α-Methylserinals as an access to α-methyl-β-hydroxyamino acids: Application in the synthesis of all stereoisomers of α- methylthreonine

Article abstract of DOI:10.1016/j.tetasy.2003.12.001

The asymmetric synthesis of all stereoisomers of α-methylthreonine using a stereodivergent synthetic route starting from (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinals is reported. The key step involves the asymmetric addition of methylmagnesium bromide to these aldehydes with a high level of asymmetric induction being observed. This methodology represents a powerful tool for the synthesis of different β-substituted α-methylserines.

Full text of DOI:10.1016/j.tetasy.2003.12.001

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 719–724
a-Methylserinals as an access to a-methyl-b-hydroxyamino acids:
application in the synthesis of all stereoisomers of
a-methylthreonine
*
*
Alberto Avenoza, Jes uꢀ s H. Busto, Francisco Corzana, Jes uꢀ s M. Peregrina,
David Sucunza and Mar ꢀı a M. Zurbano
Departamento de Qu ꢀı mica, Universidad de La Rioja, Grupo de S ꢀı ntesis Qu ꢀı mica de La Rioja, U.A.-C.S.I.C., E-26006 Logro ~n o, Spain
Received 10 November 2003; accepted 20 November 2003
Abstract—The asymmetric synthesis of all stereoisomers of a-methylthreonine using a stereodivergent synthetic route starting from
(S)- and (R)-N-Boc-N,O-isopropylidene-a-methylserinals is reported. The key step involves the asymmetric addition of methyl-
magnesium bromide to these aldehydes with a high level of asymmetric induction being observed. This methodology represents a
powerful tool for the synthesis of different b-substituted a-methylserines.
ꢀ
2003 Elsevier Ltd. All rights reserved.
1
. Introduction
In an effort to combine the two aforementioned pro-
cesses, and in connection with our research into the
asymmetric synthesis of conformationally restricted
The incorporation of conformationally constrained
amino acids into biologically active peptides has
emerged as an important route for preparing peptide-
11
amino acids, we focused our attention on b-substituted
a-methylserines. In this field, we have previously
1
–5
12
based drug molecules. The resulting peptidomimetics
have increased potency and selectivity, fewer side effects,
improved oral bioavailability and also minimize enzy-
reported the synthesis of a-methyl-b-phenylserines,
13
a,b,b-trimethylserines and a-methyl-b,b-diphenyl-
serine derivatives using Grignard additions to the
13
6
matic degradation. Among the conformationally
restricted amino acids, the a,b-disubstituted systems can
severely restrict the conformations of the peptide back-
bone and provide key information concerning the
6
conformation responsible for biological recognition.
On the other hand, serine and threonine are unique
residues because the hydroxyl groups on their side
chains are crucial for the linkages in glycopeptides. It
has been shown that O-glycosilation of serine and
threonine in peptides not only influences the physical
properties and conformations, but also protects these
chiral building blocks (S)- and (R)-1a or (S)- and (R)-1b,
which can be readily obtained from a-methylserine.
14
7
Herein we report the application of this methodology to
the asymmetric synthesis of a-methylthreonines 2 (Fig.
1) and demonstrate that our method is a powerful tool
for the synthesis of b-substituted a-methylserines.
To the best of our knowledge there are only three
methods in the literature for the synthesis of enantio-
15
merically pure 2. Seebach and co-workers described
how the enolization of two oxazolines, both prepared
8
conjugates against proteolitic attack. As a consequence,
new and versatile synthetic methodologies for the syn-
thesis of b-substituted serines have become an important
goal for organic chemists.
from L-threonine, followed by the electrophilic attack of
iodomethane and further transformations, provided
9
;10
16
(2S,3S)- and (2R,3R)-2. Ohfune and Moon obtained
four stereoisomers of amino acid 2 using an intra-
molecular version of an asymmetric Strecker synthesis.
More recently, Goodman and co-workers
7;17
reported
the enantioselective synthesis of all stereoisomers of
compound 2 using the Sharpless asymmetric dihydr-
oxylation reaction to generate the stereogenic centre in
one step.
*
0
Corresponding authors. Tel./fax: +34-941-299655; e-mail addres-
ses: alberto.avenoza@dq.unirioja.es; jesusmanuel.peregrina@dq.
unirioja.es
957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.001

720
A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 719–724
OH
H
S
O
H
H
R
a
O
S
b
H
H
R
HO C
2
O
R
N
O
OH
O
HO C
2
HO
2
C
NBoc
H N
2
NBoc
OH
OH
O
H N
2
H N
2
anti-3
4
(
2R,3R)-2
R = H: (S)-1a
(2R,3R)-2
(2R,3S)-2
R = OMe:(S)-1b
Scheme 1. Reagents and conditions: (a) NaH, DMF, 0 ꢁC, 6 h, 88%;
b) (i) 4 M HCl/THF (1:1), 25 ꢁC, 2 h; (ii) Jones reagent, acetone, 1 h,
0 ꢁC and another 4 h, 25 ꢁC; (iii) 6 M HCl reflux, 48 h; (iv) propylene
oxide/EtOH (1:3), reflux, 2 h (52% from 4).
