Optical resolution of cyclic amides by inclusion in dehydrocholic acid

Article abstract of DOI:10.1246/cl.2003.206

Dehydrocholic acid serves as an effective chiral host for the resolution of several five-, six-, and seven-membered cyclic amides by inclusion.

Full text of DOI:10.1246/cl.2003.206

2
06
Chemistry Letters Vol.32, No.3 (2003)
Optical Resolution of Cyclic Amides by Inclusion in Dehydrocholic Acid
ꢀ
y
Olga Bortolini, Marco Fogagnolo, Giancarlo Fantin, and Alessandro Medici
Dipartimento di Chimica, Via Borsari 46, 44100 Ferrara
y
Dipartimento delle Risorse Naturali e Culturali,
Corso Porta Mare 2, Universit a` di Ferrara, 44100 Ferrara, Italy
(Received November 18, 2002; CL-020980)
Dehydrocholic acid serves as an effective chiral host for the
resolution of several five-, six-, and seven-membered cyclic
amides by inclusion.
exemplified for amide 2 in milligram and multigram scale as
follows, in agreement with Scheme 1. One equivalent (100 mg) of
dehydrocholic acid, commercially available bile acid used
without further purification, is added to a solution containing 5
equivalents of the racemic amide 2, dissolved in 1 mLof ethyl
acetate–ether (1:1). After 24 h at room temperature the crystals
Bile acids represent a cheap and readily available class of
1
chiral host molecules for the direct resolution of guest racemates.
Table 1. Resolution of cyclic amides using dehydrocholic acid 1
as chiral host
The procedure is based on the ability of the bile acids, in particular
of cholic and deoxycholic acids, to incorporate enantioselectively
within their molecular structure one of the two forms of the
racemic guest, thus allowing separation and recovery of both
enantiomers. Examples include the resolution of organic sub-
Cyclic amide
1:amide
ratio
ee %b
1st cycle
ee %b
2nd cycle
Config.c
a
strates such as lactones, alcohols,3 epoxides and cyclic
2
4
1:1
1:1
42
0
80
---
(-)-(S)13
5
6
ketones. In addition, we have recently described the first report
on the use of dehydrocholic acid 1 (3,7,12-trioxo-5b-cholan-24-
oic acid) a bile acid lacking hydroxyl groups, for the resolution of
alkyl aryl sulfoxides with enantiomeric excesses up to 99%.
This approach has been extended to the resolution of several
five-, six- and seven-membered cyclic amides 2–10, owing to the
fact that the obtainment of these derivatives in high optical yield is
limited to few selected cases like 4-amino-p-chlorobutyric acid
lactam and 4-acetoxy-2-azetidinone.8 Lactams,9 in fact, are
important structural frameworks of biologically active com-
O
N
H
2
---
O
N
CH
3
3
4
7
O
N
(+)-(R)14
1
:1
64
30
92
62
H
Ph
10
11
pounds as alkaloids, b-lactam antibiotics or GABA ana-
logues.
The resolution procedure is simple and straightforward,
1
2
1:1
1:1
(+)-(R)15
O
N
H
5
O
O
(+)-(S)18
(+)
N
17
50
32
87
H
6
COOH
1.4:1
N
O
H
7
1
O
O
(+)-(S)16
1
.3:1
11
75
23
94
N
H
O
8
1
:1
(+)-(R)17
(+)-(R)17
N
H
O
9
1
:1
13
30
DHA + (R,S)-amide
DHA (S)-amide
N
H
O
1
0
(
R)-amide
a
1
b
Determined by H NMR on the formed crystals. determined by GC on
c
DHA = dehydrocholic acid
Scheme 1.
Megadex DETTBS.
comparison of [α]
the absolute configurations were established by
with literature values, see references from 13 to18.
D
Copyright ꢀ 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.3 (2003)
207
were filtered, washed with ethyl acetate–ether (1:1), analyzed by
1
Hosts’’ in ‘‘Comprehensive Supramolecular Chemistry,’’ ed.
by D. D. MacNicol, F. Toda, and R. Bishop, Pergamon,
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(2001).
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Pedrini, Chem. Commun., 2000, 365. b) V. Bertolasi, O.
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H NMR to obtain the host:guest ratio, treated with aqueous
NaHCO3 and extracted with ethyl acetate. The extracts were
analyzed by GC for the ee determination and by polarimetry to
assign the absolute configuration, see Table 1. For resolution on
multigram scale, 5 g of dehydrocholic acid were added to a
solution of 2 (5 g) dissolved in 50 mLof ethyl acetate–ether (1:1).
The crystals were collected by filtration, washed several times
with ethyl acetate–ether and (ꢁ)-2 was recovered, 1 g ca. 42% ee,
2
3
4
5
ꢂ
upon distillation using a Kugelrohr apparatus (150 C, 1 mm Hg).
When the same procedure was repeated on the partially resolved
racemate, (ꢁ)-2 was obtained with an optical yield of 80%. As
expected although not reported in the Table, depending on the
number of cycles, the complete resolution of the substrates is
obtained in all cases except for the N-methyl derivative 3. The
complete set of results, including the two-cycle procedure, is
shown in Table 1.
6
7
8
9
As reported in the second row of the Table the bile acid-to-
amide inclusion ratio is generally 1:1, however some noticeable
differences demonstrate the independence of the steric dimen-
sions of the cyclic amide with respect to the inclusion stoichio-
metry, see for example 2 and 9. The host-guest relationship of the
included molecules is well evident in a comparison between the
FT-IR spectra of the ‘‘free’’ and included amides in KBr. As an
10 K. Drandarov, Tetrahedron Lett., 36, 617 (1995).
11 F. H. Van der Steen and G. van Koten, Tetrahedron, 47, 7503
(1991).
12 R. B. Silverman and S. M. Nanavati, J. Med. Chem., 33, 931
(1990).
13 D. Enders, R. Grobner, G. Raabe, and J. Runsink, Synthesis,
1996, 941.
14 H. D. Doan, J. Gor e´ , and J. M. Vat e` le, Tetrahedron Lett., 40,
6765 (1999).
15 A. I. Meyers and L. Snyder, J. Org. Chem., 58, 36 (1993).
16 J. Aub e´ , M. Hammond, E. Gherardini, and F. Takusagawa, J.
Org. Chem., 56, 499 (1991).
17 J. Aub e´ , Y. Wang, M. Hammond, M. Tanol, F. Takusagawa,
and D. V. Velde, J. Am. Chem. Soc., 112, 4879 (1990).
ꢁ
1
example 2 gives rise to a broad signal, centered at 3201 cm
ascribable to an intermolecular N–H stretching. The same signal
,
ꢁ
1
resolved in a sharp band at 3354 cm upon inclusion in the host.
Worthy of note are the results obtained with the five-
membered amide 2 if compared with the N-methyl homologue 3.
Both derivatives include within the dehydrocholic acid in a one-
to-one ratio, however only 2 showed enantioselective incorpora-
tion in the host, thus suggesting a possible role played by the N–H
function on the enantiodiscrimination.
We are currently extending this readily accessible and low
cost methodology to the resolution of other classes of ‘‘neutral’’
organic molecules.
1
8 S. B. Davies and M. A. McKervey, Tetrahedron Lett., 40,
1229 (1999).
References and Notes
1
M. Miyata and K. Sada, ‘‘Deoxycholic Acis and Related