A concise synthesis of (R)- and (S)-α-alkyl isoserines from d- and l-malic acids

Article abstract of DOI:10.1016/j.tetasy.2006.11.033

A simple and diastereoselective method for the synthesis of (R)- and (S)-α-alkyl isoserines has been developed in four steps starting from commercially available d- and l-malic acid, respectively. This approach features stereocontrolled alkylation of 2-(2

Full text of DOI:10.1016/j.tetasy.2006.11.033

Tetrahedron: Asymmetry 17 (2006) 3152–3157
A concise synthesis of (R)- and (S)-a-alkyl isoserines
from D- and L-malic acids
Yan Huang, Yong-Bo Zhang, Zhi-Ce Chen and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, PR China
Received 11 October 2006; accepted 21 November 2006
Abstract—A simple and diastereoselective method for the synthesis of (R)- and (S)-a-alkyl isoserines has been developed in four steps
starting from commercially available D- and L-malic acid, respectively. This approach features stereocontrolled alkylation of 2-(2-tert-
butyl-5-oxo-1,3-dioxolan-4-yl)acetic acid and proceeds through a methylcarbamate via a Curtius rearrangement.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
medicinal chemistry to restrict possible low energy confor-
mations.10 For example, 20-methyl taxoids, the analogues
of paclitaxel and docetaxel (Fig. 2), with an additional
methyl substituent at the 20-position should create some
additional torsional strain associated with rotation.11
These constrained analogues display a higher cytotoxic
activity, probably due to a reduction in the degree of free-
dom of rotation at the C20 –C03 bond or of some additional
hydrophobic interactions between the 20-methyl and the
microtubule binding sites.12 With this in mind, a-substi-
tuted isoserine is of great interest since the presence of an
alkyl substituted at the 2-position favors a gauche confor-
mation about the torsion angle.13
Non-proteinogenic a-hydroxy-b-amino acids (isoserine
derivatives) are probably the most important members of
the b-amino acid family. They are an essential moiety of
a large number of well-known naturally occurring prod-
ucts, which are endowed with a powerful biological activ-
ity.1 The most striking examples are those incorporated
into many biologically active peptides, such as bestatin,2
amatatin,3 norstatine4 and taxol.5 When incorporated into
peptides their conformational restraints induce a large vari-
ety of stable secondary structures6 and tertiary structures,7
and these b-peptides are capable of adopting stable helical,
turn and sheet conformations in solution.8 These confor-
mational properties of b-peptides depend on the main
chain torsional angles h of the b-amino acid units, as
depicted in Figure 1.9
Many procedures have been developed to synthesize b-
substituted isoserines in optically active forms,14 but little
attention has been paid to the synthesis of chiral a-substi-
tuted isoserines. Only three papers have reported the syn-
thesis of enantiomerically pure a-methyl isoserine.15
Herein, a concise and efficient method is reported for the
synthesis of enantiomerically pure a-alkyl isoserines (R)-1
and (S)-1.
θ
θ
CO2H
HO2C
H2N
NH2
HO R
R
OH
(S)-1
(R)-1
Figure 1.
2. Results and discussion
Moreover, the synthesis of the constrained analogues of the
active compounds is a common procedure adopted in
Our protocol utilizes Seebach’s ‘self-regeneration of stereo-
centers (SRS)’ synthetic principle16 to build the new stereo-
center. The shortest route to enantiomerically pure a-alkyl
isoserines was developed in four steps from D- and L-malic
acids. First, dioxolanone acids (2R,4R)-4 were obtained
*
Corresponding author. Tel.: +86 931 8912500; fax: +86 931 8625657;
e-mail: xupf@lzu.edu.cn
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.033

Y. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 3152–3157
3153
O
O
O
O
O
O
OH
OH
O
O
O
O
N
H
O
O
N
H
O
O
OH
O
OH
H
HO
H
HO
O
O
O
O
O
O
O
Docetaxel
O
Paclitaxel
Figure 2.
with good yields and excellent diastereoselectivities
alcohol to give the desired carbamate (2R,4R)-5 in a mod-
erate chemical yield (Scheme 2). In order to improve the
chemical yield, we explored different conditions for the
Curtius rearrangement and the results are summarized in
Table 1.
