Tin- or magnesium-mediated diastereoselective aldol-type reactions for the asymmetric synthesis of α-substituted serines

Article abstract of DOI:10.1016/S0957-4166(98)00371-1

Diastereoselective aldol-type reactions of ethyl (5S)-3,6-diethoxy-2,5- dihydro-5-isopropyl-2-pyrazinecarboxylate (5S)-3 with achiral aldehydes 8a-d was investigated by using Sn(OSO₂CF₃)₂-N-ethylpiperizine and MgBr₂

Full text of DOI:10.1016/S0957-4166(98)00371-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3615–3618
Tin- or magnesium-mediated diastereoselective aldol-type
reactions for the asymmetric synthesis of α-substituted serines
Shigeki Sano,a Toshio Miwa,a Xiao-Kai Liu,a Takahiro Ishii,a Tomoka Takehisa,a
Motoo Shiro b and Yoshimitsu Nagao a,∗
aFaculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
bRigaku Corporation, 3-9-12, Matsubara-cho, Akishima, Tokyo 196-8666, Japan
Received 13 August 1998; accepted 8 September 1998
Abstract
Diastereoselective aldol-type reactions of ethyl (5S)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2-pyrazine-
carboxylate (5S)-3 with achiral aldehydes 8a–d was investigated by using Sn(OSO2CF3)2–N-ethylpiperizine and
MgBr2–triethylamine. The reaction with Sn(II) between (5S)-3 and aliphatic aldehydes 8a,b proved to be quite
different from that with Mg(II). On the other hand, Sn(II)- or Mg(II)-mediated aldol-type reactions of (5S)-3 with
benzaldehyde 8c and 3-methyl-2-butenal 8d each afforded the same diastereomer as the major product. These
aldol products were each converted to the corresponding α-substituted serines 6 and 7 as enantiomerically pure
compounds. © 1998 Elsevier Science Ltd. All rights reserved.
Recently, we have carried out extensive development of new methods for the synthesis of α-substituted
serines, which should be remarkably interesting from the standpoint of pharmaceutical and bioorganic
chemistry.1,2 In earlier papers, we reported the diastereoselective aldol-type reaction and alkylation
of the newly designed bislactim ether, ethyl (5R)- or (5S)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2-
pyrazinecarboxylate 3, as a chiral α-substituted serine precursor.3 Chiral α-alkylated serines can be also
synthesized by utilizing a chemoenzymatic procedure.4
Herein we describe the diastereoselective aldol-type reaction of the bislactim ether (5S)-3, readily
prepared from σ-symmetric diethyl aminomalonate 1 and L-valine (S)-2,3b with achiral aldehydes 8a–d
in conjunction with the synthesis of α-substituted serines as shown in Scheme 1. All results are shown in
Table 1. The aldol-type reaction of aliphatic aldehydes 8a,b with bislactim ether (5S)-3 in the presence
of Sn(OSO2CF3)2 and N-ethylpiperidine in THF at −78°C afforded (2R,5S,10S)-4a,b as their major
product, respectively (entries 1 and 3). Interestingly, the similar aldol-type reaction employing MgBr2
and triethylamine gave the different diastereomer (2R,5S,10R)-4a,b as each major product (entries 2
and 4). In earlier papers, we also reported that the diastereoselective mode of the Sn(II)-mediated
reaction differed from the Mg(II)-mediated one in the aldol-type reaction of (5S)-3 with chiral aliphatic
∗
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)00371-1

