S. Yamashita et al. / Tetrahedron: Asymmetry 19 (2008) 2115–2118
2117
3. Garner, P.; Sunitha, K.; Shanthilal, T. Tetrahedron Lett. 1988, 29, 3525–3528.
4. Mase, N.; Nishi, T.; Hiyoshi, M.; Ichihara, K.; Bessho, J.; Yoda, H.; Takabe, K. J.
Chem. Soc., Perkin Trans. 1 2002, 707–709.
to the double bond from less hindered face to produce the trans-
adduct.
Our first attempt of the direct deoxygenation of 10d into 12 was
unsuccessful under triethylsilane/boron trifluoride etherate-medi-
ated conditions;13 therefore, stepwise deoxygenation was next
examined. Deprotection of the silyl group using tetrabutylammo-
nium fluoride (TBAF) furnished the hydroxyl lactam 11 in 84%
yield, and subsequent deoxygenation of 11 under standard con-
ditions gave lactam (R)-12 in quantitative yield via a well-known
N-acylpyrrolidinium ion intermediate.14 The enantiopurity of
(R)-12 reached up to >99% ee by recrystallization from ethyl
acetate.15
5. Ono, N.; Kamimura, A.; Miyake, H.; Hamamoto, I.; Kaji, A. J. Org. Chem. 1985, 50,
3692–3698.
6. Hanessian, S.; Seid, M.; Nilsson, I. Tetrahedron Lett. 2002, 43, 1991–1994.
7. We tried to lower the reaction temperature to ꢀ25 °C, but low chemical yield
(45%) and no improvement in diastereoselectivity were observed after 2 d
stirring. Other organic amine base such as N,N-diisopropylethylamine was not
efficient, and no reaction was observed. Michael addition of 2-nitropropane to
9d gave the Micheal product in 95% yield as a single diastereomer.
8. Takabe, K.; Suzuki, M.; Nishi, T.; Hiyoshi, M.; Takamori, Y.; Yoda, H.; Mase, N.
Tetrahedron Lett. 2000, 41, 9859–9863.
9. Reactivity and enantioselectivity was dependent upon the nature of the lipase,
for instance, lipase A (Aspergillus niger, Amano Enzyme Co, Ltd), Lipase M
(Mucor javanicus, Amano Enzyme Co, Ltd), Lipase MY (Candida rugosa, Meito
Sangyo Co, Ltd), and Lipase OF (Candida cyclindracea, Meito Sangyo Co, Ltd) did
not catalyze the reaction. Novozym 435 (Candida antarctica, NovozymesÒ) and
ChirazymeÒL-2 (Candida antarctica (lipase B), Roche molecular biochemicals)
were also a practical catalyst for this kinetic resolution (>49% yield, >99% ee).
Compound (S)-6: (R)-323204-65-5, (S)-323204-78-0, (rac)-323204-69-9;
Finally, reduction of the nitro group was performed by hydroge-
nation in the presence of 10% Pd/C in THF to give the enantiopure
nebracetam (S)-3 in 95% yield.16 The specific rotation of the syn-
thesized chiral nebracetam (S)-3 has
a
negative value
a 2D6
ꢂ
¼ ꢀ8:0 (c 1.0, H2O), and hence the absolute configuration
Rf = 0.18 (hexane/AcOEt = 50:50);
(300 MHz, DMSO) d 4.21 (d, J = 15.4 Hz, 1H, –CH2), 4.71 (d, J = 15.4 Hz, 1H,
½
a 2D7
ꢂ
¼ ꢀ35:0 (c 1.08, CHCl3); 1H NMR
½
of the previously resolved chiral nebracetam ½a D
ꢂ
¼ ꢀ8:4 (c 1.0,
–CH2), 5.26 (d, J = 8.6 Hz, 1H, –CHOH), 6.18 (d, J = 6.0 Hz, 1H, –CH ), 6.43 (d,
a
H2O) was determined to have an (S)-configuration. The nebracetam
derivative (S)-13 was also prepared by a one-pot hydrogena-
tion and reductive amination in the presence of acetone (see
Scheme 4).17
J = 8.7 Hz, 1H, –OH), 7.08 (dd, J = 1.4, 5.9 Hz, 1H, –CHb), 7.17–7.44 (m, 5H, Ar);
13C NMR (75 MHz, DMSO) d 169.04 (C@O), 147.91 (CH), 138.25 (C), 128.57
(CH), 127.64 (CH), 127.19 (CH), 127.13 (CH), 81.96 (CH), 41.77 (CH2); ESI-
TOFMS calcd for C11H11NO2Na (MNa+) 212.0687. Found 212.0720; HPLC (Daicel
CHIRALCEL OD-H, hexane/2-PrOH = 95:5, flow rate 0.5 mL/min, k = 254 nm)
tR = 39.48 (R-isomer), 44.63 (S-isomer) min.