(
O
H
H
R
HO C
O
HO C
2
2
OH
OH
NBoc
H N
H N
2
2
oxidation and (4) acid hydrolysis using hydrochloric
acid under reflux. Liberation of amino acid 2 from its
hydrochloride salt was achieved by heating the salt
under reflux with propylene oxide in ethanol. The
spectroscopic data of this compound are identical to
R = H: (R)-1a
(
2S,3S)-2
(2S,3R)-2
R = OMe:(R)-1b
Figure 1. Chiral building blocks 1a,b and a-methylthreonines 2.
15
those previously reported in the literature.
2
. Results and discussion
In an effort to synthesize (2R,3S)-2, and bearing in mind
that it was not possible to obtain syn-3 as the major
diastereomer in the addition reaction, we focused our
attention on the stereoselective reduction of ketone (S)-
In our methodology, the oxazolidine ring of a-methyl-
serinal derivative 1a contributes the chiral amino acid
moiety with the new stereogenic centre at the b-carbon
being created by a nucleophilic attack by an organo-
metallic compound on the aldehyde group.
5
. This compound was obtained in 93% yield by treating
the mixture of anti-3 and syn-3 with DMSO and oxalyl
chloride at )78 ꢁC in THF. Unfortunately, as can be
seen in Table 2, none of the reducing agents used gave
syn-3 with high selectivity.
In the synthesis of a-methylthreonines 2, we assessed the
reaction between oxazolidine (S)-1a and MeMgBr under
different conditions of temperature and solvents (Table
1
). The best result in terms of diastereoselectivity in
Table 2. Diastereoselective reduction of ketone 5
favour of anti-3 was obtained when the reaction was
carried out at )78 ꢁC in THF (Table 1, entry 2). Under
these conditions the yield of the reaction was 87%. As
one would expect, the use of diethyl ether, a solvent
more likely to favour chelation, led to a significant
decrease in the diastereoselectivity (Table 1, entry 3). It
is important to underline that the use of MeLi gave
lower yields in all cases.
O
DMSO
anti-3 (COCl)
anti-3
+
hydride
2
+
O
syn-3
93%
syn-3
NBoc
12
(
S)-5
a
Entry
Hydride
n-Bu NBH
Solvent
anti/syn
1
2
3
4
5
4
4
MeOH
MeOH
MeOH
THF
35/65
45/55
60/40
70/30
75/25
Table 1. MeMgBr additions to a-methylserinal 1
LiBH4
NaBH
4
H
OH
HO
H
ꢂ
L-Selectride
DIBAL-H
CHO
MeMgBr
NBoc
S
S
THF
R
S
+
O
O
O
a
NBoc
NBoc
All the reactions were carried out at )78 ꢁC.
(S
)-1a
anti-3
syn-3
These results forced us to turn our attention to com-
pound (R)-6, the synthesis of which was previously
a
Entry
Solvent
T (ꢁC)
anti/syn
1
2
3
THF
THF
)50
)78
)78
87/13
95/5
65/35
19
reported by our group. The selective iodocycliza-
20;21
tion
IPy
of this allylic carbamate with NIS or
gave a mixture of compounds 7 and 8
Et
2
O
22;23
2
BF
4
a
Determined by integration of the CH signals of products anti-3 and
1
syn-3 in the H NMR spectrum.
(Table 3), which could not be separated by column
chromatography. The best diastereoselectivity in favour
of 7 was achieved when the reaction was carried out with
IPy BF in CH CN at )40 ꢁC (Table 3, entry 5).
Starting from enantiomerically pure anti-3, we synthe-
sized (2R,3R)-2 with an overall yield of 46% (Scheme 1)
in four steps: (1) intramolecular cyclization of com-
pound anti-3 to give compound 4, promoted by the
propensity of the N-Boc group to react intramolecularly
with nucleophiles, therefore compound 4 was obtained
by attack of the alkoxide ion on the carbonyl carbon of
the Boc group; (2) selective deprotection of the aceto-
nide moiety by hydrochloric acid; (3) subsequent Jones
2
4
3
In order to obtain amino acid (2R,3S)-2, we proposed
the retrosynthetic route shown in Scheme 2. However,
treatment of the mixture of compounds 7 and 8 (Table 3,
entry 5) with a variety of different reagents, such as Mg,
Bu SnH-AIBN, n-BuLi, LiAlH or LiBH , gave deriv-
18
3
4
4
ative 9 in very low yield, after column chromatography.
