J. H. Simpson et al. / Tetrahedron: Asymmetry 14 (2003) 3569–3574
3573
propyl ester, 15.7 min for toluene, 16.8 min for the
styrene 1, and 21.1 min for trans-cyclopropyl ester.
keeping the product rich aqueous phase; the upper
organic phase was extracted with 65 mL of water.
(
Note that even though phase separation was rapid, the
The following Chiral LC method was used for deter-
mining the enantiomeric ratio for the four possible
stereoisomers of the cyclopropyl acid. Equipment:
Hewlett Packard 1090 Series HPLC, Column: Chiralcel
OJ-R OCD-HJ019 S5m, 4.6×150 mm, Isocratic: 35 V%
water, 65 V% methanol (containing 0.5 mL of trifl-
uoroacetic acid per 1000 mL of water and methanol
solution), Flow rate: 1.0 mL/min, Detection @ 285 nm,
Injection volume:10 mL, Temperature: room tempera-
ture. Typical retention times were 6.7 min for (1R,2S)-
isomer, 7.5 min for (1S,2R)-isomer, 10.2 min for
phase separations were difficult due to both phases
having the same dark purple color and the presence of
a dense rag layer.) The two aqueous streams were
combined, and 730 g of MTBE were added. The mix-
ture was cooled to 0–10°C and the pH was adjusted to
pH 4.0–4.5 with 132 g of 85 wt/wt% phosphoric acid
while maintaining the batch temperature at 525°C.
(Note that at pH <4.0, it is more difficult to remove the
fumaric acid by-products.) The phases were separated,
and the upper rich organic layer was washed with two
130 g portions of water, whereby the fumaric acid
by-products in the organic phase were 50.2 area% by
HPLC analysis. The rich organic layer was quantitated
by HPLC analysis to contain 78.1 g (85 M%). This
solution was further diluted with 736 g (1000 mL) of
MTBE and 172 g (210 mL) of SDA 3A alcohol (90 V%
ethanol, 5 V% methanol, and 5 V% water). At 50±5°C
the cyclopropyl acid(ca. 382 mmol)in MTBE was
treated with a solution of (+)-dehydroabietylamine pre-
pared by dissolving 191 g (401 mmol based on 60
w/w%) of 60 w/w% (+)-dehydroabietylamine in 626 mL
of MTBE. The batch temperature was maintained at
50±5°C for 15 min, then 100 mg of seed crystals were
added. The batch was cooled over 2 h to 25±5°C, then
further cooled to 0–5°C over 1 h, and finally main-
tained at 0–5°C for 1 h. The crystalline material was
collected by filtration, washed with two 200 mL por-
tions of MTBE and dried under reduced pressure at
565°C to afford 143 g (64.8M%) of the salt.
(
1R,2R)-isomer, 12.5 min for (1S,2S)-isomer.
.2. Ethyl diazoacetate
To a solution of 18.9 g (135 mmol) of sodium tetra-
4
1
6
borate decahydrate in 380 mL of water was added
8.2 (1423 mmol) of sodium nitrite and 190 g (1355
9
mmol) of ethyl glycine hydrochloride. Dissolution was
endothermic, so the mixture was warmed to 20°C. To
the aqueous solution was added 440 mL of toluene, and
the reaction mixture was cooled to −5±5°C. At 5°C, 860
mL of a phosphoric acid solution was charged at a rate
such that the batch temperature did not exceed 20°C.
The phosphoric acid solution was prepared by charging
1
8.9 g of 85% phosphoric acid to 930 mL of water. The
temperature of the reaction mixture was maintained at
0±10°C until an aqueous sample indicated the pres-
1
ence of nitrous acid by a positive starch-iodide test. The
bottom aqueous waste was separated and treated as
described in ‘A Safe and Practical Procedure to Prepare
(Samples for chiral HPLC analysis were converted to
the free acid by the procedure described in the next
1
2
Ethyl Diazoacetate’. The upper rich organic layer was
washed with 190 mL of water followed by 380 mL of 8
wt/wt% sodium bicarbonate in water. The ethyl diazo-
acetate solution in toluene was quantitated by GC
analysis against a standard solution prepared from
Aldrich supplied material. GC quantitation indicated
that the 535 mL solution contained 128 g (83 M%).
This material was kept at 5±5°C for use in the cyclo-
propanation reaction.
paragraph, except that MTBE was used as the extract-
1
ing solvent). H NMR (300 MHz, CDCl ) l 0.9 (m,
3
1H), 1.0 (s, 3H), 1.1 (m, 1H), 1.2–1.9 (m which includes
d, 19H), 2.1 (m, 2H), 2.65 (dd, 2H), 2.85 (m, 2H), 3.1
(apparent t, 2H), 4.5 (m, 2H), 6.3 (br. S, 3H), 6.35 (d,
1H), 6.6 (d, 1H), 6.85 (s, 1H), 7.0 (m, 2H), 7.15 (d, 1H).
1
3
C NMR (CDCl3) l 16.45, 17.57, 18.44, 18.95, 22.98,
24,01, 25.19, 26.03, 28.70, 29,84, 33.45, 35.38, 36.07,
7.42, 38.06, 46.66, 51.76, 70.97, 106.96, 115.69, 123.97,
3
4
.3. (1R-trans)-2-(2,3-Dihydro-4-benzofuranyl)cyclo-
124,12, 126.08, 126.78, 128.19,134.31, 138.31,145.75,
146.71, 159.67, 179.82.
propanecarboxylic acid 2
To a reaction vessel was charged 4.5 g (9.00 mmol) of
Ru(ip-Pybox) and 65.8 g (450 mmol, 130 mL of the3
toluene solution) of 4-vinyl-2,3-dihydrobenzofuran 1.
At 60±10°C, 128 g (1125 mmol, 513 mL of the toluene
solution) of ethyl diazoacetate was added at a constant
rate over 16 h. Upon complete addition of the ethyl
diazoacetate, 52% of 1 remained by HPLC analysis.
To the reaction mixture was added 450 mL of water, 66
g (140 mmol) of 55 wt/wt% tetrabutylammonium
hydroxide (note: 55% was preferred over 40% because
If needed, the free acid 2 was liberated by dissolving
143 g (293 mmol) of the DAA-salt in 1430 mL of
toluene and 439 mL (878 mmol) of 2N sodium hydrox-
ide. This mixture was stirred at 20±5°C for 1 h, fol-
lowed by separating the phases and keeping the bottom
rich aqueous phase. To the aqueous phase was added
43 g of sodium chloride, 430 mL n-butyl acetate, and
73 mL of conc. hydrochloric acid while maintaining the
batch temperature 525°C. This mixture was stirred for
1 h before separating the phases. The bottom aqueous
phase was back-extracted with 430 mL of n-butyl ace-
tate, and the two organic streams were combined. The
organics were concentrated by distillation at atmo-
spheric pressure to 330 mL. Quantitation by HPLC
analysis indicated 56.8 g (278 mmol, 61.8 M% from the
‘styrene’) of (1R)-trans-2-(2,3-dihydro-4-benzofuranyl)-
5
5% remains a liquid whereas 40% crystallizes), and 110
g (1350 mmol) of 50 wt/wt% sodium hydroxide. The
reaction mixture was maintained at 60°C for 8 h when
5
2% of the ethyl ester remained by HPLC analysis. To
the reaction mixture was added 660 g of water and the
batch was cooled to 20°C. The phases were separated,