(3R*,4S*)-2-[2-ter t-Bu t yl-3-(4-ch lor op h en yl)-4-m et h yl-
[1,2]o x a ze t id in -4-y l]-4,4-d im e t h y l-4,5-d ih y d r o -1,3-o x -
a zole (4d ). White solid. Mp: 96-98 °C (hexane), 48%. 1H NMR
(500 MHz): δ ) 1.05 (s, 9 H), 1.24 (s, 3 H), 1.28 (s, 3 H), 1.31 (s,
3 H), 4.01 (m, 2 H), 5.42 (s, 1 H), 7.29-7.31 (m, 2 H), 7.46-7.47
(m, 2 H). 13C NMR (125 MHz) δ ) 21.2, 23.6, 28.1, 59.2, 65.0,
67.4, 77.8, 79.8, 128.3, 128.8, 133.4, 136.0, 165.3. MS (ESI) m/z:
9 H), 1.25 (s, 3 H), 1.78 (octet, J ) 6.7 Hz, 1 H), 4.03-4.09 (m,
2 H), 4.29 (dd, J ) 9.1, 7.9 Hz, 1 H), 7.30-7.31 (m, 2 H), 7.46-
7.48 (m, 2 H). 13C NMR (125 MHz): δ ) 17.9, 18.4, 21.3, 23.7,
32.4, 59.1, 65.4, 70.7, 71.8, 78.0, 128.3, 128.8, 133.4, 136.0, 166.8.
MS (ESI) m/z: 373 [M + Na]+ (100), 351 [M + H]+ (7). FT-IR
(KBr) cm-1: 2966, 1679 (CdN), 1364, 1097, 966. Anal. Calcd
for C19H27ClN2O2: C, 65.04; H, 7.76; N, 7.98. Found: C, 64.76;
H, 7.73; N, 8.03.
(4R,3′R,4′S)-(-)-10c. 90%. [R]D: -2.6 (c 1, CHCl3); ee > 96%
ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external
standard) in the presence of the CSA (R)-(-)-2,2,2-trifluoro-1-
phenylethanol, (CSA/oxazetidine molar ratio ) 3/1), δ: 1.16
(major, 9 H), 1.19 (minor, 9 H), 5.55 (major, 1 H), 5.57 (minor,
1 H).
(E)-2-(2-Cycloh exyl-1-m eth ylvin yl)-4,4-d im eth yl-4,5-d i-
h yd r o-1,3-oxa zole (6). Oil, 25%. 1H NMR (300 MHz): δ )
1.06-1.50 (m, 6 H), 1.25 (s, 6 H), 1.63-1.75 (m, 5 H), 1.92-1.93
(d, J ) 1.4 Hz, 3 H), 3.95 (s, 2 H), 6.23-6.26 (d, J ) 9.6 Hz, 1
H). 13C NMR (75 MHz): δ ) 26.1, 27.3, 27.9, 28.6, 31.0, 32.6,
44.0, 46.0, 59.5, 66.4, 70.5, 122.9, 143.4, 165.4. GC MS (70 eV)
m/z: 221 [M+] (57), 206 (100), 140 (22), 124 (57). FT-IR (film)
cm-1: 2926, 1666 (CdN), 1450, 1364.
337 [M + H]+ (100), 359 [M + Na]+ (38). FT-IR (KBr) cm-1
2977, 1655 (CdN), 1486, 1364, 1102. Anal. Calcd for C18H25
:
-
ClN2O2: C, 64.18; H, 7.48; N, 8.32. Found: C, 64.22; H, 7.77; N,
8.17.
(3R*,4R*)-2-[2-ter t-Bu t yl-3-(4-ch lor op h en yl)-4-m et h yl-
[1,2]o x a ze t id in -4-y l]-4,4-d im e t h y l-4,5-d ih y d r o -1,3-o x -
a zole (5d ). White solid. Mp 103-105 °C (hexane), 32%. 1H NMR
(500 MHz): δ ) 0.76 (s, 3 H), 1.06 (s, 9 H), 1.09 (s, 3 H), 1.72 (s,
3 H), 3.52-3.57 (2 × d, AB system, J ) 8.0 Hz, 2 H), 4.90 (s, 1
H), 7.24-7.25 (m, 2 H), 7.42-7.44 (m, 2 H). 13C NMR (125 MHz)
δ ) 23.7, 24.5, 27.9, 59.0, 67.2, 70.0, 79.2, 80.3, 127.9, 128.9,
133.6, 136.0, 164.6. MS (ESI) m/z: 337 [M + H]+ (100), 359 [M
+ Na]+ (38). FT-IR (KBr) cm-1: 2972, 1661 (CdN), 1489, 1365,
1192, 1089. Anal. Calcd for C18H25ClN2O2: C, 64.18; H, 7.48; N,
8.32. Found: C, 64.47; H, 7.74; N, 8.30.
Spirocyclic compound 7 was obtained following the same
general procedure just described for the preparation of oxazolinyl-
[1,2]oxazetidines but quenching the reaction mixture 10 min
after nitrone addition.
