Selective reductions. 59. Effective intramolecular asymmetric reductions of α-, β-, and γ-keto acids with diisopinocampheylborane and intermolecular asymmetric reductions of the corresponding esters with B-chlorodiisopinocampheylborane

Article abstract of DOI:10.1021/jo025594y

A comparison of the stereochemistry of the products obtained from the intramolecular asymmetric reduction of a series of keto acids with (-)-diisopinocampheylborane and intermolecular asymmetric reduction of the corresponding series of keto esters with (-)-B-chlorodiisopinocampheylborane ((-)-DIP-Chloride) has been made. The stereochemistry of the hydroxy acids from the reduction of keto acids is dependent only on the enantiomer of the reagent used. The stereochemistry of the products from the reduction of keto esters is also consistent, except those of aliphatic α-keto esters. α-, β-, and γ-keto acids provide the corresponding hydroxy acids in 77-98% ee, and the α- and γ-keto esters afford the hydroxy esters in 82-≥99% ee. β-Keto esters do not undergo reduction. Although the reduction of δ-keto acids does not proceed under the same reaction conditions, the reduction of δ-keto esters is facile. All of the products from the reduction of γ-keto acids and esters and δ-keto esters were converted to the corresponding lactones. This study revealed that DIP-Chloride is an efficient reagent for the reduction of α-keto esters at low temperatures.

Full text of DOI:10.1021/jo025594y

Selective Red u ction s. 59. Effective In tr a m olecu la r Asym m etr ic
Red u ction s of r-, â-, a n d γ-Keto Acid s w ith
Diisop in oca m p h eylbor a n e a n d In ter m olecu la r Asym m etr ic
Red u ction s of th e Cor r esp on d in g Ester s w ith
B-Ch lor od iisop in oca m p h eylbor a n e
P. Veeraraghavan Ramachandran,* Sangeeta Pitre, and Herbert C. Brown
Herbert C. Brown Center for Borane Research, Purdue University, West Lafayette, Indiana 47907-1393
chandran@purdue.edu
Received February 5, 2002
A comparison of the stereochemistry of the products obtained from the intramolecular asymmetric
reduction of a series of keto acids with (-)-diisopinocampheylborane and intermolecular asymmetric
reduction of the corresponding series of keto esters with (-)-B-chlorodiisopinocampheylborane ((-
)-DIP-Chloride) has been made. The stereochemistry of the hydroxy acids from the reduction of
keto acids is dependent only on the enantiomer of the reagent used. The stereochemistry of the
products from the reduction of keto esters is also consistent, except those of aliphatic R-keto esters.
R-, â-, and γ-keto acids provide the corresponding hydroxy acids in 77-98% ee, and the R- and γ-
keto esters afford the hydroxy esters in 82-g99% ee. â-Keto esters do not undergo reduction.
Although the reduction of δ-keto acids does not proceed under the same reaction conditions, the
reduction of δ-keto esters is facile. All of the products from the reduction of γ-keto acids and esters
and δ-keto esters were converted to the corresponding lactones. This study revealed that DIP-
Chloride is an efficient reagent for the reduction of R-keto esters at low temperatures.
In tr od u ction
lar asymmetric reductions of o-acylphenols, -anilines, and
-benzoic acids (eq 2).4 In all of these intramolecular
reductions, the product alcohols were obtained in opposite
stereochemistry as compared to the intermolecular re-
duction of the corresponding heteroalkylated acyl deriva-
tives with 1.4 We noticed that while the intramolecular
asymmetric reduction provided similar % ee for the
product alcohols in the case of o-acylphenols and-anilines,
the % enantiomeric excesses (ee) for the products from
the reduction of o-acylbenzoic acids with reagent 2 were
superior. This was attributed to a partial intermolecular
reduction due to an inherent equilibrium between the
keto acid and the HCl produced early in the reaction.4c
This problem was circumvented by utilizing the sodium
salt of the keto acid or conducting the reaction in the
presence of an amine.4c
B-Chlorodiisopinocampheylborane (Ipc2BCl, DIP-Chlo-
ride, 1) is very effective for the intermolecular asym-
metric reduction of various classes of ketones, such as
aralkyl ketones (eq 1), R-hindered ketones, and perfluo-
roalkyl ketones.1 It has been applied for the preparation
of intermediates for several important pharmaceutical
compounds.2
In contrast, the parent diisopinocampheylborane (2) is
a very poor reagent for intermolecular asymmetric reduc-
tions (eq 1).3 However, we have recently reported that
both of these reagents are very effective for intramolecu-
(1) (a) Brown, H. C.; Chandrasekharan, J .; Ramachandran, P. V. J .
