New syntheses of enantiopure 2-methyl isoserines

Article abstract of DOI:10.1016/j.tetasy.2003.09.051

Herein we describe the synthesis of the two enantiomerically pure 3-amino-2-hydroxy-2-methylpropionic acids - (S)- and (R)-α-methyl isoserines - starting from the chiral diols (S)- and (R)-2,3-dihydroxy-N- methoxy-2,N-dimethylpropionamides, respectively, which were obtained by Sharpless asymmetric dihydroxylation (AD) of the olefin N-methoxy-2,N- dimethylacrylamide with AD-mix α or β as chiral catalytic ligands.

Full text of DOI:10.1016/j.tetasy.2003.09.051

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 131–137
New syntheses of enantiopure 2-methyl isoserines
*
ꢀ
ꢀ
ꢀ
Alberto Avenoza, Jesus H. Busto, Francisco Corzana, Gonzalo Jimenez-Oses,
*
ꢀ
Miguel Parıs, Jesus M. Peregrina, David Sucunza and Marıa M. Zurbano
ꢀ
ꢀ
Departamento de Quꢀımica, Universidad de La Rioja, Grupo de Sꢀıntesis Quꢀımica de La Rioja, U.A.-C.S.I.C.,
26006 Logro~no, Spain
Received 15 September 2003; accepted 22 September 2003
Abstract—Herein we describe the synthesis of the two enantiomerically pure 3-amino-2-hydroxy-2-methylpropionic acids––(S)- and
(R)-a-methyl isoserines––starting from the chiral diols (S)- and (R)-2,3-dihydroxy-N-methoxy-2,N-dimethylpropionamides, re-
spectively, which were obtained by Sharpless asymmetric dihydroxylation (AD) of the olefin N-methoxy-2,N-dimethylacrylamide
with AD-mix a or b as chiral catalytic ligands.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In this sense, substituted b-amino acids are of great in-
terest, particularly 2-substituted b-amino acids since the
presence of an alkyl substituent at the 2-position favours
a gauche conformation about the h torsion angle, de-
fined by the C2–C3 bond.8 Such a conformation is
required in b-peptides for the adoption of folded con-
formations.
In recent years, several research groups have focused on
various b-amino acid containing oligomers, since such
systems are viewed as very promising tools in medicinal
chemistry.1 In particular, b-peptides are of great im-
portance because, in addition to their biological stabil-
ity,2–5 they are capable of adopting stable helical, turn
and sheet conformations in solution. On the basis of
these properties b-peptides have been used to mimic
natural peptides and proteins.6 As in a-peptides, which
are composed of a-amino acids, the conformational
properties of b-peptides, which are composed of b-
amino acids that form amide bonds, depend on the main
chain torsional angles (x, /, h and w) of the b-amino
acid units, as depicted in Figure 1.7
In connection with a research project directed towards
the synthesis of hydroxylated amino acids, we herein
report the syntheses of both enantiomers of 2-methyl
isoserine, (S)- and (R)-1 (Fig. 1). This enantiomerically
pure b-amino acid has only been synthesised on two
previous occasions. The (R)-enantiomer9 was found to
have a specific rotation of )11.2. The (S)-enantiomer10
was found to have a specific rotation of )11.3 and,
moreover, was incorporated into peptides. In order
to expand the scope of research in this area and to
clarify this apparent contradiction, we synthesised both
enantiomers of 2-methyl isoserine through two different
synthetic routes.
2. Results and discussion
2.1. Synthesis of 2-methyl isoserine via sulfites
The best method to obtain enantiomerically pure 2-
methyl isoserine is the Sharpless asymmetric amino-
hydroxylation (AA)11–15 of 2-methyl-2-propenoic acid
derivatives. However, in a recent study we demonstrated
that these reactions give good yields and regioselectivi-
ties but with poor enantioselectivities.15
Figure 1.
* Corresponding authors. Tel./fax: +34-941-299655; e-mail addresses:
alberto.avenoza@dq.unirioja.es;
unirioja.es
jesusmanuel.peregrina@dq.
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.051

132
A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 131–137
Considering these previous results, and taking into ac-
count the excellent results obtained in the Sharpless
asymmetric dihydroxylation (AD)16–18 with olefin 2 on
using AD-mix a or b,15;19 we decided to use the diols (S)-
3 and (R)-3 as starting materials in our synthetic routes.
We followed the protocol used in the synthetic method
for 2-methyl serine15 but applied the modification re-
cently described in the literature.20 Thus, diol (S)-3 was
transformed into its 2,3-cyclic sulfite (S)-4 using thionyl
chloride. Furthermore, the ring-opening reaction of this
sulfite with sodium azide at 70 ꢁC in DMF gave a
mixture of the azido alcohols (S)-5 and (R)-6 with a
regioselectivity of 4:1 in favour of the b-azido a-alcohol
(S)-5 (Scheme 1).
2.2. Synthesis of 2-methyl isoserine via mesylates
In an attempt to increase the yield of the b-amino acid
(S)-1 from the diol (S)-3, we developed a second syn-
thetic route, which involved the regioselective intro-
duction of the mesylate group at the primary alcohol
using methanesulfonyl chloride (MsCl) in the presence
of a basic medium containing diisopropylethylamine
(DIEA). This reaction gave excellent results and (S)-8
was obtained in good yield. Unfortunately, the sub-
sequent nucleophilic substitution on this compound
with sodium azide proved to be unsuccessful (Scheme 2).
