α-Alkylation versus retro-O-Michael/γ-alkylation of bicyclic N,O-acetals: an entry to α-methylthreonine

Article abstract of DOI:10.1016/j.tetasy.2008.11.031

The synthesis of a new threonine equivalent based on a bicyclic N,O-acetal substructure incorporating four stereogenic centres is developed from Boc-l-threonine methyl ester in one step. Its use as an excellent chiral building block was demonstrated in a new diastereoselective synthesis of α-methylthreonine by an α-alkylation reaction and in the synthesis of chiral α,β-dehydroamino acid derivatives, using the tandem retro-O-Michael/γ-alkylation reactions as key steps.

Full text of DOI:10.1016/j.tetasy.2008.11.031

Tetrahedron: Asymmetry 19 (2008) 2829–2834
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
a
-Alkylation versus retro-O-Michael/c-alkylation of bicyclic N,O-acetals:
an entry to a-methylthreonine
Carlos Aydillo a, Alberto Avenoza a, Jesús H. Busto a, Gonzalo Jiménez-Osés b,
a,
Jesús M. Peregrina a, , María M. Zurbano
*
*
a Departamento de Química, Universidad de La Rioja, Grupo de Síntesis Química de La Rioja, U.A.-C.S.I.C., E-26006 Logroño, Spain
b Departamento de Química Orgánica, C.S.I.C.-Universidad de Zaragoza. Pedro Cerbuna 12, E-50009 Zaragoza, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a new threonine equivalent based on a bicyclic N,O-acetal substructure incorporating
Received 10 October 2008
Accepted 20 November 2008
Available online 12 January 2009
four stereogenic centres is developed from Boc-
lent chiral building block was demonstrated in a new diastereoselective synthesis of
L
-threonine methyl ester in one step. Its use as an excel-
-methylthreonine
a
by an
a-alkylation reaction and in the synthesis of chiral
a,b-dehydroamino acid derivatives, using the
tandem retro-O-Michael/
c-alkylation reactions as key steps.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
required
centre (
a-alkyl-b-hydroxy-a-amino acids with one stereogenic
-alkylserine derivatives 1) (Scheme 1).
a
Peptides based on proteinogenic amino acids find limited appli-
cation as drugs due to rapid metabolism by proteolysis.1 The study
and design of modified peptides that incorporate non-natural ami-
no acids have therefore found increased application as surrogates
in different biological processes. Several non-natural amino acids
are already important industrial targets as drugs.2 Moreover,
non-natural amino acids are versatile building blocks in the
synthesis of chiral compounds and are useful as templates in
MeO
HO
O
(R)
(S)
H2N
(S)
O
N
(S)
R
CO2H
O
CO2Me
α-AlkylSer 1
bicyclic chiral
asymmetric synthesis. In this context, the current interest in
a,a-
Ser equivalent 2
dialkyl-
a
-amino acids3 relates to the important effects they have
MeO
on the biological activity of peptides that incorporate these quater-
nary amino acids, because they induce alterations in the conforma-
tions of the backbone and lateral chain. Among these compounds,
HO
(R)
O
(R)
(S)
(R)
(S)
H2N
O
(S)
N
chiral
a-alkyl-b-hydroxyamino acids have been extensively stud-
CO2H
α-MeThr 3
O
CO2Me
ied owing to their important roles in synthetic and biological
chemistry, particularly in glycobiology, since their hydroxyl group
is crucial for the formation of O-glycosidic linkages with
carbohydrates.4
bicyclic chiral
Thr equivalent 4
Scheme 1. Retrosynthesis of
a-alkyl-b-hydroxyamino acids from bicyclic N,O-
In this sense, we have contributed to this field by developing
acetals.
synthetic routes for
the use of five-membered cyclic N,O-acetals5 (Garner’s aldehyde
derivatives). More recently, in the context of the synthesis of -alk-
a,a-disubstituted a-amino acids based on
a
2. Results and discussion
ylserines, we have published a new methodology involving the use
of a serine equivalent as an excellent chiral building block.6 Start-
ing with the novel bicyclic N,O-acetal 2, diastereoselective enolate
alkylation reaction and subsequent acid hydrolysis gave the
With the aim of synthesizing quaternary amino acids with two
stereogenic centres, we envisioned the design of other more
complex chiral five-membered cyclic N,O-acetal derived from
threonine by incorporating a new stereogenic centre in its struc-
ture 4. Consequently, we herein report the synthesis of a new thre-
onine equivalent 4 and its reactivity as an excellent precursor of an
* Corresponding authors. Fax: +34 941 299 621 (J.M.P.).
