946
T. McElroy et al.
PAPER
( )-(5S,7R,8R)-N-Benzyl-N-methyl-7-pyrrolidin-1-yl-1-oxo-
Diol Mixture ( )-7a,b
1H NMR (CDCl3): δ = 1.72 (4 H, m), 1.76–2.12 (6 H, m), 3.77–3.96
spiro[4,5]decan-8-amine [( )-4]
(4 H, m).
A mixture of ( )-11 (43.9 g, 0.16 mol), 1,4-dibromobutane (33.7 g,
0.16 mol) and Na2CO3 (49.5 g, 0.4 mol) in THF (1.75 L) was heated
under reflux for 16 h. The mixture was then filtered and the solvent
removed by evaporation. The residue was dissolved in aq half sat.
K2CO3 (900 mL) and extracted with EtOAc (2 × 1.00 mL). The
combined organic extracts were dried (Na2SO4) and concentrated.
Subsequent chromatography of the residue on SiO2 using PE–Et2O–
Et3N (67:30:3) yielded 33 g (64%) of the title compound as a clear
oil.
Anal. Calcd for C9H16O3: C, 62.80; H, 9.30. Found: C, 62.29; H,
9.29.
The diol mixture was divided into two equal batches (66 g, 0.38
mol). Each batch was dissolved in CH2Cl2 (500 mL) and cooled in
an ice bath. A solution of SOCl2 (30 mL, 0.42 mol) in CH2Cl2 (300
mL) was added dropwise over 2 h to each chilled solution of the diol
mixture. Following the addition, the ice bath was removed and the
resultant mixture stirred for 3 h at r.t. The solvent and excess SOCl2
were then evaporated. Aq sat. K2CO3 (300 mL) was added to each
batch and each mixture extracted with EtOAc (3 × 100 mL). The
combined organic extracts from both batches were dried (MgSO4)
and evaporated to give a thick oil (139 g, 83%) that by 1H NMR con-
tained two components. This mixture was used in the next reaction
with no further purification.
1H NMR (CDCl3): δ = 1.32–1.95 (16 H, m), 2.19 (3 H, s, NCH3),
2.67–2.73 (4 H, m), 3.69–3.83 (2 H, dd, J = 6, 6 Hz), 4.05 (2 H, t,
J = 6 Hz), 6.98–7.61 (5 H, m, ArH).
(+)-(5S,7R,8R)-N-Methyl-7-pyrrolidin-1-yl-1-oxospiro[4,5]dec-
an-8-amine [(+)-12]
A mixture of intermediate ( )-4 (33 g, 0.100 mol) and 10% Pd/C (30
g) in MeOH (300 mL) was hydrogenated at 50 psig H2 for 36 h. The
mixture was filtered through a Celite pad and washed with MeOH
(2 × 200 mL). The combined filtrates and washings were concen-
trated to yield 23.9 g (99%) of ( )-12 as a white solid.
A solution of the above mixture (139 g, 0.63 mol) in MeCN (5.00
L) was treated with NaIO4 (254 g, 0.90 mol) and RuCl3⋅3H2O (0.55
g, 0.0023 mol), followed by H2O (1.00 L). (It is important to add the
H2O last to avoid clumping of the NaIO4.) The resultant heteroge-
neous mixture was stirred for 5 h at r.t., then diluted with Et2O (6.00
L) and H2O (1.00 L). After separation of the layers, the aqueous lay-
er was extracted with Et2O (3 × 1.00 L). The combined organic ex-
tracts were washed with brine (500 mL), dried (MgSO4), and
evaporated to give 145 g of a brown oil containing a mixture of cy-
clic sulfates ( )-8a,b. The mixture was chromatographed on SiO2
utilizing EtOAc–PE (4:1) to obtain 87 g (59%) of sulfate ( )-8b and
27.8 g (18%) of sulfate ( )-8a. Crystallization of cyclic sulfate ( )-
8b from Et2O–benzene afforded a white solid; mp 65–69 °C.
1H NMR (CDCl3): δ = 0.89–2.18 (18 H, overlapping m), 2.23 (3 H,
s, NCH3), 2.25–2.80 (2 H, m), 3.73 (2 H, q, J = 3 Hz).
The resolution of ( )-12 was achieved utilizing di-p-toluoyl-L-tar-
taric acid according to the literature procedure.11 The resolution af-
forded 5.76 g of (+)-12 as a freebase. The other enantiomer (–)-12
was isolated as well using di-p-toluoyl-D-tartaric acid. The ee of
these samples was found to be >97% according to the method of
Pirkle and Hoover.10
Anal. Calcd for C9H14O5S: C, 46.12; H, 5.98; S, 13.70. Found: C,
46.26; H, 5.95; S, 13.80.
