M. Nonn et al. / Tetrahedron 68 (2012) 9942e9948
9947
Rf¼0.58 (n-hexaneeEtOAc 1:3); 1H NMR (400 MHz, CDCl3):
d
¼1.26
1.61e1.78 (m, 3H, CH2, H-1), 2.27e2.37 (m, 1H, H-4), 2.73e2.82 (m,
1H, CH), 3.51e3.60 (m, 1H, H-5), 4.06e4.19 (m, 3H, OCH2, H-2), 4.23
(br s, 1H, NeH), 4.29e4.32 (m, 1H, H-3), 4.88 (br s, 1H, NeH). 13C
(t, 3H, CH3, J¼7.2 Hz), 1.43 (s, 9H, CH3), 1.54e1.76 (m, 2H, CH2),
1.99e2.08 (m, 4H, CH3, H-6), 3.18e3.30 (m, 1H, H-3a), 3.38 (d, 1H,
H-7, J¼8.9 Hz), 3.43e3.54 (m, 1H, H-7a), 4.09e4.20 (m, 2H, OCH2),
4.23e4.29 (m, 1H, H-4), 4.90 (br s, 1H, NeH), 5.08 (br s, 1H, OeH).
NMR (100 MHz, CDCl3):
d¼13.9, 22.6, 28.3, 28.3, 31.7, 42.3, 48.2,
51.9, 60.1, 65.0, 70.2, 77.0, 80.3, 92.2, 115.4, 121.0, 161.3. Anal. Calcd
for C21H38N2O8 C, 56.48; H, 8.58; N, 6.27. Found: C, 56.40; H, 8.68;
N, 6.22.
13C NMR (100 MHz, CDCl3):
d¼12.4, 14.6, 32.6, 38.9, 52.7, 56.7, 61.4,
64.8, 80.3, 90.9, 113.2, 153.1, 157.1, 165.8. Anal. Calcd for C16H26N2O6:
C, 56.13; H, 7.65; N, 8.18. Found: C, 55.92; H, 7.87; N, 8.32.
Acknowledgements
3.6.3. Ethyl (3aS*,4R*,6S*,7R*,7aS*)-7-(tert-butoxycarbonylamino)-
4-hydroxy-3-methyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazole-6-
carboxylate (16). A white solid, yield 88% (790 mg); mp 118e119 ꢀC;
We are grateful to the Hungarian Research Foundation (OTKA
No. NK81371 and KI00530) for financial support and acknowledge
the receipt of a Bolyai Janos Fellowship for L.K.
Rf¼0.29 (n-hexaneeEtOAc 1:3); 1H NMR (400 MHz, CDCl3):
¼1.30
d
ꢀ
(t, 3H, CH3, J¼7.1 Hz), 1.46 (s, 9H, CH3), 1.89e2.00 (m, 2H, CH2), 2.09
(s, 3H, CH3), 2.65e2.75 (m, 1H, H-6), 2.89e3.05 (m, 1H, H-7),
3.09e3.17 (m, 1H, H-3a), 3.77e3.85 (m, 1H, H-7a), 4.11e4.29 (m, 2H,
OCH2), 4.45e4.57 (m, 1H, H-4), 4.61 (dd, 1H, NeH, J¼3.1 Hz), 5.00
References and notes
(d, 1H, OeH, J¼9.2 Hz). 13C NMR (100 MHz, CDCl3):
d
¼13.4, 14.4,
€ € ꢀ € €
1. (a) Kiss, L.; Fulop, F. Synlett 2010, 1302; (b) Palko, M.; Kiss, L.; Fulop, F. Curr. Med.
Chem. 2005, 12, 3063; (c) Kiss, L.; Forro, E.; Fulop, F. In Synthesis of Carbocyclic
Amino Acids; Hughes, A. B., Ed.; Amino Acids, Peptides and Proteins in Organic
Chemistry; Wiley: Weinheim, 2009; Vol. 1, p 367; (d) Fulop, F. Chem. Rev. 2001,
ꢀ
€ €
b
-
28.6, 33.6, 42.5, 49.7, 56.8, 61.7, 67.9, 80.2, 81.2, 155.5, 161.4, 174.6.
Anal. Calcd for C16H26N2O6: C, 56.13; H, 7.65; N, 8.18. Found: C,
56.32; H, 7.46; N, 8.39.
