Effects of lithium salts on the enantioselectivity of protonation of enolates with chiral imide

Article abstract of DOI:10.1055/s-1998-1594

An increase in enantioselectivity was observed in the asymmetric protonation of prochiral enolates with a chiral imide using lithium salt as an additive. For example, (R)-enriched 2-n-pentylcyclopentanone 6 was obtained in high yield with 90% ee when the silyl enol ether 4 was treated with n-BuLi in the presence of 5 equiv of LiBr in Et₂O and the resulting lithium enolate 5 was then protonated by a solution of (S,S)-imide 1 in THF. In contrast, the product 6 obtained without LiBr exhibited a lower enantiomeric excess (74% ee).

Full text of DOI:10.1055/s-1998-1594

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Effects of Lithium Salts on the Enantioselectivity of Protonation of Enolates with Chiral Imide
Akira Yanagisawa, Tetsuo Kikuchi, Hisashi Yamamoto*
Graduate School of Engineering, Nagoya University, CREST, Japan Science and Technology Corporation (JST), Chikusa, Nagoya 464-01, Japan
Received 21 October 1997
Abstract: An increase in enantioselectivity was observed in the
asymmetric protonation of prochiral enolates with a chiral imide using
lithium salt as an additive. For example, (R)-enriched 2-n-
pentylcyclopentanone 6 was obtained in high yield with 90% ee when
the silyl enol ether 4 was treated with n-BuLi in the presence of 5 equiv
of LiBr in Et O and the resulting lithium enolate 5 was then protonated
2
by a solution of (S,S)-imide 1 in THF. In contrast, the product 6
obtained without LiBr exhibited a lower enantiomeric excess (74% ee).
We have previously shown that (S,S)-imide 1, a chiral imide with an
asymmetric 2-oxazoline, is an efficient chiral proton source for
1,2
asymmetric protonation of simple metal enolates. Various enolates
derived from 2-alkylcycloalkanones can be protonated with high
enantioselectivity. For instance, the reaction of lithium enolate 2 with an
equimolar amount of the chiral imide 1 gives (R)-enriched 2,2,6-
1a
trimethylcyclohexanone (3) with 87% ee (eq 1). We report here the
asymmetric protonation of prochiral enolates in which
enantioselectivity is remarkably improved using lithium bromide as an
additive. Lithium salts are known to be incorporated into lithium enolate
3
4
aggregates and often increase the degree of asymmetric induction.
Thus, we examined the effect of the addition of lithium salt on the
enantioselectivity of protonation with (S,S)-imide 1.
5
6
The silyl enol ether 4 was treated with a solution of n-BuLi/hexane
(1.1 equiv) in the presence of a metal salt in THF or ether at 0 °C for 2 h,
and the in situ-generated lithium enolate 5 was then protonated with
(S,S)-imide 1 (1.1 equiv) in THF at -78 °C for 2 h to give (R)-enriched
7
2-n-pentylcyclopentanone (6, eq 2). The results are summarized in
Table 1. In the absence of a metal salt, the reaction proceeded in THF or
a mixture of ether and THF with moderate enantioselectivity (63~74%
ee, entries 1 and 2). In contrast, when an equimolar amount of lithium
bromide was present, higher enantiomeric excesses were obtained
(entries 3 and 4). Further increases in enantioselectivity were observed
under the influence of more than one equivalent of LiBr. The use of 5
equiv of the salt in ether resulted in the highest optical purity (90% ee,
entry 8). Interestingly, protonation of the lithium enolate 5 gave better
results in a mixture of ether and THF than in THF alone regardless of
8
the amount of LiBr (entries 1-10). Although other lithium salts, sodium
bromide, and magnesium bromide were also examined as additives,
they decreased the enantiomeric ratio of the ketone 6 (entries 11-17).
n
CH Cl and MeO Pr were less effective solvents with respect to
2
2
asymmetric induction (entries 18 and 19).
We then studied the enantioselective protonation of various enolates 2,
9
5, and 7-9 with (S,S)-imide 1 in the presence of 5 equiv of LiBr (eq 3).
and 10); (2) higher enantioselectivity was attained when a lithium
enolate was generated in ether rather than THF, except in the case of 2,
which gave the best ee in the reaction without LiBr in THF (entry 9);
and (3) a lithium enolate of 2-alkylcyclopentanone is superior to that of
8
Some examples are listed in Table 2. These reactions have the following
characteristics: (1) the addition of LiBr had a positive effect for all of
the enolates tested, with the exception of the lithium enolate 2 (entries 9