E-mail addresses: jesusmanuel.peregrina@unirioja.es (J.M. Peregrina), marimar.
zurbano@unirioja.es (M.M. Zurbano).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.11.031

2830
C. Aydillo et al. / Tetrahedron: Asymmetry 19 (2008) 2829–2834
a
tres;
-alkyl-b-hydroxy-
a
-amino acid with two chiral stereogenic cen-
HMPA,
LHMDS
MeI,
MeO
O
a-methylthreonine 3, abbreviated as a-MeThr (Scheme 1).
(S) O
(R)
This new chiral building block 4 derived from threonine was ob-
tained following a similar protocol already published for its ana-
logue of serine.6a Indeed, 2,2,3,3-tetramethoxybutane (TMB) was
(R)
THF,
N
0 ºC, 24
h
(S)
O
78%
CO2Me
treated with commercially available Boc-L-threonine methyl ester
d.r.>20:1
MeO
O (R)
5 in the presence of p-toluenesulfonic acid (TsOHꢀH2O) in refluxing
toluene for 4 h, allowing the synthesis of bicyclic compound 4 in
good yield on a multigram scale (Scheme 2).
6
O
(R)
(S)
N
HMPA,
(S)
MeO
LHMD S,
O
CO2Me
THF, 0º C,
OH
O (R) (S)
then
0.5 h,
4
TMB,
N
MeI, 0.5 h
TsOH·H2O,
toluene,
MeO
O
HO
O
O
69%
CO2Me
(R)
reflux, 4 h
(R)
(R)
(S)
d.r.>20:1
BocHN
N
(Z)-7
(S)
69%
(S)
O
Scheme 3.
a-Alkylation versus retro-O-Michael/c-alkylation of bicyclic N,O-acetal 4.
d.r.>20:1
CO2Me
CO2Me
5
4
Scheme 2. Synthesis of threonine-derived chiral building block 4 from Boc-
OMe 5.
L-Thr-
Propylene
oxide,
EtOH,
6 M HCl,
100 ºC,
12 h
HO
HO
reflux,
Cl
H3N
(R)
(R)
Thisprocessproceeded witha high diastereoselectivity(dr>20:1,
as demonstrated by 1H NMR), and the absolute configuration of this
new compound 4, which contains four chiral carbons, was unambig-
uously determined by X-ray diffraction analysis7 of single crystals
obtained by slow evaporation of hexane/ethyl acetate (Fig. 1). The
bridgehead carbamate N atom is strongly pyramidalized in these
compounds, and bothfive-membered rings are folded, in accordance
with similar structures previously published.6
40 min
(S)
(S)
H2N
6
94%
43%
CO2H
3·HCl
d.r.>20:1
CO2H
3
d.r.>20:1
Scheme 5. Synthetic pathway used to obtain the quaternary amino acid a-MeThr 3.
trary to what had happened with the bicycle 2 derived from serine,
in this case, we did not detect the formation of a secondary product
(acrylate derivative) generated by the well-known retro-O-Michael
reaction involving the lithium enolate.4
The stereochemistry of this new compound 6 was unambigu-
ously determined by its transformation into a compound of known
absolute configuration (see Scheme 5). Alternatively, the stereo-
chemistry of 6 was confirmed by 2D NOESY experiments.9 2D
NOESY experiments were made using phase-sensitive ge-2D
NOESY in CDCl3 and show positive cross-peaks between the OMe
Figure 1. ORTEP3 diagram for chiral building block 4.
