Improved preparation of β-hydroxy-α-amino acids: Direct formation of sulfates by sulfuryl chloride

Article abstract of DOI:10.1016/j.tetasy.2005.10.013

Two β-(alkyl)-β-hydroxy-α-amino acids [alkyl = Bu ^t, BnO-(CH₂)₃-] have been synthesized by a sequence based on Sharpless asymmetric dihydroxylation. The key sulfate intermediates were prepared from enantiomerically enriche

Full text of DOI:10.1016/j.tetasy.2005.10.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3908–3912
Improved preparation of b-hydroxy-a-amino acids: direct
formation of sulfates by sulfuryl chloride
*
`
Monica Alonso and Antoni Riera
`
´
Unitat de Recerca en Sı´ntesi Asimetrica (URSA-PCB), Parc Cientıfic de Barcelona and Departament de Quımica
´
`
Organica, Universitat de Barcelona, Josep Samitier, 1-5, 08028 Barcelona, Spain
Received 4 October 2005; accepted 10 October 2005
Available online 9 November 2005
Abstract—Two b-(alkyl)-b-hydroxy-a-amino acids [alkyl = But, BnO–(CH2)3–] have been synthesized by a sequence based on
Sharpless asymmetric dihydroxylation. The key sulfate intermediates were prepared from enantiomerically enriched diols by direct
treatment with sulfuryl chloride. The scope and the appropriate conditions for sulfate formation have also been studied.
ꢀ 2005 Published by Elsevier Ltd.
1. Introduction
ology is highly advantageous: it is shorter, features a
simpler work-up and does not require the use of heavy
metals.
Over the last decade, we have been involved in a project
devoted to the asymmetric synthesis of non-proteino-
genic amino acids.1 b-Hydroxy-a-amino acids are an
important subclass of this family, as they are constitu-
ents of many biologically active natural products and
medicinally important compounds.2 Several stereoselec-
tive syntheses of b-hydroxy-a-amino acids have already
been reported to date.3–7 The sequence developed by
Sharpless et al.,8 which is particularly suitable for ery-
thro amino acids, includes the following steps: (a) enan-
CH3
O
OH
OH
COOH
N
O
NH
NH2
N
HOOC
1a
2
tioselective preparation of
a dihydroxy ester by
Somewhat surprisingly, the direct preparation of sul-
fates from diols using sulfuryl chloride has scarcely been
used to date; the large majority of sulfates having been
prepared by oxidation of the corresponding sulfites.
Only a few examples of cyclic or electron-deficient diols
have been reported to give good yields of sulfate when
treated with sulfuryl chloride in methylene chloride10
or ethyl acetate.11 Encouraged by the excellent results
obtained in the preparation of amino acid 1a, we were
intrigued about the scope of this reaction. Herein we
report the direct preparation of sulfates from diols and
the enantioselective synthesis of two protected b-hydroxy-
a-amino acids 1b–c by this methodology.
asymmetric dihydroxylation of an unsaturated ester,
(b) reaction of a vicinal diol with thionyl chloride to give
a cyclic sulfite; (c) ruthenium-catalyzed oxidation of the
sulfite to sulfate with periodate and (d) ring opening
with azide and reduction to amine. During the develop-
ment of a large scale synthesis for (2R,3R)-2-amino-3-
hydroxy-3-cyclohexyl-propanoic acid 1a, a key compo-
nent in the anti-inflammatory and CCR5 antagonist
drug for HIV treatment ONO-4128 2, we found that
the sequence developed by the Sharpless group was
highly convenient and was thus scaled up.9 Moreover,
the sequence was improved upon when we discovered
that the sulfate intermediate could be prepared directly
by sulfuryl chloride treatment, instead of by the usual
two step sequence of sulfite formation/ruthenium oxida-
tion.9 Compared to the Sharpless synthesis, this method-
OH
OH
COOH
BnO
COOH
NH2
1b
*
NH2
Corresponding author. Tel.: +34 93 403 7093; fax: +34 93 403
7095; e-mail: ariera@pcb.ub.es
1c
0957-4166/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.10.013

M. Alonso, A. Riera / Tetrahedron: Asymmetry 16 (2005) 3908–3912
3909
2. Results and discussion
to a 13:1 mixture of 4b/5b. Once the optimal reaction
conditions for direct sulfate formation by SO2Cl2 were
found, we decided to test the scope using different struc-
tural types of diols. Compounds 3a–c were prepared in
enantiomerically enriched forms by Sharpless dihydr-
oxylation of known alkenes, whereas 3d–f were commer-
cially available. The diols were treated with sulfuryl
chloride under the optimized conditions, the results of
which are summarized in Table 1. Diol 3b, selected as
a representative of a tertiary alkyl dihydroxypropano-
ate, gave the corresponding sulfate in excellent yield.