Scheme 2. Reagents and conditions: (a) MsCl, CH2Cl2, DIEA, rt, 2 h,
97%; (b) allylamine, reflux, 6 h, 93%; (c) (i) Pd(PPh3)4, NDMBA,
CH2Cl2, 30 ꢁC, 3 h, (ii) 6N HCl (aq.), 60 ꢁC, 8 h, (iii) propylene oxide,
EtOH, reflux, 2 h, 85%.
This problem was solved by using an excess of allylamine
so it could act as both the nucleophile and the solvent in
this substitution reaction. Compound (S)-9 was obtained
along with the side product (S)-10 in a 75/25 ratio. The
mixture of the two products was subjected to deallylation
in the presence of tetrakis(triphenylphosphine)palla-
dium(0) [Pd(PPh3)4] and N,N0-dimethylbarbituric acid
(NDMBA).21 The subsequent acid hydrolysis gave the
b-amino acid as its hydrochloride salt. This compound
was transformed into the free b-amino acid (S)-1 by the
action of propylene oxide under reflux in EtOH. The
specific rotation was determined to be +2.9 and this value
agrees with our previous result (Scheme 2).
Scheme 1. Reagents and conditions: (a) AD-mix beta, MeSO2NH2,
tBuOH/H2O (1:1), 0 ꢁC, 12 h, 81%, ee ¼ 93%; (b) SOCl2, CCl4, reflux, 4
h, 90%; (c) NaN3, D MF, 70ꢁC, 48 h, column chromatography, 69% of
(S)-5; (d) LiOHÁH2O, MeOH/H2O (3:1), 2 h, rt, then conc. HCl to
pH ¼ 1; (e) H2, Pd-C, EtOH, rt, 24 h, 96%.
The mixture of azido alcohols was separated by column
chromatography and b-azido-a-alcohol (S)-5 subjected
to hydrolysis in a basic medium to give the corre-
sponding carboxylic acid derivative (S)-7 after neutral-
isation. Subsequent hydrogenation of this compound
using EtOH as solvent and Pd/C as catalyst provided the
required 2-methyl isoserine (S)-1 in 96% yield and with a
specific rotation of +2.8 (five steps, 48% from olefin 2,
93% ee) (Scheme 1).
The latter method provided the best results in terms of
yield and, although the number of steps was greater than
in the route via sulfites, this method made available the
free amino acid in the easiest and quickest fashion. In
fact, we obtained both enantiomers of the 2-methyl
isoserine, (S)-1 and (R)-1, starting from the Sharpless
ADreaction on olefin 2 in six steps with a 62% overall
yield and 93% ee.
The other enantiomer of 2-methyl isoserine, (R)-1, was
obtained using the same strategy as described above
starting from olefin 2 but using AD-mix a instead of
AD-mix b as the chiral catalytic ligand. In this case the
specific rotation of the product was the same but op-
posite in sign.
2.3. Determination of the enantiomeric purity and
absolute configuration
The enantiomeric purity of 2-methyl isoserine deriva-
tives was determined by the transformation of b-allyl-
amino a-alcohol (R)-9, after separation of (R)-10 by

A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 131–137
133
column chromatography, into a diastereomeric deriva-
tive, which had two stereogenic centres. Firstly, the allyl
group of (R)-9 was removed as described above and the
corresponding b-amino a-alcohol reacted with (R)-2-
acetylmandelic acid chloride, in CH2Cl2 acting as the
solvent and triethylamine (TEA) as the base, to give
compound 11 in good yield (Scheme 3). Unfortunately,
single crystals of this compound could not be obtained
for the determination of its absolute configuration.
However, in order to ensure that b-amino acids (S)-1
and (R)-1 were almost enantiomerically pure, we deter-
mined the cross-contamination by conversion of a
mixture of (R)-9 and (S)-9 in a ratio 60/40 to their chiral
amide derivatives 11 and 12, respectively, via coupling
with (R)-acetylmandelic acid chloride under the same
Scheme 4. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, rt, 6 h,
85%.
1
conditions (Scheme 3). Analysis of the H NMR spec-
trum of this mixture and comparison with the spectra of
11 and 12 showed that the enantiomeric purity of (R)-9
and (S)-9 was greater than 93%, since only one isomer
was detected. Thus, the enantiomeric purity of the
starting diols (S)-3 or (R)-3 was completely retained
during the reaction sequences to obtain the final prod-
ucts.
perature ()40 ꢁC approximately) of a solution in hexane
and CH2Cl2. The absolute configurations of the stereo-
genic centres of compound 14 were found to be (S)-
for the serine moiety and (R)- for the diol moiety.
This situation is shown in the ORTEP diagram ob-
tained from the X-ray analysis of these monocrystals
(Fig. 2).ꢀ
Scheme 3. Reagents and conditions: (a) (i) Pd(PPh3)4, NDMBA,
CH2Cl2, 30 ꢁC, 3 h, (ii) (R)-acetylmandelic acid chloride, TEA,
CH2Cl2, rt, 10 h, 88%.
Figure 2. ORTEP diagram of compound 14.