Indeed, the highest yield (30%) was obtained when the

A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 719–724
Table 3. Regio- and diastereoselective iodocyclization of the allylic carbamate (R)-6
721
H
H
NIS or
IPy BF
I
I
O
2
4
O
S
N
O
S
R
S
+
O
O
NBoc
N
O
O
(
R)-6
7
8
a
Entry
Reagent
NIS
Solvent
T (ꢁC)
Yield (%)
7/8
1
2
3
4
5
CH
Dioxane
CH Cl
THF
CH CN
2
Cl
2
25
10
40
70
65
68
70
84/16
92/8
IPy
IPy
IPy
IPy
2
2
2
2
BF
BF
BF
BF
4
4
4
4
2
2
)50
)78
)40
89/11
90/10
95/5
3
a
1
Determined by integration of the CH signals of products 7 and 8 in the H NMR spectrum.
It is important to note that the heterocyclic intermediate
7 is suitable for conversion into polyfunctionalized
structures and could be a valuable precursor for bio-
logically active compounds. Work in this area is cur-
rently in progress and will be reported in due course.
H
low
H
yield
I
O
S
S
O
S
R
(2R,3S)-2
O
O
N
N
O
O
9
7
In an effort to obtain compound 9 in high yield, we
focused our attention on derivative anti-3. The intra-
molecular cyclization of anti-3, in this case with triflic
anhydride, gave bicyclic compound 9 in 88% yield by
nucleophilic attack of the carbamate group on the
activated alcohol with total inversion at the stereogenic
centre. The same strategy used to prepare amino acid
(2R,3R)-2 from 4, was used with amino acid (2R,3S)-2,
obtained from compound 9 in 52% yield. The spectro-
Scheme 2. Retrosynthetic route to obtain (2R,3S)-2 from compound 7.
reaction was carried out with LiAlH
4
in THF at 25 ꢁC.
The structure of this compound was determined by
X-ray analysis of a monocrystal obtained by crystalli-
zation from chloroform/hexane (Fig. 2).
18
scopic data of this amino acid were identical to those
7
previously reported (Scheme 3).
;16
H
OH
H
H
S
R
a
O
S
b
S
HO C
2
O
O
OH
N
NBoc
H N
2
O
anti-3
9
(2R,3S)-2
Scheme 3. Reagents and conditions: (a) Tf
2
O, 2,6-di-tert-butyl-4-
methylpyridine, CH Cl
2
2
, 0 ꢁC, 5 min, 88%; (b) (i) 4 M HCl/THF (1:1),
2
5 ꢁC, 2 h; (ii) Jones reagent, acetone, 3 h, 0 ꢁC and another 3 h, 25 ꢁC;
iii) 6 M HCl reflux, 48 h; (iv) propylene oxide/EtOH (1:3), reflux, 2 h
(
(
Figure 2. ORTEP drawing of the molecular structure of compound 9.
52% from 9).
The other enantiomers of a-methylthreonine [(2S,3S)-2
and (2S,3R)-2] were obtained using the same strategy as
described above but starting from (R)-1a (Scheme 4).
The spectroscopic data of these amino acids were iden-
tical to those of the enantiomers (2R,3R)-2 and (2R,3S)-
2, except that their specific rotations were opposite in
sign (Scheme 4).
Crystal data: (a) C
9
H
15
N
1
O
3
, M
w
¼ 185:22, colourless prism of
1 1 1
0
.7 · 0.37 · 0.2 mm, T ¼ 223 K, orthorhombic, space group P2
2 2 ,
ꢁ
ꢁ
ꢁ
Z ¼ 4, a ¼ 6:8080ð4Þ A, b ¼ 9:0645ð5Þ A, c ¼ 15:8652ð9Þ A, V ¼
ꢁ
3
ꢀ3
ꢁ
9
79:06ð10Þ A , dcalcd ¼ 1:257 g cm , F ð000Þ ¼ 400, k ¼ 0:71073 A
Mo, Ka), l ¼ 0:089 mm , Nonius kappa CCD diffractometer,
h range 1.28–27.87ꢁ, 4359 collected reflections, 2190 unique, full-
ꢀ
1
(
2
4
matrix least-squares (SHELXL97 ), R
1
¼ 0:0735, wR ¼ 0:1802,
2
(
R
1
¼ 0:1082, wR ¼ 0:2127 all data), goodness of fit ¼ 1.039, residual
2
ꢁ
ꢀ3
electron density between 0.283 and )0.261 e A . 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 Center,
3. Conclusions
1
2
2 Union Road, Cambridge, UK on quoting the depository number
21220.
In summary, we have developed a stereoselective syn-
thesis for all the stereoisomers of a-methylthreonine 2.

722
A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 719–724
SMP-20 melting point apparatus and are uncorrected.
CHO
NBoc
O
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. Microanalyses were carried out
on a CE Instruments EA-1110 analyser and are in good
agreement with the calculated values.