(de >98%) starting from D-malic acid (R)-2 (Scheme 1).17
H
H
OH
OH
O
O
O
O
O
a
b
O
O
H
R
H
H
H
H
COOH
COOH
COOH
(2R,4R)-3
O
O
O
O
O
O
(R)-2
(2R,4R)-4
O
O
O
TEA, DPPA
Bn
Bn
Bn
Scheme 1. Reagents and conditions: (a) pivaldehyde, p-toluenesulfonic
acid and concd H2SO4, pentane, reflux, 36 h, 98%; (b) (i) LHMDS, THF,
ꢀ78 ꢁC, 5 min; (ii) RX, THF, ꢀ78 ꢁC, 30 min then warm up to ꢀ23 ꢁC,
6 h (RX = EtI, additional 10 h at ꢀ5 ꢁC); (iii) quenched with 1 M HCl; 4a:
R = benzyl, 81%, 4b: R = ethyl, 63%, 4c: R = allyl, 79%, 4d: R = methyl,
80%.
NHCO2R
NHCON3
(2R,4R)-6a
COOH
(2R,4R)-5a (R = Me)
(2R,4R)-4a
(2R,4R)-5a(B) (R = Bn)
Scheme 2.
It was found that the low yields were given by treatment of
(2R,4R)-4 with triethylamine and DPPA in ROH without
another solvent (Table 1, entries 1–4). Interestingly, car-
bamoyl azide (2R,4R)-6 was obtained as the major product
when t-BuOH was used (entries 3 and 4), which provided a
good way to synthesize carbamoyl azide. Fortunately,
when a mixture of (2R,4R)-4a, triethylamine and DPPA
was stirred in either benzene or toluene at room tempera-
ture for 1 h prior to the addition of the alcohol, the yields
were improved significantly with toluene being a better
choice than benzene (entries 5 and 6). When we changed
the amount of TEA from 1.5 to 2 and 3 equiv, it was found
that 2 equiv of TEA gave the best yield (entries 6–8).
With the dioxolanone acids (2R,4R)-4 in hand, we at-
tempted to convert the carboxylic acid into the carbamate
(2R,4R)-5 via Curtius rearrangement. This approach failed
to give the desired products (2R,4R)-5 but an unidentified
mixture produced in our case according to the conditions
used for the classic Curtius rearrangement procedure.18–20
This might be due to the rapid Curtius rearrangement of
acyl azide followed by trapping of the active intermediate
isocyanate by N3ꢀ, H2O and other nucleophiles. To solve
this problem, we treated (2R,4R)-4a with triethylamine
and diphenylphosphoryl azide (DPPA) to produce the
intermediate isocyanate, which was then trapped by the
Table 1. Optimizing experimental conditions for the Curtius rearrangement of acids (R)-4aa
Entry
TEA (equiv)
DPPA (equiv)
Conditionsb
Productc
Yieldd (%)
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
2.2
1.5
1.5
2.0
3.0
2.0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
1.0
1.5
BnOH (1 equiv), refluxed 24 h
5a(B)
5a
6a
48e
59
42
76
67
77
86
82
85
MeOH (5 equiv), refluxed 10 h
t-BuOH (5 equiv), refluxed 24 h
t-BuOH (5 equiv), refluxed 24 h
Benzene, rt, 1 h, MeOH, reflux 16 h
Toluene, rt, 1 h, MeOH, reflux 16 h
Toluene, rt, 1 h, MeOH reflux 16 h
Toluene, rt, 1 h, MeOH reflux 16 h
Toluene, rt, 1 h, MeOH reflux 16 h
6a
5a
5a
5a
5a
5a
a Each reaction was carried out under an argon atmosphere and solvents were dried via a standard method.
b Entries 5–9: MeOH (5 equiv).
c (2R,4R)-6a = 6a, (2R,4R)-5a = 5a, (2R,4R)-5a(B) = 5a(B).
d Isolated yield based on 4.
e It proved difficult to separate 5a(B) from BnOH.

