Efficient intramolecular asymmetric reductions of α-, β-, and γ-keto acids with diisopinocampheylborane1

Article abstract of DOI:10.1021/ol0062291

(equation presented) α-, β-, and γ-Keto acids are reduced with diisopinocampheylborane at room temperature to the corresponding hydroxy acids with predictable stereochemistry in very high ee. The γ-hydroxy acids produced were conveniently cyclized to the corresponding lactones. This provides a simple synthesis of 4-hexanolide, a component of the pheromone secreted by the female dermestid beetle Trogoderma glabrum.

Full text of DOI:10.1021/ol0062291

ORGANIC
LETTERS
2
001
Vol. 3, No. 1
7-18
Efficient Intramolecular Asymmetric
1
Reductions of r-, â-, and γ-Keto Acids
1
with Diisopinocampheylborane
P. Veeraraghavan Ramachandran,* Herbert C. Brown, and Sangeeta Pitre
Herbert C. Brown Center for Borane Research, Purdue UniVersity,
West Lafayette, Indiana 47907-1393
chandran@purdue.edu
Received June 19, 2000
ABSTRACT
r-, â-, and γ-Keto acids are reduced with diisopinocampheylborane at room temperature to the corresponding hydroxy acids with predictable
stereochemistry in very high ee. The γ-hydroxy acids produced were conveniently cyclized to the corresponding lactones. This provides a
simple synthesis of 4-hexanolide, a component of the pheromone secreted by the female dermestid beetle Trogoderma glabrum.
The preparation of optically pure hydroxy esters or acids
and their conversion to lactones are important processes in
organic syntheses as a result of the significance of such
molecules. Asymmetric reduction of the corresponding
ketones is an efficient route to achieve this goal. We had
â-keto acids with 1 in the presence of amines have recently
appeared. We herein report the intramolecular reduction of
aliphatic keto acids with 2.
4
2
Reduction of R- and â-keto acids (3 and 5, respectively)
with 2 provided essentially similar results as described with
4
reported that one of our successful reagents, B-chlorodiiso-
1. However, the absence of hydrogen chloride in the medium
pinocampheylborane (Ipc
effective for the intramolecular asymmetric reductions of
various classes of ketones, including keto acids. The %
enantiomeric excess (ee) achieved for the products from the
2
BCl, DIP-Chloride, 1) is very
makes the reduction with 2 more efficient. The workup is
simple and the procedure can be applied to acid-sensitive
molecules as well. Our results from R- and â-keto acids are
summarized in Table 1.
3
reduction of o-acylbenzoic acids with 1 was inferior,
attributed to a partial intermolecular reduction. Utilizing the
The reduction was then extended to γ-keto acids. 3-Ben-
zoylpropanoic acid (7a) was reduced with 2 within 36 h at
room temperature. Workup provided 90% yield of the
corresponding hydroxy acid 8a, which was lactonized in the
presence of trifluoroacetic acid to the corresponding γ-lactone
3
sodium salt of the keto acid or conducting the reaction in
3
the presence of an amine circumvented this problem.
Carrying out the reduction with the parent diisopinocam-
3
pheylborane (2) also solved the difficulty. Utilizing our
a in 90% yield and 94% ee in the S-isomer (Scheme 1).5
9
procedure, two separate reports on the reduction of R- and
The reduction of an aliphatic γ-keto acid, 4-oxopentanoic
acid (7b), with 2 yielded the corresponding hydroxy acid
(1) Contribution 7 from the Herbert C. Brown Center for Borane
8
b in 98% ee. This was readily converted to the lactone 9b.
Research.
(
2) (a) Collins, I. J. Chem. Soc., Perkin Trans. 1 1999, 1377. (b) Wang,
We included the reduction of 4-oxohexanoic acid (7c) and
Z.; Meng, X. J.; Kabalka, G. W. Tetrahedron Lett. 1991 32, 4619. (c)
Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
(
3) (a) DIP-Chloride is the trademark of the Aldrich Chemical Co. (b)
Ramachandran, P. V.; Chen, G. M.; Brown, H. C. Tetrahedron Lett. 1996,
7, 2205.
(4) (a) Wang, Z.; La, B.; Fortunak, J. M.; Meng, X. J.; Kabalka, G. W.
Tetrahedron Lett. 1998 39, 5501. (b) Wang, Z.; Zhao, C.; Pierce, M. E.;
Fortunak, J. M. Tetrahedron: Asymmetry 1999, 10, 225.
3
1
0.1021/ol0062291 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/16/2000

