoxykanamycin A. J. Antibiot.,
41, 530–537 (1998).
This research was supported by the Korea Science and
Engineering Foundation (KOSEF) through the Regional
Animal Industry Research Center at Jinju National
University, Jinju, Korea. We are also grateful for the
financial support of Brain Korea 21 program.
9) Cardillo, G., Tolomelli, A., and Tomasini, C., Synthesis
of enantiomerically pure syn and anti ꢂ-hydroxy ꢃ-
amino acids through diastereoselective hydroxylation of
perhydropyrimidin-4-ones. Tetrahedron, 51, 11831–
11840 (1995).
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nin’ und ‘L-alloisothreonin’ aus L-alanin. Helv. Chem.
Acta, 70, 116–120 (1987).
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