J. Spieler, O. Huttenloch, H. Waldmann
FULL PAPER
1 H, CHPh), 2.94Ϫ2.90 (m, 2 H, NCH2eq), 2.83Ϫ2.82 (m, 1 H, CH), 73.08 (CHPh), 64.00 (CHCH3), 57.25, 55.02 (NCH2), 48.07
CHCH3), 2.72Ϫ2.68 (m, 2 H, NCH2ax), 2.31Ϫ2.28 (m, 4 H, (CHCϭO), 10.20 (CHCH3). Ϫ IR (drift): ν˜ ϭ 3399 (OH), 2974,
CH2CϭO), 1.08 (d, 3J ϭ 6.6 Hz, 3 H, CHCH3), 0.89 [s, 9 H, 2937, 2818 (Bohlmann band),[20] 1731 (CϭO), 1584, 1451, 1390,
C(CH3)3], 0.04 (s, 3 H, SiCH3), Ϫ0.27 (s, 3 H, SiCH3). Ϫ 13C NMR 1369, 1199, 1091, 1067, 764, 753, 703 cmϪ1. Ϫ MS (70 eV); m/z
(100.6 MHz, CDCl3): δ ϭ 209.86 (CϭO), 144.44 (arom. C), 127.67, (%): 408 (0.05) [Mϩ], 407 (0.2) [Mϩ Ϫ H], 345 (0.1), 301 (100) [Mϩ
126.90, 126.59 (arom. CH), 77.43 (CHPh), 66.23 (CHCH3), 49.42
(CH2N), 42.23 (CH2CϭO), 25.84 [C(CH3)3], 18.09 [C(CH3)3], 9.68
(CHCH3), Ϫ4.39, Ϫ4.93 (SiCH3). Ϫ IR (KBr): ν˜ ϭ 2957, 2929,
2857, 2804, 1721 (CϭO), 1472, 1387, 1361, 1255, 1074, 864, 837,
776, 701 cmϪ1. Ϫ MS (70 eV); m/z (%): 347 (0.1) [Mϩ], 332 (0.6)
[Mϩ Ϫ CH3], 290 (0.8) [Mϩ Ϫ tBu], 216 (1.0) [Mϩ Ϫ C6H15OSi],
205 (1.9), 173 (2.1), 126 (100) [Mϩ Ϫ C13H21OSi]; HRMS (70 eV):
calcd. for C20H33NO2Si: 347.2281; found: 347.2291.
Ϫ OBzl], 195 (22) [(Mϩ Ϫ OBzl) Ϫ C7H6O], 72 (94); HRMS: calcd.
for C25H32N2O3: 407.2335 [Mϩ Ϫ H], found: 407.2347.
3,7-Bis[(1ЈS,2ЈR)-2Ј-hydroxy-1Ј-methyl-2Ј-phenylethyl]-3,7-diaza-
bicyclo[3.3.1]nonane (9): To a mixture of bispidinone 18 (1.76 g,
4.31 mmol), hydrazine monohydrate (1.05 mL, 21.55 mmol) and di-
ethylene glycol (20 mL) at 60°C was added powdered KOH (1.81 g,
33.32 mmol). The mixture was heated to 160°C for 4 h. The tem-
perature was raised to 210°C for 45 min to remove excess hydrazine
hydrate. After cooling, the residue was treated with water (30 mL)
and extracted with diethyl ether (3 ϫ 50 mL). The combined or-
ganic layers were dried with MgSO4 and concentrated in vacuo to
a volume of 50 mL. The remaining solution was cooled to 0°C and
3,7-Bis[(1ЈS,2ЈR)-2Ј-tert-butyldimethylsiloxy-1Ј-methyl-2Ј-phenyl-
ethyl]-3,7-diazabicyclo[3.3.1]nonan-9-one (17): To a mixture of co-
arse-grained paraformaldehyde (472 mg, 15.7 mmol) and dry meth-
anol (12 mL) at 65°C was slowly added a solution of norephedrine
derivative 14[11] (1.96 g, 7.39 mmol), piperidinone 16 (2.48 g, thoroughly purged with HCl gas for 15 min. The precipitate was
7.15 mmol) and acetic acid (0.83 mL, 15.5 mmol) in dry methanol
collected by filtration and was added to a mixture of 1 KOH
(25 mL) over a period of 2 h. After completion of the addition, (30 mL) and diethyl ether (30 mL). After the solid was completely
more paraformaldehyde (472 mg, 15.7 mmol) was added and the
mixture was stirred for an additional 2 h. Water (100 mL) and 1
KOH (20 mL) was added until the solution showed a basic pH.
