The Journal of Organic Chemistry
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1H), 1.92−1.53 (m, 5H), 1.40−1.33 (m, 1H); 13C NMR (100 MHz,
DMSO, 70 °C) δ 157.2, 136.1, 128.8, 128.1, 126.1, 125.3, 124.7, 65.1,
63.0, 58.3, 57.1, 46.6, 38.8, 36.1, 33.8, 29.7, 28.5, 25.3; MS (ESI) m/z
(relative intensity) 379.08 ([M + H]+ 66%); HRMS (ESI) m/z calcd
for C20H27N2O3NaCl 401.1608 ([M + Na]+); found 401.1600.
(R)-4-Benzyl-3-((S)-3-chloro-1-((1R,6S)-6-(chloromethyl)-
cyclohex-3-enyl)propan-2-ylamino)oxazolidin-2-one (30a).
From hydrazone 26a (46 mg, 0.13 mmol) and chloroiodomethane
(0.09 mL, 1.3 mmol) by General Procedure B was obtained 30a (26
mg, 49% yield) as a colorless oil; [α]23D +6.0 (c 0.9 CHCl3); IR (film)
3286, 3026, 2916, 1754, 1432, 1401, 1218, 1092, 1027 cm−1; 1H NMR
(300 MHz, CDCl3) δ 7.35−7.23 (m, 3H), 7.18−7.16 (m, 2H), 5.67−
5.59 (m, 2H), 4.15 (dd, J = 8.8, 7.5 Hz, 2H), 4.05 (dd, J = 8.9, 5.2 Hz,
1H), 3.96−3.88 (m, 1H), 3.70−3.57 (m, 4H), 3.44 (dd, J = 13.5, 3.6
Hz, 1H), 3.41−3.34 (m, 1H), 2.61 (dd, J = 13.3, 10.1 Hz, 1H), 2.26−
2.08 (m, 3H), 2.05−1.76 (m, 4H) 1.39 (ddd, J = 14.1, 7.7, 6.6 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 159.4, 135.9, 129.3, 129.2, 127.3,
125.23, 125.15, 66.4, 60.0, 58.5, 48.3, 46.2, 39.0, 37.2, 34.4, 30.7, 29.1,
27.0; MS (ESI) m/z (relative intensity) 397.05 ([M + H]+ 100%);
HRMS (ESI) m/z calcd for C20H26N2O2NaCl2 ([M + Na]+)
419.1269; found 419.1294.
136.09, 128.8, 128.10, 128.09, 126.1 (2C), 65.1, 65.0, 63.4, 63.2, 58.5,
58.1, 57.3, 57.1, 47.4, 46.5, 44.2, 44.1, 36.1, 36.0, 34.6, 34.1, 34.0, 33.8,
31.5, 31.2, 28.8, 28.6, 25.0, 24.9 (2C), 24.7; MS (ESI) m/z (relative
intensity) 381.10 ([M + H]+ 81%), 403.16 ([M + Na]+, 100%). Anal.
Calcd for C20H29ClN2O3; C, 63.06; H, 7.67; N, 7.35. Found: C, 62.87;
H, 7.70; N, 7.33.
((1S,2R)-2-((S)-2-((S)-4-Benzyl-2-oxazolidin-3-ylamino)-3-
chloropropyl)cyclohexyl)methyl 4-Methylbenzenesulfonate
and ((1R,2S)-2-((S)-2-((S)-4-Benzyl-2-oxazolidin-3-ylamino)-3-
chloropropyl)cyclohexyl)methyl 4-Methylbenzenesulfonate
(31 and 31′). To a solution of 30e and 30e′ (dr 1:1, 70 mg, 0.18
mmol), triethylamine (0.1 mL, 0.27 mmol), and DMAP (2 mg, 0.02
mmol) in CH2Cl2 (2 mL) was added p-toluenesulfonyl chloride (42
mg, 0.22 mmol) at room temperature. After 4 h, the reaction mixture
was partitioned between CH2Cl2 and brine, dried (Na2SO4), and
concentrated. Flash chromatography (hexane/EtOAc (9:1 to 2:1)
afforded the separate diastereomers 31 and 31′ (1:1 ratio, 80 mg, 81%
yield). Relative configuration was not determined. More polar
diastereomer 31: Rf 0.5 (SiO2, 30% EtOAc/hexanes); [α]25 +24.4
D
(c 1.60 CHCl3); IR (film) 3295, 2925, 2855, 1755, 1598, 1448, 1400,
1358, 1175, 1096, 1028 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.78 (d,
J = 8.4 Hz, 2H), 7.34−7.23(m, 5H), 7.19−7.16 (m, 2H), 4.18−3.93
(m, 5H), 3.65 (dd, J = 11.7, 3.6 Hz, 1H), 3.49 (dd, J = 11.7, 3.9 Hz,
1H), 3.37−3.32 (m, 2H), 2.58 (dd, J = 13.3, 10.2 Hz, 1H), 2.43 (s,
3H), 1.83−1.68 (m, 4H), 1.38−1.11 (m, 8H), 1.10−0.90 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 158.9, 145.0, 135.9, 133.1, 130.0, 129.5,
129.1, 128.1, 127.3, 73.0, 68.2, 59.9, 58.0, 45.9, 42.1, 37.1, 35.1, 34.3,
32.2, 29.5, 25.6, 25.5, 21.9; MS (ESI) m/z (relative intensity) 557.10
([M + Na]+ 100%), 535.06 ([M + H]+, 47%). Less polar diastereomer