3154
Y. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 3152–3157
However, increasing the amount of DPPA to 1.5 equiv led
to a slightly decreased yield (entry 9).
coupling constants in hertz). IR spectra were obtained on
a Nicolet 170 SX FT-IR. Optical rotations were recorded
on a Perkin–Elmer Model 341 polarimeter. HR-MS spectra
were measured with a FT-MS Bruker Apex II mass
spectrometer.
Using the optimized reaction conditions of entry 7 in Table
1, 4-alkyl carbamate (2R,4R)-5 can also be obtained in
good yields. Deprotection of the acetal and carbamate
using 6 M HCl in a sealed tube at 110–120 ꢁC afforded
(R)-a-alkyl isoserine as its hydrochloride salt, which was fi-
nally transformed into the free b-amino acid (R)-1 by inter-
action with propylene oxide under reflux in EtOH, (four
steps, 51–66% from D-malic acid, 98% ee) (Scheme 3).
4.2. 2-((2R,4R)-2-tert-Butyl-5-oxo-1,3-dioxolan-4-yl)acetic
acid (2R,4R)-3
To a solution of pivalaldehyde (20 g, 232 mmol) in pentane
(300 mL) were added p-toluensufonic acid (2 g), concen-
trated sulfuric acid (three drops), and D-malic acid (20 g,
150 mmol). The reaction mixture was stirred under reflux
for 36 h, and then cooled to room temperature. The result-
ing suspension was filtered. The filter cake was dissolved in
CH2Cl2 (200 mL) and washed twice with 20 mL of 8%
aqueous phosphoric acid. The solution was dried over
MgSO4 and the solvent was removed under reduced pres-
H
H
O
O
O
O
HO2C
a
NH2
b
O
O
R
OH
R
R
COOH
(2R,4R)-4
NHCO2Me
(2R,4R)-5
(R)-1
sure to give a white solid. Yield 29.7 g (98%); mp 104–
22
106 ꢁC; ½aꢁD ¼ þ2:2 (c 1.2, CHCl3). IR (cmꢀ1): 3292 (br),
Scheme 3. Reagents and conditions: (a) TEA, DPPA, toluene, rt, 1 h then
MeOH, reflux, 16 h, 4a: R = benzyl, 86%, 4b: R = ethyl, 86%, 4c:
R = allyl, 84%, 4d: R = methyl, 82%; (b) (i) 6 M HCl, sealed tube, 110–
120 ꢁC, 11 h; (ii) propylene oxide, EtOH, reflux, 1 h, 1a: 94%, 1b: 96%, 1c:
95%, 1d: 96%.
1
2968 (br), 1786 (s), 1741 (s); H NMR (500 MHz, CDCl3):
d 4.67 (1H, octet, J = 1.5, 3.5, 7.5 Hz), 3.02 (1H, dd,
J = 3.5, 17 Hz), 2.84 (1H, dd, J = 7.5, 17 Hz), 0.99 (s,
9H); 13C NMR (125 MHz, CDCl3): d 174.90, 172.11,
109.88, 71.40, 34.23, 23.40.
The enantiomers, a-alkyl isoserine (S)-1, were obtained fol-
lowing the same strategy starting from L-malic acid.
4.3. 2-((2S,4S)-2-tert-Butyl-5-oxo-1,3-dioxolan-4-yl)acetic
acid (2S,4S)-3
As described for enantiomer (2R,4R)-3, compound
3. Conclusions
(2S,4S)-3 (29.7 g, 98%) was obtained from L-malic acid
22
(20 g, 150 mmol); mp 104–106 ꢁC; ½aꢁD ¼ ꢀ2:3 (c 1.5,
We have developed an efficient four-step protocol for the
synthesis of optically active a-alkyl-a-hydroxy-b-amino
acids starting from the commercially available D- or L-
malic acid in a good overall yield (51–66%) and an excellent
stereoselectivity (98% de). This approach features the ste-
reocontrolled alkylation of 2-(2-tert-butyl-5-oxo-1,3-dioxo-
lan-4-yl) acetic acid in the second step, which was the key
step to build the stereocenter of (R)-1 and (S)-1. a-Alkyl
isoserines (R)-1 and (S)-1 were successfully obtained via a
modified Curtius rearrangement in the third step. The
application of this new method in the stereoselective syn-
thesis of 2,3-dialkyl substituted isoserines is being investi-
gated and will be reported in due course.