(()-2-(2-ter t-Bu t yl-4-m et h yl-3-p h en yl[1,2]oxa zet id in -4-
yl)-4-isop r op yl-4,5-d ih yd r o-1,3-oxa zole (10a ). White solid.
1
Mp: 55-56 °C (hexane) 90%. H NMR (300 MHz): δ ) 0.89 (d,
J ) 6.7 Hz, 3 H), 0.95 (d, J ) 7.3 Hz, 3 H), 1.08 (s, 9 H), 1.30 (s,
3 H), 1.79 (octet, J ) 6.0 Hz, 1 H), 4.02-4.10 (m, 2 H), 4.30-
4.33 (m, 1 H), 5.47 (s, 1 H), 7.32-7.35 (m, 3 H), 7.52-7.53 (m,
2 H). 13C NMR (125 MHz): δ ) 17.8, 17.9, 18.5, 21.4, 23.8, 32.5,
59.1, 66.0, 70.7, 71.8, 78.2, 127.5, 128.1, 137.4, 167.0. MS (ESI)
m/z: 317 [M + H]+. FT-IR (KBr) cm-1: 2964, 1674 (CdN), 1362,
1259, 1100. Anal. Calcd for C19H28N2O2: C, 72.12; H, 8.92; N,
8.85. Found: C, 72.22; H, 8.77; N, 8.87.
(3R*,3S*,5R*)-2-ter t-Bu t yl-4-ch lor o-3-(4-ch lor op h en yl)-
4,8,8-t r im et h yl-1,6-d ioxa -2,9-d ia za sp ir o[4,4]n on a n e (7).
White solid. Mp: 122-124 °C (hexane), 35%. 1H NMR (300
MHz): δ ) 0.98 (s, 9 H), 1.22 (s, 3 H), 1.36 (s, 3 H), 1.41 (s, 3 H),
2.20-2.50 (br. s, exchanges with D2O, 1 H), 3.69 (d, J ) 7.6 Hz,
1 H), 3.87 (d, J ) 7.6 Hz, 1 H), 4.37 (s, 1 H), 6.99-7.01 (m, 1 H),
7.21-7.31 (m, 2 H), 7.84-7.86 (m, 1 H). 13C NMR (75 MHz): δ
) 21.5, 27.1, 27.8, 28.5, 56.6, 60.1, 70.4, 78.9, 79.2, 120.6, 127.8,
128.1, 129.2, 132.3, 133.9, 136.9. MS (ESI) m/z: 373 [M + H]+
(100), 395 [M + Na]+ (23). FT-IR (KBr) cm-1: 2971, 1382, 1363,
1084, 1011, 873. Anal. Calcd for C18H26ClN2O2: C, 57.91; H, 7.02;
N, 7.50. Found: C, 57.62; H, 7.31; N, 7.60.
Red u ction of Oxa zolin yl[1,2]Oxa zetid in e 4a . To a solu-
tion of 4a (1.0 mmol) in methanol (10 mL) was added Pd on
charcoal (10% w/w) and the resulting mixture hydrogenated in
a “Bu¨chi Mini Clave” apparatus at 20 bar overnight. Then the
solution was filtered on Celite pad and the solvent evaporated
in vacuo affording the amino alcohol 13 that was purified by
crystallization from hexane.
(4R,3′R,4′S)-(-)-10a . 72%. [R]D: -15 (c 1, CHCl3), ee > 96%
ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external
standard) in the presence of the CSA (R)-(-)-2,2,2-trifluoro-1-
phenylethanol, (CSA/oxazetidine molar ratio ) 3/1), δ: 1.18
(major, 9 H), 1.20 (minor, 9 H), 5.55 (major, 1 H), 5.59 (minor,
1 H).
(4S,3′S,4′R)-(+)-10a . 90%. [R]D: +13 (c 1, CHCl3), ee > 96%
ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external
standard) in the presence of the CSA (R)-(-)-2,2,2-trifluoro-1-
phenylethanol, (CSA/oxazetidine molar ratio ) 3/1), δ: 1.18
(minor, 9 H), 1.20 (major, 9 H), 5.55 (minor, 1 H), 5.59 (major,
1 H).
(1R*,2R*)-1-ter t-Bu t yla m in o-1-p h en yl-2-(4,4-d im et h yl-
4,5-d ih yd r o-1,3-oxa zol-2-yl)-2-p r op a n ol (13). White solid.