31′: Rf 0.6 (SiO2, 30% EtOAc/hexanes); [α]25D −25.3 (c 1.62 CHCl3);
IR (film) 3318, 2924, 2854, 1755, 1598, 1448, 1400, 1358, 1188, 1175,
1097, 1029 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz,
2H), 7.36−7.23(m, 5H), 7.20−7.17 (m, 2H), 4.15−3.94 (m, 6H), 3.61
(dd, J = 11.3, 3.6 Hz, 1H), 3.49 (dd, J = 11.2, 6.0 Hz, 1H), 3.34 (dd, J
= 13.4, 3.3 Hz, 1H), 3.36−3.25 (m, 1H), 2.60 (dd, J = 13.3, 10.0 Hz,
1H), 2.44 (s, 3H), 2.04−1.98 (m, 1H), 1.75−1.49 (m, 5H), 1.36−1.18
(m, 6H), 1.03−0.90 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 159.2,
145.1, 135.9, 133.0, 130.1, 129.3, 129.2, 128.1, 127.3, 72.8, 66.2, 60.5,
58.5, 47.4, 42.3, 37.2, 34.6, 34.5, 31.6, 29.6, 25.7, 25.6, 21.9; MS (ESI)
m/z (relative intensity) 557.11 ([M + Na]+ 100%), 535.06 ([M + H]+,
51%).
((1S,6R)-6-((S)-2-((R)-4-Benzyl-2-oxazolidin-3-ylamino)-3-
chloropropyl)-cyclohex-3-enyl)methyl Benzoate (30c). From
26c (80 mg, 0.18 mmol) and chloroiodomethane (0.13 mL, 1.8
mmol) by General Procedure B was obtained 30c (32 mg, 36% yield)
as a colorless oil; [α]23 +9.8 (c 0.23 CHCl3); IR (film) 3276, 2917,
D
2851, 1752, 1724, 1711, 1270, 1096 cm−1; 1H NMR (300 MHz,
CDCl3) δ 8.08−8.02 (m, 2H) 7.57−7.51 (m, 1H), 7.44−7.38 (m,
2H), 7.32−7.15 (m, 3H), 7.15−7.13 (m, 2H), 5.72−5.63 (m, 2H),
4.38−4.35 (m, 2H), 4.16−4.09 (m, 2H), 4.02 (dd, J = 8.8, 5.6 Hz,
1H), 3.93−3.85 (m, 1H), 3.64 (ABX, ΔνAB = 18.9, JAB = 11.5, JAX
=
4.4, JBX = 4.4 Hz, 2H), 3.47−3.40 (m, 1H), 3.39 (dd, J = 13.2, 3.6 Hz,
1H), 2.60 (dd, J = 13.3, 10.0, Hz, 1H), 2.34−2.21 (m, 2H), 2.09−1.80
(m, 5H), 1.50−1.40 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 166.9,
159.5, 135.8, 133.2, 129.8, 129.3, 129.22, 129.16, 128.6, 127.4, 125.5,
125.3, 67.0, 66.5, 60.0, 58.0, 46.0, 37.3, 36.7, 34.3, 31.0, 29.5, 26.6; MS
(ESI) m/z (relative intensity) 483.09 ([M + H]+ 57%); HRMS (ESI)
m/z calcd for C27H31N2O4NaCl 505.1870 ([M + Na]+); found
505.1886.
((1S,6R)-6-((S)-2-((R)-4-Benzyl-2-oxazolidin-3-ylamino)-3-
chloropropyl)-cyclohex-3-enyl)methyl Acetate (30d). From 26d
(85 mg, 0.23 mmol) and chloroiodomethane (0.16 mL, 2.3 mmol) by
General Procedure B was obtained 30d (32 mg, 33% yield) as a
colorless oil; [α]23D +9.4 (c 0.16 CHCl3); IR (film) 3285, 3227, 2916,
2848, 1755, 1737, 1729, 1453, 1365, 1240, 1030 cm−1; 1H NMR (300
MHz, CDCl3) δ 7.35−7.26 (m, 3H), 7.18−7.15 (m, 2H), 5.68−5.58
(1S,3R,4R,6R)-Di((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)
7-Oxa-bicyclo[4.1.0]-heptane-3,4-dicarboxylate (32). To a sol-
ution of (+)-4 (13.4 g, 30.2 mmol) in CH2Cl2 (200 mL) was added m-
chloroperbenzoic acid (50−60%, 15.6 g, 45.3 mmol). After 3 h, the
reaction mixture was diluted with CH2Cl2, washed successively with
saturated aqueous NaHCO3 and brine, dried (Na2SO4), and
concentrated. Flash chromatography (hexane/EtOAc 20:1 to 4:1)
(m, 2H), 4.18−4.02 (m, 5H), 3.95−3.86 (m, 1H), 3.65 (ABX, ΔνAB
=
17.9, JAB = 11.4, JAX = 4.4, JBX = 4.2 Hz, 2H), 3.43 (dd, J = 13.4, 3.2 Hz,
1H), 3.42−3.34 (m, 1H), 2.62 (dd, J = 13.2, 10.1 Hz, 1H), 2.24−2.09
(m, 2H), 2.08 (s, 3H), 2.08−1.75 (m, 5H), 1.46−1.35 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 171.5, 159.5, 135.9, 129.3, 129.2, 127.4,
125.4, 125.2, 66.61, 66.55, 60.1, 57.9, 46.0, 37.4, 36.2, 34.1, 30.7, 29.3,
26.4, 21.2; MS (ESI) m/z (relative intensity) 421.07 ([M]+, 53%);
HRMS (ESI) m/z calcd for C22H29N2O4NaCl 443.1714 ([M + Na]+);
found 443.1723.