Am. Chem. Soc. 1988, 110, 1539. (b) For a review on DIP-Chloride,
see: Ramachandran, P. V.; Brown, H. C. In Reductions in Organic
Chemistry; Abdel-Magid, A. A., Ed.; ACS Symposium Series No. 641;
American Chemical Society: Washington, DC, 1996; Chapter 5.
(2) Srebnik, M.; Ramachandran, P. V.; Brown, H. C. J . Org. Chem.
1988, 53, 2916. (b) Ramachandran, P. V.; Gong, B.; Brown, H. C.
Tetrahedron: Asymmetry 1993, 4, 2399. (c) Ramachandran, P. V.;
Gong, B.; Brown, H. C. Chirality 1995, 7, 103. (d) King, A. O,; Corley,
E. G.; Anderson, R. K.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J .;
Xiang, Y. B.; Belley, M.; Leblanc, Y.; Labelle, M.; Prasit, P.; Zamboni,
R. J . Org. Chem. 1993, 58, 3731. (e) Chong, J . M.; Clarke, I. S.; Koch,
I.; Olbach, P. C.; Taylor, N. J . Tetrahedron: Asymmetry 1995, 6, 409.
(3) Brown, H. C.; Mandal, A. K. J . Org. Chem. 1977, 42, 2996.
The above intramolecular reductions were then ex-
tended to aliphatic systems, such as hydroxy ketones and
keto acids. The intramolecular asymmetric reduction of
10.1021/jo025594y CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/29/2002
J . Org. Chem. 2002, 67, 5315-5319
5315

Ramachandran et al.
R- and â-hydroxy ketones with 1 and 2 provides the
corresponding diols in high ee.5 However, γ-hydroxy
ketones did not undergo reduction even in refluxing THF.
Similarly, aliphatic keto acids undergo asymmetric re-
duction with 1 and 2.6 However there has been no
comparison of the stereochemistry of the products ob-
tained from the corresponding keto esters, although it is
believed to be opposite. We undertook to examine this
and found that the reversal of stereochemistry is not
general. We observed differences in the stereochemistry
of the products from the reduction of aromatic and
aliphatic keto esters themselves with 1. This study also
established that 1 is a much superior reagent than earlier
reported for the reduction of R-keto esters. The details
of our study are described below.
carried out the reduction of ethyl benzoylformate (6) with
(-)-1 at -78 °C and obtained (R)-ethyl mandelate (7) in
89% ee (eq 4).
An aliphatic R-keto ester, ethyl pyruvate (8), was
reduced by (-)-1 at -78 °C to (S)-ethyl lactate (9). A
comparison of the rotation of 9 with the literature data10
revealed an optical purity of 82% (eq 4). Surprisingly, we
obtain opposite stereochemistry for the products from the
reduction of aromatic and aliphatic R-keto esters with 1.
This is similar to what we had observed for the reduction
of these keto esters with 3 as well (eq 3).7 Thus, we have
now established that 1 is an efficient reagent for the
reduction of R-keto esters at -78 °C.
Red u ction of r-Keto Acid s. Either enantiomer of
3-substituted 1(3H)-isobenzofuranones (phthalides) can
be obtained via an intermolecular asymmetric reduction
of 2-acylbenzoates or the intramolecular reduction of the
corresponding 2-acylbenzoic acids with 1 followed by
lactonization.4c Higher ee can be achieved by the reduc-
tion of acylbenzoic acids with 2 since this process avoids
an undesirable equilibrium between the keto acid and
HCl.
To determine whether the reversal in stereochemistry
observed in the reduction of aryl and alkyl R-keto esters
with 1 is comparable to the reduction of the correspond-
ing keto acids with 2, we treated benzoylformic acid (10)
with an equivalent of 2 (prepared from (+)-R-pinene) in
THF at 0 °C. Immediate evolution of 1 equiv of hydrogen,
followed by an intramolecular reduction within 10 h,
provided the intermediate, which was oxidized under
alkaline conditions to obtain mandelic acid (11) in 82%
yield (eq 5). Conversion to the corresponding methyl ester
and HPLC analysis using a Chiralcel OD-H column
revealed an ee of 95% for (R)-5. As can be seen, there is
no reversal in the stereochemistry as compared to the
reduction of the aryl keto ester!