€ €
101, 2181.
2. (a) Ishikawa, H.; Suzuki, T.; Orita, H.; Uchimaru, T.; Hayashi, Y. Chem.dEur. J.
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3.7. General procedure for isoxazoline ring-opening. Synthe-
sis of compounds 10, 11 and 17
To a solution of 8 or 9 or 15 (1.16 mmol) in 8 mL of EtOH/THF
(3:1), NiCl2 (2.32 mmol) and Boc2O (2.32 mmol) were added. After
stirring for 10 min, NaBH4 (2.32 mmol) was added in portions, the
reaction mixture was stirred at room temperature for 6 h and the
reaction was then quenched with H2O (5 mL). The reaction mixture
was filtered through a silica pad and the filtrate was evaporated in
vacuo. The crude residue was diluted with H2O (30 mL), washed
with EtOAc (3ꢂ15 mL), dried over Na2SO4 and concentrated under
reduced pressure. The residue was then purified by column chro-
matography on silica gel (n-hexaneeEtOAc), giving 10, 11 or 17.
4. (a) Watson, K. G.; Cameron, R.; Fenton, R. J.; Gower, D.; Hamilton, S.; Jin, B.;
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Chem. Pharm. Bull. 2003, 51, 1386; (e) Wyatt, P. G.; Coomber, B. A.; Evans, D. N.;
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Chem. Lett. 2001, 11, 669; (f) Lew, W.; Wu, H.; Chen, X.; Graves, B. J.; Escarpe, P.
A.; MacArthur, H. L.; Mendel, D. B.; Kim, C. U. Bioorg. Med. Chem. Lett. 2000, 10,
1257; (g) Kipassa, N. T.; Okamura, H.; Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett.
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3.7.1. Ethyl (1R*,2R*,3S*,4S*,5S*)-2-(tert-butoxycarbonylamino)-4-
(1-(tert-butoxycarbonyl)ethyl)-3,5-dihydroxycyclohexanecarboxylate
(10). A white solid, yield 58% (300 mg); mp 70e71 ꢀC; Rf¼0.29 (n-
hexaneeEtOAc 1:3); 1H NMR (400 MHz, CDCl3):
d
¼1.25e1.32 (m,
3H, CH3), 1.37 (d, 3H, CH3, J¼7.0 Hz), 1.47 (s, 9H, CH3), 1.49 (s, 9H,
CH3), 2.32e2.40 (m, 1H, CH2), 2.76e2.83 (m, 1H, CH2), 3.81e4.00
(m, 3H, H-4, H-1, CH), 4.1e4.3 (m, 4H, OCH2, H-2, H-5), 4.34e4.41
(m, 1H, H-3), 4.60e4.69 (m, 1H, NeH), 4.95 (br s, 1H, NeH). 13C NMR
(100 MHz, CDCl3):
d
¼14.4, 18.7, 28.7, 28.8, 30.1, 39.5, 44.6, 52.1, 61.6,
63.0, 67.0, 70.7, 80.1, 80.6, 157.7, 173.6, 174.1. (ESI) m/z¼469 (MþNa).
Anal. Calcd for C21H38N2O8: C, 56.48; H, 8.58; N, 6.27. Found: C,
56.30; H, 8.38; N, 6.40.
5. (a) Roberts, S.; Chittapragada, M.; Pendem, K.; Leavitt, B. J.; Mahler, J. W.; Ham,
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brano, V.; Zanardi, F.; Battistini, L.; Marzocchi, L.; Acquotti, D.; Casiraghi, G. J.
ꢀ
ꢀ
ꢀ
Org. Chem. 2002, 67, 5338; (c) Fernandez, F.; Estevez, A. M.; Estevez, J. C.;
ꢀ
3.7.2. Ethyl (1S*,2R*,3S*,4S*,5S*)-2-(tert-butoxycarbonylamino)-4-
(1-(tert-butoxycarbonylamino)ethyl)-3,5-dihydroxycyclohexanecarbo-
xylate (11). A white solid, yield 78% (400 mg); mp: 72e73 ꢀC;
Rf¼0.23 (n-hexaneeEtOAc 1:2); 1H NMR (400 MHz, CDCl3):
Estevez, R. J. Tetrahedron: Asymmetry 2009, 20, 892.