Given the easy access to chiral threonine-derived building block
4, and with the aim of assessing its use as a precursor for the asym-
metric synthesis of quaternary
a-amino acids, we attempted the
alkylation of this compound under standard conditions. Neverthe-
less, at low temperature (ꢁ78 °C) and using methyl triflate as an
electrophile the reaction did not progress, probably due to the steric
impediment of the b-methyl group arising from threonine. This fea-
ture forced us to increase the temperature (0 °C) of the alkylation
reaction, which made necessary the change of electrophile, due to
polymerization problems encountered with methyl triflate in THF
at this temperature.8 Thus, treatment of bicycle 4 with methyl iodide
(MeI) at 0 °C and 4 equiv of hexamethylphosphoramide (HMPA) in
THF as a solvent, followed by the addition of lithium hexamethyldi-
silazide (LHMDS), produced in 24 h the methylated derivative 6 as a
single diastereoisomer (dr >20:1) (Scheme 3). Fortunately and con-
Figure 2. 2D NOESY experiments for alkylation product 6.

C. Aydillo et al. / Tetrahedron: Asymmetry 19 (2008) 2829–2834
2831
and Me groups attached at 7a carbon (B, Fig. 2). This Me group
HMPA,
LHMDS,
THF,
MeO
O
shows a positive cross-peak with the H2 proton (C, Fig. 2), indicat-
ing that all these groups are located in the same face. The H2
proton displays NOE and COSY effects with the Me group attached
at the same carbon (D, Fig. 2). Finally, this Me group shows an NOE
effect with the new Me group arising from the alkylation step (E,
Fig. 2). Indeed, we could be assured that the new stereogenic qua-
ternary centre created in the alkylation reaction of bicycle 6 re-
tained the initial configuration showed in starting bicycle 4.
Therefore, a similar mechanism to that calculated for the alkylation
of the analogue serine equivalent 2 can be proposed. In this theo-
retical study, we found that the formation of a highly pyramidal-
ized ester enolate was the true source of the high
diastereoselectivity. In fact, the inversion barrier of this enolate
was calculated to be greater than any other process occurring un-
der the reaction conditions.6a
OH
(R)
0 ºC, 0.5 h
(S)
N
84%
O
CO2Me
(Z) -8
d.r.>20:1
MeO
O
HMPA,
(S) O (R)
(R)
LHMD S,
78%
N
THF, 0 º C,
0.5 h, then
ND4Cl, D2O
d.r.>20:1
(S)
O
HMPA,
CO2Me
LHMDS,
4
THF, 0 ºC,
0.5 h, then
ND4Cl, D2O
MeO
O
(S)OH
D
(R)
N
Curiously, when the same alkylation reaction of bicycle 4 was
carried out by adding the electrophile (MeI) as the last reagent
(30 min after stirring the reaction mixture at 0 °C), only the new
74%
O
d.r.>20:1
CO2Me
(Z)-9
product (Z)-7, which did not correspond to an
a-alkylation prod-
uct, was cleanly isolated in good yield after another additional
30 min of reaction. The structure of this compound corresponded
Scheme 4. Synthesis of
block 4.
a,b-dehydroamino acid derivatives from chiral building
to a c-methylation of the acrylate derivative generated in the ret-
1D DPFGE NOE pulse sequence.11 These experiments show an
NOE effect between the vinyl proton (H3, blue colour in Fig. 3)
and the methyl ester group. This fact along with the NOE effect
observed in Me4’ and OMe groups when Me4 group (red colour
in Fig. 3) is irradiated confirms the Z configuration of this alkene.
