Efficient asymmetric synthesis of (S)-2-methylasparagine

Article abstract of DOI:10.1055/s-1998-1884

(S)-2-methylasparagine was prepared from both (5S, 6R)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one ((-)-1) and its antipode ((+)-1) via stereoselective glycine enolate alkylation as a key step.

Full text of DOI:10.1055/s-1998-1884

October 1998
SYNLETT
1099
Efficient Asymmetric Synthesis of (S)-2-Methylasparagine
Yutaka Aoyagi and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received 1 April 1998
Abstract: (S)-2-methylasparagine was prepared from both (5S, 6R)-4-
(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-
one ((-)-1) and its antipode ((+)-1) via stereoselective glycine enolate
alkylation as a key step.
Scheme 1
Synthesis of nonproteogenic unnatural α-amino acids has become of
considerable interest, due to the impact such substances have made on
the design and development of enzyme inhibitors and as tools for
exploring enzymatic reaction mechanisms. As a consequence, the
literature is replete with reports concerning asymmetric synthesis of
1
optically pure amino acids. In particular, α,α-dialkylated α-amino
acids have attracted considerable attention since these substances have
proven to be invaluable constituents of potent protease inhibitors such as
2,3
4
dopa, ornithine, glutamate, (S)-adenosylmethionine decarboxylase,
5
and aspartate aminotransferase. In addition, the introduction of
α,α-dialkylated amino acids into peptide chains results in restricting the
6
available range of backbone conformations. Recently, we reported the
7
total syntheses of TAN-1057A (2)-D, which are anti MRSA
8,9
(methicillin-resistant Staphylococcus aureus) agents. In connection
with an ongoing synthetic study on the synthesis of TAN-1057A
analogues, we required optically pure (S)-2-methylasparagine.
result, dialkylated lactone 5 was obtained in 71 % yield under the
15
reaction conditions of entry 8 in Table 1.
Next, we examined an alternative synthesis of the dialkylated lactone 7
from the (+)-lactone 1. The primary distinction of this approach is that
the order of alkylation reactions of the (+)-lactone 1 occurs in the
reversed sequence relative to that employed with (-)-1. Thus, tert-
butoxycarbonylmethylation of compound (+)-1, via enolate generation
with sodium bis(trimethylsilyl)amide and quenching with tert-butyl α-
16
bromoacetate furnished 6 in 81% yield as a single diastereomer. Next,
The synthesis of α-methylated asparagine has not been previously
reported, and due to the potential use of such an amino acid in other
applications in modifying bioactive asparagine-containing peptides, we
report an efficient asymmetric synthesis of (S)-2-methylasparagine
using (5S,6R)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-
4H-1,4-oxazin-2-one ((-)-1) and its antipode ((+)-1). The approach
described herein permits access to either the (S)- or (R)-enantiomer and
should be applicable to the synthesis of a range of α-alkylated
asparagine derivatives.
methylation
of
6
was
accomplished
with
sodium
bis(trimethylsilyl)amide and 15-crown-5, followed by quenching the
enolate with methyl iodide providing the dialkylated compound 7 in
17
51% overall yield from (+)-1 as a single diastereomer (Scheme 2).
We have previously reported the asymmetric synthesis of
monosubstituted and α,α-disubstituted α-amino acids using
10-13
diphenyloxazinone derivatives (1) as templates.
First, we examined
11
alkylation of 4, which was derived from (-)-1 in the reported manner,
under several reaction conditions (Scheme 1, Table 1).
The alkylation of compound 4, which was prepared from (-)-lactone 1,
with potassium bis(trimethylsilyl)amide was, in contrast to what we
Scheme 2
11
have generally observed for this type of reaction previously, found to
14
be ineffective (entries 1-4 in table). On the other hand, a combination
With the dialkylated compounds 5 and 7 in hand, transformation of
these substances to (S)-2-methylasparagine (10) was examined and
accomplished as shown in Scheme 3.
of sodium bis(trimethylsilyl)amide and 15-crown-5 gave better results
(entries 5-8 in table). Further, best results were obtained with low
concentration of the substrate (4) (compare entries 7 vs. 8 in table). As a

1100
LETTERS
SYNLETT
Removal of the tert-butyl group from 5 and 7 with TFA was
12) Bender, D. M.; Williams, R. M. J. Org. Chem. 1997, 62, 6690 and
accomplished, followed by amination with EEDQ and ammonium
references cited herein.
18
hydrogencarbonate to give the corresponding amides 8 and 9 in good
13) The requisite diphenyloxazines 1 utilized to prepare compounds 4
and 6 are commercially available from Aldrich Chemical Co.;
(-)-1: catalog #33187-2 (CAS Registry #100516-54-9); the
antipode of (+)-1: Catalog #33185-6 (CAS Registry #105228-46-
4).