The absolute configuration of 2-methyl isoserines (S)-1
and (R)-1 was unambiguously determined via the
transformation of diol (R)-3 into a chiral derivative that
had two stereogenic centres. One of these centres was
created in the ADreaction and the second one origi-
nated from a chiral compound of known stereochemis-
try; (S)-O-benzyl-N-Boc-serine (S)-13. Therefore,
coupling22 of the primary alcohol group of diol (R)-3
with the carboxylic acid group of (S)-13 in the presence
of N,N0-dicyclohexylcarbodiimide (DCC) and 4-
dimethylaminopyridine (DMAP), using CH2Cl2 as sol-
vent, gave the chiral derivative 14 in good yield (Scheme
4). Fortunately, we were able to obtain single crystals of
this oily compound by slow evaporation at low tem-
ꢀ
Crystal data: (a) C22H34Cl2N2O8, Mw ¼ 525:41, colourless prism of
0.5 · 0.25 · 0.25 mm, T ¼ 223 K, orthorhombic, space group P212121,
ꢁ
ꢁ
ꢁ
Z ¼ 4, a ¼ 8:3816ð2Þ A, b ¼ 11:1599ð3Þ A, c ¼ 28:3281ð9Þ A, V ¼
2649:75ð13Þ A , dcalc ¼ 1:317 g cmÀ3, F ð000Þ ¼ 1112, k ¼ 0:71073 A
3
ꢁ
ꢁ
(Mo, Ka), l ¼ 0:291 mmÀ1, Nonius kappa CCDdiffractometer,
h
range 1.44–28.03ꢁ, 15,369 collected reflections, 5978 unique, full-
matrix least-squares (SHELXL97),23 R1 ¼ 0:0667, wR2 ¼ 0:1217,
(R1 ¼ 0:1587, wR2 ¼ 0:1988 all data), goodness of fit ¼ 1.044, residual
electron density between 0.259 and )0.222 e AÀ3. Hydrogen atoms
ꢁ
were located from mixed methods (electron-density maps and
theoretical positions). Further details on the crystal structure are
available on request from Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, UK on quoting the depository number
215525.

134
A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 131–137
3. Conclusions
3.31 (s, 3H, NCH3), 3.63 (d, 1H, J ¼ 11:4 Hz, CH2OH),
3.76 (s, 3H, NOCH3), 3.93 (d, 1H, J ¼ 11:4 Hz,
CH2OH); 13C NMR (CDCl3): d 21.8 (CH3), 34.0
(NCH3), 61.4 (NOCH3), 68.0 (CH2OH), 76.2
[COH(CH3)], 174.8 (CON); ESIþ ðm=zÞ ¼ 164. Anal.
Calcd for C6H13NO4: C, 44.16; H, 8.03; N, 8.58. Found:
C, 44.01; H, 8.02; N, 8.56.
The work described herein involved the synthesis of the
two enantiomerically pure 3-amino-2-hydroxy-2-meth-
ylpropionic acids––(S)- and (R)-2-methyl isoserines––
starting from the chiral diols (S)- and (R)-2,3-dihy-
droxy-N-methoxy-2,N-dimethylpropionamides, respec-
tively. These two starting materials were obtained by
Sharpless asymmetric dihydroxylation (AD) on olefin
N-methoxy-2,N-dimethylacrylamide with AD-mix a or
b as chiral catalytic ligands. The synthesis of these 2-
substituted b-amino acids was achieved by two different
synthetic routes and the absolute configurations were
unambiguously determined by X-ray analysis of a chiral
derivative.
4.3. (R)-2,3-Dihydroxy-N-methoxy-2,N-dimethyl-
propionamide (R)-3
As described for enantiomer (S)-3 but using AD-mix-a,
compound (R)-3 (2.00 g, 81%) was obtained from olefin
25
D
2 (1.95 g, 15.10 mmol). ½aŠ +4.7 (c 1.80, MeOH). Anal.
Calcd for C6H13NO4: C, 44.16; H, 8.03; N, 8.58. Found:
C, 44.05; H, 8.03; N, 8.56.
4. Experimental
4.4. (S)-4-Methyl-2-oxo-2k4-[1,3,2]dioxathiolane-
4-carboxylic acid N-methoxy-N-methylamide (S)-4
4.1. General procedures
Solvents were purified according to standard proce-
dures. Analytical TLC was performed using Polychrom
SI F254 plates. Column chromatography was performed
Diol (S)-3 (1.33 g, 8.16 mmol) was dissolved in CCl4
(30 mL) after which SOCl2 (1.46 g, 12.27 mmol) was
added. The resulting solution was heated under reflux
for 4 h. The solvent and excess SOCl2 were evaporated
and the crude product purified by column chromato-
graphy (hexane/ethyl acetate, 7:3) to give the corre-
sponding sulfite (S)-4 as a colourless liquid (1.52 g,
1
using Silica gel 60 (230–400 mesh). H and 13C NMR
spectra were recorded on a Bruker ARX-300 spec-
1
trometer. H and 13C NMR spectra were recorded in
CDCl3 with TMS as the internal standard and
in CD3OD(chemical shifts are reported in ppm on the
d scale, coupling constants in Hz). The assignment of
25
1
7.27 mmol); yield: 90%. ½aŠ +37.9 (c 1.05, MeOH); H
D
1
all separate signals in the H NMR spectra was made
NMR (CDCl3): d 1.64, 1.86 (2s, 3H, CH3), 3.18–3.23 (m,
3H, NCH3), 3.75 (s, 3H, NOCH3), 4.27 (d, 0.5H,
J ¼ 9:0 Hz, CH2O), 4.44 (d, 0.5H, J ¼ 9:0 Hz, CH2O),
5.23 (m, 1H, CH2O); 13C NMR (CDCl3): d 22.2, 22.7
(CH3), 33.4 (NCH3), 61.4 (NOCH3), 74.1, 74.4 (CH2O),
88.0, 89.3 [CO(CH3)], 169.0 (CON); ESIþ ðm=zÞ ¼ 210.