(
R)-1a
a
H
OH
0 0
.2. (4S,1 R)-N-(tert-Butoxycarbonyl)-4-(1 -hydroxy-
ethyl)-2,2,4-trimethyloxazolidine anti-3
4
R
S
O
b
NBoc
c
To a pre-cooled solution of (S)-1a (0.90 g, 3.70 mmol) in
THF (25 mL) at )78 ꢁC was added dropwise a 3 M
solution of phenylmagnesium bromide (2.5 mL,
7.40 mmol) in THF over 5 min. The resulting yellow
solution was stirred for an additional 4 h at )78 ꢁC and
then warmed to 0 ꢁC over 10 min. The reaction mixture
was diluted with diethyl ether (30 mL) and quenched
ent-anti-3
H
H
O
R
S
O
R
R
O
O
N
N
O
O
ent-4
ent-9
d
d
with saturated NH Cl solution (30 mL). The organic
4
2 4
layer was washed with brine (30 mL), dried over Na SO
H
H
and concentrated to give a pale yellow oil, which was
purified by column chromatography (hexane/ethyl ace-
tate, 4/1) to give anti-3 as a colourless oil (0.83 g,
HO C
S
HO C
2
2
S
S
R
OH
OH
H N
2
H N
2
2
D
5
1
3
NMR (CDCl
.20 mmol); yield: 87%. ½aꢁ ¼ )11.1 (c 0.91, MeOH); H
(
2S,3S)-2
(2S,3R)-2
3
): d 1.16 (d, 3H, J ¼ 6:3 Hz, CHOHCH
3
),
1
3
1
2
.40–1.60 [m, 18H, (CH ) C, C(CH )N, (CH ) CO],
3 2 3 3 3
Scheme 4. Reagents and conditions: (a) MeMgBr, THF, )78 ꢁC, 4 h,
7%; (b) NaH, DMF, 25 ꢁC, 6 h, 88%; (c) Tf O, 2,6-di-tert-butyl-4-
methylpyridine, CH Cl
, 0 ꢁC, 5 min, 88%; (d) (i) 4 M HCl/THF (1:1),
5 ꢁC, 2 h; (ii) Jones reagent, acetone, 3 h, 0 ꢁC and another 3 h, 25 ꢁC;
iii) 6 M HCl reflux, 48 h; (iv) propylene oxide/EtOH (1:3), reflux, 48 h
52% from ent-4 or ent-9).
.66–3.77 (m, 3H, CH
2
, CHOHCH
3
), 4.60–4.80 (br s,
), 21.2,
5.5, 26.6 [(CH ) C, C(CH )N], 28.3 [(CH ) CO], 67.4
8
2
13
H, OH); C NMR (CDCl ): d 18.6 (CHOHCH
3
3
2
2
2
3 2
3
3 3
[
[(CH
C(CH
)
3
)N], 70.7, 72.7 (CH
2
,
CO], 95.5 [(CH ) C], 153.5 (CO); ESI
CHOHCH
3
), 80.9
þ
(
(
3
3
3 2
ðm=zÞ ¼ 260. Anal. Calcd for C H NO : C, 60.21; H,
13
25
4
9
.72; N, 5.40. Found: C, 60.05; H, 9.61; N, 5.30.
The route involves the asymmetric addition of methyl-
magnesium bromide to the chiral building blocks (S)-1a
and (R)-1a. This methodology can be easily applied to
the asymmetric synthesis of b-substituted a-methylse-
rines by simply changing the organometallic reagent.
Moreover, the heterocyclic intermediate 7 described
herein is suitable for conversion into polyfunctionalized
structures and could therefore be used as a precursor for
biologically active compounds.
4.3. (1R,7aS)-1,5,5,7a-Tetramethyl-2,6-dioxa-4-
azapentalen-3-one 4
To a solution of anti-3 (0.35 g, 1.35 mmol) in DMF
(10 mL) at 0 ꢁC was added NaH (65 mg, 1.62 mmol). The
resulting suspension was stirred at 0 ꢁC for 6 h and then
quenched at 0 ꢁC with H O (10 mL). The resulting mix-
2
ture was concentrated to obtain a pale yellow solid,
which was washed with ethyl acetate (3 · 15 mL). This
solution was dried over Na SO , evaporated and the
4. Experimental
2
4
crude residue purified by column chromatography
(hexane/ethyl acetate, 7/3) to give 4 (0.22 g, 1.19 mmol) as
4
.1. General procedures
25
a white solid; yield: 88%. Mp: 48 ꢁC. ½aꢁ ¼ +25.5 (c 1.00,
D
1
Solvents were purified according to standard proce-
dures. Analytical TLC was performed using Polychrom
SI F254 plates. Column chromatography was performed
using Silica gel 60 (230–400 mesh). H and C NMR
spectra were recorded on a Bruker ARX-300 spec-
MeOH); H NMR (CDCl ): d 1.27 (d, 3H, J ¼ 6:6 Hz,
3
3 3 2 3
CHOCH ), 1.45, 1.46, 1.59 [3s, 9H, (CH ) C, C(CH )N],
3.58 (d, 1H, J ¼ 9:0 Hz, CH
2
), 3.81 (d, 1H, J ¼ 9:0 Hz,
1
13
13
CH ), 4.29 (q, 1H, J ¼ 6:6 Hz, CHOCH ); C NMR
2
3
(CDCl
C(CH
3
): d 16.4 (CHOC
)N], 69.0 (CH
3
3 2
), 23.7, 26.3, 28.4 [(CH ) C,
1
13
trometer. H and C NMR spectra were recorded in
CDCl with TMS as the internal standard and in D O
3
2
), 73.8 [C(CH
(CHOCH ), 94.7 [(CH ) C], 156.3 (CO); ESI
3
)N], 78.4
þ
3
2
3
3 2
with TMS as the external standard using a coaxial
microtube (chemical shifts are reported in ppm on the
d scale, coupling constants in Hz). The assignment of all
ðm=zÞ ¼ 186. Anal. Calcd for C H NO : C, 58.36; H,
9
15
3
8.16; N, 7.56. Found: C, 58.44; H, 7.99; N, 7.63.
