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164
J . Org. Chem. 1999, 64, 2164-2165
Communications
Regioselective Ca r bom eth oxyla tion of Ch ir a l
Ep oxid es: A New Rou te to En a n tiom er ica lly
P u r e â-Hyd r oxy Ester s
Ta ble 1. Ca r bom eth oxyla tion of En a n tiom er ica lly P u r e
Ter m in a l Ep oxid es
Klaus Hinterding and Eric N. J acobsen*
Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, MA 02138
Received November 30, 1998
An efficient method for the catalytic carbonylation of
aliphatic, racemic epoxides has been reported in the recent
patent literature using Co2(CO)8 (1) in the presence of
1
3
-hydroxypyridine (2) as cocatalyst. We became interested
in the possibility of applying this reaction to the carbony-
lation of enantioenriched epoxides, as the coupling of such
practical methodology to the recently developed co-catalyzed
2
hydrolytic kinetic resolution (HKR) of terminal epoxides (eq
1
) could provide novel access to synthetically valuable
â-hydroxy carbonyl derivatives in optically active form. We
describe here the successful elaboration of this strategy.
a
All reactions were run on a 5 mmol scale in a 1/1 mixture of
MeOH/THF at [3a -h ]0 ) 0.5 M and a final pressure of 600 psi
b
for 9 h, except for 3h , which was run at 670 psi. ee’s were
determined by chiral GC or by chiral HPLC using commercially
available chiral columns. See the Supporting Information.
branched byproducts 5 (linear/branched ) 50:1-4:1) and
unsatisfactory yields (<75% for the two step process). In
addition, partial racemization accompanied formation of the
branched isomers, with ee’s of ca. 40% measured for the
isolated products.
Under reducing conditions using CO/H2, carbonylation of
epoxides can lead directly to â-hydroxy carbonyl compounds
3
in the aldol oxidation state. Subjection of a series of optically
pure terminal epoxides (3a -h ) to CO/H2 (1:1, 1000 psi) in
the presence of 1 (5 mol %) led to dimeric aldol products.
Treatment with 1,3-propane diol under acidic conditions
provided the monomeric dioxolane derivatives (eq 2).
In contrast, carbomethoxylation of highly enantioenriched
1
epoxides with CO/MeOH according to the Drent protocol
proved to be high-yielding, highly regioselective, and ste-
reoretentive. Reaction of methanolic solutions of epoxides
3
a -h in the presence of 5 mol % 1 and 10 mol % 2 proceeded
under relatively mild conditions (600 psi CO, 55-65 °C) to
furnish the 3-hydroxy esters 6a -h in optically pure form
(Table 1). The experimental protocol is remarkably simple:
filtration of the crude reaction mixtures through silica gel
to remove catalysts, followed by solvent evaporation, af-
forded the products in excellent yields and >95% purity as
1
4
determined by H NMR analysis.
A range of functional groups on the epoxide are tolerated
in the carbomethoxylation reaction. For example, no delete-
rious effects were observed in substrates bearing halide (3e),
The stereochemical integrity of the reactants was pre-
served in the linear reaction products 4 (ee >99%). However,
this procedure was found to suffer from formation of
(
4) Gen er a l Exp er im en ta l P r oced u r e for th e P r ep a r a tion of Hy-
(
1) (a) Drent, E.; Kragtwijk, E. Eur. Pat. Appl. 577206, 30 Mar. 1994;
d r oxy Ester s 6a -h . An autoclave was charged under air with 1 (0.25
mmol, 85 mg) and 2 (0.5 mmol, 48 mg). THF (5 mL) and MeOH (5 mL)
were added, followed by epoxides 3a -h (5 mmol). The reaction vessel was
flushed three times with CO (15 psi) and then charged to a pressure of 600
psi (∼40 bar). After being heated and stirred under the stated conditions
(Table 1), the autoclave was cooled to room temperature, the excess gases
Chem Abstr. 1994, 120, 191517c. (b) For earlier work, see: Eisenmann, J .
L.; Yamartino, R. L.; Howard, J . F. J . Org. Chem. 1961, 26, 2102.
(2) (a) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N. Science
1
1
997, 277, 936. (b) Brandes, B. D.; J acobsen, E. N. Tetrahedron: Asymmetry
997, 8, 3927. (c) Furrow, M. E.; Schaus, S. E.; J acobsen, E. N. J . Org.
Chem. 1998, 63, 6776.
3) (a) Yokokawa, C.; Watanabe, Y.; Takegami, Y. Bull. Chem. Soc. J pn.
964, 37, 677. (b) Takegami, Y.; Yokokawa, C.; Watanabe, Y. Bull. Chem.
Soc. J pn. 1964, 37, 935. (c) Roos, L.; Goetz, R.W.; Orchin, M. J . Org. Chem.
965, 30, 3203. d) Rosenthal, A.; Kan, G. Tetrahedron Lett. 1967, 477.
2
were vented carefully, and the reaction mixture was poured into Et O (150
(
mL) to precipitate the catalysts. The suspension was stirred in air for 2 h
and then filtered through a plug of silica gel. Solvents were removed in
vacuo, affording the reaction products as colorless or slightly yellowish oils
in >95% purity as determined by 1H NMR.
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1
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0.1021/jo982336l CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/11/1999