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S. Sano et al. / Tetrahedron: Asymmetry 9 (1998) 3615–3618
Scheme 1. (a) Sn(II) or Mg(II): see footnote for Table 1, (b) RCHO (8a–d), (c) Me2(t-Bu)SiOSO2CF3/2,6-lutidine/
CH2Cl2/−45°C, (d) DIBAL/toluene/0°C, (e) 12 N HCl:CF3CO2H:i-PrOH (2:1:1)/170°C, (f) 0.2 N HCl:THF (1:1)/rt
aldehydes.3a,b However, each major product proved to be the same diastereomer (2R,5S,10R)-4c,d in the
aldol-type reaction of (5S)-3 with benzaldehyde 8c and 3-methyl-2-butenal 8d whether Sn(II) or Mg(II)
1
was employed (entries 5–8). The diastereomer ratios of 4a–d were determined by exploiting H NMR
analysis (400 MHz, CDCl3). The absolute configuration of the newly formed C2 stereogenic center in
the separable diastereomers 4a–d was determined by the 1H–1H NOE (400 MHz, CDCl3) experiments of
4a–d and/or of the corresponding derivatives 10a,b,d (Scheme 2). 1H NMR analysis (400 MHz, CDCl3)
of the Mosher ester [(R)- and (S)-methoxy(trifluoromethyl)phenylacetate (MTPA)] derivatives 11a,b,d
and X-ray crystallographic analysis of diol 12c (Fig. 1) and (S)-MTPA-11d were utilized in order to
determine the absolute configuration of the chiral C10 atom in the 10 kinds of aldol products 4a–d
(Scheme 2).5
The separable diastereoisomers 4a–d were isolated by column chromatography on silica gel. Re-
duction of the major diastereoisomers of 4a–d with DIBAL in toluene at 0°C [(2R,5S,10S)-5a: 93%,
(2R,5S,10R)-5b: 61%, (2R,5S,10R)-5c: 80%, and (2R,5S,10R)-5d: 83% yields] followed by hydrolysis
Table 1
Diastereoselective aldol-type reaction of bislactim ether (5S)-3 with aldehydes 8a–d

S. Sano et al. / Tetrahedron: Asymmetry 9 (1998) 3615–3618
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Scheme 2. (a) MOMCl/i-Pr2NEt/CH2Cl2/rt, (b) TBAF/THF/rt, (c) (S)-MTPACl/DMAP/Et3N/CH2Cl2/rt, (d) (R)-MTPACl/
DMAP/Et3N/CH2Cl2/rt
Fig. 1. Computer-generated drawing of (2R,5S,10R)-12c derived from the X-ray coordinates
with 12 N HCl:CF3CO2H:i-PrOH (2:1:1) or 0.2 N HCl:THF (1:1) afforded the corresponding α-
substituted serines 6a,b and 7c,d [(2R,3S)-6a: 26%, (2R,3R)-6b: 37%, (2R,3R)-7c: 35%, and (2R,3R)-7d:
28% yields], respectively.6
The different stereochemical outcome in the Sn(II)- or Mg(II)-mediated aldol-type reaction of (5S)-3
with aliphatic aldehydes 8a,b can be rationalized in terms of the corresponding six-membered transition
states as we previously proposed.3a,b In contrast, unsaturated aldehydes such as benzaldehyde 8c and 3-
methyl-2-butenal 8d may change the common transition state in the Sn(II)-mediated aldol-type reaction
owing to plausible π–π stacking between the bislactim ring of (5S)-3 and the unsaturated (or aromatic)
moiety of aldehydes 8c,d. Interestingly, the crystal structure of (2R,5S,10R)-12c was shown to be a folded
conformation with two stacked rings, the bislactim ring and the benzene ring (Fig. 1).3c
In conclusion, α-substituted serines were synthesized as each enantiomerically pure form by using the
aldol-type reactions of (5S)-3 with achiral aldehydes. Thus, we demonstrated that σ-symmetric diethyl
aminomalonate 1 could be utilized as the chiral serine carbanion synthon.

