The Journal of Organic Chemistry
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5.57 (d, 1H, J = 4.2 Hz), 5.40−5.23 (m, 1H), 4.96−4.81 (m, 3H),
3.96−3.92 (m, 2H), 3.70−3.46 (m, 4H), 2.44 (s, 3H), 1.51 (s, 3H),
1.49 (s, 3H), 1.24−1.16 (m, 6H); 13C NMR (50 MHz, CDCl3) δ
167.3, 143.3, 137.8, 135.4, 135.2, 129.9 (2C), 129.7 (2C), 128.2 (2C),
128.1 (2C), 127.6, 116.8, 106.3, 98.8, 73.3, 59.8, 58.3, 57.3, 48.6, 21.6,
18.5, 17.9, 15.3, 15.0. Anal. Calcd for C27H35NO7S: C, 62.65; H, 6.82;
N, 2.71. Found: C, 62.57; H, 6.95; N, 2.65.
General Procedure for the Synthesis of (2R*,3R*)-N-Tosyl-
isoserine Methyl Esters 12a,b. Compound 9a,b (1 mmol) was
dissolved in a 0.25 M solution of TMSCl in MeOH (2.0 mL, 1 mmol)
and stirred at 25 °C overnight. The solvent was then evaporated, and
1
the residue was diluted with AcOEt and washed with brine. H and
13C NMR spectra of compounds 12a,b completely matched the
literature data.23
(2R*,3R*)-Methyl 2-Hydroxy-3-(4-methylphenylsulfonami-
N-Allyl-N-{(S*)-[(2S*,5S*,6S*)(5,6-diethoxy-5,6-dimethyl-3-
oxo-[1,4]dioxan-2-yl)-(4-methoxy-phenyl)-methyl]}-4-methyl-
benzenesulfonamide (10b). Yield 542 mg, 99%; white solid, mp
do)-3-phenylpropanoate (12a). Yield 332 mg, 95%; pale yellow
1
wax. H NMR (200 MHz, CDCl3) δ 7.53−7.49 (d, 2H), 7.14−6.97
1
(m, 7 H), 5.75 (d, 1H, J = 9.5 Hz), 4.83 (dd, 1H, J = 9.5, 3.7 Hz), 4.52
(d, 1H, J= 3.7 Hz), 3.65 (s, 3H), 2.97 (bs, 1H), 2.32 (s, 3H); 13C
NMR (50 MHz, CDCl3) δ 171.7, 143.4, 137.8, 135.2, 129.5, 128.5,
128.4, 127.6, 127.2, 73.8, 59.4, 52.8, 21.6.
114−115 °C. H NMR (300 MHz, CDCl3) δ 7.82−7.78 (m, 2H),
7.33−7.26 (m, 4H), 6.71−6.66 (m, 2H), 5.49 (d, 1H, J = 4.2 Hz),
5.44−5.24 (m, 1H), 4.99−4.89 (m, 2H), 4.85 (d, 1H, J = 4.2 Hz),
3.96−3.91 (m, 2H), 3.74 (s, 3H), 3.69−3.46 (m, 4H), 2.44 (s, 3H),
1.50 (s, 3H), 1.49 (s, 3H), 1.20 (t, 3H, J = 7.0 Hz), 1.19 (t, 3H, J = 7.0
Hz); 13C NMR (75 MHz, CDCl3) δ 166.7, 159.3, 143.3, 138.0, 135.6,
131.2 (2C), 129.6 (2C), 127.6 (2C), 116.6, 113.52 (2C), 109.5, 106.2,
98.8, 73.6, 59.4, 58.2, 57.3, 55.1, 48.5, 21.5, 18.4, 17.9, 15.4, 14.9. Anal.
Calcd for C28H37NO8S: C, 61.41; H, 6.81; N, 2.56. Found: C, 61.36;
H, 6.92; N, 2.53.