Resu lts a n d Discu ssion
Red u ction of r-Keto Ester s. More than a decade ago,
we had reported the reduction of methyl benzoylformate
(4) with (-)-1 (prepared from (+)-R-pinene) in THF at
-25 °C to (R)-methyl mandelate (5). On the basis of a
gas chromatographic analysis of the corresponding R-meth-
oxy-R-(trifluoromethyl)phenyl acetate, we had reported
an ee of 70%.1a R-Alpine-borane (3) reduces 4 to (R)-5
under neat conditions at room temperature (rt) in 83%
ee (eq 3).7 The mode of action of 1 and 3 is believed to be
similar. By reducing a series of R-keto esters, we had
established that 3 is an efficient reducing agent for this
class of ketones (eq 3). However, we had not examined
the efficacy of 1 for the reduction of other R-keto esters.
During the current project, we had to compare the
stereochemistry of the products from the reduction of keto
esters and acids.
A reexamination of the reduction of 4 with (-)-1 at -25
°C and analysis of 5, this time using a Chiralcel OD-H
column8 with HPLC, revealed an ee of 84%. The optical
25
rotation, [R]D -127.88 upon comparison with that
reported in the literature confirmed the R-configuration
and ee of the hydroxy ester.9 Since the reduction was
complete within 1 h, we performed the experiment at -78
°C with the hope of improving the ee. The reaction was
complete in 2 h, and workup provided (R)-5 in 92% ee.
To verify the generality of this reduction with 1, we
(4) (a) Ramachandran, P. V.; Gong, B.; Brown, H. C. Tetrahedron
Lett. 1994, 35, 2141. (b) Ramachandran. P. V.; Malhotra, S. V.; Brown,
H. C. Tetrahedron Lett. 1997, 38, 956. (c) Ramachandran, P. V.; Chen,
G. M.; Brown, H. C. Tetrahedron Lett. 1997, 38, 2417.
(5) Ramachandran, P. V.; Lu, Z. H.; Brown, H. C. Tetrahedron Lett.
1997, 38, 761.
(6) (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. (c)
Ramachandran, P. V.; Brown, H. C.; Pitre, S. Org. Lett. 2001, 3, 17.
(7) Brown, H. C.; Pai, G. G. J . Org. Chem. 1985, 50, 1384.
(8) Chiralcel OD-H is a product of Chiral Technologies, Inc., Exton,
PA.
We then compared the reduction of an aliphatic keto
acid, 2-oxopentanoic acid (12), with 2, which was com-
plete within 12 h, and alkaline H2O2 workup provided
(R)-2-hydroxypentanoic acid (13) in 77% ee (eq 5), on the
basis of the optical rotation reported in the literature.11
(10) Deol, B. S.; Rigley, D. D.; Simpson. Aust. J . Chem. 1976, 29,
2459.
(11) Bur, D.; Luyten, M. A.; Wynn, H.; Provencher, L. R.; J ones, J .
B. Gold, M.; Friesen, J . D.; Clarke, A. R.; Holbrook, J . J . Can. J . Chem.
1989, 67, 1065.
(9) Aldrich Catalog Handbook of Fine Chemicals.
5316 J . Org. Chem., Vol. 67, No. 15, 2002

Intramolecular Asymmetric Reductions
The % ee was further confirmed by 1H NMR spectroscopic
analysis of the corresponding acetate in the presence of
Eu(hfc)3. Thus, the stereochemistry of the product hy-
droxy acid depends only on the enantiomer of reagent 2
used and not on the nature (aromatic or aliphatic) of the
keto acid reduced. It is noteworthy that there is a reversal
in the stereochemistry of the product as compared to the
product from the reduction of the corresponding keto
ester with 1. As can be seen from the stereochemistry of
the products of reduction of â- and γ-keto acids described
below, the exception to the generality is the reduction of
aliphatic keto esters with 1.
aryl ketones, we examined the reduction of ethyl 3-ben-
zoylpropanoate (20) with 1 in THF at -25 °C. The
reaction was complete in 12 h, and workup provided the
product γ-hydroxy ester 21 in 75% yield (eq 8). We
converted this to the corresponding γ-lactone 22 by
treatment with a catalytic amount of trifluoroacetic acid
to determine the optical purity and the stereochemistry.
The optical rotation13 of 22 revealed a purity of g99% in
the S-isomer, which was confirmed by HPLC analysis on
a Chiralcel OD-H column. The configurations of 21 and
22 are as expected for a reduction with 1.
