Asymmetric Nitroaldol Reaction
a solution of amine 5 (302 mg, 0.61 mmol) in Et2O (6 mL) was
added Ac2O (287 µL, 3.05 mmol), followed by Et3N (425 µL,
3.05 mmol). The progress of the reaction was monitored by
TLC. After the mixture was stirred at rt for ca. 20 min,
solvents were evaporated and the residue was purified on a
silica gel column using hexane/AcOEt to afford compound 6
(311 mg, 95%) (Rf ) 0.5 hexane/AcOEt 8:2). 1H NMR (400
MHz; CDCl3): δ 7.38-7.22 (m, 7H), 7.17-7.05 (m, 3H), 5.23
(d, J 2,3 ) 9.7 Hz, 1H), 4.90 (dd, J ) 9.7, 2.3 Hz, 1H), 4.81 (dt,
J ) 10.8, 10.8, 4.2 Hz, 1H), 4.51 (d, J ) 2.3 Hz, 1H), 2.20-
2.17 (m, 1H), 2.01 (s, 3H), 1.96-1.77 (m, 2H), 1.72-1.62 (m,
1H), 1.54-1.43 (m, 2H), 1.38 (s, 9H), 1.30 (s, 3H), 1.20 (s, 3H),
1.19-0.90 (m, 2H), 0.84 (d, J ) 6.4 Hz, 3H). 13C NMR (100
MHz; CDCl3): δ 169.3, 166.6, 154.4, 152.2, 138.3, 128.2, 128.0,
127.5, 126.2, 125.4, 79.7, 76.6, 74.7, 54.1, 50.0, 40.4, 39.2, 34.3,
31.3, 29.5, 28.2, 26.2, 22.5, 21.6, 20.3. IR (film): 3452 2959,
2927, 1765, 1744, 1722, 1502, 1368, 1212, 1164, 1088, 765, 701
cm-1. HRMS-ESI: calcd for C32H43O6NNa (M + Na)+ 560.2983,
found 560.2999. Anal. Calcd: C, 71.48; H, 8.06; N, 2.60.
(s, 3H), 0.97 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 170.3,
134.9,129.3, 128.6, 127.3, 90.2, 71.3, 65.3, 52.8, 49.2, 47.9, 44.3,
37.2, 35.4, 32.5, 26.4, 20.2, 19.8. IR (film): 3470, 2961, 1694,
1555, 1335, 1294, 1167, 1138, 1061, 753, 700, 535 cm-1. HRMS-
ESI: calcd for C20H26N2O6SNa (M + Na)+ 445.1404, found
445.1415. Anal. Calcd: C, 56.86; H, 6.20; N, 6.63, S, 7.59.
Found: C, 57.09; H, 6.31; N, 6.46, S, 7.71.; [R]20 ) -60 (c )
D
1.10; CHCl3). Rf ) 0.4 (hexane/AcOEt 7:3).
O -[(2S )-H y d r o x y -(3R )-n i t r o -4-p h e n y lb u t a n o y l]-
(1′R,2′S,5′R)-8′-p h en ylm en th ol (syn -12b). 1H NMR (500
MHz; CDCl3): δ 7.40-7.30 (m, 3H), 7.22-7.19 (m, 4H), 7.07-
7.02 (m, 2H), 6.75-6.71 (m, 1H), 4.92 (dt, J ) 10.8, 10.8, 4.5
Hz, 1H), 4.35 (ddd, J ) 2.7, 6.9, 8.5 Hz, 1H), 4.31 (ddAB, J )
13.9, 6.9 Hz, 1H), 3.07 (ddAB, J ) 13.9, 6.9 Hz, 1H), 3.01 (dd,
J ) 2.7, 6.9 Hz, 1H), 2.95 (d, J ) 6.9 Hz, 1H), 2.10 (ddd, J )
10.6, 12.1, 3.7 Hz, 1H), 1.96 (dq, J ) 13.5, 3.7, 3.7 Hz, 1H),
1.87-1.84 (m, 1H), 1.75-1.70 (m, 1H), 1.52-1.41 (m, 1H),
1.23-1.16 (m, 1H), 1.24 (s, 3H), 1.12 (s, 3H), 1.00-0.90 (m,
2H), 0.89 (d, J ) 6.5 Hz, 3H). 13C NMR (125 MHz; CDCl3): δ
170.3, 151.8, 135.0, 129.3, 128.8, 127.6, 127.4, 125.1, 125.0,
88.5, 76.9, 68.7, 50.1, 40.7, 39.1, 35.4, 34.4, 31.2, 30.6, 26.0,
21.6, 21.3. IR (film): 3567, 2960, 2920, 1718, 1546, 1367, 1282,
1126, 986, 758, 695, 491 cm-1. HRMS-ESI: calcd for C26H33O5-
NNa (M + Na)+ 462.2251, found 462.2251. Anal. Calcd: C,
Found: C, 71.32; H, 8.09; N, 2.58. [R]20 ) 18.0 (c ) 0.79;
D
CHCl3).