This last methodology opens the way for the synthesis of
ro-O-Michael reaction of bicycle 4 (Scheme 3). Similar c-alkylation
reactions of acrylate derivatives have been well-documented.10
To gain some insights of the proposed mechanism, we carried
out the reaction of bicycle 4 under the same conditions but in
the absence of electrophile (MeI), obtaining in this case the corre-
sponding non-c-methylated acrylate derivative (Z)-8. Moreover,
this compound (Z)-8 was treated in the same way but in the pres-
ence of deuterated ammonium chloride (ND4Cl), giving compound
(Z)-9, which incorporated a deuterium atom in the c-position. This
compound (Z)-9 could be also directly obtained from bicycle 4 in
one single step, using the same conditions that those described
for compound (Z)-7, but changing the electrophile from MeI to
ND4Cl (Scheme 4).
interesting chiral
considered important targets as building blocks to carry out asym-
metric reactions to prepare -amino acids, oxalamic acid deriva-
tives or
-keto acids.12 Moreover ,b-dehydroamino acids13 also
a,b-dehydroamino acid derivatives, which are
a
a
a
show exciting biological activities and have been used to modify
the conformational properties of peptides.14
On the other hand, and to show the synthetic applicability of
the highly diastereoselective
ing block 4, derived from threonine, and with the aim of expanding
this methodology to the preparation of -alkyl-b-hydroxy- -ami-
no acids with two chiral stereogenic centres, we carried out the
a-alkylation of the new chiral build-
The stereochemistry of these new
a,b-unsaturated amino acid
derivatives was assessed by NMR. As an example, we show in Fig-
ure 3 the selective NOE experiments11 performed on (Z)-8. The
selective ge-1D NOESY experiments were carried out using the
a
a
Figure 3. Selective 1D NOESY experiments on compound (Z)-8.

2832
C. Aydillo et al. / Tetrahedron: Asymmetry 19 (2008) 2829–2834
synthesis of (2S,3R)-
a
-methylthreonine 3 from the precursor 6.
The aqueous layer was extracted with more diethyl ether
(2 ꢃ 50 mL) and the organic layers were combined, washed with
brine and dried over anhydrous Na2SO4. The solvent was evapo-
rated and the crude product was purified by a silica gel column
chromatography eluting with hexane/ethyl acetate (7:3) to give
Hydrolysis of the substrate 6 in an acidic medium gave the
required amino acid 3 as an hydrochloride derivative in a 94% yield
(Scheme 5). An aliquot of this compound was treated with propyl-
ene oxide to obtain the free amino acid 3 in a 43% yield. The struc-
tural and optical properties of this compound were almost
5.30 g of product 4 (69%) as brown crystals. ½a D25
¼ ꢁ122:3 (c
ꢂ
identical to those reported in the literature (½a D25
ꢂ
¼ ꢁ13:6).5f It is
0.95, CHCl3); mp = 52.8 °C; 1H NMR (CDCl3): d 4.46 (m, 1H, CHCH3),
4.26 (d, 1H, J = 5.78 Hz, CHCO2CH3), 3.81 (s, 3H, CO2CH3), 3.46 (s,
3H, OCH3), 1.59 (s, 3H, CCH3OCH3), 1.44 (d, 3H, J = 6.06 Hz, CHCH3),
1.39 (s, 3H, CNCH3); 13C NMR (CDCl3): d 170.0 (CO2CH3), 160.6
(NCO2), 106.7 (CCH3OCH3), 101.4 (CNCH3OCH), 76.0 (CHCH3),
66.6 (CHCO2CH3), 52.4 (CHCO2CH3), 50.7 (OCH3), 20.3 (CHCH3),
16.2 (CNCH3), 15.3 (CCH3OCH3); HRMS (ESI) m/z = 282.0951 [M +
Na]+; calcd for C11H17NNaO6 = 282.0954.