19
yields. Finally, the hydrogenolysis of diphenyloxazines 8 and 9 with
H (60 psi) in the presence of PdCl was accomplished furnishing (S)-2-
2
2
20
methylasparagine (3) in essentially quantitative yields.
14) Baldwin, J. E.; Lee, V.; Schofield, C. J. Synlett 1992, 249.
15) Preparation
of
(3S,5S,6R)-4-(benzyloxycarbonyl)-3-tert-
butoxycarbonylmethyl-5,6-diphenyl-3-methyl-2,3,5,6-tetra-
hydro-4H-1,4-oxazin-2-one (5). To a THF solution (180 mL) of
11
compound 4 (1.89 g, 4.71 mmol) and 15-crown-5 (9.34 g, 47.4
mmol), 1.0 M NaN(TMS) in THF (7.1 mL, 7.1 mmol) was added
2
dropwise at -78 °C under an Ar atmosphere. After the resulting
solution was stirred at the same temperature for 30 min, tert-butyl
α-bromoacetate (2.1 mL, 2.76 g, 14.1 mmol) was added dropwise
to the reaction mixture. After the reaction mixture was stirred at -
78 °C for 20 min. To a reaction mixture, sat. NH Cl (50 mL) was
4
added. The organic layer was separated and the aqueous layer was
extracted with AcOEt (50 mL x 2). The combined organic layer
was washed with sat. NaCl (150 mL x 3), dried over anhydrous
MgSO , filtered, concentrated, and purified by silica gel flash
4
chromatography (eluted with Hexanes : EtOAc = 7 : 1) to give
Scheme 3
compound 5 (colorless solid, 1.72 g, 71 % yield from compound
i
25
4). Colorless prisms ( Pr O), mp 152-153 °C. [α] = +96.0°
2
D
In summary, the asymmetric synthesis of (S)-2-methylasparagine 3 from
both (5S,6R)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-
4H-1,4-oxazin-2-one ((-)-1) and its antipode ((+)-1) has been acheived
in 5 steps. Due to the commercial availability of both (+)-1 and (-)-1,
this approach can be directly utilized for preparing the enantiomer of 3
in an unambiguous fashion.
1
(CH Cl , c = 0.68). H NMR (300 MHz) (393 K, DMSO-d ) δ
2
2
6
TMS: 1.41 (9H, s), 1.66 (3H, s), 3.08 (1H, d, J = 14.8 Hz), 3.62
(1H, d, J = 15.0 Hz), 5.16 (2H, s), 5.66 (1H, d, J = 3.3 Hz), 6.28
(1H, d, J = 3.6 Hz), 7.00-7.04 (2H, m), 7.08-7.31 (13H, m). IR
-1
+
(KBr): 1746, 1712 (C=O) cm . MS(FAB+): 516 (M +H). Anal.
Calcd for C NO : C, 72.21; H, 6.45; N, 2.72. Found: C,
H
31 33
6
72.40; H, 6.43; N, 2.75.
Acknowledgment. This work was supported by the National Science
Foundation.
16) Preparation of (3R,5R,6S)-4-(benzyloxycarbonyl)-3-tert-
butoxycarbonylmethyl-5,6-diphenyl-2,3,5,6-tetrahydro-4H-
1,4-oxazin-2-one (6). To a THF solution (110 mL) of compound
References and Notes
(+)-1 (2.00 g, 5.17 mmol), 1.0 M NaN(TMS) in THF (5.17 mL,
2
5.17 mmol) was added dropwise at -78 °C under an Ar
atmosphere. After the resulting solution was stirred at the same
temperature for 40 min, tert-butyl α-bromoacetate (0.92 mL, 1.21
g, 6.2 mmol) in THF (10 mL) was added dropwise to the reaction
mixture. After the reaction mixture was stirred at -78 °C for 2 hr,
and poured into EtOAc (200 mL). The organic layer was washed
with water (150 mL x 2) and sat. NaCl (150 mL x 1), dried over
1)
For a review of asymmetric synthesis of α-amino acids, see:
Williams, R. M. Synthesis of Optically Active α-Amino Acids;
Pergamon Press: Oxford, 1989: Vol 7.