Mp: 83-84 °C (hexane), 98%. 1H NMR (500 MHz): δ ) 0.86 (s,
9 H), 1.03 (s, 3 H), 1.16 (s, 3 H), 1.23 (s, 3 H), 3.92 (s, 1 H), 3.95
(d, J ) 8 Hz, 1 H), 3.98 (d, J ) 8 Hz, 1 H), 7.14-7.25 (m, 5 H).
13C NMR (125 MHz): δ ) 23.0, 28.3, 30.4, 51.1, 62.2, 67.0, 73.9,
80.3, 127.0, 127.9, 128.3, 142.4, 169.2. MS (ESI) m/z: 305 [M +
H]+ (100). FT-IR (KBr) cm-1: 3347, 3218, 2968, 1665, 1164, 1093,
712. Anal. Calcd for C18H28N2O2: C, 71.02; H, 9.27; N, 9.20.
Found: C, 71.22; H, 9.33; N, 9.15.
(()-2-[2-ter t-Bu tyl-3-(4-tr iflu or om eth ylp h en yl)-4-m eth yl-
[1,2]oxa zet id in -4-yl]-4-isop r op yl-4,5-d ih yd r o-1,3-oxa zole
(10b). White solid. Mp: 66-67 °C (hexane), 93%. 1H NMR (500
MHz): δ ) 0.80 (d, J ) 6.7 Hz, 3 H), 0.86 (d, J ) 6.8 Hz, 3 H),
0.99 (s, 9 H), 1.17 (s, 3 H), 1.79 (octet, J ) 6.1 Hz, 1 H), 4.03-
4.12 (m, 2 H), 4.33 (dd, J ) 9.8, 8.5 Hz, 1 H), 5.54 (s, 1 H), 7.60-
7.68 (m, 4 H). 13C NMR (125 MHz): δ ) 17.9, 18.4, 21.5, 23.6,
32.5, 59.2, 65.6, 70.8, 71.8, 78.0, 124.0 (q, 1J CF ) 272.0 Hz), 125.1
(q, 3J CF ) 3.8 Hz), 127.8, 129.8 (q, 2J CF ) 32.0 Hz), 141.5, 166.7.
MS (ESI) m/z: 407 [M + Na]+ (100), 385 [M + H]+ (20). FT-IR
(KBr) cm-1: 2965, 1679 (CdN), 1329, 1165, 1129,1096. Anal.
Calcd for C20H27F3N2O2: C, 62.48; H, 7.08; N, 7.29. Found: C,
62.32; H, 7.07; N, 7.17.
(4R,3′R,4′S)-(-)-10b. 93%. [R]D: -18 (c 1, CHCl3), ee > 96%
ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external
standard) in the presence of the CSA (R)-(-)-2,2,2-trifluoro-1-
phenylethanol, (CSA/oxazetidine molar ratio ) 3/1), δ: 1.15
(major, 9 H), 1.16 (minor, 9 H), 5.63 (major, 1 H), 5.66 (minor,
1 H).
(4S,3′S,4′R)-(+)-10b. 90%. [R]D: +22 (c 1, CHCl3), ee > 96%
ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external
standard) in the presence of the CSA (R)-(-)-2,2,2-trifluoro-1-
phenylethanol, (CSA/oxazetidine molar ratio ) 3/1), δ: 1.15
(minor, 9 H), 1.16 (major, 9 H), 5.63 (minor, 1 H), 5.66 (major,
1 H).
(()-2-[2-t er t -Bu t yl-3-(4-ch lor op h e n yl)-4-m e t h yl[1,2]-
oxa zetid in -4-yl]-4-isop r op yl-4,5-d ih yd r o-1,3-oxa zole (10c).
White solid. Mp: 98-99 °C (hexane). 55%. 1H NMR (500 MHz):
δ ) 0.87 (d, J ) 6.7 Hz, 3 H), 0.93 (d, J ) 6.7 Hz, 3 H), 1.05 (s,
Ack n ow led gm en t. This work was carried out under
the framework of the National Project “Stereoselezione
in Sintesi Organica, Metodologie ed Applicazioni” and
the FIRB Project “Progettazione, preparazione e valuta-
zione biologica e farmacologica di nuove molecole orga-
niche quali potenziali farmaci innovativi” supported by
the Ministero dell’Istruzione, dell’Universita` e della
Ricerca (MIUR, Rome), and by the University of Bari
and CNR (Rome). We are also grateful to Prof. Marcel
Pierrot of the Centre Scientifique Saint-J erome,
Marseille, France, for performing the X-ray analysis on
compound (-)-10c.
Su p p or tin g In for m a tion Ava ila ble: Copy of the 1H NMR
spectrum of compound 6 and ORTEP view of compound (-)-
10c. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O035360U
10190 J . Org. Chem., Vol. 68, No. 26, 2003