Diol 3c, selected as a primary alkyl dihydroxypropanao-
ate also gave a good yield of sulfate 4c. Both sulfates
were converted (vide infra) into the corresponding b-
hydroxy-a-amino acids. Diethyl tartrate 3d also afforded
the known sulfate 4d in good yield (70% vs 69%
described by Sharpless et al. for their two step proce-
dure8). To determine if simple diaryl or dialkyl sulfates
could be prepared using this method, we performed
the reaction on butane-2,3-diol 3e as a representative
dialkyl substituted diol, on butane-1,2-diol 3f as a termi-
nal diol and 1,2-diphenyl-1,2-ethanediol 3g as a diaryl
substrate.12 As shown in Table 1, only 3g gave good
yields for the sulfate. The low yields obtained with sim-
ple alkyl diols are probably due to opening of the sulfate
ring during chromatographic purification.
Our first objective was to identify the key parameters of
the reaction. After some experimentation, it was
observed that the main side-reactions responsible for most
unsuccessful runs were sulfate ring opening by chloride
anion, as well as the formation of bis(chlorosulfate) 5
(reaction with two molecules of sulfuryl chloride).
3-Cyclohexyl-2,3-dihydroxy propanoate 3a was used as
a benchmark compound (Scheme 1 and Table 1). The
addition of sulfuryl chloride to a solution of diol and tri-
ethylamine in methylene chloride at ꢀ78 ꢁC (entry 1)
afforded a 1:1.7 mixture of the desired sulfate 4a and
bis(chlorosulfate) 5a. When ethyl acetate was used as a
solvent, the undesired 5a was the main reaction product
(entry 2). We reasoned that the intramolecular cycliza-
tion may require a higher temperature than the intermo-
lecular reaction. Most gratifyingly, by increasing the
temperature to 0 ꢁC, a clean reaction took place yielding
88% of sulfate 4a after work up and chromatography.
As predicted, the ratio between 4a and 5a was very sen-
sitive to dilution. Apart from temperature, solvent and
concentration, it was found that the rate of sulfuryl
chloride addition was also crucial to the success of the
reaction. For instance, the rapid addition of sulfuryl
chloride to 3a (0.4 mL/min) led to a 0.7:1 mixture of sul-
fate 4a and byproduct 5a, whereas a slow addition
(0.1 mL/min) gave exclusively the desired sulfate 4a.
This effect was also found for diol 3b, whereby a rapid
addition of reagent (0.48 mL/min) yielded a 3:1 mixture
of sulfate 4b and bis(chlorosulfate) 5b. In contrast, the
slow addition of this reagent (over 0.012 mL/min) led
As a synthetic application of this sulfate formation, we
planned to transform compounds 4b and 4c into the cor-
responding Boc-protected b-hydroxy-a-amino esters 7b
and 7c. Somewhat surprisingly, to the best of our knowl-
edge, 3-tert-butyl-3-hydroxy serine 1b had yet to be
described in the literature. Ring opening with sodium
azide afforded azido alcohol 6b in good yield. Finally,
hydrogenation and in situ protection with Boc2O
afforded the desired protected ester 7b in excellent yield
(Scheme 2).
O
OH
O
S O
O
SO2Cl2
NEt3
R'
R
R
OH
R'
Hydroxy amino acid 1c is a key intermediate in the syn-
theses of mycestericin D and F, two new lipids isolated
from Mycelia sterilia with novel type of immunosup-
pressive activity.13 It is also an unnatural amino acid
used in the preparation of new sialyl Lewis X mimetics
(SLex), potentially useful as anti-inflammatory agents14
Moreover, using simple transformations 1c has been
transformed into 3-hydroxypipecolic acid, a precursor,
3
4
SO2Cl
R'
R
SO2Cl
5
Scheme 1.