Compound (R)-9a: (R)-323204-73-5, (S)-323204-67-7, (rac)-323204-63-3;
Rf = 0.43 (hexane/AcOEt = 50:50);
½
a 2D7
ꢂ
¼ ꢀ44:7 (c 0.97, CHCl3); 1H NMR
(300 MHz, CDCl3) d 1.91 (s, 3H, –CH3), 4.41 (d, J = 15.2 Hz, 1H, –CH2–), 4.71
(d, J = 15.2 Hz, 1H, –CH2–), 6.30 (dd, J = 0.7, 6.0 Hz, 1H, –CHOAc), 6.45 (d,
H2N
O2N
N
H
a
b
J = 1.7 Hz, 1H, –CH ), 6.93 (dd, J = 1.7, 6.0, 1H, –CHb), 7.17–7.37 (m, 5H, Ar); 13
C
a
O
O
O
NMR (75 MHz, CDCl3) d 170.48 (C@O), 170.08 (C@O), 142.68 (CH), 136.96 (C),
129.90 (CH), 128.80 (CH), 128.20 (CH), 127.76 (CH), 82.53 (CH), 44.08 (CH2),
20.54 (CH3); ESI-TOFMS calcd for C13H13NO3Na (MNa+) 254.0793. Found
254.0772; HPLC (Daicel CHIRALCEL OD-H, hexane/2-PrOH = 95:5, flow rate
0.5 mL/min, k = 254 nm) tR = 33.41 (R-isomer), 43.35 (S-isomer) min.
10. If the protection reaction was carried out for prolonged time in the presence of
excess silyl reagent at room temperature, the enantioselectivity was decreased
to around 90% ee.
N
N
N
Bn
Bn
Bn
(S)-3 (95%)
(R)-12 (>99% ee)
(S)-13 (74%)
Scheme 4. Reagents and conditions: (a) Pd/C, H2 (1.4 MPa), THF, rt, 8 h; (b) Pd/C,
acetone, H2 (1.4 MPa), MeOH, rt, 3 d.
Compound (S)-9d: Rf = 0.80 (hexane/AcOEt = 50:50); ½ ꢂ ¼ þ15:5 (c 1.00,
a 2D5
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.65–7.52 (m, 4H, Ar), 7.50–7.17 (m, 9H,
Ar), 7.16–7.00 (m, 2H, Ar), 6.49 (dd, J = 1.5, 6.0 Hz, 1H, CHb), 6.03 (d, J = 6.0 Hz,
3. Conclusion
1H, CH ), 5.39 (d, J = 1.5 Hz, 1H, –CHOSi–), 5.01 (d, J = 15.4 Hz, 1H, –CH2–), 4.24
a
(d, J = 15.4 Hz, 1H, –CH2s–), 1.05 (s, 9H, But); 13C NMR (75 MHz, CDCl3) d 169.57
(C@O), 145.69 (CH), 137.53 (C), 135.92 (CH), 135.85 (CH), 132.99 (C), 132.36
(C), 130.42 (CH), 128.73 (CH), 128.14 (CH), 128.06 (CH), 127.92 (CH), 127.43
(CH), 83.18 (CH), 42.57 (CH2), 26.77 (CH3), 19.29 (C); Elemental Anal. Calcd for
C27H29NO2Si: C, 75.84; H, 6.84; N, 3.28. Found: C, 75.56; H, 6.84; N, 3.27; HPLC
(Daicel CHIRALPAK AD-H, hexane/2-PrOH = 95:5, flow rate 0.5 mL/min,
k = 254 nm) tR = 17.06 (R-isomer), 13.19 (S-isomer) min.
In conclusion, we have developed an asymmetric total synthesis
of nebracetam 3 by a chemoenzymatic strategy. Lipase-catalyzed
kinetic resolution of the lactam 6 demonstrated excellent enantio-
selectivity. The diastereoselective Michael addition of nitrometh-
ane to the chiral lactam (S)-9d afforded the Michael product 10d
in 99% yield with 86% de. It was not necessary to additionally acti-
vate the N-benzyl lactam (S)-9d, which was used directly in the
Michael addition. The chemical transformations of 10d, including
recrystallization, furnished the important intermediate lactam
(R)-12 with >99% enantioselectivity. Standard reduction of (R)-12
gave the chiral nebracetam 3 and its derivative. The absolute con-
figuration of the chiral (ꢀ)-nebracetam was determined to have an
(S)-configuration. Further studies focusing on the synthesis of
nebracetam derivatives are currently under investigation, and will
be reported in due course.