1
separate signals in the H NMR spectra was made on
the basis of coupling constants, selective proton–proton
homonuclear decoupling experiments, proton–proton
COSY experiments and proton–carbon HETCOR
experiments. Melting points were determined on a B u€ chi
4.4. (2R,3R)-a-Methylthreonine 2
To a solution of 4 (0.20 g, 1.04 mmol) in THF (7 mL)
was added aqueous 4 M HCl (7 mL). The mixture was

A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 719–724
723
stirred at 25 ꢁC for 2 h and the solvent removed to give
4S,5R)-4-(hydroxymethyl)-4,5-dimethyloxazolidin-2-
one (0.13 g, 0.90 mmol) as a white solid after purification
by column chromatography (CH Cl /MeOH, 9.5/0.5);
(CH
28.2 [(CH
(CH O), 80.9 [(CH ) CO], 95.1, 96.1 [(CH ) C], 150.7,
3
), 24.4 (COCH
3
), 24.8, 25.4, 25.7, 26.5 [(CH
3
)
2
C],
(
3
)
3
CO], 69.9, 70.3 [C(CH )N], 71.8, 72.1
3
2
3 3
3 2
þ
2
2
151.4 (NCO), 207.0 (COCH
Calcd for C13H23NO : C, 60.68; H, 9.01; N, 5.44.
4
Found: C, 60.52; H, 9.09; N, 5.61.
3
); ESI ðm=zÞ ¼ 258. Anal.
25
1
yield: 80%. Mp: 58 ꢁC. ½aꢁ ¼ +0.3 (c 0.95, MeOH); H
D
NMR (CDCl ): d 1.21 [s, 3H, C(CH )N], 1.40 (d, 3H,
3
3
J ¼ 6:9 Hz, CHOCH
3
), 3.47 (d, 1H, J ¼ 12:0 Hz, CH
2
),
3
4
.63 (d, 1H, J ¼ 12:0 Hz, CH
2
), 4.25 (br s, 1H, OH),
.38 (q, 1H, J ¼ 6:9 Hz, CHOCH ), 6.78 (br s, 1H, NH);
4.6. (1R,7aS)-1-Iodomethyl-5,5,7a-trimethyl-2,6-dioxa-
4-azapentalen-3-one 7
3
1
3
C NMR (CDCl
1.4 [C(CH )N], 64.9 (CH
3
): d 13.2 (CHOCH
3
), 21.3 [C(CH
3
)N],
), 160.4
6
3
2
), 82.2 (CHOCH
3
þ
(
CO); ESI ðm=zÞ ¼ 146. Anal. Calcd for C H NO : C,
To a solution of olefin 6 (0.43 g, 1.78 mmol) in CH CN
3
6
11
3
4
9
9.65; H, 7.64; N, 9.65. Found: C, 49.58; H, 7.48; N,
.74. To a solution of (4S,5R)-4-(hydroxymethyl)-4,5-
(10 mL) was added IPy BF (0.86 g, 2.32 mmol) at
4
2
)40 ꢁC. The mixture was stirred for 12 h at )40 ꢁC and
the reaction then quenched by the addition of 0.5 M HCl
(15 mL) and CH Cl (15 mL). The phases were sepa-
dimethyloxazolidin-2-one (0.10 g, 0.69 mmol) in acetone
10 mL) at 0 ꢁC was added a 1.5-fold excess of Jones
reagent dropwise over 5 min. The mixture was stirred at
ꢁC for 1 h and then at 25 ꢁC for 4 h. The excess Jones
(
2
2
rated and the organic phase was washed with 0.5 M HCl
(15 mL), saturated NaHCO (15 mL), 0.1 M Na SO
0
3
2
3
reagent was then destroyed with 2-propanol. The mix-
ture was partitioned between brine (10 mL) and ethyl
acetate (20 mL). The aqueous phase was extracted sev-
eral times with ethyl acetate (4 · 15 mL). The organic
(15 mL) and brine (15 mL). The organic phase was dried,
filtered and concentrated. The crude product was puri-
fied by column chromatography (hexane/ethyl acetate,
4/1) to give a mixture of 7 and 8 in a ratio 95/5 in favour
phases were combined, dried over Na
2
SO
4
and concen-
of 7 as a yellow solid (0.39 g, 1.25 mmol); yield: 70%.