Table 1. Direct formation of sulfates 4a–g from diols 3a–g by treatment with sulfuryl chloride (Scheme 1)
Entry
Diol
R
R0
mol SO2Cl2
Conditionsa
Product
Yield %b
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3b
3c
3d
3e
3f
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
tert-Butyl
BnO–(CH2)3ꢀ
COOEt
Methyl
Ethyl
Phenyl
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
Methyl
H
5
5
5
5
5
5
5
5
5
5
NEt3 (5 mol), CH2Cl2, ꢀ78 ꢁC
NEt3 (5 mol), AcOEt, ꢀ78 ꢁC
NEt3 (12 mol), CH2Cl2, 0 ꢁC
NEt3 (12 mol), AcOEt, 0 ꢁC
NEt3 (12 mol), AcOEt, 0 ꢁC
NEt3 (12 mol), AcOEt, 0 ꢁC
NEt3 (12 mol), AcOEt, 0 ꢁC
NEt3 (12 mol), AcOEt, 0 ꢁC
NEt3 (12 mol), AcOEt, 0 ꢁC
NEt3 (12 mol), AcOEt, 0 ꢁC
4a+5a (1:1.7)
5a
—
80
15
88
83
60
70
—
18
68c
4a
4a
4b
4c
4d
Mixture
4f
4g
10
3g
Phenyl
a Concentration of the substrate: 0.025 M.
b Isolated yield. Flash chromatography purification (SiO2).
c Yield determined by 1H NMR.

3910
M. Alonso, A. Riera / Tetrahedron: Asymmetry 16 (2005) 3908–3912
for instance, of swainsonine, which has shown potent
and specific a-D-mannosidase inhibitory activity.15 Fol-
lowing a sequence similar to that used for 7b, but reduc-
ing the azide with triphenylphosphine to prevent
hydrogenolysis of the benzyloxy group, a protected
form of amino acid 7c was prepared in excellent overall
yield (Scheme 2).
de Masas de la Universidad de Santiago de Compostela.
Chromatographic separations were carried out using
SiO2 or NEt3-pretreated (2.5% v/v) SiO2 (70–230 mesh)
and eluting with hexane/ethyl acetate mixtures of
increasing polarity. Ethyl 6-benzyloxy-2-hexenoate was
prepared from 4-benzyloxy-1-butanol by the standard
sequence of Swern oxidation16 and Wadsworth–
Emmons olefination.17 Compound 3a was prepared
according to Ref. 9.
O
4.2. Sharpless asymmetric dihydroxylation. General
procedure
OH
O S O
O
NaN3
COOEt
R
R
acetone, 0 oC
N3
COOEt
The ligand (DHQD)2PHAL (7.8 mg, 0.01 mmol),
K2Fe(CN)6 (990 mg, 3 mmol), K2CO3 (415 mg,
3 mmol), K2OsO4Æ2H2O (1.5 mg, 0.004 mmol) and
CH3SO2NH2 (95 mg, 1 mmol) were dissolved in a 1:1
mixture of water and tert-butyl alcohol (5 mL of each,
10 mL total) at room temperature. The vigorously stir-
red mixture was cooled to 0 ꢁC and the olefin (1 mmol)
added in one portion. After complete consumption of
the starting material the reaction was quenched at 0 ꢁC
by the addition of sodium sulfite (1.5 g) and then
warmed to room temperature and stirred for 60 min.
The reaction mixture was then extracted with CH2Cl2
(4 · 5 mL). The combined organic layers were washed
with 2 M KOH (10 mL), dried over MgSO4 and concen-
trated under vacuum. Purification by flash chromato-
graphy gave the pure diol.
4b R=tBu
4c R=BnO(CH2)3-
6b R=tBu, 68%
6c R=BnO(CH2)3-, 95%
1) PPh3,
THF, H2O
H2, Pd/C,
AcOEt,
Boc2O
2) Boc2O,
dioxane, iPrOH
90%
81%
OH
H3C
H3C
COOEt
OH
BnO
COOEt
CH3 NHBoc
NHBoc
7b
7c
Scheme 2.
4.2.1. Ethyl (2S,3R)-2,3-dihydroxy-4,4-dimethyl-propan-
oate 3b. Starting from 3-tert-butyl-acrylic acid ethyl
ester (1 g, 6.4 mmol) and following the general proce-
dure, 827 mg of 3b (68%) were obtained as a white solid.
[a]D = ꢀ7.3 (c 0.98, CHCl3). IR (film): mmax 3489, 2957,
3. Conclusion
In conclusion, we have found that under the appropriate
conditions of solvent, temperature, dilution and addi-
tion rate, the simple addition of sulfuryl chloride is a
very convenient way to prepare sulfates from diols.
