Synthesis of the Microbial ImmunosuppresiVe Agent FR901483
Hz, 1H × 0.56), 1.77-1.22 (m, 13H), 1.18-1.12 (m, 21H), 0.98
(ddd, J ) 7.6, 7.6, 4.6 Hz, 1H × 0.44); 13C NMR (75 MHz, CDCl3)
δ 157.7 (minor), 157.6 (major), 155.3, 138.8 (minor), 138.7 (major),
134.8 (minor), 134.3 (major), 132.2, 130.4 (minor), 130.2 (major),
128.3 (minor), 128.0 (major), 127.7 (minor), 127.5, 127.4 (major),
127.1 (minor), 127.6 (major), 118.1 (minor), 117.5 (major), 113.5
(minor), 113.1 (major), 79.3, 75.6 (minor), 74.6 (major), 72.0, 71.6
(minor), 71.1 (major), 58.8 (minor), 57.6 (major), 55.3 (minor),
55.2 (major), 44.1, 43.7 (minor), 42.3 (major), 34.8 (minor), 34.2
(major), 33.7 (major), 29.2 (minor), 28.6 (major), 28.4, 18.3 (minor),
18.2, 12.6 (minor), 12.4 (major); IR (neat) 3066, 3031, 1691, 1366
cm-1; HRMS (APCI) calcd for C40H62NO5Si (MH+) 664.4397,
found 664.4343.
1-Allyl-4-benzyloxy-3-(4-methoxybenzyl)-6-triisopropylsila-
nyloxy-2-azabicyclo[3.3.1]nonanes (22 and 24). To a solution of
the mixture of carbamates 21 and 23 (290 mg, 0.43 mmol) and
anisole (0.5 mL, 4.3 mmol) in CH2Cl2 (5.7 mL) at rt was added
trifluoroacetic acid (0.7 mL, 8.6 mmol). After 18 h, saturated
aqueous NaHCO3 was carefully added. The aqueous layer was
extracted with CH2Cl2. The combined organics were washed with
saturated aqueous NaHCO3 and brine, dried with Na2SO4, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (19:1-4:1, hexanes/EtOAc gradient) to give
amines 22 (125 mg, 51%) and 24 (96 mg, 39%) as colorless oils.
22: 1H NMR (400 MHz, CDCl3) δ 7.40-7.25 (m, 5H), 7.11 (d,
J ) 8.6 Hz, 2H), 6.79 (d, J ) 8.6 Hz, 2H), 5.89-5.75 (m, 1H),
5.12-5.04 (m, 2H), 4.47 (d, J ) 11.6 Hz, 1H), 4.21-4.08 (m,
2H), 3.78 (s, 3H), 3.76-3.69 (m, 1H), 3.50 (t, J ) 2.8 Hz, 1H),
2.80-2.69 (m, 2H), 2.51-2.40 (m, 1H), 2.11-1.86 (m, 5H), 1.75-
1.66 (m, 1H), 1.54 (ddd, J ) 7.9, 13.5, 13.5 Hz, 1H), 1.15 (dd, J
) 12.8, 2.6 Hz, 1H), 1.19-0.90 (m, 21H); 13C NMR (100 MHz,
CDCl3) δ 157.7, 139.2, 133.8, 131.6, 130.0, 128.2, 127.6, 127.3,
118.4, 113.6, 72.5, 71.0, 70.8, 57.0, 55.2, 50.3, 48.4, 38.4, 38.3,
35.5, 32.8, 32.4, 18.1, 18.0, 12.3; HRMS (ESI+) calcd for C35H54-
NO3Si (MH+) 564.3873, found 564.3861.
25.1; IR (film) 3388, 3064, 3027, 1611 cm-1; HRMS (ESI+) calcd
for C18H24NO2 (MH+) 286.1807, found 286.1802.