Anal. Calcd for C6H11NO5S: C, 34.44; H, 5.30; N, 6.69;
S, 15.33. Found: C, 34.37; H, 5.53; N, 6.65; S, 15.23.
Duplication of some signals was observed in the 1H and
13C NMR spectra, indicating the existence of two con-
formers in solution.
on the basis of coupling constants, selective proton–
proton homonuclear decoupling experiments, proton–
proton COSY experiments and proton–carbon
HETCOR experiments. Melting points were deter-
€
mined on a Buchi SMP-20 melting point apparatus
and are uncorrected. Optical rotations were measured
on a Perkin–Elmer 341 polarimeter in 1.0 and 0.5 dm
cells of 1.0 and 3.4 mL capacity, respectively. Micro-
analyses were carried out on a CE Instruments EA-1110
analyser and are in good agreement with the calculated
values.
4.5. (R)-4-Methyl-2-oxo-2k4-[1,3,2]dioxathiolane-
4-carboxylic acid N-methoxy-N-methylamide (R)-4
4.2. (S)-2,3-Dihydroxy-N-methoxy-2,N-dimethyl-
propionamide (S)-3
As described for enantiomer (S)-4, compound (R)-4
(0.61 g, 87%) was obtained from compound (R)-3
A round-bottomed flask was charged with tert-butyl
alcohol (80 mL), water (80 mL), AD-mix-b (21.7 g) and
methanesulfonamide (1.50 g). The mixture was stirred at
25 ꢁC until both phases were clear, and then cooled to
0 ꢁC, whereupon the inorganic salts partially precipi-
tated. Olefin 2 (2.00 g, 15.5 mmol) was added and the
heterogeneous slurry stirred vigorously at 0 ꢁC for 24 h.
The reaction was quenched at 0 ꢁC by the addition of
sodium sulfite (23.20 g) and then stirred for 1 h. The
reaction mixture was extracted with ethyl acetate
(3 · 30 mL), dried over Na2SO4 and concentrated. The
residue was purified by column chromatography (hex-
25
D
(0.48 g, 1.76 mmol). ½aŠ )38.8 (c 0.92, MeOH). Anal.
Calcd for C6H11NO5S: C, 34.44; H, 5.30; N, 6.69; S,
15.33. Found: C, 34.33; H, 5.42; N, 6.73; S, 15.21.
4.6. (S)-3-Azido-2-hydroxy-N-methoxy-2,N-dimethyl-
propionamide (S)-5
To a solution of cyclic sulfite (S)-4 (1.00 g, 4.78 mmol) in
DMF (30 mL) was added NaN3 (1.24 g, 19.11 mmol).
The mixture was stirred at 70 ꢁC for 2 d to give a mixture
of azido alcohols (S)-5 and (R)-6 in a 4:1 ratio. The
solvent was removed and the residue partitioned
between H2O (30 mL) and ethyl acetate (50 mL). The
ane/ethyl acetate, 3:7) to give compound (S)-3 as a
25
D
colourless oil (2.05 g, 12.5 mmol); yield: 81%. ½aŠ )4.6
(c 1.80, MeOH); 1H NMR (CDCl3): d 1.38 (s, 3H, CH3),

A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 131–137
135
aqueous layer was successively extracted with ethyl ac-
4.9. (R)-3-Amino-2-hydroxy-2-methylpropionic acid
(R)-1 (via sulfites)
etate (2 · 20 mL), dried over Na2SO4, concentrated and
the crude product chromatographed (hexane/ethyl ace-
tate, 7:3) to give the a-azido b-alcohol (R)-6 (0.15 g,
17%) and the b-azido a-alcohol (S)-5 (0.62 g, 3.29 mmol)
As described for enantiomer (S)-1, compound (R)-1
(0.40 g, 96%) was obtained from compound (R)-5
25
D
as colourless liquids; yield: 69%. Overall yield: 86%.
(0.66 g, 3.50 mmol). ½aŠ )2.9 (c 1.05, MeOH). Anal.
25
D
Compound (S)-5: ½aŠ )73.9 (c 0.98, MeOH); 1H NMR
Calcd for C4H9NO3: C, 40.33; H, 7.62; N, 11.76. Found:
C, 40.29; H, 7.65; N, 11.70.
