toluene, the residue was distilled under 20 mmHg at 100
°C and gave (+)-nopinone 816 (123.8 g, 81.4%).
Preparation of 2-((1R,2R,3S,5S)-2-Amino-6,6-dimeth-
ylbicyclo[3.1.1]heptan-3-yl)ethanol 6b and 2-((1R,2S,3S,5S)-
2-Amino-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)ethanol 6c.
Epimerization of 4a (Preparation of 4b). In a four-neck 1 L
flask, 4a (47.0 g, 0.21 mol), 236 mL of toluene, and 20%
sodium ethylated ethanol solution (146.0 g, 0.42 mol) were
mixed, and then the mixture was heated to 90 °C. After 170
mL of ethanol and toluene were distilled, the reaction mixture
was cooled to room temperature and poured into 465 g of 4%
HCl. The organic layer was separated and washed with aqueous
0.5% NaHCO3 (400 g). The aqueous layer was extracted with
200 mL of toluene, and then the toluene layers were combined.
The combined organic layer was evaporated, and the obtained
residue (38.07 g) of 4b was used for the next step to prepare
6b and 6c.
Procedure for Manufacturing 6a. Preparation of Ethyl
2-((1R,3R,5S)-6,6-Dimethyl-2-oxobicyclo[3.1.1]heptan-3-yl)-
acetate 4a by DiastereoselectiVe Alkylation of (+)-
Nopinone 8. In a four-neck 1 L flask, a mixture of
diisopropylamine (48.3 g, 0.48 mol) and THF (360 mL)
was cooled to -15 °C, and then a 24% hexane solution
of n-butyl lithium (127.4 g, 0.48 mol) was added dropwise
under the same temperature. Next, (+)-nopinone 8 (60.0
g, 0.43 mol) was added dropwise at -15 °C followed by
dropwise addition of DMI (46.9 mL). This mixture was
cooled to -50 °C, and ethyl bromoacetate (76.1 g, 0.46
mol) was added dropwise over 30 min under the same
temperature followed by stirring for 2 h. The reaction
termination was checked by HPLC analysis, and water
(180 mL) was added dropwise from -50 to 0 °C. After
adjustment of the pH to 7.0 with aqueous 20% HCl below
25 °C, the organic layer was separated and washed with
water (90 mL). The organic layer was evaporated, and
the obtained residue (121.5 g) of 4a was used for the next
step.
Preparation of Ethyl 2-((1R,3R,5S)-2-(Methoxyimino)-6,6-
dimethylbicyclo[3.1.1]heptan-3-yl)acetate 5 from 4a. To the
evaporated residue of 4a, toluene (193 mL), O-methylhydroxy-
lamine hydrochloride (47.2 g, 0.57 mol), pyridine (44.7 g, 0.57
mol), and methanol (97 mL) were added, and the mixture was
heated under reflux for 2 h. After the termination of the reaction
was confirmed by HPLC analysis, the reaction mixture was
cooled to 25 °C. Water (90 mL) and aqueous 35% HCl (31.7
g, 0.30 mol) were added and stirred. The organic layer was
separated and washed with water (90 mL), followed by aqueous
1% NaHCO3 (90 g). The organic layer was evaporated, and
the obtained residue (127.6 g) of 5a was used for the next step.
Preparation of Benzoic Acid Salt of 2-((1R,2R,3R,5S)-2-
Amino-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)ethanol 6a from
5a with DiastereoselectiVe Reduction. To the evaporated residue
of 5a, AlCl3 (34.7 g, 0.26 mol) dissolved in diglyme (264 mL)
was added (Caution! exothermic dissolution), and the mixture
was stirred at 35 °C. A solution of NaBH4 (26.3 g, 0.69 mol)
in diglyme (468 mL) was added dropwise to the mixture at 35
°C. The reaction mixture was stirred for 1 h under the same
conditions and then heated to 65 °C followed by stirring for
2 h. After the termination of the reaction was confirmed by
GC analysis, the reaction mixture was cooled to 10 °C. Acetone
(39.0 g) was added dropwise to the mixture at the same
temperature, and then the mixture was added dropwise to
aqueous 18% HCl (271 g, 1.34 mol) at 10-30 °C. Into this
mixture, aqueous 34% NaOH (291.6 g, 2.48 mol) was added
dropwise and toluene (840 mL) was also added. The organic
layer was separated and washed with aqueous 10% NaCl (240
g × 2). It was evaporated azeotropically. Into the obtained
residue (702 g), a solution of benzoic acid (47.7 g, 0.39 mol)
in acetone (175 mL) was added dropwise at 30 °C to obtain
white crystals and cooled to 5 °C. These crystals were filtrated,
washed with cold acetone (300 mL), and dried in vacuo. By
this procedure, 94.23 g (0.31 mol) of benzoic acid salt of 6a3
was obtained (isolated yield: 72.1%).