1-Allyl-2-benzyl-6-(triisopropylsilanyloxy)-2-azabicyclo[3.3.1]-
nonan-3-one (30). To a solution of alcohol 29 (860 mg, 3.0 mmol)
in CH2Cl2 (12 mL) at 0 °C was added triethylamine (1.1 mL, 7.5
mmol) and triisopropylsilyl trifluoromethanesulfonate (1.1 mL, 3.9
mmol). The mixture warmed to rt and stirred for 2 h, and water
(10 mL) was then added. The aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. The crude residue was
purified by flash chromatography (8:1, hexanes/EtOAc) to give silyl
ether 30 (950 mg, 72%) as a colorless oil: 1H NMR (360 MHz,
CDCl3) δ 7.32-7.16 (m, 5H), 5.57 (dddd, J ) 16.9, 10.2, 7.6, 7.6
Hz, 1H), 5.06-4.96 (m, 2H), 4.66 (ABq, J ) 15.5 Hz, ∆νAB
)
42.0 Hz, 2H), 3.91-3.81 (m, 1H), 2.75 (dd, J ) 18.4, 7.5 Hz, 1H),
2.41 (dd, J ) 13.9, 5.8 Hz, 1H), 2.36-2.28 (m, 1H), 2.21 (dd, J )
14.3, 7.9 Hz, 1H), 2.16-2.04 (m, 2H), 1.71 (ddd, J ) 4.7, 13.1,
13.1 Hz, 1H), 1.64-1.57 (m, 1H), 1.55-1.39 (m, 2H), 1.30-1.19
(m, 1H), 1.11-0.96 (m, 21H); 13C NMR (90 MHz, CDCl3) δ 171.9,
139.4, 132.6, 128.1, 127.5, 126.6, 118.9, 70.0, 58.7, 44.5, 44.3,
35.8, 33.6, 31.2, 28.4, 25.7, 17.9, 12.1; IR (neat) 3063, 3027, 1623,
1398 cm-1; HRMS (ESI+) calcd for C27H44NO2Si (MH+) 442.3141,
found 442.3103.
1-Allyl-2-benzyl-4-hydroxy-6-triisopropylsilanyloxy-2-
azabicyclo[3.3.1]nonan-3-one (31). A solution of carboxyimide
30 (1.00 g, 2.26 mmol) in THF (6.8 mL) was added dropwise via
cannula to LDA (7.14 mL, 0.47 M in THF) at -78 °C. The mixture
was warmed to 0 °C, stirred for 1 h, and recooled to -78 °C, and
2-(phenylsulfonyl)-3-phenyloxaziridine8b (886 mg, 3.39 mmol) was
added. The mixture was allowed to warm to rt overnight, saturated
aqueous NaHCO3 was added, and the aqueous layer was extracted
with Et2O. The combined organic layers were washed with saturated
aqueous NaHCO3, water, and brine, dried over MgSO4, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (4:1, hexanes/EtOAc) to give R-hydroxyimide 31
(628 mg, 60%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
7.39-7.19 (m, 5H), 5.64 (dddd, J ) 16.9, 10.3, 7.5, 6.6 Hz, 1H),
5.12 (d, J ) 8.4 Hz, 1H), 5.05 (dd, J ) 15.1, 1.6 Hz, 1H), 4.78,
4.57 (ABq, J ) 15.5 Hz, ∆νAB ) 48.2 Hz, 2H), 4.00-3.88 (m,
1H), 3.85 (s, 1H), 3.40 (s, 1H), 2.41 (dd, J ) 14.4, 6.5 Hz, 1H),
2.24 (dd, J ) 14.2, 7.7 Hz, 1H), 2.00 (ddd, J ) 12.1, 3.1, 1.3 Hz,
1H), 1.88-1.65 (m, 3H), 1.57-1.46 (m, 1H), 1.22-1.14 (m, 2H),
1.10-0.89 (m, 21H).
24: 1H NMR (300 MHz, CDCl3) δ 7.37-7.24 (m, 5H), 7.19-
7.13 (m, 2H), 6.85-6.78 (m, 2H), 5.62 (dddd, J ) 17.8, 10.2, 7.7,
7.7 Hz, 1H), 4.87 (dd, J ) 10.1, 2.2 Hz, 1H), 4.78 (d, J ) 11.5
Hz, 1H), 4.71-4.62 (m, 1H), 4.42 (d, J ) 11.5 Hz, 1H), 3.81-
3.66 (m, 4H), 3.51-3.45 (m, 1H), 3.20 (dd, J ) 13.4, 2.7 Hz, 1H),
3.06 (ddd, J ) 2.9, 9.2, 9.2 Hz, 1H), 2.41 (dd, J ) 13.4, 9.1 Hz,
1H), 2.28-2.20 (m, 1H), 2.10 (ddd, J ) 13.3, 3.6, 3.6 Hz, 1H)
1.96-1.82 (m, 2H), 1.81-1.54 (m, 2H), 1.24-0.95 (m, 24H); 13
C
1-Allyl-2-benzyl-4,6-dihydroxy-2-azabicyclo[3.3.1]nonan-3-
one (32). To a stirred solution of lactam alcohol 31 (200 mg, 0.437
mmol) in anhydrous THF (4.4 mL) was added tetrabutylammonium
