Diastereoselective alkylation of a newly designed bislactim ether towards the asymmetric synthesis of α-alkylated serines

Article abstract of DOI:10.1016/S0957-4166(98)00370-X

Diastereoselective alkylation of ethyl (5S)-3,6-diethoxy-2,5-dihydro-5- isopropyl-2-pyrazinecarboxylate (5S)-3 with alkyl halides was investigated by using NaH and n-BuLi. These alkylated products (2R,5S)-4b-d were converted to the corresponding α-alkylat

Full text of DOI:10.1016/S0957-4166(98)00370-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3611–3614
Diastereoselective alkylation of a newly designed bislactim ether
towards the asymmetric synthesis of α-alkylated serines
Shigeki Sano, Maki Takebayashi, Toshio Miwa, Takahiro Ishii and Yoshimitsu Nagao ∗
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Received 13 August 1998; accepted 8 September 1998
Abstract
Diastereoselective alkylation of ethyl (5S)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2-pyrazinecarboxylate (5S)-3
with alkyl halides was investigated by using NaH and n-BuLi. These alkylated products (2R,5S)-4b–d were
converted to the corresponding α-alkylated serines (S)-6b–d. © 1998 Elsevier Science Ltd. All rights reserved.
Nonproteinogenic amino acids, such as α-substituted α-amino acids, have attracted our attention
because of their biological activity.1 Specifically, the construction of enantiomerically pure α-substituted
serines is of considerable interest from the standpoint of synthetic and pharmaceutical chemistry.2 In
previous work, we reported the diastereoselective aldol-type reaction of a newly designed bislactim
ether, ethyl (5R)- or (5S)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2-pyrazinecarboxylate 3, as the chiral
α-substituted serines precursor.3
Herein we describe diastereoselective alkylation of the chiral bislactim ether 3 with alkyl halides
towards the enantioselective construction of α-alkylated serines as shown in Scheme 1. Bislactim ether
(5S)-3 was readily prepared from σ-symmetric diethyl aminomalonate 1 and L-valine (S)-2 according
to the previously reported procedure.3b Diastereoselective alkylation of the bislactim ether (5S)-3 with
alkyl halides was examined by employing NaH or n-BuLi under suitable conditions as shown in Table 1.
The reaction of the sodium enolate of (5S)-3 with 2 mol equiv. of alkyl halides gave alkylated products
(2R,5S)-4a–d as colorless oils in reasonable yields and 52–92% diastereomeric excess (de), respectively
(entries 1–4 in Table 1). Similar treatment of the lithium enolate of (5S)-3 with 2 mol equiv. of alkyl
halides afforded (2R,5S)-4a–c in 68–84% yields and 34–97% de (entries 5–7), but poor reactivity was
∗
Corresponding author. E-mail: ynagao@ph2.tokushima-u.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00370-X

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S. Sano et al. / Tetrahedron: Asymmetry 9 (1998) 3611–3614
observed in the reaction with n-hexyl bromide (entry 8). The absolute configuration and de of (2R,5S)-
1
4a–c were determined by H–1H NOE (400 MHz, CDCl3) experiments and by comparison with the
absolute configuration of each corresponding diastereomer, (2S,5S)-4a–c. When C2–Me protons of
(2R,5S)-4a were irradiated, an NOE enhancement of C5–H was recognized (Fig. 1). On the other
hand, irradiation of C2–Me protons of (2S,5S)-4a caused no NOE enhancement of C5–H. In the case
of (2R,5S)-4b,c, a similar NOE enhancement was observed [(2R,5S)-4b: between C5–H and phenyl
protons, (2R,5S)-4c: between C5–H and an allyl proton] as shown in Fig. 1. These alkyl substituents
must be introduced in a cis-relation manner to the proton at C5 due to the steric hindrance between
the alkyl halides and the i-propyl group at C5. Based on the reaction mechanism described above, the
absolute configuration of the major product obtained from the reaction of (5S)-3 with n-hexyl bromide
was speculated to be (2R,5S)-4d.
Scheme 1. (a) NaH/RX/THF/rt, (b) n-BuLi/RX/THF 0°C, (c) DIBAL/CH2Cl2/0°C or 0°C-→rt, (d) 0.2 N HCl/MeCN/rt
Reduction of each diastereomeric mixture of 4a–d with 2.5 mol equiv. of DIBAL in CH2Cl2 at 0°C
to room temperature followed by chromatographic separation of the resultant two diastereoisomers on
a silica gel column gave the corresponding primary alcohols (2S,5S)-5a–d as the enantiomerically pure
compound in various yields (5a: 56%, 5b: 84%, 5c: 76%, and 5d: 77%). Interestingly, a considerable
upfield shift of C5–H (δ 2.91 ppm in CDCl3, 2.92 ppm in THF-d8, 2.92 ppm in methanol-d4, and 3.13
ppm in benzene-d6) of (2S,5S)-5b was evidently recognized when compared with the chemical shift
(δ 3.72 ppm in CDCl3, 3.70 ppm in THF-d8, 3.78 ppm in methanol-d4, and 3.90 ppm in benzene-d6)
1
of (2R,5S)-5b in the H NMR (200 MHz) spectrum.4 In addition, one of the Me protons (δ −0.05
ppm in CDCl3, −0.14 ppm in THF-d8, −0.04 ppm in methanol-d4, and 0.35 ppm in benzene-d6) of
Table 1
Diastereoselective alkylation of bislactim ether (5S)-3