(2R*,3R*)-Methyl 2-Hydroxy-3-(4-methoxyphenyl)-3-(4-
methylphenylsulfonamido)propanoate (12b). Yield 360 mg,
1
95%; pale yellow wax. H NMR (300 MHz, CDCl3) δ 7.53−7.51
(m, 2H), 7.10−7.07 (m, 2H), 6.93−6.90 (m, 2H), 6.65−6.62 (m, 2H),
5.58 (d, 1H, J = 9.5 Hz), 4.78 (dd, 1H, J = 9.5, 3.5 Hz), 4.49 (d, 1H, J
= 3.5 Hz), 3.72 (s, 3H), 3.65 (s, 3H), 2.82 (bs, 1H), 2.33 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.7, 159.3, 142.9, 137.6, 129.2, 128.7,
127.3, 127.0, 113.6, 73.9, 58.8, 55.13, 52.6, 21.3.
N-Allyl-N-{(S*)-(2S*,5S*,6S*)-[1-(5,6-diethoxy-5,6-dimethyl-
3-oxo-[1,4]dioxan-2-yl)-2-methyl-propyl]}-4-methyl-benzene-
sulfonamide (10c). Yield 479 mg, 99%; white solid, mp 105−106 °C.
1H NMR (300 MHz, CDCl3) δ 7.80−7.77 (m, 2H), 7.28−7.26 (m,
2H), 6.09−5.96 (m, 1H), 5.18 (dd, 1H, J = 17.1, 1.2 Hz), 5.09 (dd,
1H, J = 10.2, 1.2 Hz), 4.41 (d, 1H, J = 10.8 Hz), 3.96−3.88 (m, 3H),
3.73−3.61 (m, 2H), 3.48−3.38 (m, 1H), 3.01−2.91 (m, 1H), 2.38 (s,
3H), 2.23−2. 2.10 (m, 1H), 1.44 (s, 3H), 1.35 (s, 3H), 1.67 (t, 3H, J =
6.9 Hz), 0.97−0.94 (m, 6H), 0.80 (t, 3H, J = 5.7 Hz); 13C NMR (75
MHz, CDCl3) δ 167.3, 143.1, 137.6, 136.4, 129.6, 127.3, 116.8, 105.8,
98.5, 72.3, 64.7, 58.1, 57.3, 47.5, 27.2, 21.4, 20.7, 19.5, 18.5, 17.6, 14.8,
14.4. Anal. Calcd for C24H37NO7S: C, 59.60; H, 7.71; N, 2.90. Found:
C, 59.52; H, 7.80; N, 2.87.
General Procedure for the One-Pot Mannich Condensation/
Morpholine Ring Closure. Synthesis of Products 13a−e.
Mannich condensation was carried out according to Method A or
Method B starting from 1 mmol of reagents, affording crude
intermediates 5a−e (1 h). Then the solvent was removed at reduced
pressure, and a 1.3 M solution of TMSCl in MeOH (10 mL, 13 mmol)
was added. The mixture was refluxed for 4 h, the solvent was removed
under vacuum, and the crude was treated with propylene oxide (87
mg, 1.5 mmol) in MeOH (5 mL) and refluxed for 1 h. After solvents
evaporation and purification of the crude by FCC, morpholines 13a−e
were isolated. Yield, chromatographic eluent, and physical and
analytical data are as follows.
General Procedure for the Synthesis of Aldehydes 11a−c by
Ozonolysis of Compounds 10a−c. A solution of N-allyl derivatives
10a−c (1 mmol) in anhydrous methanol (10 mL) and dichloro-
methane (10 mL) was saturated with ozone at −78 °C under nitrogen
atmosphere, then dimethylsulfide (31 mg, 2.5 mmol) was added, and
the mixture was allowed to warm overnight. After solvents
evaporation, purification of the crude by FCC (AcOEt/hexane 1:4),
aldehydes 11a−c were obtained.