1
trated. The resulting white solid was dissolved in aque-
ous 6 M HCl (5 mL) and heated at 100 ꢁC for 48 h. The
solution was concentrated to give 2-amino-3-hydroxy-2-
methylbutanoic acid hydrochloride as a white solid. This
compound was dissolved in 4 mL of EtOH/propylene
oxide (3/1) and the mixture then heated under reflux for
Compound 7: H NMR (CDCl
9H, 3CH
3
): d 1.48, 1.50, 1.60 (3s,
I), 3.39 (dd,
3
), 3.16 (ÔtÕ, 1H, J ¼ 10:2 Hz, CH
2
1H, J ¼ 4:8 Hz, J ¼ 10:2 Hz, CH I), 3.88 (s, 2H,
2
CH
2
O), 4.57 (dd, 1H, J ¼ 4:8 Hz, J ¼ 10:2 Hz, CHO);
3 2
13
C NMR (CDCl
[(CH ) C, C(CH )N], 68.2 [C(CH )N], 74.0 (CH O),
): d )1.9 (CH I), 18.4, 23.6, 27.8
3
2
3
3
2
þ
2
h. After this time, the amino acid precipitated as a
83.4 (CHO), 93.7 [(CH
ðm=zÞ ¼ 312. Anal. Calcd for C
3
)
2
C], 153.6 (CO); ESI
: C, 34.74; H,
4.54; N, 4.50. Found: C, 34.56; H, 4.69; N, 4.58. Spec-
25
white solid (60 mg, 0.45 mmol); yield: 65%. ½aꢁ ¼ )11.6
9 3
H14INO
D
1
(
c 0.85, H O); H NMR (D O): d 1.22 (d, 3H,
2
2
J ¼ 6:6 Hz, CHOCH
3
), 1.51 [s, 3H, C(CH
3
)N], 4.06
O): d 16.9,
0.0 [CHOCH , C(CH )N], 65.2 [C(CH )N], 69.3
troscopic data of the minor compound 8, extracted from
1
13
(
q, 1H, J ¼ 6:6 Hz, CHOCH
3
); C NMR (D
2
the mixture of compounds 7 and 8: H NMR (CDCl
3
):
2
d 1.48, 1.50, 1.60 (3s, 9H, 3CH ), 3.07 (ÔtÕ, 1H,
3
3
3
3
þ
(
for C
4
CHOCH ), 175.0 (CO); ESI ðm=zÞ ¼ 134. Anal. Calcd
J ¼ 10:2 Hz, CH I), 3.31 (dd, 1H, J ¼ 4:8 Hz,
3
2
5
H
5.33; H, 8.46; N, 10.40.
11NO
3
: C, 45.10; H, 8.33; N, 10.52. Found: C,
J ¼ 10:2 Hz, CH
2 2
I), 3.92 (s, 2H, CH O), 4.43 (dd, 1H,
J ¼ 4:8 Hz, J ¼ 10:2 Hz, CHO).
4.5. (S)-N-(tert-Butoxycarbonyl)-4-acetyl-2,2,4-trimeth-
yloxazolidine 5
4.7. (1S,7aS)-1,5,5,7a-Tetramethyl-2,6-dioxa-4-
azapentalen-3-one 9
DMSO (0.16 g, 2.08 mmol) was added to a cooled
Triflic anhydride (215 lL, 1.25 mmol) was added to a
solution of anti-3 (0.27 g, 1.04 mmol) and 2,6-di-tert-
butyl-4-methylpyridine (0.52 g, 2.50 mmol) in CH Cl
2 2
(20 mL) at 0 ꢁC. The mixture was stirred for 5 min at
0 ꢁC and the resultant white solid filtered off. The
organic phases were washed with 5% aqueous NaHCO3
(
)78 ꢁC) solution of oxalyl chloride (0.16 g, 1.25 mmol)
in CH Cl (10 mL). The resulting solution was stirred
for 5 min at )78 ꢁC and a solution of anti-3 and syn-3
0.27 g, 1.04 mmol) in CH Cl (5 mL) added. The
resulting mixture was stirred for 15 min at )78 ꢁC and
Et N (0.42 g, 4.17 mmol) added. The solution was
2
2
(
2
2
3
2 4
(10 mL), dried over Na SO and concentrated to give a
allowed to warm up to 25 ꢁC and then quenched by the
yellow oil, which was purified by column chromato-
graphy (hexane/ethyl acetate, 7/3) to give 9 (0.17 g,
0.92 mmol) as a white solid; yield: 88%. Mp: 44 ꢁC.