Since 3-alkyl-2,3-dihydroxy propanoates are amongst
the best substrates for this reaction, the optimized reac-
tion conditions have been used in the preparation of two
important b-hydroxy-a-amino acids, in what constitutes
an improved version of the known Sharpless synthetic
sequence.
1
1734, 1210, 1115 cmꢀ1. H NMR (400 MHz, CDCl3) d:
4.33 (d, 1H, J = 2 Hz, CH), 4.28 (q, 2H, J = 7 Hz, CH2),
3.55 (br, 1H, CH), 3.13 (s, 1H, OH), 2.28 (s, 1H, OH),
1.32 (t, 3H, J = 7 Hz, CH3), 1.01 (s, 9H, ((CH3)3))
ppm. 13C NMR (100 MHz, CDCl3) d: 174.9 (CO),
78.7 (CH), 70.2 (CH), 62.4 (CH2), 35.4 (C), 26.4
(CH3), 14.3 (CH3) ppm. MS (CI-NH3) m/z: 155.1
[(Mꢀ35)+, 100%], 87.1 [(Mꢀ103)+, 35%], 191.3
[(M+1)+, 8%]. HRMS (ESI): calcd for C9H18NaO4
213.1097, found 213.1094.
4. Experimental
4.1. General
4.2.2. Ethyl (2S,3R)-6-benzyloxy-2-3-dihydroxy-hexano-
ate 3c. Following the general procedure starting from
ethyl 6-benzyloxy-2-hexenoate (390 mg, 1.57 mmol)
354 mg of 3c (80% yield) were obtained. [a]D = +8.5 (c
1.00, CHCl3). IR (film): mmax 3457, 2936, 2860, 1736,
Optical rotations were measured at room temperature
on a Perkin–Elmer 241MC polarimeter (concentration
in g/100 mL). Infrared spectra were recorded on a Nico-
let 510FT-IR instrument using NaCl film or KBr
pellet techniques. NMR spectra were acquired on a
400 MHz instrument. 1H NMR were obtained at
400 MHz (s = singlet, d = doublet, t = triplet, dt = dou-
ble triplet, m = multiplet and br = broad) 13C NMR
were obtained at 100 MHz. 1H chemical shifts are
quoted relative to TMS and 13C shifts relative to solvent
signals. Carbon multiplicities have been assigned by dis-
tortionless enhancement by polarization transfer
(DEPT) experiments. High-resolution mass spectra
1
1098 cmꢀ1. H NMR (400 MHz, CDCl3) d: 7.37–7.26
(m, 5H, CH), 4.52 (s, 2H, CH2), 4.28 (q, 2H, J = 7 Hz,
CH2), 4.06 (br, 1H, CH), 3.92 (br, 1H, CH), 3.53 (m,
2H, CH2), 3.05 (br, 1H, OH), 2.63 (br, 1H, OH), 1.75
(m, 4H, CH2), 1.30 (t, 3H, J = 7 Hz, CH3) ppm. 13C
NMR (100 MHz, CDCl3) d: 173.6 (CO), 138.3 (C),
128.6 (CH), 127.86 (CH), 127.82 (CH), 73.6 (CH2),
73.2 (CH2), 72.5 (CH), 70.3 (CH), 62.1 (CH2), 31.3
(CH2), 26.4 (CH2), 14.3 (CH3) ppm. MS (CI-CH4) m/z:
91 [(Mꢀ191)+, 100%]. HRMS (CI+): calcd for
C15H22O5 282.1467, found 282.1460. HPLC Chiracel-
OD. Heptane/i-PrOH 90:10, 1 mL/min, k = 210 nm, tR
´
(CI) were measured by the Servicio de Espectrometrıa

M. Alonso, A. Riera / Tetrahedron: Asymmetry 16 (2005) 3908–3912
3911
(2S,3R isomer) = 12.1 min, tR (2R,3S isomer) =
15.1 min showing an enantiomeric purity of 96.9% for
(2S,3R isomer) and 96% for (2R,3S isomer).
CDCl3) d: 4.28 (m, 2H, CH2), 3.77 (d, 1H, J = 6 Hz,
CH), 3.64 (d, 1H, J = 6 Hz, CH), 1.34 (t, 3H,
J = 7 Hz, CH3), 0.99 (s, 9H, ((CH3)3)) ppm. 13C NMR
(100 MHz, CDCl3) d: 170.1 (CO), 79.5 (CH), 62.23
(CH), 62.18 (CH2), 35.2 (C), 26.0 (CH3), 14.2 (CH3)
ppm.