2)
Saari, W. S.; Freedman, M. B; Hartman, R. D.; King, S. W.; Raab,
A. W.; Randall, W. C.; Engelhardt, E. L.; Hirschmann, R.;
Rosegay, Ludden, C. T.; Scriabine, A. J. Med. Chem. 1978, 21,
746.
anhydrous MgSO , filtered, concentrated, and purified by silica
4
3)
Saari, W. S.; Halczenko, W.; Cochran, D. W.; Dobrinska, M. R.;
Vincek, W. C.; Titus, D. G.; Gaul, S. L.; Sweet, C. S. D. W.;
Dobrinska, M. R.; Vincek, W. C.; Titus, D. G.; Gaul, S. L.; Sweet,
C. S. J. Med. Chem. 1984, 27, 713.
gel flash chromatography (eluted with CH Cl : EtOAc = 20 : 1)
2
2
to give compound 6 (colorless solid, 2.09 g, 81 % yield from
i
25
compound (+)-1). Colorless prisms ( Pr O), mp 191-192 °C. [α]
2
D
1
= +12.1° (CH Cl , c = 1.07). H NMR (300 MHz) (393 K,
2
2
4)
5)
Ramalingam, K.; Woodard, R. W. Tetrahedron Lett. 1985, 1135.
DMSO-d ) δ TMS: 1.44 (9H, s), 3.07 (1H, dd, J = 14.3 Hz, 5.4
6
Hz), 3.14 (1H, dd, J = 14.3 Hz, 7.5 Hz), 4.97 (1H, d, J = 12.9 Hz),
5.02 (1H, d, J = 12.6 Hz), 5.23 (1H, dd, J = 7.5 Hz, 4.5 Hz), 5.25
(1H, d, J = 3.0 Hz), 6.25 (1H, d, J = 3.0 Hz), 6.57-6.60 (2H, m),
Walsh, J. J.; Metzler, D. E.; Powell, D.; Jacobson, R. A. J. Am.
Chem. Soc. 1980, 102, 7136.
6)
Paul, P. K.; Sukumar, M.; Bardi, R.; Piazzesi, A.M.; Valle, G.;
Toniolo, C.; Balaram, P. J. Am. Chem. Soc. 1986, 108, 6363.
-1
7.01-7.26 (13H, m). IR (KBr): 1741, 1726, 1696 (C=O) cm .
+
+
MS(FAB+): 502 (M +H), 446 (M -tert-Bu). Anal. Calcd for
NO : C, 71.84; H, 6.23; N, 2.79. Found: C, 71.70; H, 6.00;
7)
8)
Yuan, C.; Williams, R. M. J. Am. Chem. Soc. 1997, 119, 11777.
C
H
30 31
6
Katayama, N.; Fukusumi, S.; Funabashi, Y.; Iwai, T.; Ono, H. J.
Antibiot. 1993, 46, 606.
N, 2.79.
17) Preparation
of
(3S,5R,6S)-4-(benzyloxycarbonyl)-3-tert-
9)
Funabashi, Y.; Tsubotani, S.; Koyama, K.; Katayama, N.; Harada,
S. Tetrahedron 1993, 49, 13.
butoxycarbonylmethyl-5,6-diphenyl-3-methyl-2,3,5,6-
tetrahydro-4H-1,4-oxazin-2-one (7). To a THF solution (30 mL)
of compound 6 (0.378 g, 0.75 mmol) and MeI (0.47 mL, 1.06 g,
10) Williams, R. M.; Im, M. -N. Tetrahedron 1988, 29, 6075.
11) Williams, R. M.; Im, M. -N. J. Am. Chem. Soc. 1988, 29, 6075.
7.5 mmol), 1.0 M NaN(TMS) in THF (0.83 mL, 0.83 mmol) was
2

October 1998
SYNLETT
1101
added dropwise at -78 °C under an Ar atmosphere, followed by
(393 K, DMSO-d ) δ TMS: 1.67 (3H, s), 2.96 (1H, d, J = 15.0
6
addition of 15-crown-5 (0.99 g, 4.5 mmol). After the resulting
solution was stirred at the same temperature for 1 hr, poured into
EtOAc (60 mL). The organic layer was washed with water (30 mL
x 2) and sat. NaCl (30 mL x 1), successively, and dried over
Hz), 3.77 (1H, d, J = 15.6 Hz), 5.18 (2H, s), 5.64 (1H, d, J = 3.6
Hz), 6.50 (1H, d, J = 3.3 Hz), 6.81 (2H, brs), 7.06-7.34 (15H, m).
-1
IR (KBr): 3455, 3353 (NH), 1741, 1697 (C=O) cm . MS (FAB+):
+
+
459 (M +H), 415 (M -CONH ). Anal. Calcd for C
H N O : C,
2
27 26 2 5
anhydrous MgSO , filtered, concentrated, and purified by silica
70.73; H, 5.72; N, 6.11. Found: C, 70.74; H, 6.01; N, 5.89.
4
gel radial chromatography (eluted with Hexanes : CH Cl : Et O
2
2
2
(3S,5R,6S)-4-(benzyloxycarbonyl)-3-carbamoylmethyl-5,6-
diphenyl-3-methyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (9).