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S. Sano et al. / Tetrahedron: Asymmetry 9 (1998) 3615–3618
References
1. Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225–227 and references cited therein.
2. For recent references, see: (a) Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada, K. J. Am. Chem. Soc. 1998,
120, 908–919. (b) Grandel, R.; Kazmaier, U. Eur. J. Org. Chem. 1998, 409–417.
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. (c) Sano, S.; Takebayashi, M.; Miwa, T.; Ishii, T.; Nagao, Y. Tetrahedron: Asymmetry 1998, 9,
3611–3614 (preceding paper).
4. Sano, S.; Hayashi, K.; Miwa, T.; Ishii, T.; Fujii, M.; Mima, H.; Nagao, Y. Tetrahedron Lett. 1998, 39, 5571–5574.
5. The crystallographic data are as follows. (2R,5S,10R)-12c: C19H28N2O4, M=348.44, orthorhombic, P21212, a=15.198(2)
Å, b=24.749(3) Å, c=10.635(2) Å, V=3996.5(9) Å3, Z=8, Dcal=1.158 g/cm3. (S)-MTPA-(2R,5S,10R)-11d: C29H41F3N2O7,
M=586.65, triclinic, P1, a=9.730(3) Å, b=9.916(3) Å, c=9.642(2) Å, α=108.29(2)°, β=119.45(2)°, γ=82.76(3)°,
V=768.7(5) Å3, Z=1, Dcal=1.267 g/cm3.
27
6. (2R,3S)-6a: colorless powder (MeOH), mp 226–227°C (dec.), [α]D −26.1 (c 0.12, MeOH), 1H NMR (400 MHz, D2O)
δ 0.90 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz), 1.89 (1H, dsept, J=2.9, 6.8 Hz), 3.85 (1H, d, J=2.9 Hz), 3.86 (1H, A
of AB, J=12.2 Hz), 4.05 (1H, B of AB, J=12.2 Hz); IR (KBr) 2964, 2358, 1641, 1541, 1467, 1404, 1355, 1247 cm−1
;
HRFAB-MS calcd for C7H16NO4 M++H 178.1079, found m/e 178.1087 (M++H). (2R,3R)-6b: colorless powder (MeOH),
mp 231–232°C (dec.), [α]D26 +36.1 (c 0.06, MeOH), 1H NMR (400 MHz, D2O) δ 0.88 (3H, t, J=6.8 Hz), 1.27–1.50 (6H,
m), 3.85–3.90 (1H), 3.87 (1H, A of AB, J=11.7 Hz), 4.03 (1H, B of AB, J=11.7 Hz); IR (KBr) 2959, 1615, 1344 cm−1
;
HRFAB-MS calcd for C8H18NO4 M++H 192.1236, found m/e 192.1217 (M++H). Anal. calcd for C8H17NO4: C, 50.25;
26
1
H, 8.96; N, 7.32. Found: C, 50.19; H, 8.80; N, 7.23. (2R,3R)-7c: colorless oil, [α]D −44.9 (c 1.00, CHCl3), H NMR
(400 MHz, CDCl3) δ −0.25 (3H, s), 0.06 (3H, s), 0.89 (9H, s), 1.12 (3H, t, J=7.2 Hz), 2.04–2.18 (3H, Br), 3.66 (1H, A
of AB, J=10.4 Hz), 3.89 (1H, B of AB, J=10.4 Hz), 3.92–4.06 (2H, m), 4.89 (1H, s), 7.22–7.31 (5H, m); IR (NaCl) 3382,
2931, 2888, 2858, 1740, 1585, 1472, 1363, 1255, 1217 cm−1; HRCI-MS calcd for C18H32NO4Si M++H 354.2101, found
25
1
m/e 354.2130 (M++H). (2R,3R)-7d: colorless oil, [α]D −36.9 (c 1.01, CHCl3), H NMR (400 MHz, CDCl3) δ −0.02
(3H, s), 0.04 (3H, s), 0.86 (9H, s), 1.25 (3H, t, J=7.2 Hz), 1.65 (3H, s), 1.69 (3H, s), 2.00–2.09 (3H, Br), 3.55 (1H, A of
AB, J=10.4 Hz), 3.77 (1H, B of AB, J=10.4 Hz), 4.01–4.10 (2H, m), 4.15–4.23 (2H, m), 4.50 (1H, d, J=9.6 Hz), 5.16
(1H, d, J=10.0 Hz); IR (NaCl) 2930, 2858, 1738, 1473, 1377, 1251, 1217 cm−1; HRCI-MS calcd for C16H34NO4Si M++H
332.2257, found m/e 332.2247 (M++H).