4.3. Preparation of cyclic sulfates. General procedure
Diol 3x (1 mmol) was dissolved in ethyl acetate (40 mL)
under a nitrogen atmosphere. NEt3 (1.6 mL, 12 mmol)
was then added and the mixture cooled to 0 ꢁC. Sulfuryl
chloride (401 lL, 5 mmol) was added dropwise over a
period of 10 min. The reaction mixture was stirred at
this temperature for 15–20 min. Water was added
(15 mL) and the layers separated and the organic one
was washed twice with water and brine, dried and con-
centrated. Purification by flash chromatography affor-
ded pure sulfate.
4.3.4. Ethyl (2R,3R)-2-azido-3-hydroxy-6-benzyloxy-hex-
anoate 6c. Starting from sulfate 4c (150 mg,
0.435 mmol) and following the procedure described for
6b, 127 mg of azido alcohol 6c (95%) was obtained as
a colourless oil. [a]D +33.5 (c 0.830, CHCl3). IR (film):
mmax 3416, 2925, 2108, 1738, 1454, 1196, 1026 cmꢀ1
.
1H NMR (400 MHz, CDCl3) d: 7.40–7.21 (m, 5H,
CH), 4.52 (s, 2H, CH2), 4.28 (q, 2H, J = 7 Hz, CH2),
3.98 (m, 1H, CH), 3.93 (d, 1H, J = 6 Hz, CH), 3.52
(m, 2H, CH2), 1.78 (m, 2H, CH2), 1.58 (m, 2H, CH2),
1.32 (t, 3H, J = 7 Hz, CH3) ppm. 13C NMR
(100 MHz, CDCl3) d: 169.1 (CO), 137.9 (C), 128.6
(CH), 127.94 (CH), 127.93 (CH), 73.3 (CH2), 72.0
(CH), 70.3 (CH2), 66.3 (CH), 62.1 (CH2), 30.8 (CH2),
26.2 (CH2), 14.3 (CH3) ppm.
4.3.1.
(4S,5R)-4-Ethoxycarbonyl-5-tert-butyl-1,2,3-
dioxathiolane-2,2-dioxide 4b. Starting from: 3b
(211 mg, 1.35 mmol) and following the general proce-
dure, 310 mg of 4b (88% yield) was obtained as a colour-
less oil. [a]D = +65.2 (c 0.885, CHCl3). IR (film): mmax
2973, 1745, 1397, 1303, 1209 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d: 4.91 (d, 1H, J = 6 Hz, CH), 4.81
(d, 1H, J = 6 Hz, CH), 4.35 (m, 2H, CH2), 1.35 (t, 3H,
J = 7 Hz, CH3), 1.06 (s, 9H, ((CH3)3)) ppm. 13C NMR
(100 MHz, CDCl3) d: 166.1 (CO), 90.5 (CH), 76.3
(CH), 63.5 (CH2), 34.2 (C), 24.7 (CH3), 14.1 (CH3)
ppm. MS (CI-CH4) m/z: 253.2 [(M+1)+, 4%], 155.1
[(Mꢀ96)+, 100%]. HRMS (ESI): calcd for C9H16NaO6S
275.056, found 275.055.
4.3.5. Ethyl (2R,3R)-2-tert-butoxycarbonylamino-3-
A solution of
hydroxy-4,4-dimethyl-pentanoate 7b.
azide 6b (56 mg, 0.26 mmol) and Boc2O (68 mg,
0.31 mmol) in ethyl acetate (3 mL) was added to a sus-
pension of 10% Pd/C (10 mg) in ethyl acetate (3 mL)
under hydrogen. The mixture was stirred under a hydro-
gen atmosphere (balloon) until the starting material
could not be detected by TLC (40 h). Then, the suspen-
sion was filtered through a pad of Celite and evaporated.
Flash chromatography afforded 61 mg of 7b (81% yield)
as a colourless oil. [a]D = ꢀ7.5 (c 0.90, CHCl3). IR
(film): mmax 3443, 2978, 1873, 1716, 1506, 1169,
4.3.2. (4S,5R)-4-Ethoxycarbonyl-5-(3-benzyloxy)propyl-
1,2,3-dioxathiolane-2,2-dioxide 4c. Starting from 3c
(50 mg, 0.17 mmol) and following the general proce-
dure, 34 mg of 4c (60% yield) was obtained.
