Checked by Bai Dong-Lu and Clayton H. Heathcock.
1. Procedure
Caution! Methyl bromoacetate, used in Step B, is intensely irritating to eyes and skin. The preparation of the ester should be carried out in an efficient hood.
A.
Pyrolysis of dicyclopentadiene to form cyclopentadiene.
Cyclopentadiene is prepared from its dimeric form by distillation according to the method of Moffett.
2 The apparatus for the distillation is assembled as shown in
f.htmigure 1. The equipment consists of a
250-mL flask, a
Friedrichs condenser fitted with a Haake Model FE hot water circulator, a
Claisen head, a
thermometer, a
gas inlet tube, and a
collection receiver that is cooled to −78°C in a
dry ice–acetone bath.
In the 250-mL flask is placed
100 mL of dicyclopentadiene (Note
1). The material is heated at reflux (bath temperature 200–210°C) under a
nitrogen atmosphere (Note
2). After a 5-mL forerun is collected and discarded, the
collection receiver is cooled to −78°C and
25 mL (0.30 mol) of cyclopentadiene is rapidly distilled at bp
36–42°C. A slight positive pressure of
nitrogen is maintained throughout the distillation to prevent moisture from entering the system.
In a
500-mL, three-necked Morton flask fitted with a condenser,
mechanical stirrer, and gas inlet tube is placed
8.6 g (0.375 g-atom) of sodium and
75 mL of dry xylene (Note
6); the unstirred mixture is heated at reflux under a
nitrogen atmosphere. After the
xylene has reached its boiling point and the
sodium has melted, the solution is rapidly stirred to produce a very fine-grained sodium sand. Quickly the heating mantle is removed and stirring stopped (Note
7). After cooling, the
xylene is pipetted or siphoned away from the sodium sand and stored for future use.
The sand is washed with 3 ×
25 mL of dry tetrahydrofuran (Note
8) and then is layered with
100 mL of dry tetrahydrofuran, and the mixture is cooled to −10°C (Note
9) under a
nitrogen atmosphere. A solution of
25 mL (0.30 mol) of cyclopentadiene in
25 mL of tetrahydrofuran is added dropwise using a
dropping funnel. After the addition is complete, the mixture is stirred overnight at room temperature, by which time
hydrogen evolution has ceased. In the absence of air, the solution ranges from near colorless to bright pink (Note
10).
In a
1-L, three-necked flask fitted with a 200-mL pressure-equalizing dropping funnel, mechanical stirrer, and a gas inlet tube is placed
45.9 g (0.30 mol) of methyl bromoacetate (Note
11) and
75 mL of tetrahydrofuran and the mixture is cooled to −78°C in an inert atmosphere.
The solution of ca.
0.30 mol of cyclopentadienylsodium is decanted from residual sodium sand with a U-tube into the dropping funnel (Note
12) and is added dropwise over a 2-hr period (Note
13). A white precipitate of
sodium bromide forms during the addition. The heterogeneous solution is stirred overnight at −78°C to ensure complete formation of
methyl 2,4-cyclopentadiene-1-acetate.
In a
2-L, three-necked flask fitted with a condenser, mechanical stirrer, and a gas inlet tube is placed
90.0 g (0.66 mol) of ( − )-α-pinene (Note
15). The flask is cooled to 0°C and under an inert atmosphere a total of
300 mL (0.30 mol) of 1 M borane in
tetrahydrofuran (Note
16) is added dropwise over a 1-hr period. The solution is stirred for 18 hr at 0°C, during which time a white precipitate of
( + )-di-3-pinanylborane forms. This solution is then cooled to −78°C. The ca.
0.30 mol solution of methyl 2,4-cyclo-pentadiene-1-acetate (Section B) is transferred at −78°C to a
500-mL pressure-equalizing dropping funnel through a U-tube in an inert atmosphere and is added rapidly, in one portion, to the stirring solution of
di-3-pinanylborane at −78°C. After this mixture is stirred for 6 hr at −78°C, the bath temperature is allowed to rise to 0°C and the mixture is stirred for 16 hr at 0°C to complete the hydroboration reaction.