afforded 32 (12 g, 86% yield) as a colorless oil; [α]24 +41.6 (c 2.88
D
CHCl3); IR (film) 2954, 2869, 1937, 1726, 1453, 1387, 1370, 1307,
1242, 1171, 1021 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.67−4.57 (m,
2H), 3.22−3.17 (m, 1H), 3.16 (dd, J = 4.5, 3.9 Hz, 1H), 2.80 (ddd, J =
10.4, 10.4, 4.9 Hz, 1H), 2.59 (ddd, J = 10.4, 10.4, 6.7, 1H), 2.45 (ddd, J
= 14.7, 4.8, 1.7 Hz, 1H), 2.29 (ddd, J = 15.4, 6.6, 4.7 Hz, 1H,), 2.06−
1.79 (m, 6H), 1.66−1.62 (m, 4H), 1.52−1.31 (m, 4H), 1.08−0.81 (m,
18H), 0.73−0.69 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 174.5,
173.5, 74.7 (2C), 52.0, 50.5, 47.1, 47.1, 40.8 (2C), 40.3, 37.9, 34.4,
34.4, 31.6, 31.5, 27.4, 26.6, 26.2, 26.1, 23.3 (2C), 22.2 (2C), 21.0, 21.0,
16.10, 16.08; MS (ESI) m/z (relative intensity) 485.25 ([M + Na]+
100%), 947.3 ([2M + Na]+, 68%). Anal. Calcd for C28H46O5: C, 72.69;
H, 10.02. Found: C, 72.91; H, 10.12.
(S)-4-Benzyl-3-((S)-3-chloro-1-((1R,2S)-2-(hydroxy-methyl)-
cyclohexyl)propan-2-ylamino)oxazolidin-2-one and (S)-4-Ben-
zyl-3-((S)-3-chloro-1-((1S,2R)-2-(hydroxymethyl)-cyclohexyl)-
propan-2-ylamino)oxazolidin-2-one (30e and 30e′). From 22a
(95 mg, 0.37 mmol) and iodide ( )-6b[H] (125 mg, 0.49 mmol) by
General Procedure B was obtained 30e and 30e′ (95 mg, 67% yield, dr
1:1); the diastereomers were inseparable but were separated upon
preparation of their O-tosylate derivatives (see below). Data for
diastereomer mixture: IR (film) 3335, 3291, 2921, 2851, 1754, 1402,
(1R,2R,4R,5R)-Di((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)
4-(Benzyloxy)-5-hydroxycyclohexane-1,2-dicarboxylate (33a).
To a solution of 32 (11 g, 23.8 mmol) and benzyl alcohol (12.8 g, 119
mmol) was added Cu(OTf)2 (1.72 g, 4.76 mmol). After 1 d, the
reaction mixture was diluted with CH2Cl2, washed successively with
water and brine, dried (Na2SO4), and concentrated. Flash chromatog-
raphy (hexane/EtOAc 9:1 to 4:1) provided 33a (12.1 g, 89% yield) as
1
1218, 1094 cm−1; H NMR (400 MHz, DMSO, 70 °C) δ 7.33−7.29
(m, 2H), 7.24−7.21 (m, 3H), 4.22−4.18 (m, 1H), 4.06−3.98 (m, 2H),
3.75−3.60 (m, 2H), 3.54−3.31 (m, 4H), 3.19−3.14 (m, 1H), 2.75−
2.68 (m, 1H), 1.94−1.89 (m, 0.5H), 1.83−1.71 (m, 2H), 1.69−1.60
(m, 2H), 1.60−1.48 (m, 0.5H), 1.33−1.10 (m, 6H), 1.03−0.94 (m,
1H); 13C NMR (100 MHz, DMSO, 70 °C) δ 157.2, 157.1, 136.11,
a colorless solid; mp 103−104 °C; [α]26 +48.7 (c 1.5, CHCl3); IR
D
(film) 3491, 2955, 2927, 2869, 1736, 1726, 1710, 1452, 1369, 1241,
3173
dx.doi.org/10.1021/jo2026349 | J. Org. Chem. 2012, 77, 3159−3180