(CDCl3): d 1.40 (s, 3H, CCH3), 3.27 (s, 3H, NCH3),
3.40–3.55 (m, 2H, N3CH2), 3.69 (s, 3H, NOCH3); 13C
NMR (CDCl3): d 22.8 (CCH3), 33.5 (NCH3), 57.5
(N3CH2), 60.9 (NOCH3), 75.9 (CCH3), 173.7 (CON);
ESIþ ðm=zÞ [M+Na] ¼ 211. Anal. Calcd for C6H12N4O3:
4.10. (S)-Methanesulfonic acid 2-hydroxy-2-(methoxy-
methylcarbamoyl)propyl ester (S)-8
C, 38.29; H, 6.43; N, 29.77. Found: C, 37.95; H, 6.41; N,
25
29.71. Compound (R)-6: ½aŠ +61.6 (c 0.96, MeOH); 1H
A solution of diol (S)-3 (0.52 g, 3.18 mmol) in CH2Cl2
(20 mL) was cooled to 0 ꢁC after which MsCl (0.4 mL,
4.77 mmol) and DIEA (0.8 mL, 4.77 mmol) were added
dropwise under an argon atmosphere. The mixture was
stirred at 25 ꢁC for 2 h and 5% NaHCO3 was added
(10 mL). The aqueous layer was extracted with ethyl ac-
etate (3 · 10 mL) and the combined organic layers washed
with brine (10 mL), dried over Na2SO4 and concentrated.
The residue was purified by column chromatography
D
NMR (CDCl3): d 1.50 (s, 3H, CCH3), 3.22 (s, 3H,
NCH3), 3.65–3.85 (m, 5H, NOCH3, OCH2); 13C NMR
(CDCl3): 17.6 (CCH3), 33.2 (NCH3), 60.9 (NOCH3),
66.6 (CCH3), 68.6 (OCH2), 171.6 (CON); ESIþ ðm=zÞ
[M+Na] ¼ 211. Anal. Calcd for C6H12N4O3: C, 38.29;
H, 6.43; N, 29.77. Found: C, 37.98; H, 6.42; N, 29.74.
(hexane/ethyl acetate, 4:6) to give (S)-8 as a white solid
4.7. (R)-3-Azido-2-hydroxy-N-methoxy-2,N-dimethyl-
propionamide (R)-5
25
(0.75 g, 3.09 mmol); yield: 97%. Mp: 65 ꢁC. ½aŠ )16.5
D
(c 1.00, MeOH); 1H NMR (CDCl3): d 1.33–1.48 (m, 3H,
CH3), 2.95–3.10 (m, 3H, SO2CH3), 3.20–3.36 (m, 3H,
NCH3), 3.68–3.81 (m, 3H, NOCH3), 4.21–4.37 (m, 1H,
CH2), 4.47–4.68 (m, 2H, CH2+OH); 13C NMR (CDCl3):
21.7 (CH3), 33.8 (NCH3), 37.8 (SO2CH3), 43.3 (CCH3),
61.2 (NOCH3), 73.9 (CH2), 172.4 (CON); MS (EI)
ðm=zÞ ¼ 61, 79, 132, 153; ESIþ ðm=zÞ ¼ 242. Anal. Calcd
for C7H15NO6S: C, 34.85; H, 6.27; N, 5.81; S, 13.29.
Found: C, 34.93; H, 6.21; N, 5.72; S, 13.36.
As described for enantiomers (S)-5 and (R)-6, com-
pounds (R)-5 (0.62 g, 3.29 mmol, 69%) and (S)-6 (0.15 g,
17%) were obtained from compound (R)-4 (1.00 g,
25
4.78 mmol). Compound (R)-5: ½aŠ +75.3 (c 0.99,
D
MeOH). Anal. Calcd for C6H12N4O3: C, 38.29; H, 6.43;
N, 29.77. Found: C, 38.05; H, 6.38; N, 29.70. Com-
pound (S)-6: ½aŠ25 )60.9 (c 1.02, MeOH). Anal. Calcd for
D
C6H12N4O3: C, 38.29; H, 6.43; N, 29.77. Found: C,
37.99; H, 6.39; N, 29.82.
4.11. (R)-Methanesulfonic acid 2-hydroxy-2-(methoxy-
methylcarbamoyl)propyl ester (R)-8
4.8. (S)-3-Amino-2-hydroxy-2-methylpropionic acid
(S)-1 (via sulfites)
As described for enantiomer (S)-8, compound (R)-8
(1.00 g, 97%) was obtained from diol (R)-3 (0.70 g,
25
D
To a solution of compound (S)-5 (0.79 g, 4.20 mmol) in
H2O/MeOH (1:3, 40 mL) was added LiOHÆH2O (0.88 g,
21.1 mmol) with the resulting mixture stirred at 25 ꢁC for
2 h. The N,O-dimethylhydroxylamine formed in the re-
action along with MeOH was removed and the mixture
acidified with concd HCl to pH 1–2. The solvent was
removed and the residue partitioned between H2O
(10 mL) and ethyl acetate (20 mL). The aqueous layer
was successively extracted with ethyl acetate (2 · 20 mL),
dried over Na2SO4 and concentrated to give (S)-7
(0.60 g, 4.12 mmol) [1H NMR (CD3OD): d 1.40 (s, 3H,
CCH3), 3.37 (d, 1H, J ¼ 12:3 Hz, CH2), 3.49 (d, 1H,
J ¼ 12:3 Hz, CH2); ESIÀ ðm=zÞ ¼ 144. Anal. Calcd for
C4H7N3O3: C, 33.11; H, 4.86; N, 28.96. Found: C,
33.22; H, 4.75; N, 29.71]. This compound was dissolved
in ethanol (15 mL) after which palladium on carbon
(1:5, catalyst/substrate by weight) was added. The re-
sulting suspension was stirred at 25 ꢁC for 24 h. The
catalyst was removed by filtration and the solvent
4.29 mmol). ½aŠ +16.8 (c 1.01, MeOH). Anal. Calcd for
C7H15NO6S: C, 34.85; H, 6.27; N, 5.81; S, 13.29. Found:
C, 34.73; H, 6.23; N, 5.70; S, 13.39.
