1946
G. Cremonesi et al. / Tetrahedron: Asymmetry 20 (2009) 1940–1947
4.17. (2S)-[(2R)-Amino-3-methyl-butyrylamino]-(3S)-hydroxy-
3-[(5R)-5-phenyl-4,5-dihydroisoxazol-3-yl]-propionic acid
methyl ester 13
2.70 (4H, broad, 2OH, NH2); 3.10–3.21 (3H, m, 5-H and 20-H); 3.81
(3H, s, OCH3); 4.79 (1H, broad d, J = 1.8, 3-H); 5.16 (2H, m, 2-H and
6-H); 7.20–7.40 (5H, m, Ph); 7.90 (1H, broad d, J = 9.1, NH–CO). 13C
NMR: d 16.00, 19.54 (CH(CH3)2); 30.91 (CH(CH3)2); 47.24 (5-C);
53.04 (OCH3); 53.54 (20-C); 60.00 (2-C); 70.25 (6-C); 77.56 (3-C);
125.58, 127.86, 128.60, 142.64 (Ph); 169.47, 174.79, 208.51 (C@O
ester, ketone and amide). MS-FAB+ (m/z): 367 (MH+). IR (nujol):
Amorphous solid (58%); Rf = 0.16 (ethyl acetate/methanol =
95:5); ½a 2D0
ꢁ
¼ ꢀ80:7 (c 0.32, CHCl3). 1H NMR: d 0.86, 0.99 (6H, 2d,
J = 6.8, CH(CH3)2); 2.24 (1H, m, CH(CH3)2); 2.51–2.70 (3H, broad,
OH, NH2); 2.96 (1H, dd, J = 17.0, 9.0, 4-H isox.); 3.34 (1H, m, 20-
H); 3.62 (1H, dd, J = 17.0, 10.7, 4-H isox.); 3.77 (3H, s, OCH3);
4.94 (1H, dd, J = 8.4, 2.3, 2-H); 5.00 (1H, broad d, J = 2.3, 3-H);
5.60 (1H, dd, J = 10.7, 9.0, 5-H isox.); 7.25–7.50 (5H, m, Ph); 8.21
(1H, d, J = 8.4, NH–CO); (by deuteration the signals at 2.51–2.7
and 8.21 disappeared and the signals at 3.34, 4.94 and 5.00 turned
into three doublets with J = 4.3, 2.3 and 2.3, respectively). 13C NMR:
d 16.13, 19.53 (CH(CH3)2); 31.01 (CH(CH3)2); 42.88 (4-C-isox.);
52.87 (OCH3); 54.66 (20-C); 60.04 (2-C); 69.46 (3-C); 83.09 (5-C-
isox.); 125.87, 128.28, 128.71, 140.13 (Ph); 158.30, 169.89,
175.15 (C@N, C@O ester and amide). MS-FAB+ (m/z): 364 (MH+).
3355 (mOH, mNH, OH, NH2), 1744, 1723, 1663 (vC@O, C@O ketone, es-
ter, amide).
4.21. Single crystal X-ray structural determination of 8
The intensity data for 8 were collected on a Bruker Smart Apex
CCD area detector using graphite-monochromated Mo Ka radiation
(k = 0.71073 Å). Data reduction was made using SAINT programs;
absorption corrections based on multiscan were obtained by
28
SADABS
.
The structures were solved by SIR-9229 and refined on F2
by full-matrix least-squares using SHELXL-97.30 All the non-hydro-
gen atoms were refined anisotropically, hydrogen atoms were in-
cluded as 0riding0 and not refined. The ORTEP-III program was
used for molecular diagrams.31
IR (nujol): 3340 (mOH, mNH, OH, NH2), 1748 (vC@O, C@O), 1664 (vC@N,
C@N).
4.18. (2R)-Amino-[(3R)-hydroxy-3-(5R)-5-phenyl-4,5-dihydro-
isoxazol-3-yl]-propionic acid methyl ester 14
Crystal data and results of the refinement: colourless prism
0.40 ꢂ 0.35 ꢂ 0.15 mm, Mr = 359.42, orthorhombic, space group
P212121, a = 7.0333(7) Å, b = 11.112(1) Å, c = 24.773(3) Å, V = 1936.1
Oil (56%); Rf = 0.39 (ethyl acetate/methanol = 95:5); ½a D20
¼ ꢀ99:7
ꢁ
(3) Å3, Z = 4, T = 293(2) K,
l
= 0.087 mmꢀ1. 27,891 measured reflec-
(c 0.30, CHCl3). 1H NMR: d 2.45 (3H, broad m, OH, NH2); 3.03 (1H, dd,
J = 17.3, 8.5, 4-H isox.); 3.58 (1H, dd, J = 17.3, 11.0, 4-H isox.); 3.78 (3H,
s, OCH3); 4.03 (1H, m, 2-H); 4.71 (1H, d, J = 2.9 3-H); 5.60 (1H, dd,
J = 11.0, 8.5, 5-H isox.); 7.22–7.55 (5H, m, Ph). 13C NMR: d 43.13
(4-C-isox.); 52.60 (OCH3); 56.24 (2-C); 68.55 (3-C); 82.41 (5-C-isox.);
125.83, 128.23, 128.72, 140.57 (Ph); 158.87, 172.84 (C@N, C@O).