CHCl3). IR (cmꢀ1): 3292 (br), 2968 (br), 1788 (s), 1742
(s); 1H NMR (500 MHz, CDCl3): d 4.67 (1H, octet,
J = 1.5, 3.5, 7.5 Hz), 3.02 (1H, dd, J = 3.5, 17 Hz), 2.84
(1H, dd, J = 7.5, 17 Hz), 0.99 (s, 9H); 13C NMR
(125 MHz, CDCl3): d 174.90, 172.11, 109.88, 71.40, 34.23,
23.40.
4.4. 2-((2R,4R)-2-tert-Butyl-4-alkyl-5-oxo-1,3-dioxolan-4-
yl)acetic acid (2R,4R)-4a–d
General procedure for the reaction of the enolate from the
dioxolanone (2R,4R)-3 with various RX: Under argon,
LHMDS (2.0 mmol, in 2 mL dry THF) was added to a
solution of (2R,4R)-3 (202 mg, 1.0 mmol) in 8 mL dry
THF at ꢀ78 ꢁC. After 5 min at ꢀ78 ꢁC, the RX (1.5 mmol,
in 2 mL dry THF) was added and the reaction mixture was
stirred at this temperature for 30 min, then the temperature
was allowed to warm up to ꢀ23 ꢁC over a period of 6 h
(RX = EtI, additional 10 h at ꢀ5 ꢁC). The reaction was
quenched with 1 M aqueous HCl (4 mL). The mixture
was then extracted twice with 15 mL ether. The organic
layer was washed with brine, and water to pH 2, dried over
MgSO4, and concentrated under vacuum. The pure prod-
uct was obtained by column chromatography (petroleum
ether/ethyl acetate, 8:1–1:1) in a good yield.
4. Experimental
4.1. General procedures
All reactions were carried out under an argon atmosphere
and the solvents were purified according to the established
procedures. Reactions were monitored by thin layer chro-
matography (TLC). Column chromatography purifications
were carried out using silica gel (200–400 mesh). Melting
points were recorded on an X-4 melting point apparatus
and uncorrected. H and 13C NMR spectra were recorded
1
on a Varian Mercury-300 and 400 MHz, and Varian Inova-
500 MHz spectrometer. 1H and 13C NMR spectra were re-
corded in CDCl3 with TMS as the internal standard and in
D2O (chemical shifts are reported in ppm on the d scale,
4.4.1. 2-((2R,4R)-2-tert-Butyl-4-benzyl-5-oxo-1,3-dioxolan-
4-yl)acetic acid (2R,4R)-4a. Yield: 81%, 236 mg; mp 134–
22
136 ꢁC; ½aꢁD ¼ ꢀ64:2 (c 1.0, CHCl3). IR (cmꢀ1): 2926, 1795
1
(s), 1702 (s); H NMR (500 MHz, CDCl3): d 7.24–7.34 (m,

Y. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 3152–3157
3155
5H), 4.61 (s, 1H), 3.21 (d, 1H, J = 14 Hz), 3.03 (d, 1H,
J = 14 Hz), 2.91 (q, 1H, J = 16 Hz), 2.77 (d, 1H,
J = 16 Hz), 0.89 (s, 9H); 13C NMR (125 MHz, CDCl3): d
174.31, 133.70, 130.37, 128.67, 127.67, 108.73, 80.78,
40.13, 40.02, 34.24, 23.47. Anal. Calcd for C16H20O5: C,
65.74; H, 6.90. Found: C, 65.64; H, 6.83.
34.25, 23.18. HRMS (m/z): Calcd for C17H23NO5:
[M+Na]+ 344.1468. Found: [M+Na]+ 344.1464.