important to note that although several synthetic methods have
been reported for
there are only four methodologies (six reports) on the asymmetric
synthesis of enantiomerically pure
-methylthreonine.5f,15 The
a-methylserines, to the best of our knowledge,
a
interest in
a-methylthreonines has been recently illustrated by
our group in glycopeptide chemistry16 since it has been shown that
the replacement of the natural amino acid threonine with the non-
natural a-methylthreonine in O-glycosylated derivatives markedly
influences the conformational properties of glycopeptides.17
4.2.2. Crystal data of compound 4
Molecular formula C11H17NO6, Mw = 259.26, colourless prism of
0.7 ꢃ 0.2 ꢃ 0.2 mm, T = 100 K, monoclinic, space group P21, Z = 2,
a = 6.9030(3) Å, b = 12.0450(6) Å, c = 7.7740(3) Å, b = 96.828(2)°,
V = 641.80(5) Å3, dcalc = 1.342 g cmꢁ3, F(000) = 276, k = 0.71073 Å
3. Conclusions
(Mo, K
range 3.42–27.49°, 4786 collected reflections, 2723 unique, full-
matrix least-squares
SHELXL97),18 R1 = 0.0635, wR2 = 0.0706,
a), l
= 0.110 mmꢁ1, Nonius kappa CCD diffractometer, h
Starting from a commercially available protected threonine
derivative, we have synthesized a new chiral bicyclic threonine
equivalent as an excellent precursor of non-natural amino acids.
The chemoselectivity of the reaction between this new chiral
building block 4 and methyl iodide promoted by a base in the pres-
ence of HMPA could be modulated by the order of addition of
(
(R1 = 0.1536, wR2 = 0.1613 all data), goodness of fit = 1.092, resid-
ual electron density between 0.426 and ꢁ0.486 e Åꢁ3. 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 CCDC 702053.7
reagents. Thus, the
to obtain a quaternary amino acid that incorporates two stereogen-
ic centres ( -MeThr), while the tandem reaction (retro-O-Michael/
-alkylation) opened the way to obtain interesting ,b-unsaturated
a-alkylation reaction of bicycle 4 allowed us
a
c
a
amino acid derivatives.
4.3. Methyl (2R,3S,7R,7aS)-7-methoxy-2,3,7,7a-tetramethyl-5-
oxotetrahydro-2H-oxazolo[4,3-b]oxazole-3-carboxylate 6
4. Experimental
Compound 4 (924 mg, 3.56 mmol) was dissolved in dry THF
(90 mL) under an argon atmosphere, and HMPA (2.48 mL,
14.26 mmol) was added by syringe. The solution was stirred at
0 °C, and methyl iodide (1.33 mL, 21.36 mmol) and 1 M solution
of LHMDS in THF (14.26 mL, 14.26 mmol) were added dropwise
by syringe. After being stirred for 24 h at 0 °C, the reaction was
quenched with saturated NH4Cl solution (90 mL). The mixture
was diluted with diethyl ether and the aqueous layer was sepa-
rated and extracted with more diethyl ether. The combined organic
layers were washed with brine and dried over anhydrous Na2SO4.
The solvent was evaporated and the crude product was purified
by a silica gel column chromatography eluting with chloroform/
ethyl acetate (20:1) to give 760 mg of product 6 (78%) as a colour-
4.1. General procedures
Solvents were purified according to standard procedures. Ana-
lytical TLC was performed using Polychrom SI F254 plates. Column
chromatography was performed using Silica Gel 60 (230–
400 mesh). 1H and 13C NMR spectra were recorded on a Bruker
AVANCE 400 spectrometer. 1H and 13C NMR spectra were recorded
in CDCl3 with TMS as the internal standard and in D2O with TMS as
the external standard using a coaxial microtube (chemical shifts
are reported in ppm on the d scale, coupling constants in hertz).
The assignment of all separate signals in the 1H NMR spectra was
made on the basis of coupling constants, selective proton–proton
homonuclear decoupling experiments and COSY and HSQC exper-
iments. Melting points were determined on a Büchi SMP-20 melt-
ing point apparatus and are uncorrected. Optical rotations were
measured on a Perkin–Elmer 341 polarimeter in 1.0 dm cells of
1.0 and 0.3 mL capacity, respectively. Electrospray mass spectra
were recorded on a Bruker Microtof-Q spectrometer; accurate
mass measurements were achieved using sodium formate as an
external reference.