[a]D = +17.2 (c 1.35, CHCl3). IR (film): mmax 2934,
1019 cmꢀ1 1H NMR (400 MHz, CDCl3) d: 5.48 (br,
.
1H, NH), 4.43 (br, 1H, CH), 4.19 (m, 2H, CH2), 3.46
(br, 1H, CH), 3.12 (br, 1H, OH), 1.44 (s, 9H,
((CH3)3)), 1.31 (t, 3H, J = 7 Hz, (CH3)3), 0.96 (s, 9H,
((CH3)3)) ppm. 13C NMR (100 MHz, CDCl3) d: 172.2
(CO), 155.5 (CO), 81.2 (CH), 80.4 (C), 61.7 (CH2),
55.0 (CH), 35.3 (C), 28.4 (CH3), 26.1 (CH3), 14.3
(CH3) ppm. MS (CI-CH4) m/z: 104 [(M+1)+, 100%].
HRMS (CI+): calcd for C14H28NO5 290.1967, found
290.1978. HPLC: Chiracel OD, Hexane/IPA, 98:2;
0.5 mL/min, k = 220 nm; tR (2R, 3R isomer) =
15.6 min, tR (2S, 3S isomer) = 23.3 min. Enantiomeric
excess: 90.5%.
2861, 1769, 1744, 1397, 1210 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d: 7.40–7.29 (m, 5H, CH), 5.02
(ddd, 1H, J = 8, 6 and 4 Hz, CH), 4.87 (d, 1H,
J = 8 Hz, CH), 4.50 (s, 2H, CH2), 4.32 (dq, 2H, J = 7
and 1 Hz, CH2), 3.54 (m, 2H, CH2), 2.10 (m, 2H,
CH2), 1.83 (m, 2H, CH2), 1.33 (t, 3H, J = 7 Hz, CH3)
ppm. 13C NMR (100 MHz, CDCl3) d: 164.9 (CO),
138.2 (C), 128.6 (CH), 127.9 (CH), 127.8 (CH), 81.2
(CH), 80.0 (CH), 73.2 (CH2), 68.8 (CH2), 63.4 (CH2),
30.4 (CH2), 25.2 (CH2), 14.1 (CH3) ppm.
4.3.3. Ethyl (2R,3R)-2-azido-3-hydroxy-4,4-dimethyl-
pentanoate 6b. To a solution of 4b (65 mg, 0.26 mmol)
in a 5:1 mixture of acetone:water (2.1 mL), cooled to
0 ꢁC, NaN3 (34 mg, 0.52 mmol) was added. The reaction
was allowed to warm to room temperature and stirred
for 48 h. After evaporation of the solvent, the crude
was treated with Et2O:20% H2SO4 (1:1, 2.7 mL) and
stirred at room temperature overnight. Then, excess of
NaHCO3 was added to the reaction mixture and the
aqueous layer extracted with Et2O (3 · 3 mL). The com-
bined organic extracts were dried over MgSO4, and
evaporated to yield 38 mg of crude 6b (68% yield), which
was used in the next step without further purification.
[a]D = ꢀ52 (c 0.88, CHCl3). IR (film): mmax 3514, 2960,
4.3.6. Ethyl (2R,3R)-2-tert-butoxycarbonylamino-3-
hydroxy-6-benzyloxy-hexanoate 7b. To a solution of
6c (34 mg, 0.11 mmol) in THF (0.85 mL) and water
(16 lL), PPh3 (49 mg, 0.18 mmol, 1.7 equiv) was added
and the reaction mixture heated at 45 ꢁC. After 18 h,
the solvent was removed and the crude dissolved in
i
dioxane (0.3 mL) and PrOH (0.13 mL). Boc2O (25 mg,
0.121 mmol, 1.1 equiv) was added in one portion and
the reaction mixture stirred for 72h at room tempera-
ture. Removal of the solvent and purification by column
chromatography yielded 36 mg of 7c (90% yield, two
steps). [a]D = ꢀ14.2 (c 0.720, CHCl3). IR (film): mmax
3421, 2977, 2932, 2865, 1716, 1162 cmꢀ1 1H NMR
.
2106, 1737, 1180, 1020 cmꢀ1
.