Meth yl (2S)-Acetoxy-(3R)-ter t-bu toxyca r bon yla m in o-
3-p h en ylp r op ion a te (8). To a solution of compound 6 (300
mg, 0.61 mmol) in MeOH (10 mL) was added MeONa (69 mg,
1.22 mmol). The progress of the reaction was monitored by
TLC. After the mixture was stirred at rt for 24 h, solvents
were evaporated, H2O (1 mL) was added to the residue, and
the pH was adjusted with 6 N HCl to ca. 1. The postreaction
mixture was extracted with CH2Cl2. After drying (MgSO4) of
combined extracts, the solvents were removed under reduced
pressure. To the residue were added H2O (3 mL), CHCl3 (0.5
mL), and AcOEt (2.5 mL). The organic layer was separated,
and the water phase was extracted with CH2Cl2. Combined
organic layers were dried (MgSO4), solvents were removed
under reduced pressure, and purification was achieved on a
silica gel column using CH2Cl2/MeOH to give compound 7 (175
mg, 89%) (Rf ) 0.1, CH2Cl2/MeOH, 8:2). To a precooled (0 °C)
solution of acid 7 in Et2O (10 mL) was added the ethereal
solution of CH2N2 (5 mmol, 50 mL). After the mixture was
stirred for 16 h, solvents were evaporated, and the residue was
purified on a silica gel column using hexane/AcOEt to afford
compound 8 (165 mg, 90%) (Rf ) 0.5 hexane/AcOEt 8:2). 1H
NMR (500 MHz; CDCl3): δ 7.36-7.25 (m, 5H), 5.46-5.35 (m,
1H), 5.31 (bs, 1H), 3.77 (s, 3H), 2.07 (s, 3H), 1.42 (s, 9H). 13C
NMR (125 MHz; CDCl3): δ 169.6, 168.2, 154.8, 138.0, 128.5,
71.05; H, 7.57; N, 3.19. Found: C, 70.90; H, 7.61; N, 3.03. [R]20
) 26 (c ) 1.11; CHCl3). Rf ) 0.5 (hexane/AcOEt 8:2).
D
O -[(2S )-H y d r o x y -(3S )-n i t r o -4-p h e n y lb u t a n o y l]-
(1′R,2′S,5′R)-8′-p h en ylm en t h ol (a n ti-12b ). 1H NMR (500
MHz; CDCl3): δ 7.31-7.21 (m, 7H), 7.16-7.12 (m, 1H), 7.08-
7.025 (m, 2H), 4.94 (dt, J ) 10.8, 10.8, 4.4, 1H), 4.46 (ddd, J
) 3.9, 9.7, 4.5 Hz, 1H), 3.47 (dd, J ) 3.9, 4.6 Hz, 1H), 3.19
(ddAB, J ) 14.9, 9.7 Hz, 1H), 3.01 (d, J ) 4.6 Hz, 1H), 2.73
(ddAB, J ) 14.9, 4.5 Hz, 1H), 2.16 (ddd, J ) 10.8, 12.2, 3.6 Hz,
1H), 1.96 (dq, J ) 13.5, 3.6, 3.6 Hz, 1H), 1.80-1.71 (m, 1H),
1.53-1.41 (m, 1H), 1.23-1.16 (m, 1H), 1.29 (s, 3H), 1.18 (s,
3H), 1.10-0.91 (m, 2H), 0.90 (d, J ) 6.5, 3H). 13C NMR (125
MHz; CDCl3): δ 170.0, 151.7, 135.4, 128.9, 128.7, 128.1, 127.4,
125.4, 125.1, 90.2, 77.4, 70.2, 50.2, 41.2, 39.3, 34.3, 34.2, 31.3,
30.4, 26.1, 21.8, 21.6. [R]20 ) -21 (c ) 1.27; CHCl3).
D
O-[(3R )-t er t -Bu t oxyca r b on yla m in o-(2S )-h yd r oxy-4-
p h en ylb u t a n oyl]-(1′R,2′S,5′R)-8′-p h en ylm en t h ol
(14).
Through a solution of nitro alcohol was bubbled syn-12b (171
mg, 0.39 mmol) in MeOH (5 mL) containing catalytical
amounts of Raney Ni hydrogen. The progress of reaction was
monitored by TLC. After the mixture was stirred for ca. 16 h
at rt, the catalyst was filtered off, solvents were evaporated,
and the residue was dissolved in AcOEt and saturated aqueous
NaHCO3 (10 mL, 1:1), followed by addition (Boc)2O (93 mg,
0.43 mmol). After completion of the reaction, the layers were
separated, and the water phase was extracted with CH2Cl2.
After drying (MgSO4) of combined organic layers, solvents were
removed under reduced pressure. Purification was achieved
on a silica gel column using hexane/AcOEt to give compound
127.8, 126.3, 80.1, 74.7, 54.5, 52.6, 28.2, 20.3. [R]25 ) 26.5 (c
D
) 1.44; CHCl3) (lit.21 [R]25 ) 27.6).