N-{(S*)-[(SR*,5S*,6S*)-5,6-Diethoxy-5,6-dimethyl-3-oxo-1,4-
dioxan-2-yl]-(phenyl)methyl}-4-methyl-N-(2-oxoethyl)-
benzensulfonamide (11a). Yield 514 mg, 99%; white solid, mp
160−162 °C. 1H NMR (200 MHz, CDCl3) δ 9.45 (s, 1H), 7.85−7.78
(m, 2H), 7.39−7.12 (m, 7H), 5.64 (d, 1H, J = 4.1 Hz), 4.82 (d, 1H, J =
4.1 Hz), 3.93−3.37 (m, 6H), 2.47 (s, 3H), 1.50 (s, 3H), 1.45 (s, 3H),
1.24−1.15 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 199.3, 166.8,
144.6, 137.0, 134.5, 130.3, 129.8, 128.9, 127.7, 106.8, 99.4, 73.6, 60.0,
58.6, 57.7, 54.6, 21.8, 18.7, 17.9, 15.5, 15.2. Anal. Calcd for
C26H33NO8S: C, 60.10; H, 6.40; N, 2.70. Found: C, 60.00; H, 6.48;
N, 2.62.
(2S*,3R*,6R*)-Methyl 6-Methoxy-3-phenylmorpholine-2-
carboxylate (13a). FCC (AcOEt/hexane 1:4); 246 mg, 98%; de >
1
99%; clear wax. H NMR (200 MHz, CDCl3) δ 7.39−7.26 (m, 5H),
4.64 (dd, 1H, J = 8.3, 2.5 Hz), 4.19 (d, 1H, J = 8.8 Hz), 3.94 (d, 1H, J
= 8.8 Hz), 3.54 (s, 3H), 3.52 (s, 3H), 3.16 (dd, 1H, J = 11.4, 2.5 Hz),
2.88 (dd, 1H, J = 11.5, 8.3 Hz), 1.88 (bs, 1H); 13C NMR (50 MHz,
CDCl3) δ 168.8, 138.0, 128.7 (2C), 128.6 (2C), 128.0, 100.8, 80.4,
61.8, 56.8, 51.9, 49.8; IR (neat) 3325, 1743, 1446, 1031 cm−1. Anal.
Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 61.98; H,
7.00; N, 5.31
(2S*,3R*,6R*)-Methyl 3-(Benzo[d][1,3]dioxol-5-yl)-6-me-
thoxymorpholine-2-carboxylate (13b). FCC (AcOEt/hexane
1
1:3); 257 mg, 87%; de > 99%; yellow solid, mp 133−135 °C. H
NMR (300 MHz, CDCl3) δ 6.90 (d, 1H, J = 1.4 Hz), 6.79 (dd, 1H, J =
8.0, 1.5 Hz), 6.72 (d, 1H, J = 8.0 Hz), 5.94 (s, 2H), 4.61 (dd, 1H, J =
8.4, 2.4 Hz), 4.11 (d, 1H, J = 8.8 Hz), 3.85 (d, 1H, J = 8.9 Hz), 3.57 (s,
3H), 3.53 (s, 3H), 3.14 (dd, 1H, J = 11.4, 2.4 Hz), 2.85 (dd, 1H, J =
11.4, 8.4 Hz), 1.91 (bs, 1H); 13C NMR (75 MHz, CDCl3) δ 169.1,
148.1, 147.8, 132.3, 121.6, 108.5, 108.2, 101.5, 101.1, 81.0, 61.7, 57.0,
52.2, 50.2; IR (nujol) 3317, 1738, 1490, 1249, 1029 cm−1. Anal. Calcd
for C14H17NO6: C, 56.94; H, 5.80; N, 4.74. Found: C, 56.82; H, 5.91;
N, 4.61
N-{(S*)-[(2S*,5S*,6S*)-5,6-Diethoxy-5,6-dimethyl-3-oxo-1,4-