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175
2-alkylcyclohexanone with regard to the enantioselectivity of
protonation with 1 (compare entries 1, 2, 5, and 6).
enolate-LiBr mixed aggregate is the dominant reactant at higher
concentrations of LiBr. We have described above an improved
10
method for the enantioselective protonation of simple prochiral enolates
with (S,S)-imide 1 in the presence of LiBr as an additive.
A representative experimental procedure is given by the reaction of
lithium enolate 5 with (S,S)-imide 1 (entry 8 in Table 1 and entry 4 in
Table 2). Silyl enol ether
cyclopentenone. To a mixture of 4 (226 mg, 1.0 mmol) and LiBr (434
4 was prepared from 2-n-pentyl-2-
5
mg, 5.0 mmol) in dry Et O (5 mL) at 0 °C was added a solution of n-
2
6
BuLi (1.65 M, 0.67 mL, 1.1 mmol) in hexane under argon. After the
reaction mixture had been stirred for 2 h at 0 °C, a solution of (S,S)-
imide 1 (443 mg, 1.1 mmol) in dry THF (5 mL) was added dropwise at
-78 °C. After being stirred for 2 h, TMSCl (0.13 mL, 1.0 mmol) was
added, and stirring continued for another 30 min at this temperature. A
saturated NH Cl solution (10 mL) was then added, and the organic
4
material was extracted twice with Et O (2 x 10 mL). The combined
2
organic extracts were washed with saturated brine (20 mL), dried over
anhydrous Na SO , and concentrated in vacuo. The crude product was
2
4
purified by column chromatography on silica gel (pentane/Et O, 5/1 to
2
hexane/EtOAc, 1:2) to give the (R)-enriched ketone 6 (155 mg, >99%
isolated yield) with 90% ee as a colorless oil which showed the
11
appropriate spectral data. The enantiomeric ratio was determined by
TM
GC analysis using a chiral column (astec, Chiraldex B-TA, 80 °C, 70
Pa): t = 23.9 min (R-isomer); t = 24.7 min (S-isomer). The imide 1
R
R
was recovered (>90% yield) without a noticeable loss of optical purity.
Acknowledgments. This work was supported in part by the Ministry of
Education, Science, Sports and Culture of the Japanese Government.
T.K. also acknowledges a JSPS Fellowship for Japanese Junior
Scientists.
References and Notes
(1) (a) Yanagisawa, A.; Kuribayashi, T.; Kikuchi, T.; Yamamoto, H.
Angew. Chem. Int. Ed. Engl. 1994, 33, 107. (b) Yanagisawa, A.;
Kikuchi, T.; Watanabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett
1995, 372. (c) Yanagisawa, A.; Ishihara, K.; Yamamoto, H.
Synlett 1997, 411. (d) Yanagisawa, A.; Watanabe, T.; Kikuchi, T.;
Kuribayashi, T.; Yamamoto, H. Synlett 1997, 956.
(2) Reviews of asymmetric protonations: (a) Duhamel, L.; Duhamel,
P.; Launay, J.-C.; Plaquevent, J.-C. Bull. Soc. Chim. Fr. 1984, II-
421. (b) Fehr, C. Chimia 1991, 45, 253. (c) Waldmann, H. Nachr.
Chem., Tech. Lab. 1991, 39, 413. (d) Hünig, S. In Houben-Weyl:
Methods of Organic Chemistry; Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart,
1995; Vol. E 21, p 3851. (e) Fehr, C. Angew. Chem. Int. Ed. Engl.
1996, 35, 2566.
(3) (a) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay,
T.; Simson, M.; Seebach, D. Synthesis 1993, 1271. (b) Henderson,
K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard, P. G.; Schleyer, P. v.
R.; Bernstein, P. R. J. Am. Chem. Soc. 1996, 118, 1339.
It is not yet clear why LiBr increases the enantioselectivity of
protonation. However, a mixed aggregate might be formed, such as 10,
consisting of a lithium enolate and LiBr, and this could participate in the
reaction. In fact, it has been reported that LiBr suppresses the
concentration of a monomeric lithium enolate, and that a lithium
3
(4) Protonation: (a) Yasukata, T.; Koga, K. Tetrahedron: Asymmetry
1993, 4, 35. (b) Gerlach, U.; Haubenreich, T.; Hünig, S. Chem.