S. Sano et al. / Tetrahedron: Asymmetry 9 (1998) 3611–3614
3613
Fig. 1. Selected 1H–1H NOE enhancements (400 MHz 1H NMR, CDCl3) for (2R,5S)-4a–c
(2R,5S)-5b exhibited a significant upfield shift in comparison with the chemical shift (δ 0.58 or 0.87
ppm in CDCl3, 0.59 or 0.89 ppm in THF-d8, 0.69 or 0.95 ppm in methanol-d4, and 0.71 or 1.01 ppm in
benzene-d6) of (2S,5S)-5b.4 Such a phenomenon seems to be rationalized in terms of the shielding effect
of the phenyl moiety, which probably adopts a folded conformation with the bislactim ether moiety.5,6
Hydrolysis of (2S,5S)-5b–d with 2 mol equiv. of 0.2 N HCl in MeCN at room temperature afforded
the corresponding α-alkylated serines (S)-6b–d as each enantiomerically pure compound (6b: 58%, 6c:
16%, and 6d: 31% yields).7 Unfortunately, (S)-6a was not obtained after hydrolysis of (2S,5S)-5a under
the acidic conditions.8
In conclusion, some α-alkylated serines were synthesized, each in enantiomerically pure form, by
using chiral bislactim ether (5S)-3. Thus, we demonstrated that σ-symmetric diethyl aminomalonate 1
could be utilized as the chiral serine carbanion synthon.
References
1. Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225–227 and references cited therein.
2. For recent references, see: (a) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Nájera, C. Angew. Chem., Int. Ed. Engl. 1997,
36, 995–997. (b) Hatakeyama, S.; Matsumoto, H.; Fukuyama, H.; Mukugi, Y.; Irie, H. J. Org. Chem. 1997, 62, 2275–2279.
(c) Belokon’, Y. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Parmár, V.
S.; Kumar, R.; Kagan, H. B. Tetrahedron: Asymmetry 1998, 851–857. (d) Carda, M.; Murga, J.; Rodríguez, S.; González,
F.; Castillo, E.; Marco, J. A. Tetrahedron: Asymmetry 1998, 1703–1712. (e) Matsushita, M.; Maeda, H.; Kodama, M.
Tetrahedron Lett. 1998, 39, 3749–3752.
3. (a) Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama, S.; Fujita, T.; Nagao, Y. Tetrahedron Lett. 1995, 36,
2097–2100. (b) Sano, S.; Liu, X.-K.; Takebayashi, M.; Kobayashi, Y.; Tabata, K.; Shiro, M.; Nagao, Y. Tetrahedron Lett.
1995, 36, 4101–4104.
21
1
4. (2S,5S)-5b: colorless needles (CH2Cl2–n-hexane), mp 63–64°C, [α]D −79.7 (c 1.00, MeOH), H NMR (200 MHz,
CDCl3) δ 0.58 (3H, d, J=6.8 Hz), 0.87 (3H, d, J=6.8 Hz), 1.28 (3H, t, J=7.1 Hz), 1.34 (3H, t, J=7.1 Hz), 2.14 (1H, dsept,
J=3.2, 6.8 Hz), 2.28 (1H, X of ABX, t, JAX=JBX=6.7 Hz), 2.85 (1H, A0 of A0B0, d, J=13.0 Hz), 2.91 (1H, d, J=3.2 Hz),
3.06 (1H, B0 of A0B0, d, J=13.0 Hz), 3.71 (1H, A of ABX, dd, JAX=6.7, JAB=7.2 Hz), 3.79 (1H, B of ABX, dd, JBX=6.7,
J
AB=7.2 Hz), 3.97–4.27 (4H, m), 6.97–7.02 (2H, m), 7.14–7.20 (3H, m); IR (CHCl3) 3600, 1693, 1384, 1367, 1215 cm−1
;
HREI-MS calcd for C19H28N2O3 MW 332.2099, found m/e 332.2097 (M+). Anal. calcd for C19H28N2O3: C, 68.65; H,
21
8.49; N, 8.43. Found: C, 68.32; H, 8.51; N, 8.33. (2R,5S)-5b: colorless needles (CH2Cl2–n-hexane), mp 91–92°C, [α]D
1
+91.9 (c 0.51, CHCl3), H NMR (200 MHz, CDCl3) δ −0.05 (3H, d, J=6.8 Hz), 0.81 (3H, d, J=6.8 Hz), 1.28 (3H, t,
J=7.1 Hz), 1.36 (3H, t, J=7.1 Hz), 1.76 (1H, dsept, J=4.2, 6.8 Hz), 1.92–2.08 (1H, brs), 2.84 (1H, A of AB, d, J=12.6 Hz),
3.18 (1H, B of AB, d, J=12.6 Hz), 3.61 (1H, A0 of A0B0, d, J=10.6 Hz), 3.72 (1H, d, J=4.2 Hz), 3.78 (1H, B0 of A0B0, d,