Red u ction of r-Keto Ester s. We have already shown
that 1 is incapable of reducing â-keto esters with an
enolizable R-hydrogen atom.1 Upon mixing the reagent
with ethyl benzoyl acetate (14), 1 mol of hydrogen
chloride was liberated and a strong six-membered chelate
(15; 11B NMR δ 13 ppm) was formed (eq 6). There was
no further change in the 11B NMR spectrum, even after
leaving the reaction mixture at room temperature for
several days, indicating no further reaction.
The reduction of an aliphatic γ-keto ester (23) provided
the corresponding hydroxy ester 24 in 27% ee. This is
expected on the basis of the ineffectiveness of 1 to reduce
aliphatic ketones. Cyclization of 24 provided the corre-
sponding lactone 25 in 27% ee.
Red u ction of γ-Keto Acid s. The reduction of 3-ben-
zoylpropanoic acid (26) with 2 was complete within 36
h. Workup provided 90% yield of the corresponding
hydroxy acid 27. This was lactonized in the presence of
trifluoroacetic acid to the corresponding γ-lactone 22 in
90% yield (eq 9). The % ee of the lactone as determined
by HPLC analysis on a Chiralcel OD-H column is 94%.
A comparison of the optical rotation of 22 with that
reported in the literature13 revealed it to be the S-isomer,
similar to the alcohol obtained from the reduction and
hydrolysis of 20 with 1.
Red u ction of r-Keto Acid s. In contrast, we expected
smooth intramolecular reduction of â-keto acids with 2.
The reduction of benzoylacetic acid (16) with 2 was
complete within 55 h, and alkaline H2O2 workup provided
the product hydroxy acid 17 in 85% yield (eq 7). The
optical rotation revealed that we had obtained the (S)-
hydroxy acid in 92% ee. The ee was confirmed by
conversion of the product to the benzyl ester and analyz-
ing on a Chiralcel OD-H column using an HPLC. The
reduction of an aliphatic â-keto acid, 3-oxo-butanoic acid
(18), with 2 was complete in 32 h, and the usual workup
provided the corresponding hydroxy acid 19 in 75% yield.
Conversion of this hydroxy acid to the corresponding
benzyl ester and comparison of the maximum rotation
reported in the literature12 revealed an optical purity of
92% in the R-isomer (eq 7). The % ee was confirmed by
the HPLC analysis of the benzyl ester on a Chiralcel
OD-H column.
The stereochemistry of the product hydroxy acids is
similar for the R- and â-keto acids. Although we have no
way of comparing it with that of the corresponding
â-hydroxy esters, the predictability of the product ster-
eochemistry is a useful feature of this reduction.
The reduction of an aliphatic γ-keto acid, 4-oxopen-
tanoic acid (28), with 2 resulted in the formation of the
corresponding hydroxy acid 29 in 98% ee, as determined
by its conversion of to γ-methyl-γ-lactone (R-25) and
comparison of the optical rotation with the literature
data14 (eq 9). Thus the reduction of aliphatic γ-keto acids,
followed by esterification of the acid, is an excellent
alternative for the reduction of aliphatic γ-keto esters
with 1.
Red u ction of γ-Keto Ester s. Unlike â-keto esters,
the reduction of γ-keto esters is facile with 1. Since 1
provides high ee for the alcohols from the reduction of
(13) Brown, H. C.; Kulkarni, S. V.; Racherla, U. S. J . Org. Chem.
1994, 59, 365.
(12) Medson, C.; Smallridge, A. J .; Trewhella, M. A. Tetrahedon:
Asymmetry 1997, 8, 1049.
(14) Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990,
31, 5509.
J . Org. Chem, Vol. 67, No. 15, 2002 5317

Ramachandran et al.
TABLE 1. Red u ction of Keto Ester s w ith (-)-Ip c2BCl
keto ester RCO(CH2)nCOOR reactn cond
hydroxy ester RCH(OH)(CH2)nCOOR
no.
n
R
R′
time, h
temp, °C
no.
% yield
% ee
configa
4
4
0
0
0
0
1
1
2
2
3
Ph
Ph
Ph
Me
Ph
Ph
Ph
Me
Ph
Me
Me
Et
Et
Et
Et
Et
Et
Et
<1
1
-25
-78
-78
-78
-25
-25
-25
25
5
5
7
9
87
89
79
75
84b
92b
89b
82c
R
R
R
S
6
1
8
1
24
24
12
12
12
14
14
20
23
33
chelate formation, no reacn
chelate formation, no reacn
21
24
34
75
77
77
g99d
27
S
R
S
-25
98d
a
b
Determined by comparison of the optical rotation with that reported in the literature. See the text. % ee determined by the HPLC
analysis of the hydroxy ester on a Chiralcel OD-H column. c % ee determined by comparison of the optical rotation. % ee determined by
d
HPLC analysis of the corresponding lactone on a Chiralcel OD-H column.