less oil. ½a 2D5
ꢂ
¼ ꢁ118:3 (c 1.08, CHCl3); 1H NMR (CDCl3): d 4.72 (q,
1H, J = 6.33 Hz, CHCH3), 3.79 (s, 3H, CO2CH3), 3.46 (s, 3H, OCH3),
1.63 (s, 3H, CCH3CO2CH3), 1.53 (s, 3H, CCH3OCH3), 1.41 (s, 3H,
CNCH3), 1.33 (d, 3H, J = 6.33 Hz, CHCH3); 13C NMR (CDCl3): d
173.4 (CO2CH3), 154.5 (NCO2), 107.4 (CCH3OCH3), 99.9
(CNCH3OCH), 80.4 (CHCH3), 67.1 (CCO2CH3), 53.0 (CCO2CH3), 51.6
(OCH3), 18.0 (CNCH3), 16.7 (CCH3OCH3), 16.1 (CCH3CO2CH3), 15.7
(CHCH3); HRMS (ESI) m/z = 296.1107 [M+Na]+; calcd for
C12H19NNaO6 = 296.1110.
4.2. Methyl (2R,3S,7R,7aS)-7-methoxy-2,7,7a-trimethyl-5-
oxotetrahydro-2H-oxazolo[4,3-b]oxazole-3-carboxylate 4
4.4. (Z)-Methyl 2-((40S,50R)-40-hydroxy-50-methoxy-40,50-
dimethyl-20-oxooxazolidin-30-yl)pent-2-enoate (Z)-7
4.2.1. Synthesis of compound 4
Boc-L-threonine methyl ester 5 (6.90 g, 29.6 mmol), 2,2,3,3-
Compound 4 (104 mg, 0.40 mmol) was dissolved in dry THF
(10 mL) under an argon atmosphere, and HMPA (0.27 mL,
1.60 mmol) was added by syringe. The solution was stirred at
0 °C, and 1 M solution of LHMDS in THF (0.79 mL, 0.79 mmol)
was added by syringe. After being stirred for 30 min at 0 °C, methyl
iodide (0.07 mL, 1.20 mmol) was added by syringe. The reaction
tetramethoxybutane (15.82 g, 88.7 mmol) and p-toluenesulfonic
acid (560 mg, 2.96 mmol) were dissolved in toluene (200 mL).
The mixture was stirred and heated at reflux for 4 h. The mixture
was allowed to cool at room temperature, and was then diluted
with diethyl ether (60 mL) and washed with saturated NaHCO3.

C. Aydillo et al. / Tetrahedron: Asymmetry 19 (2008) 2829–2834
2833
was stirred for another 30 min and then quenched with NH4Cl
solution (10 mL). The mixture was diluted with diethyl ether and
the aqueous layer was separated and extracted with more diethyl
ether. The combined organic layers were washed with brine and
dried over anhydrous Na2SO4. The solvent was evaporated and
the crude product was purified by a silica gel column chromatog-
raphy eluting with hexane/ethyl acetate (1:1) to give 76 mg of
19.6 (CCH3OH), 14.1 (C@CHCH2D), 14.1 (CCH3OCH3); HRMS (ESI)
m/z = 283.1019 [M+Na]+; calcd for C11H16DNNaO6 = 283.1016.
Method B: Compound (Z)-8 (49 mg, 0.19 mmol) was dissolved in
dry THF (5 mL) under an argon atmosphere, and HMPA (0.12 mL,
0.76 mmol) was added by syringe. The solution was stirred at
0 °C, and 1 M solution of LHMDS in THF (0.38 mL, 0.38 mmol)
was added by syringe. After being stirred for 30 min at 0 °C, the
reaction was quenched with ND4Cl solution (2.5 mL). The mixture
was diluted with diethyl ether and the aqueous layer was sepa-
rated and extracted with more diethyl ether. The combined organic
layers were washed with brine and dried over anhydrous Na2SO4.
