356 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
min 110 mL of 70% perchloric acid. After an additional hour
of stirring, 150 mL of brine was added; the organic layer was
separated and then washed with 400 mL of saturated aqueous
sodium bicarbonate. The organic layer was separated and the
aqueous layer extracted twice with 100 mL each of ether. The
combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo to afford 9.9 g (90%, two steps) of
tetralin-1-carboxaldehyde.
1-Tetr a lylm eth a n ol (130). To a 0 °C solution of 9.9 g (60.7
mmol) of tetralin-1-carboxaldehyde in 160 mL of ethanol was
added 1.2 g (30.4 mmol) of sodium borohydride. After 1 h at
0 °C, the mixture was partitioned between 300 mL of ethyl
acetate and 200 mL of water. The organic layer was separated
and the aqueous layer extracted twice with 100 mL each of
ethyl acetate and 100 mL of ether. The combined organic
extracts were dried (MgSO4), filtered, and concentrated in
vacuo. Chromatography (500 g of silica gel, 30% ethyl acetate/
hexane) afforded 7.0 g (71%) of 130.
4-Cya n o-4-((tr im eth ylsilyl)oxy)ch r om a n e (132). To a
0 °C solution of 10.0 g (67.5 mmol) of 4-chromanone and 0.4 g
of zinc iodide in 200 mL of dichloromethane was added 13.5
mL (10.0 g, 101.8 mmol) of cyanotrimethylsilane. After being
stirred overnight while warming to room temperature, the
mixture was washed with 200 mL of saturated aqueous sodium
bicarbonate, and then the organic layer was dried (MgSO4),
filtered, and concentrated in vacuo to afford 16.2 g (97%) of
132.
4-Ca r boxych r om a n e (133). A mixture of 16.2 g (65.5
mmol) 132 and 56.0 g (248.3 mmol) of tin(II) chloride dihydrate
in 60 mL each of acetic acid and concentrated hydrochloric
acid was heated to reflux for 3 days, then cooled to room
temperature, and extracted three times with 150 mL each of
dichloromethane. The combined organics were washed three
times with 130 mL each of 2 N sodium hydroxide, and then
the combined basic washes were extracted twice with 100 mL
each of ether and subsequently acidified to pH 2 with 5 N
hydrochloric acid (in an ice bath). The acidic aqueous mixture
was extracted three times with 150 mL each of ethyl acetate,
and the combined organics were dried (MgSO4), filtered, and
concentrated in vacuo to afford 11.3 g (97%) of 133.
followed by venting to nitrogen the first time and then to
hydrogen the subsequent two times) and then stirred for 3.5
h at room temperature under hydrogen (in a balloon). The
mixture was filtered through diatomaceous earth and concen-
trated in vacuo. Chromatography (100 g of silica gel, 20%
ethyl acetate/hexane) of the residue afforded 1.4 g (63%) of
50.
2-Ad a m a n ta n eca r boxa ld eh d ye. To a 0 °C solution of the
ylide generated from 16.0 g (46.6 mmol) of (methoxymethyl)-
triphenylphosphonium chloride and 46 mL (46 mmol) of
sodium bis(trimethylsilyl)amide in 75 mL of THF was added
5.0 g (33.3 mmol) of 2-adamantanone in 20 mL of THF, and
the mixture was stirred for 1.5 h at 0 °C. The reaction was
quenched with 100 mL of water, and then the mixture was
extracted three times with 100 mL each of ether. The
combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo. The residue was stirred for 4 h at room
temperature in 200 mL of acetonitrile and 50 mL of 1 N
hydrochloric acid and then concentrated in vacuo to remove
most of the acetonitrile. Brine (50 mL) of was added and the
mixture extracted three times with 100 mL each of ether. The
combined organics were dried (MgSO4), filtered, and concen-
trated in vacuo, and chromatography (4′′ of silica gel in a 600
mL sintered-glass funnel, 10% ethyl acetate/hexane) of the
residue afforded 4.9 g (89%, two steps) of the title compound.