dissolved, the phases were separated and the aqueous phase was
extracted with diethyl ether (2 ϫ 30 mL). The combined organic
layers were dried with MgSO4 and concentrated in vacuo. The re-
The mixture was extracted with diethyl ether (3 ϫ 50 mL) and the sulting solid bispidine 9 was pure enough to be used in subsequent
combined organic extracts were dried with MgSO4 and concen-
trated in vacuo. The resulting orange oil was purified by flash chro-
matography on silica gel [hexane/ethyl acetate, 7:1 (v/v), Rf ϭ 0.05]
asymmetric reactions. Yield: 1.28 g (3.24 mmol, 75%). Alterna-
tively, an analytically pure sample can be obtained by flash chroma-
tography on silica gel [CHCl3/MeOH/NEt3/H2O, 6:5:1:2 (v/v/v/v),
20
to yield a colourless oil. Yield: 1.77 g (2.78 mmol, 39%). Ϫ Rf ϭ Rf ϭ 0.37]. M.p. 101°C. Ϫ [α]D ϭ Ϫ45.0 (c ϭ 0.86, CHCl3). Ϫ
20
0.32 (hexane/ethyl acetate/NEt3, 7:1:0.2 (v/v/v). Ϫ [α]D ϭ Ϫ12.7
1H NMR (400 MHz, CDCl3): δ ϭ 7.39 (d, 3J ϭ 7.5 Hz, 4 H, arom.
(c ϭ 1.42, CHCl3). Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ 7.30Ϫ7.18 CH), 7.31 (t, J ϭ 7.6 Hz, 4 H, arom. CH), 7.20 (t, J ϭ 7.2 Hz, 2
3
3
3
(m, 10 H, arom. CH), 4.49 (d, J ϭ 6.3 Hz, 2 H, CHPh), 2.94 (dd, H, arom. CH), 6.25 (br. s, 2 H, OH), 5.14 (d, 3J ϭ 3.6 Hz, 2 H,
3
2
2J ϭ 10.7 Hz, J ϭ 6.5 Hz, 2 H, NCH2eq), 2.79 (dd, J ϭ 10.4 Hz, CHPh), 3.38 (d, 2J ϭ 10.6 Hz, 2 H, NCH2eq), 3.08 (d, 2J ϭ 10.5 Hz,
3J ϭ 1.7 Hz, 2 H, NCH2eq), 2.69Ϫ2.64 (m, 6 H, NCH2ax and
2 H, NCH2eq), 2.66 (d, 2J ϭ 11.1 Hz, 2 H, NCH2ax), 2.63Ϫ2.57
CHCH3), 2.43Ϫ2.39 (m, 2 H, CHCϭO), 0.95 (d, 3J ϭ 6.7 Hz, 6 (m, 2 H, CHCH3), 2.42 (d, J ϭ 11.3 Hz, 2 H, NCH2ax), 1.94 (m,
2
3
H, CHCH3), 0.86 [s, 18 H, C(CH3)3], 0.01 (s, 6 H, SiCH3), Ϫ0.32 2 H, CHCH2), 1.60 (m, 2 H, CH2 bridge), 0.87 (d, J ϭ 6.9 Hz, 6
(s, 6 H, SiCH3). Ϫ 13C NMR (100.6 MHz, CDCl3): δ ϭ 214.22 H, CHCH3). Ϫ 13C NMR (100.6 MHz, CDCl3): δ ϭ 142.80 (arom.
(CϭO), 144.21 (arom. C), 127.77, 127.05, 126.87 (arom. CH), 77.46
C), 127.79, 126.40, 126.22 (arom. CH), 72.03 (CHPh), 65.80
(CHPh), 65.10 (CHCH3), 54.42, 53.74 (NCH2), 47.47 (CHCϭO), (CHCH3), 57.36, 54.11 (NCH2), 32.79 (CH2 bridge), 30.97
25.84 [C(CH3)3], 18.07 [C(CH3)3], 9.89 (CHCH3), Ϫ4.46, Ϫ4.90 (CHCH2), 10.33 (CHCH3). Ϫ IR (drift): ν˜ ϭ 3367 (OH), 3082,
(SiCH3). Ϫ IR (KBr): ν˜ ϭ 3027, 2955, 2929, 2856 (Bohlmann
band),[20] 1738 (CϭO), 1472, 1361, 1256, 1072, 859, 837, 776, 701 1005, 745, 706 cmϪ1. Ϫ MS (70 eV); m/z (%): 394 (0.1) [Mϩ], 393
cmϪ1. Ϫ MS (70 eV); m/z (%): 636 (0.05) [Mϩ], 635 (0.1) [Mϩ (0.5) [Mϩ Ϫ H], 317 (0.2), 287 (100) [Mϩ Ϫ C7H7O], 181 (38) [(Mϩ
2925, 2799 (Bohlmann band),[20] 1494, 1449, 1389, 1163, 1064,
Ϫ
H], 621 (0.1) [Mϩ Ϫ CH3], 579 (1.2) [Mϩ Ϫ tBu], 415 (100) [Mϩ Ϫ C7H7O) Ϫ C7H6O], 72 (84); HRMS: calcd. for C25H34N2O2:
Ϫ C13H21OSi], 221 (2.8) [C13H21OSiϩ], 193 (5.3); HRMS: calcd.