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S. Sano et al. / Tetrahedron: Asymmetry 9 (1998) 3611–3614
J=10.6 Hz), 4.01–4.28 (4H, m), 7.07–7.25 (5H, m); IR (CHCl3) 3600, 1691, 1307, 1225, 1212 cm−1; HREI-MS calcd for
C19H28N2O3 MW 332.2099, found m/e 332.2081 (M+). Anal. calcd for C19H28N2O3: C, 68.65; H, 8.49; N, 8.43. Found:
C, 68.38; H, 8.59; N, 8.29.
5. (a) Schöllkopf, U.; Hartwig, W.; Groth, U. Angew. Chem., Int. Ed. Engl. 1979, 18, 863–864. (b) Schöllkopf, U.; Hartwig,
W.; Groth, U. Angew. Chem., Int. Ed. Engl. 1980, 19, 212–213.
6. (a) Nagao, Y.; Sano, S.; Nakagawa, S.; Tanaka, M.; Shiro, M.; Taga, T. Chem. Lett. 1992, 915–918. (b) Nagao, Y.; Sano,
S.; Nakagawa, S.; Suzuki, M.; Shiro, M.; Kido, M.; Nishi, T. Heterocycles 1993, 36, 1715–1720.
24
1
7. (S)-6b: white powder, mp 47.5–49.5°C, [α]D +4.5 (c 0.69, MeOH), H NMR (200 MHz, CDCl3) δ 1.26 (3H, t, J=7.1
Hz), 2.14 (3H, brs), 2.81 (1H, A of AB, d, J=13.4 Hz), 3.10 (1H, B of AB, d, J=13.4 Hz), 3.58 (1H, A0 of A0B0, d, J=10.6
Hz), 3.84 (1H, B0 of A0B0, d, J=10.6 Hz), 4.18 (2H, q, J=7.1 Hz), 7.11–7.16 (2H, m), 7.23–7.29 (3H, m); IR (CHCl3)
3572, 3032, 2931, 1693, 1306, 1243, 1225, 1220 cm−1; HRFAB-MS calcd for C12H18NO3 M++H 224.1286, found m/e
224.1292 (M++H).
8. For the chemoenzymatic synthesis of both enantiomers of α-methylserine, see: Sano, S.; Hayashi, K.; Miwa, T.; Ishii, T.;
Fujii, M.; Mima, H.; Nagao, Y. Tetrahedron Lett. 1998, 39, 5571–5574.