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Ber. 1994, 127, 1981. Alkylation: (c) Murakata, M.; Nakajima,
M.; Koga, K. J. Chem. Soc., Chem. Commun. 1990, 1657.
(d) Hasegawa, Y.; Kawasaki, H.; Koga, K. Tetrahedron Lett.
1993, 34, 1963. (e) Imai, M.; Hagihara, A.; Kawasaki, H.;
Manabe, K.; Koga, K. J. Am. Chem. Soc. 1994, 116, 8829.
(8) A small amount of hexane (ca. 6%) was also contained in each
solvent. Hünig and coworkers have reported a similar solvent
effect, see reference 4b.
(9) The silyl enol ether of 7 was prepared from 2-methyl-2-
5
cyclopentenone according to a method similar to that for 4. The
(5) The silyl enol ether 4 was prepared by treating 2-n-pentyl-2-
silyl enol ethers of 8 and 9 were prepared by treating the
corresponding ketones with bromomagnesium diisopropylamide
®
cyclopentenone with L-Selectride in THF followed by silylation
®
(TMSCl, Et N). Selective 1,4-reduction by L-Selectride , see:
in ether followed by silylation (TMSCl, Et N, HMPA): Krafft, M.
3
3
Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41, 2194.
E.; Holton, R. A. Tetrahedron Lett. 1983, 24, 1345.
(6) n-BuLi can be used for cleavage of the Si-O bond of silyl enol
ether 4 instead of MeLi. Generation of lithium enolates: Colvin, E.
W. Silicon in Organic Synthesis; Butterworth: London, 1981;
p 217.
(10) Abu-Hasanayn, F.; Streitwieser, A. J. Am. Chem. Soc. 1996, 118,
8136.
(11) TLC R 0.28 (1:10 ethyl acetate/hexane); IR (neat) 2959, 2930,
f
2872, 2859, 1740, 1468, 1456, 1408, 1379, 1333, 1271, 1154,
-1
1
(7) The absolute configuration of 6 was determined by comparison of
its optical rotation with published data: Ohta, T.; Miyake, T.;
Seido, N.; Kumobayashi, H.; Akutagawa, S.; Takaya, H.
Tetrahedron Lett. 1992, 33, 635.
1092, 1003, 930, 831, 727 cm ; H NMR (300 MHz, CDCl )
3
δ 0.88 (t, 3 H, J = 6.9 Hz, CH ), 1.16-1.41 (m, 7 H, one proton of
3
CH and 3 CH ), 1.42-1.60 (m, 1 H, one proton of CH ), 1.67-
2
2
2
24
1.89 (m, 2 H, CH ), 1.92-2.37 (m, 5 H, CH and 2 CH ); [α]
D
2
2
-114.9 (c 2.1, CH OH).
3