81% yield from compound 7. Colorless amorphous solid, mp 69-
= 8 : 2 : 1) to give compound 7 (colorless semi-solid, 0.245 g, 63
% yield from compound 6). Colorless semi-solid, mp 48-50 °C .
25
1
[α] = +18.2° (CH Cl , c = 0.62). H NMR (300 MHz) (393 K,
25
1
D
2
2
70 °C . [α] = +15.2° (CH Cl , c = 1.08). H NMR (300 MHz)
D
2
2
DMSO-d ) δ TMS: 1.30 (9H, s), 2.00 (3H, s), 3.23 (1H, d, J =
6
(348 K, DMSO-d ) δ TMS 1.99 (3H, s), 3.28 (1H, d, J = 15.0 Hz),
6
15.3 Hz), 3.34 (1H, d, J = 15.3 Hz), 5.05 (1H, d, J = 12.3 Hz), 5.14
(1H, d, J = 12.6 Hz), 5.49 (1H, d, J = 3.3 Hz), 6.27 (1H, d, J = 3.6
Hz), 7.01-7.28 (15H, m). IR (KBr): 1758, 1735, 1701 (C=O)
3.56 (1H, d, J = 15.0 Hz), 5.05 (1H, d, J = 12.9 Hz), 5.12 (1H, d, J
= 12.3 Hz), 5.40 (1H, d, J = 3.9 Hz), 6.31 (1H, d, J = 3.6 Hz), 6.67
(2H, brs), 7.00-7.32 (15H, m). IR (KBr): 3468, 3358 (NH, OH),
-1
+
cm ). MS(FAB+): 516 (M +H). HRMS Calcd for C
for 516.2386. Found: 516.2402.
H NO
31 34 6
-1
+
1752, 1702 (C=O) cm . MS(FAB+): 459 (M +H). HRMS Calcd
+
for C
H
N O (M +H): 459.1920. Found: 459.1937.
27 27
2 5
(18) Nozaki, S.; Muramatsu, I. Bull. Chem. Soc. Jpn. 1988, 61, 2647.
(19) General Procedure for transformation of tert-butyl esters 5
and 7 to amides 8 and 9. A CH Cl solution (1.0 mL) of tert-
(20) General Procedure for hydrogenation of amides 8 and 9. A
mixture of the amide (2.73 g, 5.96 mmol), PdCl (0.32 g), THF-
2
2
2
EtOH (1 : 2) (20 mL) was stirred vigorously under H (60 psi) for
2
butyl ester (0.213 g, 0.413 mmol) and TFA (1.0 mL) was stirred at
0 °C for 10 min and then at room temperature for 1 h. After
evaporation of the solvent and excess TFA, EEDQ (0.157 g, 0.62
®
®
3 days. After filtration through Celite 545, the Celite 545 was
washed with EtOH, and the solvent was evaporated under reduced
pressure to give a residue, which was dissolved in H O (30 mL).
2
mmol), NH HCO (0.196 g, 2.48 mmol), CHCl (5 mL) were
4
3
3
The aqueous phase was washed with Et O (10 mL x 3) and H O
2
2
added to the residue, successively. The resulting mixture was
stirred at room temperature for 12 hrs and diluted with CH Cl
was evaporated at room temperature to give a pure amino acid (3)
2
2
(0.74 g, 94% yield) as a colorless solid.
(20 mL). The organic phase was washed with H O (15 mL x 2),
2
19
(S)-2-Methylasparagine (3). 98:2 er (on the basis of F-NMR of
dried over MgSO , filtered, and the solvent was evaporated under
4
the Mosher amide of compound 3) Colorless amorphous solid, mp
reduced pressure to give an oily residue, which was purified by
using radial TLC (Hexanes: AcOEt = 2 : 5).
25
1
85-87 °C. [α] = +17.7 ° (EtOH, c = 0.43). H NMR (300 MHz)
D
(300 K, D O) δ TMS: 1.60 (3H, s), 2.86 (1H, d, J = 17.4 Hz), 3.12
(3S,5S,6R)-4-(benzyloxycarbonyl)-3-carbamoylmethyl-5,6-
diphenyl-3-methyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (8).
95 % yield from compound 5. Colorless amorphous solid, Mp 92-
2
(1H, d, J = 17.4 Hz). IR (KBr): 3405, 3176 (NH, OH), 1728, 1671
-1
+
(C=O) cm . MS(FAB+): 147 (M +H). HRMS Calcd for
25
1
+
94 °C. [α] = +116° (CH Cl , c = 0.27). H NMR (300 MHz)
C H N O (M +H): 147.0770. Found: 147.0774.
D
2
2
5 11 2 3