dioxan-2-yl](4-methoxyphenyl)methyl}-N-(2-oxoethyl)4-meth-
yl-benzenesulfonamide (11b). Yield 544 mg, 99%; white solid, mp
1
155.5−157 °C. H NMR (300 MHz, CDCl3) δ 9.40 (s, 1H), 7.81−
(2S*,3R*)-Methyl 3-Isopropyl-6-methoxymorpholine-2-car-
boxylate (13c). FCC (AcOEt/hexane 1:4); 252 mg, 82%; de 80%;
clear wax. Anomeric mixture: 1H NMR (200 MHz, CDCl3) δ 4.54 (m,
1Hα), 4.43 (dd, 1Hβ, J = 7.8, 2.6 Hz), 4.29 (d, 1Hα, J = 9.7 Hz), 4.07
(d, 1Hβ, J = 8.4 Hz), 3.77 (s, 3 + 3H), 3.47 (s, 3Hβ), 3.39 (s, 3Hα)3.10
(dd, 1Hβ, J = 12.4, 2.6 Hz), 3.01−2.99 (m, 2Hα), 2.81−2.775 (m, 1 +
1H), 2.70 (dd, 1Hβ, J = 12.4, 7.9 Hz), 2.53 (bs, 1 + 1H), 1.89−1.66
(m, 1 + 1H), 1.0−0.90 (m, 6 + 6H); 13C NMR (50 MHz, CDCl3) δ
(β-anomer) 169.8, 100.2, 77.1, 60.2, 56.6, 52.2, 48.6, 28.0, 20.2, 16.7;
IR (neat) 3349, 1745, 1448, 1067 cm−1. Anal. Calcd for C10H19NO4:
C, 55.28; H, 8.81; N, 6.45. Found: C, 54.99; H, 9.03; N, 6.13.
(2S*,3R*)-Methyl 4-Benzyl-3-isopropyl-6-methoxymorpho-
line-2-carboxylate (13d). FCC (AcOEt/hexane 1:4); 267 mg,
7.79 (m, 2H), 7.36−7.33 (m, 2H), 7.26−7.23 (m, 2H), 6.69−6.66 (m,
2H), 5.59 (d, 1H, J = 3.9 Hz), 4.79 (d, 1H, J = 4.2 Hz), 3.89−3.39 (m,
9H), 2.45 (s, 3H), 1.48 (s, 3H), 1.43 (s, 3H), 1.20−1.15 (m, 6H).
Anal. Calcd for C27H35NO9S: C, 59.00; H, 6.42; N, 2.55. Found: C,
58.75; H, 6.62; N, 2.69.
N-[(S*)-1-((2S*,5S*,6S*)-5,6-Diethoxy-5,6-dimethyl-3-oxo-
1,4-dioxan-2-yl)-2-methylpropyl)-4-methyl-N-(2-oxoethyl)-
benzenesulfonamide (11c). Yield 481 mg, 99%; white solid, mp
133−134 °C. 1H NMR (300 MHz, CDCl3) δ 9.72 (s, 1H), 7.80−7.77
(m, 2H), 7.31−7.26 (m, 2H), 4.38 (d, 1H, J = 10.2 Hz), 4.08 (d, 1H, J
= 19.9 Hz), 3.90 (s, 1H) 3.71−3.61 (m, 3H), 3.48−3.39 (m, 1H),
2.29−2.88 (m, 1H), 2.40 (s, 3H), 2.07−2.04 (m, 1H), 1.43 (s, 3H),
1.30 (s, 3H), 1.29−0.87 (m, 12H). Anal. Calcd for C23H35NO8S: C,
56.89; H, 7.26; N, 2.88. Found: C, 56.77; H, 7.39; N, 2.72.
1
87%; de 75%; clear wax. Anomeric mixture: H NMR (300 MHz,
CDCl3) δ 7.30−7.26 (m, 5 + 5H), 5.01 (dd, 1Hβ, J = 7.2, 5.1 Hz), 4.50
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dx.doi.org/10.1021/jo300221y | J. Org. Chem. 2012, 77, 3454−3461