4.12. (S)-3-Allylamino-2-hydroxy-N-methoxy-2,N-
dimethylpropionamide (S)-9 and (S)-N-allyl-3-allyl-
amino-2-hydroxy-2-methylpropionamide (S)-10
Mesylate (S)-8 (0.75 g, 3.09 mmol) was dissolved in neat
light-protected allylamine (20 mL) and refluxed for 6 h
to give a mixture of the allylaminoalcohols (S)-9 and
(S)-10 in a ratio of 65:35. The excess of allylamine was
removed and the mixture washed with water (10 mL)
and extracted with ethyl acetate (3 · 20 mL). The com-
bined organic layers were dried over Na2SO4, concen-
trated and purified by flash column chromatography
(CH2Cl2/MeOH, 9:1) to give (S)-9 (0.38 g) and (S)-10
(0.20 g) as colourless oils. Overall yield: 93%. Com-
25
D
evaporated to give (S)-1 (0.48 g, 4.03 mmol); yield: 96%.
pound (S)-9: ½aŠ )12.4 (c 1.60, MeOH); 1H NMR
25
D
½aŠ +2.8 (c 1.04, H2O). Anal. Calcd for C4H9NO3: C,
(CDCl3): d 1.36 (s, 3H, CH3), 2.61 (d, 1H, J ¼ 11:6 Hz,
CH2), 3.08 (d, 1H, J ¼ 11:6 Hz, CH2), 3.15–3.27 (m, 5H,
NCH2+NCH3), 3.69 (s, 3H, NOCH3), 4.98–5.29 (m, 2H,
40.33; H, 7.62; N, 11.76. Found: C, 40.25; H, 7.66; N,
11.68.

136
A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 131–137
CCH2), 5.71–5.87 (m, 1H, CHC); 13C NMR (CDCl3): d
23.6 (CH3), 34.1 (NCH3), 52.6 (CH2C@C), 56.6 (CH2),
61.1 (NOCH3), 75.2 (CCH3), 116.2 (CH@C), 137.0
(C@CH2); 175.5 (CON); ESIþ ðm=zÞ ¼ 202. Anal. Calcd
4.16. (10R,200R)-Acetic acid 10-[200-hydroxy-200-(methoxy-
methylcarbamoyl)propylcarbamoyl]-10-(phenyl)methyl
ester 11
for C9H18N2O3: C, 53.45; H, 8.97; N, 13.85. Found: C,
(R)-9 (0.20 g, 0.99 mmol) was treated at 30 ꢁC with
Pd(PPh3)4 (0.11 g, 9 · 10À3 mmol) and N,N-dimethyl-
barbituric acid (NDMBA, 0.48 g, 2.95 mmol) in dry
degassed CH2Cl2 (40 mL) with protection from light
under an argon atmosphere. The mixture was stirred
for 3 h, the solvent evaporated and the crude product
treated with saturated Na2CO3 solution (5 mL) and ex-
tracted with CHCl3/isopropanol (3:1) (5 · 20 mL). The
solution was dried over Na2SO4 and the solvent re-
moved to give the crude amino alcohol. The product
was treated at 25 ꢁC with (R)-O-acetylmandelic acid
choride (0.32 g, 1.48 mmol) and TEA (0.15 g, 1.48 mmol)
in CH2Cl2 (20 mL) for 10 h. The reaction mixture was
washed with 5% NaHCO3 solution (5 mL) and the
aqueous layer was extracted with ethyl acetate
(3 · 20 mL); the combined organic layers were dried over
NaSO4, evaporated and purified by column chroma-
tography (hexane/ethyl acetate, 2:8) to give compound
11 as a colourless oil (0.29 g, 0.87 mmol); yield: 88%.
25
53.61; H, 8.89, N, 13.81. Compound (S)-10: ½aŠ )10.2
D
(c 1.19, MeOH); 1H NMR (CDCl3): d 1.33 (s, 3H, CH3),
2.40 (d, 1H, J ¼ 12:3 Hz, CH2), 3.19–3.25 (m, 2H,
NCH2), 3.31 (d, 1H, J ¼ 12:3 Hz, CH2), 3.31–3.39 (m,
2H, NCH2), 5.05–5.20 (m, 4H, 2CCH2), 5.72–5.90 (m,
2H, 2CHC); 13C NMR (CDCl3): d 24.7 (CH3), 41.8
(CH2C@C), 52.5 (CH2C@C), 55.9 (CH2), 74.1 (CCH3),
116.4 (CH@C), 117.0 (CH ¼ C), 134.4 (C@CH2), 136.2
(C@CH2); 176.1 (CON); ESIþ ðm=zÞ ¼ 199. Anal. Calcd
for C10H18N2O2: C, 60.58; H, 9.15; N, 14.13. Found: C,
61.01; H, 9.13, N, 14.09.