4.6.2. Methyl ((2R,4R)-2-tert-butyl-4-ethyl-5-oxo-1,3-dioxo-
lan-4-yl)methylcarbamate (2R,4R)-5b. Yield: 426 mg,
17
1
82%. ½aꢁD ¼ ꢀ18:1 (c 1.0, CH2Cl2). H NMR (400 MHz,
CDCl3): d 5.16 (s, 1H), 5.04 (br, 1H), 3.65 (s, 3H), 3.47–
3.50 (t, 2H, J = 5.6 Hz), 1.73–1.80 (dq, 2H, J = 7.2, 2.4
Hz), 0.98 (t, 3H, J = 7.2 Hz), 0.88 (s, 9H); 13C NMR
(75 MHz, CDCl3): d 173.88, 156.81, 108.79, 82.69, 52.20,
44.20, 34.46, 26.10, 23.26, 7.70. HRMS (m/z): Calcd for
C12H21NO5: [M+NH4]+ 277.1758. Found: [M+NH4]+
277.1756.
4.4.2. 2-((2R,4R)-2-tert-Butyl-4-ethyl-5-oxo-1,3-dioxolan-4-
yl)acetic acid (2R,4R)-4b. Yield: 63%, 145 mg; mp 90–
22
92 ꢁC; ½aꢁD ¼ ꢀ29:9 (c 1.0, CHCl3). IR (cmꢀ1): 3301,
2795, 1780 (s), 1743 (s); 1H NMR (500 MHz, CDCl3,
ppm): d 5.20 (s, 1H), 2.89 (d, 1H, J = 16 Hz), 2.85 (d,
1H, J = 16 Hz), 1.90 (q, 2H, J = 7.5 Hz), 1.07 (t, 3H,
J = 7.5 Hz), 0.98 (s, 9H); 13C NMR (75 MHz, CDCl3): d
174.62, 173.90, 108.29, 80.37, 38.90, 34.36, 26.69, 23.55,
7.73. Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found:
C, 57.55; H, 7.45.
4.6.3. Methyl ((2R,4R)-2-tert-butyl-4-allyl-5-oxo-1,3-dioxo-
lan-4-yl)carbamate (2R,4R)-5c. Yield: 81%, 440 mg.
17
½aꢁD ¼ ꢀ26:0 (c 1.3, CH2Cl2). 1H NMR (300 MHz,
CDCl3): d 5.80 (m, H), 5.21–5.27 (m, 3H), 4.96 (br, 1H),
3.65 (s, 3H), 3.55 (q, 2H, J = 3.9 Hz), 2.53 (q, 2H,
J = 4.5 Hz), 0.95 (s, 9H); 13C NMR (75 MHz, CDCl3): d
173.44, 156.83, 130.04, 121.08, 108.96, 82.34, 52.37,
44.89, 37.15, 34.52, 23.35. HRMS (m/z): Calcd for
C13H21NO5: [M+NH4]+ 289.1756 Found: [M+NH4]+
289.1754.
4.4.3. 2-((2R,4R)-2-tert-Butyl-4-allyl-5-oxo-1,3-dioxolan-4-
yl)acetic acid (2R,4R)-4c. Yield: 79%, 191 mg; oil;
22
½aꢁD ¼ ꢀ65:2 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
d 5.73–5.82 (m, 1H), 5.19–5.24 (m, 3H), 2.82 (s, 2H), 2.54
(d, J = 6.3 Hz, 2H), 0.91 (s, 9H); 13C NMR (75 MHz,
CDCl3): d 174.4, 173.4, 129.9, 121.2, 108.3, 79.7, 39.4,
38.0, 34.2, 23.5.
4.6.4. ((2R,4R)-2-tert-Butyl-4-methyl-5-oxo-1,3-dioxolan-4-
17
4.4.4. 2-((2R,4R)-2-tert-Butyl-4-methyl-5-oxo-1,3-dioxolan-
4-yl)acetic acid (2R,4R)-4d. Yield: 80%, 173 mg; mp 136–
yl)carbamate (2R,4R)-5d. Yield: 435 mg, 88%; ½aꢁD ¼
ꢀ9:3 (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3): d
22
1
138 ꢁC; ½aꢁ ¼ ꢀ21:2 (c 1.0, CHCl3). H NMR (300 MHz,
CDCl3): dD5.16 (s, 1H), 2.94 (d, 1H, J = 16.5 Hz), 2.81 (d,
1H, J = 16.5 Hz), 1.47 (s, 3H), 0.95 (s, 9H); 13C NMR
(75 MHz, CDCl3): d 174.5, 174.2, 107.6, 41.2, 34.2, 23.6,
19.6.