To the reaction mixture is added dropwise
90 mL of 3 N aqueous sodium hydroxide, followed by
90 mL of 30% hydrogen peroxide (Note
17). The mixture is stirred for 30 min to complete the oxidation process. A total of
3 g of sodium bisulfite,
5 g of sodium chloride, and
125 mL of ether are added and the mixture is stirred for 10 min (Note
18). On standing, the reaction mixture separates into two layers, which are separated with a
1-L separatory funnel. The organic layer is washed with
brine (2 × 50 mL). The water layer and the
brine washes are combined and extracted with
ether (3 × 125 mL). All the organic layers are then combined and dried over anhydrous
magnesium sulfate. Filtration and removal of solvent under reduced pressure yield 110 g of a pale-yellow oil containing the desired product as well as
( + )-isopinocampheol, and
( − )-α-pinene (Note
19). The product mixture is dissolved in
250 mL of ether and is extracted with
1 M aqueous silver nitrate solution (3 × 100 mL). The aqueous layers are combined and back-extracted once with
50 mL of ether. The
ether layers containing
( + )-isopinocampheol are discarded.
The aqueous layers containing the
silver(I) complex of methyl (1R,5R)-5-hydroxy-2-cyclopentene-1-acetate are then treated with an excess of saturated
brine to precipitate
silver chloride and free the desired product. After precipitation is complete, the water layer is decanted from the solid
silver chloride. The solids are washed with
ether (4 × 100 mL) and each
ether layer is used to extract the water layer (Note
20). The combined
ether layers are washed with
50 mL of brine and dried over anhydrous
magnesium sulfate. Filtration and removal of solvent under reduced pressure yield
16–19 g of crude product. The product is distilled through a
4-in.-Vigreux column at 0.1 mm pressure to yield
12.8–14.7 g (
27–31%) of
methyl (1R,5R)-5-hydroxy-2-cyclopentene-1-acetate, bp
74–78°C at 0.1 mm,
[α]D25 −132° (CH
3OH,
c 1.06) (Note
21) and (Note
22).
2. Notes
1.
Dicyclopentadiene was obtained from Ace Scientific (TX 315), practical grade, 95%.
2. The Haake water circulator was employed with the circulating water temperature at 50°C. This allows only
cyclopentadiene to distill.
3.
Cyclopentadiene is stable at −78°C but dimerizes readily at room temperature.
4. Steps B and C must be run concurrently.
6.
Xylene was obtained from Fisher Scientific Company. The
xylene is initially dried over
sodium and is saved and reused in making additional batches of sodium sand.
7. If stirring continues while the
xylene cools, the sodium sand coagulates into a large lump.
9. A
bath of carbon tetrachloride containing a little dry ice is used for cooling.
12. Care must be taken during this transfer to minimize exposure of the
cyclopentadienylsodium to air. Trace amounts of
oxygen cause the formation of a dark brown color and brown solid in the solution.
13. The drip rate should be adjusted so that the dropping funnel is not plugged by crystalline
cyclopentadienylsodium.
14. After the asymmetric hydroboration–oxidation sequence is completed, the desired product is separated via its silver(I) complex from
( + )-isopinocampheol. The desired product can also be isolated by column chromatography.
15.
( − )-α-Pinene was obtained from Chemical Samples Company. The
( − )-α-pinene was distilled from
sodium metal: bp
155–156°C;
[α]D25 −47° (neat).
17. The
hydrogen peroxide oxidation is a very exothermic process and efficient cooling and stirring are necessary.
18. After the addition of
ether, some inorganic salts precipitate. The checkers found it advantageous to remove this solid by suction filtration. The solid was washed with
ether, which was combined with the organic solution.
19. Vacuum distillation does not effectively purify the desired product from the other impurities.
22. The checkers used
( − )-α-pinene (bp 155°C, [α]D22 −42° (neat)) from Aldrich Chemical Company, Inc. and obtained a product having bp
75–80°C (0.15 mm) and
[α]D21 −126° (CH
3OH,
c 0.039).