393.2542 [Mϩ Ϫ H], found: 393.2528. Ϫ C25H34N2O2 (394.56):
for C37H60N2O3Si2: 636.4143, found: 636.4125.
calcd. C 76.10, H 8.69, N 7.10; found C 76.34, H 8.61, N 7.08.
3,7-Bis[(1ЈS,2ЈR)-2Ј-hydroxy-1Ј-methyl-2Ј-phenylethyl]-3,7-diaza-
bicyclo[3.3.1]nonan-9-one (18): To a solution of bispidinone 17
(1.63 g, 2.57 mmol) in THF (8 mL) was added tetrabutylam-
3-[(1ЈS,2ЈR)-2Ј-tert-Butyldimethylsiloxy-1Ј-methyl-2Ј-phenylethyl]-
7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one (20): This compound
was prepared by analogy to bispidinone 17 using MeOH (30 mL),
monium fluoride (1 in THF, 6.3 mL). The mixture was stirred at paraformaldehyde (622 mg, 20.7 mmol), N-methylpiperidin-4-one
room temperature overnight. The solution was concentrated to a 19 (1.07 g, 9.42 mmol), norephedrine derivative 14[11] (2.5 g,
volume of 5 mL and filtered through a plug of silica gel. After
evaporation of the solvent, the crude product was purified by flash
9.42 mmol), acetic acid (1.08 mL, 18.8 mmol), MeOH (20 mL) and
after 2 h additional paraformaldehyde (622 mg, 20.7 mmol). The
chromatography eluting first with CHCl3/MeOH, 4:1 (v/v) (Rf ϭ resulting yellow oil was purified by flash chromatography on silica
0.23) and then with CHCl3/MeOH/NEt3, 4:1:0.2 (v/v/v) (Rf ϭ 0.42) gel eluting first with CHCl3/MeOH, 4:1 (v/v) (Rf ϭ 0.25) and then
to yield a white foam. Yield: 836 mg (2.05 mmol, 80%). Ϫ [α]D20 ϭ
with CHCl3/MeOH/NEt3, 4:1:0.2 (v/v/v) (Rf ϭ 0.31) to yield a
20
Ϫ22.4 (c ϭ 1.65, CHCl3). Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ colourless oil. Yield: 2.42 g (6.01 mmol, 64%). Ϫ [α]D ϭ Ϫ20.9
7.35Ϫ7.20 (m, 10 H, arom. CH), 4.96 (d, 3J ϭ 4.1 Hz, 2 H, CHPh),
(c ϭ 0.5, CHCl3). Ϫ H NMR (400 MHz, CDCl3): δ ϭ 7.33Ϫ7.26
1
2
4.55 (br. s, 2 H, OH), 3.32 (d, J ϭ 11.1 Hz, 2 H, NCH2eq), 3.20
(m, 5 H, arom. CH), 4.45 (d, 3J ϭ 7.5 Hz, 1 H, CHPh), 2.91Ϫ2.75
2
2
3
(d, J ϭ 11.1 Hz, 2 H, NCH2eq), 2.95 (dd, J ϭ 11.2, J ϭ 3.7 Hz, (m, 6 H, NCH2 and CHCH3), 2.62 (dd, 2J ϭ 10.7 Hz, 3J ϭ 3.3 Hz,
2 H, NCH2ax), 2.83 (dd, 2J ϭ 11.2 Hz, 3J ϭ 3.6 Hz, 2 H, NCH2ax),
2 H, NCH2), 2.46Ϫ2.42 (m, 3 H, CHCϭO and NCH2), 2.39 (dd,
2.78Ϫ2.75 (m, 2 H, CHCH3), 2.44 (m, 2 H, CHCϭO), 0.91 (d, 2J ϭ 10.2 Hz, J ϭ 3.2 Hz, 1 H, NCH2), 1.99 (s, 3 H, NCH3) 1.11
3
3J ϭ 6.9 Hz, 6 H, CHCH3). Ϫ 13C NMR (100.6 MHz, CDCl3):
(d, J ϭ 6.7 Hz, 3 H, CHCH3), 0.81 [s, 9 H, C(CH3)3], 0.00 (s, 3
3
δ ϭ 214.35 (CϭO), 142.32 (arom. C), 128.08, 126.97, 126.15 (arom. H, SiCH3), Ϫ0.35 (s, 3 H, SiCH3). Ϫ 13C NMR (100.6 MHz,
396 Eur. J. Org. Chem. 2000, 391Ϫ399