(5S,7R,8R)-(–)-2-(4-Bromophenyl)-N-methyl-N-(7-pyrrolidin-
1-yl-1-oxospiro[4,5]dec-8-yl)acetamide [(–)-13b]
A solution of 4-bromophenylacetic acid (0.806 g, 0.0037 mol) in
CH2Cl2 (5 mL) was treated with oxalyl chloride (2 mL of 2 M solu-
tion in CH2Cl2) and one drop of DMF was added. The mixture was
stirred at r.t. for 3 h and concentrated. The residue was dissolved in
CH2Cl2 (10 mL) and added dropwise to (–)-12 (0.10 g, 0.0042 mol)
in CH2Cl2 (5 mL) cooled in an ice bath. Following this addition, the
mixture was stirred an additional 10 min. Et3N (3 mL, 0.021 mol)
was added by pipette below the surface of the reaction mixture, and
the resulting mixture was stirred 16 h at r.t. The mixture was diluted
with 50% NH4OH (10 mL), the layers separated, and the aqueous
layer extracted with CH2Cl2 (500 mL). The organic extracts were
combined, dried (Na2SO4), and concentrated. The resultant residue
was purified by column chromatography on SiO2 utilizing PE–
EtOAc–Et3N (10:9:1) to obtain the title compound as a white solid.
The compound was then crystallized from Et2O–hexane to obtain
0.12 g (69%) of 13b as white needles; mp 122–123 °C; Rf = 0.30
[single spot on SiO2 utilizing hexane–EtOAc–Et3N (10:9:1)].
Aziridine ( )-10
A solution of cyclic sulfate ( )-8b (146 g, 0.62 mol) and NaN3
(80.60 g, 1.25 mol) in MeOH (5.00 L) was heated under reflux for
36 h. The MeOH was then removed and the residue chromato-
graphed on SiO2 utilizing CHCl3–MeOH–concd NH4OH (80:18:2)
to obtain a white solid. This solid was dissolved in MeOH (5.00 L)
and 10% H2SO4 (2.00 L), and the mixture was heated under reflux
for 6 h. Afterwards, it was cooled in an ice bath, neutralized with
NaHCO3, and extracted with CH2Cl2 (3 × 2.00 L). The combined
organic extracts were dried (Na2SO4) and evaporated to yield 100 g
(82%) of azidoalcohols ( )-9. A solution of the azidoalcohols ( )-9
(100 g, 0.51 mol) in toluene (2.50 L) was cooled in an ice bath and
treated with a solution of PPh3 (134 g, 0.51 mol) in toluene (500
mL), added dropwise. Following the addition, the mixture was heat-
ed under reflux for 12 h, cooled to r.t., and the toluene was removed
under vacuum. Vacuum distillation of the residue (oil bath: 150 °C)
yielded 55.4 g (71%) of the title compound; bp 89–95 °C/5 mm Hg.
1H NMR (CDCl3): δ = 1.06–1.96 (14 H, overlapping m), 2.45–2.68
(6 H, overlapping m), 2.77 (3 H, s, NCH3), 3.67–4.55 (4 H, m),
7.08–7.49 (5 H, m, ArH).
1H NMR (CDCl3): δ = 1.13–1.89 (11 H, m), 3.34–4.04 (4 H, m).
A fumarate salt was prepared for elemental analysis.
Anal. Calcd for C13H19NO5⋅0.5H2O: C, 57.53; H, 7.09; N, 5.16.
Found: C, 57.49; H, 7.08; N, 5.10.
Anal. Calcd for C22H31BrN2O2: C, 60.69; H, 7.18; N, 6.43; Br,
18.35. Found: C, 60.68; H, 7.21; N, 6.44; Br, 18.35.
( )-(5S,7R,8R)-N8-Benzyl-N8-methyl-1-oxospiro[4,5]decane-
7,8-diamine [( )-11]
(5R,7S,8S)-(+)-N-Methyl-2-phenyl-N-(7-pyrrolidin-1-yl-1-oxo-
spiro[4,5]dec-8-yl)acetamide [(+)-3]
A mixture of aziridine ( )-10 (55 g, 0.36 mol), N-methylbenzyl-
amine (250 mL, 1.90 mol), NH4Cl (2.0 g, 0.035 mol) and H2O (250
mL) was heated under reflux for 14 h. After this time, the H2O and
excess N-methylbenzylamine were removed by vacuum distillation.
The residual oil was distilled bulb-to-bulb to obtain 43.9 g (43%) of
( )-11 as a thick oil; bp 170 °C/5 mm Hg. This material was used
without further characterization.
A mixture of intermediate (+)-12 (5.70 g, 0.021 mol) in CH2Cl2
(500 mL) was cooled in an ice bath. Phenylacetyl chloride (5.25
mL, 0.038 mol) was added dropwise. Following this addition, the
mixture was stirred 10 min and Et3N (10 mL, 0.071 mol) was added
by pipette below the surface of the reaction mixture. Afterwards, the
mixture was stirred for 16 h at r.t. and diluted with 50% NH4OH
(100 mL). The layers were separated, and the aqueous layer extract-
Synthesis 2008, No. 6, 943–947 © Thieme Stuttgart · New York