δ-Keto acids did not undergo intramolecular reduction with
, even in refluxing THF. Thus, the intramolecular asym-
2
2
Table 1. Reduction of Keto Acids with (-)-Ipc BH (2)
metric reduction is limited to R-, â-, and γ-keto acids.
In conclusion, we have shown that diisopinocampheyl-
borane is an excellent reagent for the intramolecular asym-
metric reduction of aliphatic and aromatic R-, â-, and γ-keto
acids. The hydroxy acids were obtained in 75-90% yields
and 77-98% ee. The reduction of δ-keto acids does not
proceed under the same conditions. This protocol has been
utilized for the convenient synthesis of γ-lactones from the
keto acid
hydroxy acid
R-CO-(CH2)nCOOH rxn time
R-CH(OH)-(CH2)nCOOH
no.
n
R
h
no. yield (%) ee (%) configa
3a
3b
5a
5b
7a
7b
7c
0
0
1
1
2
2
2
Ph
n-Pr
Ph
Me
Ph
Me
Et
10
6
4a
4b
6a
6b
8a
8b
8c
82
75
85
75
90
83
82
95b
77c,d
92d
92d
94e
R
R
S
R
S
55
32
36
17
48
7
corresponding γ-keto acids. The natural isomer of the insect
pheromone of a dermestid beetle, 4-hexanolide, has also been
synthesized.
98f
R
R
95f,g
a
Determined by comparison of the optical rotations with those reported
b
in the literature. % ee determined by the HPLC analysis of the hydroxy
ester on a Chiralcel OD-H column. c % ee determined by 1H NMR
Acknowledgment. Financial assistance from the United
States Army Research Office (DAAG55-98-1-0405) is grate-
fully acknowledged.
spectroscopic analysis of the ethyl acetoxycarboxylate in the presence of
d
Eu(hfc)3. % ee determined by HPLC analysis of the corresponding benzyl
e
ester on a Chiralcel OD-H column. % ee determined by HPLC analysis
f
of the corresponding lactone on a Chiralcel OD-H column. % ee determined
by comparison of the optical rotation. % ee determined by 1H NMR
g
OL0062291
spectroscopic analysis (in the presence of Eu(hfc)3) of the diol obtained by
8
opening the lactone with excess MeLi.
(5) The % ee and configuration are based on the optical rotation reported
in the literature. Brown, H. C.; Kulkarni, S. V.; Racherla, U. S. J. Org.
Chem. 1994, 59, 365.
(
6) (a) Mori, K.; Mori, H.; Sugai, T. Tetrahedron 1985, 41, 919 and
references therein. (b) It has been shown that T. granarium responds to
R)-9 only and not to its antipode or a racemic mixture.
7) Representative procedure for the synthesis of 4-hexanolide. An
conversion to the corresponding γ-caprolactone, 4-hexanolide
(
(9c), in 95% ee because of its importance as a component
(
of the attractant pheromone of several Trogoderma species
oven-dried, 100 mL round-bottom flask equipped with a sidearm, magnetic
stirring bar, and a connecting tube was cooled to room temperature in a
stream of nitrogen. (-)-Ipc2BH (2) (2.82 g, 10 mmol) was transferred to
the flask in a glovebag, suspended in THF (10 mL) and stirred at 0 °C.
6
of dermestid beetles, such as T. glabrum and T. granarium.
4
-Oxohexanoic acid (1.3 g, 10 mmol) dissolved in a minimum amount of
anhydrous THF was slowly added, at 0 °C, to the flask when evolution of
hydrogen was observed. The B NMR of the resultant clear solution showed
Scheme 1
11
a peak at δ 52 ppm. The mixture was warmed to room temperature. The
progress of the reaction was monitored by 11B NMR spectroscopy, which
revealed a peak at δ 32 ppm when the reaction was complete. The mixture
was oxidized by the addition of 4 mL of 3 N NaOH and 4 mL of 30%
H2O2. The aqueous layer was separated, washed several times with Et2O
to remove organics, and acidified using 1.0 M aqueous HCl. The product
hydroxy acid was extracted with EtOAc (3 × 40 mL). The organic layer
was washed with brine and dried over anhydrous MgSO4. Removal of
solvents afforded the hydroxy acid (1.1 g, 82%), which was dissolved in
CH2Cl2 (10 mL) and cooled to 0 °C, followed by the addition of 4 drops
of trifluoroacetic acid. Stirring for 6 h at room temperature completed the
lactonization, and the reaction was worked up with aqueous sodium
bicarbonate. The organic layer was washed with water, dried (MgSO4), and
20
concentrated to yield 0.76 g (80%) of 9c, [R] D ) +50.63 (c 1.5, MeOH),
which corresponds to 95% ee in the (R)-isomer.6
(8) Jakovac, I. J.; Jones, J. B. J. Org. Chem. 1979, 44, 2165.
18
Org. Lett., Vol. 3, No. 1, 2001