tions, 2541 independent reflections, 2195 reflections with I > 2r(I),
3.28 < 2h <55.00°, Rint = 0.0241. Refinement on 2541 reflections,
242 parameters. Flack parameter32 for determination of the absolute
configuration = ꢀ3.0(13). Final R = 0.0366, wR = 0.0957 for data with
F2 > 2
r D/r)max = 0.001, Dqmax = 0.103, Dqmin =
(F2), S = 1.069, (
ꢀ0.118 eÅꢀ3
.
MS-FAB+ (m/z): 265 (MH+). IR (nujol): 3435 (mOH
1723 (vC@O, C@O), 1641 (vC@N, C@N).
, mNH, OH, NH2),
Crystallographic data (excluding structure factors) for 8 have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 736008. Copies of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-1223-336033;
e-mail: deposit@ccdc.cam.ac.uk).
4.19. (2R)-[(2R)-Amino-3-methyl-butyrylamino]-(3R)-hydroxy-
3-[(5R)-5-phenyl-4,5-dihydroisoxazol-3-yl]-propionic acid
methyl ester 15
Oil (34%); Rf = 0.14 (ethyl acetate/methanol = 95:5); ½a D20
¼ ꢀ35:3
ꢁ
(c 0.15, CHCl3). 1H NMR: d 0.80, 0.97 (6H, 2d, J = 6.9, CH(CH3)2);
2.24 (1H, m, CH(CH3)2); 2.00–2.40 (3H, broad, OH, NH2); 3.00–
3.60 (3H, m, 4-H isox. and 20-H); 3.80 (3H, s, OCH3); 4.90 (1H, dd,
J = 8.7, 3.0, 2-H); 4.99 (1H, broad d, J = 3.0, 3-H); 5.61 (1H, t,
J = 10.4, 5-H isox.); 7.25–7.40 (5H, m, Ph); 8.10 (1H, d, J = 8.7,
NH–CO); (by deuteration the signals at 2.00–2.40 and 8.10 disap-
peared and the signals at 4.90 and 4.99 turned into two doublets
with J = 3.0 and 3.0, respectively). 13C NMR: d 16.15, 19.66 (CH
(CH3)2); 30.84 (CH(CH3)2); 42.30 (4-C-isox.); 52.98 (OCH3); 54.63
(20-C); 60.13 (2-C); 69.44 (3-C); 83.51 (5-C-isox.); 126.31, 128.43,
128.69, 140.22 (Ph); 158.34, 170.07, 175.32 (C@N, C@O ester and
Acknowledgement
The authors thank Dr. Christian Invernizzi for his helpful tech-
nical assistance.
References
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NH2), 1743 (vC@O, C@O), 1658 (vC@N, C@N).
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4.20. (2S,3S,6R)-2-[(2R)-2-Amino-3-methyl-butyrylamino]-3,6-
dihydroxy-4-oxo-6-phenyl-hexanoic acid methyl ester 16
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To a solution of 13 (0.4 mmol, 1 equiv) in 5/1 methanol/water
(10 mL), were added boric acid (1.2 mmol, 3 equiv) and a spatula
tip of Raney-Ni. The mixture was stirred vigorously under hydro-
gen for 3 h, and then filtered through Celite. After evaporation of
the solvent, the residue was treated with brine and extracted with
ethyl acetate (5 ꢂ 10 mL). The combined organic layers were dried
over Na2SO4 and concentrated in vacuo. Compound 16 was pure
enough for the spectroscopic and analytical characterisation.
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Amorphous solid (55%); ½a D20
ꢁ
¼ þ60:6 (c 0.42, CHCl3). 1H NMR: d
0.81, 0.96 (6H, 2d, J = 6.9, CH(CH3)2); 2.25 (1H, m, CH(CH3)2); 2.20–