5.17 (s, 1H), 5.02 (s, 1H), 3.66 (s, 3H), 3.50–3.54 (t, 2H,
J = 6.6 Hz), 1.38 (s, 1H), 0.94 (s, 9H); 13C NMR
(75 MHz, CDCl3): d 174.12, 156.87, 107.63, 79.90, 52.29,
54.74, 35.20, 23.33, and 17.23. HRMS (m/z): Calcd for
C11H19NO5: [M+NH4]+ 263.1601. Found: [M+NH4]+
263.1597.
4.5. 2-((2S,4S)-2-tert-Butyl-4-alkyl-5-oxo-1,3-dioxolan-4-
yl)acetic acid (2S,4S)-4a–d
4.7. Methyl ((2S,4S)-2-tert-butyl-4-alkyl-5-oxo-1,3-dioxo-
lan-4-yl)carbamate (2S,4S)-5a–d
As described for enantiomers (2R,4R)-4a–d, compounds
(2S,4S)-4a–d were obtained from dioxolanone (2S,4S)-3.
As described for enantiomers (2R,4R)-5a–d, compounds
(2S,4S)-5a–d were obtained from compounds (2S,4S)-4a–
d.
4.6. Methyl ((2R,4R)-2-tert-Butyl-4-alkyl-5-oxo-1,3-dioxo-
lan-4-yl)carbamate (2R,4R)-5a–d
4.8. Azido-N-(((2R,4R)-4-benzyl-2-tert-butyl-5-oxo-1,3-
dioxolan-4-yl)methyl)formamide (2R,4R)-6a
Under argon, a solution of 2-((2R,4R)-2-tert-butyl-4-alkyl-
5-oxo-1,3-dioxolan-4-yl)acetic acid (2R,4R)-4 (2 mmol), di-
phenyl phosphoryl azide (0.44 mL, 2 mmol), and triethyl-
amine (0.56 mL, 4 mmol) in dry toluene (4.0 mL) was
stirred at room temperature for 1 h. MeOH (10 mmol)
was then added. After the mixture was stirred at reflux
for 16 h, the solvent was removed under reduced pressure
to give the crude product as a pale yellow oil. The pure
product was obtained by column chromatography (petro-
leum ether/ethyl acetate, 20:1–2:1) in good yield.
Under argon, a solution of 2-((2R,4R)-2-tert-butyl-4-
benzyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (2R,4R)-4a
(290 mg, 1 mmol), diphenylphosphoryl azide (0.404 mL,
2 mmol), and triethylamine (0.28 mL, 2 mmol) in dry tolu-
ene (2.0 mL) was stirred at room temperature for 1 h.
t-BuOH (5 mmol) was then added. After the mixture was
stirred at reflux for 24 h, the solvent was removed under
reduced pressure. The residue was dissolved in CH2Cl2
(15 mL), washed with brine, saturated Na2CO3 solution,
and water, dried over MgSO4 and concentrated. The crude
product was purified by column chromatography (petro-
4.6.1. Methyl ((2R,4R)-2-tert-butyl-4-benzyl-5-oxo-1,3-
dioxolan-4-yl)carbamate
(2R,4R)-5a. Yield:
85%,
17
546 mg; ½aꢁD ¼ ꢀ30:0 (c 1.0, CH2Cl2). 1H NMR
(300 MHz, CDCl3): d 7.22–7.30 (m, 5H), 5.02 (br, 1H),
4.23 (s, 1H), 3.67 (s, 3H), 3.59 (d, 2H, J = 6.3 Hz), 3.15
(d, 1H, J = 14 Hz), 2.98 (d, 1H, J = 14 Hz), 0.82 (s, 9H);
13C NMR (75 MHz, CDCl3): d 173.75, 156.86, 133.86,
130.13, 128.65, 127.55, 109.33, 83.46, 52.38, 45.76, 39.21,
leum ether/ethyl acetate, 20:1–2:1) to give (2R,4R)-6a as
22
a white solid (252 mg, 0.76 mmol); yield: 76%. ½aꢁD
¼
ꢀ24:0 (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3): d
7.26–7.30 (m, 5H), 5.37 (s, 1H), 4.28 (s, 1H), 3.55–3.69
(m, 2H), 3.16 (d, 1H, J = 14 Hz), 2.97 (d, 1H, J =
14 Hz), 0.84 (s, 9H); 13C NMR (75 MHz, CDCl3): d

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Y. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 3152–3157
173.47, 156.75, 133.52, 130.11, 128.73, 127.71, 109.44,
83.04, 45.39, 39.18, 34.26, 23.20. HRMS (m/z): Calcd for
C16H20N4O4: [M+Na]+ 355.1377. Found: [M+Na]+
355.1368. IR (cmꢀ1): 3351 (s), 3063 (br), 2970 (s), 2935
(s), 2161 (s), 1779 (s), 1718 (s), 1543 (s), 1230 (s).