(1SR,2SR)-2-Ca r beth oxycyclop r op -1-yl 2-(2-Ad a m a n -
tyl)eth yl Keton e (53). As for 50, 2.0 g (7.6 mmol) of 135,
0.32 g (8.0 mmol) of sodium hydride, and 1.4 g (8.3 mmol) of
2-adamantanecarboxaldehdye afforded 137, which was hydro-
genated with 1.6 g of 5% Pd/C in 50 mL of ethanol at 40 °C
and 60 psi overnight. The mixture was filtered through
diatomaceous earth and concentrated in vacuo. Chromatog-
raphy (65 g of silica gel, 10% ethyl acetate/hexane) of the
residue afforded 0.7 g (42%) of 53.
Ack n ow led gm en t. The authors thank the Physical
Chemistry Department of Lilly Research Laboratories
for spectral data and elemental analyses. The authors
also especially thank J ack Campbell for the liberal use
of his high-pressure hydrogenation equipment.
Dim eth yl [(1SR,2SR)-2-(Ca r beth oxycyclop r op -1-yl)-2-
oxoeth yl]p h osp h on a te (135). To a -78 °C solution of 36.1
g (290.9 mmol) of dimethyl methylphosphonate in 560 mL of
THF was added via cannulus 200 mL (320 mmol, 1.6 M in
hexane) of butyllithium. After 30 min at -78 °C, 60.9 g (320
mmol) of copper(I) iodide was added, the mixture was stirred
for 1 h at -45 °C, and then 56.5 g (320 mmol) of 17 in 200 mL
of THF was added at a moderate rate. After 2 h of stirring at
-45 °C, and at room temperature overnight, the reaction was
quenched with 250 mL of 0.5 M (in water) ethylenediamine-
tetraacetic acid (precipitate) followed by 250 mL of water and
600 mL of dichloromethane. The mixture was filtered through
diatomaceous earth (0.75 in. layer in a 2 L sintered-glass
funnel), then the organic layer was separated, and the aqueous
layer was extracted twice with 300 mL each of dichlo-
romethane. The combined organic extracts were dried (Mg-
SO4), filtered, and concentrated in vacuo. Preparative HPLC
afforded 33.1 g (39%) of 135.
(1SR,2SR)-2-Ca r beth oxycyclop r op -1-yl 2-(1-Meth ylin -
d ol-3-yl)eth en yl Keton e (136). A solution of 2.0 g (7.6 mmol)
of 135 in 10 mL of tetrahydrofuran was added to a suspension
of 0.3 g (7.6 mmol) of sodium hydride in 15 mL of tetrahydro-
furan, and the mixture was stirred for 20 min at room
temperature. A solution of 1.3 g (7.6 mmol) of 1-methylindole-
3-carboxaldehyde in 10 mL of tetrahydrofuran was added and
the mixture stirred for 16 h at reflux. The mixture was cooled
to room temperature, diluted with 30 mL of water, and
extracted three times with 15 mL each of ether. The combined
organics were dried (MgSO4), filtered, and concentrated in
vacuo to afford 2.2 g (96%) of 136.
Su p p or tin g In for m a tion Ava ila ble: A list of all of the
names of the amino acids prepared in this paper along with
representative 1H NMR spectra for key intermediates and
products are included (7 pages). Ordering information is given
on any current masthead page.
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Synthesis of the four isomers of 4-aminopyrrolidine-2,4-
(1SR,2SR)-2-Ca r beth oxycyclop r op -1-yl 2-(1-Meth ylin -
d ol-3-yl)eth yl Keton e (50). A solution of 2.2 g (7.2 mmol)
of 136 in 50 mL of ethanol and 0.1 g of 5% palladium on carbon
was degassed (brief evacuation under vacuum for about 30 s