3. Discussion
Several highly enantioselective asymmetric hydroboration reactions with prochiral olefins have been reported
8 with the
di-3-pinanylborane reagents (
diisopinocamphenyl-boranes) discovered by Brown and Zweifel.
9 Recently, alternative reagents such as the
mono-3-pinanylboranes (
monoisopinocamphenyl boranes)
10,11 and
( + )-dilongifolyl-borane12 have been used in effecting asymmetric hydroborations on prochiral olefins. With the
di-3-pinanylborane reagents, the cis-disubstituted olefins
8,9 and 5-substituted cyclopentadienes
5,6 yield alcohols of high optical purity (80–95% e.e.). Lower asymmetric inductions (20–40% e.e.) occur when 1,1-disubstituted, trans-disubstituted, or trisubstituted olefins are employed as substrates. However, significantly higher enantioselective hydroborations occur when these olefins are treated with the
mono-3-pinanylboranes10,11 and
( + )-longifolylborane.
12 Tetrasubstituted olefins have not successfully been asymmetrically hydroborated with any of these reagents.
Several racemic
cis- or
trans-2-alkyl-3-cyclopenten-1-ols have been prepared by multistep sequences from
cyclopentadiene13,14,15,16 or from substituted 1,3-dienes.
17 However, optically active
cis- and
trans-2-alkyl-3-cyclopenten-1-ols have been prepared directly by asymmetric hydroboration reactions using prochiral 5-substituted cyclopentadienes as substrates.
5,6 This asymmetric hydroboration method, described above, gives moderate yields of highly optically active
trans-2-alkyl-3-cyclopenten-1-ols (94–96% e.e.), which are readily converted into the corresponding cis isomers.
5,6 Several of these substances are intermediates in the synthesis of such natural products as the monoterpene glycoside loganin,
5 the carbohydrate daunosamine,
18 and the prostaglandins such as PGF
2α6
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
benzophenone ketyl
brine
( − )-α-pinene
silver(I) complex of methyl (1R,5R)-5-hydroxy-2-cyclopentene-1-acetate
diisopinocamphenyl-boranes
mono-3-pinanylboranes
monoisopinocamphenyl boranes
( + )-dilongifolyl-borane
( + )-longifolylborane
METHYL (1 R,5R)-5-HYDROXY-2-CYCLOPENTENE-1-ACETATE
ether (60-29-7)
hydrogen (1333-74-0)
sodium hydroxide (1310-73-2)
sodium chloride (7647-14-5)
silver chloride (7783-90-6)
silver nitrate (7761-88-8)
sodium bromide (7647-15-6)
oxygen (7782-44-7)
nitrogen (7727-37-9)
sodium bisulfite (7631-90-5)
sodium (13966-32-0)
hydrogen peroxide (7722-84-1)
xylene (106-42-3)
magnesium sulfate (7487-88-9)
borane (7440-42-8)
Tetrahydrofuran (109-99-9)
lithium aluminum hydride (16853-85-3)
CYCLOPENTADIENE (542-92-7)
dicyclopentadiene
cyclopentadienylsodium
methyl bromoacetate (96-32-2)
( + )-isopinocampheol (27779-29-9)
( + )-α-pinene
Di-3-pinanylborane,
(+)-di-3-pinanylborane,
( + )-di-3-pinanylborane (21947-87-5)
methyl 2,4-cyclopentadiene-1-acetate,
methyl 2,4-cyclo-pentadiene-1-acetate (37455-98-4)
Methyl (1R,5R)-5-hydroxy-2-cyclopentene-1-acetate,
2-Cyclopentene-1-acetic acid, 5-hydroxy-, methyl ester, (1R-trans)- (49825-99-2)
methyl (1S,5S)-5-hydroxy-2-cyclopentene-1-acetate
(S)-α-methoxy-α-trifluoromethylphenylacetyl chloride (20445-33-4)
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