6. (a) Conti, P.; Caligiuri, A.; Pinto, A.; Roda, G.; Tamborini, L.; Nielsen, B.; Madsen,
U.; Frydenvang, K.; Colombo, A.; De Micheli, C. Eur. J. Med. Chem. 2007, 42, 1059;
(b) Mineno, T.; Miller, M. J. J. Org. Chem. 2003, 68, 6591; (c) Park, K.-H.; Olm-
stead, M. M.; Kurt, M. J. J. Org. Chem. 1998, 63, 113; (d) Park, K.-H.; Kurt, M. J. J.
Org. Chem. 2000, 65, 3520; (e) Quadrelli, P.; Piccanello, A.; Martinez, N.-V.;
Bovio, B.; Mella, M.; Caramella, P. Tetrahedron 2006, 62, 7370; (f) Pinto, A.;
Conti, P.; De Amici, M.; Tamborini, L.; Grazioso, G.; Colleoni, S.; Mennini, T.;
Gobbi, M.; De Micheli, C. Tetrahedron: Asymmetry 2008, 19, 867; (g) Quadrelli,
P.; Piccanello, A.; Mella, M.; Corsaro, A.; Pistara, V. Tetrahedron 2008, 64, 3541;
(h) Quadrelli, P.; Bovio, B.; Piccinini, A.; Caramella, P.; De Sarlo, F.; Machetti, F.
Tetrahedron 2009, 65, 10679; (i) Roda, G.; Conti, P.; De Amici, M.; He, J.; Pola-
varapu, P. L.; De Micheli, C. Tetrahedron: Asymmetry 2004, 15, 3079.
7. (a) Chand, P.; Kotian, P. L.; Dehghani, A.; El-Kattan, Y.; Lin, T.-H.; Hutchison, T. L.;
Babu, Y. S.; Bantia, S.; Elliott, A. J.; Montgomery, J. A. J. Med. Chem. 2001, 44,
4379; (b) Chand, P.; Babu, Y. S.; Bantia, S.; Rowland, S.; Dehghani, A.; Kotian, P.
L.; Hutchison, T. L.; Ali, S.; Brouillette, W.; El-Kattan, Y.; Lin, T.-H. J. Med. Chem.
2004, 47, 1919; (c) Yi, X.; Guo, Z.; Chu, F. M. Bioorg. Med. Chem. 2003, 11, 1465;
(d) Oakley, A. J.; Barrett, S.; Peat, T. S.; Newman, J.; Streltsov, V. A.; Waddington,
L.; Saito, T.; Tashiro, M.; McKimm-Breschkin, J. L. J. Med. Chem. 2010, 53, 6421;
(e) Chand, P.; Bantia, S.; Kotian, P. L.; El-Kattan, Y.; Lin, T.-H.; Babu, Y. S. Bioorg.
Med. Chem. Lett. 2005, 13, 4071.
d
¼1.21e1.35 (m, 6H, CH3), 1.41e1.47 (m, 18H, CH3), 1.50e1.62 (m,
3H, CH2, H-1), 2.27e2.37 (m, 1H, H-4), 2.72e2.78 (m, 1H, CH), 3.82
(br s, 1H, NeH), 3.89e3.95 (m, 1H, H-5), 4.06e4.25 (m, 3H, OCH2, H-
2), 4.30e4.37 (m, 1H, H-3), 4.61 (br s, 1H, NeH). 13C NMR (100 MHz,
CDCl3):
d
¼13.9, 22.6, 28.1, 28.3, 31.7, 42.3, 48.2, 51.9, 60.1, 65.1, 72.4,
77.0, 80.6, 92.2, 115.4, 121.0, 161.3. Anal. Calcd for C21H38N2O8 C,
56.48; H, 8.58; N, 6.27. Found: C, 56.36; H, 8.68; N, 6.30.
3.7.3. Ethyl (1S*,2R*,3S*,4S*,5R*)-2-(tert-butoxycarbonylamino)-4-
(1-(tert-butoxycarbonylamino)ethyl)-3,5-dihydroxycyclohex-
anecarboxylate (17). A white solid, yield 87% (450 mg); mp:
75e76 ꢀC; Rf¼0.63 (n-hexaneeEtOAc 1:5); 1H NMR (400 MHz,
CDCl3):
d¼1.21e1.31 (m, 6H, CH3), 1.43e1.46 (m, 18H, CH3),