4.13. (R)-3-Allylamino-2-hydroxy-N-methoxy-2,N-
dimethylpropionamide (R)-9 and (R)-N-allyl-3-allyl-
amino-2-hydroxy-2-methylpropionamide (R)-10
As described for enantiomers (S)-9 and (S)-10, com-
pounds (R)-9 (0.35 g) and (R)-10 (0.19 g) were obtained
from compound (R)-8 (0.70 g, 2.90 mmol). Overall yield:
½aŠ25 +45.0 (c 0.92, MeOH); 1H NMR (CDCl3): d 1.43 (s,
D
3H, CH3), 2.19 (s, 3H, COCH3), 3.11–3.38 (m, 4H,
NCH3+CH2), 3.72 (s, 3H, NOCH3), 3.90–4.10 (m, 1H,
CH2), 4.67 (s, 1H, OH), 5.98 (s, 1H, CH), 6.55 (br s, 1H,
NH), 7.28–7.55 (m, 5H, Ph); 13C NMR (CDCl3): d 21.3
(COCH3), 23.1 (CH3), 34.0 (NCH3), 46.1 (CH2), 61.4
(NOCH3), 74.6 (CCH3), 76.0 (CH), 127.4, 129.0, 129.3,
135.5 (Ph), 169.0 (NCO), 169.7 (COCH3), 174.1 (CON);
ESIþ ðm=zÞ ¼ 339. Anal. Calcd for C16H22N2O6: C,
56.80; H, 6.55; N, 8.28. Found: C, 56.89; H, 6.51; N,
8.26.
25
93%. Compound (R)-9: ½aŠ +12.2 (c 1.60, MeOH).
D
Anal. Calcd for C9H18N2O3: C, 53.45; H, 8.97; N, 13.85.
Found: C, 53.32; H, 8.96, N, 13.82. Compound (R)-10:
½aŠ
25
D
+10.1 (c 1.19, MeOH). Anal. Calcd for
C10H18N2O2: C, 60.58; H, 9.15; N, 14.13. Found: C,
60.91; H, 9.12, N, 14.10.
4.14. (S)-3-Amino-2-hydroxy-2-methylpropionic acid
(S)-1 (via mesylates)
Allylaminoalcohols (S)-9 and (S)-10 (0.11 g, 0.54 mmol)
were treated at 30 ꢁC with Pd(PPh3)4 (0.06 g,
5 · 10À3 mmol) and N,N-dimethylbarbituric acid
(NDMBA, 0.26 g, 1.61 mmol) in dry degassed CH2Cl2
(30 mL) with protection from light under an argon at-
mosphere. The reaction mixture was stirred for 3 h, the
solvent evaporated and the crude product treated at
60 ꢁC with 6 M aqueous HCl (2 mL) for 8 h. The mixture
was diluted with water (20 mL), washed with ethyl ace-
tate (2 · 10 mL) and concentrated to give the desired
amino acid hydrochloride salt along with N,O-di-
methylhydroxylamine hydrochloride and traces of
NDMBA as impurities. Treatment of this mixture with
4.17. (10R,200S)-Acetic acid 10-[200-hydroxy-200-(methoxy-
methylcarbamoyl)propylcarbamoyl]-10-(phenyl)methyl
ester 12
As described for diastereomer 11, compound 12 (0.15 g,
0.46 mmol, 83%) was obtained from compound (S)-9
25
D
(0.11 g, 0.56 mmol). ½aŠ +34.5 (c 1.57, MeOH); 1H NMR
(CDCl3): d 1.39 (s, 3H, CH3), 2.12 (s, 3H, COCH3), 3.07
(s, 3H, NCH3) 3.19–3.33 (m, 1H, CH2), 3.61 (s, 3H,
NOCH3), 3.98–4.09 (m, 1H, CH2), 4.71 (s, 1H, OH),
6.00 (s, 1H, CH), 6.72 (br s, 1H, NH), 7.18–7.48 (m, 5H,
Ph); 13C NMR (CDCl3): d 21.2 (COCH3), 22.9 (CH3),
33.7 (NCH3), 46.0 (CH2), 61.2 (NOCH3), 74.5 (CCH3),
75.7 (CH), 127.3, 127.7, 128.8, 129.1, 135.8 (Ph), 168.6
(NCO), 169.3 (COCH3), 174.1 (CON); Anal. Calcd for
C16H22N2O6: C, 56.80; H, 6.55; N, 8.28. Found: C,
56.87; H, 6.52; N, 8.30.
ethanol/propylene oxide gave 0.05 g of (S)-1 as a white
25
D
solid yield: 85% ½aŠ +2.9 (c 1.01, H2O). Anal. Calcd for
C4H9NO3: C, 40.33; H, 7.62; N, 11.76. Found: C, 40.24;
H, 7.63; N, 11.72.