4.10.3. (S)-3-Amino-2-hydroxy-2-allylpropanoic acid (S)-
18
1c. Yield: 95%; mp 243–245 ꢁC (dec); ½aꢁD ¼ þ43:5 (c
0.54, H2O).
4.10.4. (S)-3-Amino-2-hydroxy-2-methylpropanoic acid (S)-
18
1d. Yield: 94%; mp 225–227 ꢁC (dec); ½aꢁD ¼ þ11:2 (c 1.0,
4.9. (R)-3-Amino-2-hydroxy-2-alkylpropanoic acid (R)-1a–d
H2O).
Under argon, a sealed tube was charged with carbamate
(2R,4R)-5 (0.2 mmol), 6 M aqueous HCl (2 mL). The mix-
ture was stirred at 110–120 ꢁC for 1 h, the solvent removed
under reduced pressure and the residue treated at 110–
120 ꢁC with 6 M aqueous HCl (2 mL) for 10 h. The mixture
was cooled to room temperature, diluted with water
(2 mL), washed with ethyl acetate (2 · 3 mL), and concen-
trated to give the desired amino acid hydrochloride salt.
Treatment of this amino acid hydrochloride salt with etha-
nol/propylene oxide gave (R)-1 as a white solid.
Acknowledgements
This work was supported by National Natural Science
Foundation of China (NSFC, 20372027, 20572039), the
key project (02079), the Program (NCET-05-0880) and
the Doctoral Funds from Chinese Ministry of Education
of PR China.
References
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18
1a. Yield: 94%; mp 254–256 ꢁC (dec); ½aꢁD ¼ ꢀ53:0 (c
1
0.45, H2O). H NMR (400 MHz, D2O): d 7.09–7.15 (m,
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4.9.2. (R)-3-Amino-2-hydroxy-2-ethylpropanoic acid (R)-
18
1b. Yield: 96%, mp 237–239 ꢁC (dec); ½aꢁD ¼ ꢀ18:0 (c
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J = 7.2 Hz), 0.98 (t, 3H, J = 7.2 Hz). HRMS m/z Calcd
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4.9.3. (R)-3-Amino-2-hydroxy-2-allylpropanoic acid (R)-
18
1c. Yield: 95%; mp 243–245 ꢁC (dec); ½aꢁD ¼ ꢀ43:7 (c
1
0.50, H2O). H NMR (400 MHz, D2O): d 5.70 (m, 1H),
4.95–5.04 (m, 2H), 3.13 (d, J = 13.6 Hz, 1H), 2.90 (d,
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18
1d. Yield: 96%; mp 225–227 ꢁC; ½aꢁD ¼ ꢀ11:5 (c 1.0,
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4.10.1. (S)-3-Amino-2-hydroxy-2-benzylpropanoic acid (S)-
18
1a. Yield: 95%; mp 254–256 ꢁC (dec); ½aꢁD ¼ þ53:2 (c
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18
1b. Yield: 96%; mp 237–239 ꢁC (dec); ½aꢁD ¼ þ18:0 (c 1.0,
H2O).

Y. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 3152–3157
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1
17. The de value were calculated by the integration of H NMR
from Varian Inova-500M spectrometer.