1H NMR (400 MHz,
(400 MHz, CDCl3) d: 7.40–7.21 (m, 5H, CH), 5.44

3912
M. Alonso, A. Riera / Tetrahedron: Asymmetry 16 (2005) 3908–3912
Shao, H.; Goodman, M. J. Org. Chem. 1996, 61, 2582–
2583; (c) Jung, M. E.; Jung, Y. H. Tetrahedron Lett. 1989,
30, 6637–6640; (d) Schmidt, U.; Respondek, M.; Lie-
berknecht, A.; Werner, J.; Fischer, P. Synthesis 1989, 256–
261.
(dbr, 1H, J = 7 Hz, NH), 4.50 (s, 2H, CH2), 4.34 (br,
1H, CH), 4.22 (m, 2H, CH2), 3.89 (m, 1H, CH), 3.51
(td, 2H, J = 6 and 1 Hz, CH2), 3.41 (dbr, 1H,
J = 7 Hz, OH), 1.78 (m, 2H, CH2), 1.60 (m, 2H, CH2),
1.45 (s, 9H, (CH3)3), 1.27 (t, 3H, J = 7 Hz, CH3) ppm.
13C NMR (100 MHz, CDCl3) d: 170.8 (CO), 156.1
(CO), 138.2 (C), 128.5 (CH), 127.81 (CH), 127.78
(CH), 80.3 (C), 73.1 (CH, CH2), 70.3 (CH2), 61.7
(CH2), 58.7 (CH), 31.0 (CH2), 28.5 (CH3), 26.6 (CH2),
14.4 (CH3) ppm. MS (CI-CH4) m/z: 282.2 [(Mꢀ100)+,
100%], 382.7 [(M+1)+, 73%]. HRMS (CI+): calcd for
C20H32NO6 382.2230, found 382.2244.
6. Selected syntheses of b-hydroxy amino acids based on
dynamic kinetic resolution. (a) Makino, K.; Goto, T.;
Hiroki, Y.; Hamada, Y. Angew. Chem., Int. Ed. 2004, 43,
882–884; (b) Genet, J. P.; Pinel, C.; Mallart, S.; Juge, S.;
Thorimbert, S.; Laffitte, J. A. Tetrahedron: Asymmetry
1991, 2, 555–567; (c) Noyori, R.; Ikeda, T.; Ohkuma, T.;
Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.;
Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J.
Am. Chem. Soc. 1989, 111, 9134–9135.
7. Selected synthesis based on Sharpless dihydroxylation: (a)
Jiang, Z.-X.; Qin, Y.-Y.; Qing, F.-L. J. Org. Chem. 2003,
68, 7544–7547; (b) Xiong, C.; Wang, W.; Hruby, V. J. J.
Org. Chem. 2002, 67, 3514–3517; (c) Qin, D.-G.; Zha, H.-
Y.; Yao, Z.-J. J. Org. Chem. 2002, 63, 1038–1040; (d)
Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Sucunza, D.; Zurbano, M. M. Tetrahedron: Asymmetry
2001, 12, 949–957; (e) Shao, H.; Goodman, M. J. Org.
Chem. 1996, 61, 2582–2583; (f) Hale, K. J.; Manaviazar,
S.; Delisser, V. M. Tetrahedron 1994, 50, 9181–9188.
8. (a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110,
7538–7539; (b) Sharpless, K. B.; Gao, Y. (MIT), U.S.
Patent 5321143, 1994.
Acknowledgments
Financial support from CIRIT (2001SGR-00050) and
MEC (CTQ2005-000623) is gratefully acknowledged.
M.A. thanks MCYT (Spain) for a fellowship.
References
´
1. See inter alia: (a) Poch, M.; Alcon, M.; Moyano, A.;
`
Pericas, M. A.; Riera, A. Tetrahedron Lett. 1993, 34,
´
´
7781–7784; (b) Pasto, M.; Castejon, P.; Moyano, A.;
9. Alonso, M.; Santacana, F.; Rafecas, L.; Riera, A. Org.
Process Res. Dev. 2005, 9, 690–693.
`
Pericas, M. A.; Riera, A. J. Org. Chem. 1996, 61, 6033–
´
`
6037; (c) Castejon, P.; Moyano, A.; Pericas, M. A.; Riera,
10. (a) Rinner, U.; Siengalewicz, P.; Hudlicky, T. Org. Lett.