The solvent was evaporated and the crude product was purified
by a silica gel chromatography eluting with hexane/ethyl acetate
(1:1) to give 39 mg of product (Z)-9 (78%).
product (Z)-7 (69%) as a colourless oil. ½a D25
¼ ꢁ122:3 (c 1.15,
ꢂ
CHCl3); 1H NMR (CDCl3): d 7.15 (t, 1H, J = 7.44 Hz, C@CHCH2CH3),
5.28 (s, 1H, OH), 3.83 (s, 3H, CO2CH3), 3.45 (s, 3H, OCH3), 2.32–
2.19 (m, 1H, C@CHCH2CH3), 2.23–2.11 (m, 1H, C@CHCH2CH3),
1.63 (s, 3H, CCH3OCH3), 1.28 (s, 3H, CCH3OH), 1.08 (t, 3H,
J = 7.54 Hz, CH2CH3); 13C NMR (CDCl3): d 167.1 (CO2CH3), 154.5
(NCO2), 151.0 (C@CHCH2CH3), 123.6 (C@CHCH2CH3), 108.7
(CCH3OCH3), 90.5 (CNCH3OH), 53.1 (CO2CH3), 50.6 (OCH3), 21.8
(C@CHCH2CH3), 19.6 (CCH3OH), 14.2 (CCH3OCH3), 12.3
(C@CHCH2CH3); HRMS (ESI) m/z = 296.1109 [M+Na]+; calcd for
C12H19NNaO6 = 296.1110.
4.7. (2S,3R)-2-Amino-3-hydroxy-2-methylbutanoic acid 3
A round bottomed flask was charged with compound 6 (93 mg,
0.34 mmol) and an aqueous 6 M HCl solution. The mixture was
stirred overnight at reflux. The solvent was removed in vacuo,
and the residue partitioned between water and ethyl acetate. The
aqueous phase was evaporated to give the hydrochloride deriva-
tive of compound 3 (54 mg, 94%). An aliquot of this material was
treated with ethanol/propylene oxide (2:1, 3 mL) at reflux for
40 min to give the corresponding amino acid 3, abbreviated as
4.5. (Z)-Methyl 2-(40S,50R)-40-hydroxy-50-methoxy-40,50-
dimethyl-20-oxooxazolidin-30-yl)but-2-enoate (Z)-8
Compound 4 (86 mg, 0.33 mmol) was dissolved in dry THF
(10 mL) under an argon atmosphere, and HMPA (0.22 mL,
1.32 mmol) was added by syringe. The solution was stirred at
0 °C, and 1 M solution of LHMDS in THF (0.66 mL, 0.66 mmol)
was added by syringe. After being stirred for 30 min at 0 °C, the
reaction was quenched with saturated NH4Cl solution (10 mL).
The mixture was diluted with diethyl ether and aqueous layer
was separated and extracted with more diethyl ether. The com-
bined organic layers were washed with brine and dried over anhy-
drous Na2SO4. The solvent was evaporated and the crude product
was purified by a silica gel column chromatography eluting with
hexane/ethyl acetate (1:1) to give 73 mg of product (Z)-8 (84%)
a
-MeThr (19.3 mg, 0.14 mmol), as a white solid; yield 43%.
½
a 2D5
ꢂ
¼ ꢁ15:6 (c 0.97, H2O). The spectroscopic data were identical
to those reported on the literature.3f HRMS (ESI) m/z = 134.0810
[M + H]+; calcd for C5H12NO3 = 134.0817.
Acknowledgements
We thank the Ministerio de Educación y Ciencia (Project
CTQ2006-05825/BQU), Consolider Project (financial support of
G.J.-O.) and the C.S.I.C. (doctoral fellowship of C.A.).
as a colourless oil. ½a D25
ꢂ
¼ ꢁ116:5 (c 1.02, CHCl3); 1H NMR (CDCl3):
d 7.27 (q, 1H, J = 7.09 Hz, C@CHCH3), 5.28 (s, 1H, OH), 3.82 (s, 3H,
CO2CH3), 3.44 (s, 3H, OCH3), 1.82 (d, 3H, J = 7.09 Hz, C@CHCH3),
1.62 (s, 3H, CCH3OCH3), 1.28 (s, 3H, CCH3OH); 13C NMR (CDCl3):
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