D
Meth yl (3R)-ter t-Bu toxyca r bon yla m in o-(2S)-h yd r oxy-
3-p h en ylp r op ion a te (1). To a solution of ester 8 (29 mg,
0.085 mmol) in MeOH (1 mL) was added MeONa (14 mg, 0.25
mmol). The progress of the reaction was monitored by TLC.
After the mixture was stirred at rt for ca. 1.5 h, solvents were
evaporated, and to the residue were added saturated aqueous
NH4Cl (2 mL) and AcOEt (2 mL). The organic layer was
separated, and the water phase was extracted with CH2Cl2.
The combined organic layers were dried (MgSO4), and solvents
were removed under reduced pressure. Purification was
achieved on a silica gel column using hexane/AcOEt to give
compound 1 (23 mg, 90%) (Rf ) 0.1, hexane/AcOEt 8:2). 1H
NMR (500 MHz; CDCl3): δ 7.37-7.25 (m, 5H), 5.43-5.36 (m,
1H), 5.25-5.18 (m, 1H), 4.46 (bs, 1H), 3.83 (s, 3H), 3.17 (bs,
1H), 1.41 (s, 9H). 13C NMR (125 MHz; CDCl3): δ 173.3, 155.1,
1
14 (185 mg, 95%) (Rf ) 0.5 hexane/AcOEt 7:3). H NMR (500
MHz; CDCl3): δ 7.34-7.06 (m, 9H), 6.86-6.80 (m, 1H), 4.41
(dt, J ) 10.7, 10.7, 4.5 Hz, 1H), 4.62-4.54 (m, 1H), 3.84-3.75
(m, 3H), 2.98-2.93 (m, 1H), 2.86 (J ) 3.2 Hz, 1H), 2.70 (ddAB
,
J ) 7.7, 13.4 Hz, 1H), 2.63 (ddAB, J ) 8.0, 13.4 Hz, 1H), 2.11
(ddd, J ) 12.2, 14.2, 3.6 Hz, 1H), 1.96 (dq, J ) 13.5, 3.6, 3.6
Hz, 1H), 1.75-1.60 (m, 2H), 1.47-1.27 (m, 1H), 1.28 (s, 9H),
1.19 (s, 3H), 1.13 (s, 3H), 1.06-0.98 (m, 1H), 0.96-0.80 (m,
2H), 0.81 (d, J ) 6.5 Hz, 3H). 13C NMR (125 MHz; CDCl3): δ
173.5, 155.2, 152.1, 138.3, 128.8, 128.2, 126.9, 125.6, 79.5, 76.7,
70.8, 54.3, 50.3, 41.1, 39.8, 39.4, 34.8, 31.9, 30.5, 28.8, 26.7,
22.8, 22.3. IR (film): 3443 2966, 2927, 1721, 1496, 1456, 1367,
1258, 1170, 1117, 763, 700 cm-1. HRMS-ESI: calcd for
139.1, 128.5, 127.7, 126.7, 79.9, 73.5, 56.0, 53.0, 28.2. [R]25
)
D
7.4 (c ) 0.67; CHCl3) (lit.18 [R]25 ) 7.2). Mp ) 131-132 °C
D
(hexane/CH2Cl2).
(2′R)-N-[-(2S)-Hyd r oxy-(3R)-n itr o-4-p h en ylbu ta n oyl]-
bor n a n e-10′,2′-su lta m (syn -12a ). 1H NMR (500 MHz; CD-
Cl3): δ 7.34-7.25 (m, 5H), 5.34 (ddd, J ) 2.2, 5.8, 9.1 Hz, 1H),
4.92 (dd, J ) 2.2, 7.1 Hz, 1H), 3.96 (dd, J ) 4.8, 7.9 Hz, 1H),
3.58 (ddAB, J ) 9.1, 14.5 Hz, 1H), 3.27 (ddAB, J ) 5.8, 14.5 Hz,
1H), 3.13 (dAB, J ) 13.7 Hz, 1H), 3.08 (dAB, J ) 13.7 Hz, 1H),
2.01-1.81 (m, 3H), 1.49-1.29 (m, 2H), 1.20-1.08 (m, 1H), 1.19
C
31H43O5NNa (M + Na)+ 523.3033, found 523.3057. Anal.
Calcd: C, 73.05; H, 5.50; N, 2.75. Found: C, 72.85; H, 8.47;
N, 2.77. [R]20 ) 63.0 (c ) 1.10; CHCl3). Mp ) 101-103 °C
D
(hexane/CH2Cl2).
O-[(3R)-ter t-Bu t oxyca r b on yla m in o-(2S)-h yd r oxy-2,3-
is o p r o p y lid e n e -4-p h e n y lb u t a n o y l]-(1′R ,2′S ,5′R )-8′-
J . Org. Chem, Vol. 69, No. 8, 2004 2849