4.15. (R)-3-Amino-2-hydroxy-2-methylpropionic acid
(R)-1 (via mesylates)
4.18. (2S,20R)-3-Benzyloxy-2-tert-butoxycarbonylamino-
propionic acid 20-hydroxy-20-(methoxymethyl-
carbamoyl)propyl ester 14
As described for enantiomer (S)-1, compound (R)-1
(0.046 g, 72%) was obtained from a mixture of com-
25
D
pounds (R)-9 and (R)-10 (0.11 g, 0.54 mmol). ½aŠ )2.5
To a solution of (R)-3 (0.13 g, 0.82 mmol), DCC (0.26 g,
0.90 mmol) and DMAP (9 mg, 0.09 mmol) in CH2Cl2
(20 mL) was added a solution of (S)-3-benzyloxy-2-tert-
(c 1.05, MeOH). Anal. Calcd for C4H9NO3: C, 40.33; H,
7.62; N, 11.76. Found: C, 40.10; H, 7.63; N, 11.74.

A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 131–137
137
4. Seebach, D.; Abele, S.; Schreiber, J. V.; Martinoni, B.;
Nussbaum, A. K.; Schila, H.; Schulz, H.; Hennecke, H.;
Woessner, R.; Bitsch, F. Chimia 1998, 52, 734–739.
5. Seebach, D.; Overhand, M.; Kuhnle, F. N. H.; Martinoni,
B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta
1996, 79, 913–941.
6. Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev.
2001, 101, 3219–3232, and references cited therein.
7. Banerjee, A.; Balaram, P. Curr. Sci. 1997, 73, 1067–
1077.
butoxycarbonylaminopropionic acid (0.28 g, 0.94 mmol)
in CH2Cl2 (15 mL). After stirring the mixture at 25 ꢁC
for 6 h, the resulting white suspension was filtered to
remove N,N0-dicyclohexylurea. The filtrate was con-
centrated to give a white slurry, to which Et2O was
added. The resulting suspension was filtered to remove
the dicyclohexylurea and the solvent evaporated. The
residue was purified by column chromatography (hex-
ane/ethyl acetate, 6:4) to give compound 14 as a col-
25
D
ourless oil (0.30 g, 0.70 mmol); yield: 85%. ½aŠ +8.7 (c
8. Seebach, D.; Abele, S.; Gadermann, K.; Guichard, G.;
Hintermann, T.; Jaun, B.; Matthews, J. L.; Schreiber, J.
V.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta
1998, 81, 932–982.
1
1.49, CHCl3); H NMR (CDCl3): d 1.32–1.45 [m, 12H,
C(CH3)3, CH3], 3.15 (s, 3H, NCH3), 3.59 (3H, NOCH3),
3.61–3.71 (m, 1H, CH2O), 3.80–3.88 (m, 1H, CH2O),
4.12–4.21 (m, 1H, CH2O), 4.33–4.57 (m, 5H, PhCH2O,
CH2O, CHN, OH), 5.33–5.42 (m, 1H, NH), 7.20–7.35
(m, 5H, Ph); 13C NMR (CDCl3): d 21.6 (CH3), 28.2
[(CH3)3C], 33.6 (NCH3), 53.9 (CHN), 61.0 (NOCH3),
69.5 (CH2O), 70.1 (CH2O), 73.2 (PhCH2O), 73.7
[C(OH)CH3], 79.9 [(CH3)3C], 127.3, 127.7, 128.3, 137.5
(Ph), 155.3 (NCO), 170.3, 173.4 (CON, CO2); ESIþ
ðm=zÞ ¼ 441. Anal. Calcd for C21H32N2O8: C, 57.26; H,
7.32; N, 6.36. Found: C, 58.00; H, 7.36; N, 6.30.
ꢀ
ꢀ
9. Cativiela, C.; Dıaz-de-Villegas, M. D.; Galvez, J. A.
Tetrahedron: Asymmetry 1996, 52, 687–694.
10. Pires, R.; Burger, K. Synthesis 1996, 1277–1279.
11. Sharpless, K. B.; Bruncko, M.; Schlingloff, G. Angew.
Chem., Int. Ed. 1997, 36, 1483–1486.
12. Sharpless, K. B.; Tao, B.; Schlingloff, G. Tetrahedron Lett.
1998, 39, 2507–2510.
13. Song, C. E.; Oh, C. R.; Roh, E. J.; Lee, S.; Choi, J. H.
Tetrahedron: Asymmetry 1999, 10, 671–674.
14. OꢁBriean, P. Angew. Chem., Int. Ed. 1999, 38, 326–329.
15. Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Sucunza, D.; Zurbano, M. M. Tetrahedron: Asymmetry
2001, 12, 949–953.
16. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B.
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Acknowledgements
17. Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1059–1070.
ꢀ
We thank the Ministerio de Ciencia y Tecnologıa (pro-
18. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 227–
272.
19. Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett. 1993,
34, 2079–2082.
ject PPQ2001-1305), the Gobierno de La Rioja (project
ANGI-2001/30 and doctoral fellowship for D.S.) and
the Universidad de La Rioja (project API-03/04 and
doctoral fellowship for G.J.-O.).
ꢀ
20. Avenoza, A.; Busto, J. H.; Corzana, F.; Garcıa, J. I.;
Peregrina, J. M. J. Org. Chem. 2003, 68, 4506–4513.
21. Garro-Hellion, F.; Merzouk, A.; Guibe, F. J. Org. Chem.
1993, 58, 6109–6113.
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