fluoride (525 µL, 1.0 M in THF, 0.525 mmol). After the mixture
was stirred at rt for 5 h, a further portion of tetrabutylammonium
fluoride (1.0 mL, 1.0 M in THF, 1.0 mmol) was added, and the
mixture was stirred overnight. The reaction was diluted with water
and extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and concentrated in vacuo. The crude
residue was purified by flash chromatography (EtOAc) to afford
diol 32 (132 mg, 100%) as a white crystalline solid. Crystals suitable
for X-ray crystallography were obtained by recrystallization from
MeOH: 1H NMR (400 MHz, CDCl3) δ 7.31-7.20 (m, 5H), 5.62
(dddd, J ) 16.9, 10.2, 7.6, 6.7 Hz, 1H), 5.08 (d, J ) 10.7 Hz, 1H),
5.04 (dd, J ) 16.9, 1.3 Hz, 1H), 4.75, 4.61 (ABq, J ) 13.4 Hz,
∆νAB ) 28.1 Hz, 2H), 3.94 (d, J ) 2.5 Hz, 1H), 3.89 (s, 1H), 3.76
(br s, 1H), 2.41 (dd, J ) 14.4, 6.5 Hz, 1H), 2.24 (dd J ) 13.0, 7.3
Hz, 2H), 1.98-1.87 (m, 3H), 1.69 (ddd, J ) 12.8, 12.8, 3.6 Hz,
1H), 1.38-1.21 (m, 2H), 1.58-1.49 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 173.7, 138.4, 132.1, 128.5, 127.5, 127.1, 119.5, 70.2,
66.9, 59.9, 44.9, 44.3, 39.9, 28.1, 27.1, 25.7.
NMR (75 MHz, CDCl3) δ 157.9, 139.2, 133.7, 131.5, 130.2, 128.3,
127.7, 127.3, 117.9, 113.6, 78.6, 72.2, 70.7, 55.2, 54.5, 50.1, 47.5,
43.3, 39.3, 37.8, 31.5, 28.8, 18.4, 18.2, 12.7; IR (neat) 3067, 3030
cm-1; HRMS (ESI+) calcd for C35H54NO3Si (MH+) 564.3873,
found 564.3848.
1-Allyl-6-hydroxy-2-benzyl-2-azabicyclo[3.3.1]nonan-3-one (29).
To a solution of alcohol 12 (1.3 g, 4.4 mmol), p-nitrobenzoic acid
(3.2 g, 19.3 mmol), and triphenylphosphine (5.7 g, 21.9 mmol) in
benzene (83 mL) at rt was added diethyl azodicarboxylate (3.5 mL,
21.9 mmol) dropwise. After 1 h, the mixture was concentrated in
vacuo. The crude residue was dissolved with MeOH/THF (5:3, 110
mL), and a solution of K2CO3 (1.2 g, 8.8 mmol) in H2O (11 mL)
was added at rt. The mixture was stirred for 18 h, and the aqueous
layer was extracted with Et2O. The combined organic layers were
washed with water and brine, dried over Na2SO4, and concentrated
in vacuo. The crude residue was purified by flash chromatography
(1:2, hexanes/EtOAc) to give alcohol 29 (700 mg, 56%) as a white
foam: 1H NMR (300 MHz, CDCl3) δ 7.30-7.11 (m, 5H), 5.54
(dddd, J ) 16.7, 10.3, 7.9, 6.4 Hz, 1H), 5.04-4.91 (m, 2H), 4.60
(ABq, J ) 15.6 Hz, ∆νAB ) 64.5 Hz, 2H), 3.76 (d, J ) 2.5 Hz,
1H), 2.93 (br s, 1H), 2.70 (dd, J ) 18.4, 7.5 Hz, 1H), 2.36 (dd, J
) 14.4, 6.3 Hz, 1H), 2.27 (dd, J ) 18.4, 1.8 Hz, 1H), 2.22-2.06
(m, 2H), 2.05-1.97 (m, 1H), 1.72-1.38 (m, 4H), 1.32-1.22 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 172.3, 139.1, 132.5, 128.2,
127.3, 126.8, 118.9, 69.0, 58.9, 44.7, 44.4, 35.9, 32.8, 31.1, 28.1,
1-Allyl-3-oxo-6-triisopropylsilanyloxy-2-azabicyclo[3.3.1]-
nonane-2-carboxylic Acid tert-Butyl Ester (33). In a 500 mL
three-neck round-bottomed flask fitted with a coldfinger condenser
at -78 °C was condensed ammonia (60 mL). Sodium (500 mg,
27.7 mmol) followed by tert-butyl alcohol (1.0 mL, 10.9 mmol)
J. Org. Chem, Vol. 71, No. 5, 2006 2053