addition of saturated NaHCO (20 mL) and then diluted
3
with Et
organic phase washed with aqueous 1 M KHSO
tion (15 mL), saturated NaHCO3 (15 mL) and brine
15 mL). The organic phase was dried, filtered and
2
O (20 mL). The phases were separated and the
2
5
1
4
solu-
½aꢁ ¼ )18.0 (c 1.05, MeOH); H NMR (CDCl
D
1.30–1.35 (m, 6H, CHOCH , CH ), 1.47 (s, 3H, CH ),
3
): d
3
3
3
(
1.61 (s, 3H, CH
(d, 1H, J ¼ 8:7 Hz, CH
3
), 3.69 (d, 1H, J ¼ 8:7 Hz, CH
2
), 3.74
), 4.45 (q, 1H, J ¼ 6:6 Hz,
concentrated. The crude product was purified by column
chromatography (hexane/ethyl acetate, 9/1) to give 5
2
13
CHOCH ); C NMR (CDCl ): d 15.0, 20.0, 23.7, 27.9
3
3
(
0.25 g, 0.97 mmol) as a colourless oil; yield: 93%.
1
[CHOCH (CH ) C, C(CH )N], 68.6 [C(CH )N], 73.8
)
3
3 2
3
3
25
½
aꢁ ¼ )18.0 (c 1.45, MeOH); H NMR (CDCl
3
): d
C], 2.19 (s,
(CH ), 79.9 (CHOCH ), 94.3 [(CH C], 156.0 (CO);
ESI ðm=zÞ ¼ 186. Anal. Calcd for C
2
þ
3
3
2
D
.35–1.68 [m, 18H, (CH
1
3
3
)
3
CO, CH
3
, (CH
H, COCH ), 3.69–3.73 (m, 1H, CH O), 3.92 (d, 1H,
3
)
2
9 3
H15NO : C,
58.36; H, 8.16; N, 7.56. Found: C, 58.49; H, 8.20; N,
7.63.
3
2
13
J ¼ 9:3 Hz, CH
2 3
O); C NMR (CDCl ): d 19.5, 20.7

724
A. Avenoza et al. / Tetrahedron: Asymmetry 15 (2004) 719–724
4
.8. (2R,3S)-a-Methylthreonine 2
Acknowledgements
In a similar way to that described for its diastereomer
2R,3R)-2, compound (2R,3S)-2 (42 mg, 52%) was
obtained from compound 9 (112 mg, 0.61 mmol).
We thank the Ministerio de Ciencia y Tecnolog ꢀı a (pro-
ject PPQ2001-1305), the Gobierno de La Rioja (project
ANGI-2001/30) and the Universidad de La Rioja (pro-
ject API-03/04). D.S. thanks the Comunidad Aut oꢀ noma
de La Rioja for a doctoral fellowship.
(
25
1
½
aꢁ ¼ +13.4 (c 0.75, H O); H NMR (D O): d 1.25 (d,
D
2
2
3
H, J ¼ 6:3 Hz, CHOCH )N], 4.19
O): d 16.2,
7.2 [CHOCH , C(CH )N], 65.3 [C(CH )N], 69.1
3
), 1.40 [s, 3H, C(CH
3
13
(
1
q, 1H, J ¼ 6:3 Hz, CHOCH
3 2
); C NMR (D
3
3
3
þ
(
for C
CHOCH
3
), 175.8 (CO); ESI ðm=zÞ ¼ 134. Anal. Calcd
3
References and notes
5
H
5.22; H, 8.20; N, 10.40.
11NO
: C, 45.10; H, 8.33; N, 10.52. Found: C,
4
1. Huang, Z.; He, Y.-B.; Raynor, K.; Tallent, M.; Reisine,
T.; Goodman, M. J. Am. Chem. Soc. 1992, 114, 9390–
9
401.
2
3
. He, Y.-B.; Huang, Z.; Raynor, K.; Reisine, T.; Goodman,
M. J. Am. Chem. Soc. 1993, 115, 8066–8072.
. Cornille, F.; Slomezynska, U.; Smythe, M. L.; Beusen, D.
D.; Moeller, K. D.; Marshall, G. R. J. Am. Chem. Soc.
0
0
4.9. (4R,1 S)-N-(tert-Butoxycarbonyl)-4-(1 -hydroxy-
ethyl)-2,2,4-trimethyloxazolidine ent-anti-3
In a similar way to that described for its enantiomer
anti-3, compound ent-anti-3 (0.68 g, 87%) was obtained
1
995, 117, 909–917.
4. Chalmers, D. K.; Marshall, G. J. Am. Chem. Soc. 1995,
117, 5927–5937.
5. Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C.
Biopolymers (Pept. Sci.) 2001, 60, 396–419.
. Goodman, M.; Ro, S. In BurgerÕs Medicinal Chemistry and
Drug Discovery, 5th; Wolff, M. E., Ed.; John Wiley &
Sons: New York, 1995; Vol. 1, pp 803–861.