Preparation of 6b and 6c. To a four-neck 500 mL flask, the
residue of 4b 30.6 g (0.14 mmol), O-methyl hydoroxylamine
hydrochloride (14.8 g, 0.18 mol), pyridine (14.0 g, 0.18 mol),
and ethanol (123 mL) were added and heated under reflux for
4 h. After the termination of the reaction was confirmed by
TLC analysis, the reaction mixture was cooled to 25 °C and
evaporated. Toluene (200 mL) and aqueous 1 N HCl (160 mL)
were added and stirred. The organic layer was separated and
washed with water (200 mL), followed by aqueous 1%
NaHCO3 (90 g). The organic layer was evaporated, and the
obtained residue (34.2 g) of 5b was purified by silica gel
chromatography (250 g of SiO2; 70-230 mesh ASTM (Merck),
hexane/acetone ) 100/1-25/1 as an eluent). Purified 5b (22.5
g, 0.09 mol) and AlCl3 (11.8 g, 0.09 mol) were dissolved in
diglyme (170 mL) (Caution! exothermic dissolution) and stirred
at 35 °C. NaBH4 powder (8.4 g, 0.22 mol) was added over 30
min at 35 °C. The reaction mixture was stirred for 1 h under
the same conditions and then heated to 65 °C followed by
stirring for 3 h. After the reaction termination was checked by
TLC, the reaction mixture was cooled to 10 °C. Acetone (32.0
g) was added dropwise to the mixture at the same temperature,
and then the mixture was added dropwise to aqueous 11% HCl
(220 g, 0.67 mol) at 10-30 °C. Into this mixture, aqueous 48%
NaOH (107 g, 1.28 mol) was added dropwise and toluene was
also added (200 mL). The organic layer was separated and
washed with aqueous 10% NaCl (50 g × 2). It was evaporated
azeotropically. The residue included diglyme, and the extraction
was carried out again. Toluene (200 mL) and aqueous 2 N HCl
(210 mL) were added to the obtained residue, and the aqueous
layer was separated. The pH of the aqueous layer was adjusted
to over 12.3 with aqueous 48% NaOH, and then the mixture
of 6b and 6c was extracted with toluene (200 mL × 3). The
separated organic layer was washed with 10% NaCl (100 g ×
2) and evaporated to obtain the residue (15.0 g). Isomer 6b
(2.25 g) and 6c (1.26 g) were isolated by silica gel chroma-
tography of this residue. Compound 6b: mp 110-113 °C. 1H
NMR (500 MHz, CDCl3, 5 °C) 1.01 (s, 3H), 1.21 (s, 3H), 1.33
(d, J ) 10.0 Hz, 1H), 1.55 (dd, J ) 13.6, 9.4 Hz, 1H), 1.63
(brdt, J ) 14.8, ∼3 Hz, 1H), 1.93 (q-like, J ) ∼5 Hz, 1H),
1.97 (m, 1H), 2.02 (m, 1H), 2.05 (m, 1H), 2.18 (dt, J ) 10.0,
5.7 Hz, 1H), 2.49 (m, 1H), 3.50 (dd, J ) 10.0, 3.9 Hz, 1H),
3.62 (brt, J ) 10.6 Hz, 1H), 3.85 (ddd, J ) 10.6, 4.3, 2.9 Hz,
1
1H). Compound 6c: mp 58-60 °C. H NMR (600 MHz,
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