2002, 4, 115–117; (b) Tai, V. W.-F.; Imperiali, B. Tetra-
hedron Lett. 1998, 39, 7215–7218; (c) Liu, P.; Vandewalle,
M. Tetrahedron Lett. 1993, 34, 3625–3628; (d) Myers, A.
G.; Goldberg, S. D. Angew. Chem., Int. Ed. 2000, 39,
2732–2735; (e) Seimbille, Y.; Ali, H.; van Lieer, J. E. J.
Chem. Soc., Perkin Trans. 1 2002, 657–663; (f) Seimbille,
´
A. Chem. Eur. J. 1996, 2, 1001–1006; (d) Pasto, M.;
Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem. 1997,
62, 8425–8431; (e) Medina, E.; Moyano, A.; Pericas, M.
A.; Riera, A. J. Org. Chem. 1998, 63, 8574–8578; (f)
`
`
`
Medina, E.; Moyano, A.; Pericas, M. A.; Riera, A. Helv.
´
Chim. Acta 2000, 83, 972–988; (g) Martın, R.; Islas, G.;
`
Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron 2001,
´
Y.; Benard, F.; van Lieer, J. E. J. Chem. Soc., Perkin
`
57, 6367–6374; (h) Ginesta, X.; Pericas, M. A.; Riera, A.
Synth. Commun. 2005, 35, 289–297.
Trans. 1 2002, 2275–2281; (g) Vanhessche, K. P. M.;
Sharpless, B. Chem. Eur. J. 1997, 3, 517–522.
2. Amino Acids, Peptides and Proteins; Special Periodical
Reports; Chemistry Society: London, 1968–1995; Vols.
1–28.
11. (a) Fuentes, J.; Angulo, M.; Pradera, M. A. J. Org. Chem.
2002, 67, 2577–2587; (b) Tewson, T. J. J. Org. Chem. 1983,
48, 3507–3510.
3. Selected synthesis of b-hydroxy amino acids based on
aldol reactions. (a) MacMillan, J. B.; Molinski, T. F. Org.
Lett. 2002, 4, 1883–1886; (b) Ooi, T.; Taniguchi, M.;
Kameda, M.; Mauroka, K. Angew. Chem., Int. Ed. 2002,
41, 4542–4544; (c) Horikawa, M.; Busch-Petersen, J.;
Corey, E. J. Tetrahedron Lett. 1999, 40, 3843–3846; (d)
Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc.
1986, 108, 6405–6406.
4. Selected syntheses of b-hydroxy amino acids based on
Sharpless epoxidation. (a) Nagamitzu, T.; Sunazuka, T.;
Tanaka, H.; Omura, S.; Sprengeler, P. A.; Smith, A. B.,
III. J. Am. Chem. Soc. 1996, 118, 3584–3590; (b) Rao, A.
V. R.; Dhar, T. G. M.; Bose, D. S.; Chakraborty, T. K.;
Gurjar, M. K. Tetrahedron 1989, 45, 7361–7370.
5. Selected syntheses of b-hydroxy amino acids based on
catalytic non aldol reactions. (a) Amador, M.; Ariza, X.;
Garcia, J.; Sevilla, S. Org. Lett. 2002, 4, 4511–4514; (b)
12. Moye-Sherman, D.; Jin, S.; Ham, I.; Lim, D.; Scholtz, J.
M.; Burgess, K. J. Am. Chem. Soc. 1998, 120, 9435–9443.
13. (a) Nishide, K.; Shibata, K.; Fujita, T.; Kajimoto, T.;
Wong, C.-H.; Node, M. Heterocycles 2000, 52, 1191–1201;
(b) Shibata, K.; Shingu, K.; Vassilev, V. P.; Nishide, K.;
Fujita, T.; Node, M.; Kajimoto, T.; Wong, C.-H. Tetra-
hedron Lett. 1996, 37, 2791–2794.
14. (a) Cappi, M. W.; Moree, W. J.; Qiao, L.; Marron, T. G.;
Weitz-Schmidt, G.; Wong, C.-H. Bioorg. Med. Chem.
1997, 5, 283–296; (b) Cappi, M. W.; Moree, W. J.; Qiao,
L.; Marron, T. G.; Weitz-Schmidt, G.; Wong, W.-H.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2346–2348.
15. Bodas, M. S.; Kumar, P. Tetrahedron Lett. 2004, 45, 8461–
8463.
16. Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
17. Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733–1738.