TABLE 2. Red u ction of Keto Acid s w ith (-)-Ip c2BH
keto acid RCO(CH2)nCOOH
n
hydroxy acid RCH(OH)(CH2)nCOOH
no.
R
reacn time, h
no.
% yield
% ee
configa
10
12
16
18
26
28
30
36
0
0
1
1
2
2
2
3
Ph
n-Pr
Ph
Me
Ph
Me
Et
Et
10
12
55
32
36
17
17
24h
11
13
17
19
27
29
31
82
75
85
75
90
82
82
95b
77c
92d
92d
94e
98f
R
R
S
R
S
R
R
95f,g
a
b
Determined by comparison of the optical rotation with that reported in the literature. See the text. % ee determined by the HPLC
analysis of the hydroxy ester on a Chiralcel OD-H column. c % ee determined by 1H NMR spectroscopic analysis of the acetate in the
presence of Eu(hfc)3. % ee determined by HPLC analysis of the corresponding benzyl ester on a Chiralcel OD-H column. e % ee determined
d
by HPLC analysis of the corresponding lactone on a Chiralcel OD-H column. f % ee determined by comparison of the optical rotation. See
the text. % ee determined by 1H NMR spectroscopic analysis (in the presence of Eu(hfc)3) of the diol obtained by opening the lactone
g
with excess MeLi.16 There was no reaction even in refluxing THF.
h
The possibility of the formation of both aliphatic and
aromatic γ-lactones in high ee via the asymmetric reduc-
tion of γ-keto acids with 2 prompted us to include the
reduction of 4-oxohexanoic acid (30) as well since the
corresponding lactone, 4-hexanolide (32), is a component
of the pheromone secreted by the female dermestid beetle
Trogoderma glabrum. We obtained the hydroxy acid 31
in 95% ee, which was converted to the pheromone without
any loss of optical activity.
Red u ction of γ-Keto Acid s. When a δ-keto acid,
4-benzoylbutanoic acid (36), was mixed with 2, evolution
of 1 molar equiv of hydrogen was observed with the
concurrent formation of the diisopinocampheylborinate
37 as indicated by the 11B NMR spectrum. However,
unlike in the case of R-, â-, and γ-keto acids, no intramo-
lecular reduction was observed (eq 11). Heating the THF
solution to reflux made no difference. Thus, the intramo-
lecular asymmetric reduction is limited to R-, â-, and
γ-keto acids.
Red u ction of γ-Keto Ester s. Reduction of ethyl
4-benzoylbutanoate (33) with 1 in THF at -25 °C was
complete in 12 h, and the usual workup provided the
corresponding δ-hydroxy ester 34. The enantiomeric
excess was determined by converting this to the corre-
sponding δ-phenyl-δ-lactone 35 (eq 10). A comparison of
the rotation with that reported in the literature15 re-
vealed an optical purity of 98% in the S-isomer, which
was confirmed by HPLC analysis on a Chiralcel OD-H
column. The stereochemistry of 34 and 35 is as would
be expected for the reduction of such a ketone with 1.
The reduction of all of the keto esters is summarized
in Table 1, and that of keto acids is summarized in Table
2.
Con clu sion s
In conclusion, we have studied the intramolecular
asymmetric reduction of a series of R-, â-, and γ-keto acids
with (-)-diisopinocampheylborane and intermolecular
asymmetric reduction of the corresponding series of keto
(15) Downham, R.; Edwards, P. J .; Entwistle, D. A.; Hughes, A. B.;
Kim, K. S.; Ley, S. V. Tetrahedron: Asymmetry 1995, 6, 2403.
5318 J . Org. Chem., Vol. 67, No. 15, 2002

Intramolecular Asymmetric Reductions
monitored by 11B NMR spectroscopy, which revealed a peak
at δ 32 ppm when the reaction was complete. Upon completion
of the reaction, the mixture was oxidized by the addition of 4
mL of 3 N NaOH and 2 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 reasonably pure hydroxy
acid, which was further purified for recording the optical
rotation.