11. The diastereomeric mixture of Michael product 10d was solid. We tried to
separate these diastereomers by recrystallization, but it was difficult to isolate
as a single diastereomer.
Compound 10d: Registry number unknown; Rf = 0.50 (hexane/AcOEt = 70:30);
½
a 2D5
ꢂ
¼ þ15:46 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.61 (d, J = 7.0 Hz,
4H, Ar), 7.54–7.31 (m, 6H, Ar), 7.23–7.10 (m, 3H, Ar), 6.91–6.71 (m, 2H, Ar),
4.93 (d, J = 15.1 Hz, 1H, –CH2Ph), 4.80 (s, 1H, –CHOSi–), 3.81 (d, J = 15.1 Hz, 1H,
–CH2Ph), 3.78 (dd, J = 13.4, 8.0 Hz, 1H, –CH2NO2), 3.59 (dd, J = 6.4, 13.4, 1H,
–CH2NO2), 2.97 (dd, J = 17.1, 8.4 Hz, 1H, –CH2C@O), 2.93–2.77 (m, 1H,
–CHCH2NO2), 2.14 (d, J = 17.1 Hz, 1H, –CH2C@O), 1.07 (s, 9H, But); 13C NMR
(75 MHz, CDCl3) d 173.11 (C@O), 136.27 (C), 135.97 (CH), 135.92 (CH), 132.35
(C), 132.29 (C), 130.82 (CH), 130.69 (CH), 128.94 (CH), 128.51 (CH), 128.39
(CH), 128.04 (CH), 127.89 (CH), 85.10 (CH), 75.66 (CH2), 43.65 (CH2), 39.72
(CH), 32.74 (CH2), 26.85 (CH3), 19.40 (C); Elemental Anal. Calcd for
C28H32N2O4Si: C, 68.82; H, 6.60; N, 5.73. Found: C, 68.67; H, 6.63; N, 5.77;
HPLC (Daicel CHIRALPAK IA, hexane/CH2Cl2 = 70:30, flow rate 0.5 mL/min,
k = 254 nm) tR = 47.37 (R,R-isomer), 53.07 (S,R-isomer) 64.99 (S,S-isomer),
70.85 (R,S-isomer) min.
Acknowledgements
We would like to thank Amano Enzyme Co, Ltd., Meito Sangyo
Co, Ltd, NovozymesÒ, and Roche Molecular Biochemicals for a gen-
erous gift of enzymes. This work was supported in part by a Grant-
in-Aid for Scientific Research from Japan Society for the Promotion
of Science.
12. Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870–2871.
13. Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.; Garcia Ruano, J. L.
Tetrahedron Lett. 1994, 35, 2053–2056.
14. Compound 11: Registry number unknown; Rf = 0.23 (hexane/AcOEt = 50:50);
1H NMR (300 MHz, DMSO) d 2.10-3.22 (m, 3H), 3.94–4.17 (m, 1H), 4.34–5.30
(m, 4H), 6.39–6.58 (m, 1H, –CHOH), 7.17–7.43 (m, 5H, Ar); 13C NMR (75 MHz,
DMSO) d 172.47 (C@O, trans), 171.54 (C@O, cis), 137.30 (C, trans), 137.12 (C,
cis), 128.61 (CH, trans), 128.51 (CH, cis), 127.81 (CH, cis), 127.76 (CH, trans),
127.29 (CH, trans), 127.18 (CH, cis), 83.35 (CH, cis), 80.66 (CH, trans), 76.47
(CH2, cis), 73.93 (CH2, trans), 42.47 (CH2, trans), 42.26 (CH2, cis), 39.40 (CH, cis),
34.26 (CH, trans), 32.82 (CH2, cis), 31.54 (CH2, trans); ESI-TOFMS calcd for
C12H14N2O4Na (MNa+) 273.0851. Found 273.0892; HPLC (Kanto Chemical
Mightysil, hexane/2-PrOH = 80:20, flow rate 0.5 mL/min, k = 254 nm) tR = 20.08
(trans-isomer), 26.81 (cis-isomer) min.
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