25
from aldehyde (R)-1a (0.73 g, 3.0 mmol). ½aꢁ ¼ +11.7
D
: C, 60.21;
(
H, 9.72; N, 5.40. Found: C, 60.02; H, 9.55; N, 5.38.
c 0.90, MeOH); Anal. Calcd for C13
H
25NO
4
6
4.10. (1S,7aR)-1,5,5,7a-Tetramethyl-2,6-dioxa-4-aza-
pentalen-3-one ent-4
7. Shao, H.; Rueter, J. K.; Goodman, M. J. Org. Chem.
1998, 63, 5240–5244.
8
. Wormald, M. R.; Petrescu, A. J.; Pao, Y.-L.; Glithero, A.;
Elliott, T.; Dwek, R. A. Chem. Rev. 2002, 102, 371–386.
. Xiong, C.; Wang, W.; Hruby, V. J. J. Org. Chem. 2002, 67,
In a similar way to that described for its enantiomer 4,
compound ent-4 (0.22 g, 88%) was obtained from
9
25
3
514–3517.
0. Amador, M.; Ariza, X.; Garc ꢀı a, J.; Sevilla, S. Org. Lett.
002, 4, 4511–4514.
ent-anti-3 (0.35 g, 1.35 mmol). ½aꢁ ¼ )25.8 (c 1.02,
D
MeOH); Anal. Calcd for C H NO : C, 58.36; H, 8.16;
N, 7.56. Found: C, 58.42; H, 8.01; N, 7.69.
1
1
9
15
3
2
1. Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Sucunza, D.; Zurbano, M. M. In Targets in Heterocyclic
Systems; Attanasi, O. A., Spinelli, D., Eds.; Italian Society
of Chemistry, 2002; p 231–244, and references cited
therein.
4
.11. (2S,3S)-a-Methylthreonine 2
1
1
2. Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Zurbano, M. M. Tetrahedron: Asymmetry 2000, 11, 2195–
2204.
3. Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M.;
Sucunza, D.; Zurbano, M. M. Tetrahedron: Asymmetry
In a similar way to that described for its enantiomer
2R,3R)-2, compound (2S,3S)-2 (48 mg, 46%) was
obtained from compound ent-4 (144 mg, 0.78 mmol).
(
25
½
aꢁ ¼ +11.4 (c 0.80, H
2 5 3
O); Anal. Calcd for C H11NO :
D
C, 45.10; H, 8.33; N, 10.52. Found: C, 45.30; H, 8.44; N,
2003, 14, 399–405.
14. Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Sucunza, D.; Zurbano, M. M. Tetrahedron: Asymmetry
1
0.39.
2
001, 12, 949–958.
15. Weber, T.; Aeschimann, R.; Maetzke, T.; Seebach, D.
4.12. (1R,7aR)-1,5,5,7a-Tetramethyl-2,6-dioxa-4-aza-
pentalen-3-one ent-9
Helv. Chim. Acta 1986, 69, 1365–1377.
6. Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116,
405–7406.
7. Goodman, M.; Shao, H. Pure Appl. Chem. 1996, 68, 1303–
1308.
1
1
7
In a similar way to that described for its enantiomer 9,
compound ent-9 (0.17 g, 88%) was obtained from
25
ent-anti-3 (0.27 g, 1.04 mmol). ½aꢁ ¼ +18.1 (c 1.15,
D
1
1
8. Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701–2724.
9. Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Zurbano, M. M. J. Org. Chem. 1999, 64, 8220–8225.
0. Agami, C.; Couty, F.; Hamon, L.; Venier, O. J. Org.
Chem. 1997, 62, 2106–2112.
9 3
MeOH); Anal. Calcd for C H15NO : C, 58.36; H, 8.16;
N, 7.56. Found: C, 58.46; H, 8.19; N, 7.68.
2
2
1. Jord ꢀa -Gregori, J. M.; Gonzalez-Rosende, M. E.; Sep uꢀ lve-
da-Arques, J.; Galeazzi, R.; Orena, M. Tetrahedron:
Asymmetry 1999, 10, 1135–1144.
4
.13. (2S,3R)-a-Methylthreonine 2
In a similar way to that described for its enantiomer
2R,3S)-2, compound (2S,3R)-2 (36 mg, 46%) was
obtained from compound ent-9 (109 mg, 0.59 mmol).
2
2. Barluenga, J.; Gonzalez, J. M.; Campos, P. J.; Asensio, G.
Angew. Chem., Int. Ed. Engl. 1985, 24, 319–320.
3. Barluenga, J.; Campos, P. J.; Gonzalez, J. M.; Suarez, J.
L. J. Org. Chem. 1991, 56, 2234–2237.
(
2
2
D
5
½
aꢁ ¼ )13.6 (c 0.70, H O); Anal. Calcd for C H NO :
2
5
11
3
C, 45.10; H, 8.33; N, 10.52. Found: C, 45.22; H, 8.20; N,
0.40.
24. Sheldrick, G. M. SHELXL97. Program for the refinement of
crystal structures. University of G o€ ttingen, Germany, 1997.
1