Gen er a l P r oced u r e for th e In ter m olecu la r Red u ction
of Keto Ester s w ith (-)-DIP -Ch lor id e. All of the procedures
were carried out in an inert atmosphere. An oven-dried, 100
mL round-bottom flask equipped with a sidearm, magnetic
stirring bar, and connecting tube was cooled to room temper-
ature in a stream of nitrogen. To this was added 11 mmol (3.5
g) of (-)-DIP-Chloride ((-)-1) and THF (11 mL), and the
mixture was cooled to -78 °C, followed by the addition of 10
mmol of the R-keto ester. A yellow color developed indicating
a complex formation. The 11B NMR spectrum of a methano-
lyzed aliquot of the reaction mixture (δ 32 ppm) indicated
progressive disappearance of 1. The reagent was consumed
in 2 h when the mixture was warmed to 0 °C and treated with
2.2 equiv of diethanolamine. This mixture was filtered through
a silica gel and chromatographed to isolate pure hydroxy ester.
The reaction of γ- and δ-keto esters were carried out at -25
°C.
esters with (-)-B-chlorodiisopinocampheylborane and
compared the stereochemistry of the products obtained.
The hydroxy derivatives were obtained in 77-g99% ee.
The stereochemistry of the products is independent of the
keto acids and esters in all cases, except in the case of
aliphatic R-keto esters. This study has revealed that DIP-
Chloride is an efficient reagent for the reduction of R-keto
esters in 82-92% ee. The reduction of δ-keto acids does
not proceed under the same reaction conditions, and the
reduction of δ-keto esters is facile. γ- and δ-lactones were
prepared from the product γ-hydroxy acids and esters and
δ-hydroxy esters.
Exp er im en ta l Section
Gen er a l Meth od s. All operations were carried out under
an inert atmosphere. Techniques for handling air- and moisture-
1
sensitive materials have been previously described.17 The H
and 11B NMR spectra were plotted on a Varian Gemini-300
spectrometer with a Nalorac-Quad probe. The optical rotations
were measured using a Rudolph Autopol III polarimeter.
Ma ter ia ls. THF was distilled from sodium benzophenone
ketyl. â-Keto acids were prepared according to a literature
procedure.18 γ- and δ-keto acids were prepared from the
corresponding esters by base hydrolysis. Enantiomerically pure
(-)-Diisopinocampheylborane was prepared from (+)-R-pinene
and borane-methyl sulfide according to the literature proce-
dure.19
P r ep a r a tion of La cton es fr om Hyd r oxy Acid s a n d
Hyd r oxy Ester s. The following procedure for the synthesis
of 4-hexanolide is representative. The hydroxy acid 31 pre-
pared as described above (1.1 g, 82%) was dissolved in CH2-
Cl2 (10 mL), and the solution was 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
Gen er a l P r oced u r e for th e In tr a m olecu la r Red u ction
of Keto Acid s w ith Ip c2BH. All of the procedures were
carried out in an inert atmosphere. An oven-dried, 100 mL
round-bottom flask equipped with a sidearm, magnetic stirring
bar, and 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 and suspended in THF
(10 mL), and the mixture was stirred at 0 °C. The keto acid
(10 mmol) dissolved in minimum amount of anhydrous THF
was slowly added, at 0 °C, to the flask when evolution of
hydrogen was noticed. The 11B NMR of the resultant clear
solution showed a peak at δ 52 ppm. The mixture was warmed
to room temperature. The progress of the reaction was
20
concentrated to yield 0.76 g (80%) of 32, [R]D ) +50.63 (c
1.5, MeOH), which corresponds to 95% ee in the (R)-isomer.20
Ack n ow led gm en t . Financial support from the
United States Army Research Office (Grant DAAG55-
98-1-0405) and the Herbert C. Brown Center for Borane
Research is gratefully acknowledged.21
(16) J akovac, I. J .; J ones, J . B. J . Org. Chem. 1979, 44, 2165.
(17) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Syntheses via Boranes; Wiley-Interscience: New York, 1975.
Reprinted edition: Aldrich Chemical Co. Inc.: Milwaukee, WI, 1997;
Vol. 1, Chapter 9.
J O025594Y
(18) Barnick, J . W. F. K.; van der baan, J . L.; Bickelhaupt, F.
Synthesis 1979, 787.
(19) Brown, H. C.; J oshi, N. N. J . Org. Chem. 1988, 53, 4059.
(20) Mori, K.; Mori, H.; Sugai, T. Tetrahedron 1985, 41, 919.
(21) Contribution No. 18 from the Herbert C. Brown Center for
Borane Research.
J . Org. Chem, Vol. 67, No. 15, 2002 5319